Normal thyroid function during pregnancy is essential for maternal and child health [1, 2]. Thyroid hormone (TH) deficiency, due to deranged distribution, reduced synthesis, or ineffective TH, leads to a clinical syndrome called hypothyroidism [3, 4]. Hypothyroidism is characterized by an excessive level of serum thyroid-stimulating hormone (TSH), above the upper reference limit, and reduced a metabolic rate [5]. A research has demonstrated that hypothyroidism is associated with a variety of maternal-fetal complications, including fetal malformation, intrauterine growth restriction, fetal death, preterm delivery, maternal hypertension, preeclampsia, gestational diabetes, and abortion [6].

Measuring anti-thyroid peroxidase antibody (TPOAb) is not universally routine for all pregnant women but is recommended in specific situations, such as when there is a clinical suspicion of thyroid disease, a history of thyroid dysfunction, or risk factors like autoimmune disorders or recurrent miscarriages. Anti-TPOAb testing is typically suggested for women with known thyroid issues, symptoms of thyroid dysfunction, unexplained infertility, recurrent pregnancy loss, or a personal or family history of autoimmune diseases [7]. While initial thyroid function screening often occurs in the first trimester, follow-up testing, including Anti-TPOAb, is frequently performed in the second trimester to provide a more stable and accurate assessment of thyroid status [8]. This timing helps balance the natural fluctuations of thyroid hormone levels in early pregnancy and allows for the confirmation and understanding of any thyroid abnormalities detected earlier, as per clinical guidelines. This approach ensures accurate diagnosis and effective management of thyroid disorders during pregnancy, which is essential for optimizing maternal and fetal health outcomes. Previous data proposed TSH upper limits of 2.5 mU/L in the first trimester and 3.0 mU/L in the second and third trimester [9]; a recent study suggested wider ranges, and societies recommend population-adjusted trimester-specific ranges, using synthetic thyroxine (T4) over free thyroid stimulating hormone (FT4). If unavailable, an upper reference of 4 mU/L may be used [10].

The most common form of TH replacement therapy is synthetic thyroxine (T4) hormone, levothyroxine (LT4), and its main function is inhibiting TSH. There are controversial findings on the therapeutic efficacy of LT4 replacement therapy, as some experts highlight the benefits of LT4, whereas some other reports concluded this treatment could result in harmful effects [2, 11, 12, 13, 14, 15].

Hypothyroidism is divided into mild (subclinical) or severe (clinical) hypothyroidism, depending on the severity of the disorder. Subclinical hypothyroidism (SCH) is a mild or moderate thyroid dysfunction that is clinically characterized by normal levels of TH with mildly elevated TSH concentrations, with or without clinical symptoms. SCH is a common disorder among women of childbearing age with a prevalence of 3–8% worldwide [16, 17, 18]. TPOAb and antithyroglobulin antibody (Tg-Ab) are two important thyroid autoantibodies that are commonly found in patients with autoimmune thyroid diseases. The main etiology of hypothyroidism among women of childbearing age is thyroid autoimmunity (TAI), which is defined as the presence of thyroid autoantibodies, antithyroglobulin antibody (Tg-Ab) or anti-TPOAb. In recent years, the prevalence of thyroid diseases during pregnancy has been gradually increasing and has become the second major endocrine disease during pregnancy worldwide [19]. Studies around the world have confirmed that pregnancy hypothyroidism can lead to the occurrence of maternal and fetal adverse pregnancy outcomes, and affect the fetal neurodevelopment of the fetus. Early intervention can effectively reduce the occurrence of adverse pregnancy outcomes [20, 21].

Evidence has demonstrated that the synthetic thyroid hormone levothyroxine (LT4) is a cost-effective treatment of hypothyroidism, with few side effects [6, 22, 23, 24].

However, there are still controversies on the causal relationship between whether SCH can lead to adverse pregnancy outcomes and whether intervention should be taken during pregnancy. The present study aimed to investigate the associations between SCH and adverse pregnancy outcomes and whether levothyroxine replacement therapy can improve the maternal and infant outcomes of patients with SCH.

SCH is the most common thyroid dysfunction in pregnancy, varying in prevalence between 1.5% and 5% depending on definition, ethnicity, iodine intake, nutritional lifestyle, and study design [13]. SCH during pregnancy is linked to a higher risk of pre-eclampsia compared to euthyroidism, with a U-shaped relationship between TSH levels and pre-eclampsia, emphasizing the need for future studies to determine the optimal levothyroxine treatment targets to mitigate these risks [28]. Since the clinical symptoms are not typical and difficult to detect, the diagnosis is usually made by a serological examination of thyroid related indicators. Thyroid hormone is an indispensable hormone for the normal growth and development of the body [29]. It can promote tissue growth, differentiation and maturation, promote physical and intellectual development, and is very important for the development of the nervous system, bone and reproductive system. All thyroid hormones that maintain fetal growth and development in early pregnancy come from the mother. After 14 weeks of gestation, the fetus’ own thyroid begins to develop and secrete thyroxine, but some of it still comes from the mother [30]. During pregnancy, the demand for thyroid hormone is significantly increased compared with non-pregnancy, which can increase by 25% to 50%, resulting in the phenomenon of “physiological hypothyroidism”. The effect of clinical hypothyroidism on pregnancy outcomes and perinatal outcomes has been well established. A national USA assessment by Maraka et al. [31], reported that thyroid hormone treatment significantly reduced the risk of pregnancy loss in women with SCH, particularly those with pre-treatment TSH levels between 4.1 and 10 mIU/L. However, there are still controversies about the effects of SCH during pregnancy on pregnancy outcome and perinatal delivery, and whether L-T4 replacement therapy is beneficial to patients [32, 33, 34].

In the study, there were no significant differences in age, body mass index and parity between each group and the control group. To some extent, it indicates that age, body mass index and parity of pregnant women have little relation to the occurrence of SCH during pregnancy. However, in terms of gestational age of primary screening for thyroid function, the TPOAb (–) untreated subgroup was significantly larger than the TPOAb (–) treated subgroup and control group, and the difference was related to the time of the patients’ first thyroid function examination. The results of the study suggested that the SCH-untreated group has a significantly higher risk of hypertensive disease in pregnancy, premature delivery, fetal intrauterine growth restriction, and fetal death in utero than the control group. However, the effect of SCH on adverse maternal and fetal pregnancy outcomes remains controversial. A TSH screening study [17] of women six months before conception found that high levels of TSH were a risk factor for miscarriage, preterm birth and surgical delivery. In a prospective study conducted by Cleary-Goldman et al. [35], the thyroid function of 10,990 pregnant women in the first and second trimesters of pregnancy was examined, and SCH was not found to be associated with adverse pregnancy outcomes such as abortion and preterm birth. Previous studies found that SCH increased the risk of preeclampsia, fetal distress, fetal growth restriction and low birth weight in pregnant women [18, 36, 37]. A meta-analysis reported that significant SCH during pregnancy did not increase the prevalence of gestational hypertension. Männistö et al. [38, 39] analyzed the relationship between thyroid function and pregnancy outcome in 5805 cases in early pregnancy and found that SCH was not significantly associated with perinatal fetal mortality.

In the present study, the incidence of preterm birth in the treatment group was significantly lower than that in the untreated group, but higher than that in the control group, and the difference was statistically significant, while there was no significant difference in the incidence of adverse pregnancy outcomes. The results suggested that L-T4 substitution therapy can reduce the occurrence of adverse pregnancy outcomes in SCH pregnant women. In addition, the mean gestational age of thyroid function screening in the SCH-treatment group was (17.8 $\pm$ 6.7) weeks, and the incidence of preterm delivery in the treatment group was higher than that in the control group, which may be related to the late intervention in the treatment group. A meta-analysis [40] showed that L-T4 intervention in SCH pregnant women reduced the risk of miscarriage by about 50%. Oral levothyroxine significantly improves pregnancy outcomes in SCH patients in the first trimester of pregnancy, especially in patients with TPOAb positive, according to a retrospective study [41]. In the study, the positive rate of TPOAb in the treated and untreated groups was significantly higher than that in the control group, indicating that TPOAb is an independent risk factor for pregnancy complicated with SCH and one of the important thyroid autoantibodies. The incidence of preterm birth in the TPOAb (+) treated subgroup was significantly lower than that in the untreated TPOAb (+) subgroup, and the incidence of preterm birth in the TPOAb (–) treated subgroup was significantly lower than that in the untreated TPOAb (–) subgroup, indicating that for SCH pregnant women, no matter whether TPOAb is positive or not, patients can benefit from L-T4 replacement therapy. China’s 2019 guidelines recommend that TSH is higher than the upper limit of the pregnancy-specific reference value (4.0 mU/L), and LT4 treatment is recommended regardless of whether TPOAb is positive [42]. A study has shown that the thyroid function of TPOAb (+) pregnant women tends to develop into hypothyroidism [43]. A meta-analysis of 14 index studies showed that the OR for miscarriage with positive thyroid autoantibodies was 2.31 (95% confidence interval (95% CI): 1.90–2.82) [44]. Lin et al. [45] reported that the incidence of spontaneous abortion in TPOAb-positive pregnant women in early pregnancy was significantly higher than that in the negative group. The effect of positive TPOAb alone on adverse pregnancy outcomes is controversial. Our study showed that there was no significant statistical difference in adverse pregnancy outcomes between TPOAb (+) subgroup and TPOAb (–) subgroup in the control group, which did not indicate that TPOAb positive increased the occurrence of adverse pregnancy outcomes. However, most of the TPOAb (+) patients in the control group in our study were in the middle and late stages of pregnancy, which had certain limitations, and higher quality prospective studies were needed to verify the research conclusions.

There are still shortcomings in this study. First, the diagnostic criteria of SCH are outdated, and previously it has been confirmed that the upper limit of the reference range of TSH for pregnant women in China is significantly higher than the upper limit of the reference range recommended in the guidelines, which affects the accuracy of the research results to some extent [46]. On the other hand, SCH still has a certain influence on maternal and fetal pregnancy outcomes under the premise that the upper limit of the reference range of TSH is 2.5 in the first trimester and 3.0 in the middle and late trimester, and L-T4 replacement therapy can improve maternal and fetal pregnancy outcomes. Secondly, this study is a single-center study with insufficient sample size and representativeness. This study is a retrospective study, but the prospective systematic analysis of the effect of SCH on pregnancy outcome and L-T4 replacement therapy needs to be further explored by multi-center joint efforts.

The study found no significant differences in age, body mass index, and parity between the SCH and control groups, suggesting these factors have little relation to SCH during pregnancy. However, the timing of thyroid function screening differed, with untreated TPOAb (–) women screened later than their treated and control counterparts. The untreated SCH group faced higher risks of hypertensive disorders, preterm birth, fetal growth restriction, and fetal death. L-T4 therapy reduced these risks, particularly preterm birth, despite late intervention. TPOAb was identified as a significant risk factor, and L-T4 treatment benefited both TPOAb (+) and TPOAb (–) women.

The data can be obtained from the corresponding author upon reasonable request.

CL and XL contributed to conception and design of the study. CL and XL organized the database. CL and XL performed the statistical analysis. CL and XL wrote the first draft of the manuscript. Both authors contributed to manuscript revision. Both authors read and approved the final manuscript. Both authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

All experimental procedures of this study were approved by the local Medical Ethics Committee of Huai’an Maternal and Child Health Care Center (Code NO.: 2021-126), which were in complete accordance with the ethical standards and regulations of human studies of the Helsinki declaration. Written informed consent was obtained from all participants.

Not applicable.

This study was supported by Huai’an Natural Science Research Program (Joint Special Project) [No. HABL202253].

The authors declare no conflict of interest.