Hypothyroidism has been associated with adverse pregnancy outcomes in observational studies, but these associations may be influenced by residual confounding or reverse causation. We conducted a pioneering two-sample Mendelian randomization (MR) investigation using aggregated data from a large-scale genome-wide association study to examine the correlation between hypothyroidism and preeclampsia, gestational diabetes, miscarriage, placental abruption, and preterm labor. Inverse variance weighting served as the primary analytical approach, complemented by MR Egger regression, weighted median, simple modal, and weighted methods. Sensitivity analyses, including MR-PRESSO, MR-Egger regression, and leave-one-out analysis, were performed to test the robustness of the findings. Multivariable MR (MVMR), adjusting for smoking and body mass index, was further conducted to validate the MR results. The IVW analysis indicated that hypothyroidism may increase the risk of miscarriage and preeclampsia (OR = 1.004, 95% CI = 1.000–1.008, p = 0.039; OR = 1.588, 95% CI = 1.027–2.456, p = 0.038). MVMR demonstrated that the causal effect of hypothyroidism on miscarriage and preeclampsia persisted after adjusting for body mass index (OR = 0.016, 95% CI = 1.005–0.995, p = 0.005; OR = 1.7169, 95% CI = 1.065–2.767, p = 0.0264). These findings furnish compelling evidence supporting a causal association between hypothyroidism and miscarriage, as well as preeclampsia.

Na Yin, Jiaqi Li, Yangyang Wang, Xin Zhang, Tiantian Shen, Ju Zhang. Causal Relationship between Hypothyroidism and Adverse Pregnancy Outcomes: A Multivariate Mendelian Randomization Study. Frontiers in Medical Science Research(2025), Vol. 7, Issue 2: 118-124. https://doi.org/10.25236/FMSR.2025.070217.

[1] Chen A, Luo Z, Zhang J, et al. Emerging research themes in maternal hypothyroidism: a bibliometric exploration [J]. Front Immunol, 2024, 15: 1370707.

[2] Li Y, Shan Z, Teng W. The Iodine Status and Prevalence of Thyroid Disorders Among Women of Childbearing Age in China: National Cross-sectional Study [J]. Endocr Pract, 2021, 27(10): 1028-33.

[3] Dong A C, Stagnaro-green A. Differences in Diagnostic Criteria Mask the True Prevalence of Thyroid Disease in Pregnancy: A Systematic Review and Meta-Analysis [J]. Thyroid, 2019, 29(2): 278-89.

[4] Qin Y, Wu Y, Zang H, et al. Lipid Metabolism in Pregnancy Women with Hypothyroidism and Potential Influence on Pregnancy Outcome [J]. J Lipids, 2024, 2024: 5589492.

[5] Zhang Y, Wang H, Pan X, et al. Patients with subclinical hypothyroidism before 20 weeks of pregnancy have a higher risk of miscarriage: A systematic review and meta-analysis [J]. PLoS One, 2017, 12(4): e0175708.

[6] Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies [J]. Hum Mol Genet, 2014, 23(R1): R89-98.

[7] Zheng J, Baird D, Borges M C, et al. Recent Developments in Mendelian Randomization Studies [J]. Curr Epidemiol Rep, 2017, 4(4): 330-45.

[8] Burgess S, Thompson S G. Avoiding bias from weak instruments in Mendelian randomization studies [J]. Int J Epidemiol, 2011, 40(3): 755-64.

[9] Egger M, Smith G D, Phillips A N. Meta-analysis: principles and procedures [J]. Bmj, 1997, 315(7121): 1533-7.

[10] Borenstein M, Hedges L V, Higgins J P, Rothstein H R. A basic introduction to fixed-effect and random-effects models for meta-analysis [J]. Res Synth Methods, 2010, 1(2): 97-111.

[11] Burgess S, Thompson S G. Interpreting findings from Mendelian randomization using the MR-Egger method [J]. Eur J Epidemiol, 2017, 32(5): 377-89.

[12] Verbanck M, Chen C Y, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases [J]. Nat Genet, 2018, 50(5): 693-8.

[13] Knosgaard L, Andersen S, Hansen A B, et al. Maternal hypothyroidism and adverse outcomes of pregnancy [J]. Clin Endocrinol (Oxf), 2023, 98(5): 719-29.

[14] Yang Y, Guo T, Fu J, et al. Association of Preconception Thyrotropin Levels With Fecundability and Risk of Spontaneous Abortion in China [J]. JAMA Netw Open, 2022, 5(8): e2228892.

[15] Li J, Liu A, Liu H, et al. Maternal TSH levels at first trimester and subsequent spontaneous miscarriage: a nested case-control study [J]. Endocr Connect, 2019, 8(9): 1288-93.

[16] Iijima T, Tada H, Hidaka Y, et al. Effects of autoantibodies on the course of pregnancy and fetal growth [J]. Obstet Gynecol, 1997, 90(3): 364-9.

[17] Stagnaro-green A, Roman S H, Cobin R H, et al. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies [J]. Jama, 1990, 264(11): 1422-5.

[18] Chardès T, Chapal N, Bresson D, et al. The human anti-thyroid peroxidase autoantibody repertoire in Graves' and Hashimoto's autoimmune thyroid diseases [J]. Immunogenetics, 2002, 54(3): 141-57.

[19] Thangaratinam S, Tan A, Knox E, et al. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence [J]. Bmj, 2011, 342: d2616.

[20] Lee Y L, Ng H P, Lau K S, et al. Increased fetal abortion rate in autoimmune thyroid disease is related to circulating TPO autoantibodies in an autoimmune thyroiditis animal model [J]. Fertil Steril, 2009, 91(5 Suppl): 2104-9. 

[21] Mascanfroni I, Montesinos Mdel M, Susperreguy S, et al. Control of dendritic cell maturation and function by triiodothyronine [J]. Faseb j, 2008, 22(4): 1032-42.

[22] Huai J, Yang Z, Yi Y H, WANG G J. Role of mammalian target of rapamycin signaling pathway in regulation of fatty acid oxidation in a preeclampsia-like mouse model treated with pravastatin [J]. Chin Med J (Engl), 2019, 132(6): 671-9.

[23] Wang X, Zhang E, Tian Z, et al. The association between dyslipidaemia in the first trimester and adverse pregnancy outcomes in pregnant women with subclinical hypothyroidism: a cohort study [J]. Lipids Health Dis, 2024, 23(1): 13.

[24] Burns R, O'herlihy C, Smyth P P. The placenta as a compensatory iodine storage organ [J]. Thyroid, 2011, 21(5): 541-6.

[25] Dardano A, Ghladoni L, Planting Y, et al. Recombinant human thyrotropin reduces endothelium-dependent vasodilation in patients monitored for differentiated thyroid carcinoma [J]. J Clin Endocrinol Metab, 2006, 91(10): 4175-8.

[26] Silva J F, Ocarino N M, Serakides R. Maternal thyroid dysfunction affects placental profile of inflammatory mediators and the intrauterine trophoblast migration kinetics [J]. Reproduction, 2014, 147(6): 803-16.

[27] Burton G J, Jauniaux E. Pathophysiology of placental-derived fetal growth restriction [J]. Am J Obstet Gynecol, 2018, 218(2s): S745-s61.