European Journal of Cardiovascular Medicine

The definition of "recurrent" pregnancy loss (RPL) generally includes the loss of two or more pregnancies, though specific criteria may vary depending on different medical guidelines and regional standards.1 The American Society for Reproductive Medicine (2020) now defines RPL as two or more failed pregnancies confirmed by sonographic or histopathological examination.

Prevalence of recurrent pregnancy loss is 10 to 15%.

Etiology of RPL: 1) Parental chromosomal abnormalities, 2) Anatomical factors, 3) Immunological factors, 4) Endocrine factor (8 – 12%). Overt hypothyroidism and severe iodine deficiency also raise miscarriage rates. Subclinical hypothyroidism however, does not appear to increase miscarriage rates. Antithyroid antibodies are a common associate of subclinical hypothyroidism or overt hypothyroidism. Other endocrinocrinopathies are progesterone deficiency caused by luteal phase defect. hyperprolactemia, Obesity, polycystic ovarian syndrome and insulin resistance are also linked to RPL.

Over the past two decades, the relationship between subclinical hypothyroidism (SCH), thyroid autoimmunity (TAI), and adverse obstetric outcomes has been a topic of ongoing debate in endocrinology, obstetrics and gynaecology, and perinatology. Recent research has linked SCH in pregnancy to an increased risk of miscarriage, with higher maternal TSH levels observed in women who miscarried compared to those with unaffected pregnancies. Additionally, multiple meta-analyses have highlighted a significant association between TAI and miscarriage. However, previous studies primarily focused on pregnancies between 11 and 13 weeks of gestation, potentially overlooking cases of miscarriage occurring before 11 weeks. This study aims to explore the impact of SCH and TAI in early pregnancy on spontaneous miscarriage among women at low risk for thyroid disorders.

Thyroid autoantibodies, including anti-TPO and anti-Tg, are detected in approximately 2% to 17% of pregnant women, with prevalence varying by ethnicity. Women with isolated TgAb positivity exhibited significantly higher serum TSH levels than those without thyroid autoimmunity. While testing only for TPOAb may miss a subset of women with isolated TgAb, most studies on thyroid autoimmunity and clinical outcomes have relied on TPOAb measurements. Therefore, the task force recommends assessing TPOAb as the primary marker for thyroid autoimmunity screening. In women with thyroid autoimmunity, the increased demands of pregnancy can strain the thyroid, which may already have a reduced capacity to produce hormones, potentially leading to hypothyroidism.2 Subclinical hypothyroidism is characterized by elevated thyroid-stimulating hormone (TSH) levels with normal free thyroxine (FT4) concentrations. Although SCH is often asymptomatic, emerging evidence suggests its association with adverse pregnancy outcomes, including an increased risk of miscarriage.3

The primary objective of this study is to analyse the association between subclinical hypothyroidism and Anti-TPO Ab with recurrent miscarriage. The secondary objective is to estimate the prevalence of Anti-TPO Ab and subclinical hypothyroidism in recurrent miscarriage.

This is a descriptive, observational, epidemiological, prospective study conducted from July 2023 to December 2024 at a tertiary care centre in Kolkata. The study population were patients presenting at outdoor patient department of Obstetrics and Gynaecology having recurrent miscarriage and subclinical hypothyroidism, euthyroidisim. The inclusion criteria included multiparous (multigravida) women, both euthyroid & hypothyroid, with ≥2 pregnancy losses. The exclusion criteria were: anatomical causes of miscarriage & chromosomal abnormality. All the records of eligible candidates such as patient particulars, medical history & comorbidities, treatment history, past history, socioeconomic status, general physical examination (height, weight, BMI, BP), age (in years), total miscarriage (1st trimester miscarriage, 2nd trimester miscarriage), family history of RPL, maternal infection, routine investigations (complete hemogram, blood sugar, blood group), specific investigations (TSH, fT4, anti TPO antibody), transabdominal ultrasound, transvaginal ultrasound were noted in a Microsoft Excel spreadsheet (version: Office 2021, Windows 10) during the study period. Data thus collected were interpreted using Statistical Package for Social Sciences software (version 25). Institutional ethics approval was obtained from the institutional ethics committee.

The sample size for the present study was 166, calculated using the formula n = (Z²PQ/d²), where n denotes the sample size, Z² = 1.96, P represents the prevalence of anti-TPO antibodies in recurrent miscarriage (taken as 12.3%), Q = 1 − P, d = 0.05, and a 10% non-response rate was accounted for. The mean age of the study population was 28.09 ± 5.62 years. On application of Fisher’s exact test, the association between age and serum anti-TPO antibody levels, as well as between age and subclinical hypothyroidism, was found to be statistically insignificant.

With respect to socio-economic status, 56.62% of the patients belonged to the lower socio-economic class, while 38.55% belonged to the middle class. Regarding blood group distribution, 54.8% of patients were O positive, 31.3% were B positive, 9.64% were A positive, 0.6% were AB positive, and the remaining 3.6% were B negative. The mean body mass index (BMI) of the study population was 23.22 ± 2.10 kg/m². There was no statistically significant association between BMI and serum anti-TPO antibody levels.

A family history of hypothyroidism was present in 4.2% of patients. Hypothyroidism was observed in 8.4% of the study population, while 3.6% had hypertension and 1.2% had type 2 diabetes mellitus. The majority of patients (86.7%) were not on any regular medication. A total of 403 miscarriages were recorded, of which 89.1% occurred during the first trimester and 10.9% during the second trimester.

Haemoglobin assessment showed that 29 women (17%) had haemoglobin levels ≥12 g/dl, 35 women (21%) had levels between 11 and 11.9 g/dl, 97 women (58%) had haemoglobin levels between 8 and 10.9 g/dl, and 5 women (3%) had haemoglobin levels <8 g/dl. Fasting blood sugar levels were <110 mg/dl in 158 women (95.1%), and post-prandial blood sugar levels were <140 mg/dl in 158 women (95.1%).

Thyroid function assessment revealed that 44.6% of the study population had TSH levels >4.78 mIU/ml, with a mean TSH value of 4.57 ± 2.08 mIU/ml. Normal free T4 levels (0.8–1.76 ng/dl) were observed in 83.7% of patients, with a mean free T4 level of 1.13 ± 1.026 ng/dl. Among women with recurrent pregnancy loss, 91 patients were euthyroid, 73 had subclinical hypothyroidism, and 2 had overt hypothyroidism.

Anti-TPO antibody levels ≥35 IU/ml were observed in 59.6% of patients, with a mean anti-TPO value of 83.90 ± 173.80 IU/ml. A statistically significant association was found between subclinical hypothyroidism and elevated anti-TPO antibody levels (p = 0.0028), as well as between overt hypothyroidism and anti-TPO antibody levels (p = 0.0018).

According to RCOG guidelines, the age-related risk of pregnancy loss increases progressively with maternal age, ranging from 13% in women ≤19 years to 93% in those aged ≥45 years.4 In contrast, the present study observed a higher proportion of recurrent pregnancy loss among younger women, with 36.74% in the 21–25-year age group and a mean age of 28.09 ± 5.62 years. This distribution differs from that reported by Magnus MC et al.5 No statistically significant association was found between age and serum anti-TPO antibody levels or subclinical hypothyroidism, findings that are inconsistent with those of Sieiro Netto L et al.6 Most women in this study belonged to a lower socio-economic group, consistent with Coomarasamy et al., likely reflecting limited healthcare access, suboptimal nutrition, increased stress, and environmental factors.7

Women with BMI >25 kg/m² had a higher incidence of recurrent pregnancy loss, in agreement with Lashen et al. (2004).8 However, BMI was not significantly associated with serum anti-TPO antibody levels in this study, contrary to the findings of Meena M et al.9 The majority of miscarriages (89.1%) occurred in the first trimester, consistent with Meyer et al. (2012).10 Anaemia was common among affected women, supporting the observations of Bénoni et al. (2020).11 Mean FBS and PPBS values were within normal limits, consistent with findings by Lashen et al., which showed no clear association between glycaemic status and miscarriage in non-diabetic women.8

Elevated TSH levels (≥4.78 mIU/ml) were observed in 44.6% of women, consistent with studies by Glinoer et al.12 and Maraka et al.13 demonstrating increased miscarriage risk even with mild hypothyroidism. Most women had normal free T4 levels, supporting the concept of subclinical hypothyroidism as described by Stagnaro-Green et al.14 Anti-TPO antibody positivity was common, with mean levels comparable to those reported by Zegers-Hochschild et al.15 A statistically significant association between subclinical hypothyroidism and anti-TPO antibody positivity was observed, consistent with Jusmita Dutta et al. (2019).16

This observational study demonstrates a statistically significant association between subclinical hypothyroidism and anti-TPO antibody positivity in women with recurrent pregnancy loss. Elevated TSH levels with normal FT4, particularly in the presence of thyroid autoimmunity, appear to contribute to adverse reproductive outcomes. These findings highlight the importance of routine screening for thyroid dysfunction and anti-TPO antibodies in women with recurrent miscarriage, as early identification and management may improve pregnancy outcomes. Further large-scale, controlled studies are warranted to clarify causal mechanisms and guide evidence-based clinical interventions. FUNDING Nothing such. CONTRIBUTION TO AUTHORSHIP SK & AB wrote the first draft of the paper. RB statistically analyzed the data. SK, AB, RB & AJ edited and revised the article, and all the authors approved the final draft. COMPETING INTERESTS None declared. PATIENT CONSENT Obtained.

1.  European Society of Human Reproduction and Embryology (ESHRE). Recurrent pregnancy loss: ESHRE guideline. 2022.

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13. Maraka S, et al. The impact of thyroid function and dysfunction on pregnancy outcomes. Thyroid. 2016;26(4):440–5.

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15. Zegers-Hochschild F, et al. Prevalence of thyroid autoimmunity in women with recurrent miscarriage: a systematic review. Hum Reprod Update. 2013;19(3):294–308.

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