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ORIGINAL RESEARCH |
From the Departments of Neonatology, Epidemiology, and Pediatrics, and Endocrine Laboratory, Meyer Children’s Hospital, Rambam Medical Center; and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel.
Address reprint requests to: Shraga Blazer, MD, Department of Neonatology, Rambam Medical Center, 9 Ha’aliyah Street, P.O.Box 9602, Haifa, Israel 31096; E-mail: blazer{at}rambam.health.gov.il.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: Among the 27,386 full-term newborns delivered over a 6-year period, 259 were born to 250 treated hypothyroid mothers (0.9%); 246 of these newborns constituted the study group. Controls were 139 term healthy neonates from healthy group-matched mothers. The study infants and controls underwent thyroid function tests in a prospective design. A single blood sample was collected from each infant at 25–120 hours of life.
RESULTS: Compared with the controls, serum thyroid-stimulating hormone (TSH) levels were higher in the study neonates (P < .005), as were those of serum free thyroxine (T4) (P < .03), particularly at 49 hours of life or older (P < .001). At 49–120 hours, 44.7% of the study group newborns had serum free T4 levels greater than the 95th percentile of the controls (P < .001), and 16.8% had significantly higher TSH levels (P < .001). Serum free T4 correlated positively with TSH in the controls (r = .316) but not in the study newborns (r = .062, P = .36). Neonatal TSH at 49 hours or older correlated positively with maternal TSH during pregnancy in the 18 cases where maternal TSH values during pregnancy were available (r = .751, P <.001). Birth weight and head circumference were significantly lesser in the study group (P < .001).
CONCLUSION: The impaired intrauterine growth and the unduly elevated serum values of TSH and serum free T4 found in a substantial fraction of the study newborns might reflect an insufficient level of hormone replacement therapy of their hypothyroid mothers during pregnancy, despite an assumed adequate management. Gestational hypothyroidism requires close monitoring.
Thyroid disease is common in women of reproductive age, and thyroid disorders are thus often encountered in the setting of pregnancy. The frequency of thyroid deficiency varies among pregnant women in different countries and ranges between 0.19% in Japan1 and as high as 2.2% in Belgium2 and 2.5% in the United States,3 depending also on the condition definition. Many of these women have subclinical hypothyroidism. Maternal thyroid deficiency, even subclinical, has been reported to be associated with adverse pregnancy outcomes that may be improved by thyroxine (T4) replacement.4 Two recent publications have stressed the role of maternal thyroid hormone status in the neuropsychologic outcome of the offspring. Pop et al5 showed that a lower maternal free T4 concentration at 12 weeks’ gestation was associated with an impaired psychomotor development of the infant at 10 months of age. Haddow et al6 reported that the full-scale IQ score of children of women with untreated high serum thyrotropin concentration averaged seven points lower than that of matched children of control mothers. Klein et al7 demonstrated an inverse correlation between severity of maternal hypothyroidism and offspring IQ.
The human fetal thyroid gland concentrates iodine and synthesizes thyroid hormone after 10–12 weeks’ gestation. Any fetus’ requirement for thyroid hormones before this time is supplied by the mother via the placenta,8 and placental diffusion of thyroid hormones is therefore significant.9 Although the fetal hypothalamic–pituitary–thyroid axis develops later on and functions independently beyond the first trimester of pregnancy,10 the fetus continues to rely to some extent on a maternal supply of T4 throughout pregnancy.3,11
During the first period of life, thyroid hormones are critical for brain development. A case–control study of intellectual development in children with documented short-term transient congenital hypothyroidism or hyperthyrotrophinemia at birth12 showed that these children had a significantly lower global IQ at age 7 to 8 years than matched controls living in the same environmental condition but with normal thyroid function at birth.
As with other tertiary medical centers, pregnant women in our practice area are mostly followed up during gestation by their own physicians and are referred to the hospital for delivery. A large number of newborns are admitted to our ward with a diagnosis of "maternal treated hypothyroidism during pregnancy." Because their mothers were cared for by physicians with a wide variety of approaches to both the diagnosis and treatment in pregnancy, we do not actually know the thyroid status of these women and whether their treatment was adequate throughout pregnancy. Moreover, fluctuations that occur in T4 metabolism during pregnancy make it difficult to maintain meticulous normal thyroid hormone values during gestation in hypothyroid mothers.13 Pituitary–thyroid axis function in the early neonatal period of such newborns has so far not been investigated.
The working hypotheses of the present study were as follows: Some hypothyroid pregnant women may be insufficiently treated and may inadvertently undergo periods of hypothyroxinemia during gestation, such events of maternal hypothyroxinemia can influence the fetus, and this influence may be reflected by the fetal pituitary–thyroid axis function and will manifest in the immediate postnatal days.
The aim of our study was to evaluate, in the early neonatal period, pituitary–thyroid axis function of infants of apparently treated hypothyroid mothers. To this end, a large cohort of consecutively delivered infants was prospectively observed, and thyroid function tests were performed in newborns of hypothyroid mothers and in random controls.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The control group consisted of healthy term neonates, born during the 6-year study period to healthy mothers. To ascertain more definitely that these women were euthyroid during gestation, we only checked newborns from mothers who had undergone at least two documented thyroid function tests during pregnancy that produced normal results. For this reason, we managed to gather in the control group during the 6-year study period only 139 newborns who fulfilled the inclusion criteria (term infants born to healthy mothers who had at least two documented normal thyroid function tests during pregnancy). These mothers were group matched according to their age at delivery, parity, smoking during pregnancy, and presence of hypertension (chronic hypertension and/or pregnancy-induced hypertension). All control infants were born by spontaneous delivery, were appropriate for gestational age (AGA), had a normal head circumference (fifth to 95th percentile), had Apgar scores greater than 8 at 1 and 5 minutes, and no congenital anomalies.
Because the control group consisted of AGA newborns only, statistical analyses for birth weight and head circumference in the study group were performed for the whole group as well as for the AGA study neonates.
For ethical reasons, the blood samples used in this study were those obtained as part of the Neonatal Screening Program. We divided the study and the control groups by blood sampling (at 25–48 hours or at least 49 hours). Because it is well recognized that an acute surge of thyroid-stimulating hormone (TSH) normally occurs at birth and induces a rise in T4 levels within a few hours from birth, followed by a rapid decline over the ensuing 24 hours, our study did not include neonates who were tested in the first 24 hours of life. A single blood sample was collected from each infant at 25–48 hours of life (69 study neonates and 39 controls) or at 49–120 hours of life (174 study neonates and 100 controls). In 16 further study newborns blood was drawn before 24 hours of life (mainly due to early discharge), and they were excluded from thyroid function analyses.
Thyrotropin (TSH) and free T4 levels were measured upon collection by Electrochemiluminescence Immunoassay (Roche Diagnostics, Mannheim, Germany). Analytic sensitivity of the free T4 assay was 0.3 pmol/L, and that of TSH was 0.005 µIU/mL. The intraassay coefficient of variation of the free T4 assay was less than 2.9%, and the interassay coefficient of variation was less than 6.6%. The intraassay coefficient of variation of the TSH assay was less than 6.8%, and the interassay coefficient of variation was less than 8.7%.
The Rambam Medical Center Research Ethics Institutional Review Committee approved the study protocol, and informed consent was obtained from a parent of each infant enrolled in the control group.
Comparisons between two groups were made using the 
2 test for categoric variables, the t test for continuous variables, and the Mann–Whitney test when the data did not meet the assumption of the parametric test: normality (using the Kolmogorov–Smirnov one-sample test for normality), inequality of variances, or small numbers. Analysis of variance with the Scheffe post hoc test or the Kruskal–Wallis tests with Mann–Whitney test for pairwise comparison with Bonferroni correction were used to compare TSH and free T4 levels between more than two groups. The normal ranges of head circumference, birth weight, serum TSH, and free T4 were determined as values falling between the fifth and the 95th percentiles of the control group. For TSH and free T4, this range was calculated separately for measurements made on day 2 of life and on day 3 or more. The Pearson correlation coefficient was calculated to measure the relationship between TSH and free T4 and between maternal TSH during pregnancy and the neonatal TSH. The 2 test for goodness of fit was used to compare rate to a known proportion.
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RESULTS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The general characteristics of the mothers and infants are shown in Table 1
. No statistically significant differences in maternal age, parity, percentage of smokers, percentage of preexisting or pregnancy-induced hypertension, and gestational age at delivery were noted between the study and control groups. Birth weight and head circumference were significantly smaller in the study group (P < .001). In 25 infants of the AGA study group (11.3%) the birth weight was lower than the fifth percentile of the control group (P < .06), and in 27 infants of the AGA study group (12.2%) the head circumference was below the fifth percentile of the control group (P < .03). No statistically significant differences in Apgar score at 1 and 5 minutes were noted between the two groups.
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TSH and Free T4 Levels
Overall, both TSH and free T4 serum levels were significantly higher in the study group (Table 2). Thyroid-stimulating hormone levels correlated negatively with the age of sampling in both groups (P < .001). The same was true for free T4 levels in the control group (P < .001) but not in the study group (Table 2). When the study and control groups were divided into those sampled at 25–48 hours and those at 49 hours or older, free T4 levels remained significantly higher at 49 hours or older in the study group relative to controls (P < .001). Given the accepted changes that occur in TSH and free T4 values over the first postnatal days, Figure 1 shows the relationship of TSH and free T4 and the age (hours) at examination. Figure 2 was designed to show the distribution of our measurement results in smaller time units.
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). No significant difference relative to controls was noted in the percentage of divergent TSH or free T4 levels (fifth percentile or greater than 95th percentile of controls) in the study neonates tested at 25–48 hours of life.
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Relative to the controls, the 29 study infants with a TSH level above the controls’ 95th percentile had a smaller head circumference (P < .001), a lower birth weight (P < .035), and a lower free T4 level (P < .001) (Table 3).
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Relationship Between TSH and Free T4 Levels
Figure 4 shows the relationship between TSH and free T4 levels in the neonates of the study and control groups. These data indicate that free T4 levels correlated directly to TSH levels in the controls but not in infants of hypothyroid mothers, suggesting an autonomous hyper-function of the thyroid gland in the study neonates.
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shows the relationship between maternal TSH at one point during early pregnancy and neonatal TSH levels at 24–48 hours and at 49 hours or older. Maternal TSH correlated positively with neonatal TSH at 49 hours or older (r = .751, P < .001).
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Neonatal Thyroid Function According to Maternal Diagnoses
Stratifying the thyroid function results according to the etiology of maternal hypothyroidism disclosed no particular pattern at 24–48 hours of life (Table 4). Higher TSH levels were observed at 49 hours or older in newborns from mothers with autoimmune thyroiditis relative to controls. For each of the maternal diagnoses, free T4 levels in the infants were higher than in the controls.
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DISCUSSION |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although the mothers of the study group infants were all diagnosed and treated for their hypothyroidism, different approaches exist with regard to diagnosis, frequency of thyroid function testing, and management. While assessing the newborns, no data regarding exact thyroid status throughout gestation were available in most cases. Hence, the aim of the present study was to try to find out whether an imbalance between maternal and fetal requirements and T4 supply during pregnancy occurs in some of these treated mothers, an imbalance that may exert a detectable influence on the neonatal pituitary–thyroid axis.
The present study followed a prospective design and ran for 6 years to include enough patients for adequate statistical power. For ethical reasons, the blood samples used in this study were those obtained as part of the Neonatal Screening Program, as is reflected in the age distribution (in hours) of the tests within the study and control groups. The timing of blood sampling allowed us to gain a fresh view on the dynamics of pituitary–thyroid axis function during the first days of life.
The findings indicate that the mean birth weight of newborns of treated hypothyroid mothers is lower than that of controls (even when stratified to AGA infants in the study group). This difference between the groups, which denotes a relative fetal growth restriction in the study children, was independent of the etiology of the maternal hypothyroidism of the mothers. Haddow et al6 showed that infants of untreated hypothyroid mothers had a higher, albeit not statistically significant birth weight (mean 3601 g) than controls (mean 3532 g). The reason for the difference between these results and ours is not clear. Maternal hypothyroidism in rats has been shown to cause a reduction in brain size in newborn pups and a lower total body mass of rat embryos.17 The lower birth weight of newborns of treated hypothyroid mothers in our study may be related to an impairment of placental function during alternating periods of normal maternal T4 level and hypothyroxinemia or to an adverse effect of such hormone insufficiency on the thyroid functions of the fetus.
Small head circumference and low birth weight are known to increase the risk of subsequent subnormal intellectual and psychologic performance.18–20 The smaller head circumference and birth weight in our study neonates warrant investigation of their possible relationship to an impaired psychomotor development and lower IQ scores, reported in the offspring of hypothyroid mothers.5–7
Although maternal thyroid hormone supply to the fetus has been considered to become irrelevant at some time after 10–12 weeks of gestation,21,22 it is now evident that the fetal thyroid hormone requirement is supplied partly by the mother also during the middle and last trimesters,3,11 as maternal–fetal transfer of T4 accounts for up to 50% of serum T4 concentration in fetal cord blood of hypothyroid fetuses at term.10,23 Thyroid hormone secretion increases during pregnancy in normal women, to provide for their own increased needs as well as those of their fetus, but women with marginally low thyroid function might be unable to respond sufficiently to these particular needs.3,24 Mandel et al25 observed that in nine of 12 women receiving treatment for primary hypothyroidism, the replacement dosage had to be increased during pregnancy by 45%. Such requirement for an increased replacement dose was apparent already in the first trimester and persisted throughout the course of pregnancy.
A physiologic decline in TSH level occurred in both groups at or after 49 hours of life. However, the expected concurrent significant decrease of free T4 values occurred only in the control group. The distribution curves of TSH and free T4 values (Figure 3
) show that TSH and free T4 levels were similar in both groups, except for two fairly large subgroups of study newborns, where TSH and free T4 levels were higher than the 95th percentile of the controls: in 13.9% and 34.2% of the whole study group infants, respectively, and in 16.5% and 44.4% of those tested after the second day of life. Furthermore, TSH–free T4 correlation analysis indicates that the normal positive relationship that usually exists between TSH and free T4 levels was not evident in newborns of treated hypothyroid mothers.
It was recently proposed that frequent monitoring of thyroid status and adjustment of T4 dosage during pregnancy is important because of fluctuations in T4 metabolism during pregnancy.13 Periods of maternal hypothyroxinemia and resultant diminished thyroid hormone transfer to the fetus may cause a concomitant response by the fetal thyroid. Possible support of this hypothesis may come from the finding of a smaller head circumference in our study neonates, which is often a feature of hyperthyroid newborns,26 whereas newborns with congenital hypothyroidism usually have a large head circumference.27
The assumption that suboptimal maternal replacement therapy during pregnancy may cause abnormal thyroid function tests in the newborn may find support in the positive relationship that existed between maternal and neonatal TSH values (Figure 5). However, two points should be considered while evaluating these data. First, these data apply to only a small number (16%) of the study group. Second, maternal TSH values were measured only at one time and may not reflect the thyroid status throughout the pregnancy. Nevertheless, the significant correlation between maternal TSH and neonatal TSH at 49 hours or older may suggest that the fetal thyroid is affected by maternal thyroid status.
In the present study, the incidence of sporadic permanent congenital hypothyroidism (three of 258) among the offspring of hypothyroid mothers is significantly higher than expected. The chance that such a finding could be incidental is extremely remote (P < .001). The possibility that transplacental passage of maternal thyrotropin receptor–blocking immunoglobulin G antibodies resulted in permanent congenital hypothyroidism is unlikely because the hypothyroidism in such instances would be transient.11 Iodine deficiency and low maternal iodine intake as a cause of both fetal and maternal thyroid deficiency28 are also unlikely because iodine is plentiful in our region and iodine deficiency is very rare among our population. Further studies are needed to elucidate this phenomenon. Since the conclusion of this study, we encountered four additional infants with permanent congenital hypothyroidism born to mothers with hypothyroidism during pregnancy. Infants of hypothyroid mothers appear to be at increased risk to be affected by permanent congenital hypothyroidism.
In summary, it appears that a large proportion of infants of treated hypothyroid mothers display abnormal thyroid function tests, which might suggest suboptimal replacement therapy. The findings of the present report require further studies (mainly in animal models) to define the mechanisms that may upset the fetal pituitary–thyroid axis and fetal growth in infants of hypothyroid mothers. Long-term neurodevelopmental follow-up is necessary to evaluate the clinical implications. Close monitoring of thyroid function throughout pregnancy and careful adjustment of the thyroid supplementation dosage are warranted for hypothyroid pregnant women to avoid the potential ill effects of an insufficient availability of thyroid hormone to the fetus.
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Footnotes |
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Received September 6, 2002. Received in revised form March 23, 2003. Accepted April 2, 2003.
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REFERENCES |
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