Front Endocrinol: A higher maternal thyroid resistance index is associated with elevated levels of neonatal thyroid-stimulating hormone

Background: Thyroid function in pregnant women is critical
for fetal and neonatal growth and neurodevelopment.
Deficiency or excess thyroid hormone (TH) during embryonic development can lead to severe and permanent deficiencies, and even transient hypothyroidism can lead to adverse neurological consequences
in newborns.
Congenital hypothyroidism (CH), a deficiency of TH at birth, is the most common and treatable cause of intellectual disability that needs to be identified and treated
immediately.
The incidence of CH varies from 1:2000 to 1:4000 in different regions and ethnic groups
.
Since the 70s of the 20th century, a newborn screening program has been implemented
worldwide.
However, less than a third of the world's births are screened for CH, and about 29,840 CH cases each year do not benefit
from early detection and treatment.
As a result, the economic burden of disability caused by CHS remains a significant public health challenge
.
Maternal thyroid dysfunction during pregnancy has been reported to be associated
with a variety of adverse pregnancy outcomes.
However, research on the relationship between maternal TH and neonatal thyroid function is limited
.
Pregnancy increases iodine clearance from thyroid blood vessels and kidneys, and increases the fetus's need
for iodine.
Even in the case of normal thyroid function, fluctuations in maternal thyroid hormone metabolism can impair maternal-fetal metastasis
of thyroid hormones.
A decrease in fetal thyroid hormones may disrupt the development
of the pituitary axis of the newborn.
Neonatal thyroid-stimulating hormone (TSH) is considered the most sensitive for detecting primary CH and a predictive biomarker of iodine status at the population level
.
Elevated TSH in newborns indicates insufficient supply of Th in developing fetal brain tissue, so it is the only predictor
of brain damage due to iodine deficiency.

A feedback mechanism controlled by the hypothalamic-pituitary-thyroid (HPT) axis maintains blood circulation within normal limits
.
In targeted tissues or organs, the appropriate efficacy of TH depends on the capacity and availability
of TH transporters, deiodinases, and nuclear TH receptors.
In humans, genetic defects in TH signaling can lead to various defects in TH membrane transport, metabolism, or function, even though they may not alter the TH spectrum
.
Resistance to TH (RTH) is a syndrome
in which the end organs are less reactive to TH.
In 2009, Jostel et al.
first proposed calculating the TSH Index (TSHI) to assess the pituitary gland sensitivity
to THs.
Reversible acquired RTH caused by endogenous and exogenous factors such as comorbidities, malnutrition, or multiple drugs has been reported to be more common
than rare congenital RTH.
In the general population, moderately acquired RTH is thought to be associated with an increased risk of metabolic disorders and has received increasing attention
in recent years.
Due to the presence of a reverse feedback loop, TSH and TH are physiologically negatively correlated
.
However, it has been reported that in patients with metabolic disorders, high levels of T4 and TSH coexist, indicating some resistance
to TH.
This changes
a lot during pregnancy, especially in the first half of pregnancy.
However, the relationship between maternal thyroid sensitivity and neonatal TSH levels has not been studied before
.
Validating this correlation during pregnancy is important
for predicting neonatal TSH and promoting early screening for CH.

Objective: To investigate the relationship
between thyroid function, thyroid resistance parameters and neonatal thyroid-stimulating hormone (TSH) in pregnant women.

Methods: This study was a longitudinal study
.
Single pregnant women with no history of thyroid disease were recruited at their first antenatal visit from October 2018 to June 2020
.
Maternal thyroid hormone (TSH), free triiodothyronine (FT3), free thyroid hormone (FT4) and neonatal TSH
were detected by electrochemiluminescence immunoassay.
The thyroid resistance index includes the thyroid feedback quantile index (TFQI), thyroid-stimulating hormone index (TSHI), and thyroid-stimulating hormone T4 resistance index (TT4RI).

Multiple linear regression and logistic regression were used to analyze the relationship
between maternal thyroid indexes and infant TSH levels.

Results: A total of 3210 mothers and 2991 neonates with valid thyroid-stimulating hormone data were included in the analysis
.
Multiple linear regression analysis showed that the maternal thyroid variable was significantly positively correlated with the level of neonatal TSH, and the normalization coefficients were TSH 0.
085, FT3 0.
102, FT4 0.
100, TSHI 0.
076, TFQI 0.
087, TT4RI 0.
089 (all P < 0.
001).

。 Compared with the lowest quartile, the highest quartile of TSHI [odds ratio (OR)=1.
590, 95%CI: 0.
928~2.
724; P trend=0.
025], TFQI (OR=1.
746, 95%CI: 1.
005~3.
034; P trend=0.
016) and TT4RI (OR=1.
730, 95%CI: 1.
021~2.
934; P trend=0.
030) were associated with elevated neonatal thyroid-stimulating hormone ( The increased risk of >5 mIU/L) is dose-response relationship
.

Table 1 Multiple linear regression analysis
of maternal thyroid function, thyroid resistance index and infant thyroid-stimulating hormone level, and Huizhou maternal and infant cohort (n=3,210).

Table 2 Neonatal TSH level > 5mIU/L odds ratio (OR) and 95% confidence interval (CI) in the Huizhou maternal and infant cohort were calculated
by the quartile of maternal thyroid function and thyroid resistance index.

Conclusion: Maternal thyroid resistance index and thyroid hormone levels during pregnancy are positively correlated
with neonatal TSH levels.
This finding provides an additional practical suggestion
for improving current screening algorithms for congenital hypothyroidism.

Li S, Wu Y, Zhang SJ, et al.
Higher maternal thyroid resistance indices were associated with increased neonatal thyroid-stimulating hormone- analyses based on the Huizhou mother-infant cohort.
Front Endocrinol (Lausanne) 2022; 13