Endocrine Disorders During Pregnancy 2006

ENDOCRINE DISORDERS DURING PREGNANCY
CONTENTS
Foreword
Derek LeRoith
Preface
Susan J. Mandel
Adrenal Disorders in Pregnancy
John R. Lindsay and Lynnette K. Nieman
xi
xiii
In normal gestation, hypercortisolism and relative hyperaldosteronism are not usually clinically apparent. In contrast, adrenal disorders
that do occur during pregnancy contribute to significant maternal
and fetal morbidity. This article reviews the natural history, causes,
diagnosis, and treatment of adrenal causes of Cushings syndrome,
adrenocortical hypofunction, primary hyperaldosteronism, and the
management of adrenal pheochromocytoma in pregnancy.
Calcium and Bone Disorders During Pregnancy and Lactation

Christopher S. Kovacs and Ghada El-Hajj Fuleihan
21
Adaptations in mineral metabolism occur during pregnancy and

lactation, and these adaptations uniquely affect the presentation,
diagnosis, and management of disorders of calcium and bone metabolism. Maternal adaptations to pregnancy and lactation have
evolved differently over time, such that dietary calcium absorption
dominates in pregnancy, whereas the temporary borrowing of calcium from the skeleton dominates during lactation. Lactation produces an obligatory skeletal calcium loss regardless of maternal
calcium intake, but the calcium is restored to the skeleton after
weaning through mechanisms that are not understood. Although
some women experience fragility fractures as a consequence of
pregnancy or lactation, for most women, the changes in calcium
and bone metabolism during pregnancy and lactation are normal
and without adverse consequences in the long-term.
VOLUME 35
NUMBER 1 MARCH 2006
Management of Gestational Diabetes: Pharmacologic Treatment

Options and Glycemic Control
Oded Langer
53
Diabetes mellitus is one of the most common medical complications

of pregnancy; gestational diabetes mellitus accounts for approximately 90% to 95% of all cases. This article addresses pharmacologic
treatment options and glycemic control in the management of gestational diabetes. Although not universally accepted, the introduction
of insulin analogues (mainly insulin lispro [class B]), oral antidiabetic agents (mainly glyburide [class B]), and the use of intensified
therapy have altered profoundly the management approach in the
treatment of diabetes in pregnancy with outcomes comparable to
the general population.
Successful Pregnancy in Women with Type 1 Diabetes: From

Preconception Through Postpartum Care
Lois Jovanovic and Yuichiro Nakai
79
This article discusses the risks of pregnancy for mothers with type
1 diabetes and their babies, emphasizing appropriate preconception counseling and management goals; optimizing glycemic monitoring and intensifying insulin therapy during the metabolically
dynamic process of pregnancy; appropriately evaluating women
and their fetuses for complications of both diabetes and intensive
diabetes therapy during pregnancy; and peripartum and postpartum glycemic control.
Pituitary Disorders During Pregnancy

Mark E. Molitch
99
Hyperprolactinemia and Cushings syndrome may interfere with

fertility and need to be controlled to allow conception. Cushings
syndrome, acromegaly, and hyperthyroidism secondary to thyroid-stimulating hormone (TSH) hypersecretion may increase maternal morbidity and fetal morbidity and mortality. Removal of
an adrenocorticotropin hormone-secreting tumor during pregnancy is warranted to reduce fetal loss, and medical control of hyperthyroidism is indicated. Pregnancy also may cause an increase
in prolactin-secreting tumors, especially macroadenomas. In patients with hypopituitarism, thyroid hormone doses should be increased empirically because TSH levels cannot be used. Usually
no increase in glucocorticoid dose is needed except to cover the
stress of labor and delivery. Lymphocytic hypophysitis may occur
with mass effects or hypopituitarism. Appropriate evaluation and
hormone replacement are indicated in the acute and chronic forms
of Sheehans syndrome.
vi
CONTENTS
Thyroid Disorders During Pregnancy

Shane O. LeBeau and Susan J. Mandel
117
Thyroid physiology and pathophysiology during pregnancy are reviewed focusing on the distinction between thyroid disorders and
normal gravid physiology using the history, clinical examination,
and laboratory testing. Management of hypothyroidism is discussed, including the effects of insufficient maternal levothyroxine
therapy on the fetus and recommendations for optimizing maternal levothyroxine therapy. Therapy of hyperthyroidism is reviewed, with attention to the fetal effects of maternal antithyroid
therapy. In addition, diagnosis and therapy of fetal hyperthyroidism is presented. A practical evaluation of thyroid nodules during
pregnancy is presented.
Fertility in Polycystic Ovary Syndrome

Shrita M. Patel and John E. Nestler
137
Polycystic ovary syndrome (PCOS) is the most common cause of

anovulatory infertility in the United States, affecting 5% to 10%
of women of reproductive age. Several treatment options exist, including those that target insulin resistance. Once pregnancy is
achieved, however, women are faced with several potential complications, including early pregnancy loss (EPL), gestational diabetes
mellitus (GDM), and pregnancy-induced hypertensive disorders.
All these disorders are potentially linked by their association with
hyperinsulinemia and insulin resistance. Preliminary studies suggest that metformin, an insulin-sensitizing agent that is a pregnancy class B drug, may decrease the risk of EPL and GDM in
women with PCOS. Although it is reassuring that metformin administration during pregnancy appears to be safe, rigorous randomized controlled trials must be conducted to confirm metformins
efficacy and safety under these conditions before its use during
pregnancy can be recommended.
Hypertension in Pregnancy
Caren G. Solomon and Ellen W. Seely
157
New-onset hypertension complicates 5% to 10% of pregnancies.

Preeclampsia (new-onset hypertension after the 20th week of pregnancy with proteinuria) is associated with substantial risk to the
mother and fetus. Recognized risk factors include primiparity and
preexisting chronic hypertension. The "cure" for preeclampsia is delivery of the fetus; management involves close follow-up of the
mother and fetus to prolong the pregnancy as long as is safely possible. Women with a history of preeclampsia are at increased risk of
preeclampsia in subsequent pregnancies and may be at increased
risk for subsequent hypertension and cardiovascular disease.
Further research is needed to understand causes of preeclampsia
better and to identify interventions that can prevent its occurrence
and reduce subsequent risks in women who have had preeclampsia.
CONTENTS
vii
Endocrinology of Parturition
Victoria Snegovskikh, Joong Shin Park, and Errol R. Norwitz
173
Reproductive success is critical for survival of the species. The

timely onset of labor and delivery is an important determinant of
perinatal outcome. Both preterm birth (defined as delivery before
37 weeks gestation) and post-term pregnancy (defined as pregnancy continuing beyond 42 weeks) are associated with a significant increase in perinatal morbidity and mortality. The factors
responsible for the timing of labor in the human are complex
and, as yet, are not completely understood. This article reviews
the current understanding of the parturition cascade responsible
for the spontaneous onset of labor at term and discusses preterm
labor and post-term pregnancy.
Developmental Origins of Adult Metabolic Disease

Rebecca Simmons
193
The combined epidemiologic, clinical, and animal studies clearly

demonstrate that the intrauterine environment influences growth
and development of the fetus and the subsequent development
of adult diseases. There are critical specific windows during development, often coincident with periods of rapid cell division, during
which a stimulus or insult may have long-lasting consequences on
tissue or organ function after birth. Birth weight is only one marker
of an adverse fetal environment, and confining studies to this population only may lead to erroneous conclusions regarding etiology. Studies using animal models of uteroplacental insufficiency
suggest that mitochondrial dysfunction and oxidative stress play
an important role in the pathogenesis of the fetal origins of adult
disease.
Index
viii
205
CONTENTS
FORTHCOMING ISSUES
June 2006
Impaired Glucose Tolerance and Cardiovascular
Disease
Willa A. Hsueh, MD, and Preethi Srikanthan, MD
Guest Editors
September 2006
Molecular Basis of Inherited Pancreatic Disorders
Markus M. Lerch, MD, Thomas Griesbacher, MD,
and David C. Whitcomb, MD, Guest Editors
December 2006
Growth Hormones
Ken K.Y. Ho, MD, Guest Editor
RECENT ISSUES
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Endocrinology of Aging
Johannes D. Veldhuis, MD, Guest Editor
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Cushings Syndrome
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March 2005
Type 2 Diabetes and Cardiovascular Disease
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35 (2006) xixii
Foreword
Endocrine Disorders During Pregnancy
Derek LeRoith, MD, PhD

Consulting Editor
In the present issue of Endocrinology and Metabolism Clinics of North

America, Dr. Mandel has compiled articles by experts on a topic involving
endocrine disorders during pregnancy.
In the article on the gestational diabetes, Dr. Langer points out that diabetes is the commonest medical complication of pregnancy. On the important topic of therapy he further describes the issues of using insulin analogs
and oral agents in pregnancy. The article by Jovanovic and Nakai cover
similar aspects but focus more on the pregnant Type 1 diabetic patient.
Dr. Nestler approaches the patient with polycystic ovarian syndrome
(PCOS); one of the commonest causes of infertility. As is now commonly appreciated, PCOS is associated with insulin resistance and often has features
related to this metabolic disorder. Therapy with metformin (a biguanide)
or thiazolidinediones reduces insulin resistance, restores menstruation, and
often is associated with restoration of fertility.
Hypertensive disorders and pregnancy ranging from essential hypertension to the more serious condition of preeclampsia and eclampsia are
well-covered in practical terms in the article by Dr. Seely.
Adult endocrinologic disorders during pregnancy are discussed in this
issue and include pituitary, adrenal, thyroid and calcium disorders.
Dr. Molitch discusses pituitary disorders and describes the diagnosis and
management of prolactinomas, acromegaly, pituitary Cushings disease,
hypopituitary and hypophysitis, reminding the reader of the pitfalls of
hormonal measurements that are altered by the pregnant state.
0889-8529/06/$ - see front matter 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.ecl.2005.11.001
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xii
FOREWORD
In the article by Drs. Lindsay and Nieman on adrenal disorders, there is an

excellent account of some endocrine conditions that are rare in pregnancy
including Cushings disease, pheochromocytoma, primary aldosteronism,
and Addisons disease. The authors describe the pitfalls in clinical diagnosis
and testing as well as management that will be extremely informative for
many clinicians.
There are quite signicant changes in calcium and bone metabolism during pregnancy and lactation including changes in intestinal calcium absorption and calcium release from the skeleton. All of these are necessary for
fetal and neonatal development. As discussed by Drs. Kovacs and Fuleihan
the long-term consequences to the mother are minimal. However, once
again these marked changes in many of the parameters make the diagnosis
and management of the various disease syndromes in pregnancy more complicated. While hyper and hypoparathyroidsm and other metabolic bone
conditions are relatively rare, they need particular attention as described
in this article.
Drs. Mandel and LeBeau discuss thyroid disorders in pregnancy, covering the eect of pregnancy on thyroid function and thyroid hormone measurements. Conversely, thyroid metabolism aects pregnancy, and thyroid
disorders in pregnancy need particular care due to the eects on the pregnancy, the fetus, and the newborn.
Finally, there are two excellent articles that round o the topic; one covered by Dr. Norwitz on the endocrinology of parturition and the other by
Dr. Simmons on fetal imprinting and its eects on the endocrine system.
These articles bring the reader information that will have practical importance in the not too distant future.
Like Dr. Mandel, who has succeeded a timely and important issue, I believe that the reader will nd this issue both extremely informative and
practical.
Derek LeRoith, MD, PhD
Division of Endocrinology, Metabolism, and Bone Diseases
Mount Sinai School of Medicine
New York, NY, USA

35 (2006) xiiixiv
Preface
Endocrine Disorders During Pregnancy
Susan J. Mandel, MD, MPH

Guest Editor
It has been 11 years since the last publication of an issue of the Endocrinology and Metabolism Clinics of North America that focused on endocrine
disorders during pregnancy. In the preface, Lois Jovanovic, guest editor of
and contributing author in that issue, wrote that there were three endocrine
components to mammalian pregnancy: fetal, placental, and maternal endocrinology. And, of these, she observed, the maternal was the most understood and the focus of many of the articles contained in that issue.
Fortunately, in the ensuing 11 years, we have learned much about the other
two components, specically the inuences of maternal endocrine disorders
on the fetoplacental unit.
In this issue, I have selected topics that cover each of the main subspecialties (adrenal, pituitary, diabetes, thyroid, and calcium/bone) within adult
endocrinology. For each area, the authors have delineated the current
understanding of its physiology and pathophysiology during gestation as
well as outlined the maternal therapy to optimize pregnancy outcome. In addition, I have included an article on the impact of polycystic ovarian syndrome on fertility, relevant because of its prevalence and the availability
of therapy. Cardiovascular endocrinology, a newer subspecialty within
our discipline, is well-represented by the article on pregnancy and hypertensive disorders. There are two other nontraditional articles. Recently, we
have gained understanding of the eects of the intrauterine milieu on the future endocrine development of the child and this is presented in the section
on imprinting. Lastly, the conclusion of pregnancy, parturition, represents
a complex hormonal interplay that is described in the article on endocrinology of parturition.
doi:10.1016/j.ecl.2005.10.001
endo.theclinics.com
xiv
PREFACE
I have had the pleasure and honor of working with renowned experts in
their respective elds and in large part because of them, it has been a privilege to serve as the Guest Editor of this issue of the Endocrinology and Metabolism Clinics of North America. I thank my colleagues for their
outstanding contributions to this volume, which is a valuable and timely addition to its eld.
Susan J. Mandel, MD, MPH
Division of Endocrinology, Diabetes, and Metabolism
University of Pennsylvania School of Medicine
415 Curie Boulevard
611 CRB
Philadelphia, PA 19104, USA
E-mail address: smandel@mail.med.upenn.edu

35 (2006) 120
Adrenal Disorders in Pregnancy

John R. Lindsay, MD, Lynnette K. Nieman, MD*
Reproductive Biology and Medicine Branch, National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda MD, USA
The hypothalamic-pituitary-adrenal (HPA) axis and the renin-angiotensin system (RAS) are up-regulated during normal pregnancy. Pregnancy
represents a state of relative hypercortisolism, resulting from the interaction
of the maternal HPA axis and the fetal-placental unit. Consistent with
a physiologic role, the RAS maintains normal sodium balance and volume
homeostasis. In normal gestation, hypercortisolism and relative hyperaldosteronism are not usually clinically apparent. In contrast, adrenal disorders
that do occur during pregnancy contribute to signicant maternal and fetal
morbidity. This article reviews the natural history, causes, diagnosis, and
treatment of adrenal causes of Cushings syndrome, adrenocortical hypofunction, primary hyperaldosteronism, and the management of adrenal
pheochromocytoma in pregnancy.
Cushings syndrome in pregnancy

The clinical presentation of Cushings syndrome in pregnancy is similar
to that in the general population, except for the preservation of menses before conception. The cause, however, diers between the pregnant and nonpregnant state because adrenal causes of Cushings syndrome account for
over 60% of 122 previous reports in pregnancy, in contrast with 15% in
nonpregnant women [1,2]. Solitary adrenal adenomas are the most common
cause, whereas adrenal carcinoma accounts for approximately 10% of
cases [3,4]. Pheochromocytoma causing ectopic Cushings syndrome was reported on two occasions. Its rarity may be explained by the anovulation that
usually accompanies severe hypercortisolism [3,5]. Primary pigmented
* Corresponding author. Reproductive Biology and Medicine Branch, National Institute

of Child Health and Human Development, National Institutes of Health, Building 10, CRC
Room 1-3140, Bethesda MD 20892-1109.
E-mail address: niemanl@mail.nih.gov (L.K. Nieman).
0889-8529/06/$ - see front matter. Published by Elsevier Inc.
doi:10.1016/j.ecl.2005.09.010
endo.theclinics.com
LINDSAY & NIEMAN
nodular adrenal disease and adrenocorticotropic hormone (ACTH)-independent hyperplasia, caused possibly by aberrant receptor stimulation, accounted for eight cases of the pregnancies [1]. The overall increased
incidence of adrenal Cushings syndrome suggests that anovulation may
be less prevalent in this cause or that unrecognized, illicit luteinizing hormone/human chorionic gonadotropin receptor expression was considered
to be adrenal adenoma [6,7]. In the latter setting, Cushings syndrome would
not be triggered until pregnancy is established.
Cushings syndrome in gestation is associated with maternal morbidity,
including preeclampsia, hypertension, diabetes, wound breakdown, opportunistic infections, and fracture [4,8]. Maternal death was reported in two
cases [5,9]. Hypercortisolism eects on the fetus include increased rates of
spontaneous abortion, perinatal death, premature birth, and intrauterine
growth retardation [2,4]. As a result of this fetal and maternal morbidity,
early diagnosis and treatment of Cushings syndrome in pregnancy are critical. However, the physiologic changes of pregnancy complicate this goal.
Plasma cortisol, cortisol-binding protein (CBG), and urinary free cortisol
(UFC) increase during the second and third trimesters (Fig. 1) [10,11]. There
are no formal studies of how the usual diagnostic criteria should be modied
to allow for pregnancy-induced hypercortisolism.
Screening and dierential diagnosis of Cushings syndrome
The interpretation of screening tests for hypercortisolism is more dicult
in pregnancy, particularly in the second and third trimesters. In the rst trimester, cortisol excretion is similar to that of nonpregnant women. It then
increases up to threefold by term, to overlap values seen in pregnant women
with Cushings syndrome [10]. As a result, it is likely that only the UFC values in the second and third trimester greater than three times the upper limit
of normal can be interpreted as indicating Cushings syndrome. Unfortunately, there are limited data on the upper range of UFC in normal pregnancy, using modern antibody-based assays, and no reports of UFC
measured by structural assays such as mass spectrometry. Plasma cortisol
diurnal variation is preserved in normal pregnancy, albeit with a higher
nighttime nadir. Although the loss of diurnal variation is characteristic of
Cushings syndrome, diagnostic thresholds for evening plasma or salivary
cortisol levels in pregnant patients have not been developed [1,10]. Furthermore, the suppression of serum and urinary cortisol by dexamethasone is
blunted in pregnancy (Fig. 2). Thus, this screening test has an increased potential for false-positive results in pregnancy. Although the evidence is limited, the present authors suggest a combination of greater than threefold
elevation of UFC and elevated midnight salivary cortisol as a diagnostic
strategy for the identication of Cushings syndrome in pregnancy [12,13].
The rst step in the dierential diagnosis is to discriminate between
ACTH-independent and ACTH-dependent hypercortisolism, which may
ADRENAL DISORDERS IN PREGNANCY
Fig. 1. Serial increases in serum cortisol (open circles) and ACTH (closed circles) during pregnancy in normal controls throughout pregnancy. This graph was modied from the series of ve
normal pregnant women studied by Carr and colleagues (1981). The bars adjacent to the right
axis are summary data derived from a recent series [1] to denote the range of serum cortisol observed in Cushings syndrome in pregnancy (open diamonds, median and range; n 52); ACTH
values for Cushings disease (closed triangles, median and range, n 18); and adrenal Cushings
syndrome (open triangles, median and range, n 17). (Modied from Carr BR, Parker CR Jr,
Madden JD, et al. Maternal plasma adrenocorticotropin and cortisol relationships throughout
human pregnancy. Am J Obstet Gynecol 1981;139(4):41622.)
be achieved by measuring plasma ACTH levels [14]. A two-site immunometric assay is preferred to radioimmunoassay, unless the latter can reliably discriminate low or suppressed ACTH levels (%10 pg/mL [2.2 pmol/L]) [14,15].
To avoid falsely low results, it is important to collect the sample in prechilled
ethylenediaminetetraacetic acid tubes, transport it to an ice bath, and prepare it promptly by refrigerated centrifugation and plasma separation.
In the nonpregnant population, plasma ACTH suppression (%5 pg/mL
[1.1 pmol/L]) identies ACTH-independent primary adrenal causes of Cushings syndrome. However, in a recent review of Cushings syndrome in pregnancy, mean plasma ACTH levels were nonsuppressed in approximately
half of those patients who had primary adrenal disorders, perhaps because
of continued stimulation of the maternal HPA axis by placental CRH or because of placental secretion of ACTH [1,16]. As a result, the recommended
diagnostic ACTH thresholds in the general population may lead to inaccurate diagnoses in pregnancy [15].
If plasma ACTH is suppressed, no further biochemical testing is needed,
and imaging of the adrenal glands, discussed below, then will localize the
LINDSAY & NIEMAN
Fig. 2. Change in plasma cortisol before (closed circles) and after (open circles) the administration
of 1 mg of dexamethasone (Dex) in pregnant women. Blood was drawn at 8 AM. A single dose of
dexamethasone was administered orally at 11 PM, and blood was drawn at 8 AM on the following
day. (From Odagiri E, Ishiwatari N, Abe Y, et al. Hypercortisolism and the resistance to dexamethasone suppression during gestation. Endocrinol Jpn 1988;35:68590; with permission.)
abnormality to a unilateral adrenal adenoma or carcinoma or rare bilateral

adrenal disorders. A normal or elevated plasma ACTH level (R15 pg/mL
[3.3 pmol/L]) is consistent with an ACTH-producing tumor (keeping in
mind the caveats discussed above) [15]. Although the high-dose dexamethasone suppression test (HDST) has not been formally validated in pregnancy,
it may have added value for the dierential diagnosis of adrenal Cushings
syndrome, given the diculties in the interpretation of plasma ACTH and
the increased prevalence of adrenal disorders. Using a criterion of 80% suppression of serum cortisol, none of seven cases who had ACTH-independent
Cushings syndrome showed suppression in a recent small series. However
three of seven cases of Cushings disease would have been misclassied because they also failed to suppress [1].
The CRH stimulation test is useful primarily for the dierential diagnosis
of ACTH-dependent Cushings syndrome. Ovine CRH (the analog available
in the United States) is a category C drug approved by the US Food and
Drug Administration (FDA). Therefore, the present authors advocate that
its use be reserved for patients in whom adrenal disorders are unlikely after
initial testing.
Patients with borderline or low plasma ACTH or without suppression on
HDST are likely to have an adrenal cause, and such cases warrant adrenal
imaging. Ultrasonographic (US) imaging has a reported sensitivity for
detection of adrenal lesions of 89% to 97%, and its use is not limited by
pregnancy [17]. The advantages of US are that it is noninvasive, rapid, inexpensive, and readily available. However, MRI may be preferred, particularly if an ACTH-producing pheochromocytoma is being considered,
because its appearance on T2-weighted imaging is bright. MRI also may

provide better imaging resolution preoperatively. (Because gadolinium contrast is an FDA category C agent, it is not given to pregnant women at the
authors institution.) MRI alone is contraindicated in the rst trimester because of unknown potential teratogenic eects, but it is considered safe after
32 weeks. In the middle trimester, the potential benets of MRI must be
weighed against its possible risks. A suggested algorithm for the dierential
diagnosis of Cushings syndrome is shown in Fig. 3.
Treatment
There does not appear to be a rationale for supportive care as the only
treatment of Cushings syndrome in pregnancy. The live birth rate after unilateral or bilateral adrenalectomy is approximately 87% [1]. In contrast, the
prognosis for the fetus remains guarded when hypercortisolism persists. Although placental degradation of cortisol appears to protect the fetus from
glucocorticoid excess, the high incidence of adverse fetal outcomes probably
reects placental and maternal abnormalities. Thus, the present authors recommend surgical treatment of Cushings syndrome in the second trimester
of pregnancy, with medical treatment as a second choice.
The surgical approach is not altered by pregnancy, and the goal is to remove the tumor causing the condition. Thus, transsphenoidal surgery is recommended for pituitary ACTH-producing tumors (see elsewhere in this
issue), specic resection for ectopic ACTH-producing tumors, and unilateral
Clinical features of Cushings syndrome
Screening
1st or early 2nd trimester
UFC elevated
Late 2nd-3rd trimester
Elevated midnight
salivary cortisol
CS confirmed
ACTH <10 pg/ml
Adrenal Imaging
US/MRI
UFC > 3-fold normal
Investigate CD
ACTH >10 pg/ml
YES
HDST suppression < 80%

NO
Fig. 3. Diagnostic algorithm for the dierential diagnosis of Cushings syndrome (CS) in
pregnancy.
LINDSAY & NIEMAN
or bilateral adrenalectomy for primary adrenal disorders. Unless otherwise

contraindicated, a laparoscopic approach for adrenalectomy is standard. Bilateral adrenalectomy remains an option for patients needing an immediate
cure of Cushings syndrome in whom the primary tumor is occult, inoperable,
or metastatic, just as for nonpregnant patients.
Primary medical therapy has been reported in approximately 20 women
with Cushings syndrome resulting from a range of causes [18,19]. Metyrapone was used in about half the women, and, whereas it was well tolerated
generally, the side eects included hypertension and progression to preeclampsia [2022]. Therefore metyrapone is best reserved as an interim treatment, pending denitive surgical treatment [20]. Ketoconazole is an FDA
category C agent and has been used successfully in three pregnancies despite
known teratogenic eects at high dosages in rats but not in rabbits [1,18].
Given the potential risks, in the present authors opinion, ketoconazole
should be reserved for individuals who need emergent medical therapy
but cannot tolerate metyrapone [18]. Cyproheptadine is not eective in nonpregnant individuals and thus is not recommended [23]. Fetal masculinization precludes the use of aminoglutethimide [24]. Similarly, mitotane is
contraindicated because it crosses the placenta and is teratogenic [25].
Primary adrenal insuciency in pregnancy
Primary adrenal insuciency (AI) can present acutely or with a more insidious set of chronic symptoms. Primary AI (so-called Addisons disease) is
characterized by the impairment of aldosterone or cortisol secretion and adrenocortical atrophy arising from insensitivity to ACTH and angiotensin II
stimulation. The exact prevalence of AI occurring in pregnancy is unknown.
In a series reported by Albert and colleagues [26] from Tromso, Norway, the
estimated incidence of AI in pregnancy was 1 per 3000 births between 1976
and 1987.
Isolated autoimmune adrenalitis is the most common cause of primary
AI in developed countries. Although the glands are small in autoimmune
primary adrenal disease, they are large in tuberculous or fungal infection,
bilateral metastases, hemorrhage, or infarction. Less common causes of
AI, autoimmune polyglandular syndrome type 2 (APS-2) and Schmidts
syndrome (primary autoimmune hypoadrenalism, type 1 diabetes mellitus,
thyroid autoimmune disease), were reported in at least seven pregnancies
[27]. In APS-2, the appropriate management of hypothyroidism and diabetes during gestation poses a particular challenge beyond that of isolated hypoadrenalism [27].
Maternal and fetal morbidity and mortality
AI in pregnancy was associated with maternal mortality rates of 35% in
the 70-year period before 1930, which improved to 18% between 1940 and
1947 [28]. The present authors believe there have been no reports of maternal deaths from AI in pregnancy since the 1950s, with the introduction of
cortisone, earlier diagnosis, and improved antenatal care. However, a reported case of maternal death at 8 months after delivery illustrates the importance of careful postpartum follow-up [26]. Some cases that were not
diagnosed during pregnancy had normal maternal and fetal outcomes, suggesting that women with unrecognized AI benet from transplacental passage of cortisol from the fetus. Therefore, AI may only become apparent
in the immediate postpartum period [29]. In women known to have the disease, careful titration of glucocorticoid and mineralocorticoid replacement
are required to avoid an adrenal crisis and potential side eects, including
hypertension and exacerbation of preeclampsia [26,30].
Gestational AI has been associated with high rates of intrauterine growth
retardation, low birth weight [31,32], and fetal mortality [33]. A recent Italian series reported improved miscarriage rates (16 of 104 pregnancies) compared with intrauterine death rates in the 1950s of 40% to 50% [34]. Most of
the earlier reports consisted of previously unrecognized cases or preceded
the availability of modern glucocorticoid regimens [35]. These dierences
have led to the speculation that, treated properly, women do not have increased complications of gestation. There does not appear to be an increased
risk of preterm abortion or congenital anomalies resulting from AI alone,
when patients are treated adequately [36]. However, when AI is associated
with other autoimmune conditions, including positive circulating anticardiolipin antibodies, lupus anticoagulant, and diabetes, there may be additional risks of preterm abortion [3739].
Diagnosis
Clinical and laboratory features
Most cases of primary AI are diagnosed before pregnancy. During gestation, a new diagnosis should be considered in a case with classic symptoms
of excessive fatigue, malaise, weight loss, vomiting, orthostasis, abdominal
pain, hyperpigmentation, or biochemical disturbance [30,39,40]. Hypoglycemia, salt craving, malaise, seizures, or even coma should prompt testing of
the HPA axis in pregnancy. Persistent vomiting can be mistaken for hyperemesis gravidarum, potentially leading to a fatal outcome if left undiagnosed [40]. Biochemical disturbance with hyponatremia is characteristic;
however, this is usually more severe than the mild hyponatremia (5-mmol/L
decrease) that occurs in normal pregnancy. Severe hyponatremia or metabolic acidosis is associated with poor outcomes, including fetal death [33].
Hyperkalemia was reported to be absent in several cases of newly diagnosed
primary AI during pregnancy. This may reect the increase in the RAS,
rather than the severity of adrenocortical dysfunction [33,40].
LINDSAY & NIEMAN
Screening tests and dierential diagnosis of adrenal insuciency

Testing consists of assessing the functional integrity of the HPA axis followed by a search for the underlying cause of AI. In an unstable patient, empirical glucocorticoid therapy is recommended when the clinical suspicion
for adrenal crisis is high, just as in nonpregnant patients [30]. Samples for
plasma cortisol and ACTH should be obtained before treatment, whenever
possible. The existing tests of HPA reserve have not been validated formally
in pregnancy. The present authors do not recommend using metyrapone
stimulation or insulin tolerance tests in pregnancy because of the potential
risks to the fetus of precipitating maternal adrenal crisis. The CRH stimulation test is useful for dierentiating between tertiary and secondary AI in
nonpregnant patients, but it cannot be relied on for a diagnosis in pregnancy
because cortisol and ACTH responses to CRH are blunted [41].
A low early morning plasma cortisol level (%3.0 mg/dL [83 nmol/L]) conrms AI in the setting of a typical clinical presentation [42]. In the rst and
early second trimesters, the diagnosis can be excluded in a clinically stable
patient if basal plasma cortisol levels are greater than 19 mg/dL (525
nmol/L) [42,43]. Because of the normal increase in cortisol and CBG in
the late second and third trimesters, the present authors recommend formal
dynamic testing of the HPA axis at those times.
The standard cosyntropin (124 corticotropin) test (SCT) is performed by
administering a supraphysiologic dose of 250 mg, intramuscularly (IM) or
intravenously (IV), and measuring plasma cortisol levels after 30 and 60 minutes. Cosyntropin is licensed by the FDA as category C. The test may be
performed at any time of the day, and the 30-minute cuto point is considered the most consistent measure for diagnosis [44]. In the nonpregnant population, cortisol cuto points for the diagnosis of AI range from 18 mg/dL to
25.4 mg/dL (497700 nmol/L) [4547]. The standard test performs well in
nonpregnant patients who have primary AI, with high sensitivity and specicity (97% and 95%, respectively) [48], but it is less sensitive for the detection of early hypopituitarism [49]. Although conventional nonpregnant
criteria generally have been applied in pregnancy, in one series [50], plasma
cortisol responses to standard cosyntropin testing in normal pregnant women
ranged from 60% to 80% above nonpregnant responses in the second and
third trimesters. As a result, there is insucient information to determine
appropriate pregnancy-specic cuto points.
McKenna and colleagues [42] recently examined responses to the 1-mg
low-dose cosyntropin test (LCT) for diagnosis of secondary AI in women
at 2434 weeks of gestation. Using a threshold above 30 mg/dL (828
nmol/L) following LCT, the test had high sensitivity for the diagnosis of
AI. Signicantly, in most cases, the diagnosis of AI could be predicted by
an 8 AM plasma cortisol level of less than 3 mg/dL (83 nmol/L). Furthermore,
the low-dose test is more dicult to perform than the SCT with regard to
preparation, dilution, and ensuring an accurate dose administration [42].
Although criteria for diagnosing AI in pregnancy have not been developed, the previously reported 8 AM third-trimester plasma cortisol levels
and responses to the SCT in normal pregnant women and the results
from the low-dose cosyntropin stimulation testing cited above provide useful information. Taken together, the present authors consider basal or
ACTH-stimulated plasma cortisol levels in the third trimester greater than
30 mg/dL (828 nmol/L) sucient to exclude AI [42].
Tests used for the dierential diagnosis
Plasma ACTH levels dierentiate primary (elevated) from secondary adrenal failure (low or normal) and can help to conrm primary AI in nonpregnant patients who have borderline plasma cortisol levels. An ACTH
level above 100 pg/mL (22 pmol/L) is generally consistent with primary
AI, even in late pregnancy [43]. However, ACTH levels uctuate widely
day-to-day, and a single value cannot be relied on for the diagnosis of either
primary or secondary AI.
Approximately 90% of nonpregnant patients who have idiopathic AI are
positive for 21-hydroxylase antibodies, and antibodies to 17-a-hydroxylase
and side-chain cleavage enzymes are positive in approximately 30% of patients [51]. The presence of adrenal antibodies provides conrmatory evidence for an autoimmune cause, but it cannot be relied on for diagnosing
AI, given the 10% prevalence of negative test results in patients proven to
have AI. The presence of mineralocorticoid deciency is highly suggestive
of primary AI arising from adrenocortical atrophy, and in this setting, plasma
aldosterone-to-renin ratios are low in association with elevated plasma renin activity [52].
Patients who have an autoimmune cause do not require imaging. Imaging
of the adrenal glands can detect the large glands associated with other
causes, such as tuberculous or fungal infection, bilateral metastases, hemorrhage, or infarction [39,53,54]. US imaging is safe but may have limited resolution. Non-gadolinium-enhanced MRI is preferred to CT in pregnancy.
Although MRI provides excellent soft tissue enhancement and has improved
resolution compared with ultrasound [55], deferring adrenal imaging until
the postpartum period should be considered if the patient is clinically stable.
Treatment
The optimal antenatal management of AI occurs in a multidisciplinary
clinic that includes an endocrinologist. The primary roles for the endocrinologist are to provide a diagnosis, monitor the adequacy of corticosteroid or
mineralocorticoid replacement regimens during gestation, crisis, and labor,
and to ensure continuity during the postpartum period. Prepregnancy
counseling should be conducted routinely in women of childbearing age.
Women should be educated regarding the principles of self-administration
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LINDSAY & NIEMAN
of intramuscular hydrocortisone (50100 mg) for pregnancy-associated emesis before urgent medical assessment. All patients should wear a medic alert
bracelet or necklace for identication during an emergency.
Physiologic glucocorticoid and mineralocorticoid treatment appears to
be safe during pregnancy [56]. The most critical periods in pregnancy
when the adequacy of glucocorticoid replacement regimens may aect outcomes are in undiagnosed cases during the rst trimester when symptoms of
adrenal crisis can be mistaken for pregnancy-associated emesis and during
the stress of labor and delivery [33].
Several glucocorticoid regimens are available for chronic replacement
during pregnancy. Hydrocortisone is the present authors preferred choice,
at a replacement dose of 12 mg/m2 to 15 mg/m2 of body surface area [57].
Two thirds of the daily dose is given when the patient awakens, with the remainder given in the afternoon to mimic normal diurnal variation. Although this dose may lead to over-replacement in a proportion of
nonpregnant cases, in the absence of more detailed studies during pregnancy, this approach seems reasonable [58]. Glucocorticoid replacement
regimens usually remain stable during gestation, even until late in the third
trimester. Prednisone or prednisolone may be used as alternative glucocorticoid regimens. Prednisone and cortisone acetate are not useful for the
emergency management of adrenal crisis because they require the reduction
of a ketone group to a hydroxyl group on carbon-11 to active metabolites.
Furthermore, they are longer acting compared with hydrocortisone and less
suitable for physiologic replacement [59].
Oral udrocortisone, 0.1 mg daily (ranging between 0.05 mg and 0.2 mg),
is standard mineralocorticoid replacement and has largely replaced salt tablet regimens [59]. Fludrocortisone dosages are usually stable through pregnancy but occasionally may need to be reduced during the third trimester
to avoid the side eects of edema or exacerbation of hypertension [60].
The acute treatment of adrenal crisis includes prompt, rapid glucocorticoid replacement with hydrocortisone, 100 mg to 200 mg IV, as a single bolus. Thereafter a bolus of 50 mg to 100 mg is given every 6 to 8 hours during
the acute period, based on maximal cortisol production rates of 200 mg/d to
400 mg/d [30]. Women with hypoglycemia should receive 5% dextrose infusions, and those with hypotension should receive 0.9% saline. Because hydrocortisone at these dose levels contains adequate mineralocorticoid
activity, udrocortisone is not indicated in the acute period and has been associated with the side eects of pulmonary edema caused by salt and water
retention [30]. A transfer to routine oral therapy is warranted when acute
symptoms have settled or when the patient is tolerating oral uids.
During labor and the postpartum period
Routine glucocorticoid and mineralocorticoid replacement therapy can
be continued until the onset of labor, provided that the patient has no
11
symptoms of under-replacement. Normal vaginal delivery is a reasonable

expectation for women with AI. Caesarian (C)-section is considered for indications similar to those in a nonpregnant individual [26]. During labor, the
patients normal dose of hydrocortisone is doubled, provided that oral intake is tolerated. Alternatively, a single dose of hydrocortisone, 50 mg IV,
may be considered during the second stage of labor [34]. Before caesarian
section is performed, however, stress doses of hydrocortisone, 100 mg IV
or IM, are given at the onset and continued at 6- to 8-hour intervals after
delivery [57]. The doses of hydrocortisone can then be tapered over 48 hours
to a regular replacement dose [57,59].
After delivery, all women should recommence mineralocorticoid or corticosteroid replacement within the rst 24 to 48 hours, usually at the dose
used before gestation. Stress coverage may be required during recovery
from surgery or intercurrent illness. The assessment of the HPA axis is usually not necessary for infants whose mothers with AI received appropriate
physiologic glucocorticoid replacement. However, infants born to mothers
receiving pharmacologic doses of agents that cross the placenta (such as
dexamethasone) require more formal assessment to exclude AI. Physiologic
glucocorticoid replacement can continue during breast-feeding because less
than 0.5% of the absorbed dose is excreted per liter of breast milk [32,56].
Hypertension in pregnancy
Normal gestation is associated with a fall in blood pressure toward the
end of the rst trimester, reaching a nadir between 22 and 24 weeks. Hypertension during pregnancy, dened by an absolute systolic or diastolic blood
pressure exceeding 140 or 90 mmHg, respectively, complicates approximately
15% of pregnancies [61]. Increased vascular distensibility and reduced
peripheral vascular resistance occurring in pregnancy are accompanied
by physiologic changes, including sodium retention, increased extracellular
uid, and up-regulation of the RAS [62].
Hyperaldosteronism
The prevalence of primary hyperaldosteronism (PA) in nonpregnant hypertensive subjects varies between 1% and 12%, depending on the patient
population, diagnostic methods used, and conrmation by surgery [63]. In
contrast, PA is rare in pregnancy, with approximately 31 cases reported
worldwide since the original description by Crane in 1964 [64,65]. The majority of reported cases arise as a result of adrenal adenoma or hyperplasia.
However, there are rare reports of glucocorticoid-remediable hyperaldosteronism in pregnancy [66].
Plasma renin activity increases early in the rst trimester of normal pregnancy, reaching values almost three- to seven-fold greater than the normal
12
LINDSAY & NIEMAN
range by the third trimester [67,68]. The fetal-placenta unit is an additional

important site of RAS activity [67,69]. Plasma aldosterone concentrations
increase 5- to 20-fold between the rst and third trimesters, in association
with the enlargement of the zona fasiculata [70]. Corticosterone, deoxycortisol, and cortisone parallel the two- to threefold rise seen in cortisol during
gestation [70]. Although the RAS is markedly stimulated during pregnancy,
both renin and aldosterone respond physiologically, albeit at an altered set
point [71]. Aldosterone responses to salt loading, posture, diuretics, volume
depletion, and the administration of mineralocorticoid suggest that the RAS
is under tight physiologic control [62,72].
PA in pregnancy is associated typically with hypertension and associated
with hypokalemia in a high proportion of cases (16/29) in a recent review by
Okawa and colleagues [64,73]. Patients may present with symptoms that include headache, fatigue, weakness, dizziness, and muscle cramps [74]. In a
series of 27 cases progressing to delivery, pregnancy was characterized by
moderate to severe hypertension in 85% and proteinuria in 52% of patients
[64]. Placental abruption complicated the clinical course of several cases,
and two intrauterine fetal deaths occurred [65,75]. High rates of preterm delivery (52%) were partially attributable to emergent delivery for cases with
uncontrolled hypertension [75]. Hypertension may improve during gestation
in PA because elevated progesterone levels have antimineralocorticoid effects at the renal tubule [73].
The diagnosis and treatment of PA present particular challenges in the
setting of pregnancy. PA during pregnancy is characterized by elevated aldosterone and suppressed plasma renin. Although pregnancy-specic cutos
for PA have not been validated, the range of plasma aldosterone in one series was 129 pg/mL to 1093 pg/mL [64]. The peak mean third trimester pregnancy levels for plasma renin activity and aldosterone were 5.8 ng/mL/h and
594 pg/mL, respectively, in the series by Wilson and colleagues [68]. Thus,
the physiologic rise in aldosterone in normal pregnancy overlaps the values
seen with PA, making the diagnosis of PA more dicult. However, suppressed renin in the setting of hyperaldosteronism is diagnostic of PA.
The conrmation of PA during gestation with dynamic testing using intravenous saline may not be helpful, given the potential risks to the fetus
and the lack of normative data [76]. Although posture testing can sometimes
dierentiate unilateral adenoma from bilateral hyperplasia, the diagnostic
accuracy of this technique remains controversial, even in nonpregnant patients. The dierential diagnostic strategy for PA in the nonpregnant population consists of adrenal CT and adrenal vein sampling to localize an
adenoma and discriminate it from bilateral adrenal hyperplasia. In pregnancy, imaging with MRI or ultrasonography is preferable to CT, with
the appropriate precautions and limitations outlined above. In the present
authors experience, adrenal vein sampling has not been attempted during
pregnancy. It is not clear that the potential risk from uoroscopy during
the procedure would outweigh the potential benet. In nonpregnant cases
13
under the age of 40 years, it is generally considered appropriate to proceed

to unilateral adrenalectomy for patients who have unilateral adrenal macronodules (R 1 cm) and a normal contralateral gland. However, there are no
published guidelines for localization based on adenoma size alone in pregnancy. In the absence of denitive imaging ndings, deferring additional diagnostic tests and surgery to the postpartum period may be more
appropriate.
Adrenalectomy in the second trimester may be considered for cases with
PA caused by adrenal adenoma. Adrenalectomy has been reported in four
cases of PA caused by adenoma during pregnancy [7779]. In each instance,
the blood pressure normalized after surgery. The benets of successful
surgery include normalization of blood pressure, which can be expected in
approximately two thirds of nonpregnant cases, together with the normalization of serum potassium in a majority of cases. These benets have to be
balanced against the potential risks of surgery or medical therapy in
pregnancy. At least two cases illustrate successful medical management
pending denitive localization or adrenalectomy in the postpartum period
[73,80].
Medical therapy is indicated for cases that have adrenal adenoma that are
identied late in gestation or those who have adrenal hyperplasia. Therapeutic options in nonpregnant patients include spironolactone or amiloride for
specic aldosterone blockade. However, spironolactone is contraindicated
in pregnancy because it has been associated with incomplete virilization of
the male rat and has the potential for feminization of a male infant [81].
Amiloride, which is FDA class C, has been used safely in Bartter syndrome
in pregnancy, with no reported teratogenicity [82]. The antihypertensive
agents considered safe in pregnancy such as methyldopa may have limited
ecacy in treating PA. The additional disadvantages of these and other
agents are the ongoing requirements for high potassium supplementation.
Angiotensin converting enzyme inhibitors are contraindicated in pregnancy.
Although calcium channel blockers are relatively safe in pregnancy, they
may have limited ecacy in the setting of hyperaldosteronism [76].
Pheochromocytoma in pregnancy
Pheochromocytoma accounts for approximately 0.1% cases of hypertension in the general population. There have been at least 200 cases diagnosed
in pregnancy, and the estimated prevalence at term is approximately 1 in
54,000 [83,84]. Pheochromocytoma is associated with sustained or paroxysmal episodes of hypertension, pallor, headaches, and palpitations [84]. Other
presentations include chest pain, dyspnea, abdominal pain, seizure, or even
sudden death [85]. Although antenatal diagnosis is associated with improved
outcomes, pheochromocytoma can be missed because of unexpectedly normal blood pressure during gestation [83,85]. A recent case illustrated the
14
LINDSAY & NIEMAN
course of a women who was managed emergently after being diagnosed during labor [86]. However, a delayed diagnosis has been associated with maternal death caused by cerebral edema associated with cardiogenic shock [85].
Untreated pheochromocytoma is associated with increased fetal and maternal morbidity and mortality. The maternal mortality rate was 48% before
1969 and 26% in the 1970s, and subsequently it fell to 17% [8789]. Since
1990, approximately 85% of cases have been diagnosed antenatally, perhaps
because of increased awareness [84]. In one series, antenatal diagnosis reduced the maternal mortality and the fetal loss rate to less than 1% and
15%, respectively [88]. A hypertensive crisis may be precipitated by abdominal palpitation [84], drugs, including metoclopramide [87], or labor. Pheochromocytoma should be actively sought for in patients who have aected
family members with von Hippel-Lindau or multiple endocrine neoplasia
2 syndromes [90]. The lack of proteinuria in pheochromocytoma may dierentiate pheochromocytoma from hypertension associated with preeclampsia. Other potential dierential diagnoses include anxiety, cocaine use,
pulmonary embolism, and alcohol withdrawal [84].
Catecholamine production generally remains stable during gestation [91].
Screening for pheochromocytoma was traditionally undertaken by assessing
elevated 24-hour urinary epinephrine and norepinephrine excretions. Because tumor secretion may be episodic, these methods have been largely superseded by more sensitive and specic techniques. Fractionated urinary
metanephrines and plasma metanephrines are more sensitive for the diagnosis of pheochromocytoma in nonpregnant patients, but their value in pregnancy has yet to be evaluated fully [92]. Dynamic testing with clonidine has
not been validated in pregnancy [93]. Adrenal imaging is performed when
the diagnosis is conrmed biochemically using existing nonpregnant reference ranges. MRI (without gadolinium) has better specicity than ultrasonography and is preferred to CT to minimize exposure to ionizing
radiation. Pheochromocytoma is typically bright on T2-weighted MRI,
with a sensitivity of 93% to 100% [94]. Metaiodobenzylguanidine-, uorine-18 ([18F])-dopa, and [18F]-dopaminelabeled positron emission tomography scanning methods are highly specic, functional imaging modalities
that may be considered for localization in the postpartum period and
have additional utility for assessing extra-adrenal disease, which occurs in
approximately 10% of cases [94].
Adrenalectomy is the preferred denitive treatment of pheochromocytoma following adequate a- and b-blockade for at least 2 weeks before
surgery. Primary medical therapy is indicated for cases diagnosed after 24
weeks gestation because of the attendant diculties and risks of surgery performed at that time. a-Blockade with phenoxybenzamine, 10 mg to 20 mg
twice daily, is begun initially, with titration to a dose of approximately 1
mg/kg/d until hypertension is controlled. After several days of a-blockade,
b-blockers are added to minimize reex tachycardia, despite their possible
association with intrauterine growth retardation [88]. When used as
15
monotherapy, unopposed b-blockade leads to vasoconstriction and potential hypertensive crisis and should be avoided. Metyrosine is a specic inhibitor of cathecholamine synthesis through its eect on tyrosine hydroxylase.
Although it is an FDA category C agent, metyrosine was previously used in
one patient with malignant pheochromocytoma without complication [95].
There are insucient data to recommend its routine use in pregnancy, but
it may be considered for short-term emergency use in cases late in the third
trimester with refractory hypertension or arrhythmia [95]. Phentolamine,
1 mg to 5 mg, is the agent of choice for the treatment of a hypertensive crisis
[86].
The optimal timing of adrenalectomy is late in the rst or early in the second trimester. In the third trimester, a combined caesarian section followed
by adrenalectomy for cases managed conservatively with medical therapy
may be considered. Vaginal delivery is not recommended because of the potential for exacerbating a hypertensive crisis. A close liaison with the anesthesiologist is imperative before adrenalectomy, C-section, or labor.
Pregnancy and congenital adrenal hyperplasia
The prenatal diagnosis and treatment of 21-hydroxylase (CYP21 gene)
deciency are options for couples who have a previously aected infant
and may be requested by an index case before attempting pregnancy. Genetic counseling is guided by molecular investigation of the family, ideally
by CYP21 genotyping of the aected individuals and an evaluation of the
parents to exclude a new mutation in the child. Biochemical testing of the
partner of an aected individual can identify a potential heterozygote, in
which case genotyping should be performed [96].
Couples at risk for an aected infant may choose to undergo prenatal
treatment with dexamethasone coupled with prenatal diagnosis. The goal
of the treatment is to inhibit fetal ACTH and so prevent hyperandrogenism
and virilization of an aected female fetus. Thus, dexamethasone, at a divided daily dose of 20 mg/kg of prepregnancy weight, is started when pregnancy is diagnosed. Dexamethasone is the agent of choice because it is not a
ready substrate for 11-b-hydroxysteroid dehydrogenase type 2. Chorionic villous sampling is performed at 9 to 11 weeks for the evaluation of the fetus
sex and CYP21 gene. Dexamethasone is discontinued if the fetus is male or
an unaected female. As a result of this strategy, treatment would continue
in only one of eight pregnancies. The initiation of therapy before 9 weeks
has resulted in normal genitalia in 11 of 25 aected females and only mild
virilization in another 11, but later treatment or the use of a lower dose of
dexamethasone has resulted in virilization in 23 of 24 aected infants [97].
There are relatively few data on the long-term risks of prenatal dexamethasone treatment for aected or unaected fetuses. One recent study showed
that 174 children (including 48 who had CAH) who received dexamethasone
did not dier in cognitive or motor development from 313 unexposed
16
LINDSAY & NIEMAN
children, based on a maternal survey [98]. However, these children were 1 to

12 years old, and there are no data on long-term follow-up. Signicant maternal side eects, including weight gain, edema, abnormal glucose tolerance, and hypertension, occur in up to 50% of women treated until delivery.
A recent consensus statement has emphasized the ethical issues related to
the unnecessary treatment of unaected female or male fetuses, the unknown risks to the infants, and the maternal risks. The statement counsels
that only an experienced team should direct this therapy and that optimally
patients should provide written informed consent and be enrolled in a research protocol approved by an ethics committee. Additionally, the report
recommends prospective and long-term follow-up of all children receiving
prenatal treatment [99].
Summary
Adrenal disorders occurring in pregnancy are rare but are associated with
signicant maternal and fetal morbidity. The diagnosis of adrenocortical
and medullary dysfunction is more challenging than in the general population because of overlapping clinical and biochemical features of normal
pregnancy. This article illustrates the pitfalls and challenges involved in
the dierential diagnosis and treatment during gestation. Increased suspicion for the diagnosis of adrenal disorders during pregnancy would
likely facilitate early treatment and result in improved outcome for both
the mother and fetus.
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35 (2006) 2151
Calcium and Bone Disorders During

Pregnancy and Lactation
Christopher S. Kovacs, MDa,*,
Ghada El-Hajj Fuleihan, MD, MPHb,*
a
Health Sciences Centre, St. Johns, NL, Canada

Calcium Metabolism and Osteoporosis Program,
American University of BeirutMedical Center, Riad El Solh, Beirut, Lebanon
b
Mineral metabolism in the mother must adapt to the demand created by

the fetus and placenta, which together draw calcium and other minerals
from the maternal circulation to mineralize the developing fetal skeleton.
Similarly, mineral metabolism must adapt in the lactating woman to supply
sucient calcium to milk and the suckling neonate. Potential adaptations
include increased intake of mineral, increased eciency of intestinal absorption of mineral, mobilization of mineral from the skeleton, and increased renal conservation of mineral. Despite a similar magnitude of calcium demand
by pregnant and lactating women, the adjustments made in each of these reproductive periods dier signicantly (Fig. 1). These hormone-mediated adjustments normally satisfy the needs of the fetus and infant with short-term
depletions of maternal skeletal calcium content, but without long-term consequences to the maternal skeleton. In states of maternal malnutrition and
vitamin D deciency, however, the depletion of skeletal mineral content
may be proportionately more severe and may be accompanied by increased
skeletal fragility.
This article reviews present understanding of the adaptations in mineral
metabolism that occur during pregnancy and lactation and how these adaptations aect the presentation, diagnosis, and management of disorders of
calcium and bone metabolism. Animal data are cited to ll in the gaps where
* Corresponding authors. Basic Medical Sciences, Health Sciences Centre, 300 Prince
Philip Drive, St. Johns, NL, A1B 3V6 Canada (C.S. Kovacs); Calcium Metabolism and
Osteoporosis Program, American University of BeirutMedical Center, P.O. Box 11-0236,
Riad E1 Solh 4407 2020, Beirut, Lebanon (G.E.-H. Fuleihan).
E-mail addresses: ckovacs@mun.ca (C.S. Kovacs); gf01@aub.edu.lb (G.E.-H. Fuleihan).
doi:10.1016/j.ecl.2005.09.004
endo.theclinics.com
22
KOVACS & FULEIHAN
Fig. 1. Calcium homeostasis in human pregnancy and lactation compared with normal. The
thickness of arrows indicates a relative increase or decrease with respect to the normal and nonpregnant state. (Adapted from Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone
metabolism during pregnancy, puerperium and lactation. Endocr Rev 1997;18:83272. 1997
The Endocrine Society; with permission.)
human data are unavailable. The reader also is referred to several other
comprehensive reviews on the subject [13].
Adaptations during pregnancy

The developing fetal skeleton accretes about 30 g of calcium by term and
about 80% of it during the third trimester. This demand for calcium is
largely met by a doubling of maternal intestinal calcium absorption, mediated by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), or calcitriol, and possibly
by other factors.
Mineral ions and calcitropic hormones
Normal pregnancy results in altered levels of calcium and the calcitropic
hormones as schematically depicted in Fig. 2 [1]. The ionized calcium (the
physiologically important fraction of calcium) remains constant throughout
pregnancy. In contrast, the total serum calcium (sum of the ionized, complexed, and albumin-bound fractions of calcium in the circulation) decreases
in pregnancy secondary to a decline in serum albumin. In clinical practice,
the total serum calcium is more commonly measured than the ionized
calcium. The commonly observed decrease in total serum calcium should
CALCIUM & BONE DISORDERS IN PREGNANCY & LACTATION
23
Fig. 2. Longitudinal changes in calcium, phosphorus, and calcitropic hormone levels that occur
during pregnancy and lactation. Normal adult ranges are indicated by the shaded areas. The
progression in PTHrP levels is depicted by a dashed line to reect that the data are less complete; the implied comparisons of PTHrP levels in late pregnancy and lactation are uncertain
extrapolations because no reports followed patients serially. In both situations, PTHrP levels
are elevated. (Adapted from Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium and lactation. Endocr Rev 1997;18:83272. 1997 The
Endocrine Society; with permission.)
24
KOVACS & FULEIHAN
not be mistaken for evidence of physiologic hyperparathyroidism of pregnancy, an erroneous concept that has persisted in some modern texts [4,5].
The decline in total serum calcium is an unimportant artifact of a nonphysiologic measurement; the ionized calcium is the relevant measurement and always should be assayed if there is any doubt about the true value of the
serum calcium during pregnancy (or at any time). Serum phosphorus levels
also are normal during pregnancy.
As observed by longitudinal measurements during pregnancy with modern two-site intact immunoradiometric assays (IRMA), serum parathyroid hormone (PTH) decreases to the low-normal range (ie, 1030% of the
mean nonpregnant value) during the rst trimester, then increases steadily
to the mid-normal range by term [610]. As judged by the intact serum
PTH level, the parathyroids are modestly suppressed beginning early in the
rst trimester and return to apparently normal function by the end of pregnancy. First-generation PTH assays in the 1970s and 1980s were insensitive
and measured multiple, biologically inactive fragments of PTH; a few studies
with these assays had detected higher levels of PTH during pregnancy in humans. Those early studies of PTH in pregnancy, combined with the observation that total serum calcium decreases during pregnancy, reinforced the
erroneous concept that secondary hyperparathyroidism occurs during pregnancy. Modern intact assays have made it clear that in well-nourished
women, ionized calcium is normal throughout pregnancy, and that PTH is
suppressed during early pregnancy. Bio-intact PTH assays have been developed that detect true full-length PTH [11]; the levels are likely similar to
levels obtained with the more widely used intact PTH assays, but no study
has examined this. In contrast to the normal suppression of PTH during
pregnancy, there is evidence that PTH may increase above normal in late
pregnancy in women from Malay, who have very low intakes of calcium [12].
Total 1,25(OH)2D3 levels double early in pregnancy and maintain this
increase until term; free 1,25(OH)2D3 levels are increased from the third trimester and possibly earlier. The increase in 1,25(OH)2D3 may be largely independent of changes in PTH because PTH levels typically are decreasing at
the time of the increase in 1,25(OH)2D3. The maternal kidneys likely account
for most, if not all, of the increase in 1,25(OH)2D3 during pregnancy, although the decidua, placenta, and fetal kidneys may contribute a small
amount. The relative contribution of the maternal kidneys is based on several
lines of evidence [1], including the report of an anephric woman on hemodialysis who had low 1,25(OH)2D3 levels before and during a pregnancy [13].
The renal 1a-hydroxylase may be upregulated in response to factors such
as PTH-related protein (PTHrP), estradiol, prolactin, and placental lactogen
(evidence from animal studies is reviewed by Kovacs and Kronenberg [1]).
Serum calcitonin levels also increase during pregnancy, with the C cells of
the thyroid, breast, and placenta possibly contributing to the circulating level
of calcitonin. It has been postulated that calcitonin protects the maternal skeleton from excessive resorption of calcium, but this hypothesis is unproved.
25
No human studies have addressed the question, although studies in genetically

engineered mice have shown that the absence of calcitonin does not impair the
ability of mice to increase skeletal mineral content during pregnancy [14].
PTHrP levels are increased during late pregnancy, as determined by assays that detect PTHrP fragments encompassing amino acids 1 through
86. Because PTHrP is produced by many tissues in the mother and fetus (including the placenta, amnion, decidua, umbilical cord, fetal parathyroids,
and breast), it is unclear which sources contribute to the increase detected
in the maternal circulation. PTHrP may contribute to the elevations in
1,25(OH)2D3 and the suppression of PTH that are noted during pregnancy,
although there is evidence that PTHrP may not be as potent as PTH in stimulating the renal 1a-hydroxylase in vivo [15]. PTHrP has other roles during
pregnancy, including the regulation of placental calcium transport in the fetus [1,16]. PTHrP also may have a role in protecting the maternal skeleton
during pregnancy because the carboxyl-terminal portion of PTHrP (osteostatin) has been shown to inhibit osteoclastic bone resorption [17].
Pregnancy induces signicant changes in the levels of other hormones, including the sex steroids, prolactin, placental lactogen, and insulin-like growth
factor type 1. Each of these may have direct or indirect eects on calcium and
bone metabolism during pregnancy, but these issues have not been explored.
Intestinal absorption of calcium
Several clinical studies have shown that intestinal absorption of calcium
is doubled during pregnancy from 12 weeks of gestation (the earliest time
point studied); this seems to be a major maternal adaptation to meet the fetal need for calcium [1]. This increase may be the result of a 1,25(OH)2D3mediated increase in intestinal calbindin9K-D and other proteins. Based on
evidence from limited animal studies [1], prolactin and placental lactogen
(and possibly other factors) also may mediate part of the increase in intestinal calcium absorption. The increased absorption of calcium early in pregnancy may allow the maternal skeleton to store calcium in advance of the
peak fetal demands that occur later in pregnancy.
Renal handling of calcium
The 24-hour urine calcium excretion is increased by 12 weeks of gestation
(the earliest time point studied), and the amount excreted may exceed the
normal range [1]. Because fasting urine calcium values are normal or low,
the increase in 24-hour urine calcium likely reects the increased intestinal
absorption of calcium (absorptive hypercalciuria). The elevated calcitonin
levels of pregnancy also may promote renal calcium excretion.
Skeletal calcium metabolism
Animal models indicate that histomorphometric parameters of bone turnover are increased during pregnancy, which could be interpreted to mean that
26
KOVACS & FULEIHAN
mineral is mobilized from the maternal skeleton to contribute to the fetal

skeleton [18]. Serial measurements of bone mineral density by dual x-ray absorptiometry (DXA) in several strains of normal mice have shown, however,
that bone mineral content increases by 5% to 10% during pregnancy [14,19],
and the increased bone turnover of pregnancy might reect (at least in rodents) an anabolic or bone formative state, as opposed to a net bone resorptive state. As noted later in the lactation section, a net loss of bone mineral
content occurs during lactation in humans and rodents. An increase in
bone mineral content during pregnancy might serve to protect the maternal
skeleton against excessive demineralization and fragility during lactation.
Comparable histomorphometric data are not available for human pregnancy. In one study [20], 15 women who electively terminated a pregnancy
in the rst trimester (810 weeks) had bone biopsy evidence of increased
bone resorption, including increased resorption surface, increased numbers
of resorption cavities, and decreased osteoid. These ndings were not present
in biopsy specimens obtained from nonpregnant controls or in biopsy specimens obtained at term from 13 women who had elective cesarean sections.
Most human studies of skeletal calcium metabolism in pregnancy have examined changes in bone markers, that is, serum indices that reect bone
formation and serum or urine indices that reect bone resorption. These
studies have been fraught with numerous confounding variables that cloud
the interpretation of the results, including the lack of prepregnancy baseline
values; eects of hemodilution in pregnancy on serum markers; increased
glomerular ltration rate (GFR) and renal clearance; altered creatinine excretion; placental, uterine, and fetal contributions to the markers; degradation and clearance by the placenta; and lack of diurnally timed or fasted
specimens. Given these limitations, many studies have reported that urinary
markers of bone resorption (24-hour collection) are increased from early
pregnancy to mid-pregnancy (including deoxypyridinoline, pyridinoline,
and hydroxyproline). Conversely, serum markers of bone formation (generally not corrected for hemodilution or increased GFR) often decrease from
prepregnancy or nonpregnant values in early pregnancy or mid-pregnancy,
increasing to normal or greater before term (including osteocalcin, procollagen I carboxypeptides and bone-specic alkaline phosphatase). It is conceivable that the bone formation markers are artifactually lowered by normal
hemodilution and increased renal clearance of pregnancy, obscuring any
real increase in the level of the markers. One study that adjusted for the confounding eects of hemodilution and altered GFR showed that osteocalcin
production was not reduced in pregnancy [21]. Total alkaline phosphatase increases early in pregnancy largely because of contributions from the placental fraction and is not a useful marker of bone formation in pregnancy.
Based on the scant bone biopsy data and the measurements of bone
markers (with the aforementioned confounding factors), one cautiously
may conclude that bone turnover is increased in human pregnancy from
10 weeks of gestation. There is comparatively little maternal-fetal calcium
27
transfer occurring at this stage of pregnancy compared with the peak rate
of calcium transfer in the third trimester. One might have anticipated that
markers of bone turnover would increase particularly in the third trimester;
however, no further increase was seen at that time.
Changes in skeletal calcium content have been assessed in humans through
the use of sequential bone density studies during pregnancy. Because of concerns about fetal radiation exposure, few such studies have been done. Such
studies are confounded by changes in body composition and weight during
normal pregnancy, which can lead to artifactual changes in bone density. Using single-photon or dual-photon absorptiometry (SPA/DPA), several prospective studies did not nd a signicant change in cortical or trabecular
bone density during pregnancy [1]. Several more recent studies have used
DXA before conception (range 18 months prior, but not always stated)
and after delivery (range 16 weeks postpartum) [2127]. Most studies involved 16 or fewer subjects. One study found no change in lumbar spine
bone density measurements obtained preconception and within 1 to 2 weeks
postdelivery [23], whereas the other studies reported decreases of 4% to 5% in
lumbar spine bone density with the postpartum measurement taken 1 to 6
weeks postdelivery. The puerperium is associated with bone density losses
of 1% to 3% per month in women who lactate (see lactation section), and
it is important that the postpartum measurement be done as soon as possible
after delivery. Other longitudinal studies have found a progressive decrease
during pregnancy in indices thought to correlate with bone mineral density,
as determined by ultrasound measurements at a peripheral site, the os calcis
[28]. Although the longitudinal studies with SPA/DPA suggested no change
in trabecular or cortical bone density during pregnancy, the subsequent evidence from preconception and postdelivery DXA measurements and peripheral ultrasound measurements suggests that there may be a small net loss of
maternal bone mineral content during normal human pregnancy. None of all
the aforementioned studies could address the question as to whether skeletal
calcium content increases early in pregnancy in advance of the third trimester,
as has been observed in normal mice. Further studies, with larger numbers of
patients, are needed to clarify the extent of bone loss during pregnancy.
It seems certain that any acute changes in bone metabolism during pregnancy do not normally cause long-term changes in skeletal calcium content
or strength. Numerous studies of osteoporotic or osteopenic women have
failed to nd a signicant association of parity with bone density or fracture
risk [1,29]; however, a few studies of women with extremely low calcium or
vitamin D intake found that pregnancy may compromise skeletal strength
and density (see later). Although most clinical studies could not separate
out the eects of parity from the eects of lactation, it may be reasonable
to conclude that if parity has any eect on bone density or fracture risk,
it normally must be only a modest eect. A more recent study of twins indicated that there may be a small protective eect of parity and lactation on
maintaining bone mineral content [30].
28
KOVACS & FULEIHAN
Adaptations during lactation

About 280 to 400 mg of calcium is lost through breast milk daily, with
losses of 1000 mg or more in women who are nursing twins. A temporary
demineralization of the skeleton seems to be the main mechanism by which
lactating women meet these calcium requirements. This demineralization
does not seem to be mediated by PTH or calcitriol, but may be mediated
by PTHrP in the setting of a decrease in estrogen levels.
Mineral ions and calcitropic hormones
The normal lactational changes in maternal calcium, phosphorus, and
calcitropic hormone levels are schematically depicted in Fig. 2 [1]. The
mean ionized calcium level of exclusively lactating women is increased, although it remains within the normal range. Serum phosphorus levels also
are higher during lactation, and the level may exceed the normal range. Because reabsorption of phosphorus by the kidneys seems to be increased, the
increased serum phosphorus levels may reect the combined eects of the
increased ux of phosphorus into the blood from diet and from skeletal resorption in the setting of decreased renal phosphorus excretion.
Intact PTH, as determined by a two-site IRMA assay, has been found
to be reduced 50% or more in lactating women during the rst several
months. It increases to normal at weaning, but may rise above normal after
weaning (levels of bio-intact PTH have not been reported yet during lactation). In contrast to the high 1,25(OH)2D3 levels of pregnancy, maternal free
and bound 1,25(OH)2D3 levels decrease to normal within days of parturition and remain there throughout lactation.
PTHrP levels are signicantly higher in lactating women and mice than
in nonlactating controls, as measured by two-site IRMA assays. The
source of PTHrP seems be the breast or mammary tissue because PTHrP
has been detected in milk at concentrations exceeding 10,000 times the
level found in the blood of patients with hypercalcemia of malignancy
or normal human controls. A small increase in the maternal level of
PTHrP can be shown after suckling [31]. Blood levels of PTHrP were reduced in lactating mice that had the PTHrP gene ablated only from mammary tissue compared with normal lactating mice [32]. PTHrP seems to
play several roles within the breast, as indicated by studies in animals
that suggest PTHrP may regulate mammary development and blood
ow. The calcium-sensing receptor is expressed in the breast during lactation, where it regulates PTHrP production and the calcium and water content of the milk (Fig. 3) [33].
PTHrP plays a key role during lactation in regulating the demineralization of the skeleton. In response to suckling [31] and in response to signaling
from the calcium-sensing receptor expressed by lactating mammary tissue
(see Fig. 3) [33], PTHrP reaches the maternal circulation from mammary
29
Fig. 3. The calcium receptor (represented schematically) is expressed in mammary tissue during
lactation (but not pregnancy), wherein it has several key functions as elucidated from studies in
mice [33]. The calcium receptor monitors the systemic concentration of calcium to control
PTHrP synthesis and the supply of calcium to the breast. An increase in systemic calcium or
the administration of a calcimimetic inhibited PTHrP, whereas a decrease in systemic calcium
stimulated PTHrP. The calcium receptor also directly regulates the calcium and uid composition of milk. The administration of calcium or a calcimimetic stimulated the transport of calcium into the breast, and the administration of a calcimimetic enhanced the entry of water
into the milk, making it less viscous. (From Kovacs CS. Calcium and bone metabolism during
pregnancy and lactation. J Mammary Gland Biol Neoplasia 2005;10(2):10518. 2005 Springer
Science and Business Media BV; with permission.)
tissue and stimulates resorption of calcium from the maternal skeleton, renal
tubular reabsorption of calcium, and (indirectly) suppression of PTH
(Fig. 4). In a sense, the breast becomes an accessory parathyroid gland during lactation, but the hyperparathyroidism of lactation is increased secretion of PTHrP, not PTH. The strongest evidence in support of this model
comes from the study of mice in which the PTHrP gene was ablated at
the onset of lactation, but only within mammary tissue [32]. The lactational
decrease in bone mineral content was signicantly blunted in the absence of
mammary gland production of PTHrP. Other evidence for the central role
of PTHrP in lactation comes from humans, in that PTHrP levels correlate
negatively with PTH levels and positively with the ionized calcium levels
of lactating women [31,34], and that higher PTHrP levels correlate with
greater losses of bone mineral density during lactation in humans [35]. Observations in aparathyroid women provide evidence of the impact of PTHrP
in calcium homeostasis during lactation (see later).
Calcitonin levels are elevated in the rst 6 weeks of lactation. Studies in
mice lacking the gene that encodes calcitonin indicate that calcitonin may
modulate the rate of skeletal resorption during lactation. Calcitonin-null
mice lost more than 50% of skeletal mineral content during 3 weeks of
30
KOVACS & FULEIHAN
Fig. 4. The breast is a central regulator of skeletal demineralization during lactation. Suckling
induces release of prolactin. Suckling and prolactin inhibit the hypothalamic gonadotropin-releasing hormone (GnRH) pulse center, which suppresses the gonadotropins (luteinizing hormone [LH], follicle-stimulating hormone [FSH]), leading to low levels of the ovarian sex
steroids (estradiol and progesterone). PTHrP production and release from the breast is controlled by several factors, including suckling, prolactin, and the calcium receptor. PTHrP enters
the bloodstream and combines with systemically low estradiol levels to upregulate bone resorption markedly. Increased bone resorption releases calcium and phosphate into the bloodstream,
which reach the breast ducts and are actively pumped into the breast milk. PTHrP also passes
into the milk at high concentrations, but whether PTHrP plays a role in regulating calcium
physiology of the neonate is unknown. Calcitonin (CT) may inhibit skeletal responsiveness to
PTHrP and low estradiol. (From Kovacs CS. Calcium and bone metabolism during pregnancy
and lactation. J Mammary Gland Biol Neoplasia 2005;10(2):10518. 2005 Springer Science and
Business Media BV; with permission.)
lactation, approximately twice that of normal littermate sisters [14,36]. The

calcitonin-depleted mice still regained all of the lost mineral content after
weaning, which indicates that although calcitonin is needed in the shortterm to prevent severe losses of mineral content and potential skeletal fragility, calcitonin is not required in the long-term because the skeletal losses of
mineral are restored anyway. The human equivalent of absence of calcitonin
might explain some cases of osteoporosis of lactation (see later).
Intestinal absorption of calcium
Intestinal calcium absorption decreases to the nonpregnant rate from the
increased rate of pregnancy. This decrease in absorption corresponds to the
decrease in 1,25(OH)2D3 levels to normal.
31
Renal handling of calcium

In humans, the GFR decreases during lactation, and the renal excretion
of calcium typically is reduced to very low levels. This situation suggests that
tubular reabsorption of calcium must be increased, to account for reduced
calcium excretion in the setting of increased serum calcium.
Skeletal calcium metabolism
Histomorphometric data from animals consistently show increased bone
turnover during lactation, with losses of 30% of bone mineral achieved during 2 to 3 weeks of normal lactation in the rat [1], whereas a similar amount
is lost in the lactating mouse within 21 days [19]. The loss is greatest in the
trabecular bone of rats and mice. Comparative histomorphometric data are
lacking for humans, and in place of that, serum markers of bone formation
and urinary markers of bone resorption have been assessed in numerous
cross-sectional and prospective studies of lactation. Some confounding factors discussed with respect to pregnancy apply to the use of these markers in
lactating women. During lactation, GFR is reduced, and the intravascular
volume is more contracted. Urinary markers of bone resorption (24-hour
collection) increase two to three times above normal during lactation and
are higher than the levels attained in the third trimester. Serum markers
of bone formation (not adjusted for hemoconcentration or reduced GFR)
are generally high during lactation and increase over the levels attained during the third trimester. Total alkaline phosphatase declines immediately
postpartum owing to loss of the placental fraction, but still may remain
above normal because of the elevation in the bone-specic fraction. Despite
the confounding variables, these ndings suggest that bone turnover is signicantly increased during lactation.
In women, serial measurements of bone density during lactation (by SPA,
DPA, or DXA) have shown a decline of 3% to 10% in bone mineral content
after 2 to 6 months of lactation at trabecular sites (lumbar spine, hip, femur
and distal radius), with smaller losses at cortical sites [1,29,37]. The peak
rate of loss is 1% to 3% per month, far exceeding the rate of 1% to 3%
per year that can occur in women with postmenopausal osteoporosis, who
are considered to be losing bone rapidly. Loss of bone mineral from the maternal skeleton seems to be a normal consequence of lactation and may not
be preventable by increasing the calcium intake above the recommended dietary allowance. Several studies have shown that calcium supplementation
does not reduce signicantly the amount of bone lost during lactation
[3841]. The lactational decrease in bone mineral density correlates with
the amount of calcium lost in the breast milk [42].
The mechanisms controlling the rapid loss of skeletal calcium content are
not fully understood. The reduced estrogen levels of lactation are important,
but are unlikely to be the sole explanation. To estimate the eects of estrogen deciency during lactation, it is worth noting the alterations in calcium
32
KOVACS & FULEIHAN
and bone metabolism that occur in reproductive-age women who have estrogen deciency induced by gonadotropin-releasing hormone agonist therapy for endometriosis and other conditions. Six months of acute estrogen
deciency induced by gonadotropin-releasing hormone agonist therapy
leads to 1% to 4% losses in trabecular (but not cortical) bone density, increased urinary calcium excretion, and suppression of 1,25(OH)2D3 and
PTH levels [1]. During lactation, women are not as estrogen decient, but
they lose more bone mineral density (at trabecular and cortical sites),
have normal (as opposed to low) 1,25(OH)2D3 levels, and have reduced
(as opposed to increased) urinary calcium excretion. The dierence between
isolated estrogen deciency and lactation may be due to the eects of other
factors (eg, PTHrP) that add to the eects of estrogen withdrawal in lactation (Fig. 5). The relative inuences of estrogen deciency and PTHrP have
been partially discerned in normal mice, in which it has been shown that
treatment with pharmacologic doses of estrogen blunted, but did not abolish, the normal demineralization that occurs during lactation [43].
The bone density losses of lactation are substantially reversed during weaning at a rate of 0.5% to 2% per month [1,29,40]. The mechanism for this restoration of bone density is uncertain and largely unexplored, but preliminary
evidence from animal models suggests that PTH, calcitriol, calcitonin, and estrogen may not be required to achieve that restoration. In the long-term, the
consequences of lactation-induced depletion of bone mineral seem clinically
unimportant in most women. Most epidemiologic studies of premenopausal
Fig. 5. Acute estrogen deciency (eg, gonadotropin-releasing hormone analogue therapy) increases skeletal resorption and raises the blood calcium; PTH is suppressed, and renal calcium
losses are increased. During lactation, the combined eects of PTHrP (secreted by the breast)
and estrogen deciency increase skeletal resorption, reduce renal calcium losses, and raise the
blood calcium, but calcium is directed into the breast milk. (From Kovacs CS, Kronenberg
HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium and lactation.
Endocr Rev 1997;18:83272. 1997 The Endocrine Society; with permission.)
33
and postmenopausal women have found no adverse eect of a history of

lactation on peak bone mass, bone density, or hip fracture risk [1,29].
Disorders of bone and mineral metabolism during pregnancy and lactation
As previously discussed, pregnancy is a state of hyperabsorptive hypercalciuria, characterized by high levels of calcitriol, increasing levels of
PTHrP, suppressed PTH levels, stable serum ionized calcium levels, and
enhanced urinary calcium excretion (see Fig. 2). Lactation is characterized
by further increments in PTHrP levels, whereas calcitriol levels return to
normal. The estimated daily increase in calcium requirements (0.3 g/d) to
meet the fetal demands for bone mineralization and the maternal requirements for milk synthesis are largely through enhanced intestinal calcium absorption during pregnancy and through maternal bone resorption during
lactation [42]. Disorders of bone and mineral homeostasis that occur in
the nonpregnant state may manifest dierently during pregnancy and lactation as a result of the diering hormonal changes that occur in these two distinct reproductive intervals.
Primary hyperparathyroidism
Primary hyperparathyroidism occurs rarely during pregnancy; the true
incidence is unknown because hyperparathyroidism may remain asymptomatic and go undiagnosed in uncomplicated pregnancies. In the general population, the estimated incidence of hyperparathyroidism increased from 16/
100,000 before 1974 (before routine automated screening) to a peak of 112/
100,000 years later, then subsequently declined to 4/100,000 [44]. Most subjects were older than age 45 years [44]. The incidence of hyperparathyroidism in women of childbearing age in an older series was estimated to be
approximately 8/100,000 per year [45]. Approximately 150 cases have
been reported in the English literature to date [46,47]. Two studies retrospectively evaluated 850 parathyroidectomies during the period 19601991 and
750 parathyroidectomies during 19751996 and revealed that parathyroidectomies during pregnancies accounted for 1.4% and 0.8% of total surgeries
[46,48]. The diagnosis may be obscured by the normal pregnancy-induced
changes that decrease the total serum calcium and suppress PTH; nding
the ionized calcium to be increased and the PTH to be detectable would indicate primary hyperparathyroidism in most cases.
Hyperparathyroidism in a pregnant patient can mean considerable morbidity for the mother and the fetus. Complications have been reported in
67% of mothers and 80% of fetuses and neonates [49], complications that
are in large part due to maternal hypercalcemia. The histopathologic distribution in hyperparathyroidism of pregnancy is comparable to that reported
in large series spanning all age groups [50]. A series of 100 cases of hyperparathyroidism diagnosed during pregnancy or postdelivery revealed adenomas in 89%, hyperplasia in 9%, and carcinoma in 2% [46].
34
KOVACS & FULEIHAN
Manifestations and complications in pregnant women

In a report of 45 pregnant women with hyperparathyroidism, 38% complained of nausea, vomiting, or abdominal pain; 24% reported renal colic;
22% had muscular weakness; 22% manifested mental symptoms; and
11% complained of skeletal pain or fatigue; only 20% were asymptomatic
[51]. Other clinical manifestations included hyperemesis gravidarum, weight
loss, seizure, or other symptoms mimicking preeclampsia [46,48]. Many of
the aforementioned symptoms are nonspecic and could have been due to
the pregnancy itself. Objective ndings included the following: 24% had
nephrolithiasis or nephrocalcinosis, 16% had urinary tract infections,
13% had bone disease on radiograph, and 11% had pancreatitis [51]. In another large series of 63 cases, 38% had evidence of bone disease, 54% had
evidence of renal disease, and 30% had evidence of both [52]. The high prevalence of stone disease may be explained by pregnancy-induced hyperabsorptive hypercalciuria that augments the hypercalciuria that otherwise
would occur secondary to hyperparathyroidism itself. The prevalence of
pancreatitis complicating hyperparathyroidism varied among reports (range
613%) [51,5355] and usually occurred during the second or third trimester
[56]. In a series of 75 cases, pancreatitis was the presenting illness in 5 cases,
2 of which had concomitant hypercalcemic crisis [55]. Of the few other cases
of acute parathyroid crisis reported during pregnancy [53,57], one became
clinically apparent 3 days postpartum followed by rapid deterioration, pancreatitis, respiratory failure, shock, and unsuccessful resuscitation [57]. The
patient had been hypercalcemic at 16 weeks of gestation, but was asymptomatic at that time, leading the authors to suggest that the increased fetal
need for calcium may have protected the mother from severe hypercalcemia
before delivery [57]. Susceptibility to fractures owing to hyperparathyroidism during pregnancy is uncommon. Bilateral femoral neck fractures and
rib fractures have been reported in two cases of severe hyperparathyroidism
diagnosed during pregnancy, wherein PTH levels were 20-fold above the upper limit of normal, and in one case, the hyperparathyroidism was due to
parathyroid carcinoma [58,59].
Complications in Fetuses
The most frequent serious complications in fetuses include stillbirth, miscarriage, and neonatal tetany. The percentage of aected pregnancies terminating in stillbirth, neonatal death, and neonatal tetany declined over the
decades from 13% to 2%, from 8% to 2%, and from 38% to 15% [52].
Perinatal death occurred in 25% to 30% of neonates, whereas neonatal
complications were noted in 50%, with tetany being at the forefront in infants born to untreated mothers [46,6062]. Neonatal tetany is a common
presentation of unrecognized hyperparathyroidism during pregnancy. The
pathophysiology of the hypocalcemia and tetany is the suppression of fetal
parathyroid function from maternal hypercalcemia, which becomes clinically evident when the maternal calcium ow is interrupted at birth [63].
35
Although the neonatal hypocalcemia and hypoparathyroidism are usually

transient, resolving with treatment within 3 to 5 months [52], it has been reported to occur initially as late as 2.5 months postpartum [64] and may be
permanent [52,61,65]. Bottle-fed infants were more likely to develop hypocalcemia than breastfed ones because of the higher phosphate-to-calcium ratio in cows milk compared with breast milk [52].
Management of the mother and neonate
Parathyroidectomy performed during pregnancy prevents fetal and neonatal morbidities. The rst successful parathyroidectomy during pregnancy
was performed by Petit and Clark in 1947 [66]. A review comparing the outcomes of 109 mothers with hyperparathyroidism during pregnancy who
were treated medically (n 70) or surgically (n 39) revealed that neonates
of mothers with untreated hypercalcemia run a greater risk of complications
[46]. In patients treated medically, there were 53% neonatal complications
and 16% neonatal deaths, as opposed to a 12.5% incidence of neonatal
complications and 2.5% neonatal deaths in patients who underwent parathyroidectomy [46]. Parathyroidectomy is best performed during the second
trimester, after completion of organogenesis in the fetus and to avoid the
poor outcomes of surgery during the third trimester [51,52,54,62]. In one series, premature labor with neonatal death occurred in four of seven third-trimester surgeries [54]. Parathyroidectomy in the third trimester is warranted,
however, when the risks outweigh the benets, and the procedure has been
performed successfully in such cases [47,67].
Treatment options for hyperparathyroidism in pregnancy are inuenced
by the symptoms and severity of disease and gestational age. Optimal management requires a multidisciplinary approach; surgery should be performed
only by an experienced parathyroid surgeon. Symptomatic and severe disease
should be treated surgically, preferably in the second trimester, whereas mild
asymptomatic disease diagnosed in the third trimester may continue to be observed until after delivery. A consensus for other cases is missing, however.
Medical treatment includes adequate hydration and correction of electrolyte
abnormalities [49]. Pharmacologic agents to treat hypercalcemia have not
been studied adequately in pregnancy. Calcitonin, a pregnancy category B
medication of the US Food and Drug Administration, does not cross the placenta and has been used safely in pregnancy [49]. Oral phosphate, a pregnancy
category C medication, has been used in pregnancy; its most common side effects are diarrhea and hypokalemia. It should be avoided in patients with
renal failure or high serum phosphate because of the risk of soft tissue calcications [49]. Bisphosphonates and mithramycin are contraindicated because
of their adverse eects on fetal development; bisphosphonates in particular
may interfere with normal endochondral bone development. High-dose magnesium has been suggested as a therapeutic alternative for hyperparathyroidism in pregnancy, although its eectiveness is uncertain. This divalent cation
decreases serum PTH and calcium levels by activating the calcium-sensing
36
KOVACS & FULEIHAN
receptor, and at the same time it treats premature labor associated with hypercalcemia [68,69]. Experience with any of the aforementioned pharmacologic therapies is limited to individual case reports [49]; consequently, no
medical therapy can be claimed to be better than any other. Medical therapy
should be coupled with maternal surveillance and the monitoring of serum
calcium and electrolytes and the initiation of antenatal testing with serial fetal
ultrasound starting at 28 weeks of gestation. Parathyroidectomy is recommended postpartum in cases that were followed medically during pregnancy.
Lactation is not contraindicated in women with untreated hyperparathyroidism, but worsening of hypercalcemia and accelerated skeletal losses may be
anticipated because of the combined eects of PTHrP and hyperparathyroidism to stimulate bone resorption.
Neonatal hypoparathyroidism secondary to maternal hyperparathyroidism is usually transient (see earlier) and is treated with calcium supplementation and calcitriol. These neonates also should be fed milk formulas high
in calcium and low in phosphate to minimize the risk of hypocalcemia. The
prevalence and severity of complications from hyperparathyroidism in
mothers and neonates have and will continue to decrease over time, owing
to increased surveillance, earlier intervention, and improved surgical and anesthetic technology [52,60,61].
Familial benign hypocalciuric hypercalcemia
Familial benign hypocalciuric hypercalcemia (FBHH) is an autosomal
dominant disorder that is caused by inactivating mutations in the calciumsensing receptor that cause hypercalcemia and hypocalciuria [70,71]. In
contrast to patients with hyperparathyroidism, patients with FBHH do
not experience bone demineralization or nephrolithiasis. FBHH has been
reported in pregnancy with no clinical sequelae in the mother [72]. As anticipated, maternal hypercalcemia has caused suppression of PTH synthesis in the fetus, however, and subsequent hypocalcemia and tetany in the
neonate [72,73]. The treatment of neonates is similar to that of children
born to mothers with hyperparathyroidism (see earlier).
The calcium-sensing receptor is expressed in the epithelial ducts of breast
tissue and has been shown to modulate the production of PTHrP and the
transport of calcium into milk in a mouse model [33]. Activating mutations
of this receptor in women with FBHH theoretically could enhance the degree of skeletal demineralization during lactation and the calcium content
of milk, but this has not been studied.
Hypoparathyroidism
Patients usually are known to have hypoparathyroidism or aparathyroidism before pregnancy, and the therapeutic dilemma revolves around adjustment of the treatment, which may vary widely. In 1966, OLeary et al [74]
reported two cases of hypoparathyroidism treated with high doses of
37
calcium and vitamin D wherein the mothers gave birth to healthy infants
after uncomplicated pregnancies. Despite physiologic increments in endogenous calcitriol levels during pregnancy, several studies since have documented increased requirements for exogenous calcium and calcitriol therapy
as pregnancy progressed in patients with hypoparathyroidism [7578]. Conversely, in numerous other case reports, women with hypoparathyroidism
have been reported to require less calcium and vitamin D supplementation
during pregnancy [1]. Potential explanations for requiring less supplementation during pregnancy include pregnancy-induced increments in calcitriol
from placental sources, the potential eect of PTHrP in the maternal circulation to stimulate the renal 1a-hydroxylase, and other pregnancy-related
factors (eg, prolactin or placental lactogen) that may stimulate the renal
1a-hydroxylase or enhance intestinal calcium absorption independently of
calcitriol. The last-mentioned has been reported exclusively in animal models [1]. In some case reports, it seems that the normal, artifactual decrease in
total serum calcium during pregnancy was the parameter that led to treatment with increased calcium and calcitriol supplementation. Although few
cases report measurements of ionized calcium, several do mention that the
increments in vitamin D were due to maternal symptoms of hypocalcemia
or tetany.
Consequently, there is no established therapeutic regimen for the treatment of hypoparathyroidism during pregnancy, but numerous principles exist that help to guide treatment decisions. Calcitriol levels normally increase
during pregnancy and contribute (at least in part) to the enhanced intestinal
calcium absorption of pregnancy; most women should receive an increase in
the dosage of calcitriol at least initially. The total serum calcium is less informative, and the ionized calcium should be monitored in these patients.
Undertreatment results in maternal hypocalcemia; increases the risk of premature labor and of neonatal secondary hyperparathyroidism; and may lead
to neonatal skeletal demineralization, subperiosteal bone resorption, and osteitis brosa cystica [79]. Conversely, overtreatment may lead to maternal
hypercalcemia and neonatal hypoparathyroidism and raises the potential
concerns of teratogenicity that has been shown using older vitamin D preparations [80,81]. The active forms of vitamin D, such as calcitriol and 1a-calcidiol, have the advantages of a shorter half-life and lower risk of toxicity. A
study reported the outcome of pregnancy in 10 women treated with calcitriol
at doses of 0.25 mg/d to 3.25 mg/d [75]. In 8 of 10 pregnancies, healthy infants
were delivered. In two cases, serious adverse events occurred, including premature closure of the frontal fontanelle and stillbirth, but the causative role
of calcitriol could not be established [75]. Details regarding nine additional
cases of hypoparathyroidism and vitamin Dresistant rickets were provided
in the same publication and conrmed the lack of toxicity or teratogenicity
from vitamin D supplementation during pregnancy [75].
In contrast to the conicting literature on the eects of pregnancy on
hypoparathyroidism, calcium and vitamin D or calcitriol requirements in
38
KOVACS & FULEIHAN
hypoparathyroid patients have been shown consistently to decrease during

lactation [77,78], such that the patients become hypercalcemic unless the
supplements are reduced substantially or discontinued. The decreased requirement for calcium and calcitriol occurs at a time when circulating
PTHrP levels are high in the maternal circulation of these hypoparathyroid
women [76,82,83]. PTHrP may stimulate endogenous calcitriol formation; in
one patient, the calcitriol level initially declined below the lower limit of normal when calcium and calcitriol were discontinued, but thereafter the calcitriol level remained in the lower half of the normal range as lactation
proceeded [82]. PTHrP also facilitates maternal bone resorption in the presence of postpartum estrogen deciency. The aforementioned activity may
explain why lactation can eliminate temporarily the requirement for supplemental calcium and calcitriol in hypoparathyroid women.
The management of hypoparathyroidism during pregnancy and lactation
is challenging. The use of calcium supplementation with calcitriol is recommended, along with monitoring of symptoms of hypocalcemia and of serum
ionized calcium levels (not the total serum calcium) to titrate the calcitriol
dose as pregnancy progresses. In general, the requirements in calcitriol
vary during the second half of pregnancy, but are expected to decrease during lactation.
Pseudohypoparathyroidism
In case reports of pseudohypoparathyroidism, a state characterized by inherited resistance to PTH, patients have hypocalcemia, hypophosphatemia,
and high PTH levels. Such patients have been reported to become normocalcemic during pregnancy without ingesting therapeutic amounts of calcium
and vitamin D [84]. The mechanism by which pseudohypoparathyroidism
is improved in pregnancy is unclear. It may include increased placental secretion of calcitriol, wherein levels have been reported to double or triple
in two case reports during the second and third trimesters [84].
The impact of lactation on calcium metabolism in pseudohypoparathyroidism is less well documented. These patients do not have skeletal resistance to PTH, and it is possible that calcium and vitamin D requirements
may decrease secondary to enhanced skeletal resorption owing to the combined eects of endogenous high PTH levels, increasing PTHrP release from
the breast, and lactation-induced estrogen deciency. Women with pseudohypoparathyroidism might be expected to lose more bone density than normal during lactation, but this has not been studied.
Osteoporosis associated with pregnancy and lactation
Osteoporosis associated with pregnancy and lactation has been recognized for more than 5 decades [85] and usually presents during late pregnancy or early postpartum [8588]. It is still debatable whether pregnancy
39
and lactation are causal or accidentally associated with the condition. It is

equally unclear whether these osteoporotic fractures reect architectural
deterioration of a previously abnormal skeleton or whether pregnancy
and lactation themselves account in large part for the bone loss and fragility
fractures, situations that may be compounded by low calcium intake and
vitamin D deciency. As reviewed previously, skeletal demineralization normally occurs during lactation as a consequence of the actions of mammary
glandderived PTHrP in the setting of low estradiol levels and is not preventable by increased calcium intake; osteoporotic fractures may occur in
some women during lactation when the demineralization is excessive or
the skeleton is unable to tolerate the normal lactational losses of mineral.
PTHrP levels were high in one case of lactational osteoporosis and were
found to remain elevated for months after weaning [89]. One study, which
followed 13 women with pregnancy-associated osteoporosis for 8 years,
showed that bone mineral density at the spine and hip increased signicantly,
leading the investigators to conclude that a large part of the bone loss
had been related to the pregnancy itself [86]. Conversely, a high prevalence
of fractures in 35 subjects presenting with pregnancy-associated osteoporosis raised the possibility of a genetic factor [90]. The recognition that absence
of endogenous calcitonin in mice more than doubles the lactational losses
raises the consideration that some women might have a genetic deciency
in calcitonin, its receptor, or some other factor [14,36]. Because bone density
is not normally measured in premenopausal women, the bone density before
pregnancy or at the end of lactation is usually unknown, and the debate regarding the relative contribution of pregnancy or lactation-associated bone
changes versus preexisting abnormalities in the skeleton will continue.
Clinical features
Patients present at a mean age of 27 to 28 years, usually in the setting of
a rst pregnancy, and no clear association with parity has been found [86
88]. In more than 60% of cases, patients complain of back pain in the lower
thoracic or lumbar area, pain that can be quite debilitating secondary to
vertebral collapse [8688]. In such cases, the pain usually improves spontaneously over weeks, but in a few the severe pain may persist for several years
[87]. Others present with hip pain, otherwise known as transient osteoporosis of the hip, as part of a syndrome of monarticular or polyarticular pain
over other lower extremity joints, including the ankles, which is accentuated
with the use of the joint [8688,91]. Of the more than 200 cases of transient
osteoporosis of the hip that have been reported, one third occurred in
women in their third trimester of pregnancy or in the early postpartum period [9193]. The dierential diagnosis of this condition includes inammatory joint disorders, avascular necrosis of the hip, bone marrow edema, and
reex sympathetic dystrophy. In contrast to the last-mentioned condition,
patients with transient regional osteoporosis of the hip lack a history of
trauma and the typical physical ndings of muscle spasm and skin changes
40
KOVACS & FULEIHAN
[92]. In contrast to vertebral osteoporosis, recurrences in transient regional

osteoporosis of the hip have been described in 40% of total cases, but no
series has described this syndrome exclusively in pregnant women [91].
Pathogenesis and laboratory ndings

The pathogenesis of pregnancy-associated osteoporosis (presenting with
vertebral compression fractures) and transient osteoporosis of the hip differs. In a few cases of the former, secondary causes of bone loss could be
identied, including anorexia nervosa, hyperparathyroidism, osteogenesis
imperfecta, and corticosteroid or heparin therapy [87,88,90]. One report described pregnancy-associated osteoporosis after oocyte donation in a woman
with ovarian failure [94]. Serum calcium and phosphate levels were normal,
and no consistent abnormalities in the calciotropic hormones were reported
[87,88]. Bone biopsy specimens obtained in some cases have conrmed the
diagnosis of osteoporosis, and no osteomalacia was found [87,88]. Bone
density tended to be low when measured [86,88]. In a series of 24 patients,
the mean Z-score was 1.98 (G1.5, n 15) at the lumbar spine and
1.48 (G1.5, n 15) at the total hip [88]. In transient osteoporosis of the
hip, radiographs or MRI revealed reduced bone density and increased water
content of the marrow cavity [91].
Diagnostic studies and therapeutic interventions

Patients should be screened for secondary causes of bone loss, a large
proportion of which may be treatable. Most cases improve symptomatically
within a few weeks with conservative measures [87,91]. Myriad pharmacologic agents have been used in individual cases, including calcium, vitamin
D, testosterone, estrogen, calcitonin, and bisphosphonates, with increments
in bone mineral density reaching 27% at the spine and 7% at the hip in
patient case treated with alendronate for 6 months [87]. Because these are
usually reports on individual cases and lack controls, the ecacy of such
interventions is unproved, and the interventions are not warranted.
In severe cases of osteoporosis, it may be prudent to discourage breastfeeding, the rationale being that the skeleton may not be able to tolerate
the normal demineralization that lactation would induce. Patients should
be cautioned against carrying heavy weights to avoid additional stress on
the spine, and the use of a supportive corset may be helpful. Patients should
be reassured that substantial increments in bone mineral density will occur
over time [86], and that the condition in cases of vertebral collapse is unlikely to recur. In cases of transient osteoporosis of the hip, patients usually
do well with conservative measures, including bed rest. Symptoms and radiograph abnormalities resolve within a few months of their onset [91],
but may recur, in contrast to cases with vertebral fracture symptoms, which
usually do not recur.
41
Disturbances in bone and mineral metabolism from the administration of

magnesium sulfate during pregnancy
The administration of intravenous magnesium sulfate for 24 to 72 hours
is one of the mainstay therapies for the treatment of preterm labor and for
the treatment of preeclampsia and eclampsia. Its eect is mediated by action
on the myoneural junction. In vitro at high doses, magnesium suppresses
PTH levels, similarly to other divalent and trivalent cations, albeit with
a lower potency than calcium. This eect now is recognized to occur
through the calcium-sensing receptor, a receptor heavily expressed in the
parathyroid glands and kidneys [70,95]. Long-term tocolytic therapy using
magnesium sulfate generally has been considered safe [96], although few reports have raised concerns about its safety to mothers and neonates.
Maternal complications
Hypocalcemia has been described in several cases in which the women received magnesium to suppress premature labor [9799]. In a study of seven
such cases, a loading dose of 6 g of intravenous magnesium sulfate followed
by a maintenance dose of 2 g/h resulted in a rapid increase in the mean serum magnesium level from 2 mg/dL to 6 mg/dL within 1 hour, coupled with
an almost concomitant decline in the serum PTH levels, which only partially
recovered in 3 hours despite substantial decrements in total and ionized serum calcium levels below the lower limit of normal [98]. A similar pattern
for maternal and neonatal proles was noted in a study of 15 women treated
with magnesium sulfate [99]. A Medline literature search for articles published in English in the period 19662002 on magnesium sulfate and hypocalcemia revealed four cases of maternal symptomatic hypocalcemia, with
serum calcium levels reaching 5.3 mg/dL in one case. Two mothers had
a positive Chvostek and Trousseau sign or tetany; three of these cases
were noted to have concomitant low PTH levels [100].
Although the short-term administration of magnesium sulfate may lower
maternal serum calcium through an eect on PTH secretion, long-term administration for 2 to 3 weeks was associated with increments in serum PTH
levels, possibly as an appropriate adaptive mechanism to prolonged hypocalcemia. It has been suggested that urinary loss of calcium may be a major
pathophysiologic mechanism for the hypocalcemia and in such instances
may result in ultimate impairment of bone mineralization [101]. In a study
of 20 subjects given intravenous magnesium sulfate for premature labor, serum magnesium and phosphorus levels increased, serum calcium levels decreased concomitantly with an increase in serum PTH, and substantial
increments in urinary magnesium and calcium were noted, reaching mean
levels two to three times the upper limit of normal [101]. Prolonged magnesium administration for several weeks also has been associated with maternal forearm bone loss prospectively, osteoporosis by bone mineral density,
and bilateral calcaneal stress fractures postpartum [101103].
42
KOVACS & FULEIHAN
Neonatal complications
Administration of intravenous magnesium to mothers before delivery increased neonatal serum magnesium and decreased PTH levels, whereas the
eect on neonatal total and ionized calcium levels varied [97,99]. Studies
evaluating the impact of neonatal hypermagnesemia on neonatal outcomes
have yielded conicting results [97,104106]. Respiratory depression and hypotonia were reported in 16 cases of neonatal hypermagnesemia [106]. A follow-up study of 35 infants born to toxemic mothers treated with magnesium
sulfate for 2 to 4 days suggested that neonates whose mothers had received
prolonged administration may be more likely to manifest respiratory depression [105]. Cord blood and neonatal serum magnesium levels were of little
diagnostic value to the clinical picture except in cases of severe hypermagnesemia [105,107], conrming the general observation that circulating serum
magnesium levels do not reect intracellular and total body magnesium
stores. Conversely, a study of 118 infants born to mothers who had received
intramuscular magnesium in doses of 10 to 95 g concluded that the neonatal
death rate was lower than that of the total newborn population [104]. Respiratory depression, hypotonia, and need for intubation were not evaluated in
that report, however [104]. Neonatal bone abnormalities have been reported
with long-term use of magnesium sulfate. The rst report by Lamm et al
[108] described a congenital form of rickets manifested by defective ossication of bone and enamel in the teeth of the ospring of mothers who had
received magnesium sulfate during pregnancy. Several cases of abnormal
mineralization of metaphyses since have been reported in neonates born
to mothers who received prolonged intravenous magnesium and had high
serum magnesium levels [109111]. The proposed mechanism for defective
mineralization of bones involves the inhibition of calcication of osteoid
in which calcium-binding sites are occupied by magnesium [109,110].
Some of these conicting ndings regarding neonatal morbidity from maternal administration of magnesium sulfate may be explained by the route
and duration of magnesium sulfate administration, by the variability in
the ranges of cord magnesium levels reached, and by the gestational age
of the neonates. Postdelivery, there was a delay in normalization of the serum magnesium level for a few days resulting from the limitation of magnesium excretion by the newborns immature kidneys [97].
Management issues
There are no guidelines for the monitoring of pregnant women receiving
magnesium sulfate. Neonates born to mothers receiving long-term magnesium sulfate and experiencing severe hypermagnesemia (O 7 mg/dL) are
more likely to have hypotonia, respiratory depression, and bone abnormalities [97,105,107,111]. Subjects receiving such therapy for periods exceeding
1 or 2 days should be monitored carefully, with the measurement of maternal serum calcium and magnesium levels, coupled with monitoring the
fetal movement. Symptomatic neonates can be managed by maintaining
43
ventilation for 24 to 48 hours and providing intravenous uids for electrolyte balance for a few days, after which marked clinical improvement is usually noted [105]. Intravenous calcium to antagonize the central nervous
system depression and peripheral neuromuscular blockade has been used,
with careful monitoring of the heart rate [105].
Low calcium intake
There are limited data that low calcium intake in the mother may adversely
aect fetal mineral accretion and maternal bone mineral metabolism [112].
In women with low dietary calcium intake, there are diering results as to
whether or not calcium supplementation during pregnancy improved maternal or neonatal bone density [3]. There is short-term evidence that maternal
turnover was reduced when 1.2 g of calcium was given for 20 days to 31 Mexican women with a mean calcium intake of 1 g during weeks 25 to 30 of gestation [113]. In a double-blind study conducted in 256 pregnant women, 2 g of
calcium supplementation improved bone mineral content in infants of supplemented mothers who were in the lowest quintile of calcium intake [114].
During lactation, there is no rm evidence that low calcium intake leads
to impaired breast milk quality or accentuates maternal bone loss [115].
Even in women with very low calcium intakes, the same amount of mineral
was lost during lactation from the skeleton compared with women who had
supplemented calcium intakes, and the breast milk calcium content was
unaected by calcium intake or vitamin D status [116118]. Conversely,
because high calcium intakes do not aect the degree of skeletal demineralization that occurs during lactation [3841], it is unlikely that increasing calcium supplementation above normal would aect skeletal demineralization.
In general, the physiologic changes in calcium and bone metabolism that
usually occur during pregnancy and lactation are likely to be sucient for
fetal bone growth and breast milk production in women with reasonably
sucient calcium intake [115]. The inclusion of calcium supplementation
for pregnant women with low calcium intake could be defended, however,
and is strengthened further by the possible link between low calcium intake,
preeclampsia, and increased blood pressure in the ospring [112]. Increased
calcium intake also is recommended in adolescent mothers to meet the need
of reproduction and maternal bone growth [115]. There is evidence that the
skeleton of an undernourished adolescent recovers fully from lactational
losses, but there is some concern that peak bone mass might not be attained
subsequently [119].
Vitamin D deciency
In humans and in animal models, vitamin D deciency or the absence
of the vitamin D receptor can lead to adverse neonatal outcomes, including neonatal rickets, craniotabes, decreased wrist ossication centers, and
44
KOVACS & FULEIHAN
impaired tooth enamel formation [120]. These features generally are not
present at birth, but appear postnatally as intestinal calcium absorption becomes vitamin D dependent. Although vitamin D supplementation of pregnant mothers at risk for vitamin D deciency improved neonatal serum
calcium concentrations and resulted in a trend for greater height and length
in the ospring [112], a Cochrane review of 232 women in two trials reported conicting results [121]. Although there is no evidence to indicate
a benecial eect of vitamin D supplementation during pregnancy above
the amounts needed to prevent vitamin D deciency, optimal levels for vitamin D supplementation are unclear [122]. An arbitrary daily recommended
intake has been set at 400 IU/d, but likely needs revision upward [123]. Recommendations for vitamin D supplementation either for women of childbearing age or for lactating women were not mentioned in the new US
dietary guidelines issued in 2005 [124].
Scientic data pertaining to vitamin D supplementation during lactation
are even scarcer than data on vitamin D supplementation during pregnancy.
An arbitrary daily recommended intake has been set at 400 IU/d, but
may be insucient [123]. Whether vitamin D deciency impairs the ability
to restore maternal skeleton postweaning is unclear [1]. Lactating mothers
supplemented with 1000 IU to 2000 IU of vitamin D for 15 weeks experienced increments in circulating maternal 25-hydroxyvitamin D3 levels of
16 ng/mL to 23 ng/mL [122]. It has been suggested that vitamin D supplementation of lactating mothers would improve vitamin D nutrition in the
mother and the breastfeeding infant; this has not been shown yet, but is currently under investigation [122]. Breastfed infants of vitamin Ddecient
mothers should receive vitamin D supplementation to avoid nutritional rickets [125]. There is low penetrance of vitamin D into breast milk, and it is
more ecient to give the vitamin D supplement directly to the infant, although supplementing the mother with high doses has been shown to
work [126].
Hypercalcemia of malignancy
Hypercalcemia of malignancy, an extremely rare occurrence, has been reported in two casesdone in metastatic breast cancer and the other in renal
cell carcinoma [127,128]. In both reports, the disease was rapidly progressive
and resulted in premature delivery at 29 and 32 weeks of gestation and maternal demise within 4 months postpartum. On the rst day postdelivery,
both infants were hypercalcemic, and one subsequently developed hypocalcemia from transient hypoparathyroidism. Intravenous pamidronate was
used shortly before delivery in one case with normalization of maternal serum calcium within 5 days of pamidronate administration [128]. Treatment
in such cases includes adequate aggressive hydration with close monitoring,
furosemide, and possibly calcitonin. Because bisphosphonates cross the placenta, their use should be reserved for life-threatening situations.
45
Neonatal hypoparathyroidism from maternal therapy with radioactive

iodine
Inadvertent maternal therapy with radioactive iodine during pregnancy
may result in neonatal hypoparathyroidism, similar to what has been reported in adults treated with high-dose radioactive iodine. A mother was reported to have received 103 mCi of iodine-131 (131I) for thyroid carcinoma
at 10 weeks of gestation when she was unaware of her pregnancy. Her neonate experienced occasional episodes of stiening and turning blue during
the rst 2 months that accelerated and led to a hospital admission for respiratory distress, tonic-clonic seizures, and ultimate tracheostomy [129]. The
infant was found be hypocalcemic, with documented hypoparathyroidism
and severe hypothyroidism. The infant was discharged after 1 month of hospitalization with a tracheostomy and ongoing treatment with calcium, dihydrotachysterol, and thyroid hormone. It is likely that the fetal thyroid gland
accumulated sucient amounts of 131I to result in destruction of fetal thyroid and parathyroid tissue from the emitted b particles [129].
Summary
Studies of pregnant women indicate that the fetal calcium demand is met
largely by intestinal calcium absorption, which from early pregnancy onward more than doubles. The studies of biochemical markers of bone turnover, DXA, and ultrasound are inconclusive, but suggest that the maternal
skeleton also contributes calcium to the developing fetus. In contrast, during
lactation, skeletal calcium resorption is the dominant mechanism by which
calcium is supplied to the breast milk; renal calcium conservation is also apparent. Lactation produces an obligatory skeletal calcium loss regardless of
maternal calcium intake, but the calcium is completely restored to the skeleton after weaning through mechanisms that are not understood. The adaptations during pregnancy and lactation lead to novel presentations and
management issues for known disorders of calcium and bone metabolism,
such as primary hyperparathyroidism, hypoparathyroidism, and vitamin
D deciency. Finally, although some women experience fragility fractures
as a consequence of pregnancy or lactation, in most women the changes
in calcium and bone metabolism during pregnancy and lactation are normal
and without adverse consequences in the long-term.
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bone health in women who were vitamin D-decient in pregnancy, and in their infants. Med
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[126] Hollis BW, Wagner CL. Vitamin D requirements during lactation: high-dose maternal supplementation as therapy to prevent hypovitaminosis D for both the mother and the nursing
infant. Am J Clin Nutr 2004;80(Suppl):1752S8S.
[127] Usta IM, Chammas M, Khalil AM. Renal cell carcinoma with hypercalcemia complicating
a pregnancy: case report and review of the literature. Eur J Gynaecol Oncol 1998;19:5847.
[128] Illidge TM, Hussey M, Godden CW. Malignant hypercalcaemia in pregnancy and antenatal administration of intravenous pamidronate. Clin Oncol (R Coll Radiol) 1996;8:2578.
[129] Richards GE, Brewer ED, Conley SB, Saldana LR. Combined hypothyroidism and hypoparathyroidism in an infant after maternal 131I administration. J Pediatr 1981;99:1413.

35 (2006) 5378
Management of Gestational Diabetes:

Pharmacologic Treatment Options
and Glycemic Control
Oded Langer, MD, PhD*
Department of Obstetrics and Gynecology, St. LukesRoosevelt Hospital Center,
University Hospital of Columbia University, New York, NY, USA
Diabetes mellitus is one of the most common medical complications of

pregnancy; gestational diabetes mellitus (GDM) accounts for approximately
90% to 95% of all cases. GDM is dened as carbohydrate intolerance of
variable severity with onset or rst recognition during pregnancy. The definition is applicable regardless of whether insulin is used to treat the disease
or if the condition persists after pregnancy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated the pregnancy
[1]. In the United States, approximately 135,000 to 200,000 women are diagnosed annually with GDM. Approximately 9% to 12% of undiagnosed type
2 diabetes is included in the GDM population. The overall increase in obesity including women of reproductive age parallels the increase in GDM and
type 2 diabetes [2].
Pregnancy is characterized by hyperinsulinemia and insulin resistance in
response to the diabetogenic eects of normal carbohydrate metabolism [3].
During the rst trimester and early in the second trimester, increased insulin
sensitivity occurs secondary to the relatively higher levels of estrogen. In
contrast, in the late second and early third trimesters, there is increased insulin resistance and reduced sensitivity to insulin action. A variety of hormonesdplacental lactogen, leptin, progesterone, prolactin, cortisol and
adiponectindare instrumental in these changes.
GDM and type 2 diabetes share impaired insulin secretion and insulin resistance. Insulin resistance results in decreased glucose uptake in skeletal
* Department of Obstetrics and Gynecology, St. LukesRoosevelt Hospital Center,

University Hospital of Columbia University, 1000 Tenth Avenue, Suite 10A, New York,
NY 10019.
E-mail address: odlanger@chpnet.org
doi:10.1016/j.ecl.2005.09.007
endo.theclinics.com
54
LANGER
muscles, white adipose tissue, and liver and suppression of hepatic glucose
production. The risk factors associated with type 2 diabetes and GDM
are comparable (eg, obesity, ethnicity, family history). b-Cell adaptation
to insulin resistance is impaired in women with GDM and may be a universal
response to insulin resistance because it is found in many ethnic groups.
Women with a history of GDM are at an increased risk for subsequent development of type 2 diabetes (50%80%). Type 2 diabetes and GDM arguably may be the same disease with dierent names [46].
Adverse perinatal outcome

Maternal hyperglycemia with resultant fetal hyperinsulinemia is central
to the pathophysiology of diabetic complications in pregnancy. The infants
of GDM women are at a 3 to 8 fold increased risk for stillbirth and aberrant
fetal growth (macrosomia and growth restriction) and metabolic (eg, hypoglycemia and hypocalcemia), hematologic (eg, bilirubinemia and polycythemia), and respiratory complications that increase neonatal intensive care
unit admission rates and birth trauma (eg, shoulder dystocia) [7,8].
Congenital anomalies and spontaneous abortions are more serious complications in pregestational diabetes than in GDM. Because of the relatively
high rate of undiagnosed type 2 diabetic women in the GDM population
(10%), a concerted eort should be made to rule out the presence of congenital malformations. Approximately 50% of all pregnancies are unplanned
and do not have the advantages of preconception care. GDM in most cases
is diagnosed between 20 and 30 weeks of gestation (after the organogenesis
period), decreasing the rate of congenital malformations in this population
is dicult to achieve [912]. In these cases, the main role of the obstetrician
is early diagnosis in lieu of prevention. In addition, these patients and their
fetuses are exposed to long-term complications, such as obesity in adolescence and later in life [13,14], higher rates of diabetes and potential intellectual impairment of the infant [15,16].
Achieving a normal glucose prole in pregnancy

Good glycemic control achieved with intensied therapy prevents microvascular and macrovascular complications [17] and improves pregnancy
outcome and the overall quality of life [18]. The glucose proles of normal
pregnant women without diabetes are based on studies with small sample
sizes, conducted for a single day during the third trimester in a hospital environment under strict dietary limitations [19,20]. One study [21] reported
a gradual increase in mean blood glucose in the third trimester, whereas another study [22] measured continuous blood glucose in obese and nonobese
nondiabetic women. The results of both studies imply that currently recommended normoglycemia criteria as targets for glycemic control in women
55
MANAGEMENT OF GESTATIONAL DIABETES
with diabetes do not target the actual normal levels in pregnancies of nondiabetic women (Table 1) [1,23,24].
Optimizing clinical outcome for various diabetic complications in pregnancy occurs at dierent levels of blood glucose. A decreased rate of congenital anomalies was observed when the postprandial threshold was less
than 140 mg/dL or the preprandial threshold was less than 120 mg/dL
[2528]. In contrast, a mean blood glucose of less than 100 mg/dL to 110
mg/dL was associated with fewer large-for-gestational-age (LGA) or macrosomic newborns [10,18,2931]. This association suggests that there are clinical thresholds for optimizing pregnancy rather than an absolute number for
normoglycemia that in many cases is unobtainable. Because macrosomia
and fetal hyperinsulinemia are the central complications in GDM, the targeted threshold needs to be mean blood glucose of 90 mg/dL to 100 mg/dL
and postprandial blood glucose of 110 mg/dL to 120 mg/dL.
Intensied therapy in pregnancy

It is well established that the level of metabolic control in nonpregnant
patients with pregestational diabetes inuences the incidence and development of retinopathy, nephropathy, and neuropathy. The levels of glycemia
achieved in studies on nonpregnant subjects (DCCT, UKPDS) [17,32] were
signicantly higher, however, than the targeted levels of glycemia during
pregnancy.
Managing women with either pregestational diabetes or GDM using intensied therapy helps to establish adequate glycemic control. Such intensive therapy involves using memory-based self-monitoring blood glucose,
Table 1
Recommended therapeutic thresholds for pregnant and nonpregnant subjects compared with
the glycemic prole in nondiabetic pregnant women
Glycemic prole
in nondiabetics
(rst author [Ref.])
Therapeutic objective studies [Ref.]

Criteriaa
DCCT [17]b ACOG [23] ADA [24] 4th Intl [1] Parretti [21] Yogev [22]
Fasting (mg d/L)

Premeal (mg/dL)
Postmeal (mg/dL)
1h
2h
90120 min
2 AM6 AM
(mg/dL)
Mean (mg/dL)
70120
70120
6090
60105
! 105
d
! 95
d
5560 G 5
NA
75 G 12
78 G 11
d
d
! 180
O 65
! 130140
! 120
d
6090
! 155
! 130
d
d
! 140
! 120
d
d
98105 G 5
8595 G 6
d
6065 G 5
97.0 G 11
105 G 13
d
68.3 G 10
NA
100
74.7 G 5.2
84.0 G 18
Abbreviation: NA, not available.

a
To convert glucose values from mg/dL to mM/L, multiply by 0.056.
b
Data for the nonpregnant state.
56
LANGER
multiple injections of insulin or its equivalent, diet, and an interdisciplinary

team eort. Regardless of the treatment strategy, the purpose of intensied
therapy is to achieve the targeted level of glycemic control that diminishes
the rate of hypoglycemia and ketosis and maximizes perinatal outcome. Although there is ample evidence associating glycemic control and the occurrence of maternal/fetal complications, association does not prove cause and
eect. It does provide the rationale for glucose control, however.
In a prospective study involving 1145 intensied therapy and 1316 conventional therapy GDM patients, the author observed that intensied therapy resulted in a pregnancy outcome comparable to that in the general
population [18]. Independent of the type of diabetes and the treatment modality employed, capillary self-monitoring blood glucose accurately quanties blood glucose, providing sucient data to make suitable adjustments in
the timing and dose of insulin. Diabetic patients seem to accept the selfmonitoring blood glucose technique readily, which provides a sense of
empowerment and involves patients in the eorts to improve pregnancy outcome. These performance measures seem comparable for all ethnic groups
[3335]. When the pregnancy outcome of conventional therapy patients
was compared with that of untreated GDM patients, there were similar rates
of adverse outcome. This nding suggests the inability of conventional therapy to maintain targeted levels of glycemic control.
In a pilot randomized study in 1997, Garner and coworkers [36] studied
the eect of strict glycemic control and tertiary care versus routine obstetric
care in the management of women with normal fasting glucose levels (dietcontrolled GDM). Among 300 GDM women studied, there were no dierences in mean birth weight, macrosomia, or birth trauma. The mode of
delivery also was similar between the two groups, whereas the treatment
group did have lower preprandial and postprandial glucose levels during
the third trimester.
This feasibility study reveals several areas of concern. The rate of macrosomia was 19% in the untreated group and 16% in the treated group. These
macrosomia rates are 40% to 80% above the baseline rate reported in Canada for nondiabetic populations and raise the question of the quality of glycemic control in this study. The women in the control arm could have been
self-treating by modifying their own diet on the basis of self-education. Ideally the control group should be unaware that they have GDM and should
be blinded to their oral glucose tolerance test results. It is possible that the
women in the control group received feedback from knowing the results of
home glucose monitoring, with resultant behavioral changes. Ten percent of
the untreated control group who tested their blood glucose levels 1 day each
week were removed from the study and treated for hyperglycemia. Finally,
the authors stated that there is . no dierence in maternal or fetal outcomes; the sample size was not large enough to allow any conclusions or recommendations on the eect of treatment versus no treatment in gestational
diabetes mellitus [36]. Nonetheless, regardless of the limitations of sample
57
size, they chose to conclude that . The study suggests that intensive treatment of GDM may have little eect on birth weight, birth trauma, operative
delivery, or neonatal metabolic disorders [36].
Treatment modalities in gestational diabetes
The introduction of new pharmacologic alternatives for treatment (insulin analogues and oral antidiabetic agents) and their use in pregnancy make
it worthwhile to consider proven and potential benets during gestation.
Although treatment modalities for achieving targeted levels of glycemic
control in type 1 diabetes, type 2 diabetes, and GDM dier, diet, exercise,
insulin, and oral antidiabetic drugs are the chief means of reducing blood
glucose concentrations. In pregnant women with type 2 diabetes, oral antidiabetic drugs have not been tested adequately in terms of whether targeted
glycemic levels can be achieved.
Diet and exercise: modalities that enhance glucose control
Diet is the mainstay of treatment in GDM whether or not pharmacologic
therapy is introduced. Dietary control with a reduction in fat intake and the
substitution of complex carbohydrates for rened carbohydrates seeks to
achieve and maintain the maternal blood glucose prole essential during gestation. Two current approaches are recommended: decreasing the proportion
of carbohydrates to 35% to 40% in a daily regimen of three meals and three
to four snacks [1,23,24,37] or lowering the glycemic index so that carbohydrates account for approximately 60% of daily intake. The assignment of
daily caloric intake is similar for women with either GDM or pregestational
diabetes and is calculated based on prepregnancy body mass index (BMI)
[1,23,24]. In general, for normal-weight women (BMI 2025), 30 kcal/kg
should be prescribed; for overweight and obese women (BMI O 2534),
calories should be restricted to 25 kcal/kg; and for morbidly obese women
(BMI O 34), calories should be restricted to 20 kcal/kg or less. Caloric restrictions of 30% in obese patients are associated with the same rate of macrosomia as in the general population. When caloric restrictions are applied,
free fatty acids and ketone bodies may increase (starvation ketosis), requiring
daily assessment of the ketones in the morning urine; if positive, blood assessment needs to be done [38]. A moderate exercise program for pregnant diabetic women who are willing and able may improve postprandial blood
glucose levels and insulin sensitivity [24,39]. Some women are less able to exercise owing to issues of socioeconomic limitations, obesity, and multiparity.
Insulin therapy
Types of insulin to manage diabetes in pregnancy
Insulin production has progressed from animal species to human insulin
preparations produced with recombinant DNA technology to the current
58
LANGER
insulin analogues designed primarily to improve pharmacokinetic features

for subcutaneous administration. This succession of advances represents
almost a century of research [40,41]. When comparing insulin lispro
(Humalog) and human insulins, placental transfer, ecacy, and the cost-tobenet ratio must be considered. Insulin lispro, insulin aspart and human
insulin have few dierences in receptor binding and metabolic and mitogenic
potency, although insulin lispro has slightly increased binding to the insulinlike growth factor-1 receptor [4143]. Continuous subcutaneous infusion of
insulin lispro in nonpregnant subjects with either type 1 diabetes or type 2
diabetes was associated with a decreased frequency of severe hypoglycemic
episodes, limited postprandial glucose excursions, and a possible decrease in
glycosylated hemoglobin. Insulin lispro provides greater convenience in the
timing of administration (analogues administered 15 minutes after start of
meal compared with soluble insulin taken 30 minutes before a meal)
[41,43]. Currently, data are limited on the ecacy of the drug.
Human insulin is recommended during pregnancy because data using insulin analogues are lacking [24] (only 282 women, mostly type 1 diabetics,
treated with insulin lispro and 15 women treated with aspart reported in
the literature). Studies on insulin lispro showed an improvement in glycemic
control, increased patient satisfaction, and a decrease in hypoglycemic episodes, but scant data on maternal and neonatal outcomes (Table 2). In the
nonpregnant state, insulin glargine has been reported to have a theoretical
toxicologic eect for the development of mammary, ovarian, and bone tumors and the development of retinopathy. There are currently seven case reports on the use of insulin glargine and no data on the use of detemir in
pregnancy [41,43].
Insulin analogues: placental transfer and safety concerns
The association between proliferative retinopathy and type of insulin analogue used in gestation is controversial. In one report, 3 of 10 women, with
type 1 or type 2 diabetes who had no evidence of retinopathy before pregnancy developed proliferative retinopathy that required laser therapy during
the third trimester while receiving insulin lispro [44]. This observation has
been hotly debated (see Table 2) [4460]. The aected patients had abnormal glycemic levels; it is likely that poor glycemic control, not insulin lispro,
led to proliferative retinopathy.
There are anecdotal case reports of congenital anomalies with the use of
insulin analogues. The issue of whether insulin lispro and other analogues
cross the placenta also is debated. Bauman and Yalow [61] showed that insulin by itself does not cross the placenta, but does so when complexed to
insulin antibodies. Menon and coworkers [62] reported that animal and human insulin crossed the placenta in 51 mothers with type 1 diabetes in an
amount directly related to the level of the mothers anti-insulin antibodies.
In another study, 4 of 19 women with gestational diabetes being treated
with insulin lispro received intravenous infusion of the drug during
Table 2
Studies reporting the use of insulin analogs in pregnancy
Study
design
Type of
diabetes
No. of patients treated

L
Diamond, 1997 [46]

Jovanovic, 1999 [45]
Kitzmiller, 1999 [44]
Bhattacharyya, 1999 [47]
Buchbinder, 2000 [48]
Bhattacharyya, 2001 [49]
CR
RCT
Retro
Retro
Retro
Retro
1
GDM
1 and 2
1 and 2
1
1 and 2, GDM
2
19
10
16
12
20
d
23
d
21
42
57
Persson, 2002 [50]

Loukovaara, 2003 [51]
Durand-Gonzales, 2003 [52]
Garg, 2003 [53]
RCT
Prosp
CR
Retro
1
1
GDM
1
16
36
1
25
17
33
35
Mecacci, 2003 [54]

Carr, 2004 [55]
Idama, 2001 [56]
Cypryk, 2004 [57]
RCT
RCT
Retro
Retro
GDM
Diabetes
1
PGDM
25
9
7
25
24
d
d
46
Masson, 2003 [58]

Pettitt, 2003 [59]
Devlin, 2002 [60]
Retro
RCT
CR
1
GDM
1
50
d
d
26
d
d
Neonatal outcome
Other
DPR
Anomalies
Complications
LGA
2/2
d
d
d
0/12
L: 1/20
H
H: 9/57
d
d
d
L: 2/25
H: 2/35
d
d
0/7
d
d
d
6/76
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
Hypoglycemia
Lispro: 17%
Human: 23%
Hypoglycemia: 41%
d
d
d
16%
d
d
d
d
d
d
d
d
d
24%
Macrosomia O 4000 g
d
d
57%
15a
1b
d
d
3/10
NP
NP
d
d
d
d
NP
d
d
d
d
NP
d
d
d
d
P (6 cases)
d
d
Lispro: 44%
Human: 30%
35%
d
d
59
Abbreviations: CR, case report; DPR, diabetes proliferative retinopathy; H, human; L, lispro; NP, no progression; P, progression; Prosp, prospective;
RCT, randomized control trial; Retro, retrospective; d, no data.
a
Insulin aspart.
b
Insulin glargine.
Study
(rst author, year [Ref.])
60
LANGER
labor; insulin lispro was not detected in the umbilical cord blood of the
infants [45].
Using an in vitro model in which human placentas were perfused, Challier and coworkers [63] reported evidence of human insulin in the fetal perfusate after infusion into the maternal compartment of the placenta.
Boskovic and coworkers [64] evaluated 11 term human placentas obtained
from uncomplicated pregnancies immediately after delivery. No placental
transfer was detected during perfusion with insulin lispro (100 mU/mL and
200 mU/mL). In contrast, there was a concentration-dependent transfer to
the fetal perfusate at insulin lispro levels of 580 mU/mL and higher. Finally,
the investigators compared actual maternal serum level and administered
doses of insulin lispro. Mothers treated with 50 U of insulin lispro achieved
serum concentrations greater than 200 mU/mL with an apparent linear correlation between dose and levels [64]. The investigators did not evaluate placentas of diabetic mothers, however. Placentas generally are aected by the
disease, which may inuence the perfusion characteristics. One can speculate
that even in the presence of lower insulin doses, placental transfer may occur. Although it is unlikely that insulin lispro in therapeutic doses would
cross the placenta, the high dose of insulin required in pregnancy, especially
in GDM and type 2 diabetes, to achieve established levels of glycemic control needs to be weighed against the potential for placental transfer and adverse outcome for the fetus.
Before using insulin analogues to treat pregnant women, several issues
need to be addressed: Can pregnant women achieve targeted levels of glycemic control with the use of insulin lispro? The response is yes; the quality of
glycemic control parallels the accepted criteria recommended during pregnancy. Is the quality of glycemic control during pregnancy with the use of
insulin lispro comparable to that with the use of regular insulin? Is the incidence of hypoglycemic incidents similar? Six published studies compared the
use of insulin lispro and regular insulin in pregnancy. Most of the studies
found no signicant dierence with respect to glycemic control and the incidence of hypoglycemia. Two of the studies were performed on women with
GDM with a total of 60 women treated with insulin lispro. In the study by
Persson and coworkers [50], there was a lower postprandial glucose concentration after breakfast and a slightly higher rate of hypoglycemia (! 55 mg/dL)
in the insulin lispro group. If there is no advantage in using insulin lispro
compared with regular insulin, is insulin lispro as safe in pregnancy as regular insulin? Insulin lispro may be more user-friendly with negligible dierences in glycemic control and hypoglycemia. These assets cannot currently
justify extensive use of the drug, however, before establishing its safety in
well-controlled clinical trials.
Which patients should receive pharmacologic therapy?
When diet fails to achieve targeted levels of glycemic control, insulin and
antidiabetic agents are validated treatment options. Available guidelines
61
dier regarding the threshold of fasting plasma glucose at which pharmacologic therapy (glyburide or insulin) should be initiated [23,24,65]. Some authors recommend a threshold of fasting plasma glucose 95 mg/dL or greater
[1,65] whereas others recommend a threshold of 105 mg/dL or greater
[23,24]. Using a fasting plasma glucose threshold of 95 mg/dL or greater decreases the rate of macrosomia and LGA infants [66,67].
Most authorities agree on initiation of drug therapy with elevated postprandial values (R 120 mg/dL for 2 hours or R 140 mg/dL for 1 hour).
Using these standards, approximately 30% to 50% of women with GDM
require pharmacologic therapy when diet therapy alone fails to reduce glycemic levels. When patients who qualied for diet therapy were evaluated,
only patients who achieved established levels of glycemic control improved
insulin secretion and sensitivity. Patients who failed to achieve glycemic
control, although exhibiting slightly improved insulin sensitivity, did not
achieve the same level of insulin response and sensitivity as nondiabetic
women [68]. Studies using continuous blood glucose monitoring have shed
new light on the existing controversy whether to test blood glucose at 1 or
2 hours postprandial in pregnant women. The author found that the time
from start of meal to the postprandial peak is approximately 80 to 90 minutes depending on the type of diabetes and regardless of level of glycemia. In
nondiabetic pregnant women, the peak postprandial value was 110 mg/dL.
The association between this physiologic characteristic and pregnancy outcome needs to be evaluated before changing current clinical thresholds
[22,69].
Can the fetus provide a marker for pharmacologic initiation?
Three randomized controlled studies addressed the use of fetal abdominal
circumference to guide insulin therapy. This approach combined maternal
glucose and fetal growth parameters. The studies suggest that some women,
despite glucose levels above established targets (R 105 mg/dL) may not derive a fetal benet from intensied therapy [7072]. In a randomized study
with a large sample size, the author found similar results. In the authors
study, subjects who did not achieve targeted levels of glycemic control
had higher rates of macrosomia and LGA infants, however, regardless of
abdominal circumference [73]. The limitation of the use of abdominal circumference at 28 weeks gestation as a measure for insulin initiation is
that it is snapshot information, whereas fetal growth is longitudinal. Most
environmental eects (eg, glucose) occur during the third trimester, which
is also the time of most fetal growth. A fetus at 28 weeks gestation in the
40th percentile of growth can double its weight and reach the 85th percentile
under the inuence of elevated blood glucose. Using the fetus as an additional marker for the decision-making process in initiating pharmacologic
therapy is an attractive approach. It should not be used as a single predictor,
but in conjunction with GDM severity parameters and level of glycemic
control throughout pregnancy.
62
LANGER
How long is diet therapy maintained before initiating pharmacologic

treatment?
Consensus and hard data are lacking regarding how long diet therapy
should be maintained before initiating pharmacologic treatment. In a study
by the author, 70% of the subjects with initial fasting plasma glucose less
than 95 mg/dL achieved targeted levels of glycemia within 2 weeks of dietary
management, but no signicant improvement occurred thereafter [74]. The
failure to initiate insulin therapy in a timely manner may lead to fetal hyperinsulinemia and associated complications. Premature initiation of insulin
therapy without knowing whether glycemic control can be achieved with
diet alone may cause unnecessary drug treatment. When GDM is diagnosed
after 30 to 33 weeks of gestation, and minimal time is available for achieving
targeted glycemic control, pharmacologic therapy should be initiated. There
is greater exibility in treatment modalities when GDM is diagnosed early in
the third trimester.
Insulin requirements in gestational diabetes
To evaluate the insulin dose required to achieve targeted levels of glycemic control, multiple blood glucose determinations should be performed
[18,75]. Insulin requirements may change during GDM. The author observed a biphasic increase in insulin requirements among 57 women with
GDM who then had normal oral glucose tolerance tests postpartum [76].
The rst phase was characterized by a signicant weekly increase until the
30th week of gestation, after which the insulin dose remained unchanged.
Insulin requirements for obese subjects in the study were 0.9 U/kg compared
with 0.8 U/kg for nonobese patients. There was a signicant dierence in
variability as measured by the coecient of variation (45% versus 25%;
P ! .01). The total insulin dose required to reach the established level of
glycemic control for most patients is 40 U to 90 U (body-weightdependent). Women with GDM seem to benet from frequent visits during the
20th to 30th weeks of gestation for insulin adjustment.
In a pregnant diabetic patient, the rationale for insulin therapy is based
on mimicking the physiology of insulin secretion. The basal insulin is supplied by the administration of NPH/lente/ultralente insulin at bedtime or before breakfast and at bedtime. The meal-related (glucose excursion) insulin
includes the use of insulin lispro before meals (015 min) or Regular insulin
before meals (3045 min). This algorithm provides the foundation for the
use of intensied therapy (multiple injections daily) versus conventional
therapy (one to two injections daily) [77].
The calculation for the insulin dose in GDM women is based on prepregnancy BMI. For nonobese patients, 0.8 U/kg is used and for overweight and
obese women, 0.9 to 1 U/kg is used, then current maternal pregnancy weight
is multiplied by the amount of insulin. A woman at 28 weeks gestation
currently weighing 85 kg but based on prepregnancy BMI, classied
as overweight/obese would require a total calculated insulin dose of
63
85 1 (unit) 85. The total insulin dose is divided so that two thirds is administered in the morning, which is further split in a ratio of 2:1 (intermediate and rapid-acting), and one third is administered with supper and
bedtime in a ratio of 1:1 (rapid-acting and intermediate). The rapid-acting
dose is administered with supper, and the intermediate dose is taken before
bedtime. If after 3 to 7 days the GDM patient has not achieved the desired
level of glycemic control, the total insulin dose should increase by 10% to
20% and thereafter adjusted when needed. The actual total insulin dose in
GDM women is 40% higher than the calculated (starting) dose [76]. The decreased insulin sensitivity characterizes pregnancy and in particular GDM
patients. As a rule of thumb, before every insulin administration, self-monitoring blood glucose assessment needs to occur.
Oral antidiabetic agents as alternatives to insulin therapy
A variety of oral agents may be alternatives to insulin therapy for women
with GDM. Sulfonylureas are insulin secretagogues (eg, glyburide and
glipizide). The primary action of glyburide is to increase insulin secretion, decreasing hepatic glucose production with resultant reversal of hyperglycemia and indirect improvement of insulin sensitivity [78] Antidiabetic
drug groups include meglitinides (insulin secretagogues, such as the rapidacting repaglinide, which limit postprandial hyperglycemia), biguanides
(eg, metformin, which decreases insulin resistance), a-glucosidase inhibitors
(eg, acarbose, which reduces intestinal absorption of starch and glucose),
and thiazolidinediones (eg, rosiglitazone and pioglitazone). All have been
used successfully in the treatment of nonpregnant patients with type 2 diabetes.
Each may be used alone or in combination with other oral agents or insulin.
Most of these drugs have not been studied in pregnancy or only minimally so. The most data regarding safety in pregnancy for oral antidiabetic
drugs are with the use of glyburide. To date, 1261 women treated with glyburide have been reported in the literature. For insulin analogues and oral
antidiabetic drugs, none of the studies were blinded (Table 3). Many experts
and authoritative bodies have recommended using glyburide as an alternative to insulin [65,7983]. Others have not rmly advocated the use of oral
agents in pregnancy and recommend further evaluation [24,84,85]. The
use of oral agents is a pragmatic alternative to insulin therapy in pregnancy
because of ease of administration and patient satisfaction with a noninvasive
treatment. However valid these reasons, the introduction of a new drug is
unjustied if improvements in pregnancy outcome and cost-eectiveness
are not evaluated denitively.
Is there increased risk for fetal anomalies with the use of oral
antidiabetic drugs?
For a drug to be potentially eective and safe in pregnancy, it should not
cross the placenta or should not be detrimental to the fetus at concentrations
64
Table 3
Studies reporting use of oral antidiabetic agents in pregnancy
No. of patients
Type of
Regular
diabetes Glyburide insulin Metformin Other
Achievement
of good control
Langer,
2000 [78]
RCT
GDM
201
203
82% and 88%
Lim,
1997 [93]
Prosp, observ
GDM
33
21
No signicant
dierence
Conway,
2004 [94]
Kremer,
2004 [95]
Chmait,
2004 [96]
Prosp, observ
GDM
75
84%
Prosp, observ
GDM
73
81%
Prosp, observ
GDM
69
82%
Neonatal outcome
Complications
LGA
No dierence in
metabolic
complications,
congenital
anomalies, and
PNM
No signicant
dierence
in metabolic
complications
and PNM
NA
12% and 13%
Caesarean
section: 36%
No signicant
dierence
NA
Macrosomia:
19%
Macrosomia: 7%
LANGER
Study
(rst author, Study
year [Ref.]
design
Prosp, observ
GDM
22
22
82%
Fines,
2003 [98]
Retro
case-control
GDM
40
44
NA
Velazques,
2003 [99]
Case series
GDM
31
Improved level
of glycemic
control in the
glyburide
group: 82%
Improved level
of glycemic
control
Pendsey,
RCT
2002 [100]
23
Repaglinide: 23
Glueck,
2004 [90]
Prosp, observ
PCOS
42
Glueck,
2002 [91]
Prosp and
PCOS
retro, observ
33
w/o metformin: 39
No signicant
No signicant
dierence
dierence in
between insulin
the rate
between
and glyburide
groups
insulin- and
glyburidetreated groups
No dierence in
Less macrosomia
ponderal index
in the glyburide
group (5/40 vs
between the
groups
11/44)
No hypoglycemic LGA in the
events in the
glyburide and
glyburide group
in the insulin
group: 16%
and 29%
GDM developed
in 7.1% of
patients
GDM developed
in 3% of
patients treated
with metformin
vs 27% w/o
treatment
Gilson,
2002 [97]
(continued on next page)
65
66
Table 3 (continued )
Study
(rst author, Study
year [Ref.]
design
Type of
Regular
diabetes Glyburide insulin Metformin Other
2
Achievement
of good control
78
GDM
and 2
GDM
and 2
Neonatal outcome
Complications
Drug deemed safe
in rst trimester
Reduced PNM
126
60
GDM: 81.4%
Type 2 diabetes:
46.2%
Hellmuth,
Prosp, observ
2000 [104]
GDM
42
50
Sulfonylurea: 68
No signicant
dierence in
neonatal
morbidity.
Higher rate of
preeclampsia
(32% vs 10%)
and PNM
(11.6% vs
1.3%) in
metformin
group
LGA
LANGER
Coetzee,
Retro
1984 [101]
Coetzee,
Retro
1986 [102]
Coetzee,
Prosp, observ
1979 [103]
No. of patients
Notelovitz,
RCT
1971 [105]
GDM
and 2
GDM
Moore,
RCT
2005 [107]
Ramos,
Retro
2005 [108]
GDM
GDM
25
30
31
236
316
32
Tolbutamide
chlorpropamin:
2 52
Using oral
hypoglycemic:
80%
Diet treated: 27
Using insulin:
36%
Mean blood
glucose similar
in all groups
Blood glucose
similar
Blood glucose
similar
No signicant
dierence in
PNM,
metabolic
complications,
and congenital
anomalies
Signicantly
lower rate
of maternal
hypoglycemia
in glyburide
group
Perinatal outcome
similar
Perinatal outcome
similar
Abbreviations: NA, not available; Observ, observational; PNM, perinatal mortality; Prosp, prospective; RCT, randomized controltrial; Retro, retrospective; w/o, without.
Yogev,
Prosp
2004 [106]
52
67
68
LANGER
that are clinically indicated for the mother. Case reports and small retrospective studies in women receiving rst-generation sulfonylureas raised concern
about congenital anomalies [86,87]. Potential eects on the fetus, mainly hypoglycemia and growth stimulation [87], were reported. A report of increased
rates of congenital malformations involved 20 type 2 diabetes patients who
had hyperglycemia before conception (hemoglobin A1c O 8). It is impossible
to determine if the reported rate of anomalies was due to the use of the drug
or the preexisting hyperglycemia [86]. In contrast, several studies showed that
anomalies in the infants of women who received oral antidiabetic agents were
associated with altered maternal glucose metabolism and not the drug [88]. A
meta-analysis failed to show an increased risk for fetal anomalies with sulfonylureas [89]. Metformin seems to be unassociated with congenital malformations in patients with polycystic ovary syndrome and reduces the
occurrence of GDM and spontaneous abortion (see Table 3) [9092].
Does glyburide cross the placenta?
The placenta of the diabetic mother is characterized by capillary dilation,
relatively immature villous structure, and chronic disturbances in intervillous circulation. The author examined the placentas of nondiabetic and diabetic mothers in vitro and showed that glyburide (glibenclamide) does not
cross the human placenta from the maternal to fetal circulation in signicant
amounts. There was virtually no drug transport even when concentrations
three to four times higher than peak therapeutic levels were employed
[109111]. The author also showed that rst-generation sulfonylureas diffused across the placenta most freely [109111]. There is evidence that the
qualitative aspects of transfer are comparable between placentas obtained
during the rst and third trimesters [64,112]. In mothers treated with therapeutic plasma concentrations of glyburide, the drug was undetectable in the
cord blood of their neonates [78]. No data exist on the long-term eects on
the infant when oral antidiabetic drugs and insulin analogues are used in the
mother. Glyburide exhibits less transfer across the placenta compared with
other agents, underscoring its potential therapeutic usefulness.
Because glyburide does not cross the placenta, it cannot aect neonatal
hypoglycemia or fetal anomalies. In addition, most GDM patients are identied between 24 and 28 weeks gestation. The fetus is not exposed to the
drug during organogenesis. In rare cases of early diagnosis in the rst trimester (perhaps type 2) and recognized type 2 diabetes, current data suggest
that the use of glyburide or metformin would not increase the rate of anomalies inuenced by the level of glycemic control. Although a randomized
study would be the ideal model to address this issue, it is highly unlikely
that it would be performed for ethical considerations (see Table 3).
Glyburide pharmacology and administration
The pharmacologic mechanism of action of glyburide is to increase insulin secretion, and its secondary eect is to decrease insulin resistance by
69
reducing glucose toxicity. Its onset of action is approximately 4 hours, and

duration of action is about 10 hours. After achieving the targeted therapeutic level, the drug covers the basal requirement and the postprandial excursions of glucose. The starting dose is 2.5 mg orally in the morning. If the
targeted level of glycemia has not been reached, 2.5 mg is added to the
morning dose. If indicated (after 37 days), 5 mg is added in the evening.
Thereafter, the dose is increased by 5 mg to a total of 20 mg/day. If patients
fail to achieve established levels of glycemic control, long-acting insulin can
be added to the regimen [78].
The abnormal level of glycemia in GDM can be controlled by monotherapy with glyburide and probably metformin. Can monotherapy with glyburide achieve targeted levels of glycemia required in pregnancy in type 2
patients? Although this issue has not been studied extensively, one can speculate that monotherapy may not be sucient. Combination therapy with
other oral antidiabetic drugs, with proven ecacy and safety, would help
subjects achieve established levels of glycemic control. Another alternative
is the combination of insulin and glyburide, which would result in a lower
dose of insulin compared with the use of monotherapy with insulin.
Glyburide compared with insulin
Several studies evaluated the ecacy of oral antidiabetic agents during
pregnancy (see Table 3). Most studies showed that these agents were comparable to insulin in achieving established levels of glycemic control and
pregnancy outcome. The author compared glyburide with standard insulin
therapy in a randomized controlled trial in 404 GDM women [78]. The primary outcome was the ability to achieve established levels of glycemic control; insulin and glyburide had comparable results. The success in achieving
glycemic control with glyburide was reconrmed by several studies (Tables 3
and 4). Adequate glycemic control was obtained with signicantly fewer hypoglycemic episodes in the glyburide group compared with the insulin group
[78]. Using a continuous glucose monitoring system that recorded data every
5 minutes for 72 continuous hours with 288 measurements per day, asymptomatic hypoglycemic events (O 30 consecutive minutes of glucose values
! 50 mg/dL) occurred in 63% of subjects receiving insulin compared
with 28% of subjects receiving glyburide [106].
The insulin-treated patients and glyburide-treated patients achieved comparable results in many variables: cord-serum insulin concentrations, incidence of macrosomia, increased Ponderal index, LGA infants, neonatal
metabolic complications (hypoglycemia, polycythemia, and hyperbilirubinemia), respiratory complications, and cesarean delivery [78]. The perinatal
outcome in the glyburide and the intensied therapy subjects was comparable (see Table 4).
The author analyzed the association among glyburide dose, GDM severity, and selected maternal and neonatal factors [113]. Glyburide and insulin
were equally ecacious for treatment of women with GDM of varying
70
LANGER
Table 4
Comparison of selected pregnancy outcomes in conventional versus intensied insulin therapy,
glyburide versus insulin, and nondiabetic subjects
Therapy
comparison [18]a
Criteria
LGA (%)b
Macrosomia (%)
Ponderal index O 2.85
Overall Caesarean section (%)
Induction of labor (%)
PET (%)
CHTN (%)
5-Min Apgar score ! 7 (%)
Neonatal ICU admission (%)
Hypoglycemia (%) ! 40 mg/dL
Polycythemia (%) O 60%
Hyperbilirubinemia (%)
O 11 mg/dL
Hypocalcemia (%) ! 8 mg/dL
Respiratory complications (%)
Shoulder dystocia
Perinatal mortality
Stillbirth
Neonatal death
Comparison [78]
Nondiabetic
Conventional Intensied Glyburide Insulin [8,18]
20.1
13.6
21.7
21.5
27
5.6
6.1
3.2
25.6
20.0
12.0
17.5
13.1
7.1
13.8
15.0
22
5.9
5.8
2.1
6.3
3.8
0.7
7.9
12.0
7.2
9.0
23.0
33
6.0
6.0
3.1
6.0
9.0
2.0
6.0
13.0
4.7
12.0
24.0
34
6.0
9.1
4.2
7.0
6.0
3.0
4.0
11.9
8.1
22.0
13.7
13.0
7.6
6.2
2.5
4.7
2.5
1.4
6.4
4.0
6.2
1.4
0.3
2.3
0.4
1.0
2.0
1.5
1.0
3.0
1.6
NA
2.1
0.5
4/1000
2/1000
1/1000
3/1000
5/1000
5/1000
5/1000 4/1000
5/1000 4.7/1000
Abbreviations: CHTN, chronic hypertension; ICU, intensive care unit; NA, not available;
PET, preeclampsia.
a
Conventional therapy: fasting plasma glucose and 2-h postprandial once weekly, visualized
self-monitoring blood glucose 4 times daily; intensied therapy: memory-based self-monitoring
blood glucose 7 times daily.
b
LGA O 90th percentile; macrosomia R 4000 g.
severity when fasting plasma glucose results were between 95 mg/dL and 139
mg/dL. Of patients, 71% required a 10-mg daily dose of glyburide to
achieve glycemic control. In all disease severity levels, glyburide and insulin-treated subjects had similar success rates in achieving targeted glucose
levels and pregnancy outcomes [113]. Achieving the established level of glycemic control, not the mode of therapy, seems to be the key to improving
pregnancy outcome in GDM.
Is glyburide therapy less costly than insulin therapy?
The costs of alternative therapies should be addressed when dierent
medications exhibit similar eectiveness and safety. Goetzel and Wilkins
[114] compared the costs of insulin and glyburide and observed that glyburide is considerably less costly (average savings per patient of $166$200
based on rates in 2000). Glyburide is a cost-eective, patient-friendly, potentially adherence-enhancing therapy that produces perinatal outcome comparable to insulin therapy.
Drug (trade name)
Mechanism of action
Sulfonylureas
Glimepiride (Amaryl)
Glipizide (Glucotrol)
Glipizide-GITS (Glucotrol XL)
Glyburide (DiaBeta, Glynase,
Micronase)
Increase insulin secretion
Meglitinides
Nateglinide (Starlix)
Repaglinide (Prandin)
Increase insulin secretion
Biguanide
Metformin (Glucophage)
Decreases hepatic gluconeogenesis;

increases insulin sensitivity
Glitazones
Increase insulin sensitivity;

decrease hepatic glucose
production
Pioglitazone (Actos)
Rosiglitazone (Avandia)
Pregnancy
category
Decrease in
FPG (mg/dL)
Decrease in
hemoglobin A1C (%)
6070
1.52
C
C
d
B
921
C
C
Unknown
Minimal
d
No
Unknown
Unknown
d
No
Unknown
Unknown
Unknown
Unknown
Yes
No
Unknown
Unknown
Animals
Animals
0.92
B
5980
Excreted in
breast milk
0.50.8
C
C
5978
Cross
placenta
Table 5
Oral antidiabetic drug classication
1.42.6
71
(continued on next page)
72
Table 5 (continued )
Drug (trade name)
Mechanism of action
Alpha-glucosidase inhibitors
Acarbose (Precose)
Miglitol (Glyset)
Slow absorption of carbohydrates

in the intestine
Decrease in
FPG (mg/dL)
Decrease in
hemoglobin A1C (%)
2030
0.51
B
B
Dose-dependent
B
B
B
B
B
C
B
Cross
placenta
Excreted in
breast milk
Unknown
Unknown
Animals
Animals
Unknown
Minimal
No
No
No
Unknown
No
No
No
No
No
No
No
No
Dose-dependent
LANGER
Insulin
Aspart (Novolog)
Lispro (Humalog)
Regular
NPH
Lente
Glargine (Lantus)
Ultralente
Pregnancy
category
73
Glyburide and lactation

Data are scant on the eect of oral antidiabetic drugs on lactation. Data
from two centers, in Canada and in California, suggested that glyburide is
not present in the milk of lactating mothers when measured in vivo and
in vitro [115].
Summary
Although not universally accepted, the introduction of insulin analogues
(mainly insulin lispro, class B), oral antidiabetic agents (mainly glyburide
[class B]) (Table 5), and the use of intensied therapy have altered profoundly
the management approach in the treatment of diabetes in pregnancy with
outcomes comparable to the general population (see Table 4). Insulin lispro
is not likely to cross the placenta with the clinically used dose in most type 1
and type 2 diabetic patients. The benets of this drug are the reduction of
nocturnal hypoglycemic episodes and postprandial levels and the ease of patient use. With the establishment of the ecacy for the use of glyburide (and
possibly metformin), there is an equally eective alternative to insulin
therapy. Glyburide is a cost-eective, patient-friendly, and potentially
compliance-enhancing therapy that produces perinatal outcome in GDM
pregnancies comparable to traditional insulin therapy. For GDM patients
who require pharmacologic therapy, glyburide is the drug of choice, and
only patients who fail to achieve glycemic control should begin insulin
therapy.
The major obstacles to the creation of evidence-based criteria to guide
benet/risk in pharmacologic therapy in obstetrics is the fear of the potential
adverse drug eects on the fetus and the resultant paucity of research. The
history of the Food and Drug Administration regulations for prescription
drug labeling in pregnancy adds an additional layer of diculty. The ethical,
legal, and medical rhetoric surrounding this dilemma may have exaggerated
the potential for fetal harm. There may be greater risk to the fetus in withholding certain medications than in prescribing them. The current evidencebased data for insulin lispro and glyburide support their use in pregnancy. A
large-scale multicentric study to evaluate glyburide and insulin analogues
would be a practical and enlightening endeavor.
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Diabetes Care 2005;28:18515.

35 (2006) 7997
Successful Pregnancy in Women with

Type 1 Diabetes: From Preconception
Through Postpartum Care
Lois Jovanovic, MDa,b,c,*, Yuichiro Nakai, MDd
a
Keck School of Medicine, University of Southern California at Los Angeles,

Los Angeles, CA, USA
b
University of California at Santa Barbara, Santa Barbara, CA, USA
c
Sansum Diabetes Research Institute, Santa Barbara, CA, USA
d
Department of Medicine, University of California Davis Health Systems,
Sacramento, CA, USA
Using 2002 birth data [1], it is estimated that diabetes aects an estimated
8% of the more than 4 million pregnancies that come to term annually in the
United States. Identifying women who require aggressive monitoring and
treatment of their diabetes to minimize both maternal and fetal complications during and after pregnancy is a signicant challenge for physicians
and the health system because almost 75% of pregnancy-related diabetes occurs in women with gestational diabetes or undiagnosed type 2 diabetes.
Conversely, although type 1 diabetes is estimated to account for only 1%
to 2% of the pregnancies complicated by diabetes (w6000 births in the United
States annually), screening is not an issue because the diagnosis of type 1
diabetes is generally well established in a womans preconception years.
As recently as the 1980s, type 1 diabetes and pregnancy were a deadly combination for mothers and especially for fetuses, with rates of fetal perinatal
mortality as high as 25% to 30% [2]. Advances over the past 2 decades
in home glucose monitoring and insulin administration have provided
the technology needed to not only allow women to successfully survive pregnancy but also to decrease the risks of diabetic fetopathy to those of the
nondiabetic population [3,4].
Pregnancy in diabetic women is associated with an increase in risk to
both the fetus and the mother. Early in the pregnancy there is an emergency
* Corresponding author. Sansum Diabetes Research Institute, 2219 Bath Street, Santa
Barbara, CA 93105.
E-mail address: ljovanovic@sansum.org (L. Jovanovic).
doi:10.1016/j.ecl.2005.09.008
endo.theclinics.com
80
JOVANOVIC & NAKAI
to normalize the blood glucose to prevent congenital anomalies and spontaneous abortions. As the pregnancy progresses, the mother is at an increased
risk for syncope, hypoglycemia, or diabetic ketoacidosis, all of which need
emergency attention. Later in the pregnancy, she is at risk for accelerated
retinopathy, with the risk of blindness, pregnancy-induced hypertension
and preeclampsia-eclampsia, urinary tract infections, including pyelonephritis, and polyhydramnios. The greatest concern is the increased risk of sudden death in utero for the fetus. All of these dreaded complications can
be obviated or at least minimized with careful planning of the pregnancy
and attention to glucose control.
The additional risks of pregnancy for mothers with type 1 diabetes and
their babies place the emphasis of optimizing maternal and fetal health of
these pregnancies and the focus of this article on (1) appropriate preconception counseling and management goals; (2) optimizing glycemic monitoring
and intensifying insulin therapy during the metabolically dynamic process of
pregnancy; (3) appropriately evaluating women and their fetuses for complications of both diabetes and intensive diabetes therapy during pregnancy;
and (4) peripartum and postpartum glycemic control.
Congenital anomalies
There is an increased prevalence of congenital anomalies and spontaneous abortions in diabetic women who are in poor glycemic control during
the period of fetal organogenesis, which is nearly complete at 7 weeks postconception [5]. Thus, a woman may not even know she is pregnant at this
time. For this reason, prepregnancy counseling and planning are essential
in women of childbearing age who have diabetes. Because organogenesis
is complete so early in the fetus development, if a woman presents to her
health care team and announces that she has missed her period by only
a few days, if the blood glucose levels are normalized immediately [610],
there is still is a chance to prevent cardiac anomalies by swiftly normalizing
the glucose levels (although the neural tube defects are probably already set
by the time the period is missed).
Women with type 2 diabetes are less likely to have preconception care
and counseling, often because the diabetes has not yet been diagnosed,
and thus, they are at even greater risk of bearing a birth-defective child.
In one study [11], 40% of women with type 1 diabetes but only 14% with
type 2 diabetes received preconception care.
Another problem for some women with type 2 diabetes is gaining access
to adequate medical care before and after conception. Nowhere is this more
evident than in Hispanic women, in whom the higher prevalence of obesity,
type 2 and gestational diabetes, and increased fertility rates place them at
higher risk for maternal and neonatal complications [1214]. Pima Indian
women are also at increased risk; they have a 19-fold higher incidence of
SUCCESSFUL PREGNANCY IN WOMEN WITH TYPE 1 DIABETES
81
type 2 diabetes compared with the general United States population, with an
age-adjusted prevalence rate approximately eight times higher [15,16].
A measurement of glycosylated hemoglobin A1c (HbA1c) can, in early
pregnancy, estimate the level of glycemic control during the period of fetal
organogenesis. There are two important observations in this regard: rst,
HbA1c values early in pregnancy are correlated with the rates of spontaneous abortion and major congenital malformations [1719]. Although most
studies have been performed in women with type 1 diabetes, the same risk
of hyperglycemia applies to those with type 2 diabetes [20,21]; and second,
normalizing blood glucose concentrations before and early in the pregnancy
can reduce the risks of spontaneous abortion and congenital malformations
nearly to that of the general population [22,23].
One report compared 110 women who were 6 to 30 weeks pregnant at
the time of referral with 84 women who were recruited before conception
and then put on a daily glucose-monitoring regimen [19]. The mean blood
glucose concentration was between 60 and 140 mg/dL (3.3 mmol/L and 7.8
mmol/L) in 50% of the latter group of women. The incidence of anomalies
was 1.2% in the women recruited before conception versus 10.9% in those
rst seen during pregnancy. Very similar ndings were noted in another
study: 1.4% versus 10.4% incidence of congenital abnormalities [23]. Major congenital malformations, which either require surgical correction or
signicantly aect the health of the child, are more common in infants of diabetic mothers (13% versus 2% in infants of nondiabetic mothers) [24].
The increased rate of spontaneous abortion in poorly controlled diabetic
women is believed to be secondary to hyperglycemia, maternal vascular disease, including uteroplacental insuciency, and possibly immunologic factors [25]. In addition, animal studies suggest that hyperglycemia regulates
the expression of an apoptosis (programmed cell death) regulatory gene as
early as the preimplantation blastocyst stage, resulting in increased DNA
fragmentation [26]. These ndings emphasize the importance of glycemic
control at the earliest stages of conception.
Ideally, if a diabetic woman plans her pregnancy there is time to create
algorithms of care that are individualized, and a woman can be given
choices. When a diabetic woman presents in her rst few weeks of pregnancy, there is no time for individualization; rather, rigid protocols must
substituted urgently to provide optimal control within 24 to 48 hours.
Deleterious eects of strict glycemic control
Despite the clear benets to the fetus of strict glycemic control, there
is a hazard of hypoglycemia. Major complications of hypoglycemia can usually be prevented with careful monitoring and education of the mother
[7,23,27]. Very strict glycemic control (mean blood glucose % 56 mg/dL)
may be deleterious to the fetus and should be avoided. In one study, the
most common cause of maternal mortality was related to hypoglycemia [28].
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JOVANOVIC & NAKAI
Retinopathy
There are three reported situations in which the rapid normalization of
blood glucose level increases the risk for the deterioration of diabetic retinopathy: puberty [29], pregnancy [30], and insulin-like growth factor
(IGF)-1 treatment [31]. If two of these events occur in the same patient,
the risk for retinopathy progression is potentiated [30,32]. All three situations are associated with increased serum concentrations of growth-promoting factors. It is hypothesized that when the blood glucose level is rapidly
decreased, there is increased retinal extravasation of serum proteins. If there
is a concomitant increase in the concentration of serum growth-promoting
factors, a predisposed retina may deteriorate [3335].
Pregnancy per se is the condition most frequently reported in which the
rapid normalization of blood glucose is associated with retinal deterioration
[7,32, 3436]. Normal pregnancy is associated with a high concentration of
many growth-promoting factors [3638]. Hill and colleagues [33] have reported that a potent mitogenic and angiogenic factor normally absent
from the adult circulation becomes detectable by 14 weeks of gestation
and is maximal at 22 to 32 weeks of gestation. A placental growth hormone
variant had been found to increase throughout pregnancy, along with the
human somatomammotropin prolactin [36]. Maternal IGF-1 production
has also been shown to increase signicantly above nonpregnant levels
[37]. It is well known that diabetes mellitus is associated with perturbations
of growth hormone IGF-1 in cases of poor metabolic control [38].
If treatment with lispro insulin, a short-acting insulin analog, allows for
increasing the rate whereby the hyperglycemic state is normalized, then lispro insulin may play a role in causing the rapid deterioration of retinopathy.
It is unlikely, in the few case reports of rapid deterioration of retinopathy in
patients taking lispro insulin, that deterioration was caused by the IGF-1 activity of this insulin, because pregnancy alone has such elevated IGF-1
levels.
Human insulin binds to the IGF-1 receptor with an anity of 0.1% to
0.2% of the anity of IGF-1. A comparison of lispro and human insulin
was made to determine the relative IGF-1 receptor binding anity in human
placental membranes, skeletal muscle, smooth muscle cells, and mammary
epithelial cells. Lispro had a slightly higher anity for the human placental
membranes compared with human insulin. No other dierences were observed in any other cell lines. Despite the suggested increased anity, it
should be noted that the absolute anity for the IGF-1 receptor is extremely
low for both lispro and human insulin. Concentrations more that 1000 times
above normal physiologic range are needed to reach a receptor binding afnity of 50%. IGF-1 is a much larger protein chain than insulin, and there is
a 49% homology between human insulin and IGF-1. The reversal of the
Asx28 and Asx29 amino aids in lispro increases this homology to 51% because of the analogous position in the IGF-1 molecule. It has been shown
83
that insulin lispro has the same anity for the IGF-1 receptor as human insulin and that the dissociation kinetics of insulin lispro on the insulin receptor are identical to those of insulin, indicating that insulin lispro should have
no excess mitogenic eect through the IGF-1 or insulin receptor [39,40].
Phelps and colleagues [32] have clearly shown that the deterioration of
retinopathy correlated signicantly with the levels of plasma glucose at entry
and with the magnitude of improvement in glycemia during the rst 6 to 14
weeks after entry, although the 13 patients with no retinopathy at baseline
did not progress to proliferative retinopathy. However, one of the women
developed moderate hemorrhages, exudates, and intraretinal microaneurysms. Of their 20 patients with an initial background of retinopathy, two patients progressed to proliferative retinopathy. Laatikainen and colleagues
[41] conrmed that the decrease in hemoglobin HbA1c levels was the most
rapid in the two patients with the worst progression. They concluded that
a rapid near-normalization of glycemic control during pregnancy can accelerate the progression of retinopathy in poorly controlled diabetic patients.
The Diabetes in Early Pregnancy (DIEP) study [42] reported the results of
155 type 1 diabetic women who underwent retinal angiography in the rst
few weeks of gestation and then at term (within 1 week before delivery).
In the 140 patients who did not have proliferative retinopathy at baseline,
the progression of retinopathy was seen in 10.3%, 21.1%, 18.8%, and
54.8% of patients with no retinopathy, microaneurysms only, mild nonproliferative retinopathy, and moderate to severe nonproliferative retinopathy
at baseline, respectively. Proliferative retinopathy developed in 6.3% of patients with mild and 29% of patients with moderate to severe baseline retinopathy. The elevated glycosylated hemoglobin at baseline and the
magnitude of improvement of glucose control through week 14 were associated with a higher risk of progression of retinopathy (the adjusted odds ratio
[OR] for progression in those with a glycohemoglobin level R 6 standard
deviations [SD] above the control mean versus those ! 2 SD was 2.7;
95% condence interval [CI], 1.1%7.2%; P 0.039). Independent of retinal status, the DIEP study also reported that the duration of diabetes increased the risk of progression such that after 6 years duration of
diabetes the OR was 3.0 (95% CI, 0.5%17.4%); after 11 to 15 years, the
OR was 9.7 (95% CI, 1.9%49.0%); and after more than 16 years, the
OR was 15.0 (95% CI, 3.0%74.5%); however, hyperglycemia was a stronger risk factor. Additional evidence has been reported by the Diabetes Control and Complications Trial [30]. For women in the conventional care
group who became pregnant and thus had immediate intensication of glucose control (n 135), the retinal status worsened in 47% of the patients,
and the OR for progression by the second trimester was 2.6, compared
with diabetic women in the conventional group who did not become
pregnant.
There is one case report in the literature, which clearly shows that the
combination of pregnancy and rapid normalization of severe hyperglycemia
84
JOVANOVIC & NAKAI
is sucient to explode a previously normal retina. Hagay and colleagues [43]

reported a case of a woman with no previously documented hyperglycemia
who presented at 8 weeks of gestation with an HbA1c level of 16% and
whose ophthalmic examination was reported to be completely normal.
She was treated with intensive insulin therapy, and at 12 weeks, her HbA1c
level was 5.9%. By the second trimester, she had severe bilateral proliferative
diabetic retinopathy that required treatment by photocoagulation.
Based on the above literature review, clearly the ve risk factors, which
emerge for the prediction of those pregnant diabetic women who will progress to proliferative retinopathy, are baseline evidence of some retinopathy,
elevated HbA1c levels at conception, rapid normalization of blood glucose,
duration of diabetes for greater than 6 years, and proteinuria.
Because the use of the rapid-acting insulin analogs facilitates the rapid
normalization of blood glucose levels [44,45], their use may play a role in
the progression of retinopathy, and the clinician must be aware of the retinal
status and obtain consultation with a retinal specialist when rapid normalization of blood glucose is undertaken. The literature shows clearly the danger in quickly normalizing blood glucose, regardless of the type of insulin
used, in pregnant women with a long duration of diabetes and elevated
HbA1c levels in the rst trimester, proteinuria, and perhaps type of diabetes.
The schedule of busy clinics may decrease the ability to completely examine the retinae. Mild background retinopathy may be missed, even in the
best of settings. Any retinopathy increases the risk, especially if the blood
glucose level is elevated. Rather than recommending angiography to all
women before each pregnancy is planned, in the case of no retinopathy
seen on retinal examination, it is prudent to improve the glucose control
slowly. These case reports reinforce the need to intensify preconception
care programs to allow the luxury of slowly normalizing the blood glucose
and plan the pregnancy only after blood glucose levels have been stabilized
within the normal ranges for at least 6 months [42].
When a patient who is already pregnant presents with high glycosylated
hemoglobin levels, regardless of the retinal status, she needs to have an ophthalmology consultation on the rst day of admission. As the glucose normalization protocol is being initiated, a retinal specialist needs to be on
the team, be vigilant, and treat with laser therapy if the retina deteriorates.
Thyroid disease
Type 1 diabetes is associated commonly with other autoimmune endocrine disorders. Thyroid autoantibodies occur more frequently in these patients than in the normal population [46]. Furthermore, an increased
prevalence of subclinical hypothyroidism has been reported in pregnant diabetic women [4649]. Several studies have found a wide range (10%25%)
in the prevalence of postpartum thyroid dysfunction in type 1 diabetic patients [50]. In a report by Haddow and colleagues [51], there is the
85
suggestion that screening pregnant women for hypothyroidism by measuring thyrotropin may be worthwhile and that treating women with serum
thyrotropin concentrations at or above the 98th percentile could lead to
an increase of approximately 4 points in IQ scores in their children. Because there is an increased risk of gestational hypothyroidism in diabetic
women, all diabetic pregnant women should be screened for hypothyroidism
early in their pregnancy and treated immediately if hypothyroidism is documented [51]. Notably, Graves disease is not more common in type 1 diabetic
women than in the general population [46].
Diabetic ketoacidosis
Diabetic ketoacidosis, a complication associated with a high mortality
rate in the fetus, may occur. In addition, ketonemia during pregnancy has
been associated with decreased intelligence in ospring [5254], but in these
reports there is no mention of an association with fetal malformations. In
early pregnancy, ketonuria sometimes occurs in women who are limiting
their caloric intake because of nutritional recommendations [55]. Ketonuria
resulting from caloric restriction has been shown subsequently not to be associated with decreased intelligence in the ospring, unless it is also associated with severe hyperglycemia (blood glucose levels O 180 mg/dL). Thus,
women with moderate to large ketonuria associated with hyperglycemia
should immediately alert their physician. Also, if a type 1 diabetic woman
is using an insulin infusion pump [53], even short periods of interruption
in the infusion may result in ketoacidosis caused by the increased metabolic
rate in pregnancy. Thus, many centers are recommending the use of an additional injection of neutral protamine Hagedorn (NPH) insulin at bedtime,
in a volume that is 0.1 times the patients weight in kg, for an appropriate
adjustment in the overnight basal metabolism [27,55].
Pregnancy-induced hypertension
Normal rst trimester blood pressure is less than 120/80 mmHg [56]. Fetal complications from maternal hypertension include intrauterine growth
retardation and fetal demise. The only antihypertensive mediations that
have been proven to be safe over the past two generations are methyldopa
and hydralazine. When additional medication is needed to maintain normotension, the use of labetolol has been recommended, along with the judicious
use of calcium channel blockers and even diuretics. Nifedipine has also been
reported to be safe when added after the rst trimester. The use of angiotensin converting enzyme (ACE) inhibitors in pregnancy have been associated
with congenital anomalies, specically renal agenesis or renal failure, and
thus, they are absolutely contraindicated in pregnancy [57]. However,
Hod and colleagues [57] have shown that when ACE inhibitors are used
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JOVANOVIC & NAKAI
before conception, they decrease the degree of proteinuria, and when they
are discontinued at the time of conception, the decreased proteinuria is sustained throughout pregnancy, with an improved maternal and fetal outcome. Although the management of elevated blood pressure in a diabetic
pregnant woman is an urgent priority, the means to achieve these goals
are limited in pregnancy.
Diabetic nephropathy
Diabetic nephropathy, when not associated with hypertension, does not
have an impact on fetal outcome unless the kidney function is more than
50% impaired. Normal creatinine clearance is increased in pregnancy because of the increased metabolic rate and the increased cardiac output by
the 10th to 12th week of gestation. Thus, a depression of the creatinine
clearance below 50 mL/min is associated with increased fetal loss. Proteinuria greater than 250 mg/dL in the rst trimester has been associated with
nephrotic syndrome by the third trimester, requiring bed rest and in some
cases replacement of protein losses with parenteral supplementation of albumin [25]. Maternal anasarca is not associated with fetal hypdrops, as long as
the maternal nutrition includes enough protein for fetal growth [55].
Monitoring glycemic control during pregnancy

The development of accurate, fast, and portable glucose reectance meters provides patients with the technology to self-assess glycemic control
and initiate diabetes management changes numerous times daily, with
a goal of normoglycemia. To eectively use newer insulin analogs and dosing strategies to their fullest potential, both the physician and the pregnant
patient must understand the techniques, goals, and potential pitfalls of intensifying not only self-monitored blood glucose testing (SMBG) but also
HbA1c monitoring and urine ketone testing as well.
The consideration of glycemic goals in the pregnant diabetic woman must
take into account the normal glucose ranges in nondiabetic pregnant women.
Recently reexamined with the use of continuous glucose monitoring systems, mean fasting glucose values have been shown to range from 61 mg/
dL to 75 mg/dL [5860], decreasing over the course of gestation [59]. In diabetic and nondiabetic pregnancies, maximal postprandial glucose excursions
occur between 60 and 90 minutes after meal ingestion and correlate more
closely with 1-hour than 2-hour postprandial measurements [6062]. The
mean peak 1-hour postprandial glycemic excursions have been shown to
range from 97 to 120.9 mg/dL in nondiabetic women, with negative 3-hour,
100-g oral glucose tolerance tests performed at 24 to 28 weeks gestation,
depending on whether the patients passed or failed their 1-hour, 50-g oral glucose challenge test [58]. For diabetic women, fasting and preprandial SMBG
87
must be monitored with treatment goals that are lower than those that are
used outside of pregnancy, to goals of 60 to 90 mg/dL. Understanding these
nondiabetic pregnancy, normal glucose ranges provides additional support to
the previous observation that the macrosomia risk increases with increasing
maximal postprandial hyperglycemia R 120 mg/dL [4]. While striving to
achieve normoglycemia in a type 1 diabetic womans pregnancy, fasting, preprandial, and 1-hour postprandial SMBG testing [4,63] must be carried out to
dose insulin safely yet meet the fasting-preprandial glucose goals of 60 mg/dL
to 90 mg/dL and 1-hour postprandial glucose goals of 100 mg/dL to 120 mg/
dL [64].
Because of the high frequency of SMBG testing required in pregnancy,
the use of alternative site SMBG testing is appealing, but the dynamically
changing blood glucose concentrations after eating may be identied at nger sites before they are detected at forearm or thigh sites [65]. Because no
studies have evaluated the use of blood glucose values from alternative sites
in pregnancy, alternative site SMBG testing must be discouraged. The eventual availability of real-time continuous glucose monitoring sensors holds
the promise of not only signicantly reducing the number of nger-stick
blood glucose assessments but also raising the awareness of glycemic excursions [66,67], which can occur commonly, particularly in women with type 1
diabetes, between SMBG measurements. At the time of this writing, no such
system is available currently for commercial use.
Glycosylated hemoglobin testing
Until real-time continuous glucose monitoring systems are in routine
clinical use to accurately assess 24-hour glycemia, frequent HbA1c monitoring will remain valuable as an assessment of blood glucose excursions occurring at non-SMBG time points. Whereas the HbA1c testing frequency in a
nonpregnant population is commonly timed to assess a new steady state of
glycemic control, during the compressed time frame of pregnancy (in which
2 weeks represents 5% of a normal gestation), the need to recognize and
treat worsening glycemic control as promptly as possible can be facilitated
by examining HbA1c changes because they reect trends in glycemic control.
Because clinically and statistically signicant dierences in HbA1c can be detected at 2-week intervals [68,69], HbA1c assessment every 2 weeks during
gestation is recommended.
Nondiabetic pregnant women evaluated by continuous glucose monitoring systems maintain mean blood glucose levels of or less than 100 mg/dL
[60], and treating diabetic pregnant women to this mean glucose goal signicantly decreases perinatal mortality [70]. Knowing that a mean blood
glucose goal of 100 mg/dL correlates with an HbA1c goal of 5% [71], discordant SMBG and HbA1c results should prompt investigation because poor
control, undetected by the patients current SMBG routine, is assumed. Additionally, when using HbA1c measurement as an indicator of glycemic
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JOVANOVIC & NAKAI
control during pregnancy, it is important to establish a normal HbA1c

range, created to reect the fact that the mean blood glucose levels of nondiabetic pregnant women are approximately 20% lower than in the nonpregnant state [72,73].
Urinary ketone testing

In the nonpregnant state, home urine ketone assessments can be
performed in times of hyperglycemia (blood glucose concentration O 180
mg/dL) to assess for evidence of diabetic ketoacidosis. Although many clinicians still use urinary ketone monitoring in pregnancy to ensure maternal
nutrition, there are several reasons that this is of limited value when the maternal blood glucose concentration is less than 180 mg/dL in an otherwise
uncomplicated diabetic pregnancy. Urinary ketones are frequently positive,
without positive serum ketones or acidosis caused by extremely ecient renal ketone clearance [73,74], and are frequently found in urine specimens
from nondiabetic pregnant women [75]. Rat models of pregnancy aected
by diabetes have demonstrated embryonic malformations in vitro when exposed to markedly elevated ketones [76], but prospective human studies
have not found correlations between ketonemia and fetal malformation or
pregnancy loss [53]. In a separate study [52], the presence of ketonuria
was not correlated with an impaired intellectual growth of the ospring
when the maternal blood glucose was controlled adequately. As long as adequate maternal nutrition, reected by appropriate maternal weight gain, is
maintained and the pregnant woman is not ill or hyperglycemic, routine
morning urinary ketone testing is of limited value. Additional insulin should
be prescribed based on evidence of hyperglycemia, not evidence of ketonuria. Furthermore, increasing carbohydrate intake for the sole purpose of
preventing positive urine ketones can result in overfeeding and worsening
glycemic control, potentially increasing the risk of macrosomia.
Treatment
There are several components to the treatment of diabetes in pregnant
women, the administration of insulin, exercise, and diet.
Insulin doses
The starting insulin dose is calculated to be 0.7 U/kg/d, divided into three
to four injections of short- and intermediate-acting insulin. Thecapillary
glucose needs to be measured before and 1 hour after each meal, at bedtime, and at 3 AM to assure that there is around-the-clock glucose control.
Each day the insulin is adjusted based on the blood glucose measurements
such that the optimal dose of insulin is derived on a daily basis. Only human
89
insulin should be used in pregnant women. Most women with type 1 diabetes require at least three injections per day [41,45,48]. A two-injection regimen can cause nocturnal hypoglycemia if the evening meal dose of
intermediate-acting insulin peaks during the middle of the night [27].
Total daily insulin requirements typically rise during gestation. This is
caused primarily by the eects of human placental lactogen, which has somatotropic properties. The average insulin requirement in pregnant women
with type 1 diabetes rises from 0.7 U/kg/d in the rst trimester, often increasing to 0.8 U/kg/d for weeks 18 to 26, 0.9 U/kg/d for weeks 26 to 36,
and 1.0 U/kg/d for weeks 36 to term. Massively obese women may need
initial doses of 1.5 U/kg/d to 2.0 U/kg/d to overcome the combined insulin
resistance of pregnancy and obesity [54]. Declining insulin requirements
may occur at 9 to 12 weeks of gestation and again at 38 to 40 weeks of
gestation [27]. These changes in insulin requirement are thought to be
caused by the luteal-placental shift in progesterone seen in the late rst trimester and to the onset of labor, with increased glucose use that occurs
when uterine contractions commence.
The total daily dose is divided such that 50% is given as a basal dose, using an insulin infusion pump or NPH insulin, divided into two to three daily
injections spaced 8 to 12 hours apart. The meal-related dose then is the other
50% of the insulin requirement. Recent reports have shown that insulin lispro is safe in pregnancies complicated by type 1 diabetes [77]. However, the
studies using insulin aspart and the long-acting insulin analogs detemir and
glargine have not yet been published.
Some clinicians have recommended using insulin pumps to achieve optimal
glycemic control during pregnancy [78,79]. Most pregnant women require at
least three infusion rates in a 24-hour period, in particular a low-dose basal
from 12 midnight to 4 AM, an increased rate in the early morning hours,
from 4 AM to 10 AM, to counteract the increased release of the anti-insulin hormones cortisol and growth hormone, and an intermediate basal during the
rest of the day, from 10 AM to 12 midnight. A protocol for calculating infusion
rates has been described elsewhere [80].
Role of exercise
Gestational diabetes diers from a pregnancy in type 1 diabetes because
the former is a disorder primarily of impaired glucose clearance. As a result,
therapies that overcome peripheral resistance to insulin, such as exercise, are
preferable to insulin. In comparison, in women with type 1 diabetes who are
already taking insulin, the benets of exercise are not so clear. Exercise can
contribute to the brittleness of diabetes, with the risk of exercise-induced
hypoglycemia. Women who exercised before pregnancy can usually continue under the supervision of their obstetrician. However, exercise is not recommended in women who are deconditioned and did not exercise before
pregnancy [80].
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JOVANOVIC & NAKAI
Diet
The optimal diet takes into account caloric intake, carbohydrate content,
and the distribution of meals throughout the day. The appropriate caloric
intake depends on the pregravid weight, with the following general
recommendations:

w30 kcal/kg/d if the woman is at her ideal body weight

w24 kcal/kg/d if the woman R 20% to 50% above ideal body weight
1218 kcal/kg/d if the woman is O 50% above ideal body weight
3640 kcal/kg/d if the woman is O 10% below ideal body weight
The recommended distribution of calories is 40% to 50% carbohydrate,

20% protein, and 30% to 40% fat. Many physicians nd that maintaining
glycemic control requires a diet in which carbohydrate accounts for no more
than 40% of calories [3,54]. Postprandial blood glucose values depend largely
on the carbohydrate content of the meal, and it is the postprandial blood
glucose concentration that has the most important role in macrosomia
[4,63].
Most programs recommend three meals and three snacks per day. An acceptable caloric distribution would be 10% of calories at breakfast, 30% at
both lunch and dinner, and 30% as snacks. A daily supplement of ferrous
sulfate and folate is also recommended.
Fetal surveillance
The high perinatal mortality once associated with a diabetic pregnancy
has decreased signicantly, largely caused by improved glycemic control
[81]. In the past, unexplained fetal death occurred in 10% to 30% of type
1 diabetic pregnancies, typically after the 36th week of gestation in women
with poor glycemic control, associated with macrosomia, hydramnios, preeclampsia, and vascular disease. Fetal surveillance, therefore, is of utmost
importance in optimizing a good outcome for both mother and fetus, especially in the perilous third trimester. Ultrasonography is the most useful tool
for the assessment of the fetus. It can be used to (1) estimate gestational age;
(2) screen for structural anomalies; (3) evaluate growth; (4) assess amniotic
uid volume; and (5) determine fetal status dynamically through Doppler
and biophysical studies.
Ultrasonographic estimates of gestational age are most accurate if they
are performed in early pregnancy. The gestational age, determined by
a crownrump length measured in the rst trimester, will be accurate within 5
days. Ultrasonographic estimates of gestational age are not reliable after the
28th week and cannot be used to determine the estimated date of delivery
[82].
Macrosomia is more apparent in some fetal structures, such as the liver
and abdomen. As a result, ultrasonographic estimates that use the fetal
91
abdominal circumference to calculate fetal weight may not be as accurate as

in normal fetuses in which growth is proportional. Macrosomia is usually
dened as fetal weight greater than 4.0 kg to 4.5 kg or birth weight above
the 90th percentile for gestational age [8385]. Macrosomic fetuses are at
an increased risk for a prolonged second stage of labor, shoulder dystocia,
operative delivery, and perinatal death [83].
Macrosomia occurs in approximately 88% of fetuses in whom the abdominal circumference and estimated fetal weight both exceed the 90th percentile [61,85]. The biparietal diameter and head circumference appear to be
less predictive of macrosomia. Undiagnosed macrosomia may lead to birth
trauma if vaginal delivery ensues. Before the onset of labor, an assessment of
the fetal size is paramount.
In contrast to macrosomia, intrauterine growth retardation (usually
dened as birth weight below the 10th percentile for gestational age) is uncommon in diabetic pregnancies. It is associated with uteroplacental insufciency and occurs primarily in pregnancies complicated by diabetic
vasculopathy or preeclampsia [25].
Ultrasonography is essential for the evaluation of congenital anomalies.
A structural ultrasonogram can detect both neural tube defects and major
cardiac defects by this time. Infants of diabetic mothers are at an increased
risk for neural tube defects, which occur in approximately 2% of diabetic
pregnancies (versus 0.1%0.2% in the general population) [86]. Other congenital anomalies that occur with higher frequency in infants of diabetic
mothers include anencephaly, microcephaly, caudal regression syndrome,
and genitourinary and gastrointestinal anomalies. Congenital heart disease
is also common, including a specic type of hypertrophic cardiomyopathy,
atrial and ventricular septic defects, transposition of the great vessels, and
coarctation of the aorta. Hydramnios can occur because of increased amniotic uid osmolality and polyuria secondary to fetal hyperglycemia [87]. Ultrasonography is performed in the third trimester for the assessment of
growth and development and the presence of macrosomia.
Maternal diabetes alone does not increase the risk for chromosomal abnormalities such as Down syndrome. As a result, the indications for invasive
testing, such as amniocentesis and chorionic villous sampling, are the same
as in the general population.
Guidelines for antepartum surveillance vary and usually depend on the
clinical situation and the discretion of the physician. In women who have
diet-controlled gestational diabetes, fetal surveillance is not initiated usually
until 40 weeks gestation, because these women are at very low risk for complications. More rigorous monitoring is recommended for women who have
additional indications for closer fetal surveillance. Most centers defer testing
until the 35th week of gestation if there is excellent glycemic control, but
testing is started much earlier in women who have poor control, nephropathy, or hypertension. In these women, antepartum testing is begun at 26 to
28 weeks, when fetal survival is likely if delivery were to occur. Antepartum
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JOVANOVIC & NAKAI
fetal testing should be performed twice per week. Doppler umbilical artery
velocimetry has shown increased placental resistance in women with vasculopathy and poor glycemic control, which increase the risk of intrauterine
growth retardation and preeclampsia [82,88].
Labor and delivery

Maternal hyperglycemia is the major cause of neonatal hypoglycemia. As
a result, the peripartum maintenance of maternal euglycemia is essential.
The following general recommendations can be made: insulin is still required before active labor and can be given subcutaneously or by intravenous infusion, with a goal of maintaining blood glucose concentrations
between 70 mg/dL and 90 mg/dL. One method of insulin infusion consists
of the intravenous administration of 15 U of regular insulin in 150 mL of
normal saline at a rate of 1 U/h to 3 U/h. Normal saline may be sucient
to maintain euglycemia when labor is anticipated. As the mother enters
active labor, insulin resistance decreases rapidly (because expulsion of the
fetoplacental unit leads to the cessation of production of somatomammotropin, which has a short half-life), and insulin requirements drop to zero.
Thus, continuing insulin therapy is likely to lead to hypoglycemia. To prevent hypoglycemia, glucose should be infused at a rate of 2.5 mg/kg/min
should be given [89]. Capillary blood glucose should be measured hourly.
The glucose infusion should be doubled for the next hour if the blood glucose value is less than 60 mg/dL. On the other hand, values of 120 mg/dL or
more require the administration of regular insulin subcutaneously or intravenously until the blood glucose value falls to 70 mg/dL to 90 mg/dL. At
this time, the insulin dose is titrated to maintain normoglycemia while glucose is infused at a rate of 2.5 mg/kg/min. Bolus doses of glucose should not
be given because they can raise maternal blood glucose concentrations and
increase the risk of neonatal hypoglycemia, fetal hypoxia, and fetal or neonatal acidosis. If a cesarean section is planned, the bedtime NPH insulin
dose may be given on the morning of surgery and every 8 hours thereafter
if surgery is delayed [90].
Postpartum
Insulin requirements drop sharply after delivery, and the new mother may
not require insulin for 24 to 72 hours. Insulin requirements should be recalculated at this time, at approximately 0.6 U/kg/d, based on postpartum weight.
Postpartum caloric requirements are approximately 25 kcal/kg/d and somewhat higher (27 kcal/kg/d) in lactating women.
Glycemic control is somewhat more erratic in lactating diabetic women,
with more frequent episodes of hypoglycemia. Because the risk of lifethreatening hypoglycemia is increased in the immediate postpartum period,
93
especially if a woman is lactating, preventing postpartum hypoglycemia is

the primary goal. Hypoglycemia occurring in the middle of the night can
be prevented if the NPH dose before bed is deleted and regular insulin is
given instead at 3 AM in low doses, after the mother has nished nursing
the infant [91].
Summary
Although the successful outcome rate of pregnancies complicated by diabetes is now approaching the rate seen in a normal healthy pregnant population, this improvement is realized only when careful attention is paid to
the metabolic, hemodynamic, and vascular perturbations associated with
the changes of pregnancy. The diabetic woman must not only pay attention
to her nutrition but also blunt momentary swings in her blood glucose by
taking frequent blood glucose determinations and perfectly calculated doses
of insulin. In addition, she must be under constant surveillance for a host of
other complications of pregnancy, such as hypertension, retinopathy, infection, acidosis, thyroid dysfunction, nephropathy, and sudden death in utero.
Any or all of these problems become medical emergencies if left untreated.
Thus, rigorous vigilance to sustain normoglycemia, normotension, retinal
health, normal thyroid function, renal health, and fetal well-being are all
paramount in the management of pregnancies complicated by diabetes.
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normal and diabetic subjects. J Am Coll Nutr 1989;8:12531.

35 (2006) 99116
Pituitary Disorders During Pregnancy

Mark E. Molitch, MD*
Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine,
Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Anterior pituitary gland and pregnancy

Pituitary adenomas are common in women, constituting 5.7% of intracranial (malignant and nonmalignant) neoplasms, with an age-adjusted incidence rate of 0.82 cases/100,000 person-years [1]. These adenomas may
cause problems in women because of oversecretion of hormones by the tumor and hypopituitarism. Hormonal dysfunction caused by pituitary adenomas may aect fertility and pregnancy outcome if pregnancy does
ensue. In addition, the pregnancy itself alters hormone secretion and pituitary function, complicating the evaluation of patients with pituitary neoplasms. The need for preventing harm to the developing fetus inuences
therapeutic decisions for the mother.
During pregnancy, the normal pituitary gland enlarges considerably as
a result of the estrogen-stimulated hyperplasia and hypertrophy of the prolactin-producing lactotrophs [2,3]. Concomitantly, prolactin levels increase
gradually throughout gestation [4]. The elevated prolactin levels found at
term prepare the breast for lactation. The nding of amenorrhea associated
with hyperprolactinemia could be due to pregnancy and not due to pathologic hyperprolactinemia.
MRI scans of the pituitary during pregnancy show a size increase secondary to the lactotroph hyperplasia, with the peak size occurring in the rst 3
days postpartum when gland heights of 12 mm may be seen [57]. After delivery, there is a rapid involution of the gland so that normal pituitary size is
found by 6 months postpartum [6,7]. This stimulatory eect of pregnancy
on the pituitary has important implications for a patient with a prolactinoma
who desires pregnancy.
* Division of Endocrinology, Metabolism, and Molecular Medicine, Department of

Medicine, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue,
Tarry 15-731, Chicago, IL 60611.
E-mail address: molitch@northwestern.edu
doi:10.1016/j.ecl.2005.09.011
endo.theclinics.com
100
MOLITCH
Beginning in the second half of pregnancy, pituitary growth hormone

(GH) secretion decreases, and the circulating level of a GH variant made
by the syncytiotrophoblastic epithelium of the placenta increases to 10 to
20 ng/mL [8,9]. The decreased production of normal pituitary GH likely
is caused by negative feedback eects of insulin-like growth factor type 1,
which is stimulated by the placentally produced GH variant [8,9]. In patients
with acromegaly who have autonomous GH secretion and become pregnant, both forms of GH persist in the blood throughout pregnancy [10].
During gestation, cortisol levels progressively increase, resulting in a 2 to
3 fold increase by term [11]. Most of the elevation of cortisol levels is due to
the estrogen-induced increase in cortisol-binding globulin levels [12]. The
bioactive free fraction also is elevated 3-fold, and the cortisol production
rate is increased so that there is a 2 to 3 fold elevation in urinary free cortisol
level [11,12]. Adrenocorticotropic hormone (ACTH) levels have been variously reported as being normal, suppressed, or elevated early in gestation
[11,13]. Later in the pregnancy, however, there is a progressive increase, followed by a nal surge of ACTH and cortisol levels during labor [11]. ACTH
does not cross the placenta, but it is manufactured by the placenta [13]. The
amounts of ACTH in serum that are of placental compared with pituitary
origin at various stages of gestation are unknown. Corticotropin-releasing
hormone (CRH) also is produced by the placenta and is released into maternal plasma [14]. The CRH is bioactive and may release ACTH from the placenta, in a paracrine fashion, and from the maternal pituitary [14]. The role
of placental CRH in regulating ACTH and cortisol secretion during pregnancy in humans is unclear.
Thyroid-stimulating hormone (TSH) levels decrease in the rst trimester,
in response to the increased thyroid hormone levels that are stimulated by
human chorionic gonadotropin, but return to the normal range by the third
trimester [15]. In response to placental sex steroid production, hypothalamic
gonadotropin releasing hormone (GnRH) and pituitary gonadotropin (follicle-stimulating hormone and luteinizing hormone) levels decline in the rst
trimester of pregnancy, with a blunted gonadotropin response to GnRH [16].
Prolactinoma
Hyperprolactinemia is responsible for about one third of all cases of female
infertility [17]. Hyperprolactinemia impairs the hypothalamic-pituitaryovarian axis at several levels, the primary site of inhibition being at the
hypothalamus, where it inhibits the pulsatile secretion of GnRH [18]. The
dierential diagnosis of hyperprolactinemia is extensive [18].
For patients with prolactinomas, the choice of therapy may have important consequences for decisions regarding pregnancy. Transsphenoidal surgery is curative in 50% to 60% of cases and rarely causes hypopituitarism
when it is performed on women with microadenomas. For patients with
PITUITARY DISORDERS DURING PREGNANCY
101
macroadenomas, surgery cures a much smaller number with a considerably

greater risk of causing hypopituitarism and may aect fertility [18].
Dopamine agonists, including bromocriptine, pergolide (approved for
the treatment of Parkinsons disease but not hyperprolactinemia in the
United States), quinagolide (not approved in the United States), and cabergoline, have become the primary mode of therapy for almost all patients
with prolactinomas. Bromocriptine, pergolide, and quinagolide can restore
ovulatory menses in 70% to 80% of women, and cabergoline can restore
ovulatory menses in greater than 90% [1820]. When this restoration has
been accomplished, and if pregnancy is desired, mechanical contraception
is used until the rst two or three cycles have occurred so that an intermenstrual interval can be established. In this way, a woman knows when she has
missed a menstrual period, a pregnancy test can be performed quickly, and
the precise gestational age of the fetus can be known. In this way, these
drugs will have been given for only about 3 to 4 weeks of the gestation. Because of its long half-life in the body, however, cabergoline cessation at that
point still results in a further fetal exposure for an additional 1 or more
weeks.
In addition to their ecacy in lowering prolactin levels, the dopamine agonists often reduce tumor size of prolactin-secreting macroadenomas. Bromocriptine reduces the size by 50% or more in 50% to 75% of patients
[18,20,21]. Pergolide reduces the size in 80% to 90% of patients, and cabergoline achieves such reductions in greater than 90% of patients in some series [18,2023].
Eects of pregnancy on prolactinoma growth
In women with prolactinomas, the stimulatory eect of the hormonal
milieu of pregnancy may result in signicant tumor enlargement during gestation (Fig. 1). A review summarized 16 series reported during the years
19791985 totaling 246 women with microadenomas and 91 women with
macroadenomas who became pregnant [24]. Subsequently, three series totaling an additional 130 women with microadenomas and 60 women with
macroadenomas have been reported [2527]. When these data are combined
[2427], only 6 of the 376 women (1.3%) with microadenomas had symptoms of tumor enlargement (headaches or visual disturbances or both)
(Table 1). In no case was surgical intervention necessary. These series included 86 patients with macroadenomas who had not had prior surgery
or irradiation. Of these, 20 (23.2%) had symptomatic tumor enlargement.
During pregnancy, surgery was required in 4 patients, and bromocriptine
was required in 15. Seventy-one women with macroadenomas had been treated with irradiation or surgery before pregnancy; only 2 of the 71 (2.8%)
had symptomatic tumor enlargement, If tumor enlargement occurs, reinstitution of bromocriptine and cabergoline usually is successful in reducing the
size of the tumor, but transsphenoidal surgery may be necessary [24,28].
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MOLITCH
Fig. 1. Coronal and sagittal MRI scans of an intrasellar prolactin-secreting macroadenoma in

a woman before conception (top) and at 7 months of gestation (bottom). Note the marked tumor enlargement at the latter point, at which time the patient was complaining of headaches.
(From Molitch ME. Medical treatment of prolactinomas. Endocrinol Metab Clin North Am
1999;28:14370.)
Eects of hyperprolactinemia and its treatment on pregnancy

Bromocriptine taken for only the rst few weeks of gestation has not been
associated with any increase in spontaneous abortions, ectopic pregnancies,
trophoblastic disease, multiple pregnancies, or congenital malformations
(Table 2) [29,30]. Long-term follow-up studies of 64 children between ages
6 months and 9 years whose mothers took bromocriptine in this fashion
have shown no ill eects [31]. Experience with the use of bromocriptine
Table 1
Eect of pregnancy on prolactinomas
Tumor type
Prior therapy
No. of patients
Symptomatic
enlargementa
Microadenomas
Macroadenomas
Macroadenomas
None
None
Yes
376
86
71
6 (1.3%)
20 (23.2%)
2 (2.8%)
103
Table 2
Eect of bromocriptine on pregnancies
Bromocriptine
Criteria
No.
Normal population (%)
Pregnancies
Spontaneous abortion
Termination
Ectopic
Hydatidiform moles
6239
620
75
31
11
100.0
9.9
1.2
0.5
0.2
100.0
10.015.0
d
0.51.0
0.050.7
Deliveries (known duration)

At term (O 38 wk)
Preterm (! 38 wk)
4139
3620
519
100.0
87.5
12.5
100.0
85.0
15.0
Deliveries (known outcome)

Single births
Multiple births
5120
5031
89
100.0
9.3
1.7
100.0
8.7
1.7
Infants (known details)

Normal
Who have malformations
Who have perinatal disorders
5213
5030
93
90
100.0
96.5
1.8
1.7
100.0
95.0
3.04.0
O2.0
Data from Krupp P, Monka C, Richter K. The safety aspects of infertility treatments. In:
Program of the Second World Congress of Gynecology and Obstetrics. Rio de Janeiro, Brazil,
August 1988. p. 9.
throughout gestation is limited to only slightly more than 100 women, but
no abnormalities were noted in the infants except one with an undescended
testicle and one with a talipes deformity [32]. Because bromocriptine crosses
the placenta [33], however, it should not be used any longer than necessary
during pregnancy.
Pergolide has been shown to cross the placenta in mice, but no teratogenicity was seen in doses of 60 mg/kg/d [34]. Detailed data are available on
the safety during early gestation for only one patient treated with pergolide
for Parkinsons disease [35]. In this pregnancy, no teratogenicity or developmental abnormalities were found in the child, but the authors stated in this
report that, in premarketing studies of pergolide for endocrine disorders,
two major and three minor congenital abnormalities were described among
38 pregnancies, but a causal relationship has not been established [35].
Other information from the manufacturer (Eli Lilly & Co) stated that
they had only limited data on pregnancies in which the fetus was exposed
to pergolide, nding that 7.2% of pregnancy outcomes resulted in spontaneous abortions, 7.2% in minor malformations, 14.3% in intentional abortions, and 28.6% in healthy infants; for 43.4%, no information was
available [36]. This limited information is sucient to recommend against
using pergolide when a woman wishes to get pregnant.
Some early publications reported no detrimental eects on pregnancy or
fetal development in women who became pregnant during treatment with
104
MOLITCH
quinagolide [37]. A more recent review of 176 pregnancies, in which quinagolide was maintained for a median duration of 37 days, reported 24 spontaneous abortions, 1 ectopic pregnancy, and 1 stillbirth at 31 weeks
gestation [38]. Nine fetal malformations were reported in this group: spina
bida, trisomy 13, Down syndrome, talipes, cleft lip, arrhinencephaly, and
Zellweger syndrome [38]. Quinagolide also should not be used if pregnancy
is desired.
Cabergoline has been shown to cross the placenta in animal studies [16],
but such data are lacking in humans. Data on exposure of the fetus or embryo during the rst several weeks of pregnancy have been reported in more
than 350 cases, and such use has not shown an increased percentage of spontaneous abortion, premature delivery, multiple gestation, or congenital
abnormalities [3943]. No alterations in newborn weights were observed
[3943]. Available data from 107 infants followed for 1 to 72 months showed
normal physical and mental development [39].
With respect to using a dopamine agonist to facilitate ovulation and fertility, bromocriptine has the largest safety database and has a proven safety
record for pregnancy. Although the database for cabergoline use in pregnancy is much smaller, it does not seem to exert any deleterious eects on
pregnant women, and the incidence of malformation in their ospring is
not greater than in the general population. For a woman who is intolerant
to bromocriptine and who is doing well with cabergoline, continuation of cabergoline for facilitating pregnancy seems reasonable. The safety databases
for pergolide and quinagolide are limited, but they seem to raise considerable
concerns, so these drugs should not be used when fertility is desired. The effects of transsphenoidal surgery during gestation are not known specically,
but would not be expected to be signicantly dierent from the eects of
other types of surgery (unless hypopituitarism should ensue) [44].
Management of prolactinoma in pregnancy
The risks of surgery versus medical therapy for prolactinoma should be
explained in detail to each patient. For patients with microadenomas or intrasellar macroadenomas, bromocriptine or cabergoline therapy generally is
preferred to surgery because it is safe for the fetus when discontinued early
in gestation, and it poses only a small risk of tumor enlargement for the
mother. Such patients should be seen each trimester and assessed for symptoms such as headaches or visual problems; visual eld testing needs to be
done only when clinically indicated. When the tumor is large or extends
to the optic chiasm or into the cavernous sinus, the following approaches
should be considered: (1) preoperative surgical debulking, (2) intensive monitoring without bromocriptine therapy, or (3) continuous bromocriptine
therapy. The safety of the last approach has not been established, but based
on the few cases cited earlier, it probably is not harmful. Patients with macroadenomas should be seen monthly for such assessments, and visual elds
105
should be tested each trimester. Prolactin levels, which normally increase in

pregnancy, may not increase in women with prolactinomas [45]. Prolactin
levels may not always increase with pregnancy-induced tumor enlargement
[45]; periodic measurements of prolactin levels are of little benet.
When there is evidence of tumor enlargement during pregnancy, bromocriptine therapy should be reinstituted immediately and the dosage increased
as rapidly as tolerated. Such therapy must be monitored closely. If there is
no response to bromocriptine, switching to cabergoline, transsphenoidal
surgery, or delivery (if the pregnancy is far enough advanced) should be considered [24].
Although suckling stimulates prolactin secretion in normal women for
the rst few weeks to months postpartum, there are no data to suggest
that breastfeeding can cause tumor growth. There seems to be no reason
to discourage nursing in women with prolactinomas.
Acromegaly
Reports of pregnancy in patients with acromegaly are uncommon
(!100 cases) [4654], perhaps because 30% to 40% of such patients have hyperprolactinemia [55]. Correction of hyperprolactinemia with bromocriptine
may be necessary to permit ovulation and conception in these patients [47,53].
Diagnosis of acromegaly during pregnancy
Conventional radioimmunoassays for GH cannot distinguish between
normal pituitary GH and the placental GH variant [8]. Special radioimmunoassays using antibodies that recognize specic epitopes on the two hormones [8] must be used. When such specic assays are not available, it
may be necessary to wait until after delivery to assess pituitary GH secretion
accurately because the placental variant decreases to undetectable levels
within 24 hours [8]. There are two dierences between the secretion of the
placental GH variant and the secretion of pituitary GH during acromegaly,
however, that may allow a distinction to be made during pregnancy. First,
pituitary GH secretion in acromegaly is highly pulsatile, with 13 to 19 pulses
per 24 hours [56], whereas secretion of the pregnancy GH variant is nonpulsatile [9]. Second, in acromegaly, about 70% of patients have a GH response
to thyrotropin-releasing hormone [57], whereas the placental GH variant
does not respond to this hormone [10].
Eects of pregnancy on tumor size and acromegaly
Only two patients with tumors secreting GH have been reported to have
enlargement of their tumors with a resultant visual eld defect in one during
pregnancy [25,58]. Patients with acromegaly should be monitored for symptomatic tumor enlargement in a fashion similar to that for patients with prolactin-secreting macroadenomas. There is some evidence that pregnancy
106
MOLITCH
may cause an exacerbation of acromegaly in a few cases [47], but this does
not seem to be a sucient enough risk to advise against pregnancy.
Eects of acromegaly on pregnancy
Certain complications of acromegaly are potentially harmful to the mother
and the fetus. Carbohydrate intolerance is present in 50% of patients with
acromegaly, and overt diabetes is seen in 10% to 20% [55]. Insulin resistance secondary to the increased levels of GH may increase the risk of gestational diabetes. There is increased salt retention, and hypertension occurs
in 25% to 35% of patients. In addition, cardiac disease is present in about
one third of patients. There may be a specic cardiomyopathy associated
with acromegaly, and coronary artery disease may be increased [55]. The
risks for gestational diabetes, hypertension, and heart disease likely are increased in women with acromegaly during pregnancy.
Management of acromegaly and pregnancy
The considerations regarding the use of bromocriptine and cabergoline in
women with prolactinomas also apply to women with acromegaly. For most
patients, these drugs should not be continued during pregnancy. Data on the
use of octreotide during pregnancy are limited. Only 14 pregnant patients
treated with octreotide, octreotide long-acting-release, and lanreotide have
been reported; no malformations were found in their children [54]. Octreotide crosses the placenta [59] and can aect developing fetal tissues. It does
not bind with high anity to the placenta and has no eect on the placental
GH variant [60]. Because octreotide crosses the placenta, and because data
documenting safety are limited, it is recommended that octreotide and other
somatostatin analogues be discontinued if pregnancy is considered, and that
contraception be used when these drugs are administered. Considering the
prolonged nature of the course of most patients with acromegaly, interruption of medical therapy for 9 to 12 months should not have a particularly
adverse eect on the long-term outcome. These drugs can control tumor
growth, and for enlarging tumors, their reintroduction during pregnancy
may be warranted versus operating.
Cushings syndrome
Slightly more than 100 cases of Cushings syndrome in pregnancy have
been reported [6176]. The distribution of causes of Cushings syndrome in
pregnancy diers markedly from that in the nonpregnant population. Less
than 50% of pregnant patients described had pituitary adenomas, a similar
number had adrenal adenomas, and more than 10% had adrenal carcinomas
[6173]. Only three reports have described pregnancies associated with the
ectopic ACTH syndrome [63,67]. In many cases, the hypercortisolism rst
became apparent during pregnancy, with improvement after parturition,
107
leading to the speculation that unregulated placental CRH was instrumental

in causing this pregnancy-induced exacerbation [62,63,67,73]. Rarely, recurrent Cushings syndrome may be associated with pregnancy only to remit
completely after delivery; the cause for this has not been found [74,75].
Diagnosis of Cushings syndrome during pregnancy
Diagnosing Cushings syndrome during pregnancy may be dicult. Both
conditions may be associated with weight gain in a central distribution, fatigue, edema, emotional upset, glucose intolerance, and hypertension. The
striae associated with the weight gain and increased abdominal girth are
usually white in normal pregnancy and red or purple in Cushings syndrome. Hirsutism and acne may point to excessive androgen production.
The laboratory evaluation of Cushings syndrome during pregnancy is
not straightforward. Elevated total and free serum cortisol and ACTH levels
and urinary free cortisol excretion are compatible with that of normal pregnancy. The overnight dexamethasone test usually shows inadequate suppression during normal pregnancy [64]. At least in the latter part of the
third trimester, the elevated cortisol levels are not suppressed during the
low-dose dexamethasone test, but are suppressed during the high-dose
test, similar to what is observed in patients with Cushings syndrome [62].
ACTH levels are normal to elevated in pregnant patients with all forms of
Cushings syndrome [6166]. These normal rather than suppressed levels
of ACTH in patients with adrenal adenomas may result from the production
of ACTH by the placenta or from the nonsuppressible stimulation of pituitary ACTH by placental CRH.
A persistent circadian variation in the elevated levels of total and free serum cortisol during normal pregnancy may be most helpful in distinguishing
Cushings syndrome from the hypercortisolism of pregnancy because this
nding is characteristically absent in all forms of Cushings syndrome
[12]. Salivary cortisol measurements may be useful in this regard, but normal limits for midnight levels of salivary cortisol during pregnancy have
not yet been standardized [73]. In many cases, MRI of the pituitary (without
contrast enhancement) or ultrasound of the adrenal may be required, although MRI of the pituitary in patients with Cushings syndrome is often
nondiagnostic. Little experience has been reported with newer techniques,
such as CRH stimulation testing or petrosal venous sinus sampling during
pregnancy. Ross and colleagues [65] found the typical exaggerated ACTH
response to CRH in a woman with Cushings syndrome, but Mellor and colleagues [72] found only a doubling of cortisol levels in response to CRH; neither patient had ill eects from such testing. In two patients studied by
Lindsay and colleagues [76], ACTH levels increased more than threefold,
but cortisol level increases were less than twofold. CRH testing during petrosal sinus sampling was performed without ill eects in one woman by
Pinette and colleagues [68] and in four women by Lindsay and colleagues
108
MOLITCH
[76], but catheterization was performed via the direct jugular vein approach
rather than the femoral vein approach to minimize fetal irradiation; in these
cases, clearly increased central-to-peripheral ACTH gradients were found.
Eects of Cushings syndrome on pregnancy
Cushings syndrome is associated with a fetal mortality of 25% from
spontaneous abortion, stillbirth, and early neonatal death because of extreme prematurity [6173,76]. Premature labor occurs in more than 50%
of cases, regardless of cause [6173,76]. The passage of cortisol across the
placenta occasionally results in suppression of the fetal adrenals [69]. This
passage seems to be uncommon, but the neonate should be tested for this
potential problem and given exogenous corticosteroids until the results of
the evaluation are known.
Maternal complications also may occur. Hypertension develops in most
patients. Diabetes and myopathy are frequent. Postoperative wound infection and dehiscence are common after cesarean section. The pregnancy
seems to induce an amelioration of Cushings syndrome in some patients,
but an exacerbation in others [6167,73].
Management of Cushings syndrome during pregnancy
In data from the literature summarized from two reviews [61,64], fetal
loss rates of 9% and 24% and premature labor rates of 20% and 47%
were found in 11 and 17 women who were treated during pregnancy compared with fetal loss rates of 30% and 38% and premature labor rates of
48% and 72% in 26 and 43 women in whom treatment was delayed. Treatment during pregnancy has been advocated [61,64,76].
Medical therapy for Cushings syndrome during pregnancy is not very
eective [63,64,73]. A few case reports have documented the ecacy of metyrapone [76]. Ketoconazole has been given to two patients with complications
of intrauterine growth retardation, but no malformations or other perinatal
disorders [70,71]. Use of other drugs, such as aminoglutethimide, mitotane,
bromocriptine, and cyproheptadine, has been limited [73]; because of potential toxicity to the fetus, aminoglutethimide and mitotane should be
avoided. Transsphenoidal resection of a pituitary ACTH-secreting adenoma
has been performed successfully in several patients during the second trimester [62,65,68,69,72,73,76]. Although any surgery poses risks for the mother
and fetus [44], with Cushings syndrome, the risks of not operating seem to
be considerably higher than the risks of proceeding with surgery.
Thyroid-stimulating hormonesecreting tumors

Only three cases of pregnancy occurring in women with TSH-secreting
tumors have been reported [7779]. In one of these cases, octreotide, which
109
had been stopped, had to be reinstituted to control tumor size [77], and in
a second, octreotide was continued during pregnancy for tumor size control.
The most pressing issue with such tumors is the need to control hyperthyroidism during pregnancy, and that can be done with standard antithyroid
drugs [78]. With growing macroadenomas, octreotide may be necessary for
tumor size control [77,79].
Clinically nonfunctioning adenomas
Pregnancy would not be expected to inuence tumor size in patients with
clinically nonfunctioning adenomas, and only two cases have been reported
in which tumor enlargement during pregnancy resulted in a visual eld defect [25,80]. The lactotroph hyperplasia that occurs during pregnancy can be
quite signicant, however [2,3]. MRI obtained during pregnancy and the immediate postpartum period has shown that this hyperplasia may cause the
normal pituitary to increase to 12 mm in height [57]. It would be expected
that if this lactotroph hyperplasia were to occur in a patient with a preexisting clinically nonfunctioning adenoma, this hyperplasia could push up
the clinically nonfunctioning adenoma to cause chiasmal compression or
headaches. In the second case reported, the patient responded rapidly to
bromocriptine treatment, probably owing to shrinkage of the lactotroph hyperplasia with decompression of the chiasm and probably with little or no
direct eect on the tumor itself [80]. Most clinically nonfunctioning adenomas are gonadotroph adenomas [81]. Two patients have been reported who
had gonadotroph adenomas secreting intact follicle-stimulating hormone
with a resultant ovarian hyperstimulation syndrome [82,83]; both became
pregnant, one after having the follicle-stimulating hormone hypersecretion
controlled by bromocriptine [82] and the second after surgical removal of
the tumor [83].
Hypopituitarism
Hypopituitarism may occur because of tumor compression of the hypothalamus or pituitary stalk or from prior neurosurgery. Hormone decits
can be partial or complete, and loss of gonadotropin secretion is common.
Induction of ovulation may be dicult, and a variety of techniques have
been used, including administration of human chorionic gonadotropin
and follicle-stimulating hormone (in the past as human menopausal gonadotropin) [8487], pulsatile GnRH [8890], and in vitro fertilization [91].
In women, the only hormone replacements to be considered during pregnancy are thyroid and adrenal hormones. Because of the increased thyroxine
turnover that occurs during pregnancy, thyroxine levels decrease, and TSH
levels increase with a xed thyroxine dose over the course of gestation
[15,92]. The average increase in thyroxine needed in these patients is about
0.05 mg/d. Because patients with hypothalamic-pituitary dysfunction may
110
MOLITCH
not elevate their TSH levels normally in the face of increased need for thyroxine, it may be appropriate to increase the thyroxine supplementation by
0.025 mg after the rst trimester and by an additional 0.025 mg after the second trimester. There are no data to support this approach, however.
Because the cortisol production rate normally is increased in pregnancy
[11,12], the dose of long-term glucocorticoid replacement theoretically ought
to be increased during pregnancy. This dose increase does not seem to be
necessary in practice, however, and patients usually can be kept on their
standard replacement doses of glucocorticoids. Additional glucocorticoids
are needed for the stress of labor and delivery, such as 75 mg of hydrocortisone intravenously every 8 hours with rapid tapering postpartum. If there
is signicant stress during the pregnancy, such as infection, that would require prolonged high doses of glucocorticosteroids, the steroid of choice is
prednisolone, which does not cross the placenta [93]. Even high doses of
prednisone are generally quite safe [94], however, and suppression of neonatal adrenal function in ospring of women taking prednisone during pregnancy is rare [95]. Glucocorticoids also may pass to the neonate in breast
milk, but the amounts (0.14% of maternal blood levels) are not sucient
to alter neonatal adrenal function, even with large maternal doses of prednisone [96].
Lymphocytic hypophysitis
Lymphocytic hypophysitis usually presents in the peripartum period as
a mass lesion indistinguishable from a pituitary adenoma. It is characterized
by massive inltration of the pituitary by lymphocytes and plasma cells with
destruction of the normal parenchyma. The disorder is thought to have an
autoimmune basis. Most cases occur in association with pregnancy, and
women present during pregnancy or postpartum with symptoms of varying
degrees of hypopituitarism or symptoms related to the mass lesion, such as
headaches or visual eld defects. Mild hyperprolactinemia and diabetes insipidus also may be found. On CT or MRI, a sellar mass is found, which
may extend in an extrasellar fashion and may cause visual eld defects.
The condition usually is confused with that of a pituitary tumor and cannot
be distinguished from a tumor except by biopsy. By virtue of the hypopituitarism it produces, lymphocytic hypophysitis also can be confused clinically
with Sheehans syndrome except that there is no history of obstetric hemorrhage [97,98].
The diagnosis of lymphocytic hypophysitis should be considered in women
with symptoms of hypopituitarism or mass lesions of the sella during pregnancy or postpartum, especially in the absence of a history of obstetric hemorrhage. An evaluation of pituitary function and CT or MRI are
warranted. If prolactin levels are only modestly elevated (! 150 ng/mL)
in the presence of a large mass, the diagnosis is unlikely to be an enlarging
prolactinoma and more likely to be hypophysitis or a nonsecreting tumor.
111
Hormone replacement therapy should be instituted promptly when hypopituitarism is determined to be present. For unclear reasons, there seems
to be a particular predilection for impaired ACTH secretion, and this
axis must be evaluated carefully and treated to avoid adrenal insuciency
[99]. Unless there are visual eld defects, uncontrollable headaches, or radiologic evidence of progressive enlargement of the sellar mass, rapid surgical intervention is not warranted because some women may undergo
a spontaneous regression of the mass and return of pituitary function
[99101]. Surgery generally does not result in improvement in endocrine
function, however [102,103]. Although high doses of glucocorticoids
have been advocated to reduce the inammation [103], there have been
no controlled studies documenting the benet of this approach, and the
author does not recommend this.
Sheehans syndrome
Sheehans syndrome consists of pituitary necrosis secondary to ischemia
occurring within hours of delivery [104,105]. It is usually secondary to hypotension and shock from an obstetric hemorrhage. Pituitary enlargement during pregnancy apparently predisposes to the risk for ischemia with occlusive
spasm of the arteries to the anterior pituitary and stalk [104,105]. The degree
of ischemia and necrosis dictates the subsequent patient course. Modern obstetric techniques have resulted in Sheehans syndrome being found rarely in
current practice [106].
Acute necrosis is suspected in the setting of an obstetric hemorrhage in
which hypotension and tachycardia persist after adequate replacement of
blood products. In addition, the woman fails to lactate and may have hypoglycemia [104,105,107]. Investigation should include levels of ACTH, cortisol, prolactin, and free thyroxine. The ACTH stimulation test would be
normal because the adrenal cortex would not be atrophied. Thyroxine levels
may prove normal initially because the hormone has a half-life of 7 days.
Prolactin levels are usually low, although they are generally 5- to 10-fold elevated in the puerperium. Treatment with saline and stress doses of corticosteroids should be instituted immediately after drawing the blood tests.
Additional pituitary testing with subsequent therapy should be delayed until
recovery. Diabetes insipidus also may occur secondary to vascular occlusion
with atrophy and scarring of the neurohypophysis [108].
When milder forms of infarction occur, the diagnosis of Sheehans syndrome may be delayed for months or years [107,108]. These women generally have a history of amenorrhea, decreased libido, failure to lactate, breast
atrophy, loss of pubic and axillary hair, fatigue, and symptoms of secondary
adrenal insuciency with nausea, vomiting, diarrhea, and abdominal pain
[107,108]. Some women experience only partial hypopituitarism and may
have normal menses and fertility [109]. Although women may have episodes
of transient polydipsia and polyuria, many have impaired urinary
112
MOLITCH
concentrating ability and decient vasopressin secretion [110]. CT or MRI

generally reveal partial or completely empty sellae [111].
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35 (2006) 117136
Thyroid Disorders During Pregnancy

Shane O. LeBeau, MDa, Susan J. Mandel, MD, MPHb,*
a
Division of Endocrinology and Metabolism, Department of Medicine, University of

Pittsburgh Medical Center, Pittsburgh, PA, USA
b
Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of
Medicine, Philadelphia, PA, USA
Thyroid disorders are common among women of childbearing years.

Thyroid dysfunction often is overlooked in pregnant women, however, because of nonspecic symptoms and the hypermetabolic state of normal pregnancy. Compounding the diagnosis further is the alteration in thyroid
physiology that normally occurs during gestation. A clinician rst must consider thyroid dysfunction a possibility, then dierentiate normal physiologic
changes from true disease. When thyroid dysfunction is recognized, proper
management is essential for a healthy pregnancy. Abnormalities in maternal
thyroid function can adversely aect the fetus directly by way of the transplacental passage of abnormal maternal hormone concentrations, thyroidstimulating hormone (TSH) receptor antibodies, or prescribed antithyroid
medications and indirectly by way of the altered maternal gravid physiology.
Normal gravid thyroid physiology

Several alterations in thyroid physiology occur during normal pregnancy.
These changes take place at dierent times of gestation, are reversible postpartum, and collectively stimulate the maternal thyroid gland. Hypothyroid
women who receive levothyroxine replacement require a 25% to 47% average dosage increase during pregnancy to maintain normal serum TSH concentrations [13]. Thyroidal stimulation is supported further by the ndings
of increased serum thyroid stimulating hormone (TSH) and thyroglobulin
concentrations, relative hypothyroxinemia, and occasional goiter formation
in pregnant women from areas of borderline iodine suciency [4].
* Corresponding author. Division of Endocrinology, Diabetes, and Metabolism,

Department of Medicine, University of Pennsylvania School of Medicine, 415 Curie
Boulevard, 611 CRB, Philadelphia, PA 19104.
E-mail address: smandel@mail.med.upenn.edu (S.J. Mandel).
doi:10.1016/j.ecl.2005.09.009
endo.theclinics.com
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LEBEAU & MANDEL
The most recognized alteration in maternal thyroid physiology is the increase in thyroxine-binding globulin (TBG). This increase begins early in the
rst trimester, plateaus during midgestation, and persists until shortly after
delivery [5]. Elevated TBG results from a decrease in its hepatic clearance,
owing to estrogen-induced sialylation [6]. The increased concentration of
TBG expands the extrathyroidal pool, triggering a concomitant increase
in maternal thyroid hormone synthesis and elevation of total thyroxine
(T4) and triiodothyronine (T3) levels [5]. In addition to TBG, maternal glomerular ltration rate is increased during early gestation and maintained
throughout pregnancy; this results in an increased renal clearance of iodide,
which indirectly stimulates the maternal thyroid machinery [7]. Lastly,
transplacental passage of T4 and iodide and placental metabolism of iodothyronines stimulate the maternal thyroid by depleting the maternal circulation of thyroid hormone and its precursors [8].
In addition to indirect stimuli, there is strong evidence that human chorionic gonadotropin (hCG) has intrinsic thyrotropic activity. A signicant
degree of homology exists between the hormone-specic b-subunits and
the extracellular receptor binding domains of hCG and TSH [9,10]. hCG secretion begins shortly after conception, peaks around gestational week 10,
and gradually declines thereafter to a nadir by about week 20 [5]. It is believed that the high serum concentrations of hCG during early pregnancy
directly activate the TSH receptor. This belief is substantiated by the nding
that serum hCG concentrations during early pregnancy are negatively correlated with serum TSH concentrations and positively correlated with free
T4 concentrations [5,11]. Serum TSH concentrations vary throughout pregnancy, with the rst-trimester values being lower than the values before conception and during the second and third trimesters [12]. Using an assay with
a detection limit of 0.05 mU/L, researchers found that during the rst trimester, 9% of pregnant women without thyrotoxic symptoms had subnormal serum TSH concentrations (O 0.05 mU/L, but ! 0.4 mU/L), whereas
an additional 9% had suppressed concentrations (! 0.05 mU/L) [13]. Ultimately, the nadir of maternal serum TSH levels mirrors the peak in
hCG concentrations [5]. A more recent study has reported the upper 95%
condence interval (CI) for serum TSH levels in the rst trimester to be
2.5 mU/L [14].
Although consistent patterns of total T4 and TSH during pregnancy
are well documented, the same is not true for free T4 concentrations, particularly during the rst trimester. Free T4 concentrations during this time
have been reported to be higher, lower, and the same as concentrations before conception [5]. These discrepant ndings are likely due to a combination
of shortcomings in methodology and dietary iodine intake among study participants [12]. Based on the available data, it is likely that free T4 and T3 concentrations increase slightly during the rst trimester in response to elevated
hCG. Subsequently, free T4 values decline as pregnancy progresses and nadir during the third trimester with measured values in commercial assays
THYROID DISORDERS DURING PREGNANCY
119
that may be lower than the assays published reference ranges [12]. Currently, none of the manufacturers of the automated free T4 assays has provided trimester-specic reference ranges. Until this information is available,
the serum total T4 concentration may be a better reection of T4 production
during pregnancy. To account for the increased thyroid hormone production
during gestation, the normal reference range for total T4 should be adjusted
by a factor of 1.5 for pregnant patients [12,15].
Hypothyroidism
Screening studies have shown that an elevated serum TSH concentration
is found in 2.5% of pregnancies [16,17]. In an iodine-sucient environment,
hypothyroidism during pregnancy is caused primarily by Hashimotos thyroiditis and prior radioactive iodine treatment or surgical ablation of
Graves disease [18]. Nevertheless, the clinician should keep in mind the
less common causes (eg, overtreatment of hyperthyroidism with thionamides, transient hypothyroidism owing to postpartum thyroiditis, medications that alter the absorption or metabolism of levothyroxine, and
pituitary/hypothalamic disease) because the diagnosis and management of
these patients may be dierent.
Diagnosis
The diagnosis of hypothyroidism during pregnancy is crucial because of
its potential adverse eects on the mother and the child. Only 20% to 30%
of patients with overt hypothyroidism develop symptoms consistent with
disease, however, whereas most patients with subclinical disease are entirely
asymptomatic [19,20]. When symptoms do exist, the diagnosis often is overlooked, and a womans complaints may be attributed to pregnancy itself.
The diagnosis of primary hypothyroidism is made by documenting an elevated serum TSH concentration; however, most commercial laboratories
have not established trimester-specic reference ranges. Patients with central
hypothyroidism resulting from pituitary or hypothalamic disease do not
manifest an elevated serum TSH level during pregnancy.
Pregnancy outcome
Despite the association between overt hypothyroidism and infertility, hypothyroid women may become pregnant [21]. The likelihood that either maternal or fetal complications will arise depends on the severity of disease and
adequacy of treatment. Gestational hypertension occurs more often in
overtly hypothyroid women (36%) than in women with subclinical disease
(25%) or the general population (8%) [22]. A separate study reported
a markedly increased use of cesarean section because of fetal distress among
women who were severely hypothyroid (56%) at their initial antenatal visit
120
LEBEAU & MANDEL
compared with women who were mildly hypothyroid or euthyroid (3%)

[23]. In addition, some investigators have found that women with overt hypothyroidism are more likely to develop placental abruption, anemia, and
postpartum hemorrhage than women with subclinical disease, although
these ndings have been disputed [19]. A prospective study of women
with untreated subclinical hypothyroidism found that compared with euthyroid women, they were three times more likely (95% CI 1.88.2) to develop
placental abruption and 1.8 times more likely (95% CI 1.12.3) to experience preterm labor (! 37 completed weeks) [24]. Finally, very preterm delivery (! 32 completed weeks) was reported to occur more frequently (odds
ratio [OR] 3.13; 95% CI 1.029.63) in women with a serum TSH level greater
than 3 mU/L at 16 weeks [25]. This analysis included adjustments for gestational hypertension.
The children of hypothyroid women also can be adversely aected. Research has shown that the incidence of low-birth-weight neonates is markedly
increased in cases of overt hypothyroidism (22%) compared with subclinical disease (9%) and the general population (7%) [22]. Although some experts attribute these ndings to premature delivery, others believe there is
an association between maternal thyroid status and somatic development,
as supported by a report of severe growth retardation reversal in the fetus
of a hypothyroid woman (TSH 72 mU/L) after adequate levothyroxine replacement. In this particular case, the fetal biparietal diameter and femur
length were below the third decile and normalized over the course of 10
weeks after an increase in levothyroxine and normalization of maternal serum TSH [26].
Research also shows the signicant role of maternal thyroid hormone in
fetal neurologic development. Although the fetal thyroid does not begin to
function until approximately 12 weeks gestation, T3 is present in the fetal
brain by 7 weeks [2729]. It is thought that this T3 originates from intracellular deiodination of transplacentally transferred maternal T4 [29]. An association between maternal hypothyroidism and impaired cognitive function
among ospring was rst described in the 1960s [30]. Investigators compared the results of several neuropsychological testing parameters between
children born to mothers who were hypothyroid (TSH O 98th percentile)
and euthyroid (TSH ! 98th percentile) at 17 weeks gestation [14]. After
correcting for socioeconomic factors, the 62 children born to hypothyroid
mothers scored an average of 4 points lower (P .06) on the Wechsler Intelligence Scale for Children (full-scale IQ test) compared with controls. The
decrease in IQ was more signicant (7 points; P .005), when only the children of untreated hypothyroid mothers (48 children) were compared with
the control group. Because the IQ scores of the children born to levothyroxine-treated hypothyroid mothers (14 children) did not dier from controls,
the authors hypothesized that perhaps rst-trimester maternal thyroid hormone levels were adequate earlier in gestation when the fetal need may have
been greatest [14]. Pop et al [31] performed a similar study in which they
121
compared development between children born to women with hypothyroxinemia (free T4 % 10th percentile) and normal serum TSH concentrations
(! 2.2 mU/L) at gestational week 12 with children of controls (free T4
50th90th percentiles and normal TSH). They found a signicant delay in
mental and motor development for 1-year-olds and 2-year-olds born to
the women with hypothyroxinemia. Infants of mothers with hypothyroxinemia at 12 weeks that normalized during pregnancy did not dier signicantly
from controls. In addition, infants in the control group whose mothers became hypothyroxinemic after 12 weeks of gestation did not show impaired
development [31]. The potential inuences of iodine nutrition and other maternal comorbidities were not addressed in this study. Although the relative
contribution of maternal versus fetal thyroid hormone to neurologic development is not fully understood, these ndings suggest that maternal hormone is important during the rst trimester, before the fetal thyroid gland
begins to function, and later in gestation.
Treatment
The treatment of hypothyroidism during pregnancy depends on the timing of diagnosis, the severity of disease, and possibly the cause of thyroid
dysfunction (Box 1). The starting levothyroxine dose for women with overt
hypothyroidism should be 2 mg/kg/d ) [12]. This dosage is higher than that
required for full replacement in nonpregnant patients and accounts for the
increased thyroidal demand of normal pregnancy. If the initial serum TSH
level is only slightly elevated (ie, TSH ! 10 mU/L), an initial dose of 0.1
mg/d of levothyroxine may be sucient [32].
The likelihood that hypothyroid women who receive levothyroxine replacement will need a dosage increase may depend on the cause of their thyroid dysfunction. In one study, 76% of hypothyroid women versus 47% of
women with Hashimotos thyroiditis required an increase in levothyroxine
dosage during pregnancy [2]. In addition, because women with Hashimotos
thyroiditis may have residual thyroid function that can respond partially to
the stimulatory eects of pregnancy, they require a smaller mean dosage increase (25%) than hypothyroid women (45%) [2].
As previously discussed, the stimulatory eects in pregnancy begin early
in the rst trimester and persist until delivery. Maternal requirements must
be monitored closely throughout gestation. A serum TSH level should be
checked as soon as pregnancy is conrmed. In a prospective study, the median time for dosage increase was 8 weeks gestation [1]. In addition, 25% of
women with a normal TSH concentration during the rst trimester and 37%
with a normal TSH in the second trimester eventually require an increase
in levothyroxine dosage [2]. Women with a serum TSH level less than
2.5 mU/L at initial screening should have their thyroid function re-evaluated
every 3 to 4 weeks during the rst half of pregnancy and every 6 weeks during the latter half.
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Box 1. Guidelines for clinical management of maternal

hypothyroidism during pregnancy
1. Check serum TSH level as soon as pregnancy is confirmed.
2. For newly diagnosed hypothyroid women, initial
levothyroxine dosage is based on severity of hypothyroidism.
For overt hypothyroidism, administer 2 mg/kg/d. If TSH is
< 10 mU/L, initial dose of 0.1 mg/d may be sufficient.
3. For previously diagnosed hypothyroid women, monitor
serum TSH every 34 weeks during first half of pregnancy and
every 6 weeks thereafter.
4. Adjust levothyroxine dosage to maintain serum TSH
2.5 mU/L.
5. Monitor serum TSH and total T4 levels 34 weeks after
every dosage adjustment. When levothyroxine dosage
achieves equilibrium, resume monitoring TSH alone.
6. Levothyroxine ingestion should be separated from prenatal
vitamins containing iron, iron and calcium supplements,
and soy products by at least 4 hours to ensure adequate
absorption.
7. After delivery, reduce levothyroxine to prepregnancy
dosage, and check serum TSH in 6 weeks.
Levothyroxine dosage should be adjusted to maintain a maternal serum

TSH concentration 2.5 mU/L or less [12]. Kaplan [2] proposed a set of
guidelines for adjusting levothyroxine replacement according to the elevation in serum TSH:
1. Serum TSH concentration ! 10 mU/L, increase 0.05 mg/d.
2. Serum TSH concentration 1020 mU/L, increase 0.075 mg/d.
3. Serum TSH concentration O 20 mU/L, increase 0.1 mg/d.
Thyroid function should be re-evaluated by serum TSH and total T4
measurements 3 to 4 weeks after every change in dosage. The normal range
for total T4 concentrations during pregnancy is 1.5 times the nonpregnant
range [12]. When a levothyroxine dosage equilibrium has been achieved,
a clinician may resume monitoring maternal thyroid function with serum
TSH concentrations alone. As with all patients on levothyroxine therapy,
pregnant women should be instructed to separate dosage ingestion from prenatal vitamins containing iron, iron and calcium supplements, and soy products by approximately 4 hours to ensure adequate absorption. In addition,
for adequate iodine nutrition, it is important to check that the prenatal vitamin contains the recommended daily requirement for pregnancy (220 mg/
day) [33]. Women should resume their prepregnancy levothyroxine dosage
123
immediately after delivery and have their serum TSH level re-evaluated in 6
weeks.
Euthyroidism with autoimmune thyroid disease

The prevalence of thyroid autoimmunity among euthyroid women of
childbearing age is quite high. According to data from the third National
Health and Nutrition Examination Survey, 12.6% and 13.6% of women
39 years old or younger, without known thyroid disease, tested positive
for thyroperoxidase (12.6%) and thyroglobulin (13.6%) antibodies [34].
These women may be at an increased risk for several pregnancy-related
complications, including spontaneous miscarriage, subclinical hypothyroidism, and postpartum thyroiditis [35]. (Postpartum thyroiditis is not discussed in this article.)
A meta-analysis of 10 prospective studies of euthyroid women revealed
that women with antithyroid antibodies were more than twice as likely to
experience a miscarriage (odds ratio 2.30; 95% CI 1.802.95) [36]. The presence of these antithyroid antibodies is not associated with that of other organ-specic antibodies [37]. Although the nature of the association between
thyroid autoimmunity and increased incidence of miscarriage is unknown,
several possible hypotheses exist. Some investigators believe that the presence of antibodies signies a generalized heightened autoimmune state
that adversely aects the fetoplacental unit [36]. Others speculate that the
link is related to subtle hypothyroidism among aected women [35].
Euthyroid women with thyroid autoimmunity may experience an increase
in serum TSH levels during pregnancy compared with controls [35]. Although most of these women likely maintain normal serum TSH concentrations, one study reported that 16% of these women developed subclinical
hypothyroidism during pregnancy based on an elevated TSH [38]. This
study was conducted in a region of borderline iodine suciency and requires
validation. Nevertheless, it suggests that the presence of antithyroid antibodies may signify a lack of thyroidal reserve in response to the stimulatory
eects of pregnancy. The authors recommend initiating levothyroxine therapy in women with antithyroid antibodies before pregnancy if the serum
TSH level is greater than 2.5 mU/L. Serum TSH should be monitored
throughout pregnancy in all antithyroid antibodypositive women, with initiation or adjustment of levothyroxine to maintain the TSH concentration at
2.5 mU/L or less.
Hyperthyroidism
The prevalence of hyperthyroidism during pregnancy ranges from
0.1% to 0.4%, with Graves disease accounting for 85% of cases [32,39].
Single toxic adenoma, multinodular toxic goiter, and subacute thyroiditis
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constitute most of the remaining cases during pregnancy, whereas exogenous thyroid hormone and hydatidiform molar disease are extremely rare
[40].
Gestational thyrotoxicosis and hyperemesis gravidarum

As discussed previously, research strongly suggests that the high serum
concentrations of hCG during early pregnancy activate the TSH receptor
[5,11,41,42]. The stimulatory eect of hCG results in a wide spectrum of
clinical scenarios ranging from a slight decrease in maternal TSH concentration (18% of women without thyrotoxic symptoms) [13] to transient thyrotoxicosis, known as gestational thyrotoxicosis (elevated serum free T4 and
suppressed serum TSH levels).
Hyperemesis gravidarum is a syndrome aecting some pregnant women
and is dened by severe nausea and vomiting leading to a 5% loss of body
weight, dehydration, and ketosis. Of women with hyperemesis gravidarum,
60% have a subnormal serum TSH level (! 0.4 mU/L), and nearly 50%
have an elevated serum free T4 concentration [43]. In addition, the severity
of symptoms experienced by a woman with hyperemesis gravidarum is positively correlated with maternal free T4 levels [43]. Despite the apparent correlation, hyperemesis gravidarum does not seem to be directly related to
thyroid function. Only 12% of such women have an elevated free T3 index
[43]. Some investigators believe that another compound stimulated by the
increased concentrations of hCG (eg, estradiol) may be the causative agent
[43]. Whether symptomatic or not, gestational thyrotoxicosis usually resolves spontaneously by 20 weeks gestation when hCG declines. Treatment
with antithyroid medications is generally not necessary. If gestational thyrotoxicosis continues beyond 20 weeks, a repeat evaluation for other causes of
hyperthyroidism should be considered.
Graves disease
Graves disease is the most common cause of hyperthyroidism during
pregnancy [32,39]. Similar to other autoimmune diseases, the activity level
of Graves disease may uctuate during gestation, with exacerbation during
the rst trimester and gradual improvement during the latter half. Patients
with Graves disease also may experience an exacerbation shortly after delivery [44]. With this possibility in mind, there are several dierent clinical
scenarios by which a woman may present with Graves disease during pregnancy. First, a woman with stable Graves disease receiving thionamide
therapy may experience an exacerbation during early pregnancy. Second,
a woman in remission may experience a relapse of disease. Lastly, a woman
without prior history may be diagnosed with Graves disease de novo during
pregnancy.
125
Diagnosis
The diagnosis of Graves disease may be dicult to make clinically because of the presence of hypermetabolic symptoms in normal pregnancy,
such as palpitations, irritability, and heat intolerance. The thyroid examination is often dierent from that of normal pregnancy, hyperemesis gravidarum, and gestational thyrotoxicosis. Women with Graves disease usually
have a goiter (with or without bruit), but the accompanying autoimmune
syndromes of ophthalmopathy and possibly dermopathy are still quite rare.
Laboratory studies also are helpful, revealing a suppressed serum TSH
level and usually elevated free and total T4 serum concentrations. As described previously, however, 60% of women with hyperemesis gravidarum
have a subnormal serum TSH, and nearly 50% have an elevated serum
free T4 concentration [45]. In situations in which doubt exists, measurement
of serum total T3 concentration and T3 resin uptake may be helpful because
only 12% of women with hyperemesis gravidarum have an elevated free T3
index [45]. Finally, TSH receptor antibodies are usually present with
Graves disease and may aid in conrming the diagnosis.
Pregnancy outcome
The risk of complications for the mother and the child is related to the
duration and control of maternal hyperthyroidism. The highest incidence
occurs in cases with the poorest control, and the lowest incidence occurs
in cases with adequate treatment [40,4648]. The frequency of preterm labor
is highest among untreated mothers (88%) compared with partially treated
mothers (25%) and adequately treated mothers (8%) [46]. In addition, untreated women are twice as likely to develop preeclampsia during pregnancy
than women receiving antithyroid medication [40]. As for the fetus, stillbirth
is much more common among untreated women (50%) than either partially
treated women (16%) or adequately treated women (0%) [46]. Finally, studies have indicated that children born to mothers with uncontrolled hyperthyroidism are more likely to be small for gestational age and to have
congenital malformations unrelated to thionamide therapy [47,48].
Treatment
The most important thing to remember when treating Graves disease
during pregnancy is that two patients are involved, the mother and fetus.
The goal of therapy is to control maternal disease, while minimizing to potential for fetal hypothyroidism and hyperthyroidism (Box 2).
Thionamides
Thionamide antithyroid drugs, propylthiouracil (PTU) and methimazole
(MMI), are the mainstay of treatment of Graves disease during pregnancy.
These medications decrease thyroid hormone production by inhibiting
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LEBEAU & MANDEL
Box 2. Guidelines for clinical management of maternal

hyperthyroidism during pregnancy
1. Use the lowest dosage of thionamide (preferably PTU) to
maintain maternal total T4 concentrations in the upper one
third of normal to slightly elevated range for pregnancy.
Normal range of total T4 during pregnancy is estimated
to be 1.5 times the nonpregnant state [46].
2. Monitor maternal total T4 serum concentration every 24
weeks, and titrate thionamide as necessary. Monitoring
serum TSH may become useful later.
3. Measure TSH receptor antibodies (thyroid-stimulating
immunoglobulins or TSH receptor binding inhibitory
immunoglobulins) at 2628 weeks to assess risk of
fetal/neonatal hyperthyroidism. TSH receptor antibody
measurement is crucial in hypothyroid levothyroxine-treated
women with a prior history of Graves disease, who do not
appear thyrotoxic.
4. Perform fetal ultrasound at weeks 2628 to assess potential
fetal response to thionamide treatment and effect of TSH
receptor antibodies on fetal thyroid function.
5. Consider thyroidectomy if persistently high doses of
thionamide (PTU > 600 mg/d or MMI > 40 mg/d) are required,
or if the patient cannot tolerate thionamide therapy.
6. b-Adrenergic blocking agents and low doses of iodine
may be used perioperatively to control hyperthyroid state.
7. Check fetal cord blood at delivery for TSH and T4.
iodine organication and iodotyrosine coupling by thyroidal peroxidase. A

study found the median time to normalization of maternal thyroid function
to be 7 weeks with PTU and 8 weeks with MMI [49].
Although equally eective, concern exists regarding a possible dierence
in the transplacental passage of the thionamides. PTU is known to be more
highly bound to albumin than MMI [32]. This fact has led some authors to
theorize that MMI crosses the placenta in higher concentrations and may
place the fetus at greater risk of hypothyroidism. Convincing evidence of
this phenomenon has not been established. One study of six women, without
thyroid disease, receiving a single injection of either sulphur-35 [35S]-PTU or
[35S]-MMI before therapeutic abortion in the rst half of pregnancy, revealed that PTU may cross the placenta to a lesser degree than MMI [50].
A perfusion study conducted on placental tissue from women without thyroid disease, undergoing cesarean section at term, revealed similar placental
transfer kinetics for PTU and MMI [51].
127
To minimize the occurrence of fetal hypothyroidism, the clinician must

assume that both thionamides cross the placenta. Data concerning a correlation between maternal antithyroid drug dosage and fetal thyroid function
are conicted, however. Three studies [47,52,53] reported a direct relationship between maternal dosage and fetal function, whereas four studies
[5457] showed a lack of correlation. The most recent study reported that
21% of the neonates born to mothers taking less than 100 mg of PTU daily
and 14% of neonates born to mothers taking less than 10 mg of MMI daily
still had an elevated serum TSH level at birth [57].
The lack of correlation between maternal thionamide dosage and fetal
thyroid function is multifactorial. Absorption of antithyroid medications
and serum concentrations are dierent for each mother. Additionally,
each woman with Graves disease has a dierent titer of TSH receptor antibodies. Research has shown a strong correlation between maternal TSH receptor antibodies and fetal and neonatal exposure [28,53,58]. These
antibodies may be either stimulatory or inhibitory; however, most women
with Graves disease possess immunoglobulins that stimulate the fetal thyroid. Stimulation becomes clinically relevant near the end of the second trimester and continues until delivery [27].
In light of the role that TSH receptor antibodies play and the lack of correlation between thionamide dose and fetal thyroid function, it is not surprising that a better means of following therapy exists. Momotani et al
[56] reported that treatment decisions could be made safely according to maternal thyroid status in women not previously treated with ablative therapy.
According to their work, when maternal serum free T4 concentrations were
either slightly elevated or within the upper third of normal, 95% of neonates
had cord free T4 values within the normal range. Conversely, when maternal
serum free T4 concentrations were either within the bottom two thirds of
normal or below the lower limit of normal, 36% and 100% of neonates
had free T4 concentrations below normal [56].
Avoiding fetal hypothyroidism from thionamide treatment of maternal
Graves disease is crucial. Excessive treatment may result in fetal TSH stimulation, goiter formation, and possibly respiratory compromise after delivery owing to tracheal compression. Fetal hypothyroidism resulting from
overtreatment of maternal Graves disease potentially could aect neurocognitive development (see earlier). In addition to following maternal thyroid hormone concentrations, fetal response to therapy should be
evaluated by ultrasound during gestational weeks 26 to 28. If a fetal goiter
is identied, the clinician must determine whether it is due to fetal hypothyroidism or hyperthyroidism (see later). This decision usually can be made
clinically. If the mother is biochemically hyperthyroid and the fetus is tachycardic, fetal hyperthyroidism is more likely [59]. If the mothers serum total
T4 or free T4 values are in the mid-normal to lower range, however, it is
more likely that the fetus is hypothyroid [56]. If the fetal goiter is related
to hypothyroidism, rapid improvement may occur after a decrease, or
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LEBEAU & MANDEL
discontinuation, of thionamide treatment [60]. If improvement is not apparent, consideration should be given to more aggressive diagnostic testing,
such as periumbilical blood sampling, with treatment tailored to the specic
ndings (eg, intra-amniotic levothyroxine therapy for persistent hypothyroidism) [61,62].
Aside from the hypothyroidism, the other potential side eects of thionamide therapy must be considered. The maternal side eects are the same for
any individual taking these medications, the most common being a rash. As
for the fetus/neonate, several cross-sectional studies have found no eect on
cognitive or somatic development among infants exposed to PTU or MMI
[6366]. Several rare birth defects have been observed in neonates born to
mothers taking MMI during pregnancy (eg, aplasia cutis, choanal atresia,
esophageal atresia, and minor dysmorphic features) [67,68]. None of these
ndings has been reported with PTU. The authors prefer PTU as rst-line
therapy. If a woman is unable to tolerate PTU, the authors prescribe
MMI, especially after rst-trimester organogenesis.
Treatment guidelines
The initial dosage of antithyroid medication depends on the severity of
disease. PTU should be used preferentially given the multiple case reports
of congenital defects and dysmorphic features occurring in infants exposed
to MMI [67,68]. If one is allergic or intolerant of PTU, however, MMI
should be substituted (especially after rst-trimester organogenesis) before
recommending thyroidectomy. Antithyroid medication should be titrated
to maintain maternal T4 concentrations within the upper third, or slightly
above, of the normal range for pregnancy. Because pregnancy reference
ranges have not been reported for most free T4 assays, the authors recommend using the serum total T4 concentration for thionamide dose titration.
In addition, the authors adopt a pregnancy reference range for total T4 to be
1.5 times the nonpregnant reference range owing to thyroidal stimulation
during pregnancy (see section on normal gravid thyroid physiology) [15].
Clinicians should re-evaluate maternal thyroid function every 2 to 4 weeks
and adjust thionamide therapy accordingly. Serum TSH levels are not helpful in the management of Graves disease during early pregnancy because of
the lag time that exists between the normalization of thyroid hormones and
TSH, but may be useful later in gestation when the disease is controlled. The
authors do not exceed 600 mg/d of PTU or 40 mg/d of MMI for extended
periods. One should continue to titrate PTU to the lowest possible dose that
maintains control. Graves disease may ameliorate as pregnancy progresses.
As a result, thionamide therapy may be discontinued in 30% of women during the nal weeks of pregnancy [69]. Cord blood testing for TSH and T4
is recommended in all infants born to mothers with active Graves disease.
In addition, to assess the risk for fetal or neonatal hyperthyroidism, measurement of TSH receptor antibodies at 26 to 28 weeks gestation is recommended (see later).
129
b-Adrenergic blockers
b-Adrenergic blockers are used often in the treatment of hyperthyroidism
because of the presence of adrenergic signs and symptoms (eg, tachycardia,
palpitations, and diaphoresis). A retrospective analysis reported, however,
an increased frequency of rst-trimester miscarriages in mothers treated
for 6 to 12 weeks with a thionamide and propranolol (24%) compared
with a thionamide alone (5.5%) [70]. This dierence existed despite similar
thyroid hormone concentrations. Although this was a small study, the authors recommend avoiding b-adrenergic blocking agents if possible in the
rst trimester.
Iodides
Because of past reports of neonatal hypothyroidism after exposure to iodine, its use during pregnancy has been severely limited. Most published
work consists of case reports, however, in which euthyroid mothers were exposed to iodine-rich food, medicine, contrast media, or disinfectant agents
or hyperthyroid mothers were simultaneously treated with iodine and thionamides [71]. A study investigating the use of low-dose iodine (640 mg/d of
potassium iodide) for the treatment of Graves disease during pregnancy revealed improved maternal thyroid function and normal neonatal outcome
[71]. Specically, none of the neonates exposed to potassium iodide exhibited a goiter, and only 6% had an elevated TSH by way of the cord
blood. Although this evidence does not make iodine a rst-line therapy
for pregnant women with Graves disease, it does suggest that low-dose potassium iodide may be considered in special circumstances, such as in preparation for thyroidectomy or in thionamide-intolerant patients refusing
surgery.
Surgery
Subtotal thyroidectomy for the treatment of Graves disease during pregnancy is reserved for specic situations: when persistently high dosages of
thionamides (PTU O 600 mg/d, MMI O 40 mg/d) are required to control
maternal disease, if a patient is allergic or intolerant of both thionamides, if
a patient is noncompliant with medical therapy, or if compressive symptoms
occur in the mother because of goiter size [32]. Historically, it has been
recommended that surgery occur during the second trimester, before gestational week 24, in an attempt to minimize the risk of miscarriage [59]. Women who are persistently hyperthyroid before surgery should be prepared with
a b-adrenergic blocking agent and a 10- to 14-day course of potassium iodide with the intent of treating the hyperthyroid state and minimizing the
potential for perioperative disease exacerbation.
Radioactive iodine therapy
Radioactive iodine therapy is contraindicated for the treatment of
Graves disease during pregnancy. Fetal tissue is more radiosensitive than
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LEBEAU & MANDEL
adult tissue and may be susceptible to congenital defects during early development [72]. Additionally, the fetal thyroid gland begins to concentrate iodine after gestational week 10, predisposing the fetus/neonate to congenital
hypothyroidism [73,74].
Fetal or neonatal hyperthyroidism

Fetal or neonatal hyperthyroidism occurs in 1% of pregnancies complicated by active or previously ablated Graves disease [75]. In both instances,
hyperthyroidism results from the transplacental passage of maternal TSH
receptor antibodies that stimulate the fetal (or neonatal) thyroid gland.
The passage of immunoglobulins and the potential for fetal hyperthyroidism
become clinically signicant at the end of the second trimester [76].
Commercial assays for thyroid-stimulating immunoglobulins may not be
as helpful as levels of TSH receptor binding inhibitory immunoglobulins.
Thyroid-stimulating immunoglobulin levels greater than 35% and TSH receptor binding inhibitory immunoglobulin levels greater than 40% have
been associated with fetal thyrotoxicosis [53,58,77]. If either antibody titer
is suspiciously high, a careful fetal ultrasound examination should be performed. In the presence of fetal tachycardia and goiter, fetal thyrotoxicosis
should be suspected [59]. The necessity of cordocentesis to conrm the diagnosis in the clinical setting of fetal tachycardia and a mother with either active or previously treated Graves disease is controversial [58,78].
There are two possible clinical scenarios in which fetal Graves disease is
observed. First, a woman may have active Graves disease. In this case, the
maternal thyroid function serves as a biosensor that reects the fetal thyroid. Maternal and fetal thyroid synthetic function are subject to stimulation by the thyroid-stimulating antibodies and inhibition by the maternal
thionamide medication. If the maternal hyperthyroidism is controlled appropriately, fetal thyrotoxicosis should not occur. The second scenario concerns a woman who is hypothyroid on levothyroxine replacement therapy
after either radioactive iodine or thyroidectomy for Graves disease. Although she is still producing thyroid-stimulating antibodies, her thyroid
function tests do not reect their stimulatory inuence. The transplacental
passage of these antibodies still may aect the fetus, however, resulting in
fetal thyrotoxicosis. In this situation, the maternal thyroid does not serve
as a biosensor for the fetal thyroid. The fetal thyroid is exposed only to
the stimulating antibodies without the concomitant inhibitory eect of the
maternal thionamide therapy.
Treatment of fetal hyperthyroidism begins by increasing the dosage of
maternal thionamide if the mother has active Graves disease or initiating
PTU therapy in the case of previously ablated mothers. PTU should be initiated at 150 mg/d and crosses the placenta to inhibit the synthesis of fetal
thyroid hormone. The fetus should be re-evaluated for clinical improvement
131
(heart rate, goiter resolution) by ultrasound in 2 weeks [28]. It is crucial to

remember that although fetal tachycardia is seen with fetal hyperthyroidism,
fetal bradycardia may not be present with fetal hypothyroidism resulting
from overtreatment from maternal PTU. As soon as the fetal heart rate normalizes, the PTU dose should be reduced systemically with frequent monitoring of fetal heart rate to maintain it in the normal range. Many patients
with Graves disease have a continued decrease in thyroid-stimulating antibody production after 32 weeks, and often PTU can be stopped before delivery [44]. For previously ablated hyperthyroid mothers, levothyroxine
therapy may need to be increased if hypothyroxinemia develops while treating fetal hyperthyroidism with PTU.
Although maternal TSH receptor antibody titers usually decline toward
delivery, neonatal thyrotoxicosis still may be observed if the stimulating
antibodies are present in high titers near term [53,58]. Neonatal manifestations of hyperthyroidism may not be apparent until after a few days of life if
a mother was maintained on thionamide treatment until delivery [79]. Affected neonates require antithyroid medication until the maternal antibodies
are cleared from their system at approximately 3 months of age, after which
time, signs of hyperthyroidism resolve, and thyroid function testing normalizes [79].
Thyroid nodules and thyroid cancer

The prevalence of clinically apparent thyroid nodules is higher in women
than in men [80,81]. In addition, the incidence of nodular disease increases
with age to a greater extent in women [8284]. A retrospective study suggested that the increased prevalence of thyroid nodules among women
may be related to pregnancy. The prevalence of nodular disease, as detected
by ultrasonography, was three times as high in women who had experienced
at least one pregnancy compared with women who had never been pregnant
[85]. A more recent prospective study found that the incidence of incipient
thyroid nodules increased from 15% during the rst trimester to 24% 3
months postpartum, whereas existing nodules experienced a signicant
amount of growth during the same time period [86]. Despite the increase
in thyroid nodule formation and growth, there is no evidence to suggest
that thyroid cancer arises de novo more frequently during pregnancy than
in the nonpregnant state.
The evaluation of a thyroid nodule discovered during pregnancy is similar to that of the nonpregnant patient. A laboratory evaluation of thyroid
function should be obtained, keeping in mind normal gravid thyroid physiology. At the same time, sonographic evaluation should be performed to
characterize the nodule further, and a subsequent ne-needle aspiration
should be performed (with or without ultrasound guidance) if indicated
[87]. The spectrum of cytologic results is the same as in the nonpregnant
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LEBEAU & MANDEL
state [88]. Nodules with benign cytology should be observed and followed by
an endocrinologist after delivery. Nodules with cytologic ndings consistent
with follicular neoplasm may require further evaluation after delivery with
radioactive iodine imaging, which is contraindicated during pregnancy,
and possibly surgery. If the ne-needle aspiration cytology is consistent
with thyroid cancer, surgery is recommended. Currently, there is no consensus on the appropriate timing of surgery. Some experts recommend operating during the second trimester, before 24 weeks gestation, to minimize the
risk of miscarriage [21]. Thyroid cancer discovered during pregnancy is not
more aggressive, however, than that diagnosed in a similar aged group of
nonpregnant women, leading other experts to advocate postponing denitive surgery until after delivery in most patients [89,90]. A retrospective
study of pregnant women with dierentiated thyroid cancer found there
to be no dierence in either recurrence or survival rates between women operated on during or after their pregnancy [90].
The authors have adopted a clinical practice inuenced by both schools
of thought. If a malignant nodule is discovered early in pregnancy, it should
be monitored with repeat ultrasound at midtrimester. If the nodule has
grown signicantly, surgery should be considered with the assistance of an
experienced anesthesiologist. Postoperative radioactive iodine therapy, if indicated, must be delayed until after the delivery. Conversely, if the nodule
size is stable, or the malignancy is not discovered until the second half of
pregnancy, surgery can occur after the patient has delivered. In all women
with cytology indicative of papillary thyroid cancer, regardless of surgical
timing, levothyroxine suppression therapy should be initiated to maintain
the serum TSH in the subnormal, but detectable, range (ie, 0.10.3 mU/L).
In addition, women with previously diagnosed or treated dierentiated
thyroid cancer require an increased levothyroxine dosage during pregnancy.
The recommended schedule for serum TSH testing is the same as that outlined for hypothyroid women (see Box 1). The authors adopt a therapeutic
target for serum TSH of 0.1 to 0.8 mU/L for patients with papillary or follicular thyroid cancer, depending on their risk of recurrence, and less than
2.5 mU/L for patients with medullary thyroid cancer.
Summary
Thyroid disorders are common among pregnant women. Diagnosis of
thyroid dysfunction is complicated, however, by nonspecic symptoms,
the hypermetabolic state of pregnancy, and normal gravid thyroid physiology, which results in alterations of maternal serum TSH and thyroxine concentrations. If untreated, hypothyroidism and hyperthyroidism may
adversely aect the mother and fetus. In cases of primary hypothyroidism,
maternal serum TSH concentrations should be monitored throughout pregnancy, and the levothyroxine dosage should be adjusted to maintain
133
maternal serum TSH levels at 2.5 mU/L or less. Conversely, in cases of true
hyperthyroidism (e.g., Graves disease), maternal thyroid function should be
evaluated every 2 to 4 weeks, and thionamide therapy (preferably PTU)
should be given, titrated to achieve maternal serum total T4 concentration within the upper one third of normal to slightly elevated range for pregnancy. Fetal ultrasonography and measurement of maternal serum TSH
receptor antibody concentrations should be employed to prevent fetal/neonatal complications. Finally, the evaluation of nodular thyroid disease and
cancer is similar in pregnant and nonpregnant patients. Use of radioactive
iodine is contraindicated during pregnancy, however, and should be postponed until after delivery.
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35 (2006) 137155
Fertility in Polycystic Ovary Syndrome

Shrita M. Patel, MDa, John E. Nestler, MDb,*
a
Division of Endocrinology, Diabetes, and Metabolism, Center for Clinical Epidemiology

and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
b
Division of Endocrinology and Metabolism, Department of Internal Medicine,
Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA
Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in the United States, aecting 5% to 10% of women of reproductive age [1,2]. It is typically characterized by hyperandrogenism and
chronic anovulation. Hyperandrogenism may present as hirsutism, acne, or
male-pattern alopecia. Anovulation manifests as irregular menstrual cycles,
usually amenorrhea or oligomenorrhea, and infertility [3]. In the past, abnormally regulated luteinizing hormone (LH) levels alone were believed to
account for these symptoms. However, recent evidence suggests that hyperinsulinemic insulin resistance plays a pathogenic role in PCOS by increasing
circulating ovarian androgen concentrations, perhaps via P450c17a stimulation [4,5], thus impeding ovulation [68]. Obese as well as lean women with
PCOS manifest insulin resistance independent of fat mass [6,9]. Presumably
as a result of their insulin resistance, women with PCOS have also been
found to be at increased risk for the development of type 2 diabetes mellitus
[10], dyslipidemia [11], and possibly cardiovascular disease.
The presence of hyperinsulinemic insulin resistance in PCOS creates an
interesting paradox because peripheral tissues, such as skeletal muscle, are
resistant to insulin in terms of glucose metabolism, whereas the ovary remains sensitive to insulin with regard to stimulation of testosterone biosynthesis, suggesting tissue-specic dierences in insulin sensitivity. The exact
underlying mechanism of insulin resistance in PCOS remains poorly characterized. Although recent studies have implicated a post-insulin receptor
* Corresponding author. Division of Endocrinology and Metabolism, Department of

Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, PO Box
980111, Richmond, VA 232980111.
E-mail address: nestler@hsc.vcu.edu (J.E. Nestler).
doi:10.1016/j.ecl.2005.09.005
endo.theclinics.com
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PATEL & NESTLER
defect as the likely mechanism [1215], further work must be done to elucidate a specic target. Of note, attention is concurrently being focused on the
possibility of PCOS as a genetic disorder, expressing itself only after interaction with other environmental factors [1618].
Infertility treatment in polycystic ovary syndrome

Seventy-ve percent of women with PCOS suer from infertility, which is
primarily related to anovulation and a high rate of early miscarriage [19].
Several modalities are available to restore ovulation in aected women.
Therapeutic options target direct and indirect stimulation of the ovaries
by follicle-stimulating hormone (FSH) and, more recently, amelioration of
insulin resistance.
In obese women with PCOS, weight loss as a means of improving insulin
sensitivity is often a primary goal because loss of 5% to 10% of body weight
over 6 months is sucient to re-establish ovarian function in more than
50% of patients [19]. Unfortunately, weight loss is dicult for many patients, and it is even more dicult to maintain. Furthermore, lean patients
with PCOS do not benet from such measures. Therefore, drug therapy is
often warranted in most patients with PCOS.
Clomiphene citrate, an indirect stimulator of FSH secretion, has long been
used to treat anovulatory infertility in women with PCOS. Ovulation is restored in approximately 80% of patients who are given clomiphene, approximately half of whom become pregnant, usually within the rst three cycles of
treatment [19]. The apparent discrepancy between ovulation and pregnancy
rates may be explained by clomiphenes antiestrogenic eects at the level of
the endometrium and cervical mucus, perhaps preventing spermatic penetration and embryonic implantation. Alternatively, recent evidence suggests
that insulin resistance may adversely aect expression of endometrial cellsurface proteins involved in implantation and maintenance of pregnancy
[20], irrespective of clomiphene treatment. Nevertheless, clomiphene is
a safe oral medication with few adverse eects other than an increased multiple pregnancy rate [21]. For those who do not respond to clomiphene,
adjuvant therapy with dexamethasone has proven benecial by way of suppressing adrenal androgen secretion and reducing LH levels [22]; however,
side eects of long-term glucocorticoid use often make it unappealing.
Another option for infertility treatment is direct gonadotropin therapy
with FSH. The current approach uses a low-dose step-up protocol that,
when compared with conventional dosing, yields an improved pregnancy
rate while signicantly decreasing the incidence of multiple pregnancies
and the ovarian hyperstimulation syndrome (OHSS) [19]. Although clinically
eective, this approach requires a high degree of skill, extensive hormone
and ultrasound monitoring, low tolerance of multiple follicles, and high
cost [21]. Multiple cycles of therapy may be required.
FERTILITY IN POLYCYSTIC OVARY SYNDROME
139
Aside from weight loss, other therapies for anovulatory infertility that
target insulin resistance have become widely popular in recent years because
of the growing recognition that insulin resistance likely hampers fertility and
decreases the ecacy of other pharmacologic therapies in PCOS. Of the
insulin-sensitizing drugs, metformin, an oral biguanide used to treat type
2 diabetes mellitus, is the most comprehensively evaluated drug, with proven
eectiveness in lean as well as obese women with PCOS [4,5,23]. An
improvement in insulin sensitivity and reduction in circulating insulin by
metformin may enhance ovulation in PCOS by decreasing intraovarian concentrations of androgens, normalizing gonadotropin secretory dynamics, or
a combination of these and other processes.
The ecacy of metformin monotherapy in promoting ovulation and
fertility in PCOS was recently conrmed in a meta-analysis by Lord and
colleagues [24]. The meta-analysis consisted of 13 randomized controlled
clinical trials that included 428 women with PCOS. Ovulation was achieved
in 46% of women with PCOS who received metformin compared with 24%
who received placebo (odds ratio [OR] 3.88, 95% condence interval [CI]:
2.256.69) [24]. Subsequently, a pilot study comparing metformin and lifestyle modication showed no dierence in ovulation rates between the
two groups; however, the study had a 39% dropout rate, potentially biasing
the results [25]. A further study showed that the addition of metformin to
a hypocaloric diet in obese women with PCOS resulted in improvement in
menstrual irregularity when compared with the placebo and hypocaloric
diet arm [26]. Similarly, in clomiphene-resistant patients, the combination
of clomiphene and metformin has been shown to improve ovulation [27]
and pregnancy rates [24,28] when compared with clomiphene alone.
Newer insulin sensitizers known as the thiazolidinediones (TZDs) have
also received attention with regard to their potential role in the treatment
of PCOS. Troglitazone, the rst drug of this class, has been shown to improve ovulation rates, hyperandrogenemia, and insulin resistance compared
with placebo [29]. Its mechanism of action, although partially systemic, is
also thought to involve direct ovarian action because thecal cells possess
the peroxisome proliferatoractivated receptor-g (PPARg) nuclear receptors that these drugs target. In thecal cell cultures, troglitazone impedes
stimulation of androgen biosynthesis by the combination of LH and insulin [30]. However, troglitazone was withdrawn from the worldwide market
because of hepatocellular toxicity.
Rosiglitazone is another TZD that is commercially available, and it has
also been shown to normalize menses and improve insulin resistance in
women with PCOS [31]. Additionally, when rosiglitazone was administered
to nonobese women who had PCOS with normal insulin sensitivity, ovulation frequency and androgen levels improved compared with placebo even
though insulin parameters did not change [32]. This supports the theory
that TZDs as a class may have direct inhibitory eects on ovarian androgen
biosynthesis. Pioglitazone, the most recently developed TZD, also improved
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PATEL & NESTLER
ovulation frequency, hyperandrogenism, and insulin resistance [33]. When

added to metformin in metformin nonresponders, pioglitazone continued
to improve these parameters [34].
More invasive options exist in case these treatments fail. Laparoscopic
ovarian drilling (LOD) involves puncturing the ovary, ideally in three to
six places, with electrocoagulation or a laser [35], simulating ovarian wedge
resection. LOD most benets lean women who have PCOS with high LH
concentrations [19]. After surgery, LH concentrations fall signicantly. An
advantage of laparoscopy is that tubal patency can be checked simultaneously in a single procedure. Disadvantages include surgical complications
and anesthetic risks. Additionally, concerns have been raised that LOD may
result in adhesions leading to tubal obstruction [21]. Similar pregnancy rates
were found with LOD after 6 to 12 months of follow-up compared with
three to six cycles of gonadotropin therapy, with a lower incidence of multiple pregnancies and OHSS with LOD [36]. Notably, when LOD was compared with metformin therapy in clomiphene-resistant women, ovulation
rates were similar between the two groups. Pregnancy, miscarriage, and
live birth rates were signicantly improved in the latter group, however, suggesting an overall superior benet in reproductive outcomes with metformin
therapy [37], perhaps because of the favorable eects of metformin on the
endometrium or oocyte.
In vitro fertilization (IVF) oers a last resort in women with PCOS resistant to these strategies. Although there are some questions regarding oocyte
and embryo quality in women with PCOS as a cause of lower fertilization
rates, some believe that this is compensated for by the increased number
of available oocytes in these women [38]. Also, future therapies such as in
vitro maturation of oocytes and the use of aromatase inhibitors, such as letrozole, are currently being developed [19].
Given these strategies, it is clear that lifestyle modication, clomiphene
citrate, and metformin are safe, eective, and low-cost options for improving fertility in women with PCOS. At present, the optimal initial pharmacologic approach to the treatment of infertility in PCOS is unknown. This
question should soon be answered by the Pregnancy in Polycystic Ovary
Syndrome (PPCOS) study, which is a National Institutes of Health
(NIH)sponsored multicenter, randomized, double-blind clinical trial whose
purpose is to establish which of the following drug regimens results in the
highest live birth rate in women with PCOS: metformin XR, clomiphene,
or the combination of these two drugs.
Insulin resistance and normal pregnancy
Insulin resistance, mediated by human placental lactogen (HPL), progesterone, cortisol, and estradiol in pregnancy, and compensatory hyperinsulinemia increase throughout normal gestation and are maximal in the third
trimester [39]. Corresponding markers of insulin resistance increase as
141
well, including plasma concentrations of triglycerides, small dense low-density lipoprotein (LDL) particles, free fatty acids, plasminogen activator
inhibitor-1 (PAI-1), tissue plasminogen activator antigen (TPA Ag), vascular
cell adhesion molecules (VCAMs), leptin, and tumor necrosis factora
(TNF-a) [39]. Thus, normal pregnancy itself is a state of heightened insulin resistance. Further, in women with PCOS, pregnancy may augment the
preexisting insulin resistance and hyperinsulinemia, resulting in fatal and
nonfatal complications.
Complications of pregnancy in polycystic ovary syndrome

Early pregnancy loss
Early pregnancy loss (EPL), dened as miscarriage of a clinically recognized pregnancy during the rst trimester, occurs in 10% to 15% of normal
women. Women with PCOS, however, suer a threefold higher risk [40].
Multiple studies support this link, many of which initially implicated elevated plasma LH levels as the main culprit [4144]. In one study, long-term
pituitary suppression with a gonadotropin-releasing hormone analogue
(GnRHa) decreased the miscarriage rate in patients with PCOS compared
with gonadotropin treatment alone [45]. A subsequent study by Cliord
and coworkers [46] reported that suppression of endogenous LH release before conception in women with elevated LH levels and a history of recurrent
miscarriage did not improve the live birth rate, however.
Thereafter, investigators turned to alternative hypotheses to explain the
increased risk of EPL in PCOS. One hypothesis involved hyperandrogenemia as a potential risk factor. A retrospective study of women with a history
of recurrent miscarriage found that they had elevated androgen levels compared with normal fertile controls [47]. Further, there were no dierences in
plasma LH levels between the two groups. One possible explanation for the
association between androgen excess and EPL is that high androgen levels
antagonize estrogen and thereby adversely aect endometrial development
and embryonic implantation [47]. This work was supported by a prospective
study that found similar results [48].
Another hypothesis suggested high plasminogen activator inhibitor activity (PAI-Fx) as a risk factor for EPL in women with PCOS. A study of 41
women with PCOS revealed that PAI-Fx positively correlated with the number of miscarriages [49]. Further, PAI-Fx was shown to be an independent
reversible risk factor for miscarriage in women with PCOS, presumably because it induces a hypobrinolytic state causing placental insuciency [49].
Arguably, the most compelling hypothesis has come from research on the
eect of obesity on miscarriage rates. An early retrospective cohort study
found that moderate obesity in women with PCOS, treated with low-dose
gonadotropin, was associated with an increased risk of miscarriage [50].
Subsequently, Fedorcsak and colleagues [51] studied a cohort of 383 lean
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PATEL & NESTLER
and obese women who conceived after IVF or intracytoplasmic sperm injection (ICSI) to determine their miscarriage rates. Obese women were again
found to have an increased risk of EPL (22% versus 12%; P .03) and a decreased live birth rate compared with lean women. Obesity, characterized by
hyperinsulinemic insulin resistance, was shown to be an independent risk factor for EPL [51].
Investigators have examined the eects of insulin-sensitizing drugs on the
rate of miscarriage in PCOS. Glueck and colleagues [52] performed a prospective cohort pilot study of women with PCOS, comparing those treated
with metformin before conception who continued the drug throughout pregnancy with historical controls who did not receive metformin. Results
showed that the rate of rst trimester pregnancy loss was 39% in the historical controls but only 11% in the metformin group. Ten women in the metformin group had had previous pregnancies while not receiving metformin.
In this subcohort, the miscarriage rate decreased from 73% to 10% with the
addition of metformin (P ! .002). Overall, no evidence of teratogenicity
was noted in the metformin group. Before metformin therapy, fasting serum
insulin levels correlated positively with PAI activity (r 0.60, P .004).
Over a median treatment period of 6 months (before conception), a reduction in fasting serum insulin was also positively correlated with a reduction
in PAI activity (r 0.65, P .04), suggesting that hyperinsulinemia and
PAI activity may be closely related; perhaps both can help to explain the etiology of EPL in PCOS.
Glueck and coworkers [53] went on to complete a follow-up prospective
study conrming that EPL decreased from 62% to 26% (P ! .0001) when
women with PCOS continued metformin throughout pregnancy. Again, no
teratogenic adverse events occurred. In this study, PAI activity was again
lower on metformin compared with premetformin entry levels. However,
logistic regression revealed that entry fasting serum insulin was the only signicant variable associated with total (previous and current) rst trimester
miscarriage (OR 1.32 for each 5-mIU/mL increment in insulin, 95% CI:
1.091.60, P .005).
A larger retrospective study of women with PCOS performed by an independent group also showed a decrease in EPL in those who continued metformin throughout pregnancy compared with controls (8.8% versus 42%;
P ! .001) [40]. This trend remained signicant in the subgroup analysis
of women with a prior history of miscarriage. No adverse fetal outcomes
were noted in the metformin group, except for 1 of 62 live births that suffered from achondroplasia, a hereditary condition thought to be unrelated
to metformin. Additionally, those women who remained on metformin
had signicantly decreased serum androgen concentrations and improved
insulin sensitivity during pregnancy compared with controls; both are plausible explanations for the decrease in miscarriage rate.
Given the consistency among these studies, insulin resistance seems to
play an important role in EPL in women with PCOS. It is plausible that
143
insulin resistance with hyperinsulinemia is the inciting event, which in turn

causes hyperandrogenemia and high PAI activity. The resulting abnormal
endometrial development and placental blood ow would then create a hostile environment for fetal growth. Also, insulin resistance is associated with
decreased uterine vascularity [20]. Recent evidence further suggests that hyperinsulinemia decreases levels of glycodelin and insulin growth factor
binding protein-1 (IGFBP-1) [20], two major endometrial proteins. This
has been corroborated in women with PCOS during the rst trimester, implicating endometrial epithelial and stromal dysfunction during peri-implantation and early pregnancy as possible mechanisms for EPL in PCOS [20].
When comparing women with PCOS who experienced EPL with those who
did not have such a history, serum glycodelin was signicantly lower during
gestational weeks 3 through 8 (P ! .02) and serum IGFBP-1 was signicantly
lower during gestational weeks 9 through 11 (P .003) in the former [20].
Aside from being associated with hyperandrogenemia, increased PAI activity, decreased uterine vascularity, and lower serum glycodelin and
IGFBP-1 levels, hyperinsulinemic insulin resistance is most likely also associated with a host of as yet unidentied chemical and hormonal changes
that, together, contribute to EPL in women with PCOS.
In summary, metformin may oer an inexpensive and eective treatment
for EPL in women with PCOS, even in those with a history of EPL. Metformin is a pregnancy class B drug, and thus is not contraindicated in pregnancy.
However, none of the studies to date indicate the duration of time that metformin would need to be administered during pregnancy to prevent EPL, or if
simply conceiving while taking metformin might confer full benet. The latter
idea is supported by the nding of a 50% reduction in miscarriages in women
with PCOS who underwent mock laparoscopy and were then treated with metformin for 6 months, with the metformin being discontinued when a diagnosis
of pregnancy was made, compared with women who underwent LOD and
were then treated with a placebo [37].
Of all the insulin sensitizers, metformin may be the safest option, given
that the TZDs are pregnancy class C drugs. The safety of metformin in pregnancy has come under question, however. Hellmuth and colleagues [54] performed a cohort study of pregnant diabetic women treated with metformin
compared with women treated with sulfonylurea or insulin. They found an
increased incidence of preeclampsia and perinatal mortality in the metformin group. The authors acknowledge that the reference group selected
was not an ideal one, however, because the women in the metformin group
had a signicantly higher body mass index (BMI) and worse diabetes control, both of which predispose to preeclampsia, than the women treated
with sulfonylurea or insulin. In contrast, Glueck and colleagues [55] performed a recent prospective study to assess the growth and motor-social development in 126 live births to 109 women with PCOS, who conceived on
and continued metformin throughout pregnancy. The authors found that
metformin was not teratogenic and did not adversely aect birth length
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PATEL & NESTLER
and weight, growth, or motor-social development in the rst 18 months of

life. Several studies have further substantiated this claim [40,56]. Given
the conicting data, however, randomized controlled trials need to be performed to assess metformins safety prole in pregnancy more denitively.
Gestational diabetes
Gestational diabetes mellitus (GDM), dened as diabetes or impaired
glucose tolerance (IGT) with onset in pregnancy, complicates 3% to 5%
of all pregnancies in the United States [57]. GDM develops because pregnancy induces or aggravates insulin resistance, thus placing stress on pancreatic b-cells which cannot respond appropriately [58]. Alarmingly, the yearly
cumulative incidence of GDM increased between 1991 and 2000, independent of changes in age and ethnicity [59].
Up to 80% of obese and 30% of lean women with PCOS demonstrate
insulin resistance before conception, and as many as 30% are aected by
IGT later in life [9]. Because of relative infertility, women with PCOS frequently conceive at an older age, which is another risk factor for GDM
[58]. Because women with PCOS have multiple risk factors for GDM and
its subsequent complications, the existence of a possible association between
these clinical entities has been investigated.
A prospective cohort study by Lanzone and coworkers [60] followed 12
women with PCOS who became pregnant after FSH therapy. None of the
women had IGT or diabetes at baseline. At 23 to 29 weeks of gestation,
a 100-g oral glucose tolerance test (OGTT) was performed on all patients.
According to OSullivans criteria, 3 patients developed IGT and 2 developed GDM; all these women had a history of pregestational hyperinsulinemia. Further, the severity of hyperglycemia seemed to be related to the
degree of pregestational insulin secretion [60]. The study supported the hypothesis that women with PCOS and pregestational hyperinsulinemia are at
increased risk of IGT and GDM and also suggested that there may exist
a dose-response relation between the level of pregestational hyperinsulinemia and subsequent degree of glycemic dysfunction.
Holte and colleagues [61] went on to characterize potential dierences between women who had a 3- to 5-year history of GDM and those with uncomplicated pregnancies, who were matched for age and delivery date.
Polycystic ovaries, diagnosed by ultrasound, were found in 41% of the
GDM group versus 3% of the control group (P ! .0001). Hirsutism and
irregular menstrual cycles were also more common in the GDM group.
A subgroup analysis of the GDM subjects allowed investigators to determine if signicant dierences existed between women with polycystic ovaries
compared with those with normal ovaries. BMI was similar between the two
groups; however, truncal obesity was higher in the polycystic ovary group.
No dierences in gestational age at delivery, birth weight of the ospring, or
mode of delivery between the groups were found. Also, glycemic responses
145
during OGTTs or intravenous glucose tolerance tests during pregnancy were

similar. Women with polycystic ovaries showed greater insulin responses
during these tests compared with women with normal ovaries, however.
Based on the insulin and glucose measurements, the polycystic ovary group
demonstrated insulin resistance as the primary problem during the index
pregnancy, whereas the normal ovary group demonstrated b-cell dysfunction. Additionally, women with polycystic ovaries had higher plasma androstenedione, testosterone, and free androgen index (FAI) levels
independent of BMI and age. Thus, among women with prior GDM, those
with polycystic ovaries formed a distinct subgroup that may be more prone
to developing various features of the metabolic syndrome compared with
women with normal ovaries [61].
A similar study was performed, this time matching the GDM group and
controls for age and BMI, which conrmed that polycystic ovaries diagnosed by ultrasound were more common in women with a history of
GDM [62]. Of note, by using polycystic ovaries as a surrogate for PCOS,
both studies may have overestimated the true prevalence of PCOS in
GDM because polycystic ovaries can be found in normal ovulatory women.
Thereafter, investigators interest in the relation between PCOS and
GDM increased. Radon and coworkers [63] performed a retrospective cohort study of GDM in women with PCOS, comparing them with age- and
weight-matched controls. The authors showed that GDM developed in
41% of women with PCOS versus 3% of controls (OR 22.2, 95% CI:
3.8170), but no comparison had been performed with regard to the ability
of obesity or PCOS to predict GDM independently. Mikola and colleagues
[64] performed a retrospective cohort study of GDM and preeclampsia in
women with PCOS compared with an unselected control population and
found that GDM developed in 20% of women with PCOS versus 8.9% of
controls (P ! .0001). After logistic regression analysis, however, BMI greater
than 25 kg/m2 was found to be the strongest predictor of GDM, whereas
PCOS remained a lesser but still independent predictor. This information suggests that the intrinsic insulin resistance of PCOS, which is independent of
body weight, may explain the increased risk of GDM in patients with PCOS
[64]. This idea was supported by Urman and coworkers [65] who found that
even when lean patients with PCOS were compared with lean controls, the incidence of GDM remained signicantly higher in patients with PCOS.
To clarify further the eect of insulin resistance on the development of
GDM, Bjercke and colleagues [66] prospectively followed women with
PCOS, grouped by insulin resistance status, and normal controls. GDM
was again more frequent in women with PCOS compared with controls
(7.7% versus 0.6%; P ! .01). Surprisingly, however, the development of
GDM in women with PCOS was independent of pregestational insulin
resistance status. Given the small sample size (23 insulin-resistant and 29
non-insulin-resistant women with PCOS), the authors may have missed a
dierence if one truly existed. Conversely, if no dierence in GDM existed
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PATEL & NESTLER
between those with and without pregestational insulin resistance, one might
consider other determinants of PCOS as possible explanations.
The hypothesis that PCOS is associated with GDM has not been supported by all studies. For example, a retrospective cohort study by Haakova
and coworkers [67] compared pregnant women with PCOS with age- and
weight-matched pregnant controls and found no statistical dierence in
the development of GDM. Nevertheless, consistency among many studies
combined with their large magnitudes of eect is supportive evidence in favor of insulin resistance causing women with PCOS to be at increased risk
for developing GDM. This eect has been noted independent of age and
BMI. Several reports prospectively document insulin resistance preceding
GDM, implying a cause-eect relation. Further, the association is biologically feasible because insulin resistance is the main oender implicated in
type 2 diabetes mellitus.
Consequences of GDM are signicant and include the long-term risk of
developing diabetes later in life as well as signicant immediate perinatal
risks, including macrosomia, hypoglycemia, stillbirth, jaundice, and respiratory distress syndrome. Rates of birth trauma and cesarean section are also
increased. Another potential complication is the development of pregnancyinduced hypertensive disorders (PIHDs), such as preeclampsia and gestational hypertension. A recent case-control study examined this relation
and found that women with GDM have a 1.5-fold increased risk of developing PIHDs [68]. Ethnicity was found to modify the association, with the
greatest risk existing among black women [68].
Given the signicant attendant complications, some investigators have
examined potential drug therapy to prevent the onset of GDM in women
with PCOS. One study compared women with PCOS who conceived while
taking metformin and continued taking it throughout pregnancy with
women with PCOS who conceived without metformin therapy [58]. GDM developed in 3% of the metformin pregnancies compared with 31% of the
nonmetformin pregnancies (OR 0.093, 95% CI: 0.0110.795; P .03).
After adjustment for age at delivery, metformin was associated with a 10fold reduction in GDM in women with PCOS. Further, metformin was
shown to decrease BMI, insulin levels, insulin resistance, and insulin secretion; these eects were maintained throughout pregnancy. Metformin did
not result in any major fetal malformations or fetal hypoglycemia, again
supporting its safety in pregnancy. Nevertheless, the utility of metformin administration to women with PCOS during pregnancy to prevent development of GDM has not been rigorously tested in a randomized clinical trial.
Pregnancy-induced hypertensive disorders
PIHDs complicate 3% to 5% of pregnancies in previously normotensive
women [39] and usually develop during the third trimester. Although hypertension in these women typically resolves by 6 weeks postpartum, they are at
147
increased risk of developing essential hypertension later in life. Gestational

hypertension is diagnosed as elevated blood pressure without systemic
symptoms. Preeclampsia, conversely, is dened by elevated blood pressure
in conjunction with proteinuria (urine protein O300 mg in 24 hours). Other
manifestations associated with preeclampsia include disseminated intravascular coagulation, hemolysis, elevated liver function tests, and seizures [39].
Until now, delivery has been the only denitive treatment, increasing risk to
the newborn. With new insights into the etiology of this spectrum of illnesses, potentially safer alternatives may become available.
The etiology of PIHDs is likely multifactorial, involving immune, genetic,
and placental abnormalities [39]. It has been well described that women with
PIHDs demonstrate an exaggerated hyperinsulinemia relative to normal
pregnancy [6972], suggesting that metabolic abnormalities may also be signicant. For example, Hamasaki and colleagues [71] reported in a prospective cohort study that the relative risk of developing gestational
hypertension in women with hyperinsulinemia compared with normal controls was 1.19 (95% CI: 1.031.38) after adjusting for age, parity, and BMI.
Additionally, preeclampsia has been shown to be associated with insulin resistance and its ensuing metabolic changes, including glucose intolerance,
elevated plasma triglycerides, low high-density lipoprotein (HDL), and increased small dense LDL as well as increased leptin, TNF-a, and PAI-1
[39]. Reduced serum sex hormonebinding globulin (SHBG) levels in the
rst trimester and elevated total and free testosterone adjusted for BMI
are also associated with preeclampsia [39]. It would be reasonable to hypothesize that hyperinsulinemic insulin-resistant women with PCOS may
be at increased risk for PIHDs.
One of the earliest studies to describe a relation between women with
PCOS and preeclampsia was published in 1982 by Diamant and coworkers
[73]. These investigators found the incidence of preeclamptic toxemia to
be 11 fold higher in pregnant patients with PCOS, all of whom conceived after
ovulation induction, compared with a control group. Further, this disorder
occurred more frequently in patients with PCOS compared with anovulatory
patients in whom PCOS was excluded. The investigators concluded that pregnancies after ovulation induction are associated with a higher incidence of hypertensive disorders compared with controls. Of note, this group had no data
on BMI, a potential risk factor for the development of preeclampsia.
Subsequently, a prospective study by Gjonnaess [74] revealed that preeclampsia occurred in 13% of women with PCOS who conceived after
LOD, which was higher than in the general population. When the women
with PCOS were then stratied by weight, however, an increased risk of preeclampsia was found only in the heavier women, and it was concluded that
an increased risk of preeclampsia in women with PCOS was associated with
moderate or severe obesity. However, even women who were mildly overweight demonstrated a 13% incidence of preeclampsia suggesting that
PCOS itself may play some role in the association.
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PATEL & NESTLER
A retrospective case-control study of preeclampsia in women with PCOS

compared with age- and parity-matched controls was performed by de Vries
and colleagues [75]. Although the overall incidence of PIHDs was similar between the two groups, the incidence of preeclampsia in women with PCOS
was 14% compared with 2.5% in controls (P .02). These ndings could
not be explained by obesity because BMI was similar between the groups.
Further, among patients with PCOS, BMI was similar in those with preeclampsia and those without PIHDs. To account for BMI more accurately,
a retrospective cohort study of preeclampsia in women with PCOS compared with age- and weight-matched controls was conducted [63]. In this
study, preeclampsia also occurred more frequently in women with PCOS
than in controls, with a highly signicant OR of 15.0 (95% CI: 1.9
121.5). Although there was a higher degree of parity among the controls,
the former study by de Vries and colleagues [75] had controlled for parity
and maintained a signicant association. These ndings were supported
by Urman and coworkers [65] who found that even when lean patients
with PCOS were compared with lean controls, the incidence of PIHDs remained signicantly higher in the patients with PCOS. Thus, some factor
other than obesity was contributing to the increased risk of preeclampsia
in women with PCOS.
Some experts would argue that dierent ovulation induction methods, or
perhaps ovulation induction itself, may be responsible for the increased risk
of preeclampsia seen in women with PCOS. To address this, de Vries and
colleagues [75] stratied women with PCOS by treatment regimens for ovulation induction and found no relation between the method used and the development of preeclampsia. Additionally, the incidence of preeclampsia was
similar between the patients with PCOS who underwent ovulation induction
compared with those who conceived spontaneously. Further, in the previously cited study by Gjonnaess [74], all women with PCOS conceived without ovulation induction. Another study by Kashyap and colleagues [76]
examined patients with PCOS and infertile controls, all of whom were given
gonadotropin therapy with human menopausal gonadotropin (hMG) for
ovulation induction. Women in both groups had similar age, BMI, parity,
and other gestational hypertension risk factors. Pregnant patients with
PCOS had a 31.8% incidence of gestational hypertension compared with
a 3.7% incidence in the infertile controls (OR 12.1, 95% CI: 1.3566.8;
P .016). Collectively, the evidence suggests that neither type of ovulation
induction method nor ovulation induction itself contributes to the development of PIHDs in women with PCOS. These ndings again support PCOS
as a potential independent risk factor for PIHDs.
In 2002, Bjercke and colleagues [66] prospectively assessed the impact of
insulin resistance on the development of PIHDs in women with PCOS. Controls consisted of women with singleton pregnancies who had conceived after assisted reproduction. Overall, the frequency of gestational hypertension
was signicantly increased in pregnancies in women with PCOS compared
149
with controls (11.5% versus 0.3%; P ! .05), and preeclampsia was found
more frequently among insulin-resistant patients with PCOS than in noninsulin-resistant patients with PCOS (22% versus 7%; P ! .05) and controls. BMI was similar among the insulin-resistant and noninsulin-resistant
women with PCOS. This was the rst prospective study in women with
PCOS to support the association between hyperinsulinemia and PIHDs
proposed earlier by other investigators.
Nonetheless, some of the available data do not support the proposed hypothesis. A study by Mikola and coworkers [64] found no signicant dierence in the incidence of preeclampsia between women with PCOS and
a normal control population. After multiple logistic regression, nulliparity
was the only signicant risk factor for preeclampsia; BMI greater than
25 kg/m2, multiple pregnancy, and PCOS had no predictive value. When
de Vries and colleagues [75] matched cases and controls for parity, however,
women with PCOS maintained a signicant association with preeclampsia.
A more recent study by Haakova and coworkers [67] also retrospectively analyzed the relationship between women with PIHDs and women with
PCOS. Although a trend toward increased PIHDs occurred in the women
with PCOS, no statistically signicant dierence was found when compared
with age- and weight-matched controls.
Clearly, the limited data on the association between PCOS and PIHDs
are conicting. The eects of age, BMI, ovulation induction, and parity
have been studied, however, and the magnitude of association among positive studies remains quite large.
Taken one step further, the impact of insulin resistance in women with
PCOS who develop preeclampsia has also been examined, suggesting a possible mechanistic link. Several reports document hyperinsulinemia or hyperglycemia developing before preeclampsia, providing support for insulin
resistance in disease pathogenesis [69,77,78]. Additionally, insulin resistance
or its associated features have been shown to occur many years after a preeclamptic rst pregnancy [7982]. Persistence of insulin resistance postpartum
further suggests a role for its causality in the development of preeclampsia
[82]. Laivuori and colleagues [83] found an association between preeclamptic
pregnancy and the existence of hyperandrogenemia 17 years after delivery,
suggesting that these women could have had hyperinsulinemic PCOS during
their reproductive years (although all reportedly had normal menstruation)
and may be at risk for its metabolic consequences after menopause.
Several theoretic mechanisms exist whereby hyperinsulinemia could predispose to PIHDs in women with PCOS. For example, hyperinsulinemia
may increase renal sodium reabsorption [84] and stimulate the sympathetic
nervous system [85]. Insulin resistance or associated hyperglycemia may impair endothelial function [86]. Endothelial dysfunction may decrease prostacyclin production [87]. Studies in animal models have shown that androgens
increase vasoconstriction in response to pressors [88] and also decrease the
synthesis of prostacyclin [89], potentially playing a further role in the
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PATEL & NESTLER
development of PIHDs. Interestingly, the plasma total renin level was found
to be higher in normotensive women with PCOS compared with healthy
controls, independent of insulin resistance [90]. Although many possible theories exist, more studies need to be done to conrm a mechanistic link between hyperinsulinemia and preeclampsia.
Preeclampsia may have acute and chronic consequences. Acute problems
primarily revolve around delivery complications and increased perinatal
morbidity. Chronic eects, however, are more dicult to study because
women who develop these problems often have a remote diagnosis of
PIHD that is dicult to ascertain [39]. One study was able to show that
the risk of hypertension is increased almost threefold after 2 to 24 years
of follow-up in women with a history of preeclampsia or eclampsia compared with controls [91]. Other long-term consequences that have been reported include hypertriglyceridemia, hyperuricemia, hyperandrogenemia,
and abnormal brachial artery ow-mediated (endothelium-dependent) dilatation [39], consistent with the eects of insulin resistance.
Given this increase in cardiovascular risk factors, some investigators have
attempted to determine if mortality attributable to cardiovascular causes is
increased among women with a prior history of preeclampsia. One study
found that mortality attributable to cardiovascular causes was increased
among Norwegian women who had preeclampsia and preterm delivery
(ie, severe preeclampsia) compared with preeclamptic women with term delivery or women with preterm delivery alone [92]. Another study found that
women with a discharge diagnosis of preeclampsia were twice as likely to be
admitted to the hospital for or to die from ischemic heart disease compared
with women with uncomplicated pregnancies [93]. These ndings suggest
that preeclampsia may serve as a marker for future cardiovascular disease.
Whether this association is independent of obesity and other predictors of
cardiovascular risk still remains to be seen.
Given the available evidence, it is possible to imagine that interventions
targeted at improving insulin sensitivity may decrease the likelihood of preeclampsia and later life complications, including risk of cardiovascular
events. For instance, weight reduction before pregnancy and avoidance of
excessive weight gain during pregnancy may contribute to improved insulin
sensitivity and decreased risk for developing preeclampsia. When lifestyle
modication cannot be maintained, however, incentive to use insulin-sensitizing drug therapy, such as metformin, may exist. Studies that examine the
eect of metformin on the incidence of preeclampsia and its complications
in women with PCOS are currently needed.
Future directions
In summary, infertility in PCOS has multiple facets (eg, anovulation, decreased implantation), and several treatment options exist including those
that target insulin resistance. Once pregnancy is achieved, however, women
151
are faced with several potential complications, including EPL, GDM, and
PIHDs. All these disorders are potentially linked by their association with
hyperinsulinemia and insulin resistance. Hence, it is notable that preliminary studies suggest that metformin, which is an insulin-sensitizing agent
that is a pregnancy class B drug, may decrease the risk of EPL and GDM
in women with PCOS. Furthermore, given the long-term metabolic consequences of PCOS, including type 2 diabetes, hyperlipidemia, and cardiovascular disease, some experts speculate as to whether administering metformin
during pregnancy may not only prevent pregnancy complications but also
retard or prevent some of these long-term health risks. In fact, the occurrence of EPL, GDM, and PIHDs may be identied as predictors of cardiovascular risk in women with PCOS.
Although it is reassuring that metformin administration during pregnancy
appears to be safe, rigorous randomized controlled trials must be conducted
to conrm metformins ecacy and safety under these conditions before
its use during pregnancy can be recommended.
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35 (2006) 157171
Hypertension in Pregnancy
Caren G. Solomon, MD, MPHa, Ellen W. Seely, MDb,*
a
Divisions of General Medicine and Womens Health, Harvard Medical School,

Brigham and Womens Hospital, Boston, MA, USA
b
Endocrinology, Diabetes, and Hypertension Division, Harvard Medical School,
Brigham and Womens Hospital, Boston, MA, USA
Hypertension complicates 5% to 10% of pregnancies and is a major

cause of maternal and neonatal morbidity and mortality. Pregnancy-related
hypertension has been classied into four categories by the National High
Blood Pressure Education Program Working Group Report on High Blood
Presure in Pregnancy (Box 1) [1]. New-onset hypertension in pregnancy includes preeclampsia and gestational hypertension. The diagnosis of either
condition requires at least measurement of two elevated blood pressures
(R 140 mm Hg systolic or R 90 mm Hg diastolic) in the second half of pregnancy in a previously normotensive woman. Preeclampsia is distinguished
by the presence of proteinuria [2] and often is accompanied by other systemic
manifestations. Proteinuria in pregnancy is formally dened as 300 mg or
more of protein in a 24-hour specimen. If there is insucient time to collect
a 24-hour urine specimen, measurement of protein and creatinine on a timed
urine collection may be used to estimate 24-hour excretion [1]. A dipstick
protein measurement of 2 or greater also may suggest proteinuria in excess
of 300 mg over 24 hours, but this measurement varies with urine concentration and may be unreliable [3]. A denitive diagnosis of gestational hypertension is impossible until the pregnancy is completed because women with
apparent isolated increases in blood pressure initially may develop systemic
disease later. In contrast to the substantial risks (reviewed subsequently)
associated with preeclampsia, women who have only hypertension,
without systemic manifestations, throughout their course tend to do well
in pregnancy.
Hypertensive disorders of pregnancy also include hypertension antedating the pregnancy. Chronic hypertension is dened as a blood pressure
* Corresponding author. Endocrinology, Diabetes, and Hypertension Division, Harvard
Medical School, Brigham and Womens Hospital, 221 Longwood Avenue, Boston, MA
02115.
E-mail address: eseely@partners.org (E.W. Seely).
doi:10.1016/j.ecl.2005.09.003
endo.theclinics.com
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SOLOMON & SEELY
Box 1. Classification of hypertension in pregnancy

Preeclampsia
Systolic blood pressure 140 mm Hg or diastolic blood
pressure 90 mm Hg occurring 20 weeks gestation in
a previously normotensive woman
Proteinuria 300 mg in a 24-hour urine collection
Gestational hypertension
Systolic blood pressure 140 mm Hg or diastolic blood
pressure 90 mm Hg 20 weeks gestation in a previously
normotensive woman, but without proteinuria
Chronic hypertension
Systolic blood pressure 140 mmHg or diastolic blood
pressure 90 mm Hg that is documented < 20th week of
gestation
Preeclampsia superimposed on chronic hypertension
New-onset or greatly increased proteinuria
Sudden exacerbation of hypertension or other signs of
multisystem involvement such as thrombocytopenia or
transaminitis in a woman with prior hypertension
Data from Gifford RW, August PA, Cunningham G. Report of the National High
Blood Pressure Education Program Working group on high blood pressure in
pregnancy. Am J Obstet Gynecol 2000;183:S122.
greater than 140/90 mm Hg before pregnancy or before the 20th week of

gestation. Most women with chronic hypertension do well in pregnancy except when proteinuria or superimposed preeclampsia occurs [4]. It may be
dicult in some cases to distinguish new-onset hypertension from chronic
hypertension; blood pressure typically decreases in the late rst and early
second trimesters, then increases to prepregnancy levels in the third trimester [5]. In women for whom prepregnancy blood pressures are not available,
this return to baseline blood pressure may be misdiagnosed as new-onset hypertension. The possibility of secondary hypertension also should be considered in women with hypertension in pregnancy, particularly when severe. A
history of symptoms or signs suggesting secondary causes (eg, hypokalemia
suggesting hyperaldosteronism or episodic hypertension and symptoms suggesting pheochromocytoma) should prompt further evaluation.
Two severe complications of preeclampsia are (1) the HELLP syndrome,
characterized by the constellation of hemolysis, elevated liver enzymes, and
low platelets, and (2) eclampsia, characterized by the development of seizures.
Both conditions are rare, but associated with a particularly poor prognosis.
HYPERTENSION IN PREGNANCY
159
Clinical manifestations of preeclampsia

Maternal
In addition to the elevated blood pressure and proteinuria required for
the diagnosis of preeclampsia, women with this condition often have signs
or symptoms indicating dysfunction of any of several organ systems, including the renal, gastrointestinal, coagulation, and central nervous systems.
Cardiac complications are rare in preeclampsia, but heart failure may occur,
generally in women with preexisting heart disease.
Renal
Involvement of the renal system is characteristic of preeclampsia, and the
presence of proteinuria is part of the denition of the disorder. Histologically,
the kidneys show glomerular endotheliosis [6] (ie, swelling of the glomerular endothelium resulting primarily from hypertrophy of endothelial and
mesangial cells). With increasing severity of disease, creatinine clearance declines; acute tubular necrosis and frank renal failure may occur. Because in
normal pregnancy, creatinine clearance increases, serum creatinine levels in
the normal range for nonpregnant women (eg, creatinine O 0.8 mg/dL)
may suggest clinically signicant renal dysfunction in pregnancy.
Other manifestations of renal involvement in preeclampsia include reduced urinary excretion of uric acid [7] and calcium [8]. The hypouricosuria
results in serum uric acid levels that, as with creatinine, are often still within
the normal nonpregnant range but are elevated for pregnancy. Hypocalciuria
seems to result from insucient circulating levels of 1,25-dihydroxyvitamin
D3, likely owing to insucient placental 1-hydroxylation of 25-hydroxyvitamin
D3 and relative secondary hyperparathyroidism [9].
Hepatic
Pathologic changes in the liver in women with preeclampsia reect ischemic damage. Transaminase elevations are well described and indicate hepatocellular necrosis. Severe liver involvement occurs as part of the HELLP
syndrome.
Hematologic
Low platelet counts may complicate preeclampsia, along with or as part
of the HELLP syndrome. Microangiopathic hemolytic anemia may be present and is believed to be secondary to endothelial damage. In severe disease,
disseminated intravascular coagulopathy may occur.
Neurologic
The most severe complication of preeclampsia is eclampsia. Headache,
blurred vision, photophobia, or mental status changes may be early signs
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SOLOMON & SEELY
of impending eclampsia, but eclampsia also may occur in the absence of

these manifestations. There are no reliable predictors for development of
eclampsia in women with preeclampsia. Only about 50% of women who
have a seizure have severe hypertension (dened as R 160/110 mm Hg)
[10], and the absence of severe hypertension does not exclude the possibility of seizure.
Fetal/neonatal
Preeclampsia is associated with decreased fetoplacental perfusion, which
frequently results in intrauterine growth restriction and small-for-gestationalage infants. Preeclampsia is one of the leading causes of prematurity because of the frequent need for early delivery in aected women.
Risk factors for preeclampsia
Several risk factors are recognized for the development of preeclampsia
(Box 2) [11,12]. Primiparity is considered one of the most powerful predictors of increased risk, increasing the likelihood of preeclampsia by 5- to
10-fold [13]; a proposed explanation for this observation is that it may represent a maternal immunologic reaction to paternal antigens. Although extremes of age have been suggested to be risk factors for preeclampsia, the
relationship between young age and increased risk for preeclampsia seems
to be explained by the association between younger age and rst pregnancy.
The higher risk that has been observed in older women may be explained at
least in part by other age-related risk factors for preeclampsia, including
obesity and chronic hypertension.
Box 2. Established risk factors for preeclampasia

Primiparity
Prior personal or family history of preeclampsia
Obesity
Hypertension
Diabetes mellitus
Renal disease
Collagen vascular disease
Thrombophilia
Multiple gestation
Data from Roberts JN, Pearson GD, Cutler JA, Lindheimer MD. Summary
of the NHLBI Working Group on Research on Hypertension in Pregnancy. Hypertension Preg 2003;22:10927; and Duckitt K, Harrington D. Risk factors for preeclampsia at antenatal booking: systematic review of controlled studies. BMJ
2005;330:565.
161
Even in the absence of frank obesity, increasing body mass index (BMI) is
associated with increased risk for preeclampsia [13]; similarly, increased
blood pressure even within the normal range is a recognized risk factor
[14]. Black race also may predispose, although the association between black
race and preeclampsia may be explained by the high prevalence of obesity
and chronic hypertension in this population.
Other recognized risk factors for preeclampsia include a prior personal or
family history of preeclampsia [12]. A maternal history of preeclampsia increases the risk of preeclampsia in a womans daughter and her sons female
partner [15]. There may be several susceptibility genes for preeclampsia. Associations have been described between risk for preeclampsia and polymorphisms the genes for factor V Leiden, angiotensinogen, and endothelial
nitric oxide synthase, although these have not been conrmed consistently
in other populations [16]. Conditions linked to preeclampsia, in addition
to preexisting hypertension, include diabetes mellitus, renal disease, collagen
vascular disease [1], and possibly polycystic ovary syndrome [17].
An increased risk of preeclampsia also has been reported in multiparous
women when there is a change in paternity [18], with shorter length of sexual
relationship, and with prior use of barrier contraceptives; these observations
have been suggested to support a possible immunologic cause of the disorder. More recent data have suggested, however, that relationships between
these factors and preeclampsia may be explained by other confounding factors [19]. The risk associated with a change in paternity may be explained by
the length of the interval between pregnancies; longer intervals seem to predispose to preeclampsia regardless of paternity [20].
Women who are current cigarette smokers during pregnancy seem to have
a decreased risk of developing preeclampsia, even after adjustment for BMI
[21]; in contrast, women who stop smoking before pregnancy do not have decreased risk. Possible mediators of the risk reduction associated with cigarette
smoking include increase in nitric oxide production, decrease in thromboxane production, or alteration in cell immunity; better understanding of these
factors might lead to preventive strategies without the hazards of smoking.
Decreased placental perfusion is considered a central feature of preeclampsia (see section on pathophysiology later). Conditions associated
with increased placental size, such as multiple gestation [22], increase the
risk for preeclampsia. The risk for severe preeclampsia was reported to be signicantly greater with triplet pregnancy compared with twin pregnancy [23].
Assessment of risk factors for preeclampsia should be a part of routine
prenatal care. Women who have identied risk factors may benet from
closer surveillance during pregnancy [24].
Pathophysiology of preeclampsia
Despite decades of research, the cause of preeclampsia remains uncertain.
Many theories have been proposed.
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SOLOMON & SEELY
Maternal factors
Endothelial dysfunction is a hallmark of preeclampsia and involves the
placental and systemic circulations [25]. It is unclear whether endothelial
dysfunction is primary (causal) or a secondary manifestation of disease.
Signs of endothelial dysfunction include hypertension, proteinuria, microangiopathic hemolytic anemia, and organ hypoperfusion. Several laboratory
abnormalities consistent with abnormal endothelial function have been observed in women with preeclampsia, including decreased levels of prostacyclin (with an increased ratio of thromboxane to prostacyclin) [26] and
increased levels of endothelin-1 [27] (a growth factor derived from endothelial cells that causes vasoconstriction). Increased pressor responsiveness to
angiotensin II (in contrast to the refractoriness to this substance observed
in normal pregnancy) also is characteristic of preeclampsia.
Insulin resistance is a well-recognized correlate of endothelial dysfunction
and may play a role in the pathogenesis of preeclampsia [28]. In normal
pregnancy, insulin resistance increases with gestation, and insulin resistance
is greater in women with preeclampsia. Studies of women with established
preeclampsia revealed higher levels of insulin and glucose, increased levels
of triglycerides and free fatty acids [29], and elevated levels of cytokines
(eg, tumor necrosis factor-a [30]) associated with the insulin-resistant state.
Although abnormalities observed in cross-sectional studies of preeclampsia could be a result rather than a cause of disease, several of these abnormalities have been shown to precede the development of preeclampsia.
Prospective studies of pregnant women who subsequently developed preeclampsia have shown higher levels of glucose [31], insulin [32], triglycerides,
free fatty acids [33], and tumor necrosis factor-a [34] and lower levels of highdensity lipoprotein [35] and sex hormonebinding globulin [36] than in women
who remain normotensive through pregnancy [28]. More recently, elevated
levels of the cytokine soluble fms-like tyrosine kinase-1(st-1) and lower
levels of placental growth factor (PlGF) were reported to antedate the development of preeclampsia [37]; high levels of st-1 are proposed to antagonize
vasodilatory eects of PlGF-1 and vascular endothelium-derived growth factor, resulting in placental vascular insuciency and other systemic eects.
Follow-up studies of women with a history of preeclampsia have revealed
several metabolic abnormalities, including increased insulin resistance [38]
and abnormal endothelial relaxation [39]. These observations, coupled
with the abnormalities observed in women before the development of preeclampsia, have suggested the importance of underlying maternal factors
and factors specic to the pregnancy in the pathogenesis of disease.
Fetoplacental factors
During normal pregnancy, fetal trophoblasts transform maternal spiral
arteries from resistance muscular vessels to low-resistance vessels by
163
replacing endothelial cells and smooth muscle cells of the media [40]. Several
factors (eg, nitric oxide and vascular adhesion molecules) seem to play a role
in successful trophoblastic transformation. In preeclampsia, the trophoblastic invasion is incomplete such that spiral arteries maintain increased vascular tone, leading to decreased placental perfusion. It is currently uncertain
which mediators of trophoblastic invasion are defective in preeclampsia.
Predictors of preeclampsia
Given the increased maternal and fetal morbidity and mortality associated
with preeclampsia, attempts have been made to identify markers predictive of the development of preeclampsia. Several purported markers (eg,
hyperinsulinemia and hypocalciuria) have been associated with a higher
risk of preeclampsia, but the overlap in levels between women who have
and have not developed the disease is too great for them to serve as useful
discriminators in practice. Assessments of vascular function also have been
proposed as discriminatory markers; however, assessment of angiotensin II
pressor response [41] is too invasive and impractical and Doppler assessment of uterine artery blood ow is too nonspecic [42] for clinical use. It
is currently uncertain whether serum levels of st-1 or serum or urinary levels of PlGF [43] will prove to be useful in distinguishing between pregnant
women who will and will not develop preeclampsia.
Prevention of preeclampsia
The lack of predictive markers for the development of preeclampsia has
complicated eorts to prevent the disease. Nonetheless, several interventions
have been studied in populations considered to be at increased risk based on
historical factors, such as primiparity.
Aspirin
Based on the observation of relative increases in thromboxane relative to
prostacylin levels in women with preeclampsia, aspirin or other antiplatelet
agents have been proposed as preventive agents. Although several small trials suggested a benet to aspirin, a large multicenter, placebo-controlled,
randomized trial [44] including 6927 women at increased risk for preeclampsia found no signicant reduction overall in the risk of preeclampsia with
aspirin therapy (60 mg/d). Subgroup analyses indicated a possible benet
in reducing risk in women who delivered before 32 weeks gestation, but
such women could not be reliably identied prospectively. Another large
randomized trial of low-dose aspirin (60 mg/d) in high-risk women also
showed no signicant benet [45].
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SOLOMON & SEELY
Calcium
Similar to aspirin, calcium supplementation seemed to be a promising
preventive strategy in small studies. In a multicenter, placebo-controlled,
randomized trial of 4589 healthy nulliparous women [46], supplementation
with 2 g of elemental calcium daily did not reduce signicantly the risks of
preeclampsia or pregnancy-associated hypertension among the group overall or among women with low calcium intake or low urinary calcium levels
at baseline.
Antioxidants
Because preeclampsia has been considered to reect a state of increased
oxidant stress, it has been hypothesized that supplementation with antioxidants might reduce risk for this disorder. A randomized trial of supplementation with vitamins E and C was terminated early, however, after the rates
of preeclampsia did not dier materially between women receiving and not
receiving supplementation [47]. Low levels of u-3 fatty acids have been associated with increased rates of preeclampsia [48], but it is not known
whether supplementation reduces this risk.
Lifestyle modications
Women who are lean before pregnancy have a lower risk of preeclampsia
than women with higher pregravid BMI [12]. It is not known, however, if
weight loss before pregnancy in obese women reduces risk. Some retrospective data have indicated that higher levels of leisure-time physical activity in
the rst 20 weeks of pregnancy are associated with a signicantly reduced
risk for preeclampsia [49]. However, another retrospective report found
no signicant reduction in the risk for preeclampsia with greater leisuretime or nonleisure-time physical activity [50].
Management of preeclampsia
Women with established or suspected preeclampsia require close clinical
surveillance. The goal is to avoid the development of eclampsia or other complications in the mother, but prolong the pregnancy as long as possible, as
long as the mother and fetus are stable. Indications for immediate delivery
have been outlined by the Working Group on High Blood Pressure in Pregnancy and include maternal and fetal factors [1]. Maternal indications include gestational age 38 weeks or greater; platelet count less than 100,000
cells/mm3; progressive decline in either liver or renal function; signs of placental abruption; or symptoms of persistent severe headaches, visual
changes, severe epigastric pain, nausea, or vomiting. Fetal indications for delivery include abnormal nonstress testing or ultrasound scans indicating severe growth restriction, unfavorable biophysical prole, or oligohydramnios.
165
Maternal and fetal monitoring

Clinical monitoring of the mother includes frequent blood pressure determinations, questioning for symptoms (eg, abdominal pain, headache, visual
changes, or photophobia), and laboratory testing (urine protein measurement, preferably on a 24-hour urine sample, platelet count, creatinine,
and transaminases). Laboratory testing is recommended on at least a weekly
basis in patients considered to have mild stable disease. Monitoring of the
fetus includes fetal ultrasound (to assess fetal size and amniotic uid volume) and nonstress testing (to assess fetal heart rate reactivity) or determination of biophysical prole (to assess fetal well-being). Intervals for
maternal and fetal testing are not well dened, but more frequent testing
is recommended when disease is more severe.
In women who develop preeclampsia at less than 34 weeks gestation, an
approach of expectant management has been advocated [51]. Women are
admitted to the hospital for close maternal and fetal monitoring, and antihypertensive therapy is initiated when indicated (see later). In a randomized
trial comparing this approach with immediate delivery, expectant management prolonged pregnancy 2 weeks and resulted in fewer days in the neonatal intensive care unit and higher birth weight, although there was an
increased rate of infants small for gestational age [51]. Other trials have suggested similar benets to expectant management involving close monitoring
of the mother and the fetus under supervision of physicians experienced in
managing such pregnancies [52,53].
Antihypertensive therapy
Antihypertensive medications are used in women with severe chronic hypertension or severe preeclampsia to decrease the maternal risk of stroke
and intracerebral hemorrhage. A possible risk of lowering the mothers
blood pressure is hypoperfusion of the fetoplacental unit, which already is
compromised in severely hypertensive pregnancy. Studies of women with
mild preeclampsia [54,55] have shown no benet to pharmacologic therapy
(either labetalol or calcium channel blockers) and suggested that antihypertensive therapy may increase the risk of intrauterine growth restriction. Recommended thresholds for starting pharmacologic therapy for elevated
blood pressure levels are higher than the thresholds outside of pregnancy.
The Working Group Report on High Blood Pressure in Pregnancy recommends initiation of antihypertensive therapy for a diastolic blood pressure
105 mm Hg or greater [1].
No antihypertensive medication is specically approved by the US Food
and Drug Administration (FDA) for use in pregnant women, although the
FDA classies medications based on available data regarding safety in pregnancy. Medications commonly used in pregnancy and their FDA classications are reviewed in Table 1.
166
SOLOMON & SEELY
Table 1
Pharmacologic therapy for hypertensive pregnancy
Agent
Route of
administration
Chronic treatment of hypertensionb

Methyldopa
By mouth
Beta-blockers
By mouth
Labetalol
By mouth
Calcium channel
blockers
By mouth
Contraindications
d
May exacerbate asthma and heart
failure
failure
Caution when used with magnesium
sulfate
Acute management of severe hypertensionc

Hydralazine
IV
d
Labetolol
IV
failure
Nitroprusside
IV
Risk of cyanide toxicity to mother
and fetus
FDA
classicationa
B
C
C
C
C
C
C
a
Categories: A (not listed), adequate and well-controlled studies have failed to show a risk
to the fetus in the rst trimester of pregnancy (and there is no evidence of risk in later trimesters); B, animal reproduction studies have failed to show a risk to the fetus and there are no
adequate and well-controlled studies in pregnant women; C, animal reproduction studies
have shown an adverse eect on the fetus and there are no adequate and well-controlled studies
in humans, but potential benets may warrant use of the drug in pregnant women despite potential risks; D (not listed), positive evidence of human fetal risk based on adverse reaction data
from investigational or marketing experience or studies in humans, but potential benets may
warrant use of the drug in pregnant women despite potential risks; and X (not listed), studies in
animals or humans have showed fetal abnormalities and/or there is positive evidence of human
fetal risk based on adverse reaction data from investigational or marketing experience, and the
risks involved in use of the drug in pregnant women clearly outweigh potential benets.
b
ACEIs and ARBs are contraindicated in the second and third trimesters of pregnancy because of the risk of fetal or neonatal renal failure and other complications (category D).
c
Short-acting calcium channel blockers have been used in this setting, but are not approved
for treating hypertensive crisis even in nonpregnant patients, and may increase risk for cardiovascular events.
There is no evidence that antihypertensive therapy in women with

mild-to-moderate chronic hypertension reduces the risk for developing preeclampsia. A meta-analysis of randomized trials of the treatment of mild-tomoderate hypertension in pregnancy (including 17 that compared dierent
pharmacologic therapies with one another and 24 that compared pharmacologic therapy with placebo) showed no reduction in the rate of preeclampsia
with antihypertensive therapy overall or with any specic agent [56].
For women who require antihypertensive medication in pregnancy, methyldopa has the longest record of use of pregnancy and often is considered
a rst-line choice for management. Follow-up of children born to mothers
who took methyldopa during pregnancy revealed no negative eects on development at 7.5 years of age [57]. b-Blockers and labetalol also are used,
167
but may increase risk of intrauterine growth restriction [54,58]. Calcium

channel blockers are considered an alternative, although data also are limited for this class.
Angiotensin-converting enzyme inhibitors are considered contraindicated
in the management of hypertension in pregnancy as a result of the observation of cases of fetal and neonatal renal failure in infants of mothers treated
with these agents [59]. Based on their similar mechanisms of action and case
reports describing adverse outcomes (including oligohydramnios, fetal
growth restriction, stillbirth or neonatal death, and neonatal renal failure)
in ospring of exposed women, angiotensin receptor blockers likewise are
contraindicated in the management of hypertension in pregnancy [60].
Emergency treatment of hypertension in pregnancy
For severe hypertension (dened as sustained systolic blood pressure R
160 mm Hg or diastolic blood pressure R 105 mm Hg [1]) unresponsive
to oral medications, intravenous therapy is warranted. Medications recommended in this setting include hydralazine and labetalol [61,62]. Nitroprusside has been used, specically in cases unresponsive to these medications,
but its use may be complicated by cyanide toxicity in the fetus or mother.
Short-acting oral nifedipine has been suggested as an alternative to intravenous medication; however, reports of cardiovascular events after its administration [63] argue against its use. An additional concern with use of
calcium channel blockers is the increased risk for neuromuscular depression
when used in combination with magnesium sulfate, which may result in paralysis or cardiac failure (see Table 1) [64].
Seizure prophylaxis
Magnesium sulfate is the agent of choice for the prevention of seizures in
women with preeclampsia [65]. In a randomized, placebo-controlled trial including more than 10,000 women with preeclampsia, the group assigned to
magnesium sulfate had a 58% reduction in the risk for eclampsia (0.8% versus 1.9%). Randomized trials also have conrmed the superiority of magnesium sulfate to phenytoin [66] and nimodipine [67] in seizure prevention.
Implications of preeclampsia for later life risks
Although the clinical manifestations of preeclampsia resolve after delivery, women who have had this disorder may be at increased cardiovascular
risk later in life [68]. A study of 406 women with severe preeclampsia or
eclampsia in their rst pregnancy showed a 2.6-fold increased risk for hypertension over 2 to 24 years of follow-up compared with 409 women with a history of normotensive pregnancy [69]. In a population-based cohort study,
women with preeclampsia and preterm delivery (which is considered to indicate more severe disease) had an 8-fold increased risk of cardiovascular
168
SOLOMON & SEELY
mortality compared with women who were normotensive and gave birth at
term [70]. Studies of long-term risks may be biased, however, by possible
misdiagnosis of chronic hypertension as preeclampsia, and further research
is needed to better understand the long-term risks associated with a history
of preeclampsia and to identify eective interventions. Currently, lifestyle
interventions to control BMI and reduce insulin resistancedincluding dietary changes and increased physical activitydare reasonable and should
be encouraged.
Summary
New-onset hypertension complicates 5% to 10% of pregnancies. Preeclampsia is associated with substantial risk to the mother and the fetus.
Recognized risk factors include primiparity and preexisting chronic hypertension. Many biochemical abnormalities (eg, hyperinsulinemia, hyperlipidemia, elevated levels of tumor necrosis factor-a, and, more recently, elevated
levels of st-1 and reduced levels of PlGF) also have been recognized to predispose to disease. Currently, there is no marker for disease that has proved
suciently discriminatory to be used in practice, and no interventions are
known to be eective in preventing the disease. The cure for preeclampsia
is delivery of the fetus, but delivery earlier than necessary poses major risks
to the fetus; management involves close follow-up of the mother and the
fetus to prolong the pregnancy as long as is safely possible. Although
no antihypertensive medications are approved for use in pregnancy, clinical experience has supported certain choices (including methyldopa,
b-blockers, and calcium channel blockers for long-term management and
hydralazine, labetalol, and nitroprusside for acute management). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated in the second and third trimesters of pregnancy. Women with
a history of preeclampsia are at increased risk of preeclampsia in subsequent
pregnancies and may be at increased risk for subsequent hypertension and
cardiovascular disease. Further research is needed to understand causes of
preeclampsia better and to identify interventions that can prevent its occurrence and reduce subsequent risks in women who have had preeclampsia.
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35 (2006) 173191
Endocrinology of Parturition
Victoria Snegovskikh, MDa,*,
Joong Shin Park, MD, PhDb,
Errol R. Norwitz, MD, PhDa
a
Department of Obstetrics, Gynecology, and Reproductive Sciences,

Yale University School of Medicine, New Haven, CT, USA
b
Department of Obstetrics and Gynecology, Seoul National University
College of Medicine, Seoul, Korea
Reproductive success is critical for survival of the species. The timely onset of labor and delivery is an important determinant of perinatal outcome.
Preterm birth (dened as delivery before 37 weeks gestation) and post-term
pregnancy (dened as pregnancy continuing beyond 42 weeks) are both associated with a signicant increase in perinatal morbidity and mortality. The
factors responsible for the timing of labor in the human are complex and, as
yet, are not completely understood. This article reviews the current understanding of the parturition cascade responsible for the spontaneous onset
of labor at term and discusses preterm labor and post-term pregnancy.
Historical context
Considerable evidence suggests that the fetus is in control of the timing of
labor. Horsedonkey crossbreeding experiments in the 1950s resulted in
a gestational length intermediate between that of horses (340 days) and
that of donkeys (365 days) [13], suggesting a role for the fetal genotype in
the initiation of labor. The mechanism by which the fetus triggers labor at
term has been demonstrated elegantly in domestic ruminants such as sheep
and cows and involves the activation at term of the fetal hypothalamicpituitary-adrenal (HPA) axis, leading to a surge in adrenal cortisol production. Fetal cortisol then acts to up-regulate directly the activity of placental
17a-hydroxylase/17,20-lyase (CYP17) enzyme, which catalyzes the conversion of pregnenolone to 17b-estradiol. The switch in progesterone:estrogen
* Corresponding author.
E-mail address: vica@inbox.ru (V. Snegovskikh).
doi:10.1016/j.ecl.2005.09.012
endo.theclinics.com
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SNEGOVSKIKH
et al
ratio at term provides the impetus for uterine prostaglandin production and
labor [49]. However, human placentae lack the CYP17 enzyme, which is
critical to this pathway [2], and, as such, this mechanism does not apply in
humans. During the Hippocratic period, it was believed that the fetus presented head down so that it could kick its legs up against the fundus of
the uterus and propel itself through the birth canal. Although we have
moved away from this simple and mechanical view of labor, the factors responsible for the initiation and maintenance of labor at term are not well dened. The slow progress in our understanding of labor in humans is the
result, in large part, of the absence of an adequate animal model. Parturition
in most animals results from changes in circulating hormone levels in the maternal and fetal circulations at the end of pregnancy (endocrine events),
whereas labor in humans results from a complex dynamic biochemical dialog
that exists between the fetoplacental unit and the mother (paracrine and autocrine events).
Diagnosis of labor
Labor is the physiologic process by which a fetus is expelled from the uterus
and is common to all viviparous species. Labor remains a clinical diagnosis. It
requires the presence of regular painful uterine contractions, which increase in
frequency and intensity, leading to progressive cervical eacement and dilatation. In normal labor, there appears to be a time-dependent relationship
between these elements: the biochemical connective tissue changes in the
cervix usually precede uterine contractions that, in turn, precede cervical
dilatation. All of these events occur usually before spontaneous rupture of
the fetal membranes [10]. The mean duration of human singleton pregnancy
is 280 days (40 weeks) from the rst day of the last normal menstrual period.
Term is dened as the period from 37.0 to 42.0 weeks of gestation.
Parturition cascade at term

It is likely that a parturition cascade exists at term that removes the mechanisms maintaining uterine quiescence and recruits factors promoting uterine
activity (Fig. 1) [8,9]. Given its teleologic importance, such a cascade would
likely have multiple redundant loops to ensure a fail-safe system of securing
pregnancy success and ultimately the preservation of the species. In such
a model, each element is connected to the next in a sequential fashion, and
many of the elements demonstrate positive feed-forward characteristics typical of a cascade mechanism. The sequential recruitment of signals that serve
to augment the labor process suggests that it may not be possible to single out
any one signaling mechanism as being responsible for the initiation of labor.
It may therefore be prudent to describe such mechanisms as being responsible for promoting, rather than initiating, the process of labor [11].
ENDOCRINOLOGY OF PARTURITION
175
Fig. 1. Proposed parturition cascade for labor induction at term. The spontaneous induction
of labor at term in the human is regulated by a series of paracrine-autocrine hormones acting
in an integrated parturition cascade responsible for promoting uterine contractions. COX-2,
cyclooxygenase 2; OT, oxytocin; PGDH, prostaglandin dehydrogenase; PGEM, 13,14dihydro-15-keto-PGE2; PGFM, 13,14-dihydro-15-keto-PGF2a; PLA2, phospholipase A;
SROM, spontaneous rupture of the fetal membranes; 11b-HSD, 11b-hydroxysteroid dehydrogenase; 16-OH DHEAS, 16-OH-dehydroepiandrostendione sulfate.
176
SNEGOVSKIKH
et al
Regardless of whether the trigger for labor begins within or outside the
fetus, the nal common pathway for labor ends in the maternal tissues of
the uterus and is characterized by the development of regular phasic uterine
contractions. As in other smooth muscles, myometrial contractions are mediated through the ATP-dependent binding of myosin to actin. In contrast
to vascular smooth muscle, however, myometrial cells have a sparse innervation, which is further reduced during pregnancy [12]. The regulation of
the contractile mechanism of the uterus is therefore largely humoral or dependent on intrinsic factors within the myometrial cells.
Autocrine and paracrine mediators of parturition

Labor at term may be regarded best physiologically as a release from the
inhibitory eects of pregnancy on the myometrium rather than as an active
process mediated by uterine stimulants [13]. For example, strips of quiescent
term myometrial tissue placed in an isotonic water bath will contract vigorously and spontaneously without added stimuli [13,14]. In vivo, however, it
is likely that both mechanisms are important. A comprehensive analysis of
each of the individual paracrine-autocrine pathways implicated in the process of labor has been reviewed in detailed elsewhere [8,9,11,15,16]. Briey,
human labor at term is a multifactorial physiologic event involving an integrated set of changes within the maternal tissues of the uterus (myometrium,
decidua, and uterine cervix), which occur gradually over a period of days to
weeks. Such changes include but are not limited to an increase in prostaglandin synthesis and release within the uterus, an increase in the myometrial
gap junction formation, and up-regulation of myometrial oxytocin receptors. Once the myometrium and cervix are prepared, endocrine or paracrine-autocrine factors from the fetoplacental unit bring about a switch in
the pattern of myometrial activity from irregular to regular contractions.
The fetus may coordinate this switch in myometrial activity through its inuence on placental steroid hormone production, through the mechanical
distention of the uterus and through the secretion of neurohypophyseal hormones and other stimulators of prostaglandin synthesis. The nal common
pathway toward labor appears to be the activation of the fetal HPA axis and
is probably common to all viviparous species.
Role of the fetal hypothalamic-pituitary-adrenal axis in the onset of labor
Activation of the fetal HPA axis results in enhanced fetal pituitary adrenocorticotropin hormone (ACTH) secretion that leads, in turn, to the release
of abundant C19 estrogen precursor dehydroepiandrostenedione sulfate
(DHEAS) from the intermediate (fetal) zone of the fetal adrenal. This is because the human placenta is an incomplete steroidogenic organ, and estrogen
synthesis by the human placenta has an obligate need for C19 steroid precursor
177
(see Fig. 1) [16]. DHEAS is converted in the fetal liver to 16-hydroxy DHEAS
and then travels to the placenta where it is metabolized into estradiol (E2),
estrone (E1), and estriol (E3). In the rhesus monkey, an infusion of C19 precursor (androstenedione) leads to preterm delivery [17]. This eect is blocked
by the concurrent infusion of an aromatase inhibitor [18], demonstrating that
conversion to estrogen is important. However, a systemic infusion of estrogen failed to induce delivery, suggesting that the action of estrogen is likely
paracrine-autocrine [17,19,20]. In addition to DHEAS, the fetal adrenal
glands also produce copious amounts of cortisol. Cortisol acts to prepares
fetal organ systems for extrauterine life and to promote expression of a number of placental genes, including corticotropin releasing hormone (CRH),
oxytocin, and prostaglandins (especially prostaglandin E2 [PGE2]).
CRH is a peptide hormone released by the hypothalamus but is also expressed by placental and chorionic trophoblasts and amnionic and decidual
cells [2123]. CRH stimulates pituitary ACTH secretion and adrenal cortisol
production. In the mother, cortisol inhibits hypothalamic CRH and pituitary
ACTH release, creating a negative feedback loop. In contrast, cortisol
stimulates CRH release by the decidual, trophoblastic, and fetal membranes
[2326]. CRH, in turn, further drives maternal and fetal HPA activation,
thereby establishing a potent positive feed-forward loop. In normal pregnancy,
the increased production of CRH from decidual, trophoblastic, and fetal
membranes leads to an increase in circulating cortisol beginning in midgestation [27]. The eects of CRH are enhanced by a fall in maternal plasma
CRH-binding protein near term [28]. CRH also enhances prostaglandin production by amnionic, chorionic, and decidual cells [23]. Prostaglandins, in
turn, stimulate CRH release from the decidual and fetal membranes [24].
The rise in prostaglandins ultimately results in parturition [29]. CRH also
can directly aect myometrial contractility [30]. Taken together, these factors
suggest that placental CRH serves as a placental clock that controls the timing of labor [31,32]. A longitudinal measurement of CRH throughout pregnancy suggests that the placental clock may be set to run fast or slow as early
as the rst or second trimester of pregnancy [31,3335]. Once the speed of the
placental clock is set, the timing of delivery may be predetermined.
Role of estrogens in the onset of labor
Human pregnancy is characterized by a hyperestrogenic state of unparallel magnitude in the entire mammalian kingdom. The placenta is the primary source of estrogens, and concentrations of estrogens increase in the
maternal circulation with increasing gestational age. Placental estrone and
17b-estradiol are derived primarily from maternal C19 androgens (testosterone and androstenedione), whereas estriol is derived almost exclusively from
the fetal C19 estrogen precursor (DHEAS). Estrogens do not themselves
cause uterine contractions but do promote a series of myometrial changes,
including increasing the number of prostaglandin receptors, oxytocin
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receptors, and gap junctions, and up-regulating the enzymes responsible for
muscle contractions (myosin light chain kinase, calmodulin) [3639] that enhance the capacity of the myometrium to generate contractions.
Role of progesterone in the onset of labor
The administration of a progesterone receptor antagonist such as RU486 readily induces abortion if given before 7 weeks (49 days) of gestation
[40]. Similarly, the surgical removal of the corpus luteum, the source of progesterone, before 7 weeks results in pregnancy loss [41]. Taken together,
these data suggest that adequate production of progesterone by the corpus
luteum is critical to the maintenance of early pregnancy until the placenta
takes over this function at approximately 7 to 9 weeks of gestation (hence,
its name: pro-gestational steroid hormone). The role of progesterone in later
pregnancy, however, is less clear.
In contrast to most animal species, the circulating levels of progesterone
during human labor are similar to levels measured 1 week prior [2,42], suggesting that the systemic withdrawal of progesterone is not a prerequisite for
labor in humans. This is in contrast to most laboratory animals (with the
noted exceptions of the guinea pig and armadillo) in which progesterone
withdrawal is an essential component of parturition. However, circulating
hormone levels do not necessarily reect tissue levels, and there is increasing
evidence from both in vitro [4345] and in vivo studies [4648] that the spontaneous onset of labor at term may be preceded by a physiologic (functional)
withdrawal of progesterone activity at the level of the uterus. In one clinical
trial, Meis and colleagues [47] randomly assigned 459 patients at high risk
for preterm delivery by virtue of a previous preterm birth to receive a weekly
intramuscular injection of 17a-hydroxyprogesterone caproate (250 mg) or
a matching placebo, beginning at 16 to 20 weeks of gestation and continuing
until 36 weeks. Prophylaxis with 17a-hydroxyprogesterone signicantly reduced the risk of delivery at less than 37 weeks (36% versus 55% in the placebo
group [relative risk [RR], 0.66; 95% CI, 0.54%0.81%]), less than 35 weeks
(21% versus 31% [RR, 0.67; 95% CI, 0.48%0.93%]), and less than 32 weeks
(11% versus 20% [RR, 0.58; 95% CI, 0.37%0.91%]). Progesterone likely
maintains uterine quiescence during the latter half of pregnancy by limiting
the production of stimulatory prostaglandins and inhibiting the expression
of contraction-associated protein genes (ion channels, oxytocin and prostaglandin receptors, and gap junctions) within the myometrium [9,49]. The molecular mechanisms by which progesterone maintains uterine quiescence are
not known, but the progesterone receptor is likely critical to its action. In support of this hypothesis, the administration of the progesterone receptor antagonist RU-486 at term leads to increased uterine activity and the induction of
labor [50].
Cortisol and progesterone appear to have antagonistic actions within the
fetoplacental unit. For example, cortisol increases prostaglandin production
179
by the placental and fetal membranes by up-regulating cyclooxygenase-2

(amnion and chorion) and down-regulating 15-hydroxyprostaglandin dehydrogenase (15-OH-PGDH) (chorionic trophoblast), thereby promoting cervical ripening and uterine contractions. Progesterone has the opposite eect
[51]. In addition, cortisol has been shown to compete with the inhibitory action of progesterone in the regulation of placental CRH gene expression
in primary cultures of human placenta [52]. It is likely, therefore, that the
cortisol-dominant environment of the fetoplacental unit just before the onset of labor may act through a series of autocrine-paracrine pathways to
overcome the eorts of progesterone to maintain uterine quiescence and
prevent myometrial contractions.
Role of other autocrine-paracrine hormones in the onset of labor
Placental oxytocin acts directly on the myometrium to cause contractions
and indirectly by up-regulating prostaglandin production, especially prostaglandin F2a (PGF2a) by the decidua [53]. PGF2a, in turn, is produced primarily by the maternal decidua and acts on the myometrium to up-regulate
oxytocin receptors and gap junctions, thereby promoting uterine contractions. PGE2 is primarily of fetoplacental origin and is likely more important
in promoting cervical ripening (maturation) and spontaneous rupture of the
fetal membranes.
Preterm labor and birth
Preterm (premature) birth, dened as delivery between 20 and 37 weeks,
complicates 7% to 10% of all deliveries [54,55]. Despite intense eorts, the
ability of obstetric care providers to prevent preterm labor and birth is limited. Instead of decreasing, the incidence of preterm birth in the United
States has continued to rise over the past 2 decades, reaching a peak of
12.1% in 2002 (Fig. 2) [56]. Based on these data, there are approximately
460,000 preterm births in the United States each year. Prematurity is the
leading cause of perinatal death in nonanomalous newborns in the United
States. Even at gestational ages in which survival is relatively assured, significant morbidity is still common. For example, Robertson and colleagues [57]
reported that, at 30 weeks gestation, the risk of respiratory distress syndrome in surviving infants is 50%, and necrotizing enterocolitis will develop
in 11% and intraventricular hemorrhage in 5%.
Causes of preterm birth
Preterm labor likely represents a syndrome rather than a single diagnosis
because the causes are varied. Approximately 20% of all preterm deliveries
are iatrogenic and are performed for maternal or fetal indications, including intrauterine growth restriction, preeclampsia, placenta previa, and
nonreassuring fetal testing [8]. Of the remaining cases of preterm birth,
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SNEGOVSKIKH
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Incidence of preterm birth

(% of all live births)
16
12
10.6 10.8 10.7 11.0 11.0
11.0 11.0
11.9
11.4 11.6 11.8 11.6
12.1
0
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Fig. 2. Preterm births in the United States, 19902002. (Data from the National Center for
Health Statistics, nal natality data, and the March of Dimes Perinatal Data Center, 2003.
Available at http://marchofdimes.com/peristats.)
approximately 30% occur in the setting of preterm premature rupture of the

membranes (pPROM), 20% to 25% result from intra-amniotic infection,
and the remaining 25% to 30% are caused by spontaneous (unexplained)
preterm labor (Fig. 3) [8,58].
Preterm labor may reect a breakdown of the normal mechanisms responsible for maintaining uterine quiescence throughout gestation. For example,
the choriodecidua is enriched selectively with 15-OH-PGDH, the enzyme responsible for degrading the primary (biologically active) prostaglandins. A
deciency in choriodecidual 15-OH-PGDH activity may impair the ability
of the fetal membranes to metabolize the primary prostaglandins, thereby
allowing PGE2 to reach the myometrium and initiate contractions. Such a
deciency has been described and may account for up to 15% of idiopathic
preterm labor [59]. Alternatively, premature labor may represent a
Non-iatrogenic
preterm births
Iatrogenic
preterm births
Preterm births
for maternal or
fetal indication
Preterm PROM
30%
Intra-amniotic
infection
20%
25%
25%
Spontaneous
(idiopathic) preterm
labor
- Diabetes
- IUGR
- Preeclampsia
- Placenta previa
- Placental abruption
Fig. 3. Causes of preterm births. (Data from Tucker JM, Goldenberg RL, Davis RO, et al. Etiologies of preterm birth in an indigent population: is prevention a logical expectation? Obstet
Gynecol 1991;77:3437.)
181
short-circuiting or overwhelming of the normal parturition cascade. Indeed,

a feature of the proposed parturition cascade would be the ability of the
fetoplacental unit to trigger labor prematurely if the intrauterine environment
became hostile and threatened the well being of the fetus. For example, up
to 30% of preterm labors are believed to result from intra-amniotic infection
[58]. In many patients with infection, elevated levels of lipoxygenase and cyclooxygenase pathway products can be demonstrated [58,60]. There are also
increased concentrations of cytokines (including interleukin [IL]-1b, IL-6,
and tumor necrosis factor [TNF]-a) in the amniotic uid of such women
[61]. Cytokines and eicosanoids appear to accelerate each others production
in a cascade-like fashion, which may act to overwhelm the normal parturition cascade, resulting in preterm labor. Recently, thrombin has been shown
to be a powerful uterotonic agent [62,63], providing a physiologic mechanism for preterm labor secondary to placental abruption.
Molecular mechanisms of preterm labor
Clinical and experimental evidence links most preterm births to four distinct pathogenic processes. Although these four pathogenic processes can
and often do occur simultaneously, each has a unique biochemical and biophysical signature with variable temporal manifestations and distinct epidemiologic proles. Regardless of the initiating event, these processes converge
on a nal common biologic pathway characterized by cervical and fetal
membrane extracellular matrix degradation and myometrial activation,
leading to uterine contractions that increase in frequency and intensity cervical change (preterm labor) with or without pPROM.
Premature activation of the maternal or fetal
hypothalamic-pituitary-adrenal axis
Premature activation of the fetal or maternal HPA axes is evident in up to
33% of preterm births [64]. Maternal physical and psychologic stress leads
to the premature activation of the maternal HPA axis and has been linked
consistently to preterm birth [6567]. The activation of the fetal HPA axis
has been associated with preterm delivery, and uteroplacental insuciency
is a source of fetal stress [64,68,69]. Indeed, chronic hypertension and severe
pregnancy-induced hypertension are associated with an increase of 36% and
300%, respectively, in spontaneous preterm birth [70]. Both maternal and
fetal stress likely cause preterm labor by increasing the release of placental
CRH, which, in turn, programs the placental clock (Fig. 4) [71,72]. Recent
studies have noted elevated second trimester maternal serum CRH concentrations among patients who deliver preterm [33,73,74].
Decidual and amniochorionic inammation
Laboratory and clinical data show a consistent association between spontaneous preterm labor and genital tract infections [75,76]. The nal common
182
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et al
Fetal stress
Maternal stress
(uteroplacental insufficiency)
Activation of maternal HPA axis
Activation of fetal HPA axis

ACTH
Adrenal
Cortisol
cox-2 in amnion
PGDH in chorion
Decidua
Placenta
Membranes
DHEAS
Placenta
Membranes
Estrogen
CRH
+
Prostaglandins
Contractions
Myometrial OTR, PGs, MLCK,

calmodulin, gap junctions
Cervical
change
Rupture of
membranes
Fig. 4. Maternal and fetal HPA axis and preterm birth. COX-2, cyclooxygenase 2; MLCK,
myosin light chain kinase; OTR, oxytocin receptors; PGDH, prostaglandin dehydrogenase.
pathway is a maternal or fetal inammatory response that is likely triggered

by infection in the decidua or amniochorion, with release of inammatory
mediators (cytokines, matrix metalloproteinases [MMPs]) by activated macrophages and granulocytes. In one histopathologic study [77], for example,
evidence of chorioamnionitis was observed in 70% of patients with preterm
birth associated with pPROM. IL-1, IL-6, and TNF-a directly stimulate
PGE2 and PGF2a production and inhibit their metabolism in the chorion
[78,79]. Cytokines also induce MMPs (collagenase, gelatinase, and stromelysins) that weaken the fetal membranes and ripen the cervix by disrupting
the normally rigid collagen extracellular matrix (Fig. 5). TNF-a may play an
additional role because it can induce apoptosis. Elevated circulating levels of
TNF-a have been associated with pPROM [80].
Midtrimester cervicovaginal IL-6 [81] and plasma granulocyte colonystimulating factor levels [82] also are elevated in asymptomatic women
who subsequently deliver preterm, but the sensitivity and positive predictive
values of these tests are only approximately 50%. The fetus can also initiate
a systemic inammatory cytokine response leading to labor. One study of 41
women who had pPROM showed that microbial invasion of the uterine cavity elicited an increase in fetal IL-6 levels that was associated with impending
preterm labor and birth [83]. Taken together, these data support the hypothesis that many instances of spontaneous preterm labor results from an
inammatory process associated with the activation of the genital tract
183
Inflammation of decidua / amniochorion
IL-6
CRH
Cytokines (TNF, IL-1)
Uterotonins
(PGs, endothelin)
FasL
IL-8
Proteases
(MMPs)
Apoptosis
Contractions
Cervical
change
Rupture of
membranes
Fig. 5. Inammation of decidua-amniochorion and preterm labor. FasL, fas ligand.
cytokine network and the presence of cytokines in the maternal or fetal compartment several weeks before delivery.
Decidual hemorrhage
Decidual hemorrhage (abruption) presenting as vaginal bleeding in more
than one trimester of pregnancy is associated with a three- and sevenfold increased risk, respectively, of preterm birth [84] and pPROM [85]. The risk of
preterm birth is even higher (100-fold) in such women if they also had
a previous pregnancy complicated by pPROM [86]. The causes of decidual
hemorrhage-associated preterm birth include older, parous, married, and
college-educated women [87], a prole quite distinct from that of both infection- and stress-mediated preterm labor.
Thrombin, a plasma protease that converts brinogen into brin, is
formed from prothrombin by the action of prothrombinase (factor Xa). Recent studies have shown that thrombin stimulates myometrial contractions
by activating phosphatidylinositol-signaling pathways in a dose-dependent
fashion [88]. Thrombin also increases expression of plasminogen activators
and MMPs (Fig. 6) [89,90]. The release of thrombin associated with placental abruption may therefore directly initiate the nal common pathway leading to preterm labor.
Pathologic uterine distention
Excessive uterine stretching caused by multiple-birth pregnancy or polyhydramnios is associated with preterm labor. Preterm birth rates exceed
50% for twin pregnancies, 80% for triplet pregnancies, and 90% for quadruplet pregnancies. The mechanism is not clear but appears to involve a signal initiated by the mechanical stretching of uterine myometrial, cervical,
and fetal membrane cells that is transmitted through the cellular
184
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et al
Hemorrhage
Decidual activation with release of clotting
factors including factor Vlla / tissue factor
Xa
X
Va
thrombin (IIa)
prothrombin (II)
fibrin
fibrinogen
plasminogen
uPA / tPA
PAI-1
plasmin
clot
+
active MMPs
ECM degradation
Contractions
Cervical
change
Rupture of
membranes
Fig. 6. Hemorrhage and preterm labor. ECM, extracellular matrix; PAI-1, plasminogen activator inhibitor 1; tPA, tissue-type plasminogen activator; uPA, urokinase plasminogen activator.
cytoskeleton and leads to the activation of cellular protein kinases (Fig. 7)

[91]. Three genes have recently been identied whose expression in the membranes is up-regulated by acute distention in vitro and in association with
labor: an interferon-stimulated gene encoding a 54-kD protein, the gene
for Huntington-interacting protein 2 (an ubiquitin-conjugating enzyme),
and a novel as yet unidentied transcript [92]. The precise role of these factors in parturition is not known.
Post-term pregnancy
Post-term (prolonged) pregnancy is dened as a pregnancy that has extended to or beyond 42 weeks (294 days) from the rst day of the last normal
menstrual period or 14 days beyond the best obstetric estimate of the date of
delivery [93]. Because of the heterogeneity of populations, denitions, the use
of ultrasonography, and local practice patterns (such as the routine induction of labor at term and the management of parturients who previously
have undergone cesarean delivery), the reported incidence of pregnancies
continuing beyond the estimated date of delivery varies widely. In the United
States, approximately 18% of all births occur after 41 weeks, 3% to 14%
(mean 10%) occur after 42 weeks and are therefore post-term, and 4% of
pregnancies will continue to or beyond 43 weeks in the absence of obstetric
intervention [94,95]. The routine early use of ultrasonography to accurately
date pregnancies can reduce the rate of false-positive diagnoses and thereby
185
Uterine distention
Uterine expansile capacity
Myometrial
activation
_
+
Fetal membrane
activation
Cytokine production
Contractions
Cervical
change
Rupture of
membranes
Fig. 7. Uterine distension and preterm labor.
the overall rate of post-term pregnancy from 10% to approximately 1% to

3% [9699].
Causes of post-term pregnancy
As discussed previously, the most common cause of prolonged pregnancy
is an error in gestational age dating. In most cases, the cause of true postterm pregnancy is not known. Risk factors include nulliparity and a previous
post-term pregnancy [100,101]. Recent data have also shown an association
with male fetuses [102]. Rarer causes include placental sulfatase deciency,
fetal adrenal insuciency, or fetal anencephaly (in the absence of polyhydramnios). The increased risk of post-term pregnancy in women who have
had previous post-term pregnancy suggests an underlying biologic or genetic
cause, which has yet to be dened adequately [101,103].
Complications of post-term pregnancy
Recent studies have shown that the risks to the fetus [104108] and mother
[107,109,110] of continuing the pregnancy beyond the estimated date of
delivery is greater than appreciated originally. Antepartum stillbirths account for more perinatal deaths than either complications of prematurity
or sudden infant death syndrome [106]. Once a fetus is delivered, it is no longer at risk of intrauterine fetal demise (stillbirth). When pregnancies exceed
42 weeks, perinatal mortality (stillbirths plus early neonatal deaths) increases to 4 to 7 per 1000 deliveries compared with 2 to 3 per 1000 deliveries
at 40 weeks [111,112]. Perinatal mortality at 43 weeks gestation is fourfold
higher than that at 40 weeks and is ve- to sevenfold higher at 44 weeks
[112]. Post-term pregnancy is also an independent risk factor for neonatal
encephalopathy [113] and for death in the rst year of life [105107]. Since
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et al
the risks of the routine induction of labor (primarily failed induction leading to
cesarean delivery) are lower than reported previously [114,115], recent consensus opinions recommend the routine induction of labor at an earlier gestation
age, specically 41 weeks gestation [93,107].
Summary
Labor is a complex physiologic process involving fetal, placental, and
maternal signals. The timely onset of labor and birth is an important determinant of perinatal outcome. Both preterm labor and delivery and post-term
pregnancy are associated with increased perinatal morbidity and mortality.
Considerable evidence suggests that the fetus is in control of the timing of
labor and, thus, its birth, but exactly how this is achieved in the human is still
unknown. A better understanding of the mechanisms responsible for the
process of labor will further our knowledge about disorders of parturition,
such as preterm labor, and improve the ability of obstetric care providers
to secure a successful pregnancy outcome.
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35 (2006) 193204
Developmental Origins of Adult

Metabolic Disease
Rebecca Simmons, MDa,b,*
a
Department of Pediatrics, Childrens Hospital of Philadelphia, Philadelphia, PA, USA

b
University of Pennsylvania, Philadelphia, PA, USA
The combined epidemiologic, clinical, and animal studies clearly demonstrate that the intrauterine environment inuences growth and development
of the fetus and the subsequent development of adult diseases. There are
critical specic windows during development, often coincident with periods
of rapid cell division, during which a stimulus or insult may have long-lasting consequences on tissue or organ function after birth. Birth weight is only
one marker of an adverse fetal environment, and conning studies to this
population only may lead to erroneous conclusions regarding etiology.
Studies using animal models of uteroplacental insuciency suggest that mitochondrial dysfunction and oxidative stress play an important role in the
pathogenesis of the fetal origins of adult disease.
Low birth weight

It is becoming increasingly apparent that the in utero environment in
which a fetus grows and develops may have long-term eects on subsequent
health and survival [1,2]. The landmark cohort study of 300,000 men by
Ravelli and colleagues [3] showed that exposure to the Dutch famine of
1944 through 1945 during the rst half of pregnancy resulted in signicantly
higher obesity rates at the age of 19 years. Subsequent studies demonstrated
a relation between low birth weight and the later development of cardiovascular disease [4] and impaired glucose tolerance [58] in men in England.
Other studies of populations in the United States [911], Sweden [12],
France [13,14], Norway [15], and Finland [16] have all demonstrated
* University of Pennsylvania, 421 Curie Boulevard, BRB II/III, Room 1308, Philadelphia,
PA 19104.
E-mail address: rsimmons@mail.med.upenn.edu
doi:10.1016/j.ecl.2005.09.006
endo.theclinics.com
194
SIMMONS
a signicant correlation between low birth weight and the later development
of adult diseases. The associations with low birth weight and increased risk
of coronary heart disease, stroke, and type 2 diabetes remain strong even after adjusting for lifestyle factors, such as smoking, physical activity, occupation, income, dietary habits, and childhood socioeconomic status, and occur
independent of the current level of obesity or exercise [17].
High birth weight

Higher birth weight is associated with higher body mass index (BMI) and
increased prevalence of obesity in adult life, although the eect size is relatively small [18]. The impact of intrauterine life in relation to later obesity
may be in determining the vulnerability of individuals to increased body
mass in childhood or adult life. Those who become obese as adults tend
to have been heavier at birth and to have had an accelerated gain in body
mass through childhood and adolescence. Factors in early childhood may
lead to obesity through metabolic programming (discussed elsewhere in
this article) or establishment of lifestyle behaviors. During infancy, breastfeeding may protect against the development of excess weight during childhood. Most but not all epidemiologic studies demonstrate this protective
eect, which could be mediated by behavioral or physiologic mechanisms.
Confounding cultural factors associated with the decision to breastfeed
and later obesity are possible, however. Recent data also suggest that rapid
weight gain during infancy is associated with obesity later in childhood, perhaps reecting a combination of genetically determined catch-up growth
and postnatal environmental factors [18].
Role of catch-up growth

The highest risk for the development of type 2 diabetes is among adults
who were born small and became overweight during childhood [1921]. Insulin resistance is most prominent in Indian children and in Indian men and
women who were born small for gestational age (SGA) but had a high fat
mass between the ages of 2 and 12 years [20,21]. Similar ndings were reported in 10-year-old children in the United Kingdom [22]. In contrast, in
two recent preliminary studies from the United Kingdom, catch-up growth
in the rst 6 months of life was not clearly related to blood pressure as
a young adult, although birth weight was [23,24]. Interpretation of these
studies is complicated by the vague denitions of catch-up growth. Catchup growth can refer to the rst 6 to 12 months of life to as late as 2 years
after birth and usually refers to realignment of ones genetic growth potential after intrauterine growth retardation (IUGR). This denition allows for
fetal growth retardation at any birth weightdeven large fetuses can be
growth retarded relative to their genetic potential. Although it is likely
ADULT METABOLIC DISEASE: DEVELOPMENTAL ORIGINS
195
that accelerated growth confers an additional risk to the growth-retarded fetus, these conicting results demonstrate the need for additional carefully
designed studies to determine just how childhood growth rates inuence
the later development of cardiovascular disease and type 2 diabetes.
Size at birth and insulin secretion and insulin action

The mechanisms underlying the association between size at birth and impaired glucose tolerance or type 2 diabetes are unclear. A number of studies
in children and adults have shown that non- or prediabetic subjects with low
birth weight are insulin resistant and thus predisposed to the development of
type 2 diabetes [9,1214,1927]. IUGR is known to alter the fetal development of adipose tissue, which is closely linked to the development of insulin
resistance [28,29]. In a well-designed case-control study of 25-year-oldadults, individuals born SGA at 37 weeks or later had a signicantly higher
percentage of body fat [14]. Insulin sensitivity, even after adjusting for BMI
or total fat mass, was markedly impaired in these SGA subjects. There were
no signicant dierences between the SGA and control groups with respect
to parental history of type 2 diabetes, cardiovascular disease, hypertension,
or dyslipidemia. Of importance to generalizing the ndings to other populations, the causes of IUGR were gestational hypertension (50%), smoking
(30%), maternal short stature (7%), congenital anomalies (7%), and unknown (6%).
It was originally thought that the adverse eect of IUGR on glucose homeostasis was mediated through programming of the fetal endocrine pancreas [1]. Growth-retarded fetuses and newborns have been shown to have
a reduced population of pancreatic b-cells [30]. Low birth weight has been
associated with a reduced insulin response after glucose ingestion in young
nondiabetic men; however, a number of other studies have found no impact
of low birth weight on insulin secretion in human beings [12,26,27]. None of
these earlier studies adjusted for the corresponding insulin sensitivity, however, which has a profound impact on insulin secretion. Therefore, Jensen
and colleagues [31] measured insulin secretion and insulin sensitivity in
a well-matched white population of 19-year-old glucose-tolerant men with
birth weights below the 10th percentile (SGA) or between the 50th and
75th percentiles (controls). To eliminate the major confounders, such as diabetes genes, none of the participants had a family history of diabetes, hypertension, or ischemic heart disease. There was no dierence between the
groups with regard to current weight, BMI, body composition, or lipid prole. When controlled for insulin sensitivity, insulin secretion was reduced by
30%. Insulin sensitivity was normal in the SGA subjects, however. The investigators hypothesized that defects in insulin secretion may precede defects
in insulin action and that once SGA individuals accumulate body fat, they
develop insulin resistance [31].
196
SIMMONS
Epidemiologic challenges
These data suggest that low birth weight is associated with glucose intolerance, type 2 diabetes, and cardiovascular disease. The question remains as
to whether these associations reect fetal nutrition or other factors that contribute to birth weight and the observed glucose intolerance. Because of the
retrospective nature of the cohort identication, many confounding variables were not always recorded, such as lifestyle, socioeconomic status, education, maternal age, parental build, birth order, obstetric complications,
smoking, and maternal health. Maternal nutritional status, directly in the
form of diet history or indirectly in the form of BMI, height, and pregnancy
weight gain, were usually not recorded. Instead, birth anthropometric measures were used as proxies for presumed undernutrition in pregnancy.
Genetics versus environment
Several epidemiologic and metabolic studies of twins and rst-degree relatives of patients with type 2 diabetes have demonstrated an important genetic component of diabetes [3235]. The association between low birth
weight and risk of type 2 diabetes in some studies could theoretically be explained by a genetically determined reduced fetal growth rate. In other
words, the genotype responsible for type 2 diabetes may itself cause retarded
fetal growth in utero. This forms the basis for the fetal insulin hypothesis,
which suggests that genetically determined insulin resistance could result
in low insulin-mediated fetal growth in utero as well as insulin resistance in
childhood and adulthood [36]. Insulin is one of the major growth factors in
fetal life, and monogenic disorders that aect fetal insulin secretion or fetal
insulin resistance also aect fetal growth. Mutations in the gene encoding
glucokinase that result in low birth weight and maturity onset diabetes of
the young have been identied [37,38]. Such mutations are rare, however,
and no analogous common allelic variation has yet been discovered.
Recent genetic studies suggest that the increased susceptibility to type 2 diabetes of subjects who are born SGA results from the combination of genetic
factors and an unfavorable fetal environment. Polymorphisms of PPARg2,
a gene involved in the development and metabolic function of adipose tissue,
have been shown to modulate the susceptibility of subjects who are born SGA
to develop insulin resistance later in life [39,40]. The polymorphism is only associated with a higher risk of type 2 diabetes if birth weight is reduced [39,40].
There is obviously a close relation between genes and the environment.
Not only can maternal gene expression alter the fetal environment; the maternal intrauterine environment also aects fetal gene expression.
What animal models can tell us
Animal models have a normal genetic background on which environmental eects during gestation or early postnatal life can be tested for their role
197
in inducing diabetes. The most commonly used animal models are caloric or
protein restriction, glucocorticoid administration, or induction of uteroplacental insuciency in the pregnant rodent. In the rat, maternal dietary protein restriction (approximately 40%50% of normal intake) throughout
gestation and lactation has been reported to alter glucose homeostasis and
hypertension in the adult ospring [4146]. Ospring are signicantly growth
retarded, remain growth retarded throughout life, and develop mild b-cell secretory abnormalities in some cases [4145] and insulin resistance in others
[43,4650]. Aged rats develop hyperglycemia, which is characterized by defects in insulin signaling in muscle, adipocytes, and liver [4750].
Fetal overexposure to glucocorticoids via maternal administration or by
inhibition of placental 11bhydroxysteroid dehydrogenase1 in the rat induces hypertension, glucose intolerance, and abnormalities in hypothalamo-pituitary-adrenocortical (HPA) function after birth [5154].
To extend these experimental studies of growth retardation, we developed
a model of uteroplacental insuciency (IUGR) in the rat that restricts fetal
growth [55,56]. Growth-retarded fetal rats have critical features of a metabolic prole characteristic of growth-retarded human fetuses: decreased levels of glucose, insulin, insulin-like growth factor-I (IGF-I), amino acids, and
oxygen [5759]. By 6 months of age, IUGR rats develop diabetes with a phenotype remarkably similar to that observed in the human being with type 2
diabetes: progressive dysfunction in insulin secretion and insulin action.
Thus, the studies in various animal models support the hypothesis that an
abnormal intrauterine milieu can induce permanent changes in glucose homeostasis after birth and lead to type 2 diabetes in adulthood.
Cellular mechanisms: mitochondrial dysfunction and oxidative stress

The intrauterine environment inuences development of the fetus by
modifying gene expression in pluripotential cells or terminally dierentiated
and poorly replicating cells. The long-range eects on the ospring (into
adulthood) depend on the cells undergoing dierentiation, proliferation,
or functional maturation at the time of the disturbance in maternal fuel
economy. The fetus also adapts to an inadequate supply of substrates (eg,
glucose, amino acids, fatty acids, oxygen) by metabolic changes, redistribution of blood ow, and changes in the production of the fetal and placental
hormones that control growth.
The fetus immediate metabolic response to placental insuciency is catabolismdit consumes its own substrates to provide energy. A more prolonged reduction in availability of substrates leads to a slowing in growth.
This enhances the fetus ability to survive by reducing the use of substrates
and lowering the metabolic rate. Slowing of growth in late gestation leads to
disproportion in organ size, because organs and tissues that are growing
rapidly at the time are aected the most.
198
SIMMONS
Uteroplacental insuciency caused by such disorders as preeclampsia,

maternal smoking, and abnormalities of uteroplacental development is
one of the most common causes of fetal growth retardation. The resultant
abnormal intrauterine milieu restricts the supply of crucial nutrients to the
fetus, thereby limiting fetal growth. Multiple studies have now shown that
IUGR is associated with increased oxidative stress in the human fetus
[6066]. A major consequence of limited nutrient availability is an alteration
in the redox state in susceptible fetal tissues, leading to oxidative stress. In
particular, low levels of oxygen, evident in growth-retarded fetuses, decrease
the activity of complexes of the electron transport chain, which generates increased levels of reactive oxygen species (ROS). Overproduction of ROS initiates many oxidative reactions that lead to oxidative damage not only in
the mitochondria but in cellular proteins, lipids, and nucleic acids. Increased
ROS levels inactivate the iron-sulfur centers of the electron transport chain
complexes and tricarboxylic acid cycle aconitase, resulting in shutdown of
mitochondrial energy production.
A key adaptation enabling the fetus to survive in a limited energy environment may be the reprogramming of mitochondrial function [67,68].
These alterations in mitochondrial function can have deleterious eects,
however, especially in cells that have a high-energy requirement, such as
the b-cell. The b-cell depends on the normal production of ATP for nutrient-induced insulin secretion [6976] and proliferation [77]. Thus, an interruption of mitochondrial function can have profound consequences for
the b-cell.
Mitochondrial dysfunction can also lead to increased production of ROS,
which leads to oxidative stress if the defense mechanisms of the cell are overwhelmed. b-Cells are especially vulnerable to attack by ROS, because the expression of antioxidant enzymes in pancreatic islets is low [78,79] and b-cells
have a high oxidative energy requirement. Increased ROS impair glucosestimulated insulin secretion [80,81], decrease gene expression of key b-cell
genes [8286], and induce cell death [8791].
We have found that uteroplacental insuciency induces mitochondrial
dysfunction in the fetal b-cell, leading to increased production of ROS,
which, in turn, damage mitochondrial DNA (mtDNA). A self-reinforcing
cycle of progressive deterioration in mitochondrial function leads to a corresponding decline in b-cell function. Finally, a threshold in mitochondrial
dysfunction and ROS production is reached, and diabetes ensues [92].
Mitochondrial dysfunction is not limited to the b-cell in the IUGR animal. IUGR animals exhibit marked insulin resistance early in life (before
the onset of hyperglycemia), which is characterized by blunted wholebody glucose disposal in response to insulin and impaired insulin suppression of hepatic glucose output [93]. Basal hepatic glucose production is
also increased [93]. Oxidation rates of pyruvate, glutamate, succinate, and
a-ketoglutarate are signicantly blunted in isolated hepatic mitochondria
from IUGR pups (before the onset of diabetes) [94]. This derangement in
199
oxidative phosphorylation predisposes the IUGR rat to increased hepatic

glucose production by suppressing pyruvate oxidation and increasing gluconeogenesis [94].
Mitochondria in muscle of IUGR young adult rats, before the onset of
hyperglycemia, exhibit signicantly decreased rates of state-3 oxygen consumption with pyruvate, glutamate, a-ketoglutarate, and succinate [95]. Decreased pyruvate oxidation in IUGR mitochondria is associated with
decreased ATP production, decreased pyruvate dehydrogenase activity,
and increased expression of pyruvate dehydrogenase kinase 4 (PDK4).
Such a defect in IUGR mitochondria leads to a chronic reduction in the
supply of ATP available from oxidative phosphorylation. Impaired ATP
synthesis in muscle compromises energy-dependent GLUT4 recruitment to
the cell surface, glucose transport, and glycogen synthesis, which contributes
to insulin resistance and hyperglycemia of type 2 diabetes [95].
Our studies are likely to have important clinical applicability as well. A
recent study in young adult ospring of patients with type 2 diabetes demonstrated that those subjects with insulin resistance had a 30% reduction in
mitochondrial phosphorylation compared with age-matched controls [96].
The investigators speculated that insulin resistance in the skeletal muscle
of insulin-resistant ospring of patients with type 2 diabetes was attributable
to an inherited defect in mitochondrial oxidative phosphorylation [96].
Thus, our studies elucidate the molecular mechanisms underlying the link
between mitochondrial dysfunction, whether hereditary or secondary to
an environmental insult, and the later development of type 2 diabetes.
Summary
The combined epidemiologic, clinical, and animal studies clearly demonstrate that the intrauterine environment inuences growth and development
of the fetus and the subsequent development of adult diseases. There are
critical specic windows during development, often coincident with periods
of rapid cell division, during which a stimulus or insult may have long-lasting consequences on tissue or organ function after birth. Birth weight is only
one marker of an adverse fetal environment, and conning studies to this
population only may lead to erroneous conclusions regarding etiology.
Studies using animal models of uteroplacental insuciency suggest that mitochondrial dysfunction and oxidative stress play an important role in the
pathogenesis of the fetal origins of adult disease.
References
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35 (2006) 205218
Index
Note: Page numbers of article titles are in boldface type.
A
Abortion, spontaneous, gestational Type I
diabetes associated with, 54, 81
Acromegaly, during pregnancy, 105106
Addisons disease, in pregnancy, 611. See
also Primary adrenal insuciency.
Adenomas, pituitary, during pregnancy,
clinically nonfunctioning, 109
Cushings syndrome with,
12, 56
endocrine changes with,
99100
prolactinoma, 100105
thyroid-stimulating
hormone-secreting,
100, 108109
for pheochromocytoma, during

pregnancy, 14
optimal timing of, 15
Adrenocorticotropic hormone (ACTH),
fetal, labor onset role of, 176177
in pregnancy screening, for Cushings
syndrome, 24
for primary adrenal insuciency,
89
pituitary adenomas and, during
pregnancy, 100, 106108
a-Adrenergic blockade, for
pheochromocytoma, during
pregnancy, 14
Amiloride, for hyperaldosteronism, during
pregnancy, 13
Adrenal crisis, during pregnancy, medical

management of, 10
Amniochorion, inammation of, premature

birth associated with, 181183
Adrenal disorders, in pregnancy, 120

congenital adrenal hyperplasia
and, 1516
Cushings syndrome, 16
hyperaldosteronism, 1113
hypertension, 11, 1314
overview of, 1, 16
pheochromocytoma, 1315
primary adrenal insuciency,
611
Angiotensin-converting enzyme inhibitors,

for preeclampsia, 167
Adrenal hyperplasia, congenital, pregnancy

and, 1516
Adrenal insuciency (AI), in
pregnancy, 611. See also Primary
adrenal insuciency.
Adrenal vein sampling, in
pregnancy screening, for
Adrenalectomy, for Cushings
syndrome, during pregnancy,
56
for hyperaldosteronism, during
pregnancy, 13
Animal models, of adult metabolic disease,

196197
Anterior pituitary gland, disorders of. See
Pituitary disorders.
pregnancy impact on, 99100
Antidiabetic agents, insulins. See Insulins
and insulin therapy.
oral. See Oral antidiabetic agents.
Antihypertensive therapy, for preeclampsia,
165167
Antioxidants, for preeclampsia prevention,
164
Aspirin, for preeclampsia prevention, 163
Autocrine mediators, of parturition,
176179
Autoimmune thyroid disease, euthyroidism
with, during pregnancy, 123
b-Adrenergic blockade, for Graves disease,
during pregnancy, 129
doi:10.1016/S0889-8529(05)00132-5
endo.theclinics.com
206
b-Adrenergic blockade (continued )
for pheochromocytoma, during
pregnancy, 1415
for preeclampsia, during pregnancy,
166167
B
Biophosphonates, for primary
hyperparathyroidism, during
pregnancy, 3536
Birth size, in adult metabolic disease, insulin
inuence, 195
Birth weight, adult metabolic disease and,
193194
insulin factors, 195
Blood pressure, elevated, in pregnancy,
157171. See also Hypertension.
Body mass index (BMI), adult metabolic
disease and, 193194
insulin factors, 195
as preeclampsia risk factor, 160161,
164
infertility and, 147149
Bone biopsy, for skeletal calcium
metabolism, during pregnancy, 2627
Bone metabolism, in pregnancy and
lactation, 2151
adaptations during lactation,
2833
adaptations during pregnancy,
2227
disorders of, 3345
Breast(s), skeletal demineralization role of,
30
Bromocriptine, for acromegaly, during
pregnancy, 106
for Cushings syndrome, during
pregnancy, 108
for hyperprolactinemia, during
pregnancy, 101
eects on pregnancy,
102103
indications for, 104105
for lactotroph hyperplasia, during
pregnancy, 109
C
Cabergoline, for acromegaly, during
pregnancy, 106
pregnancy, 101, 104105
Calcitonin, for primary
pregnancy, 35
INDEX
mineral ions and, adaptations during

lactation, 2830
2325
Calcitriol, for hypoparathyroidism, during
pregnancy, 3738
Calcitropic hormones, mineral ions and,
adaptations during lactation, 2830
2225
Calcium, adaptations during lactation,
intestinal absorption of, 30
low intake and, 43
mineral ions and, 2830
renal handling of, 31
skeletal metabolism of, 3133
intestinal absorption of, 25
low intake and, 43
mineral ions and, 2225
renal handling of, 2526
skeletal metabolism of, 2527
for preeclampsia prevention, 164
Calcium channel blockers, for preeclampsia,
166167
Calcium metabolism, in pregnancy and
lactation, 2151
2833
2227
disorders of, 3345
Calcium supplements, for
hypoparathyroidism, during
pregnancy, 3738
for neonatal hypoparathyroidism, 36
Cancer, thyroid, during pregnancy, 132
Cardiovascular disease, developmental
adult metabolic disease and, 193199
preeclampsia as risk factor for, 150,
167168
Catch-up growth, adult metabolic disease
and, 194195
Chronic hypertension, in pregnancy,
classicational denition of, 157158
preeclampsia superimposed on,
157158, 168
Cigarette smoking, preeclampsia risk and,
161
Clomiphene citrate, for infertility, 138
Clonidine test, in pregnancy screening, for
207
INDEX
Computed tomography (CT), in pregnancy

screening, for hyperaldosteronism, 12
inammation of, premature birth

associated with, 181183
Congenital adrenal hyperplasia, pregnancy

and, 1516
Dehydroepiandrostenedione (DHEAS),
Congenital anomalies, gestational Type I

oral antidiabetic agents and,
63, 68
Dexamethasone, initiation during

pregnancy, for congenital adrenal
hyperplasia prevention, 1516
Corticosteroid replacement. See specic

agent.
Dexamethasone suppression test, high-dose,

syndrome, 4
Corticotropin-releasing hormone (CRH),

pituitary adenomas and, during
pregnancy, 100, 107
Diabetes mellitus, gestational, 7997. See

also Type I diabetes, in pregnancy.
management of, 5378
Type 2, in pregnancy, 5354
Corticotropin-releasing hormone (CRH)

stimulation test, in pregnancy
screening, for Cushings syndrome,
34, 107
8
Diabetic ketoacidosis, with gestational Type

I diabetes, 85
Cortisol level, plasma, in pregnancy

screening, for hypopituitarism, 110
for primary adrenal
insuciency, 89
Cortisone, for primary adrenal insuciency,
Cosyntropin tests, in pregnancy screening,
for primary adrenal insuciency, 89
Counseling, for primary adrenal
insuciency, prepregnancy, 910
Cushings syndrome, in pregnancy, 16
causes of, 12
clinical presentation of, 1
diagnosis of, 107108
dierential diagnosis of, 25
eects on pregnancy, 108
incidence of, 2, 106
maternal morbidity associated
with, 2
pathogenesis of, 106107
pituitary dysfunction with,
106108
screening tests for, 2
treatment of, 56, 108
Cyproheptadine, for Cushings syndrome,
during pregnancy, 6, 108
Cytology, for thyroid nodules, during
pregnancy, 131132
D
Decidua, hemorrhage of, in premature
birth, 183184
Diabetic nephropathy, gestational Type I

diabetes associated with, 86
Diet, for gestational Type I diabetes, 57, 62,
90
Dopamine agonists, for acromegaly, during
pregnancy, 106
pregnancy, 101
eects of, 102104
indications for, 104105
Dual x-ray absorptiometry (DXA), of
skeletal calcium metabolism, during
lactation, 31
E
Early pregnancy loss (EPL), with polycystic
ovary syndrome, 141144
Emergency management, of preeclampsia,
167
Endocrinology consult, for primary adrenal
insuciency, during pregnancy, 9
Endothelial dysfunction, in preeclampsia,
fetoplacental, 162163
maternal, 162
Environmental factors, of adult metabolic
disease, 196
Estrogen(s), labor onset role of, 177178
Euthyroidism, with autoimmune disease,
Exercise, for gestational Type I diabetes, 57,
89
208
INDEX
F
Familial benign hypocalciuric
hypercalcemia (FBHH), in pregnancy,
36
Gestational endocrine disorders. See

Pregnancy.
Fertility, in polycystic ovary syndrome,

137155
early pregnancy loss with,
141144
future directions for, 150151
gestational diabetes with,
144146
infertility treatment and, 138140
insulin resistance in,
hyperinsulinemic, 137138,
149
normal pregnancy and,
140141
pregnancy complications of,
141150
pregnancy-induced hypertensive
disorders with, 146150
prevalence of, 137
Gestational thyrotoxicosis, 124
Fetal hyperthyroidism, 130131

Fetal hypothalamic-pituitary-adrenal axis,
labor onset role of, 176177
premature, 181182
Gestational hypertension, classicational

denition of, 157158
Glucocorticoids, for hypopituitarism,

Glucose monitoring, for gestational Type I
diabetes, 81
by self, 8687
Glucose tolerance, impaired, developmental
adult metabolic disease and, 193199
in gestational diabetes mellitus,
144145
Glyburide, use during pregnancy, 6367
administration of, 69
cost of, 70
insulin versus, 6970
lactation and, 73
pharmacology of, 6869
placental transfer of, 68
Fetal monitoring, for preeclampsia, 165
Glycemic control, for gestational Type I

diabetes, 81
goals for, 55, 8687
monitoring methods for, 8788
normal prole in, 5455
Fetal risks, with gestational Type I diabetes,

7980, 90
surveillance of, 9092
Glycosylated hemoglobin A1c monitoring,

for gestational Type I diabetes, 81,
8788
Fetoplacental factors, of preeclampsia,

160163
Gonadotroph adenomas, during pregnancy,

109
Fetus, preeclampsia manifestations in,

159160
Gonadotrophin-releasing hormone
(GnRH), in skeletal calcium
metabolism, during lactation, 30, 32
Fetal hypothyroidism, 120121

avoiding, 127128
Fine-needle aspiration, of thyroid nodules,

Fludrocortisone, for primary adrenal
Follicle-stimulating hormone (FSH), in
infertility, 138
G
Genetics, of adult metabolic disease, 196
Gestational diabetes mellitus (GDM),
7997. See also Type I diabetes, in
pregnancy.
management of, 5378
with polycystic ovary syndrome,
144146
Gonadotrophins, for infertility, 138

Graves disease, during pregnancy, 124130
diagnosis of, 125
epidemiology of, 124
pregnancy outcomes with, 125
treatment of, 125130
b-adrenergic blockers, 129
guidelines for, 126, 128
iodides for, 129
radioactive iodine therapy,
129130
surgery indications, 129
thionamides for, 125128
Growth factors, preeclampsia impact on,
162163
209
INDEX
Growth hormone (GH), pituitary adenomas

and, during pregnancy, 100
acromegaly association
with, 105106
H
Hematologic system, preeclampsia
manifestations in, 159
Hemoglobin A1c monitoring, glycosylated,
for gestational Type I diabetes, 81,
8788
Hemorrhage, decidual, in premature birth,
183184
Hepatic system, preeclampsia
High-dose dexamethasone suppression test
(HDST), in pregnancy screening, for
Human chorionic gonadotropin (hCG),
pregnancy physiology of, thyroid
function and, 118, 124
Hydralazine, for preeclampsia, 166167
Hydrocortisone, for primary adrenal
21-Hydroxylase antibodies, in pregnancy
screening, for primary adrenal
insuciency, 9
21-Hydroxylase deciency, pregnancy and,
1516
Hyperaldosteronism, primary, in
pregnancy, 1113. See also Primary
hyperaldosteronism.
dopamine agonists for, 101

gestational prolactinoma growth,
101102
incidence of, 100
management of, 104105
surgical treatment of, 100101
Hypertension, in pregnancy, 11, 157171
chronic antenatal disorders of,
157158
classication of, 157158
clinical manifestations of,
159160
complications of, 158
later life risks associated with,
167168
pathophysiology of, 161163
polycystic ovary syndrome and,
146150
predictors of, 163
prevention of, 163164
risk factors for, 160161
with hypothyroidism, 119120
with pheochromocytoma,
1314
with Type I diabetes, 8586
Hyperthyroidism, during pregnancy,
123130
Graves disease, 124130
hyperemesis gravidarum, 124
prevalence of, 123124
fetal, 130131
neonatal, 130131
Hypercalcemia of malignancy, during

pregnancy, 44
Hypocalcemia, neonatal, with maternal

primary hyperparathyroidism, 34
with magnesium sulfate administration
Hypercortisolism, In pregnancy. See

Cushings syndrome.
Hypoglycemia, with gestational Type I

diabetes, 81
Hyperemesis gravidarum, hyperthyroidism

associated with, 124
Hypoparathyroidism, during pregnancy,

3638
neonatal, with maternal primary
hyperparathyroidism, 3436
with maternal radioactive iodine
therapy, 45
Hyperinsulinemia, in preeclampsia, 149,

162163
Hyperinsulinemic insulin resistance,
137138, 149
Hypermagnesemia, in neonates, 4243
Hyperparathyroidism, primary, during
pregnancy, 3336
Hyperprolactinemia, during pregnancy,
100105
Hypopituitarism, during pregnancy,

109112
causes of, 109
hormone replacement for,
109110
lymphocytic hypophysitis,
110111
Sheehans syndrome, 111112
210
Hypothalamic-pituitary-adrenal (HPA)
axis, fetal, labor onset role of, 176177
premature, 181182
Hypothyroidism, during pregnancy,
119123
causes of, 119
diagnosis of, 119
pregnancy outcomes with,
119121
fetal, 120121
avoiding, 127128
neonatal, 120121
I
Immunoradiometric assays (IRMA), for
calcium and bone adaptations, during
pregnancy and lactation, 2324, 28
Impaired glucose tolerance (IGT),
developmental adult metabolic disease
and, 193199
in gestational diabetes mellitus,
144145
In vitro fertilization (IVF), for infertility,
140
Infertility, body mass index and, in
preeclampsia risks, 147149
INDEX
requirements for, 6263

types of, 5759
Intestines, calcium absorption by, during
lactation, 30
Intrauterine growth retardation (IUGR),
adult metabolic disease and, 194195,
197
Intravenous saline test, in pregnancy
screening, for primary adrenal
insuciency, 12
Iodides, for Graves disease, during
pregnancy, 129
Iodine therapy, radioactive, for Graves
disease, during pregnancy, 129130
maternal, neonatal
hypoparathyroidism from,
45
K
Ketoconazole, for Cushings syndrome,
Ketone testing, urinary, for gestational
Type I diabetes, 88
Infertility treatment, polycystic ovary

syndrome and, 138140, 143, 150
L
Labetalol, for preeclampsia, 166167
Insulin resistance, in preeclampsia, 149, 162

hyperinsulinemic, 137138, 149
normal pregnancy and, 140141
Labor and delivery, endocrinology of,

173191
autocrine mediators of, 176179
estrogens role, 177178
fetal HPA axis role, 176177
historical context of, 173174
oxytocin role, 179
paracrine mediators of, 176179
parturition cascade at term,
174176
physiologic diagnosis in, 66, 174
post-term pregnancy and,
184186
preterm birth and, 179184. See
also Preterm (premature)
birth.
progesterone role, 178179
gestational Type I diabetes
management during, 92
primary adrenal insuciency
Insulin secretion/action, in adult metabolic

disease, birth size role, 195
Insulin sensitizers, for infertility, 139140,
143
Insulins and insulin therapy, during
pregnancy, diet therapy versus, 62
doses for, 8889
evidence-based criteria for, 73
fetal markers for initiation of, 61
intensive strategies for, 5557
labor and delivery
considerations, 92
oral antidiabetic agents versus,
6367, 6970
patient indications for, 6061
placental transfer and safety
concerns, 58, 60
postpartum requirements, 9293
rapid-acting, retinopathy
progression risks with,
8184
Lactation, calcium and bone metabolism

during, 2151
2227
adaptations of, 2833
211
INDEX
disorders of, 3345

hypoparathyroidism with, 3638
low calcium intake during, 43
osteoporosis associated with,
3840
pseudohypoparathyroidism with,
38
Lactotroph hyperplasia, during pregnancy,
109
Laparoscopic ovarian drilling (LOD), for
infertility, 109, 140
Levothyroxine, for hypothyroidism, during
pregnancy, 121123
Lifestyle modications, for polycystic ovary
syndrome, 139140, 150
for preeclampsia prevention, 164
Lymphocytic hypophysitis, during
pregnancy, 110111
M
Macrosomia, with gestational diabetes,
9092
Magnesium sulfate, administration during
pregnancy, 4143
bone and mineral impact of, 41
management issues with, 4243
maternal complications of, 41
neonatal complications of, 42
Magnetic resonance imaging (MRI), in
pregnancy screening, for Cushings
syndrome, 45
for hyperaldosteronism, 12
for pheochromocytoma, 14
9
Maternal factors, of preeclampsia, 160162
Maternal monitoring, for preeclampsia, 165
Metabolic disease/disorders, in
preeclampsia, 150, 162
origins of adult, 193204
animal models of, 196197
birth size and insulin, 195
catch-up growth, 194195
cellular mechanisms, 197199
epidemiologic challenges of, 196
genetic versus environment, 196
high birth weight, 194
low birth weight, 193194
mitochondrial dysfunction and,
197199
oxidative stress and, 197199
with insulin resistance, 140141, 150
Metformin, for infertility, 139, 143

Methimazole (MMI), for Graves disease,
Methyldopa, for preeclampsia, 166167
Metyrapone, for Cushings syndrome,
Metyrosine, for pheochromocytoma, during
pregnancy, 15
Mineral ions, calcitropic hormones and,
adaptations during lactation, 2830
2225
Mineral metabolism, in pregnancy and
lactation, 2151
2833
2227
disorders of, 3345
Mineralocorticoids, for primary adrenal
Miscarriage, with polycystic ovary
syndrome, 141144
Mitochondrial dysfunction, adult metabolic
disease and, 197199
Mitotane, for Cushings syndrome, during
pregnancy, 6, 108
Molecular mechanisms, of premature birth,
181
Multiparity, as preeclampsia risk factor,
160161
Multisystem organ dysfunction,
preeclampsia-related, 159
N
Neonatal hyperthyroidism, 130131
Neonatal hypoparathyroidism, with
maternal primary
with maternal radioactive iodine
therapy, 45
Neonatal hypothyroidism, 120121
Neonates, magnesium sulfate
administration during pregnancy
impact on, 42
preeclampsia manifestations in,
159160
Neurologic system, preeclampsia
212
Nifedipine, for preeclampsia, 167
Nitroprusside, for preeclampsia, 166167
Nodules, thyroid, during pregnancy,
131132
O
Obesity, as preeclampsia risk factor,
160161, 164
infertility and, 147149
Octreotide, for acromegaly, during
pregnancy, 106
for thyroid-stimulating hormonesecreting tumors, during
pregnancy, 108109
Oral antidiabetic agents, during pregnancy,
anomalies risks with, 63, 68
cost of, 70
insulin therapy versus, 6367,
6970
lactation and, 73
Osteoporosis, with pregnancy and lactation,
3840
clinical features of, 3940
diagnostic studies of, 40
hormonal factors of, 39
laboratory ndings, 40
pathogenesis of, 40
prevalence of, 3839
therapeutic interventions for, 40
Oxidative stress, adult metabolic disease
and, 197199
Oxytocin, labor onset role of, 179
P
Paracrine mediators, of parturition,
176179
Parathyroid hormone (PTH), magnesium
sulfate administration during
pregnancy impact on, 41
maternal, 41
neonatal, 42
mineral ions and, adaptations during
lactation, 2830, 32
2325
Parathyroidectomy, for primary
pregnancy, 3536
INDEX
Parturition, endocrinology of, 173191. See

also Labor and delivery.
Pergolide, for hyperprolactinemia, during
pregnancy, 101, 103
Phenoxybenzamine, for
pheochromocytoma, during
pregnancy, 14
Pheochromocytoma, in pregnancy, 1316
clinical presentations of, 13
diagnosis of, 14
fetal morbidity/mortality with, 14
maternal morbidity/mortality
with, 14
treatment of, 1415
Phosphorus, mineral ions and, adaptations
during lactation, 2830
2325
Pituitary disorders, in pregnancy, 99116
acromegaly, 105106
adenomas, clinically
nonfunctioning, 109
12, 56
99100
thyroid-stimulating
hormone-secreting,
100, 108109
tumor-related, 12, 56
hypopituitarism, 109112
normal anterior gland physiology
versus, 99100
Pituitary tumors, during pregnancy,
clinically nonfunctioning, 109
Cushings syndrome with, 12
surgical approach to, 56
endocrine changes with, 99100
thyroid-stimulating hormonesecreting, 100, 108109
Placenta, insuciency of, adult metabolic
disease associated with, 197199
perfusion of, preeclampsia risks and,
160161
transfer mechanisms, of insulin
therapy, 58, 60
of oral antidiabetic agents, 68
Placental growth factor (PIGF), in
preeclampsia, 162163
Polycystic ovary syndrome (PCOS), fertility
in, 137155
213
INDEX
early pregnancy loss with,

141144
future directions for, 150151
gestational diabetes with,
144146
infertility treatment and, 138140
insulin resistance in,
hyperinsulinemic, 137138,
149
normal pregnancy and,
140141
pregnancy complications of,
141150
pregnancy-induced hypertensive
disorders with, 146150
prevalence of, 137
Positron emission tomography (PET), in
pregnancy screening, for
Post-term pregnancy, causes of, 185
endocrinology of, 184185
Postpartum period, gestational Type I
diabetes management during, 9293
Prednisolone, for hypopituitarism, during
pregnancy, 110
Prednisone, for hypopituitarism, during
pregnancy, 110
Preeclampsia, classicational denition of,
157158
clinical manifestations of, 159160
later life risks associated with, 167168
antihypertensive therapy,
165167
emergency treatment, 167
fetal monitoring, 165
maternal monitoring, 165
seizure prophylaxis, 167
surveillance goals, 164
146150
predictors of, 163
infertility and body mass index,
147149
superimposed on chronic
hypertension, 157158
Pregnancy, acromegaly during, 105106
adrenal disorders in, 120
congenital adrenal hyperplasia
and, 1516
hypertension, 11, 1314
overview of, 1, 16
primary adrenal insuciency,
611
calcium and bone metabolism during,
2151
2833
adaptations of, 2227
disorders of, 3345
Cushings syndrome in, 16
causes of, 12
clinical presentation of, 1
diagnosis of, 107108
dierential diagnosis of, 25
maternal morbidity associated
with, 2
pathogenesis of, 106107
pituitary dysfunction with,
106108
screening tests for, 2
euthyroidism with autoimmune
disease during, 123
familial benign hypocalciuric
hypercalcemia in, 36
Graves disease in, 124130
diagnosis of, 125
epidemiology of, 124
pregnancy outcomes with, 125
b-adrenergic blockers, 129
guidelines for, 126, 128
iodides for, 129
radioactive iodine therapy,
129130
surgery indications, 129
thionamides for, 125128
hyperaldosteronism in, 1113
diagnosis of, 1213
prevalence of, 11
RAS activity with, 1112
treatment of, 13
hypercalcemia of malignancy in, 44
hyperemesis gravidarum with, 124
hypertension in, 11, 157171
214
Pregnancy (continued )
chronic antenatal disorders of,
157158
clinical manifestations of,
159160
later life risks associated with,
167168
predictors of, 163
with pheochromocytoma, 1314
with polycystic ovary syndrome,
146150
with Type I diabetes, 8586
hyperthyroidism during, 123130
Graves disease, 124130
hyperemesis gravidarum, 124
prevalence of, 123124
hypoparathyroidism during, 3638
hypopituitarism during, 109112
causes of, 109
hormone replacement for,
109110
syndromes of, 110112
hypothyroidism during, 119123
causes of, 119
diagnosis of, 119
pregnancy outcomes with,
119121
insulin resistance during, 140141, 162
labor and delivery, endocrinology of,
173191. See also Parturition.
gestational Type I diabetes
low calcium intake during, 43
lymphocytic hypophysitis during,
110111
magnesium sulfate administration
during, bone and mineral impact
of, 4143
osteoporosis associated with, 3840
pheochromocytoma in, 1316
diagnosis of, 14
with, 14
treatment of, 1415
pituitary disorders in, 99116
acromegaly, 105106
INDEX
adenomas, clinically
nonfunctioning, 109
12, 56
99100
thyroid-stimulating
hormone-secreting,
100, 108109
tumor-related, 12, 56
hypopituitarism, 109112
normal anterior gland
physiology, 99100
polycystic ovary syndrome
post-term, causes of, 185
endocrinology of, 184185
primary adrenal insuciency in, 611
causes of, 6
diagnosis of, 79
clinical features, 7
dierential, 89
tests used for, 9
laboratory features, 7
screening tests, 8
with, 67
treatment of, 910
during labor, 1011
postpartum, 11
primary hyperparathyroidism during,
3336
fetal complications of, 3435
incidence of, 33
management of, 3536
maternal manifestations/
morbidity with, 33
prolactinoma in, 100105
gestational tumor growth,
101102
incidence of, 100
pseudohypoparathyroidism during, 38
Sheehans syndrome during, 111112
thyroid disorders during, 117136
cancer, 132
common incidence of, 117,
132133
disease, 123
215
INDEX
fetal/neonatal hyperthyroidism,
130131
hyperthyroidism, 123130
hypothyroidism, 119123
nodules, 131132
normal gravid thyroid physiology
versus, 117119
thyroid function during, normal
gravid, 117119
thyrotoxicosis during, 124
Type I diabetes in, 7997
congenital anomalies associated
with, 54, 63, 68, 8081
diabetic ketoacidosis with, 85
diabetic nephropathy with, 86
diet for, 57, 62, 90
exercise for, 57, 89
fetal risks with, 54, 7980, 90
fetal surveillance with, 9092
glucose monitoring for, 81
by self, 8687
glycemic control for, 5378, 81
goals for, 55, 8687
monitoring methods for,
8788
glycosylated hemoglobin A1c
monitoring for, 81, 8788
hypertension with, 8586
hypoglycemia hazards with, 81
insulin therapy for, diet therapy
versus, 62
doses for, 8889
fetal markers for initiation
of, 61
oral antidiabetic agents
versus, 6367
patient indications for,
6061
concerns, 58, 60
risks of rapid-acting, 8184
types of, 5759
intensied therapy for, 5557
labor and delivery
considerations, 92
management of, 5378
maternal risks with, 7980
oral antidiabetic agents for,
anomalies risks with, 63, 68
cost of, 70
insulin therapy versus,
6367, 6970
lactation and, 73
postpartum management of,

9293
prevalence of, 53, 79
retinopathy progression risks
with, 8184
spontaneous abortion rate with,
54, 81
thyroid disease associated with,
8485
evidence-based criteria for,
73
intensive, 5557
Type 2 diabetes versus, 5354
urinary ketone testing for, 88
vitamin D deciency during, 4344
Pregnancy-induced hypertensive disorders
(PIHD), 157171. See also
Hypertension, in pregnancy.
Preterm (premature) birth, endocrinology
of, 179184
amniochorionic inammation
and, 181183
causes of, 179181
decidual hemorrhage and,
183184
decidual inammation and,
181183
denition of, 179
fetal HPA axis activation in,
181182
incidence of, 179180
molecular mechanisms of, 181
uterine distention and, 183184
Primary adrenal insuciency, in pregnancy,
611
causes of, 6
diagnosis of, 79
clinical features, 7
dierential, 89
tests used for, 9
laboratory features, 7
screening tests, 8
with, 67
treatment of, 910
during labor, 1011
postpartum, 11
Primary hyperaldosteronism (PA), in
pregnancy, 1113
diagnosis of, 1213
prevalence of, 11
RAS activity with, 1112
treatment of, 13
216
INDEX
Primary hyperparathyroidism, during

pregnancy, 3336
fetal complications of, 3435
incidence of, 33
management of, 3536
maternal manifestations/
morbidity with, 33
S
Seizure prophylaxis, for preeclampsia, 167
Primiparity, as preeclampsia risk factor, 160
Single-photon absorptiometry (SPA), of

skeletal calcium metabolism, during
lactation, 31
Progesterone, labor onset role of, 178179

Prolactinoma, in pregnancy, 100105
gestational tumor growth,
101102
incidence of, 100
Propylthiouracil (PTU), for Graves disease,
Pseudohypoparathyroidism, during
pregnancy, 38
PTH-related protein (PTHrP), mineral ions
and, adaptations during lactation,
2830, 32
2325
Q
Quinagolide, for hyperprolactinemia,
R
Radioactive iodine therapy, for Graves
maternal, neonatal
hypoparathyroidism from, 45
Reactive oxygen species (ROS), adult
metabolic disease and, 198199
Renal system, calcium handling by, during
lactation, 31
preeclampsia manifestations in, 159
Renin level, plasma, in pregnancy screening,
for hyperaldosteronism, 1112
Retinopathy, progression risks with rapidacting insulins, in gestational Type I
diabetes, 8184
Rosiglitazone, for infertility, 139140
Self-monitored blood glucose (SMBG)

testing, for Type I diabetes, during
pregnancy, 8687
Sheehans syndrome, during pregnancy,
111112
Spironolactone, for hyperaldosteronism,

Spontaneous abortion, gestational Type I
Subtotal thyroidectomy, for Graves
T
Tetany, neonatal, with maternal primary
Thiazolidinediones (TZDs), for infertility,
139140, 143
Thionamides, for Graves disease, during
pregnancy, 125128
Thyroid cancer, during pregnancy, 132
Thyroid disorders, during pregnancy,
117136
cancer, 132
common incidence of, 117,
132133
disease, 123
fetal/neonatal hyperthyroidism,
130131
hyperthyroidism, 123130
hypothyroidism, 119123
nodules, 131132
normal gravid thyroid physiology
versus, 117119
Thyroid function, during pregnancy,
dysfunctional, 119132. See also
Thyroid disorders.
gestational Type I diabetes and,
8485
normal gravid, 117119
Thyroid nodules, during pregnancy,
131132
Thyroid-stimulating hormone (TSH),
pregnancy physiology of, 117118
INDEX
malignant thyroid nodules and,

132
pituitary adenomas and, 100,
108109
with hyperthyroidism, 124128
with hypopituitarism, 109110
Thyroidectomy, subtotal, during pregnancy,
for Graves disease, 129
Thyrotoxicosis, gestational, 124
Thyroxine (T4), pregnancy physiology of,
118119
with hypopituitarism, 109110
Thyroxine-binding globulin (TBG),
pregnancy physiology of, 118
Triiodothyronine (T3), pregnancy
physiology of, 118119
Troglitazone, for infertility, 139
Tumors, pituitary. See Pituitary tumors.
Type 2 diabetes, in pregnancy, 5354
origins of, 194199
Type I diabetes, in pregnancy, 7997
congenital anomalies associated
with, 54, 63, 68, 8081
diabetic ketoacidosis with, 85
diabetic nephropathy with, 86
diet for, 57, 62, 90
exercise for, 57, 89
fetal risks with, 54, 7980, 90
fetal surveillance with, 9092
glucose monitoring for, 81
by self, 8687
glycemic control for, 5378, 81
goals for, 55, 8687
monitoring methods for,
8788
glycosylated hemoglobin
A1c monitoring for, 81,
8788
hypertension with, 8586
hypoglycemia hazards with, 81
insulin therapy for, diet therapy
versus, 62
doses for, 8889
fetal markers for initiation
of, 61
oral antidiabetic agents
versus, 6367
patient indications for,
6061
217
concerns, 58, 60
risks of rapid-acting,
8184
types of, 5759
intensied therapy for, 5557
labor and delivery
considerations, 92
management of, 5378
maternal risks with, 7980
oral antidiabetic agents for,
anomalies risks with,
63, 68
cost of, 70
insulin therapy versus,
6970
lactation and, 70, 73
144146
postpartum management of,
9293
prevalence of, 53, 79
retinopathy progression risks
with, 8184
spontaneous abortion rate with,
54, 81
thyroid disease associated with,
8485
evidence-based criteria
for, 73
intensive, 5557
Type 2 diabetes versus, 5354
urinary ketone testing for, 88
U
Ultrasonography, for fetal surveillance,
gestational diabetes indications for,
9092
syndrome, 4
for pheochromocytoma,
14
for primary adrenal
insuciency, 9
for thyroid nodules, 131132
Urinary free cortisol (UFC), in pregnancy
screening, for Cushings syndrome, 2
Urinary ketone testing, for gestational Type
I diabetes, 88
218
Uterine distention, in premature birth,
183184
V
Vitamin D deciency, during pregnancy,
4344
osteoporosis associated with, 39
INDEX
Vitamin D supplementation, during

pregnancy, 44
for hypoparathyroidism, 3738
W
Weight loss, for infertility, 138139, 150

Endocrine Disorders During Pregnancy 2006

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ENDOCRINE DISORDERS DURING PREGNANCY

Calcium and Bone Disorders During Pregnancy and Lactation

Adaptations in mineral metabolism occur during pregnancy and

NUMBER 1 MARCH 2006

Management of Gestational Diabetes: Pharmacologic Treatment

Diabetes mellitus is one of the most common medical complications

Successful Pregnancy in Women with Type 1 Diabetes: From

Pituitary Disorders During Pregnancy

Hyperprolactinemia and Cushings syndrome may interfere with

Thyroid Disorders During Pregnancy

Fertility in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common cause of

New-onset hypertension complicates 5% to 10% of pregnancies.

Reproductive success is critical for survival of the species. The

Developmental Origins of Adult Metabolic Disease

The combined epidemiologic, clinical, and animal studies clearly

THE CLINICS ARE NOW AVAILABLE ONLINE!

Endocrinol Metab Clin N Am

Endocrine Disorders During Pregnancy

Derek LeRoith, MD, PhD

In the present issue of Endocrinology and Metabolism Clinics of North

In the article by Drs. Lindsay and Nieman on adrenal disorders, there is an

Endocrinol Metab Clin N Am

Endocrine Disorders During Pregnancy

Susan J. Mandel, MD, MPH

Endocrinol Metab Clin N Am

Adrenal Disorders in Pregnancy

Cushings syndrome in pregnancy

* Corresponding author. Reproductive Biology and Medicine Branch, National Institute

LINDSAY & NIEMAN

ADRENAL DISORDERS IN PREGNANCY

LINDSAY & NIEMAN

abnormality to a unilateral adrenal adenoma or carcinoma or rare bilateral

ADRENAL DISORDERS IN PREGNANCY

because its appearance on T2-weighted imaging is bright. MRI also may

Late 2nd-3rd trimester

ACTH <10 pg/ml

UFC > 3-fold normal

ACTH >10 pg/ml

HDST suppression < 80%

LINDSAY & NIEMAN

or bilateral adrenalectomy for primary adrenal disorders. Unless otherwise

ADRENAL DISORDERS IN PREGNANCY

LINDSAY & NIEMAN

Screening tests and dierential diagnosis of adrenal insuciency

ADRENAL DISORDERS IN PREGNANCY

LINDSAY & NIEMAN

ADRENAL DISORDERS IN PREGNANCY

symptoms of under-replacement. Normal vaginal delivery is a reasonable

LINDSAY & NIEMAN

range by the third trimester [67,68]. The fetal-placenta unit is an additional

ADRENAL DISORDERS IN PREGNANCY

under the age of 40 years, it is generally considered appropriate to proceed

LINDSAY & NIEMAN

ADRENAL DISORDERS IN PREGNANCY

LINDSAY & NIEMAN

children, based on a maternal survey [98]. However, these children were 1 to

ADRENAL DISORDERS IN PREGNANCY

LINDSAY & NIEMAN