Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis

Freddy J K Toloza, Arash Derakhshan, Tuija Männistö, Sofie Bliddal, Polina V Popova, David M Carty, Liangmiao Chen, Peter Taylor, Lorena Mosso, Emily Oken, Eila Suvanto, Sachiko Itoh, Reiko Kishi, Judit Bassols, Juha Auvinen, Abel López-Bermejo, Suzanne J Brown, Laura Boucai, Aya Hisada, Jun YoshinagaEkaterina Shilova, Elena N Grineva, Tanja G M Vrijkotte, Jordi Sunyer, Ana Jiménez-Zabala, Isolina Riaño-Galan, Maria-Jose Lopez-Espinosa, Larry J Prokop, Naykky Singh Ospina, Juan P Brito, Rene Rodriguez-Gutierrez, Erik K Alexander, Layal Chaker, Elizabeth N Pearce, Robin P Peeters, Ulla Feldt-Rasmussen, Mònica Guxens, Leda Chatzi, Christian Delles, Jeanine E Roeters van Lennep, Victor J M Pop, Xuemian Lu, John P Walsh, Scott M Nelson, Tim I M Korevaar, Spyridoula Maraka*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Scopus)


BACKGROUND: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia.

METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585.

FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT4 concentrations were not associated with the outcomes measured.

INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies.

FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.

Original languageEnglish
Pages (from-to)243-252
Number of pages10
JournalThe Lancet Diabetes and Endocrinology
Issue number4
Publication statusPublished - Apr 2022

Bibliographical note

SM was supported by the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000, and by the US Department of Veterans Affairs Health Services Research & Development Service of the VA Office of Research and Development, under Merit review award number 1I21HX003268–01A1. UF-R's research salary was supported by an unrestricted grant from Kirsten and Freddy Johansen's Fund. SB was supported by a grant from Sygesikring Danmark. NSO was supported by the National Cancer Institute of the National Institutes of Health (award number K08CA248972). PT was supported by the British Thyroid Foundation and the Association of Physicians of Great Britain and Ireland. EO was funded by the US National Institutes of Health (R01 HD034568, UH3 OD 023286). PVP's research was supported by the Ministry of Health Care of Russian Federation (governmental funding research number 121031100288–5, governmental research topic number 39). AD, RPP, and TIMK were supported by the Netherlands Organization for Scientific Research (grant 401·16·020). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, Department of Veterans Affairs, or the US Government. Cohort-specific grants can be found in appendix pp 23–24.

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