0021-972X/07/$15.

00/0 The Journal of Clinical Endocrinology & Metabolism 92(8):3141–3147

Printed in U.S.A. Copyright © 2007 by The Endocrine Society
doi: 10.1210/jc.2007-0238

High Risk of Congenital Hypothyroidism in

Multiple Pregnancies
Antonella Olivieri, Emanuela Medda, Simona De Angelis, Herbert Valensise, Mario De Felice,
Cristina Fazzini, Isabella Cascino, Viviana Cordeddu, Mariella Sorcini, Maria Antonietta Stazi,
and The Study Group for Congenital Hypothyroidism

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Dipartimento di Biologia Cellulare e Neuroscienze (A.O., S.D.A., C.F., V.C., M.S.), Centro Nazionale di Epidemiologia (E.M.,
M.A.S.), Sorveglianza e Promozione della Salute - Istituto Superiore di Sanità, 00161 Roma, Italy; Dipartimento di
Chirurgia (H.V.), Università Tor Vergata, 00133 Roma, Italy; Dipartimento di Biologia e Patologia Cellulare e Molecolare
(M.D.F.), Università Federico II Napoli, 80126 Napoli, Italy; and Istituto di Biologia Cellulare (I.C.), Consiglio Nazionale
delle Ricerche, Monterotondo scalo, 00015 Roma, Italy

Context: In Italy, the surveillance of congenital hypothyroidism (CH) in 10,000) and single deliveries (3.2 in 10,000 live births). Signifi-
is performed by the Italian National Registry of Infants with CH cantly higher frequencies of in situ gland as well as lower TSH mean
(INRICH). Up to now, about 3600 infants with CH are recorded in the level at screening were found in twin than in singleton CH babies. The
INRICH, and a high number of twins are included. concordance rate for permanent CH was very low (4.3%) and due to
only three concordant couples. However, a high recurrence risk for CH
Objective: Our objective was to estimate the risk of CH in multiple was estimated in siblings of affected babies recorded in the INRICH,
and single deliveries and to compare neonatal features of CH twins including twins considered as siblings.
with twins from the general population.
Conclusions: The high CH incidence observed in twins is worthy of
Design: The Italian population of CH infants recorded in the INRICH interest for the high number of induced pregnancies in Italy as well
from 1989 –2000 was investigated. as in other Western countries. Moreover, the low concordance rate for
CH among twins together with a high recurrence risk for the disease
Results: A more than 3-fold higher frequency of twins was found in among siblings indicates that environmental risk factors may act as
the CH population than in the general population, and for the first a trigger on a susceptible genetic background in the etiology of the
time, it was possible to estimate the CH incidence in multiple (10.1 disease. (J Clin Endocrinol Metab 92: 3141–3147, 2007)

C ONGENITAL HYPOTHYROIDISM (CH) is the most

frequent endocrine disease that occurs in the early
phases of life (1). The early deficit of thyroid function causes, if
North America, the twinning rate has averaged between 12–14
per 1000 pregnancies (3). However, the occurrence of twinning
is increasing in the general population and has been shown to
not promptly treated, serious and irreversible damage to the be due to the increasing use of techniques of assisted repro-
nervous system with consequent mental retardation. The early duction and drugs inducing ovulation (4). Twins are widely
diagnosis and the prompt institution of the replacement ther- reported to have more morbidity than singletons, mainly be-
apy has been achieved by the implementation of newborn cause of a higher preterm birth rate. In fact, preterm delivery is
screening programs by using blood spotted on filter paper. As the major cause of adverse outcomes (both short-term and long-
a result of these screening programs, virtually all cases of CH term) and is directly related to fetal number (5). It is well known
are now identified. In Italy, the incidence of CH in the last 10 that prematurity can affect thyroid function. Fetal thyroid sys-
yr has been about one in 2700 live births (www.iss.it/rnic/). In tem metabolism is characterized by relatively high circulating
our country, CH babies diagnosed by neonatal screening are TRH and TSH concentrations, immature T4 feedback control of
recorded in the Italian National Registry of Infants with CH TSH secretion, immature thyroid gland T4 biosynthesis and
(INRICH). This was established in Italy in 1987 as a program of secretory processes, and limited effects of T4 on responsive gene
the Health Ministry and is coordinated by the National Insti- transcription events (6 – 8). All these processes mature progres-
tutes of Health (2). Up to now, 3600 infants with confirmed sively with advancing gestational age.
diagnosis of CH are recorded in the INRICH, and a high num- Up to now, no extensive studies have been performed to eval-
ber of twins are included. uate the occurrence of CH in twin pregnancies. In this study, the
Twin birth is a relatively common event. In Europe and in Italian population of CH infants recorded in the INRICH was
investigated with the aim of 1) estimating the risk of CH in mul-
tiple and single deliveries and 2) comparing neonatal features of
First Published Online May 8, 2007
Abbreviations: CH, Congenital hypothyroidism; CI, confidence in- CH twins with twins from the general population.
terval; CM, congenital malformations; DZ, dizygous; FT4, free T4;
INRICH, Italian National Registry of Infants with CH; MZ, monozygous; Patients and Methods
SRR, sibling recurrence risk; TH, transient primary hypothyroidism.
Diagnosis ascertainment
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the en- In Italy, the neonatal screening for CH is performed by a network of
docrine community. 26 regional or interregional centers. A biochemical assessment of TSH,

3141
3142 J Clin Endocrinol Metab, August 2007, 92(8):3141–3147 Olivieri et al. • Congenital Hypothyroidism in Twins

and in 11 of the 26 centers also of T4, is performed within a few days from zygosity) and one triplet (two girls and one boy with in situ
birth. In all the centers, positive results of screening tests are confirmed gland) from a medically induced pregnancy were concordant
by definitive tests of thyroid function on serum, and thyroid ultrasound
and/or scintigraphy are generally performed to complete the CH di-
for CH at birth. The proportion of multiple deliveries ob-
agnosis. According to international guidelines (9, 10), when the defin- served in the CH population between 1989 and 2000 (75 of
itive diagnosis is not established in the neonatal period and a suspicion 2154, 3.5%) was 3-fold higher than that (1.1%) estimated in
of transient primary hypothyroidism (TH) is present, a reevaluation of the Italian general population in the same period (12).
diagnosis is performed at the age of 2–3 yr after a withdrawal of the Between 1991 and 2003, a reevaluation of the diagnosis, at
replacement therapy to ascertain the persistence of CH. At that time, T4,
free T4 (FT4), and TSH levels are measured, and ultrasound imaging, the age of 2–3 yr after a withdrawal of the replacement
scintigraphy, and clinical evaluation are performed to establish the therapy, was performed in 267 CH infants who presented a
definitive diagnosis. Babies with transient hyperthyrotropinemia on the suspicion of TH during the first years of life. The prevalence
basis of spontaneous normalization of TSH between screening and di- of twins was 1.9% (three females and one male) in the 214
agnosis are not recorded in the Register.

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A registration form is filled in at diagnosis. It includes anonymous
reevaluated infants who were affected by permanent CH and
data concerning CH infants such as screening and confirmatory labo- 13.2% (five females and two males) in the 53 babies who were
ratory tests, information on demographic data and details on clinical affected by TH (P ⬍ 0.01). Among these 53 babies, there was
state in neonatal period, diagnostic investigations (biochemical deter- the triplet concordant at birth. Seventy-three permanent CH
minations, radiography of the knee, thyroid scan, and ultrasound), in- twins were then considered for the statistical analysis pre-
formation regarding pregnancy, birth, and family background, and
starting and dose of the replacement therapy (2). Since 1991, the Register sented in this study (Fig. 1). It is important to note that,
started collecting specific data on the occurrence of congenital anomalies because statistical analysis was performed after 2003, virtu-
(detected during neonatal period) other than those of the thyroid gland ally all babies with TH born between 1989 and 2000 were
by using a specific reporting form. In this study, the classification of diagnosed and excluded from the analysis.
additional congenital malformations (CM) as minor or major malfor-
mations was performed as previously described (11).
After excluding the 53 TH babies, the frequency of mul-
tiple deliveries in the CH population was reestimated. It was
Zygosity assessment still higher (3.3%; 95% CI, 2.6 – 4.2%) than that found in the
general population. Moreover, it has been possible to esti-
Because the INRICH is a pathology register performing the surveil- mate the CH incidence both in singleton and multiple de-
lance of CH in our country, no information is regularly collected about
the co-twins found negative at screening. This did not allow us to know
liveries by comparing the INRICH data with data concerning
how many twin pairs were the same or opposite sex. However, it was deliveries in the Italian general population, given by the
possible to know zygosity in 24 of the 80 CH twins recorded in the Italian Central Institute of Statistics. The estimated CH in-
Register between 1989 and 2000. In 15 of these 24 twins, zygosity in- cidence was 3.2 per 10,000 singleton and 10.1 per 10,000 twin
formation was obtained by follow-up center, which they referred on the
live births. A relative risk of CH occurrence in twin deliveries
basis of a strikingly similar physical appearance beyond the neonatal
period and placenta information. For the remaining nine cases, parents of 3.1 (95% CI, 2.5–3.9) was also calculated. As already dem-
gave consent to analyze DNA. Zygosity was assigned using fingerprint- onstrated in other patient series, also in the Italian population
ing only in same-sex twin pairs on the basis of nine short tandem repeats of CH twins, the pairwise concordance rate for permanent
(microsatellites) all localized on different chromosomes. For typing of CH was very low (4.3%; 95% CI, 0.93%–7.6%) and due to only
microsatellites, PCR were performed using forward primers labeled at
the 5⬘ end with fluorescent dye. The diluted (1:200) amplified products three concordant couples (all boys with in situ gland). Besides
were run by capillary electrophoresis on an ABI prism 310 genetic these three couples of twins, in the INRICH were also present
analyzer (Applied Biosystems, Foster City, CA). Genotyping was per- eight siblings concordant for CH. Specifically, four were
formed by GENESCAN and GENOTYPER softwares (Applied Biosys- concordant for thyroid dysgenesis (two couples with ectopic
tems). Probability of identity by chance is approximately 10⫺4.
thyroid in one brother and agenesis in the other) and four
concordant for in situ gland (two couples). Given the fact that
Statistical analysis zygosity was unknown in most of the 73 twins with CH,
Pairwise concordance rate of CH, calculated as the proportion of twins were considered as siblings to calculate the genetic risk
concordant pairs over the sum of concordant and discordant pairs, and for CH. The estimated SRR was 35.4 (95% CI, 4.7–269.3),
95% confidence intervals (CI) were estimated in twins. The recurrence
risk for CH was also calculated among siblings of affected babies with
indicating a higher risk for CH in siblings of affected babies
CH (SRR). For this estimate, twins were assumed as siblings. The SRR than in a baby of the general population. It is important to
represents the ratio between the probandwise concordance rate among note that assuming twins as siblings may represent a possible
siblings of CH babies and the Italian CH prevalence. underestimation of the real recurrence risk in twins.
Student’s t test was used to evaluate differences between mean values Among the 24 twins with known zygosity (all discordant
of continuous variables, whereas differences between proportions were
examined statistically with ␹2 test. The log-normal transformation was for CH), 19 had permanent CH (four monozygous, MZ; 15
used for not normally distributed data. The percentage mean increase dizygous, DZ) and five were affected by TH. Among these,
in TSH levels between screening and diagnosis was estimated as one was MZ (female) and four DZ (3 females, 1 male). A
(TSHdiagnosis⫺ TSHscreening/TSHscreening) ⫻ 100. A multiple regression description of the 19 twins with permanent CH is shown in
analysis was also performed.
Table 1.
Results
Comparison between the Italian births and CH population
Between 1989 and 2000, 2159 CH babies were diagnosed
in Italy by neonatal screening and recorded in the INRICH. Comparison of neonatal features between CH population
All of the babies received the replacement therapy with l-T4. (n ⫽ 2106) and the Italian births (available data for the period
Among them, 80 were twins, mostly discordant for CH. Only 1991–1996) is shown in Table 2. As expected, the sex ratio
three couples (all boys with in situ gland and unknown (female/male) was significantly higher in singleton CH ba-
Olivieri et al. • Congenital Hypothyroidism in Twins J Clin Endocrinol Metab, August 2007, 92(8):3141–3147 3143

CH infants recorded in the INRICH 1989 - 2000

2106 53
Permanent CH Transient CH

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2033 73 46 7
Singletons Twins Singletons Twins

3 3
67 4
Concordant Concordant
Discordant Discordant
for CH for CH
for CH for CH
(3 couples) (one triplet)

FIG. 1. CH infants recorded in the INRICH from 1989 –2000.

bies than in singletons from the general population, whereas of singletons with CH. In Fig. 2, the distribution of CH
no significant differences were observed between CH twins diagnoses are shown. Although a similar frequency of ec-
and the Italian twin newborns. Mean values of birth weight topic gland was found in both singletons and twins, a sig-
and gestational age were found significantly lower in sin- nificantly higher prevalence of in situ thyroid as well as a
gletons and twins with CH than in the Italian singletons and lower frequency of agenesis were observed (␹2 ⫽ 8.02; P ⬍
twins, respectively. As concerns maternal age, it was signif- 0.02) in twin than in singleton CH babies. Among babies with
icantly higher in CH singletons than in the Italian single in situ gland, the frequency of hypoplasia, representing a
babies, whereas it was similar in both groups of twins. further manifestation of thyroid dysgenesis, was similar in
twins and singletons (16 and 19%, respectively). Among the
Clinical features in twin and singleton CH babies 16 twins with known zygosity and CH diagnosis (Table 1),
Thyroid scintigraphy and/or ultrasound evaluation were eight had thyroid dysgenesis, and among these, four were
performed before starting therapy in 51% of twins and in 61% MZ (two agenesis, two ectopy). Concerning the mean age at

TABLE 1. Subgroup of permanent CH twins with known zygosity

Twins Gender Zygosity Diagnosis TSH screening TSH diagnosis

a
1 F MZ Agenesis 61 199
2 F MZ Agenesisa 91 395
3 F MZ Ectopy 57 53
4 F MZ Ectopy 49 200
5 M DZ Ectopy 140 114
6 F DZ Ectopy 169 147
7 F DZ Ectopy 50 200
8 F DZ Ectopy 260 310
9 F DZ In situ 6 6b
10 F DZ In situ 350 100
11 M DZ In situ 30 20
12 F DZ In situ 11 30
13 F DZ In situ 14 525
14 F DZ In situ 47 210
15 F DZ In situ 220 380
16 F DZ In situ 408 414
17 M DZ Unknown 10 200
18 M DZ Unknown 177 100
19 M DZ Unknown 51 100
F, Female; M, male.
a
Thyroid scintigraphy confirmed by ultrasound evaluation.
b
With serum FT4 and FT3 below the normal range.
3144 J Clin Endocrinol Metab, August 2007, 92(8):3141–3147 Olivieri et al. • Congenital Hypothyroidism in Twins

TABLE 2. Neonatal features in permanent CH babies and the Italian births

CH babiesa Italian birthsb

Singletons Twins Singletons Twins
(n ⫽ 2033) (n ⫽ 73) (n ⫽ 3,194,887) (n ⫽ 71,891)
Sex ratio (F/M) 1.73 1.09 0.94 0.97
Birth weight, mean ⫾ SD (g) 3,233 ⫾ 658c 2,046 ⫾ 737d 3,290 ⫾ 496 2,371 ⫾ 567
Male 3,205 ⫾ 638c 2,011 ⫾ 744d 3,353 ⫾ 503 2,416 ⫾ 587
Female 3,286 ⫾ 681c 2,084 ⫾ 739d 3,221 ⫾ 479 2,323 ⫾ 559
Gestational age, mean ⫾ SD (wk) 39.2 ⫾ 2.7c 33.6 ⫾ 4.4d 39.3 ⫾ 1.7 36.4 ⫾ 3.0
Maternal age, mean ⫾ SD (yr) 29.3 ⫾ 5.3c 30.2 ⫾ 6.3 28.8 ⫾ 5.0 29.5 ⫾ 4.8
a
CH infants recorded in the INRICH between 1989 and 2000.
b

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Available data concerning neonatal features in the Italian general population,1991–1996.
c
CH singletons vs. Italian singletons, P ⬍ 0.01.
d
CH twins vs. Italian twins, P ⬍ 0.01.

starting therapy, it was similar in both singleton and twin CH CM found in singletons and twins with CH was signifi-
babies (26.4 ⫾ 25.7 and 27.8 ⫾ 13.6 d, respectively) as well as cantly higher than that found in the Italian general pop-
the median values (22 and 25.5 d, respectively). ulation (1.0 –2.0%, including Down’s syndrome). How-
Table 3 shows T4 and TSH mean levels at screening and ever, differently from that found in the general population
diagnosis. No significant difference between groups was in which twins are at greater risk of CM than singletons
observed in T4 values either at screening or diagnosis. (14), in the population of CH babies, the frequency of
However, a significant lower TSH mean concentration at major CM was similar in the two groups. It was 8.2% in
screening was found in the twin group than in singletons, singletons and 9.2% in twins with CH. The CH diagnosis
whereas no difference was present at diagnosis. The mean in the six twins with additional CM were two in situ gland,
percentage increase in TSH levels between screening and one ectopy, and three unknown. All the CH twins with
diagnosis was then calculated. It was significantly higher additional CM had unknown zygosity and were discor-
in the twin CH babies compared with singletons (308 vs. dant for CH. Nevertheless, a same sex pair (two girls) was
129%, P ⬍ 0.01). To verify whether the low mean TSH concordant for CM occurrence (index case with unknown
value found at screening in the twin group was a conse- CH diagnosis and bilateral microphthalmia, euthyroid co-
quence of the high frequency of in situ gland or the effect twin with congenital cerebral cysts).
of some factors related to the twin status, a multivariate Finally, an analysis of maternal anamnesis during preg-
analysis was performed. The following variables were nancy has also been performed. No significant differences
considered: twin status, gender, gestational age, scintig- between CH singletons and twins were found in the fre-
raphy, and/or ultrasound diagnosis and age at screening. quency of maternal diabetes (3.6 and 3.5%, respectively),
Results of the multivariate analysis (Table 4) showed that hypothyroidism (included autoimmune etiology), and/or
the variability of TSH levels found at screening was neg- goiter (6.1 and 4.5%, respectively), hyperthyroidism (2.1 and
atively associated with the twin status independently from 1.5%, respectively), iodine exposure during pregnancy (3.3
the other considered variables (␤ coefficient ⫽ ⫺0.40; P ⫽ and 5%, respectively) and smoking (10.3% and 13.0%,
0.02). respectively).
Regarding additional CM, the frequency of CM was
estimated in the population of twin and singleton CH Discussion
babies diagnosed between 1991 and 2000 with the exclu-
sion of 15 babies with Down’s syndrome, given the known In this study, the analysis of the INRICH data showed
association of this syndrome with transient thyroid dys- a more than 3-fold higher frequency of twins in the CH
function (13). Our data showed that the frequency of major population than in the general population. According to
previously reported highly discordant twin series, also in
the Italian CH twin population, the concordance rate for
CH TWINS CH SINGLETONS
the disease was very low (4.3%). Specifically, among the
Eutopic 73 permanent CH twins diagnosed during the study pe-
gland Eutopic riod, only three couples (all boys with in situ gland and
Ectopy
(49%) gland
Ectopy (42%) unknown zygosity) were concordant for CH. These find-
(38%) (29%)
ings strongly suggest that the sporadic occurrence of the
disease is likely due to noninheritable postzygotic events
that may include epigenetic modifications and early so-
matic mutations. However, a genetic risk for the disease
cannot be excluded. In fact, the high recurrence risk for CH
estimated in siblings of affected babies recorded in the
Agenesis Agenesis INRICH indicates that environmental risk factors may act
(13%) (29%) as a trigger on a susceptible genetic background. More-
FIG. 2. Thyroid scintigraphy and/or ultrasound diagnosis in twins over, the fact that one (with bilateral microphthalmia) of
and singletons with permanent CH. the six CH twins with additional malformations had the
Olivieri et al. • Congenital Hypothyroidism in Twins J Clin Endocrinol Metab, August 2007, 92(8):3141–3147 3145

TABLE 3. T4 and TSH levels at screening and diagnosis in twins and singletons with permanent CH

CH singletons CH twins P
Screening
T4, mean ⫾ SD (␮g/dl) 3.7 ⫾ 2.7 3.2 ⫾ 2.3 NS
TSH, mean ⫾ SD (␮IU/ml) 229 ⫾ 185 178 ⫾ 210 ⬍0.01a
Diagnosis
T4, mean ⫾ SD (␮g/dl) 3.4 ⫾ 2.9 3.2 ⫾ 2.6 NS
TSH, mean ⫾ SD (␮IU/ml) 299 ⫾ 264 276 ⫾ 274 NS
% increase in TSH levels between screening and diagnosis 129% 308% ⬍0.01
NS, Not significant.
a
Log normal TSH.

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same-sex co-twin (F-F) concordant for CM occurrence mester of pregnancy, reflected by a decrease in the circu-
(congenital cerebral cysts) supports the hypothesis that lating concentrations of TSH and an increase in FT4 and
genes involved in the development of thyroid and other FT3 levels (17), is more profound in twin than in singleton
organs may be affected during the early stages of embry- pregnancy. This is probably because peak concentrations
ogenesis. The recently reported significant association be- of human chorionic gonadotropin are greater and remain
tween CH and congenital anomalies of nervous system, increased for longer in twin pregnancies (18). Moreover, it
eyes, and heart, which represent the most precocious has been demonstrated that in multiple pregnancy, ma-
structures in the developing embryo (11), further supports ternal thyroid activity increases with fetal numbers (19). It
this hypothesis. Again, the possible involvement of genes is known that an even mild iodine deficiency may result
controlling development of thyroid and other organs in in relative hypothyroxinemia during pregnancy (20) and
the etiology of CH is further supported by the fact that no that during the first trimester, the fetus is exposed to
difference was found in the frequency of CM between concentrations of FT4 ultimately depending on the circu-
twins and singletons in the CH population. This finding is lating maternal T4 and FT4 levels (21). Therefore, given the
different from that found in the general population in high discordance rate for CH, we cannot exclude the pos-
which twins are more likely than singletons to be affected sibility that competitive conditions regarding metabolic
by congenital malformations, events that represent one factors in utero may occur and that differences in the sup-
major cause of mortality and serious morbidity in twin ply of blood, oxygen, or other nutrients (including iodine)
early life (14, 15). Finally, the fact that eight of the 16 may alter or disrupt the developmental processes of the
permanent CH twins with known zygosity and CH diag- thyroid gland.
nosis (Table 1) had thyroid dysgenesis, and among these, Our study demonstrated an increased risk for both per-
four were MZ (two agenesis, two ectopy), seems to suggest manent and transient CH in multiple than in single de-
a higher risk of thyroid dysgenesis in MZ than in DZ twins. liveries, and for the first time it was possible to estimate
However, additional studies are needed to confirm this the incidence of CH in multiple and single deliveries sep-
hypothesis and to verify whether the frequency of MZ arately. It was found 3-fold higher in multiple (10.1 in
twins in the CH population is the same as that observed 10,000 live births) than in single deliveries (3.2 in 10,000
in the general population. live births). Moreover, the analysis of the reevaluated in-
The analysis of the INRICH data showed that the oc- fants with high suspicion of TH recorded in the INRICH
currence of in situ thyroid was significantly more frequent showed a high prevalence of twins among infants who
in twin than in singleton CH babies. This finding can be were affected by TH. This finding confirms an additional
explained by the fact that iodine deficiency, which is still risk of TH in multiple compared with single deliveries. It
present in our country as mild to moderate deficiency (16), is well known that newborn twins are at greater risk of
can have a role in the increasing risk for CH with in situ morbidity than singletons because of their increased
gland in twins. It is well known that the physiological chance of prematurity. Also, thyroid function can be af-
increase in maternal thyroid activity during the first tri- fected by prematurity. In our study, the comparison of the
INRICH data set with available data of the Italian births
TABLE 4. Multiple linear regression of the effect of clinical and showed a lower birth weight and gestational age in twins
neonatal features on log TSH levels at screening
with permanent CH than in twins from the general pop-
Coefficient ␤ 95% CI ulation. This finding is consistent with the fact that the risk
Twins ⫺0.40 ⫺0.75 ⫺0.05 of not only transient but also permanent CH is higher in
Gender (male) ⫺0.10 ⫺0.22 ⫺0.01 babies with low birth weight (22–24). Therefore, as im-
Gestational age (wk) 0.02 ⫺0.004 0.53 provements in perinatal and neonatal care have increased
Age at screening (d) 0.01 ⫺0.001 0.02 the survival rate of an increasing number of preterm ba-
Diagnosis
Ectopy 0.95 0.80 1.11 bies, to improve the long-term developmental outcome of
Agenesisa 0.76 0.62 0.89 these babies, either permanent or transient forms of hy-
The analysis was performed on infants with thyroid scintigraphy
pothyroidism need to be treated as soon as they are iden-
and/or ultrasound evaluation (number of observations ⫽ 970). tified to avoid consequences of the early thyroid deficit.
a
Thyroid scintigraphy confirmed by ultrasound evaluation. This implies rapid and effective screening procedures.
3146 J Clin Endocrinol Metab, August 2007, 92(8):3141–3147 Olivieri et al. • Congenital Hypothyroidism in Twins

At present, the mass screening procedures allow us to (Catania), R. Caldarera (Messina), M. Cappa (Roma), M. R. Casini
virtually diagnose all infants with transient or permanent (Cagliari), A. Cassio (Bologna), L. Cavallo (Bari), V. Cherubini (An-
cona), G. Chiumello (Milano), L. Chiovato (Pavia), M. Cicchetti (Cam-
forms of CH. However, a second sample for CH screening pobasso), M. P. Cicciò (Messina), A. Cicognani (Bologna), G. V. Coppa
at 14 d of age in at least same-sex twins has been suggested (Ancona), A. Coppola (Napoli), C. Corbetta (Milano), R. Cordova
(25). This is because fetal blood mixing between twins may (Potenza), A. Correra (Napoli), P. Costa (Roma), F. Dammacco (Bari),
occur. Specifically, the vascular connections present in at F. De Luca (Messina), C. De Santis (Torino), S. Di Maio (Napoli), G.
least 70% of monozygotic placentas may result in delayed Gallicchio (Potenza), R. Gastaldi (Genova), G. Giovannelli (Parma), G.
Grasso (Caltanissetta), R. Gurrado (Taranto), L. Lasciarrea (Bari), A.
or missed CH diagnoses during the first days of life (25). Lelli (Roma), D. Leonardi (Catania), A. Liotta (Palermo), S. Loche
In fact, vascular connections between a hypothyroid and (Cagliari), R. Lorini (Genova), G. Manente (Taranto), G. Minelli (Fog-
a euthyroid twin could allow the transfer of T4 between gia), F. Monaco (Chieti), L. Moschini (Roma), M. A. Musarò (Siena),
fetuses and, hence, maintain a normal TSH level in the G. C. Mussa (Torino), T. Narducci (Foggia), S. Pagliardini (Torino),
L. Palillo (Palermo), G. Parlato (Catanzaro), E. Pasquini (Firenze), L.

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hypothyroid one until a few days after delivery, causing Peruzzi (Siena), S. Piazzi (Bologna), A. Pinchera (Pisa), M. Pizzolante
a lowering of TSH at screening in the twin with transient (Lecce), R. Puggioni (Cagliari), A. Rizzo (Lecce), G. Saggese (Pisa), D.
or permanent form of CH. Our findings confirm a high Sala (Napoli), C. Salerno (Napoli), R. Salti (Firenze), L. Sava (Catania),
discordance rate in the CH population, and a significantly D. Scognamiglio (Napoli), V. Stoppioni (Fano), L. Tatò (Verona), M.
lower TSH mean level at screening was found in the twin Tonacchera (Pisa), R. Vigneri (Catania), G. Vignola (Potenza), M. C.
Vigone (Milano), C. Volta (Parma), and G. Weber (Milano).
group than in singletons. After adjustment by multivariate Disclosure Statement: The authors have nothing to disclose.
analysis, a significant association of low TSH levels at
screening with the twin status was confirmed. Moreover,
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