Hyperglycemia and Adverse Pregnancy Outcome Study: Neonatal Glycemia

Boyd E. Metzger, Bengt Persson, Lynn P. Lowe, Alan R. Dyer, J. Kennedy

Cruickshank, Chaicharn Deerochanawong, Henry L. Halliday, Anselm J. Hennis,
Helen Liley, Pak C. Ng, Donald R. Coustan, David R. Hadden, Moshe Hod, Jeremy J.
N. Oats, Elisabeth R. Trimble and for the HAPO Study Cooperative Research Group
Pediatrics 2010;126;e1545; originally published online November 15, 2010;
DOI: 10.1542/peds.2009-2257

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/126/6/e1545.full.html

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 ARTICLES

Hyperglycemia and Adverse Pregnancy Outcome

Study: Neonatal Glycemia
AUTHORS: Boyd E. Metzger, MD,a Bengt Persson, MD, WHAT’S KNOWN ON THIS SUBJECT: Newborn infants of mothers
PhD,b Lynn P. Lowe, PhD,c Alan R. Dyer, PhD,c J. Kennedy with preexisting overt diabetes mellitus are at risk for
Cruickshank, MD,d Chaicharn Deerochanawong, MD,e hypoglycemia that is associated with fetal hyperinsulinemia.
Henry L. Halliday, MD,f Anselm J. Hennis, MB, BS, PhD,g
Helen Liley, MB, ChB,h Pak C. Ng, MD,i Donald R. Coustan, WHAT THIS STUDY ADDS: For newborn infants of mothers who
MD,j David R. Hadden, MD,k Moshe Hod, MD,l Jeremy J. N.
do not have overt diabetes, neonatal glucose concentrations are
Oats, DM,m and Elisabeth R. Trimble, MD,n for the HAPO
Study Cooperative Research Group
associated with cord blood C-peptide levels but are relatively
stable during the first 5 hours of life.
Departments of aMedicine and cPreventive Medicine, Feinberg
School of Medicine, Northwestern University, Chicago, Illinois;
bDepartment of Pediatrics, Karolinska Institute, Stockholm,

Sweden; dDepartment of Medicine, Central Manchester

University Hospitals and St Mary’s Hospital, University of
Manchester, Manchester, United Kingdom; eDepartment of
Endocrinology, Rajavithi Hospital, Bangkok, Thailand;
abstract +

Departments of fChild Health and nEndocrinology, Queen’s OBJECTIVE: The goal was to describe the temporal pattern of neonatal
University, Belfast, United Kingdom; gChronic Disease Research plasma glucose levels and associations with maternal glucose levels,
Centre, University of the West Indies, Bridgetown, Barbados;
hDepartment of Pediatrics, Mater Misericordiae Mothers’ cord serum C-peptide levels, and neonatal size and adiposity.
Hospital, University of Queensland, Brisbane, Australia; METHODS: A total of 17 094 mothers and infants were included in the
iDepartment of Pediatrics, Prince of Wales Hospital, Chinese

University of Hong Kong, Hong Kong; jDepartment of Obstetrics Hyperglycemia and Adverse Pregnancy Outcome Study (15 centers in 9
and Gynecology, Women and Infants Hospital of Rhode Island countries). Mothers underwent a 75-g, 2-hour, oral glucose tolerance
and Warren Alpert Medical School, Brown University, test (OGTT) at 24 to 32 weeks of gestation. Cord blood and neonatal
Providence, Rhode Island; kDepartment of Endocrinology, Royal
Victoria Hospital, Belfast, United Kingdom; lDepartment of
blood samples were collected. Biochemical neonatal hypoglycemia
Obstetrics and Gynecology, Helen Schneider Hospital for Women, was defined as glucose levels of ⬍10th percentile (2.2 mmol/L). Clini-
Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv cally identified hypoglycemia was ascertained through medical record
University, Tel Aviv, Israel; and mDepartment of Obstetrics and
review and associations were assessed.
Gynecology, Royal Women’s Hospital, University of Melbourne,
Melbourne, Australia RESULTS: Plasma glucose concentrations were stable during the first
KEY WORDS 5 hours after birth. Maternal glucose levels were weakly positively
size at birth, neonatal hypoglycemia, cord C-peptide levels, associated with biochemical neonatal hypoglycemia (odds ratios:
maternal glucose levels
1.07–1.14 for 1-SD higher OGTT glucose levels). Frequency of neonatal
ABBREVIATIONS
hypoglycemia was higher with higher cord C-peptide levels (odds ratio:
OGTT—oral glucose tolerance test
HAPO—Hyperglycemia and Adverse Pregnancy Outcome 11.6 for highest versus lowest C-peptide category). Larger and/or fat-
OR—odds ratio ter infants were more likely to have hypoglycemia (P ⬍ .001), and
CI—confidence interval infants with hypoglycemia tended to have a higher frequency of cord
www.pediatrics.org/cgi/doi/doi:10.1542/peds.2009-2257 C-peptide levels of ⬎90th percentile.
doi:doi:10.1542/peds.2009-2257
CONCLUSIONS: Mean neonatal plasma glucose concentrations varied
Accepted for publication Aug 11, 2010 little in the first 5 hours after birth, which suggests normal postnatal
Address correspondence to Boyd E. Metzger, MD, Northwestern adjustment. Biochemical and clinical hypoglycemia were weakly re-
University Feinberg School of Medicine, Endocrinology, 645 N
Michigan Ave, Suite 530-22, Chicago, IL 60611. E-mail: bem@
lated to maternal OGTT glucose measurements but were strongly
northwestern.edu associated with elevated cord serum C-peptide levels. Larger and/or
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). fatter infants were more likely to develop hypoglycemia and hyperin-
Copyright © 2010 by the American Academy of Pediatrics sulinemia. These relationships suggest physiologic relationships be-
FINANCIAL DISCLOSURE: The authors have indicated they have
tween maternal glycemia and fetal insulin production. Pediatrics 2010;
no financial relationships relevant to this article to disclose. 126:e1545–e1552
Funded by the National Institutes of Health (NIH).

PEDIATRICS Volume 126, Number 6, December 2010 e1545

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The objective of the Hyperglycemia and gestation available, unable to com- sure to identify patients with hypergly-
Adverse Pregnancy Outcome (HAPO) plete the oral glucose tolerance test cemia above a predefined threshold.
Study was to clarify the risk of adverse (OGTT) by 32 weeks of gestation,
outcomes associated with degrees of multiple-fetus pregnancy, conception Unblinding
glucose intolerance during pregnancy through gonadotropin ovulation induc- To facilitate timely clinical decisions,
less severe than overt diabetes melli- tion or in vitro fertilization, glucose fasting and 2-hour OGTT and random
tus. Increased size at birth, delivery testing before recruitment, diagnosis plasma glucose samples were ana-
through cesarean section, clinical neo- of diabetes during the current preg- lyzed enzymatically at field center lab-
natal hypoglycemia, and fetal hyperin- nancy, diabetes predating the preg- oratories.4 Values were unblinded if
sulinemia were the predefined pri- nancy treated with medication, partic- fasting plasma glucose levels were
mary outcomes, and continuous ipation in another study that might ⬎5.8 mmol/L, 2-hour plasma glucose
relationships of maternal glucose lev- interfere with the HAPO Study, known levels were ⬎11.1 mmol/L, random
els below those diagnostic of diabetes HIV positivity or hepatitis B or C infec- plasma glucose levels were ⱖ8.9
with each of these outcomes were re- tion, previous participation in the HAPO mmol/L, or any plasma glucose level
ported.1 These observations provide Study, or inability to converse in the was ⬍2.5 mmol/L. Otherwise, women,
strong support for and extend the ma- languages used for field center forms caregivers, and HAPO Study staff mem-
ternal hyperglycemia-fetal hyperinsu- without the aid of an interpreter.1 Ges- bers (except laboratory personnel) re-
linemia hypothesis proposed by Ped- tational age and expected date of deliv- mained blinded to glucose values. To
ersen2 in 1952. ery were determined from the date of avoid center-to-center analytical varia-
The primary objective of this report is the last menstrual period if the partic- tions, aliquots of all OGTT specimens
to describe the temporal pattern of ipant was certain of the date. If the and neonatal plasma glucose samples
neonatal plasma glucose concentra- participant was uncertain, then the ex- collected for research purposes were
tions in the first 5 hours after birth for pected date of delivery was deter- analyzed at the HAPO Study central
⬎17 000 infants of mothers with glu- mined from an ultrasound scan per- laboratory.4
cose levels below those that are diag- formed between 6 and 24 weeks of
nostic of diabetes. We also examine the gestation. The final expected date of Prenatal Care, Delivery, and
association of neonatal hypoglycemia delivery also was determined from ul- Neonatal Care
with maternal glucose levels, fetal in- trasound scans if (1) gestational dat-
Prenatal care, timing of delivery, and
sulin levels (cord C-peptide concentra- ing from the last menstrual period dif-
fered from ultrasound dating by ⬎5 neonatal care, including clinical and
tions), and newborn size and adiposity. laboratory assessments for neonatal
days in cases in which ultrasonogra-
phy was performed between 6 and 13 hypoglycemia, were determined ac-
METHODS
weeks or (2) dating differed by ⬎10 cording to standard practices at each
Approval and Consent center, because participants were not
days in cases in which ultrasonogra-
The institutional review boards at all phy was performed between 14 and 24 classified as being at high risk. No field
15 field centers approved the study weeks. center arbitrarily delivered infants be-
protocol. All participants provided fore term or routinely performed ce-
written informed consent. An external Oral Glucose Tolerance Test sarean delivery at a specified maternal
data monitoring committee provided All participants underwent a standard or gestational age.
oversight. Study methods were re- 75-g OGTT between 24 and 32 weeks of According to protocol, non– glucose-
ported previously.1,3,4 A brief overview gestation (as close to 28 weeks as pos- containing fluids were used for oxyto-
is presented here. sible). Height, weight, and blood pres- cin infusion if labor was induced.
sure were measured at the OGTT visit Glucose-containing solutions were not
Participants by using standardized procedures and used during labor or delivery unless
All pregnant women at each field cen- calibrated equipment. Personal and duration exceeded 8 hours or there
ter were eligible to participate unless demographic data were collected by was a medical indication. If oral intake
they had ⱖ1 exclusion criterion, that using standardized questionnaires. of clear liquids was permitted during
is, age of ⬍18 years, planned delivery Race/ethnicity was self-identified. A labor, then participants were given
at another hospital, date of last men- sample for random plasma glucose glucose/sucrose-free liquids. Mothers
strual period uncertain and no ultra- measurement was collected at 34 to 37 were permitted to feed their infants
sound estimation from 6 to 24 weeks of weeks of gestation, as a safety mea- soon after delivery, if desired, because

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 ARTICLES

a pilot study showed no difference in prick, into a microtube containing so- Percent Body Fat of ⬎90th Percentile
plasma glucose concentrations ac- dium fluoride, immediately placed in Fat mass was calculated from birth
cording to feeding status.5 Neonatal ice water, transferred to the labora- weight, length, and flank skinfold thick-
anthropometric measurements were tory, centrifuged and separated within ness, according to the equation used
obtained by using standardized meth- 60 minutes (median separation time: by Catalano et al.9 Percent body fat was
ods.6 Medical records were abstracted 30 minutes), and frozen for sub- then calculated as 100 ⫻ fat mass/
to obtain data regarding the prenatal, sequent glucose analysis at the cen- birth weight. Percent body fat of ⬎90th
labor and delivery, postpartum, and tral laboratory. For determination of percentile for gestational age (36 – 44
newborn courses. whether neonatal plasma glucose con- weeks only) was defined by using the
centrations decrease progressively in same methods as described above for
Cord Serum C-peptide and Plasma healthy newborns, rather than show- birth weight of ⬎90th percentile.
Glucose Samples ing an early postdelivery plateau, 5% of
Cord blood samples for assessment of infants were selected randomly before Birth Weight of ⬍10th Percentile
fetal ␤-cell function (C-peptide levels) delivery to have a second sample The 10th percentiles were calculated
and measurement of glucose levels drawn 4 hours after birth. by using similar methods as for birth
were collected as soon as possible af- weight of ⬎90th percentile.
ter clamping of the cord. Cord serum Outcomes
levels of C-peptide (secreted in Biochemical Neonatal Hypoglycemia Cord C-peptide Levels of ⬎90th
equimolar concentrations with insu- Percentile
lin) were used as the index of fetal Central laboratory–measured plas-
The 90th percentile for the total HAPO
␤-cell function, rather than insulin lev- ma glucose concentrations of ⬍2.2
Study cohort (1.7 ␮g/L) was used.
els, because degradation of insulin is mmol/L, representing the 10th percen-
increased in the presence of even tile of the 17 094 HAPO Study values, Statistical Analyses
slight hemolysis, ⬃15% of cord sam- were used to define biochemical hypo-
glycemia. The 5th percentile was 1.9 Descriptive statistics included means
ples showed detectable hemolysis, and SDs for continuous variables and
and the concentrations of C-peptide mmol/L.
numbers and proportions for categor-
are not altered by hemolysis.7 ical variables. For analyses of associa-
Clinical Neonatal Hypoglycemia
The C-peptide samples were collected tions of maternal glycemia with bio-
into plain phlebotomy tubes. The glucose This was defined by ⱖ1 clinical crite- chemical hypoglycemia and cord
samples (in sodium fluoride-containing rion, that is, a notation of neonatal hy- serum C-peptide levels with both bio-
tubes) were placed in ice water, trans- poglycemia in the medical record and chemical and clinical hypoglycemia,
ported to the laboratory, and separated symptoms or treatment with glucose glucose and cord C-peptide measure-
within 60 minutes after collection (me- infusion or laboratory-reported glu- ments were considered as both cate-
dian separation time: 45 minutes). Ali- cose levels of ⱕ1.7 mmol/L in the first gorical and continuous variables in
quots were frozen and analyzed later at 24 hours after birth or ⱕ2.5 mmol/L multivariate logistic regression analy-
the central laboratory by using a Vitros after the first 24 hours.8 Meter mea- ses. In categorical analyses, each mea-
750 analyzer (Ortho Clinical Diagnostics, surements of glucose were not in- sure of glycemia and cord C-peptide
Rochester, NY) for glucose and an Au- cluded in this determination. Data on levels was divided into 7 categories.1,6
todelfia instrument (Perkin Elmer, Bos- clinical hypoglycemia were available as indicated in Tables 2 and 3.
ton, MA) for C-peptide.4 The Wales Exter- for 23 227 infants (excluding fetal
For glucose measurements as a con-
nal Quality Assessment Scheme used by deaths).
tinuous variable, odds ratios (ORs)
the central laboratory ensured accept- were calculated for each plasma glu-
able accuracy of glucose measurements Birth Weight of ⬎90th Percentile
cose measurement higher by 1 SD.
at 2.0 mmol/L of ⫾6%. The functional The 90th percentile values for gesta- Squared terms were added to assess
sensitivity of the C-peptide assay was 0.2 tional age (30 – 44 weeks) were deter- whether the logarithm of the odds of
␮g/L.4 mined for 8 newborn gender/ethnicity biochemical hypoglycemia was lin-
groups (white, other, black, Hispanic, early related to glucose levels. Interac-
Neonatal Glucose Samples or Asian), with adjustment for gesta- tions of glucose measurements as a
At 1 to 2 hours after birth, capillary tional age, field center, and parity (0, 1, continuous variable with field center,
blood was collected, through heel or ⱖ2), by using quantile regression. BMI, age, height, and mean arterial

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pressure also were examined. Be- TABLE 1 Characteristics of Study Participants With Measurements of Neonatal Glucose Levels
cause of the large sample size in the No. of Participants Finding
HAPO Study and the large number of Maternal characteristics
Age, mean ⫾ SD, y 17 094 29.1 ⫾ 5.8
infants with biochemical hypoglyce-
BMI, mean ⫾ SD, kg/m2a 17 094 27.5 ⫾ 5.0
mia, squared terms and interaction Mean arterial pressure, mean ⫾ SD, mm Hga 17 094 80.5 ⫾ 8.2
terms were considered statistically Plasma glucose level, mean ⫾ SD, mmol/La
Fasting 17 094 4.5 ⫾ 0.4
significant for this outcome only for P
1h 17 094 7.5 ⫾ 1.7
⬍ .001. Cord C-peptide levels also were 2h 17 094 6.2 ⫾ 1.3
examined as a continuous variable Neonatal characteristics
Gestational age at delivery, mean ⫾ SD, wk 17 094 39.4 ⫾ 1.6
with both linear and squared terms for Birth weight, mean ⫾ SD, g 17 086 3298 ⫾ 494
each outcome. Because the squared Cord serum C-peptide level, mean ⫾ SD, ␮g/L 16 429 1.00 ⫾ 0.59
term was significant for both biochem- Cord plasma glucose level, mean ⫾ SD, mmol/L 16 416 4.5 ⫾ 1.1
First neonatal glucose level, mean ⫾ SD, mmol/L 3.2 ⫾ 0.9
ical (P ⬍ .001) and clinical (P ⬍ .05) Second neonatal glucose level, mean ⫾ SD, mmol/L
17 094
574 3.3 ⫾ 0.8
hypoglycemia, only results of categor- Obstetric outcomes, n (%)
ical analyses are reported. Primary cesarean sectionb 15 285 2557 (16.7)
Preeclampsiab 17 094 713 (4.2)
Two logistic models (models I and II) Newborn outcomes, n (%)
were fit for each outcome, with model I Birth weight of ⬎90th percentile 17 086 1647 (9.6)
Percent body fat of ⬎90th percentile 14 823 1454 (9.8)
including adjustment for field center
Birth weight of ⬍10th percentile 17 086 1618 (9.5)
(data not shown). Model II included ad- Cord C-peptide level of ⬎90th percentile 16 429 1346 (8.2)
ditional adjustment for multiple pre- Biochemical neonatal hypoglycemia 17 094 1554 (9.1)
Clinical neonatal hypoglycemia 17 094 313 (1.8)
specified potential confounders, in- Premature deliveryb 17 094 1007 (5.9)
cluding maternal age, BMI, height, Shoulder dystocia/birth injury 17 094 203 (1.2)
gestational age and mean arterial pres- Hyperbilirubinemia 17 094 1401 (8.2)
Intensive neonatal careb 17 094 1213 (7.1)
sure at the OGTT, hospitalization before aMaternal BMI, mean arterial pressure, and plasma glucose level were measured at the OGTT visit.
delivery, smoking status, and alcohol use bThese outcomes were found more frequently in the subset of neonates for whom HAPO Study samples for neonatal glucose
and family history of diabetes. measurements were not collected (P ⬍ .001).

The ␹2 test was used for comparisons

of proportions and the 2-sample t test
tire cohort1 and of those described 15-minute intervals of collection time
for comparisons of mean cord
here were similar (Table 1). (45–180 minutes) after delivery. For a
C-peptide levels for subjects with and
By using the protocol for intravenous subset of 574 randomly selected neo-
without hypoglycemia, in subgroups
fluid administration during labor and nates, a second heel-stick sample was
defined according to birth weight and
delivery described above, glucose was collected. Second-sample collection
percent body fat. All analyses were
administered in only 7% of cases. Glu- times were divided into 5 periods.
conducted with SAS 9.1 (SAS Institute, Forty-nine samples were collected be-
cose concentrations in plasma from
Cary, NC) or Stata 10.0 (Stata Corp, Col- tween 120 and 180 minutes after deliv-
mixed arterial and venous cord blood
lege Station, TX). ery. Times for the other samples are
at birth and from heel-stick capillary
blood samples from neonates are presented in 30-minute intervals from
RESULTS 181 to 300 minutes after delivery. Over-
shown in Fig 1. Cord blood was col-
Pregnancies with glucose values lected as soon after birth as possible all, plasma glucose concentrations
blinded, birth weight recorded, gesta- (median time: 2.0 minutes [interquar- varied by no more than 0.2 mmol/L dur-
tional age determined, and obstetric tile range: 1.0 –5.0 minutes]). The ing the first 5 hours after delivery. Simi-
and neonatal records available (N ⫽ mean ⫾ SD cord plasma glucose con- lar results were noted in comparison of
23 316) were included in the initial re- centration was 4.5 ⫾ 1.1 mmol/L. values for the first and second samples
port.1 Results presented in Table 1 are Among the 16 613 neonates with a de- for the subgroup of 544 neonates for
for the 17 094 of those pregnancies livery time recorded, 430 had the first whom 2 samples were collected by de-
with central laboratory– determined, sample collected at ⱕ45 minutes sign and for whom times from delivery
1- to 2-hour neonatal plasma glucose (mean plasma glucose concentration: were available (data not shown).
levels. Maternal and neonatal charac- 3.3 mmol/L). Values for mean plasma We found a modest positive correla-
teristics of the participants in the en- glucose concentrations are plotted at tion between cord plasma glucose con-

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 ARTICLES

FIGURE 1
Temporal patterns of cord plasma glucose and neonatal plasma glucose (NG) concentrations.

centrations and neonatal plasma glu- Table 2 shows the unadjusted frequen- poglycemia tended to increase with in-
cose concentrations (r ⫽ 0.256; P ⬍ cies and fully adjusted model II ORs and creasing maternal glucose levels.
.001). As indicated in Table 1, cord 95% confidence intervals (CIs) for as- Adjusted ORs differed significantly
plasma glucose concentrations gener- sociations of maternal OGTT glucose from 1.0 only for the highest category
ally were not increased (4.5 ⫾ 1.1 measurements with biochemical neo- of fasting plasma glucose levels, the
mmol/L). natal hypoglycemia. Frequency of hy- second highest category of 1-hour
plasma glucose levels, and the 5 high-
TABLE 2 Relationship Between Maternal OGTT Glucose Measurements and Biochemical Neonatal est categories of 2-hour plasma glu-
Hypoglycemia cose levels. For glucose levels as a con-
N n (%) OR (95% CI)a tinuous variable in model II, there were
Fasting plasma glucose level weak but positive associations with
⬍4.2 mmol/L 3103 254 (8.2) 1.00
biochemical hypoglycemia (ORs of
4.2–4.4 mmol/L 5555 490 (8.8) 1.06 (0.90–1.24)
4.5–4.7 mmol/L 4520 386 (8.5) 1.01 (0.85–1.19) 1.07–1.14 for glucose levels higher by 1
4.8–4.9 mmol/L 1960 200 (10.2) 1.17 (0.95–1.44) SD). We previously reported relatively
5.0–5.2 mmol/L 1339 141 (10.5) 1.12 (0.89–1.41)
weak associations of OGTT glucose
5.3–5.5 mmol/L 480 54 (11.3) 1.11 (0.80–1.54)
ⱖ5.6 mmol/L 137 29 (21.2) 2.68 (1.71–4.20) measurements with clinical neonatal
Continuous variableb 17 094 1554 (9.1) 1.07 (1.01–1.14) hypoglycemia.1
1-h plasma glucose level
⬍5.8 mmol/L 3102 273 (8.8) 1.00 Frequency of biochemical neonatal hy-
5.9–7.3 mmol/L 5490 451 (8.2) 0.90 (0.77–1.06) poglycemia increased progressively
7.4–8.6 mmol/L 4406 404 (9.2) 0.99 (0.84–1.17) from 5.5% for the lowest category of
8.7–9.5 mmol/L 2042 196 (9.6) 1.05 (0.85–1.28)
9.6–10.7 mmol/L 1377 142 (10.3) 1.12 (0.89–1.40) C-peptide levels (ⱕ0.5 ␮g/L) to 36.9%
10.8–11.7 mmol/L 493 66 (13.4) 1.47 (1.09–1.99) for the highest category (ⱖ3.1 ␮g/L)
ⱖ11.8 mmol/L 184 22 (12.0) 1.26 (0.78–2.03) (Table 3). ORs for biochemical hypogly-
Continuous variableb 17 094 1554 (9.1) 1.07 (1.01–1.13)
2-h plasma glucose level cemia were higher in each category,
⬍5.0 mmol/L 3108 245 (7.9) 1.00 compared with those for clinical hypo-
5.1–6.0 mmol/L 5436 437 (8.0) 1.03 (0.87–1.22) glycemia, and reached 11.61 in the
6.1–6.9 mmol/L 4352 417 (9.6) 1.24 (1.04–1.47)
7.0–7.7 mmol/L 2231 221 (9.9) 1.27 (1.04–1.55) highest category. ORs for clinical hypo-
7.8–8.7 mmol/L 1281 142 (11.1) 1.46 (1.16–1.84) glycemia were increased in the high-
8.8–9.8 mmol/L 513 69 (13.5) 1.74 (1.29–2.34) est 3 categories and reached 5.26.
ⱖ9.9 mmol/L 173 23 (13.3) 1.74 (1.08–2.80)
Continuous variableb 17 094 1554 (9.1) 1.14 (1.07–1.20) Table 4 shows the association of neo-
a Adjusted (model II) for field center, maternal age, BMI, mean arterial pressure, height, gestational age at the OGTT, parity, natal anthropometric outcomes with
smoking, alcohol use, and hospitalization before delivery, family history of diabetes mellitus, and infant’s gender.
b OR for a 1-SD increase in the glucose level (0.4 mmol/L for fasting plasma glucose levels, 1.7 mmol/L for 1-hour plasma
the frequency of biochemical and clin-
glucose levels, and 1.3 mmol/L for 2-hour plasma glucose levels). ical neonatal hypoglycemia. When in-

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TABLE 3 Relationship Between Cord Serum C-Peptide Levels and Neonatal Hypoglycemia fants with values in ⱕ90th percentile
Cord Serum C-Peptide Level N n (%) OR (95% CI)a (P ⬍ .001). The frequencies of clinical
Biochemical neonatal hypoglycemiab hypoglycemia differed significantly be-
ⱕ0.5 ␮g/L 2409 133 (5.5) 1.00
tween small-for-gestational age neo-
0.6–0.8 ␮g/L 5454 317 (5.8) 1.08 (0.88–1.34)
0.9–1.2 ␮g/L 4875 448 (9.2) 1.77 (1.44–2.17) nates (birth weights in ⬍10th percen-
1.3–1.5 ␮g/L 1701 223 (13.1) 2.63 (2.09–3.30) tile for gestational age) and those with
1.6–2.1 ␮g/L 1344 190 (14.1) 2.97 (2.33–3.77) birth weights in ⱖ10th percentile;
2.2–3.0 ␮g/L 459 109 (23.7) 5.86 (4.40–7.81)
ⱖ3.1 ␮g/L 187 69 (36.9) 11.61 (8.12–16.60) however, there was no difference in
Clinical neonatal hypoglycemiac the frequencies of biochemical hypo-
ⱕ0.5 ␮g/L 2915 60 (2.1) 1.00 glycemia between these 2 groups.
0.6–0.8 ␮g/L 6537 87 (1.3) 0.70 (0.50–0.98)
0.9–1.2 ␮g/L 5900 88 (1.5) 0.82 (0.59–1.16) Table 5 shows the frequency of ele-
1.3–1.5 ␮g/L 2077 42 (2.0) 1.16 (0.77–1.75) vated cord serum C-peptide levels and
1.6–2.1 ␮g/L 1639 58 (3.5) 1.97 (1.35–2.89)
2.2–3.0 ␮g/L 571 25 (4.4) 2.50 (1.52–4.11)
mean cord C-peptide concentrations
ⱖ3.1 ␮g/L 244 18 (7.4) 5.26 (2.96–9.34) for infants with anthropometric out-
a Adjusted (model II) for field center, maternal age, BMI, mean arterial pressure, mean arterial pressure squared, height, comes, with or without biochemical or
gestational age at the OGTT, parity, smoking, alcohol use, hospitalization before delivery, family history of diabetes mellitus,
and infant’s gender.
clinical neonatal hypoglycemia. For
b Biochemical neonatal hypoglycemia indicates neonatal glucose concentrations of ⬍10th percentile for the study popula- each neonatal anthropometric pheno-
tion (⬍2.2 mmol/L).
c Clinical neonatal hypoglycemia indicates that there was a notation of neonatal hypoglycemia in the medical record and
type, infants with hypoglycemia tended
symptoms or treatment with a glucose infusion or there was a laboratory report of a glucose level of ⱕ1.7 mmol/L in the to have a higher frequency of cord
first 24 hours after birth or ⱖ2.5 mmol/L after the first 24 hours. C-peptide levels in ⬎90th percentile
and a higher mean cord C-peptide con-
TABLE 4 Association of Neonatal Hypoglycemia With Neonatal Anthropometric Measurements centration, compared with those with-
n/N (%) out hypoglycemia.
Biochemical Neonatal Clinical Neonatal
Hypoglycemia Hypoglycemia DISCUSSION
Birth weight Neonatal hypoglycemia in association
⬎90th percentile 202/1647 (12.3) 75/2219 (3.4)
ⱕ90th percentile 1349/15 439 (8.7) 394/20 963 (1.9) with fetal hyperinsulinemia repre-
P ⬍ .001 P ⬍ .001 sents the crux of the Pedersen hypoth-
⬍10th percentile 162/1618 (10.0) 102/2253 (4.5) esis,2 and the concept has been vali-
ⱖ10th percentile 1389/15 468 (9.0) 367/20 929 (1.8)
P ⫽ .169 P ⬍ .001 dated repeatedly for offspring of
Percent body fat mothers with preexisting diabetes10 or
⬎90th percentile 176/1454 (12.1) 39/1892 (2.1) gestational diabetes.11 Our data indi-
ⱕ90th percentile 1081/13 369 (8.1) 208/17 435 (1.2)
P ⬍ .001 P ⫽ .001 cate that the relationship spans the
range of maternal glycemia below the
level of overt diabetes mellitus. Also, in
fants were larger or fatter (birth age), both biochemical and clinical the newborn period, after the initial de-
weight or percent of newborn body fat neonatal hypoglycemia occurred with crease in glucose concentrations that
in ⬎90th percentile for gestational greater frequency, compared with in- follows the cessation of mother-fetus de-

TABLE 5 Neonatal Anthropometric Measurements, Neonatal Hypoglycemia, and Cord Serum C-Peptide Levels
Outcome Biochemical Neonatal Hypoglycemia Clinical Neonatal Hypoglycemia
Present Absent P Present Absent P
Birth weight of ⬎90th percentile
C-peptide level of ⬎90th percentile, n/N (%) 77/199 (38.7) 235/1401 (16.8) ⬍.001 19/60 (31.7) 365/1895 (19.3) .017
C-peptide concentration, mean, ␮g/L 1.77 1.23 ⬍.001 1.68 1.30 .017
Percent body fat of ⬎90th percentile
C-peptide level of ⬎90th percentile, n/N (%) 57/169 (33.7) 198/1248 (15.9) ⬍.001 11/33 (33.3) 306/1678 (18.2) .027
C-peptide concentration, mean, ␮g/L 1.69 1.21 ⬍.001 1.58 1.28 .017
Birth weight of ⬍10th percentile
C-peptide level of ⬎90th percentile, n/N (%) 14/148 (9.5) 35/1371 (2.6) ⬍.001 8/79 (10.1) 54/1752 (3.1) .001
C-peptide concentration, mean, ␮g/L 1.06 0.79 .001 0.94 0.81 .095

e1550 METZGER et al
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 ARTICLES

livery of glucose, plasma glucose con- glucose homeostasis. Our data suggest controversy regarding the definition of
centrations remain relatively stable. that this concept may require further clinically significant neonatal hypogly-
These data confirm that the vast majority evaluation. We did find a lower mean cemia, and differences in ascertain-
of infants born of healthy mothers who cord serum C-peptide concentration for ment are likely to be present among
do not have overt diabetes mellitus suc- infants with birth weights of ⬍10th per- clinicians. Nevertheless, associations
cessfully make the early transition to the centile; however, among those infants of maternal glycemia from the OGTT at
metabolism of endogenously derived nu- we also found a higher C-peptide concen- 28 weeks of gestation, cord serum
trient substrates. tration and a higher rate of C-peptide val- C-peptide levels, and neonatal anthro-
On the basis of comparisons for a rel- ues of ⬎90th percentile for infants with pometric measurements with clinical
atively small number of infants of nor- hypoglycemia, compared with infants neonatal hypoglycemia were similar to
mal mothers or mothers with type 1 who did not develop biochemical or clin- the associations found with biochemi-
diabetes mellitus, Pedersen12 con- ical hypoglycemia. cally defined hypoglycemia.
cluded many years ago that most in- An important strength of the HAPO Study
CONCLUSIONS
fants achieve stable glucose concen- is derived from the rigorous protocol
trations within a few hours after birth that was followed to minimize glycolysis Our data from plasma glucose measure-
and remain free of hypoglycemia. Our of the neonatal glucose samples. The ments for ⬎17 000 infants of mothers
results from measurements of plasma ⬎17 000 glucose measurements that without diabetes provide useful clinical
glucose levels obtained through heel were performed for infants of mothers information. Our findings of strong con-
stick in the first several hours after without overt diabetes mellitus repre- tinuous associations between maternal
birth from a large cohort support sent a major resource that, in the future, OGTT measurements and cord C-peptide
those suggestions convincingly. might be used to derive a consensus def- levels and between cord C-peptide levels
inition of hypoglycemia in early postnatal and neonatal hypoglycemia and exces-
For women with preexisting diabetes,
life, regarding which there is longstand- sive size at birth are consistent with and
efforts generally are made to avoid
ing debate.15–19 extend the Pedersen hypothesis. The fact
maternal hyperglycemia during labor
that these relationships extend across
and delivery, through concern that hy- There also are some potential limita-
the entire range of maternal glycemia
perglycemia might stimulate fetal in- tions. We could not justify extending the
suggests a physiologic relationship be-
sulin secretion, which in turn might in- protocol for repeated collection of blood
tween maternal glycemia and fetal insu-
crease the risk of hypoglycemia in the samples for glucose measurements be-
lin production.
early neonatal period.13 HAPO Study par- yond the early neonatal period in this
ticipants did not have overt diabetes, population of overall healthy newborns. ACKNOWLEDGMENTS
they did not receive intravenous glucose The HAPO Study was an observational The study was funded by the National In-
administration during labor in 93% of study of normal, rather than high-risk, stitute of Child Health and Human Devel-
cases, and they generally had normal mothers and infants. There was some opment and the National Institute of Dia-
cord plasma glucose concentrations at potential bias in the sample used for the betes, Digestive, and Kidney Diseases
delivery. In this setting, we found a posi- neonatal glucose measurements re- (grants R01-HD34242 and R01-HD34243),
tive correlation between cord glucose ported here, because the protocol- by the National Center for Research Re-
concentrations and 1- to 2-hour neonatal defined collection of heel stick samples sources (grants M01-RR00048 and M01-
glucose concentrations. was omitted more frequently by caregiv- RR00080), and by the American Diabetes
Findings of higher frequencies of bio- ers if cord blood was not collected, if in- Association. Support also was provided
chemical and clinical hypoglycemia fants were born through cesarean deliv- to local field centers by Diabetes UK
among the larger and fatter newborns ery, preterm, or from mothers with (grant RD04/0002756), Kaiser Perma-
who also had higher cord serum preeclampsia, or if infants were admit- nente Medical Center, KK Women’s and
C-peptide levels are consistent with the ted to the NICU. Although this might lead Children’s Hospital, Mater Mothers’ Hos-
Pedersen hypothesis and the putative to an underestimate of the frequency of pital, Novo Nordisk, the Myre Sim Fund of
role of fetal hyperinsulinemia. It is biochemical hypoglycemia, no bias the Royal College of Physicians of Edin-
known that the risk of neonatal hypogly- would be expected in clinical assess- burgh, and the Howard and Carol Ber-
cemia is increased for infants born ments for neonatal hypoglycemia. nick Family Foundation. A complete list of
small for gestational age,14 but it is Overall, the frequency of a diagnosis of authors in the HAPO Study Cooperative
thought that factors other than hyperin- clinical neonatal hypoglycemia was Research Group is available in the Sup-
sulinemia account for the disturbance in low in the HAPO Study cohort. There is plemental Appendix.

PEDIATRICS Volume 126, Number 6, December 2010 e1551

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e1552 METZGER et al
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 Hyperglycemia and Adverse Pregnancy Outcome Study: Neonatal Glycemia
Boyd E. Metzger, Bengt Persson, Lynn P. Lowe, Alan R. Dyer, J. Kennedy
Cruickshank, Chaicharn Deerochanawong, Henry L. Halliday, Anselm J. Hennis,
Helen Liley, Pak C. Ng, Donald R. Coustan, David R. Hadden, Moshe Hod, Jeremy J.
N. Oats, Elisabeth R. Trimble and for the HAPO Study Cooperative Research Group
Pediatrics 2010;126;e1545; originally published online November 15, 2010;
DOI: 10.1542/peds.2009-2257
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References This article cites 15 articles, 2 of which can be accessed free
at:
http://pediatrics.aappublications.org/content/126/6/e1545.full.
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