Meta-Analysis

. 2022 Apr;10(4):243-252.

doi: 10.1016/S2213-8587(22)00007-9. Epub 2022 Mar 4.

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 Toloza¹, Arash Derakhshan², Tuija Männistö³, Sofie Bliddal⁴, Polina V Popova⁵, David M Carty⁶, Liangmiao Chen⁷, Peter Taylor⁸, Lorena Mosso⁹, Emily Oken¹⁰, Eila Suvanto¹¹, Sachiko Itoh¹², Reiko Kishi¹², Judit Bassols¹³, Juha Auvinen¹⁴, Abel López-Bermejo¹⁵, Suzanne J Brown¹⁶, Laura Boucai¹⁷, Aya Hisada¹⁸, Jun Yoshinaga¹⁹, Ekaterina Shilova²⁰, Elena N Grineva²¹, Tanja G M Vrijkotte²², Jordi Sunyer²³, Ana Jiménez-Zabala²⁴, Isolina Riaño-Galan²⁵, Maria-Jose Lopez-Espinosa²⁶, Larry J Prokop²⁷, Naykky Singh Ospina²⁸, Juan P Brito²⁹, Rene Rodriguez-Gutierrez³⁰, Erik K Alexander³¹, Layal Chaker², Elizabeth N Pearce³², Robin P Peeters², Ulla Feldt-Rasmussen⁴, Mònica Guxens³³, Leda Chatzi³⁴, Christian Delles³⁵, Jeanine E Roeters van Lennep³⁶, Victor J M Pop³⁷, Xuemian Lu⁷, John P Walsh³⁸, Scott M Nelson³⁹, Tim I M Korevaar², Spyridoula Maraka⁴⁰

Affiliations

¹ Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA; Department of Medicine, MetroWest Medical Center, Tufts Medical School, Framingham, MA, USA.
² Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands; Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands.
³ Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; Northern Finland Laboratory Center Nordlab, University of Oulu, Oulu, Finland.
⁴ Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁵ Department of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg, Russia; Institute of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg, Russia; World-Class Research Center for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russia; Department of Internal Diseases and Endocrinology, St Petersburg Pavlov State Medical University, Saint Petersburg, Russia.
⁶ Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, UK; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
⁷ Department of Endocrinology and Rui'an Center of the Chinese-American Research Institute for Diabetic Complications, Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁸ Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK.
⁹ Department of Endocrinology and Centro Traslacional en Endocrinologia, Pontificia Universidad Catolica de Chile, Santiago, Chile.
¹⁰ Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Obstetrics and Gynecology, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
¹² Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan.
¹³ Maternal-Fetal Metabolic Research Group, Girona Biomedical Research Institute, Dr Josep Trueta Hospital, Girona, Spain.
¹⁴ Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; Center for Life Course Health Research, University of Oulu, Oulu, Finland.
¹⁵ Pediatric Endocrinology Research Group, Girona Biomedical Research Institute, Dr Josep Trueta Hospital, Girona, Spain.
¹⁶ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
¹⁷ Division of Endocrinology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell University, New York, NY, USA.
¹⁸ Center for Preventive Medical Sciences, Chiba University, Chiba, Japan.
¹⁹ Faculty of Life Sciences, Toyo University, Gunma, Japan.
²⁰ Institute of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg, Russia; Department of Gynecology and Endocrinology, DO Ott Research Institute of Obstetrics and Gynecology, Saint Petersburg, Russia.
²¹ Department of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg, Russia; Institute of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg, Russia.
²² Department of Public Health, Amsterdam UMC, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, Netherlands.
²³ ISGlobal, Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Hospital del Mar Medical Research Institute, Barcelona, Spain.
²⁴ Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain; BIODONOSTIA Health Research Institute, San Sebastian, Spain; Public Health Division of Gipuzkoa, Basque Government, San Sebastian, Spain.
²⁵ Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain; AGC Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain; IUOPA-Departamento de Medicina-ISPA, Universidad de Oviedo, Oviedo, Spain.
²⁶ Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain; Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Faculty of Nursing and Chiropody, Universitat de València, Valencia, Spain.
²⁷ Mayo Clinic Libraries, Mayo Clinic, Rochester, MN, USA.
²⁸ Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA; Division of Endocrinology, Department of Medicine, University of Florida, Gainesville, FL, USA.
²⁹ Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
³⁰ Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA; Division of Endocrinology, Department of Internal Medicine, University Hospital Dr Jose E Gonzalez, Autonomous University of Nuevo León, Monterrey, Mexico; Plataforma INVEST Medicina UANL-KER Unit, Universidad Autónoma de Nuevo León, Monterrey, México.
³¹ Division of Endocrinology, Hypertension and Diabetes, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³² Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, MA, USA.
³³ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, Netherlands; ISGlobal, Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain.
³⁴ Department of Population and Public Health Sciences, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
³⁵ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
³⁶ Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
³⁷ Department of Medical and Clinical Psychology, Tilburg University, Tilburg, Netherlands.
³⁸ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia; Medical School, University of Western Australia, Crawley, WA, Australia.
³⁹ School of Medicine, University of Glasgow, Glasgow, UK.
⁴⁰ Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA. Electronic address: smaraka@uams.edu.

PMID: 35255260
PMCID: PMC10314731
DOI: 10.1016/S2213-8587(22)00007-9

Meta-Analysis

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 et al. Lancet Diabetes Endocrinol. 2022 Apr.

. 2022 Apr;10(4):243-252.

doi: 10.1016/S2213-8587(22)00007-9. Epub 2022 Mar 4.

Authors

Affiliations

¹ Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA; Department of Medicine, MetroWest Medical Center, Tufts Medical School, Framingham, MA, USA.
² Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands; Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, Netherlands.
³ Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; Northern Finland Laboratory Center Nordlab, University of Oulu, Oulu, Finland.
⁴ Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁵ Department of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg, Russia; Institute of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg, Russia; World-Class Research Center for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russia; Department of Internal Diseases and Endocrinology, St Petersburg Pavlov State Medical University, Saint Petersburg, Russia.
⁶ Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary, Glasgow, UK; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
⁷ Department of Endocrinology and Rui'an Center of the Chinese-American Research Institute for Diabetic Complications, Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁸ Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK.
⁹ Department of Endocrinology and Centro Traslacional en Endocrinologia, Pontificia Universidad Catolica de Chile, Santiago, Chile.
¹⁰ Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Obstetrics and Gynecology, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.
¹² Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan.
¹³ Maternal-Fetal Metabolic Research Group, Girona Biomedical Research Institute, Dr Josep Trueta Hospital, Girona, Spain.
¹⁴ Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland; Center for Life Course Health Research, University of Oulu, Oulu, Finland.
¹⁵ Pediatric Endocrinology Research Group, Girona Biomedical Research Institute, Dr Josep Trueta Hospital, Girona, Spain.
¹⁶ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
¹⁷ Division of Endocrinology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell University, New York, NY, USA.
¹⁸ Center for Preventive Medical Sciences, Chiba University, Chiba, Japan.
¹⁹ Faculty of Life Sciences, Toyo University, Gunma, Japan.
²⁰ Institute of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg, Russia; Department of Gynecology and Endocrinology, DO Ott Research Institute of Obstetrics and Gynecology, Saint Petersburg, Russia.
²¹ Department of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg, Russia; Institute of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg, Russia.
²² Department of Public Health, Amsterdam UMC, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, Netherlands.
²³ ISGlobal, Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Hospital del Mar Medical Research Institute, Barcelona, Spain.
²⁴ Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain; BIODONOSTIA Health Research Institute, San Sebastian, Spain; Public Health Division of Gipuzkoa, Basque Government, San Sebastian, Spain.
²⁵ Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain; AGC Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain; IUOPA-Departamento de Medicina-ISPA, Universidad de Oviedo, Oviedo, Spain.
²⁶ Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain; Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Faculty of Nursing and Chiropody, Universitat de València, Valencia, Spain.
²⁷ Mayo Clinic Libraries, Mayo Clinic, Rochester, MN, USA.
²⁸ Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA; Division of Endocrinology, Department of Medicine, University of Florida, Gainesville, FL, USA.
²⁹ Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
³⁰ Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA; Division of Endocrinology, Department of Internal Medicine, University Hospital Dr Jose E Gonzalez, Autonomous University of Nuevo León, Monterrey, Mexico; Plataforma INVEST Medicina UANL-KER Unit, Universidad Autónoma de Nuevo León, Monterrey, México.
³¹ Division of Endocrinology, Hypertension and Diabetes, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³² Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, MA, USA.
³³ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, Netherlands; ISGlobal, Barcelona, Spain; Pompeu Fabra University, Barcelona, Spain; Spanish Consortium for Research on Epidemiology and Public Health, Instituto de Salud Carlos III, Madrid, Spain.
³⁴ Department of Population and Public Health Sciences, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.
³⁵ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
³⁶ Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
³⁷ Department of Medical and Clinical Psychology, Tilburg University, Tilburg, Netherlands.
³⁸ Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia; Medical School, University of Western Australia, Crawley, WA, Australia.
³⁹ School of Medicine, University of Glasgow, Glasgow, UK.
⁴⁰ Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA. Electronic address: smaraka@uams.edu.

PMID: 35255260
PMCID: PMC10314731
DOI: 10.1016/S2213-8587(22)00007-9

Abstract

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.

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Conflict of interest statement

Declaration of interests SB declares consulting fees from Sonic Healthcare. PT reports a travel grant from Society for Endocrinology (leadership development award). EO reports grants from the National Institutes of Health. ENG received speaker's fees and payment for expert testimony from Merck and consulting fees from Brunel Rus. TGMV reports grants from the Netherlands Organization for Health Research and Development. EKA reports consultancy with Roche Diagnostics. LC received travel support by Pfizer. CD reports grants from the Chief Scientist Office (Scotland) and the British Heart Foundation. JERvL declares grant or contract support from the Dutch Heart Foundation and Amryt. SMN has received consultancy, speakers' fees, or travel support from Access Fertility, Beckman Coulter, Ferring Pharmaceuticals, Merck, Modern Fertility, Roche Diagnostics, and The Fertility Partnership. SMN also reports payments for medical–legal work and investment in The Fertility Partnership. TIMK reports lectureship fees from Berlin-Chemie, Goodlife Healthcare, Institut Biochimique SA, Merck, and Quidel. All other authors declare no competing interests.

Figures

**Figure 1.**
Flowchart of the study and participant selections

**Figure 2.**
Association of thyroid function test abnormalities with gestational hypertension and preeclampsia

**Figure 3.**
Association of thyroid-stimulating hormone (TSH) concentrations with gestational hypertension (HTN) and preeclampsia

**Figure 4.**
Association of free thyroxine (FT4) concentrations with gestational hypertension (HTN) and preeclampsia

See this image and copyright information in PMC

Comment in

From preeclampsia to thyroid dysfunction: a long and winding road.
Vermiglio F, Moleti M. Vermiglio F, et al. Lancet Diabetes Endocrinol. 2022 Apr;10(4):232-233. doi: 10.1016/S2213-8587(22)00040-7. Epub 2022 Mar 4. Lancet Diabetes Endocrinol. 2022. PMID: 35255259 No abstract available.

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

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

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