To study the effects of third trimester maternal isolated hypothyroxinemia (serum low free thyroxine and normal thyroid stimulating hormone level) on pregnancy outcomes, we performed a retrospective cohort study in women with singleton pregnancy between February 2009 and June 2012. Pregnant women were assigned to two groups, a hypothyroxinemia group (with maternal isolated hypothyroxinemia in the third trimester and normal thyroid function in the first and second trimesters) and a control group (with normal serum thyroid functions). The pregnancy outcomes, including preterm birth, fetal distress, birth weight, premature rupture of membranes, and Apgar score at one minute after the birth, were recorded and compared between the two groups. A total of 3,945 pregnant women (median age 26 year old) were included in the study, with 195 women in the hypothyroxinemia group and 3,750 women in the control group. Compared with the women in the control group, women in the hypothyroxinemia group had higher incidences of premature rupture of membranes and low Apgar score at one minute after the birth. The multivariate logistic regression analysis showed that the low third trimester serum thyroxine level was the independent risk factor for the premature rupture of membranes and low Apgar score. There were no statistically significant differences in preterm birth, macrosomia, and intrauterine fetal distress between two groups. Third trimester maternal isolated hypothyroxinemia was associated with adverse pregnancy outcomes. The maternal serum thyroxine level should be monitored during late pregnancy and necessary management should be applied to improve the pregnancy outcomes.

MATERNAL THYROID HORMONES are crucial for normal pregnancy and fetal growth and development [1]. Many studies have demonstrated the associations between the abnormal maternal thyroid hormones and adverse outcomes in pregnant women and fetuses [2]. Since the fetal thyroid gland can reach its maturity by the end of the first trimester and starts to secrete thyroid hormones in the middle of the second trimester [3], it was commonly believed that maternal thyroid hormones were more important to the fetus in early pregnancy rather than late pregnancy. Therefore, most previous studies on the effects of the maternal thyroid hormones on the fetus were focused on the women with the low first or second trimester thyroid hormone levels, or women with pre-existing thyroid diseases, with limited studies performed in women in their third trimester [4-8]. However, an increasing number of studies have shown that the adverse feto-maternal outcomes could be caused by abnormal maternal thyroid hormones in all three trimesters of pregnancy [9]. Several studies have shown that abnormal maternal thyroid function in the third trimester could increase the risk of adverse pregnancy outcomes [10-12]. A recent meta-analysis study found that a low serum free thyroxine (FT4) level in the third trimester could have approximately 3- and 1.5-fold greater effect to result in higher birthweight than a low FT4 level in the first and second trimesters, respectively [13]. Therefore, more investigations are required to study the association between abnormal thyroid function in the third trimester and pregnancy outcomes.

Various studies have reported that 2–20% of women could have abnormal thyroid functions during the pregnancy [14-16]. The most common thyroid disease during pregnancy is subclinical hypothyroidism, in which patients have a normal FT4 level but a high thyroid stimulating hormone (TSH) level [17]. Another abnormal thyroid condition with low serum FT4 and normal TSH levels is called maternal isolated hypothyroxinemia (MIH) [18], which has a prevalence of up to 64.1% in pregnant women, as reported by different studies [19, 20]. MIH in the first trimester could lead to adverse feto-maternal outcomes, such as gestational diabetes and hypertension, fetal distress, preterm birth, placental abruption, and spontaneous abortion. During the second trimester, MIH has been associated with an increased incidence of macrosomia and gestational hypertension [21]. However, there are a limited number of studies performed in MIH women in their third trimester. It is therefore unclear if MIH in the third trimester could lead to adverse pregnancy outcomes.

In the present study, we investigated the association between MIH in the third trimester and pregnancy outcomes with the purpose to provide evidence for a better prenatal screening strategy during the third trimester to achieve improved pregnancy outcomes.

We performed a retrospective cohort study and reviewed the medical records on pregnant women from the Third Affiliated Hospital of Wenzhou Medical University, Zhejiang, China, between February 2009 and June 2012. The study protocol was approved by the hospital’s ethics committee (Ref. No. LZM2018003).

Isolated hypothyroxinemia is typically defined as an FT4 concentration in the lower 2.5th–5th percentile of a given population, in conjunction with a normal maternal TSH concentration and negative thyroid autoimmune antibody according to the 2017 American Thyroid Association guidelines [22]. Based on our hospital’s normal range in pregnant women with negative thyroglobulin antibody (TGAb) and/or thyroid peroxidase antibody (TPOAb), MIH was defined as TSH 0.8–6.1 mIU/L and FT4 <5.1 ng/L. The inclusion criteria were women who: 1) had a singleton pregnancy; 2) were in their third trimester; 3) were diagnosed with MIH; and 4) had a normal serum FT4 and TSH level before the third trimester. The exclusion criteria were patients who: 1) received thyroid hormones or antithyroid medications currently or previously; 2) had a history of thyroid disease, including hyperthyroidism and hypothyroidism, or autoimmune diseases; 3) had a history of congenital heart disease or heart failure; 4) had high serum transaminase or creatinine level; 5) had a malignant tumor currently or previously; 6) had a history of hypertension or diabetes before pregnancy; 7) had an injury, infection, or other stressful condition(s); 8) received assisted reproductive technology; or 9) had incomplete medical records.

Medical records were reviewed to document age, obstetric history, educational history, gestational weeks for blood collections, gestational weeks for delivery, gestational diabetes, and gestational hypertension. The laboratory tests were performed in an automatic chemiluminescence immunoassay analyzer (DX2800, Beckman Corp., Germany) in the hospital laboratory. Pregnancy outcomes, including preterm birth, fetal distress, birth weight, premature rupture of membranes, and newborn Apgar score at one minute after the birth, were recorded.

Preterm birth was defined as delivery occurring at <37 weeks of gestation. Fetal distress was defined as fetal heart rate <120 or >160 beats/min, with meconium, abnormal fetal movements, and fetal scalp pH <7.2 [23]. Macrosomia was defined as newborn weight ≥4,000 g. Premature rupture of membranes was defined as rupture of the amniotic sac and chorion before the onset of labor [24]. Apgar score was calculated as previously described. An Apgar score <7 was considered a low score [25].

The included pregnant women were assigned into either the hypothyroxinemia group (MIH) or the control group (normal serum FT4 and TSH levels). The continuous data were presented as mean with standard deviation or median with interquartile range and were compared by the Student t test or Mann-Whitney U test, when appropriate. The categorical data were presented as number with percentage and were compared by a Chi square analysis or Fisher exact test. The logistic analysis was also applied to look for the risk factor associated with the adverse pregnancy outcomes. All statistical analyses were performed in SPSS (version 25.0. IBM, New York, USA). A p < 0.05 was considered as statistically significant.

A total of 3,945 pregnant women were included in the present study, with the median age of 26 (interquartile range 24–30) years old. There were 195 patients in the hypothyroxinemia group and 3,750 patients in the control group (Fig. 1). In our present study, the prevalence of MIH was 4.9%. Their baseline characteristics are shown in Table 1. The serum FT4 level was statistically significantly lower in the hypothyroxinemia group than in the control group (p < 0.001).

Fig. 1

Patient selection flowchart.

Compared to the control group, the hypothyroxinemia group had a statistically significantly higher incidence of preterm birth (p = 0.030) and premature rupture of membranes (p = 0.012). There were no statistically significant differences in macrosomia, fetal distress, and low Apgar score at one minute after birth between the two groups (Table 2).

In the multivariate logistic regression analysis, after corrections for the age, gestational weeks for blood collection, pregnancy history, educational level, gestational diabetes, gestational hypertension, gestational weeks for delivery, TPOAb, and TGAb, there were statistically significant associations between the MIH and the premature rupture of membranes and a low Apgar score at one minute after birth. The low third trimester serum thyroxine level was the independent risk factor for the premature rupture of membranes and low Apgar score (Table 3).

According to the definition by the 2017 American Thyroid Association guidelines, MIH is a condition where the serum TSH is within the normal range for pregnancy but the serum FT4 is below the 2.5th–5th percentile of the pregnancy-specific reference range [22]. Different hospitals and different laboratories can have different reference ranges for the serum TSH and FT4 levels [26-28]. In addition, the ethnicity, iodine deficiency status, and the gestational weeks when blood is collected can all influence the serum TSH and FT4 test results [29, 30]. In the present study, the prevalence of third trimester MIH in our pregnant women was 4.9%. This was lower than the prevalence in women in their third trimester of pregnancy reported previously by other studies. Avramovska et al. reported a prevalence of 64.1% MIH in a pregnant population in North Macedonia [20] and Li Y et al. reported a prevalence of 11.1% MIH in a pregnant population in Shanghai, China [31]. One of the reasons for the significant difference between our MIH prevalence and previously reported MIH could be the inclusion criteria of our study. Since our study was focused on the effects of third trimester MIH on pregnancy outcomes, we only studied the pregnant women with third trimester MIH but with normal thyroid functions during the first and second trimesters. The high prevalence of MIH reported in other studies included all pregnant women with MIH onset from the first to the third trimester [20]. The exact mechanism of MIH is still under the investigation, although iodine deficiency could be the main cause [19]. In addition, studies have shown that obesity and iron deficiency are also important factors of MIH [32, 33].

There are only a few reports examining the effect of third trimester MIH on pregnancy outcomes, with most studies focused on the birth weight of the newborns. The results of these studies are conflicting. A large prospective cohort study performed in 46,186 pregnant women in China showed that persistent low free T4 levels in both early and late pregnancy were associated with increased birth weight and an increased risk of macrosomia [10]. Another study from Henan, China showed similar findings in that pregnant women with hypothyroxinemia had a 1.22-fold (95% confidence interval: 1.13–4.85) increased risk of delivering a macrosomic baby and a lower Apgar score in newborns than in the normal thyroid function group (p = 0.013) [34]. However, this study only included a small number of pregnant women and did not analyze these women in different trimesters. Another study in 11,564 Chinese pregnant women did not find an association between late pregnancy MIH and abnormal newborn birth weight [35]. In the study from Avramovska et al. in Macedonia, 54% of women in late pregnancy also showed no association between MIH and preterm birth, intrauterine growth restriction, low birth weight, or low Apgar scores at one minute after birth [20].

In the present study, most baseline characteristics were comparable between the control and hypothyroxinemia groups suggesting that the differences in the pregnancy outcomes were not caused by these factors, including gestational weeks, obstetric and educational history, gestational diabetes and hypertension, TPOAb, and TGAb. We found that pregnant women with third trimester MIH had higher incidences of premature rupture of membranes and preterm birth compared to the women in the control group. However, there was no association between MIH and low Apgar scores at one minute after birth, macrosomia, and intrauterine fetal distress. Considering that some studies have reported that the thyroid autoimmune antibodies might be associated with adverse pregnancy outcomes [36, 37], we performed multivariate logistic regression analysis and found that the third trimester MIH was the independent risk factor for the premature rupture of membranes and low Apgar score after correcting for the thyroid autoantibodies. The premature rupture of membranes could increase the risk of intrauterine infection [24]. One center found that 14% of women with previable premature rupture of membranes experienced significantly increased maternal morbidities, including: sepsis; transfusion; hemorrhage; infection; acute renal injury; and readmission [38-40]. A low Apgar score could result in fetal nerve damage and increase the risk of neonatal cerebral palsy and autism disorder [41-43]. A decreased Apgar score has also been associated with a significantly higher risk of neonatal and maternal adverse outcomes, as well as increased infant mortality [44, 45].

The underlying mechanisms between hypothyroxinemia and adverse pregnancy outcomes are still under investigation [1, 46]. Thyroid hormones are essential for the fetal growth. They can trigger the fetal brain and body development in early gestation, as well as promoting fetal tissue differentiation in later pregnancy. They can also indirectly affect fetal growth by regulating and influencing the bioavailability and effectiveness of other hormones and growth factors, such as glucocorticoids, catecholamines, and insulin-like growth factors. At the molecular level, thyroid hormones can play a role in the anabolic effects of the fetus and stimulate oxygen consumption by affecting mitochondrial respiration and adenosine triphosphate synthesis. Thyroid hormones ultimately regulate the tissue proliferation and differentiation to ensure the activation of physiological processes that are critical for survival at birth, such as pulmonary gas exchange, heat generation, hepatic gluconeogenesis, and cardiac activity. In addition, abnormal thyroid function could disrupt the transfer of maternal nutrition to the fetus, affecting fetal growth and development.

The strengths of our study were its large sample size and the focus on women in their third trimester of pregnancy, in which there is a dearth of research currently. The limitations of our study included its single center research and retrospective study design. In addition, we did not have the pre-pregnancy body mass index in these women. The pre-pregnancy body mass index is considered to correlate with the poor pregnancy outcomes [47]. In addition, although iodine deficiency is a common reason for maternal isolated hypothyroxinemia in late pregnancy and a recent study found that our local area had a significant prevalence of iodine deficiency in pregnant women [48, 49], we were not able to define the causes of hypothyroxinemia in the present study due to the retrospective study design. Future prospective studies should include the etiology study for maternal isolated hypothyroxinemia.

In summary, third trimester MIH was the independent risk factor for the premature rupture of membranes and low Apgar score at one minute after the birth. The maternal serum level of thyroxine level should be monitored during the late pregnancy and necessary managements should be applied to improve pregnancy outcomes.

This work was supported in part by the Medical Science Research Foundation of Zhejiang Province (Grant No. 2009A198), Medical and Health Science and Technology Project of Zhejiang Province (Grant No. 2023KY1165).

The authors declare that they have no conflict of interest.

The study protocol was approved by the hospital’s ethics committee (Ref. No. LZM2018003). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Written informed consent was obtained from individual participants.

Not applicable.

The datasets generated and analyzed during the present study are available from the corresponding author on reasonable request.

Not applicable.

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