Maternal mild hypothyroidism is a common endocrine condition and occurs in 5%–18% of all pregnancies, depending on the definition used and population studied (1–3). Thyroid hormone is essential for optimum neurodevelopment of the fetus, acting on various stages of fetal neurological development, including neuronal migration, synaptogenesis, glial cell proliferation, and glial cell myelination (4, 5). Because the fetal thyroid gland is not functional until mid-gestation, the fetus predominantly depends on the supply of maternal thyroid hormone during that period (6). Therefore, maternal mild hypothyroidism may impair the neurodevelopment in offspring.

Results from animal studies have shown that shortage of thyroid hormone is associated with impaired brain development (7). Data from a large case–control study have demonstrated reduced scores on tests of intelligence, attention, and visual-motor performance at 8 years of age among children of mothers with untreated overt hypothyroidism (OH) during pregnancy compared to euthyroid controls (8, 9). Evidence from observational studies has demonstrated that maternal isolated hypothyroxinemia (IH) is predominantly associated with various types of neurodevelopmental disorders in children (10–12). However, the detrimental effects of maternal subclinical hypothyroidism (SCH) on fetal neurodevelopment remain less well established. Some studies have demonstrated that the offspring of women with SCH have decreased intelligence and motor ability or increased risk for delay in neurodevelopment (13–15), whereas others have shown conflicting results (10, 16, 17). This variation may be attributed to the different criteria for elevated thyroid-stimulating hormone (TSH) used in different studies (18).

Previous international guidelines have recommended using fixed upper limits of 2.5 mIU/L for the first trimester and 3.0 mIU/L for the second and third trimesters (1–3). Because studies have demonstrated that using these fixed upper limits in the 2011 guidelines results in overdiagnosis of SCH (19–22), the upper limit of TSH at 4.0 mIU/L for each trimester of pregnancy was advocated by the American Thyroid Association (ATA) 2017 guidelines (18). Moreover, only a few studies have investigated infant neurodevelopment among women with TSH concentrations between 3.0 and 4.0 mIU/L. Thus, the present study aimed to examine the association of maternal mild hypothyroidism with infant neurodevelopment, especially in women with high-normal TSH concentrations (3.0–4.0 mIU/L).

From December 2018 to September 2020, a total of 1,693 singleton infants born in Nanjing Maternal and Child Health Hospital had reached 1 year old. Data on TSH, FT4 and TPOAb were obtained for 1,533 mothers. In total, 178 mother–infant pairs were excluded because they met exclusion criteria, and 562 mother–infant pairs were excluded because the infants did not have neurodevelopment assessment at the age of 1 year. Thus, the final study population was composed of 793 mother–infant pairs. Of these 793 mother–infant pairs, 4.92% of the women were identified as SCH, 3.65% of the women were identified as IH, and only 0.38% of the women were identified as OH according to the 2017 ATA guidelines; 2.52% (20/793) of the women who had elevated concentrations of FT4 or suppressed TSH were excluded ( Figure 2 ). The remaining 773 pairs had 1.0%, 1.3%, 1.3%, and 2.2% missing values of pre-pregnancy BMI, drinking during pregnancy, maternal education, and duration of breastfeeding.

Compared to euthyroid women (ET group), the SCH group was more likely to have consumed alcohol during pregnancy, and the IH group was more likely to have higher childbearing age, higher pre-pregnancy BMI, and lower educational levels ( Table 1 ). Comparisons of the characteristics of the mother–infant pairs grouped by neurodevelopment assessment data availability according to different groups showed no differences between participants and non-participants. However, the ET group of mother–infant pairs with available neurodevelopment data had higher mean pre-pregnancy BMI, and the SCH group of mother–infant pairs had lower FT4 concentration ( Table S1 )

Multivariate linear regression models showed that maternal SCH during pregnancy was associated with decreased receptive communication scores at 1 year of age (β = −0.68, p = 0.034). Infants exposed to maternal IH had decreased gross motor scores (β = −0.83, p = 0.008), while no significant difference was observed in infants of mothers with OH, which may be attributed to the small sample size ( Table 2 ). When the 2011 ATA guidelines were used, similar results were obtained, and the infants exposed to maternal OH had lower gross motor scores (β = −1.11, p = 0.021) ( Table S2 ). The stratified analysis results revealed that there was no statistically significant association of Group SCH^a-ET^b (TSH 3.0–4.0 mIU/L and normal FT4) with infant neurodevelopment compared to Group ET^a-ET^b (TSH 0.2–3.0 mIU/L and normal FT4), but Group SCH^a-SCH^b (TSH >4.0 mIU/L and normal FT4) showed decreased receptive communication scores (β = −0.73, p = 0.025). Group IH^a-IH^b (TSH 0.2–3.0 mIU/L and FT4 < 10.55 pmol/L) was associated with lower gross motor scores, but there was no significance after adjustment for potential confounders. However, Group OH^a-IH^b (TSH 3.0–4.0 mIU/L and FT4 < 10.55 pmol/L) had lower gross motor scores (β = −1.19, p = 0.032) ( Table 3 ). In the sensitivity analyses, we repeated our main analysis restricting to infants born at full term (37 weeks or greater) or in women without diseases during pregnancy, and the results were not significantly altered ( Tables S3, S4 ).

In this population-based prospective cohort study, we observed impaired neurodevelopment in infants prenatally exposed to maternal mild hypothyroidism. Interestingly, associations differed in magnitude by subtype of maternal mild hypothyroidism and domains of infant neurodevelopment. Infants of women with maternal SCH were associated with decreased receptive communication scores only with maternal TSH levels greater than 4.0 mIU/L. For gross motor ability, maternal IH was predominant, and the effect was mainly attributed to mothers with high-normal TSH levels (3.0–4.0 mIU/L). To the best of our knowledge, this is the first study to evaluate the association of maternal mild hypothyroidism with offspring neurodevelopment as stratified by maternal TSH concentration.

Our findings in this prospective cohort study agreed with previous results (13, 14). A retrospective study from China has demonstrated that the offspring of women with SCH (TSH > 4.21 mIU/L) tend to have lower mental development index (MDI) and psychomotor development index (PDI) scores (14). Similarly, a meta-analysis of 39 original articles, including 909,176 individuals, has shown that maternal SCH has distinctly higher risk of intellectual disability in offspring (36). In contrast, a retrospective study of the Danish National Birth Cohort has indicated no adverse association between SCH (TSH beyond 2.5 mIU/L), and offspring verbal IQ was found (10, 16). These findings indicate that the different TSH cutoff values may be important confounders in various studies, thereby underlining the importance of performing in-depth analyses of observed associations.

Our study identified a significant association between maternal SCH (TSH > 4.0 mIU/L) and decreased receptive communication score in infants, while no significance was observed when maternal TSH levels were greater than 3.0 mIU/L but within the normal range (TSH < 4.0 mIU/L). These findings confirmed that the use of 4.0 mIU/L as the cutoff for TSH avoids the potential risk of overdiagnosis in women with SCH, thereby strengthening the association between SCH during pregnancy and adverse neurodevelopment, mainly when the TSH level is greater than 4.0 mIU/L. In summary, our results further validated and enhanced the current body of evidence suggesting that SCH diagnosed by the ATA 2017 standards is appropriate for screening high-risk women.

We also observed that maternal IH was associated with lower gross motor score in infants. Because maternal OH increases the risk of motor neurodevelopmental delay (37), most studies have shown that IH during early pregnancy is associated with an increased risk of a delay in infant motor development (10, 38). Furthermore, findings from animal studies support the observed associations. Animal studies have demonstrated that the primary brain region affected by decreased availability of maternal FT4 includes the cerebellum, which plays a critical role in motor coordination and motor activity (39). However, the present study is the first to elucidate the association of high-normal TSH levels with offspring neurodevelopment. In the present study, maternal IH with TSH levels between 3.0 and 4.0 mIU/L resulted in significantly decreased gross motor scores in infants compared to infants of mothers with TSH levels lower than 3.0 mIU/L (1.19 vs. 0.70).

Clinical guidelines clearly indicate that OH in pregnant women should be treated (18). Although the above studies have reported adverse outcomes in children born to mothers with IH, no interventional data have yet been published demonstrating the beneficial effects of levothyroxine (LT4) therapy (17, 40). Additionally, a recent guideline from the American College of Obstetrics and Gynecology (ACOG) provides a more conservative approach, essentially advocating treatment only for OH (41). In the present study, among 29 women identified as IH, 9 of them were originally diagnosed as OH according to the ATA 2011 guidelines, indicating that they were previously advised to be treated but later were not. Therefore, these women deserve more attention considering the worse effects on neurodevelopment compared to those with TSH levels below 3.0 mIU/L. Additionally, the lack of treatment effects in large randomized clinical trials (RCTs) should be reviewed. Current RCTs lack stratification of TSH concentration, which may indicate that the treatment effect on the low-risk group (e.g., TSH < 2.5 or 3.0 mIU/L) is diluted, leading to the conclusion of no benefit of treatment. Therefore, further studies should be conducted to identify the optimal treatment threshold of TSH where the benefits of LT4 administration outweigh the risks.

The strengths of the present study included its population-based prospective design, the long follow-up period, and our findings were obtained from TPOAb-negative pregnant women. We observed that maternal SCH was associated with detrimental neurodevelopment of infants, even in women with negative tests for TPOAb, which provided robust evidence to support LT4 treatment of pregnant women with TSH levels ranging from 4.0 to 10.0 mIU/L independent of their thyroid autoantibody status (42). Although the Bayley-III screening test is a validated instrument, it is not a diagnostic tool, and relying on one informant for assessment of neurodevelopment is a major limitation. We did not collect data for thyroid hormone parameters of the offspring after birth, but studies have shown that maternal thyroid function with child neurodevelopment is not mediated or modified by differences in postnatal child thyroid function (43). In addition, the present study was conducted in a single center and had a small sample size. Therefore, our conclusion needs to be further confirmed by multicenter studies with large sample sizes.

In summary, the present study demonstrated that maternal SCH is associated with decreased receptive communication scores in infants at 1 year of age. In addition, maternal TSH concentrations greater than 4.0 mIU/L and maternal IH are associated with impaired gross motor ability, especially in women with high-normal TSH concentrations (3.0–4.0 mIU/L). In addition, these findings suggest that clinicians should actively determine the primary cause of the decline in FT4 concentration for pregnant women in the higher end of the normal range (3.0–4.0 mIU/L) of TSH and low concentrations of FT4. Further studies are required to identify specific subgroups of women who may benefit from LT4 treatment.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study was approved by the institutional review board of Nanjing Medical University, China NJMUIRB (2017) 002. Written informed consent was obtained from all the participants or the infants' parents or guardians.

QW, YJ, and HL drafted the manuscript, analyzed the data, and interpreted the data. QW, TJ, and GZ designed the study, supervised the study, and critically revised the manuscript. All authors contributed to data collection, critically reviewed the article, and approved the final version to be published.

This study was funded by the National Natural Science Foundation of China (81803305 and 82103854), the Natural Science Foundation of Jiangsu Province (BK20180683), and the Maternal and Child Health Association of Jiangsu Province (FYX202031).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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