Journal of Medical Sciences and Health

Introduction

Thyroid disease is the second most common endocrine disorder in women of child-bearing age and is the most common congenital endocrine disorder. ¹ The prevalence of hypothyroidism in pregnancy in India is 13.13%. ² In the newborn, congenital hypothyroidism is the most common cause of preventable intellectual disability, hence it is imperative to diagnose and treat it early.

Studies have proved a relationship between maternal and foetal thyroid profiles, 3, 4, 5, 6, 7 hence proving hypothyroidism in pregnancy to be a real risk factor for congenital hypothyroidism. During the initial months of pregnancy, the foetus depends on the maternal thyroid hormones, which play a crucial part in normal brain development and the deprivation of it can have permanent effects on the foetus. Earlier research discovered that children born to mothers with hypothyroidism during pregnancy had lower IQ, impaired psychomotor development, increased risk for ADHD, autism, abortions, foetal anomalies, heart defects, lower birth weight and increased risk of hyperbilirubinaemia and neonatal hyper or hypothyroidism. ⁸

Despite apparently optimal maternal thyroid status, due to the gestational T4 metabolism fluctuations, this makes it difficult to maintain meticulous normal thyroid hormone values in hypothyroid mothers during pregnancy. ^1, 9 This imbalance of thyroid status which occurs during pregnancy is one factor which could decrease the maternal-foetal transfer of thyroxine, thereby causing hypothyroidism in the newborn. ¹⁰

Women, who have been diagnosed to be hypothyroid before pregnancy, usually have anti-thyroid antibodies and hence considered to be more likely to have babies with the highest values of TSH. On the other hand, it has been seen that mothers with pregestational hypothyroidism, have less fluctuations in their thyroid hormone values during pregnancy, as they are known to be compliant with their medications, in comparison to those mothers with gestational hypothyroidism – thus leading to lesser adverse effects in the newborn.

Neonatal thyroid hormone screening is now being done universally; however, many units perform extra thyroid tests on neonates of adequately treated hypothyroid mothers. In the past neonates with deranged thyroid profile were often misdiagnosed as having permanent congenital hypothyroidism, when in fact majority were actually transient hypothyroidism, ^11, 12 including transient hyperthyrotropinaemia.

It is important to understand precisely the impact of maternal thyroid disease on the newborn thyroid function, so that we do not miss neonatal hypothyroidism and can carefully treat these babies. ¹³ This study aimed to determine whether maternal hypothyroidism is a strong risk factor for congenital hypothyroidism and if there is a difference in thyroid hormonal status in babies born to mothers with pregestational versus gestational hypothyroidism.

Material and Methods

Study Design and Duration and Data Source: This is a prospective cohort study done over 18 months, from November 2019 – October 2021, in the postnatal wards and NICU of a medical college and teaching hospital in Mangalore.

Sample size and Inclusion criteria: 102 consecutive mothers admitted during this period with laboratory proven hypothyroidism on treatment and their respective newborns were included in the study.

Data Collection procedure: Informed consent was taken and explained in the local language. Institutional ethical (FMMCIEC/CCM/360/2019) and scientific committee approval for the study were obtained on 23/10/2019.

The diagnosis of maternal hypothyroidism, dosage of thyroid replacement medication and management was done throughout pregnancy by the treating obstetricians and endocrinologist. If there was a change in the thyroid replacement medication dosages in the mothers during pregnancy, the highest dose given to the mothers was taken as the final dosage.

The newborn cord blood TSH at birth, the venous blood TSH and free T4 between 2-7 days and 2-6 weeks of life were noted. Group 1 consisted of all the newborns born to mothers with hypothyroidism (diagnosed first time during pregnancy). Group 2 was made up of all the newborns born to mothers with hypothyroidism (diagnosed before pregnancy).

A neonate was considered to have congenital hypothyroidism when there was elevated serum TSH and decreased free T4 as per gestational and postnatal age values at birth and this had to persist beyond 2 to 6 weeks of life to confirm the diagnosis. ¹⁴

The infants who had high TSH values and normal free T4 at the first week but normal levels after the first week, were considered to have transient hyperthyrotropinemia (THT) and if it persisted beyond the first week were labelled as persistent hyperthyrotropinaemia (PHT). ¹¹ The decision to start treatment in the neonates was made by the treating paediatrician.

Sampling technique: The venous blood and cord blood of newborns were collected and TSH was measured by chemi-luminescence assay and free T4 was measured using radio-immunoassay technique.

Statistical analysis: Sample size was calculated using correlation coefficient of 0.37 and a p-value <0.05 was taken as significant.10 Independent t-test, Chi-square test, Pearson correlation, Fischer exact and ANOVA-p tests was used to compare, find the association and correlation between the groups and parameters respectively.

Results

Discussion

Basnet et al ¹⁵ had studied 100 hypothyroidism women and their babies and found that the mean TSH values at 72 hours of life was 2.95 ± 2 µIU/L in group A (pregestational hypothyroidism group) and 2.99 ± 2.1 µIU/L in group B (gestational hypothyroid mothers group) - similarly in our study, between 2-7 days of life, the mean serum TSH in the group consisting of pregestational hypothyroid mothers was 5.37 mIU/L and in the gestational hypothyroidism group it was 5.98 mIU/L.L.

Blazer Shraga et al, ¹⁰ studied 2 groups of women, group 1 being hypothyroid mothers (n = 250), out of which 51 (20.4%) women in the group had gestational hypothyroidism and the rest 199 (79.6%) had pregestational hypothyroidism. Whereas our study had 58 (57%) women with hypothyroidism detected prior to pregnancy and 44 (43%) detected during pregnancy. Both studies had adequately treated the hypothyroid mothers during pregnancy with thyroid replacement medications.

Blazer Shraga et al 10 had found that 161 neonates had qualified for being studied at 49 hours or older, out of which it was seen that TSH levels were above 95th percentile in 16.8% and below the fifth percentile in 7.5%. The fT4 values were above 95th percentile in 44.7% and below 5th percentile in 15.5%. ¹⁰ However in our study, elevated TSH levels beyond 48 hours was seen in 3.9% and fT4 was in 67.6% babies. Furthermore, in their study, ⁹ it showed that fT4 levels correlated directly to TSH levels of control group infants but not in infants of hypothyroid mothers, suggesting an autonomous hyperfunction of the thyroid gland in the study neonates.

Ozdemir Hulya et al ⁹ had their TSH level cut-off at 20 mIU/L during the first postnatal week. On the third week, if serum TSH >7mIU/L and fT4 <1ng/dL – the infant was considered to have congenital hypothyroidism and, in our study, we had used gestational and postnatal age based thyroid level cut-offs.14 In their study in group 2 (hypothyroid mothers without antibodies), 5 infants (23.8%) had serum TSH levels > 20 mIU/L in the first week and only 2 infants had serum TSH levels >7 mIU/L by third postnatal week. According to their definition, 2 babies in group 2 had congenital hypothyroidism and after they repeated the thyroid tests in eighth postnatal week, the values had normalised in their study. ⁹ Whereas we had 7 neonates with cord TSH level above 20 mIU/L, only 1 neonate had a serum TSH more than 20 mIU/L after 48 hours of life and by 2 to 6 weeks we had 1 baby with serum TSH >7 mIU/L (in whom thyroid levels were normal in the first week of life).

Medici Marco et al ³ had studied 5393 pregnant womens’ thyroid levels and 3036 newborns’ cord TSH values. They had excluded mothers with known thyroid diseases and those taking any sort of thyroid medication. They had found that the maternal and cord TSH and fT4 levels were positively correlating, which means that the higher the maternal TSH, the higher the cord TSH and free T4 values in the newborns – which was not the case in our study, possibly due to the pregestational hypothyroid group mothers having more stable thyroid levels and euthyroidism, due to prolonged usage of thyroid medication. They had also noted the importance of using population-specific reference ranges instead of standard ones, as we have used.

Sreelatha et al ¹ had studied 100 mothers with thyroid disorders (96 of which had subclinical hypo-thyroidism and 4 had subclinical hyper-thyroidism), out of which zero babies had neonatal hypothyroidism. Similar to our study where out of 102 babies, we did not have any babies with overt hypothyroidism and only 4 babies with subclinical hypothyroidism.

Cuestas Eduardo et al ¹¹ found out that out of 5040 newborns in their study, 301 (5.97%) had transient elevated TSH levels, compared to ours - which was 2 (1.92%) out of 102 babies born to hypothyroid mothers. They had followed up 65 children from the transiently elevated neonatal TSH group and 185 children from the normal cohort, 6 years later. Six infants out of 65 (9.2%) transient neonatal hyperthyrotropinemia (TNH) babies consequently developed persistent hyperthyrotropinaemia (PH), whereas only 3 infants out of 185 (1.6%) babies from the non-TNH control group subsequently developed PH. This tells us that persistent hyperthyrotropinaemia is a condition that can arise from a neonate who has apparently normal thyroid status at first week of life. In our study, we had one neonate who had normal screening TSH but subsequently had elevated TSH on follow up.

The strengths of our study were that: all 102 consecutive patients were included in the final analysis and there were no dropouts, and this is one of the few studies, that has delved into the difference between neonatal thyroid levels born to mothers with pregestational and gestational hypothyroidism.

Limitations: there was no control group. The population size studied was relatively small and follow-up was not continued beyond 2-6 weeks of life. A large multicentric and randomised controlled study would be needed for more reliable results.

Conclusion

Thyroid hormone status of newborns born to hypothyroid mothers (who are adequately treated) are within normal limits, hence they are not at a greater risk of hypothyroidism compared to the general population. Furthermore, there is no difference in thyroid hormone status of such newborns, born to mothers with pregestational and gestational hypothyroidism. In those babies with normal cord TSH and normal TSH levels between 2-7 days, further testing between 2-6 weeks is probably not required.

Disclosure