O-077 Novel findings of thyroid dysfunction in pregnancy loss – suggestions for screening and further research

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Abstract Study question Do women experiencing pregnancy loss have undetected high thyroid stimulating hormone (TSH) levels? Is thyroid (dys)function associated with the risk of a euploid pregnancy loss? Summary answer Few women with pregnancy loss and high TSH were detected with current guidelines. High total triiodothyronine (TT3) and thyroxine (TT4) increased euploid pregnancy loss risk. What is known already Thyroid dysfunction has been associated with adverse reproductive events including pregnancy loss which affects >20 million women worldwide each year. Approximately 55% of pregnancy losses are due to lethal chromosome abnormalities (aneuploid losses), whereas fetuses with a normal number of chromosomes (euploid) are potentially viable. Pregnancy loss of a euploid fetus is suspected to be due to maternal comorbidity e.g. thyroid dysfunction. However, no guidelines address TSH screening in women experiencing pregnancy loss until they have had recurrent pregnancy losses, and studies of thyroid function and pregnancy loss have not previously distinguished between euploid and aneuploid losses. Study design, size, duration Prospective cohort study aiming at including 3,000 women experiencing missed abortions or ongoing spontaneous abortions of confirmed intrauterine pregnancies. The study started in November 2020 and continues inclusions until May 2025. Based on patient records and questionnaires, we included women without known thyroid disease who participated in the study from November 2020 until May 2024. Regional laboratory data from hospitals and general practitioners provided information on thyroid function tests performed before the inclusion. Participants/materials, setting, methods Women presenting with pregnancy loss at three Danish university hospitals had blood drawn at the time of pregnancy loss upon informed consent. We measured TSH, free T4 and TT4, TT3, human chorionic gonadotropin (hCG), thyroid peroxidase and thyroglobulin antibodies (TPOAb, TgAb). Antibody positivity: >60 kIU/L. Fetal chromosome status was determined by cell-free fetal DNA or fetal tissue sequencing to detect aneuploidy. Logistic regression covariates: age, body mass index, gestational week at inclusion. Main results and the role of chance Among 2,010 included women, 60 (3.0%) had a TSH>4 mIU/L (American Thyroid Association (ATA) pregnancy guidelines cut-off) and 15 (0.7%) a TSH>6 mIU/L (proposed treatment indication in 2025 ATA guidelines). Of these, TSH had been measured as part of current practice in 8 of 60 (13.3%) and 3 of 15 (20.0%) during pregnancy. Two women had a TSH>100 mIU/L. We then assessed if thyroid function was associated with euploid pregnancy loss (constituting 51% of the losses). There was a significant positive association between the risk of euploid pregnancy loss and TT3 (adjusted odds ratio (aOR) 2.0, 95% confidence interval (CI) 1.5;2.6) and TT4 (aOR 1.09 (1.05;1.13)). This remained significant when adjusting for TSH, TPOAb, TgAb, and hCG (TT3 aOR 2.7 (1.44;5.33), TT4 aOR 1.16 (1.06;1.27)). There was no association between euploid pregnancy loss and TSH (aOR 0.9 (0.8;1.1)), FT4 (aOR 1.0 (1.0;1.0)), TPOAb positivity (aOR 0.99 (0.68;1.43)), nor TgAb positivity (aOR 0.96 (0.66;1.41)). Euploid loss rate was higher in women with TT3 >2.6 nmol/L (laboratory cut-off) vs TT3≤2.6 nmol/L (n = 61/85, 71.8% vs. n = 470/1,521 48.6%, p < 0.001) and TT4 >140 nmol/L (laboratory cut-off) vs ≤ 140 nmol/L (n = 248/425 58.4% vs. n = 552/1,180 46.8%, p < 0.001). Limitations, reasons for caution The findings are observational and cannot inform of causality. However, levothyroxine treatment is recommended to women with a high TSH during pregnancy, or planning pregnancy, if this is detected. The findings that high TT3 and TT4 are associated with ploidy status need further investigation before treatment options can be considered. Wider implications of the findings Women with pregnancy loss constitutes a black box in current screening programs. Few women with high TSH had been tested before or during pregnancy. TSH screening of women experiencing a pregnancy loss should be considered. Future studies should explore if gestational thyrotoxicosis is a risk to potentially viable fetuses. Trial registration number No

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