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High Risk of Congenital Hypothyroidism in Multiple Pregnancies

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

Address all correspondence and requests for reprints to: Antonella Olivieri, Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Roma, Italy. E-mail: antonella.olivieri{at}iss.it.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: In Italy, the surveillance of congenital hypothyroidism (CH) is performed by the Italian National Registry of Infants with CH (INRICH). Up to now, about 3600 infants with CH are recorded in the INRICH, and a high number of twins are included.

Objective: Our objective was to estimate the risk of CH in multiple and single deliveries and to compare neonatal features of CH twins with twins from the general population.

Design: The Italian population of CH infants recorded in the INRICH from 1989–2000 was investigated.

Results: A more than 3-fold higher frequency of twins was found in the CH population than in the general population, and for the first time, it was possible to estimate the CH incidence in multiple (10.1 in 10,000) and single deliveries (3.2 in 10,000 live births). Significantly higher frequencies of in situ gland as well as lower TSH mean level at screening were found in twin than in singleton CH babies. The concordance rate for permanent CH was very low (4.3%) and due to only three concordant couples. However, a high recurrence risk for CH was estimated in siblings of affected babies recorded in the INRICH, including twins considered as siblings.

Conclusions: The high CH incidence observed in twins is worthy of interest for the high number of induced pregnancies in Italy as well as in other Western countries. Moreover, the low concordance rate for CH among twins together with a high recurrence risk for the disease among siblings indicates that environmental risk factors may act as a trigger on a susceptible genetic background in the etiology of the disease.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
CONGENITAL 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 not promptly treated, serious and irreversible damage to the nervous system with consequent mental retardation. The early diagnosis and the prompt institution of the replacement therapy has been achieved by the implementation of newborn screening programs by using blood spotted on filter paper. As a result of these screening programs, virtually all cases of CH are now identified. In Italy, the incidence of CH in the last 10 yr has been about one in 2700 live births (www.iss.it/rnic/). In our country, CH babies diagnosed by neonatal screening are recorded in the Italian National Registry of Infants with CH (INRICH). This was established in Italy in 1987 as a program of the Health Ministry and is coordinated by the National Institutes of Health (2). Up to now, 3600 infants with confirmed diagnosis of CH are recorded in the INRICH, and a high number of twins are included.

Twin birth is a relatively common event. In Europe and in 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 be due to the increasing use of techniques of assisted reproduction and drugs inducing ovulation (4). Twins are widely reported to have more morbidity than singletons, mainly because of a higher preterm birth rate. In fact, preterm delivery is the major cause of adverse outcomes (both short-term and long-term) and is directly related to fetal number (5). It is well known that prematurity can affect thyroid function. Fetal thyroid system metabolism is characterized by relatively high circulating TRH and TSH concentrations, immature T₄ feedback control of TSH secretion, immature thyroid gland T₄ biosynthesis and secretory processes, and limited effects of T₄ on responsive gene transcription events (6, 7, 8). All these processes mature progressively with advancing gestational age.

Up to now, no extensive studies have been performed to evaluate the occurrence of CH in twin pregnancies. In this study, the Italian population of CH infants recorded in the INRICH was investigated with the aim of 1) estimating the risk of CH in multiple and single deliveries and 2) comparing neonatal features of CH twins with twins from the general population.

	Patients and Methods

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Diagnosis ascertainment

In Italy, the neonatal screening for CH is performed by a network of 26 regional or interregional centers. A biochemical assessment of TSH, and in 11 of the 26 centers also of T₄, is performed within a few days from birth. In all the centers, positive results of screening tests are confirmed by definitive tests of thyroid function on serum, and thyroid ultrasound and/or scintigraphy are generally performed to complete the CH diagnosis. According to international guidelines (9, 10), when the definitive diagnosis is not established in the neonatal period and a suspicion of transient primary hypothyroidism (TH) is present, a reevaluation of diagnosis is performed at the age of 2–3 yr after a withdrawal of the replacement therapy to ascertain the persistence of CH. At that time, T₄, free T₄ (FT₄), and TSH levels are measured, and ultrasound imaging, scintigraphy, and clinical evaluation are performed to establish the definitive diagnosis. Babies with transient hyperthyrotropinemia on the basis of spontaneous normalization of TSH between screening and diagnosis are not recorded in the Register.

A registration form is filled in at diagnosis. It includes anonymous data concerning CH infants such as screening and confirmatory laboratory tests, information on demographic data and details on clinical state in neonatal period, diagnostic investigations (biochemical determinations, radiography of the knee, thyroid scan, and ultrasound), information regarding pregnancy, birth, and family background, and starting and dose of the replacement therapy (2). Since 1991, the Register started collecting specific data on the occurrence of congenital anomalies (detected during neonatal period) other than those of the thyroid gland by using a specific reporting form. In this study, the classification of additional congenital malformations (CM) as minor or major malformations was performed as previously described (11).

Zygosity assessment

Because the INRICH is a pathology register performing the surveillance 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 how many twin pairs were the same or opposite sex. However, it was possible to know zygosity in 24 of the 80 CH twins recorded in the Register between 1989 and 2000. In 15 of these 24 twins, zygosity information was obtained by follow-up center, which they referred on the basis of a strikingly similar physical appearance beyond the neonatal period and placenta information. For the remaining nine cases, parents gave consent to analyze DNA. Zygosity was assigned using fingerprinting only in same-sex twin pairs on the basis of nine short tandem repeats (microsatellites) all localized on different chromosomes. For typing of microsatellites, PCR were performed using forward primers labeled at the 5' end with fluorescent dye. The diluted (1:200) amplified products were run by capillary electrophoresis on an ABI prism 310 genetic analyzer (Applied Biosystems, Foster City, CA). Genotyping was performed by GENESCAN and GENOTYPER softwares (Applied Biosystems). Probability of identity by chance is approximately 10^–4.

Statistical analysis

Pairwise concordance rate of CH, calculated as the proportion of concordant pairs over the sum of concordant and discordant pairs, and 95% confidence intervals (CI) were estimated in twins. The recurrence risk for CH was also calculated among siblings of affected babies with CH (SRR). For this estimate, twins were assumed as siblings. The SRR represents the ratio between the probandwise concordance rate among siblings of CH babies and the Italian CH prevalence.

Student’s t test was used to evaluate differences between mean values of continuous variables, whereas differences between proportions were examined statistically with ² test. The log-normal transformation was used for not normally distributed data. The percentage mean increase in TSH levels between screening and diagnosis was estimated as (TSH_diagnosis– TSH_screening/TSH_screening) x 100. A multiple regression analysis was also performed.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Between 1989 and 2000, 2159 CH babies were diagnosed in Italy by neonatal screening and recorded in the INRICH. All of the babies received the replacement therapy with L-T₄. Among them, 80 were twins, mostly discordant for CH. Only three couples (all boys with in situ gland and unknown zygosity) and one triplet (two girls and one boy with in situ gland) from a medically induced pregnancy were concordant for CH at birth. The proportion of multiple deliveries observed in the CH population between 1989 and 2000 (75 of 2154, 3.5%) was 3-fold higher than that (1.1%) estimated in the Italian general population in the same period (12).

Between 1991 and 2003, a reevaluation of the diagnosis, at the age of 2–3 yr after a withdrawal of the replacement therapy, was performed in 267 CH infants who presented a suspicion of TH during the first years of life. The prevalence of twins was 1.9% (three females and one male) in the 214 reevaluated infants who were affected by permanent CH and 13.2% (five females and two males) in the 53 babies who were affected by TH (P < 0.01). Among these 53 babies, there was the triplet concordant at birth. Seventy-three permanent CH twins were then considered for the statistical analysis presented in this study (Fig. 1). It is important to note that, because statistical analysis was performed after 2003, virtually all babies with TH born between 1989 and 2000 were diagnosed and excluded from the analysis.

View larger version (9K): [in this window] [in a new window]   FIG. 1. CH infants recorded in the INRICH from 1989–2000.

Among the 24 twins with known zygosity (all discordant for CH), 19 had permanent CH (four monozygous, MZ; 15 dizygous, DZ) and five were affected by TH. Among these, one was MZ (female) and four DZ (3 females, 1 male). A description of the 19 twins with permanent CH is shown in Table 1.

Comparison of neonatal features between CH population (n = 2106) and the Italian births (available data for the period 1991–1996) is shown in Table 2. As expected, the sex ratio (female/male) was significantly higher in singleton CH babies than in singletons from the general population, whereas no significant differences were observed between CH twins and the Italian twin newborns. Mean values of birth weight and gestational age were found significantly lower in singletons and twins with CH than in the Italian singletons and twins, respectively. As concerns maternal age, it was significantly higher in CH singletons than in the Italian single babies, whereas it was similar in both groups of twins.

Thyroid scintigraphy and/or ultrasound evaluation were performed before starting therapy in 51% of twins and in 61% of singletons with CH. In Fig. 2, the distribution of CH diagnoses are shown. Although a similar frequency of ectopic gland was found in both singletons and twins, a significantly higher prevalence of in situ thyroid as well as a lower frequency of agenesis were observed (² = 8.02; P < 0.02) in twin than in singleton CH babies. Among babies with in situ gland, the frequency of hypoplasia, representing a further manifestation of thyroid dysgenesis, was similar in twins and singletons (16 and 19%, respectively). Among the 16 twins with known zygosity and CH diagnosis (Table 1), eight had thyroid dysgenesis, and among these, four were MZ (two agenesis, two ectopy). Concerning the mean age at starting therapy, it was similar in both singleton and twin CH babies (26.4 ± 25.7 and 27.8 ± 13.6 d, respectively) as well as the median values (22 and 25.5 d, respectively).

View larger version (13K): [in this window] [in a new window]   FIG. 2. Thyroid scintigraphy and/or ultrasound diagnosis in twins and singletons with permanent CH.

Finally, an analysis of maternal anamnesis during pregnancy has also been performed. No significant differences between CH singletons and twins were found in the frequency of maternal diabetes (3.6 and 3.5%, respectively), hypothyroidism (included autoimmune etiology), and/or goiter (6.1 and 4.5%, respectively), hyperthyroidism (2.1 and 1.5%, respectively), iodine exposure during pregnancy (3.3 and 5%, respectively) and smoking (10.3% and 13.0%, respectively).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In this study, the analysis of the INRICH data showed a more than 3-fold higher frequency of twins in the CH 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 the disease was very low (4.3%). Specifically, among the 73 permanent CH twins diagnosed during the study period, only three couples (all boys with in situ gland and unknown zygosity) were concordant for CH. These findings strongly suggest that the sporadic occurrence of the disease is likely due to noninheritable postzygotic events that may include epigenetic modifications and early somatic 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 INRICH indicates that environmental risk factors may act as a trigger on a susceptible genetic background. Moreover, the fact that one (with bilateral microphthalmia) of the six CH twins with additional malformations had the same-sex co-twin (F-F) concordant for CM occurrence (congenital cerebral cysts) supports the hypothesis that genes involved in the development of thyroid and other organs may be affected during the early stages of embryogenesis. The recently reported significant association between CH and congenital anomalies of nervous system, eyes, and heart, which represent the most precocious structures in the developing embryo (11), further supports this hypothesis. Again, the possible involvement of genes controlling development of thyroid and other organs in the etiology of CH is further supported by the fact that no difference was found in the frequency of CM between twins and singletons in the CH population. This finding is different from that found in the general population in which twins are more likely than singletons to be affected by congenital malformations, events that represent one major cause of mortality and serious morbidity in twin early life (14, 15). Finally, the fact that eight of the 16 permanent CH twins with known zygosity and CH diagnosis (Table 1) had thyroid dysgenesis, and among these, four were MZ (two agenesis, two ectopy), seems to suggest a higher risk of thyroid dysgenesis in MZ than in DZ twins. However, additional studies are needed to confirm this hypothesis and to verify whether the frequency of MZ twins in the CH population is the same as that observed in the general population.

The analysis of the INRICH data showed that the occurrence of in situ thyroid was significantly more frequent in twin than in singleton CH babies. This finding can be explained by the fact that iodine deficiency, which is still present in our country as mild to moderate deficiency (16), can have a role in the increasing risk for CH with in situ gland in twins. It is well known that the physiological increase in maternal thyroid activity during the first trimester of pregnancy, reflected by a decrease in the circulating concentrations of TSH and an increase in FT₄ and FT₃ levels (17), is more profound in twin than in singleton pregnancy. This is probably because peak concentrations of human chorionic gonadotropin are greater and remain increased for longer in twin pregnancies (18). Moreover, it has been demonstrated that in multiple pregnancy, maternal thyroid activity increases with fetal numbers (19). It is known that an even mild iodine deficiency may result in relative hypothyroxinemia during pregnancy (20) and that during the first trimester, the fetus is exposed to concentrations of FT₄ ultimately depending on the circulating maternal T₄ and FT₄ levels (21). Therefore, given the high discordance rate for CH, we cannot exclude the possibility that competitive conditions regarding metabolic factors in utero may occur and that differences in the supply of blood, oxygen, or other nutrients (including iodine) may alter or disrupt the developmental processes of the thyroid gland.

Our study demonstrated an increased risk for both permanent and transient CH in multiple than in single deliveries, and for the first time it was possible to estimate the incidence of CH in multiple and single deliveries separately. It was found 3-fold higher in multiple (10.1 in 10,000 live births) than in single deliveries (3.2 in 10,000 live births). Moreover, the analysis of the reevaluated infants with high suspicion of TH recorded in the INRICH showed a high prevalence of twins among infants who were affected by TH. This finding confirms an additional risk of TH in multiple compared with single deliveries. It is well known that newborn twins are at greater risk of morbidity than singletons because of their increased chance of prematurity. Also, thyroid function can be affected by prematurity. In our study, the comparison of the INRICH data set with available data of the Italian births showed a lower birth weight and gestational age in twins with permanent CH than in twins from the general population. This finding is consistent with the fact that the risk of not only transient but also permanent CH is higher in babies with low birth weight (22, 23, 24). Therefore, as improvements in perinatal and neonatal care have increased the survival rate of an increasing number of preterm babies, to improve the long-term developmental outcome of these babies, either permanent or transient forms of hypothyroidism need to be treated as soon as they are identified to avoid consequences of the early thyroid deficit. This implies rapid and effective screening procedures.

At present, the mass screening procedures allow us to virtually diagnose all infants with transient or permanent forms of CH. However, a second sample for CH screening at 14 d of age in at least same-sex twins has been suggested (25). This is because fetal blood mixing between twins may occur. Specifically, the vascular connections present in at least 70% of monozygotic placentas may result in delayed or missed CH diagnoses during the first days of life (25). In fact, vascular connections between a hypothyroid and a euthyroid twin could allow the transfer of T₄ between fetuses and, hence, maintain a normal TSH level in the hypothyroid one until a few days after delivery, causing a lowering of TSH at screening in the twin with transient or permanent form of CH. Our findings confirm a high discordance rate in the CH population, and a significantly lower TSH mean level at screening was found in the twin group than in singletons. After adjustment by multivariate analysis, a significant association of low TSH levels at screening with the twin status was confirmed. Moreover, the mean percentage increase in TSH between screening and diagnosis was higher in twins as compared with singletons. Although we could not separate monochorionic twins from the others, taken together, these results may suggest the possible occurrence of fetal blood mixing between a hypothyroid and a euthyroid fetus and underline the need for special guidelines for twin CH screening procedures. However, if we assume that in the CH population there is a frequency of MZ twins similar to that observed in the general population (about 30% of all twins), the occurrence of fetal blood mixing may explain the low TSH at screening only partially. Possible other factors related to the twin status remain to be clarified.

In conclusion, this is the first report presenting such population-based results on CH in multiple deliveries. The high discordance rate found in the INRICH data set as well as in other series of CH babies demonstrates the importance of environmental risk factors and suggests the occurrence of noninheritable postzygotic events in the etiology of CH. Nevertheless, the results concerning the high incidence of CH in multiple deliveries are worthy of interest for the high number of induced pregnancies, in Italy as well in other Western countries (26, 27), because of the increasing use of techniques of assisted reproduction and drugs inducing ovulation. In this view, great attention should be paid to multiple pregnancies, which are at greater risk for both permanent and transient CH than single pregnancies.

	Acknowledgments

 
The skillful technical assistance of Mrs. F. Latini and Mrs. D. Rotondi is gratefully acknowledged.

	Footnotes

 
The Study Group for Congenital Hypothyroidism includes R. Altamura (Brindisi), U. Angeloni (Roma), I. Antonozzi (Roma), M. Baserga (Catanzaro), R. Berardi (Siena), S. Bernasconi (Parma), G. Bona (Novara), M. Burroni (Fano), E. Cacciari (Bologna), F. Calaciura (Catania), R. Caldarera (Messina), M. Cappa (Roma), M. R. Casini (Cagliari), A. Cassio (Bologna), L. Cavallo (Bari), V. Cherubini (Ancona), G. Chiumello (Milano), L. Chiovato (Pavia), M. Cicchetti (Campobasso), M. P. Cicciò (Messina), A. Cicognani (Bologna), G. V. Coppa (Ancona), A. Coppola (Napoli), C. Corbetta (Milano), R. Cordova (Potenza), A. Correra (Napoli), P. Costa (Roma), F. Dammacco (Bari), F. De Luca (Messina), C. De Santis (Torino), S. Di Maio (Napoli), G. Gallicchio (Potenza), R. Gastaldi (Genova), G. Giovannelli (Parma), G. Grasso (Caltanissetta), R. Gurrado (Taranto), L. Lasciarrea (Bari), A. Lelli (Roma), D. Leonardi (Catania), A. Liotta (Palermo), S. Loche (Cagliari), R. Lorini (Genova), G. Manente (Taranto), G. Minelli (Foggia), F. Monaco (Chieti), L. Moschini (Roma), M. A. Musarò (Siena), G. C. Mussa (Torino), T. Narducci (Foggia), S. Pagliardini (Torino), L. Palillo (Palermo), G. Parlato (Catanzaro), E. Pasquini (Firenze), L. Peruzzi (Siena), S. Piazzi (Bologna), A. Pinchera (Pisa), M. Pizzolante (Lecce), R. Puggioni (Cagliari), A. Rizzo (Lecce), G. Saggese (Pisa), D. Sala (Napoli), C. Salerno (Napoli), R. Salti (Firenze), L. Sava (Catania), D. Scognamiglio (Napoli), V. Stoppioni (Fano), L. Tatò (Verona), M. Tonacchera (Pisa), R. Vigneri (Catania), G. Vignola (Potenza), M. C. Vigone (Milano), C. Volta (Parma), and G. Weber (Milano).

Disclosure Statement: The authors have nothing to disclose.

First Published Online May 8, 2007

Abbreviations: CH, Congenital hypothyroidism; CI, confidence interval; CM, congenital malformations; DZ, dizygous; FT₄, free T₄; INRICH, Italian National Registry of Infants with CH; MZ, monozygous; SRR, sibling recurrence risk; TH, transient primary hypothyroidism.

Received January 31, 2007.

Accepted May 2, 2007.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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