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Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2023 July 01.
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Published in final edited form as:

Lancet Diabetes Endocrinol. 2022 April ; 10(4): 243–252. doi:10.1016/S2213-8587(22)00007-9.
Association of maternal thyroid function with gestational

hypertension and preeclampsia: a systematic review and
individual participant data meta-analysis
Freddy J.K. Toloza, MD1,2,48,*, Arash Derakhshan, MD3,4,*, Tuija Männistö, MD45, Sofie
Bliddal, MD12, Polina V. Popova, MD5,6,7, David M. Carty, FRCP9,10, Prof. Liangmiao
Chen, MD11, Peter Taylor, FRCP13, Lorena Mosso, MD14, Prof. Emily Oken, MD15, Eila
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Suvanto, MD16, Sachiko Itoh, PhD17, Prof. Reiko Kishi, MD17, Judit Bassols, PhD18, Prof.
Juha Auvinen, MD19, Abel López-Bermejo, MD20, Suzanne J. Brown, BSc (Hons)21, Laura
Boucai, MD22, Aya Hisada, PhD23, Prof. Jun Yoshinaga, PhD24, Ekaterina Shilova, MD7,25,
Prof. Elena N. Grineva, MD5,7, Tanja G.M. Vrijkotte, PhD26, Prof. Jordi Sunyer, MD27,28,29,
Ana Jiménez-Zabala, PhD30,31, Isolina Riaño-Galan, MD29,32, Maria-Jose Lopez-Espinosa,
PhD29,33,34, Larry J. Prokop, MLS47, Naykky Singh Ospina, MD35,36, Juan P. Brito, MD36,
Prof. Rene Rodriguez-Gutierrez, MD36,37,38, Prof. Erik K. Alexander, MD39, Layal Chaker,
MD3,4, Prof. Elizabeth N. Pearce, MD40, Prof. Robin P. Peeters, MD3,4, Prof. Ulla Feldt-
Rasmussen, MD12, Mònica Guxens, MD27,28,29,41, Prof. Leda Chatzi, MD42, Prof. Christian
Delles, MD10, Jeanine E. Roeters van Lennep, MD3, Prof. Victor J.M. Pop, MD8, Prof.
Xuemian Lu, MD11, Prof. John P. Walsh, MB21,43, Prof. Scott M. Nelson, MRCOG44, Tim
I. M. Korevaar, MD3,4,§, Spyridoula Maraka, MD1,2,46,§
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1.Division
of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little
Rock, AR, USA.
Corresponding author: Spyridoula Maraka, MD, MS, Assistant Professor of Medicine, Division of Endocrinology and Metabolism,
University of Arkansas for Medical Sciences, 4301 W. Markham St., #587, Little Rock, AR 72205-7199, 501-686-5130 (phone),
smaraka@uams.edu.
*equal contribution
§equal contribution
Contributors
FJKT, AD, TIMK, and SM made the analysis plan, performed analyses, and were involved in writing of the manuscript. LP performed
the systematic search and FJKT and SM were involved in study selection. All other authors were involved in data collection and
provided substantial contributions to drafting of the work including critical revision for important intellectual content. TIMK and SM
verified the underlying data, supervised analyses, and directed the project.
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Declaration of interests
EO reports grants from the National Institutes of Health. TGMV reports grants from the Netherlands Organization for Health Research
and Development. EKA reports consultancy with Roche Diagnostics. CD reports grants from the Chief Scientist Office (Scotland) and
the British Heart Foundation. 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 declares payments for
medical-legal work and investment in The Fertility Partnership. ENG received speaker’s fees and payment for expert testimony from
Merck and consulting fees from Brunel Rus LLC. PT reports a travel grant from Society for Endocrinology (leadership development
award). LC received travel support by Pfizer. SB declares consulting fees from Sonic Healthcare. JRVL declares grant or contract
support from the Dutch Heart Foundation and Amryt. TIMK reports lectureship fees from Berlin-Chemie, Goodlife Healthcare, IBSA,
Merck, and Quidel. All other authors declare no competing interests.
Data sharing
A protocol of this study is available at the PROSPERO website (CRD42019128585). Deidentified individual participant data are
available from the Consortium on Thyroid and Pregnancy. A data dictionary with details of the definitions of the variables used in the
study is available upon request.
Toloza et al. Page 2
2.Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and
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Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA.

3.Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the
Netherlands.
4.Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, the
Netherlands.
5.Department of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg,
Russia.
6.Department of Internal Diseases and Endocrinology, St. Petersburg Pavlov State Medical
University, Saint Petersburg, Russian Federation.
7.Institute of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg,
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Russia.
8.Departments of Medical and Clinical Psychology, Tilburg University, Tilburg, The Netherlands.
9.Department of Diabetes, Endocrinology and Clinical Pharmacology, Glasgow Royal Infirmary,
Glasgow, United Kingdom.
10.Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United
Kingdom.
11.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.
12.Department of Medical Endocrinology and Metabolism, Copenhagen University Hospital,
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Rigshospitalet, Copenhagen, Denmark.

13.ThyroidResearch Group, Institute of Molecular and Experimental Medicine, School of
Medicine, Cardiff University, Cardiff, United Kingdom.
14.Departments of Endocrinology, Pontificia Universidad Catolica de Chile, Santiago, Chile.
15.Division
of Chronic Disease Research Across the Lifecourse, Department of Population
Medicine, Harvard Medical School, Boston, MA, USA.
16.Department of Obstetrics and Gynecology and Medical Research Center Oulu, University of
Oulu, Oulu, Finland.
17.Center for Environmental and Health Sciences, Hokkaido University, Sapporo, Japan.
18.Maternal-Fetal
Metabolic Research Group, Girona Biomedical Research Institute (IDIBGI), Dr.
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Josep Trueta Hospital, Girona, Spain.

19.Medical
Research Center Oulu, Oulu University Hospital, and Center for Life Course Health
Research, University of Oulu, Oulu, Finland.
20.Pediatric
Endocrinology Research Group, Girona Biomedical Research Institute (IDIBGI), Dr.
Josep Trueta Hospital, Girona, Spain.
21.Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western
Author Manuscript
Australia, Australia.
22.Department of Medicine, Division of Endocrinology, Memorial Sloan-Kettering Cancer Center,
Weill Cornell University, New York, NY, USA.
23.Center for Preventive Medical Sciences, Chiba University, Chiba, Japan.
24.Faculty of Life Sciences, Toyo University, Japan.
25.Departmentof Gynecology and Endocrinology, The Research Institute of Obstetrics,
Gynecology and Reproductology Named after D.O.Ott, Saint Petersburg, Russia.
26.Departmentof Public Health, Amsterdam UMC, University of Amsterdam, Amsterdam Public
Health Research Institute, Amsterdam, the Netherlands
27.ISGlobal, Barcelona, Spain.
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28.Pompeu Fabra University, Barcelona, Spain.

29.SpanishConsortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de
Salud Carlos III, Madrid, Spain.
30.BIODONOSTIA Health Research Institute, San Sebastian, Spain.
31.Public Health Division of Gipuzkoa, Basque Government, San Sebastian, Spain.
32.AGC Pediatrics, Hospital Universitario Central de Asturias (Oviedo), Spain. IUOPA-
Departamento de Medicina-ISPA, Universidad de Oviedo, Oviedo, Spain.
33.Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-
Universitat de València, Valencia, Spain.
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34.Faculty of Nursing and Chiropody, Universitat de València, Valencia, Spain.

35.University of Florida, Division of Endocrinology, Department of Medicine, Gainesville, FL, USA.
36.MayoClinic, Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes,
Metabolism and Nutrition Rochester, MN, USA.
37.Division
of Endocrinology, Department of Internal Medicine, University Hospital “Dr. Jose E.
Gonzalez,” Autonomous University of Nuevo León, Monterrey, Mexico.
38.Plataforma
INVEST Medicina UANL-KER Unit (KER Unit México), Universidad Autónoma de
Nuevo León, Monterrey, México.
39.Division
of Endocrinology, Hypertension and Diabetes, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA.
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40.Section
of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine,
Boston, MA, USA.
41.Departmentof Child and Adolescent Psychiatry, Erasmus MC, University Medical Centre,
Rotterdam, The Netherlands.
42.Department of Population and Public Health Sciences, University of Southern California, Keck
School of Medicine, Los Angeles, CA, USA.
43.Medical School, University of Western Australia, Crawley, Western Australia, Australia.

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44.School of Medicine, University of Glasgow, Glasgow, United Kingdom.

45.Northern Finland Laboratory Center Nordlab and Medical Research Center Oulu, Oulu
University Hospital and University of Oulu, Oulu, Finland.
46.Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
47.Mayo Clinic Libraries, Mayo Clinic, Rochester, MN, USA.
48.Department of Medicine, MetroWest Medical Center, Tufts Medical School, Framingham, MA,
USA.
SUMMARY
Background—Adequate maternal thyroid function during pregnancy is important for an
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uncomplicated pregnancy. Although multiple observational studies have evaluated the association
of thyroid dysfunction with hypertensive disorders of pregnancy, the methods and definitions
of thyroid function test abnormalities were heterogeneous, and the results were conflicting.
We hypothesized that maternal thyroid dysfunction as a risk factor in pregnancy could be
due to an association between thyroid dysfunction and hypertensive disorders of pregnancy
such as gestational hypertension and preeclampsia. We performed a systematic review and
individual participant data meta-analysis to assess whether thyroid function test abnormalities
were associated with gestational hypertension and preeclampsia.
Methods—We searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of
Systematic Reviews from inception to December 27, 2019, for prospective cohort studies with data
on maternal thyroid-stimulating hormone (TSH), free thyroxine (FT4), and/or thyroid peroxidase
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(TPO) antibody concentrations and gestational hypertension and/or preeclampsia, and we issued
open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy
and share the individual participant data. We excluded participants who had preexisting thyroid
disease, were taking medications which affect thyroid function, or had multifetal pregnancy.
The primary outcomes were documented gestational hypertension and preeclampsia. Individual
participant data were analyzed using logistic mixed-effects regression models adjusting for
maternal age, body mass index, smoking, parity, ethnicity, and gestational age at blood sampling.
The study protocol was registered at the International Prospective Register of Systematic Reviews,
CRD42019128585.
Findings—We identified 1 539 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 women had sufficient data
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(TSH and FT4 concentrations and TPO antibody status) to be classified according to their
thyroid function status. Of those, 1 275 (3.2%) had subclinical hypothyroidism, 933 (2.3%)
had isolated hypothyroxinemia, 619 (1.6%) had subclinical hyperthyroidism, and 377 (0.9%)
had overt hyperthyroidism. Subclinical hypothyroidism was associated with a higher risk of
preeclampsia (3.6% vs 2.1%; OR, 1.53 [95%CI, 1.09 to 2.15]) compared to euthyroidism.
Subclinical hyperthyroidism, isolated hypothyroxinemia, or TPO antibody positivity were not
associated with gestational hypertension or preeclampsia. In continuous analyses, both a higher
and a lower TSH concentration were associated with a higher risk of preeclampsia (P=0.0001).
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The FT4 concentration was not associated with the outcomes measured.
Interpretation—Subclinical hypothyroidism during pregnancy was associated with a higher risk

of preeclampsia. There was a U-shaped association of TSH with preeclampsia. These results
quantify the risks of gestational hypertension or preeclampsia in women with thyroid function test
abnormalities, adding to the total body of evidence on the risk of adverse maternofetal 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.
INTRODUCTION
Hypertensive disorders of pregnancy are some of the leading causes of maternal, fetal
and perinatal mortality worldwide, especially in middle- and low-income countries.1–3
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The group of pregnancy-induced hypertensive disorders includes gestational hypertension,

preeclampsia (de novo or superimposed on chronic hypertension), and eclampsia, whose
common characteristic is the increase in blood pressure leading to various degrees of
multi-organ compromise.4 Gestational hypertension affects 10–15% of pregnancies and of
these, up to 10–25% of women will eventually develop proteinuria and other end-organ
failure consistent with the diagnosis of preeclampsia.5,6 Preeclampsia is a major risk factor
for intrauterine growth retardation, placental abruption, and preterm birth.7,8 Moreover,
preeclampsia is a significant risk factor for maternal morbidity including pulmonary
edema, liver failure, eclampsia, and cardiovascular events, and may be responsible for
approximately 15% of maternal deaths.9 Despite its relatively high incidence and associated
severe complications, the pathogenesis of pregnancy-induced hypertensive disorders is not
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yet fully elucidated.
Adequate maternal thyroid function during pregnancy is important for an uncomplicated

pregnancy. Overt hyperthyroidism due to Graves’ disease and overt hypothyroidism
have both been associated with adverse pregnancy outcomes including pregnancy loss,
intrauterine growth retardation, preterm birth, and preeclampsia.10–15 Thyroid hormones
are involved in the regulation of placental development, endothelial function and blood
pressure regulation, and therefore, thyroid hormone aberrations might have a relevant role
in the development of hypertensive disorders during pregnancy.16–20 The association of
thyroid function test abnormalities with hypertensive disorders of pregnancy has been
assessed in multiple prospective and retrospective cohort studies during recent decades.
While some studies showed a higher risk of hypertensive disorders of pregnancy in
mothers with thyroid function test abnormalities such as subclinical hypothyroidism or
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overt hyperthyroidism, with odds ratios (ORs) ranging from 1.6 to 3.4,15,21–25 others did
not.26–30 Several factors, including the use of different definitions of thyroid function test
abnormalities, variable gestational age at thyroid function assessment, the lack of controlling
for potential confounders, and inadequate statistical power, may explain the considerable
heterogeneity and inconsistency in the results of previous studies. In an effort to overcome
these methodological issues and to better quantify potential risks, we performed a systematic
literature review and individual participant data meta-analysis to assess the association of
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thyroid function test abnormalities with gestational hypertension and preeclampsia.
PARTICIPANTS AND METHODS

The current project followed the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) guidelines for Individual Patient Data and a protocol of this study
has been preregistered in the PROSPERO website (CRD42019128585).
Search strategy and selection criteria

For this systematic review and meta-analysis, with the help of an experienced librarian (L.P.)
we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic
Reviews from database inception to December 27, 2019, with no language restrictions to
identify studies on the association of thyroid function and/or autoimmunity with gestational
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hypertension, preeclampsia, or both (appendix pp 2–3). Additionally, open invitations were

sent to relevant journals, international conferences, social media and personal contacts to
identify unpublished cohorts.31,32 We included prospective cohort studies with data available
on thyroid-stimulating hormone (TSH), free thyroxine (FT4), and/or thyroid peroxidase
(TPO) antibodies as well as gestational hypertension and/or preeclampsia. These studies
must have had participants consecutively recruited from the general population or without
active selection based on health status (such as comorbidities or thyroid disease). We
excluded interventional studies in which participants received treatment based on abnormal
thyroid function tests.
Potential studies eligible for inclusion were reviewed independently and in duplicate by two
of the authors (F.J.K.T. and S.M.) for inclusion and exclusion criteria, and any disagreement
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was resolved by consensus. Investigators from each eligible study were invited to participate
in the study and join the Consortium on Thyroid and Pregnancy if they were not already
members. This consortium is a collaboration of birth cohorts that aims to study the
association of maternal thyroid function and autoimmunity with adverse pregnancy and
child outcomes. After participation approval, we requested the primary investigators to send
us individual participant data using a standardized codebook and the data were checked for
completeness, improbable values, and missing items. Study quality and risk of bias were
assessed using the Newcastle-Ottawa Scale.33 All cohorts were approved by a local review
board and had acquired informed consent from participants or had been granted exemption
from it by the local ethics committee.
After obtaining individual participant data from the included cohorts and applying exclusion
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criteria, all participants with data on TSH, FT4, or TPO antibodies, and gestational
hypertension or preeclampsia were included in the study. We excluded participants who
had preexisting thyroid disease, were taking medications which affect thyroid function and
those with multifetal pregnancy.
Primary and secondary outcomes

Primary outcomes were documented gestational hypertension and preeclampsia as separate
entities. The secondary outcome was the composite outcome of gestational hypertension or
preeclampsia in those cohorts with data on both preeclampsia and gestational hypertension
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or studies that did not report individually on gestational hypertension and preeclampsia.
Exposures
We assessed the following exposure variables: thyroid function test abnormalities
(subclinical hypothyroidism, overt hyperthyroidism, subclinical hyperthyroidism, isolated
hypothyroxinemia), continuous thyroid function test measurements (TSH and FT4
concentrations), and TPO antibody positivity. We did not examine the association of
overt hypothyroidism with gestational hypertension or preeclampsia because treatment for
this disease entity is noncontroversial and because its low prevalence, in combination
with the relatively large number of women who were excluded because of pre-existing
thyroid disease, indicates that women with true overt hypothyroidism were only selectively
represented in the studies included. In contrast, overt hyperthyroidism was examined as this
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was considered to be a biochemically defined entity without an indication for treatment with
antithyroid drugs (participants who were started on antithyroid treatment, presumably for
Graves’ disease, were excluded from this study). We defined thyroid function test reference
ranges using cohort-specific 2.5th and 97.5th population percentiles for TSH and FT4
concentrations after exclusion of TPO antibody positive women, therefore cohorts without
TPO antibody data were not included in analyses on thyroid function test abnormalities.
Euthyroidism was defined as TSH and FT4 concentrations within the reference range
(2.5th-97.5th percentile). Subclinical hypothyroidism was defined as a TSH concentration
above the 97.5th percentile and a FT4 concentration within the reference range (2.5th-97.5th
percentile). Overt hyperthyroidism was defined as a TSH concentration below the 2.5th
percentile and a FT4 concentration above the 97.5th percentile. Subclinical hyperthyroidism
was defined as a TSH concentration below the 2.5th percentile and a FT4 concentration
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within the reference range. Isolated hypothyroxinemia was defined as a FT4 concentration
below the 2.5th percentile and a TSH concentration within the reference range. We defined
TPO antibody positivity according to cutoffs established by the manufacturer or cohort-
specific cutoffs. Serum values of TSH and FT4 for all cohorts were log-transformed and
then standardized to population-specific standard deviation scores (Z-scores) after removal
of outliers (±4 SD from the mean).
Statistical analyses
We studied the association of thyroid function test abnormalities (with euthyroid women
as the reference group), TSH and FT4 concentrations as continuous variables, and TPO
antibody positivity with gestational hypertension, preeclampsia, and the composite outcome
of gestational hypertension or preeclampsia using generalized logistic mixed models with a
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random intercept for each cohort. Binomial distribution with logit link function was used
to fit generalized linear mixed model. The primary analyses were repeated with a 2-step
approach by using random effect models according to the Der-Simonian and Laird method
to pool estimates and the Firth bias reduction method in case of near or complete separation
in smaller cohorts.34,35 Heterogeneity across studies was assessed using the I2 statistic. To
evaluate potential publication bias, funnel plots and Egger’s tests were used.36 All analyses
were adjusted for maternal age, body mass index (BMI), smoking, parity, ethnicity and
gestational age at blood sampling. Results are reported as adjusted odds ratio (OR) and 95%
confidence interval. Natural splines with 3 knots were used to assess non-linear associations
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according to Type III Wald chi-square tests. We used multilevel multiple imputation for
missing data on covariates.37 Five imputed datasets were created and pooled for analyses
using Rubin’s rules.38 We performed prespecified sensitivity analyses to explore whether the
association of TSH and FT4 concentration differed according to differences in gestational
age at the time of blood sampling (≥24 weeks vs <24 weeks) or TPO antibody status. A
2-sided threshold for statistical significance of <0.05 was used. All statistical analyses were
performed using SPSS, RevMan and R version 3.6.2 (R Project for Statistical Computing).
Role of the funding source

The funders had no role in the design and conduct of the study, in the collection,
management, analysis, and interpretation of the data, in the preparation, review, approval of
the manuscript, or the decision to submit the manuscript for publication. The corresponding
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author had full access to all the data and the final responsibility to submit for publication.
RESULTS
From the initial literature search, 1 539 published studies were identified, which included
79 publications involving cohort studies that were potentially eligible for inclusion based
on title/abstract review (Figure 1). There were no individual participant data meta-analyses
about this topic identified with our search strategies. After the evaluation of full text, a
total of 33 cohorts were identified and invited to participate in this meta-analysis. Finally,
a total of 19 cohorts from Denmark, Chile, the Netherlands, Spain, Finland, Greece, United
Kingdom, Russia, Japan, China, Australia, and the United States, with data collection dates
from July 1985 to December 2016, responded to the invitation and were able to participate.
Of those, all cohorts had data on TSH concentration, one cohort did not have data on
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FT4 concentration but had data on FT4 index, three cohorts did not have data on TPO
antibody status, and five cohorts did not have data on either gestational hypertension [three]
or preeclampsia [two].
After applying the exclusion criteria, the final study population comprised 46 528
participants with a mean maternal age of 29.1 years (SD 5.2) and median gestational age
at blood sampling of 12.5 weeks (95% range 7.0–39.7) (Table 1). Gestational hypertension
and preeclampsia occurred in 1 717/43 082 (4.0%) and 809/38 147 (2.1%) pregnancies,
respectively. The composite outcome occurred in 1 963/34 973 (5.6%) pregnancies.
Discrepancies between the composite outcome with the sum of its individual components
are explained by the way the composite outcome was defined (please refer to participants
and methods section) and because women who developed both gestational hypertension and
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preeclampsia were only counted once for the composite outcome.
Of the entire population, 39 826 women had sufficient data (TSH and FT4 concentrations,
and TPO antibody status) to be classified according to their thyroid function status. Of those,
1 275 (3.2%) had subclinical hypothyroidism, 933 (2.3%) had isolated hypothyroxinemia,
619 (1.6%) had subclinical hyperthyroidism, and 337 (0.9%) had overt hyperthyroidism
(appendix p 4). Additionally, 3 005/39 736 (7.6%) were TPO antibody positive (appendix
p 6). Cohort-specific population characteristics, cohort-specific number of participants
with available thyroid function measurements, data quality assessment by the Newcastle-
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Ottawa Scale, missing data on specific covariates and cohort-specific percentile cutoffs for
thyroid function test abnormalities are shown in the appendix (appendix pp 5-10). Data
on covariates were missing for participants [and cohorts] as follows: maternal age: 1.1%
[0 cohorts], gestational age at the time of blood sampling: 0.6% [0 cohorts], parity: 7.1%
[1 cohort], smoking status: 3.1% [0 cohorts], and BMI: 29.8% [2 cohorts] (appendix p 7).
Pregnant women who were not included due to missing outcome data had a similar mean
TSH and FT4 concentrations to those who were included (0.02 SD vs −0.0008 SD; P =0.38,
and 0.016 SD vs −0.0006 SD; P =0.47, respectively), but had a higher proportion of TPO
antibody positivity (9.9% vs 6.5%; P < .001) (appendix p 11).
Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk
of preeclampsia (3.6% vs 2.1%; OR, 1.53 [95%CI, 1.09 to 2.15]), but not with gestational
hypertension (5.7% vs 4.2%; OR, 1.18 [95%CI, 0.91 to 1.53]) (Figure 2). Subclinical
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hypothyroidism was also associated with a higher risk of the composite outcome (8.9%
vs 5.6%; OR, 1.45 [95%CI, 1.14 to 1.85], appendix p 14). Overt hyperthyroidism was
not associated with gestational hypertension (6.0% vs 4.2%; OR, 1.59 [95%CI, 0.97 to
2.60]) or preeclampsia (2.9% vs 2.1%; OR, 1.43 [95%CI, 0.70 to 2.92]), but was associated
with a higher risk of the composite outcome (9.3% vs 5.6%; OR, 1.90 [95%CI, 1.21
to 2.99]) (Figure 2 and appendix p 14). Neither subclinical hyperthyroidism nor isolated
hypothyroxinemia were associated with the outcomes evaluated (Figure 2 and appendix p
14).
When TSH and FT4 were examined as continuous variables, there was a U-shaped
association of TSH with preeclampsia (P=0.0001; Figure 3) and the composite outcome
(P<0.0001; appendix p 15). When this analysis was restricted to TSH within the reference
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range, the association of a lower TSH with a higher risk of preeclampsia (Figure 3) and the
composite outcome persisted (appendix p 15). There was no association of FT4 with any
of the outcomes evaluated, neither when the full range nor the normal range was assessed
(Figure 4 and appendix p 15).
There was no association of TPO antibody positivity, as compared to TPO antibody

negativity with gestational hypertension or preeclampsia (appendix p 16). Similar results
were found in subsequent stratified analyses of TPO antibody positive women with TSH
within normal range, TSH concentration above 2.5 mIU/L and TSH concentration above 4.0
mIU/L (appendix p 16).
The results of the primary analyses were similar using a 2-step approach (appendix pp
17-21), except that in a two-step analysis subclinical hyperthyroidism was associated with
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preeclampsia (OR 2.02, [95%CI 1.14 to 3.59]. Neither the funnel plots or Egger’s tests
indicated relevant publication bias (all P values for the tests for asymmetry ranged from 0.06
to 0.85) and the I2 values were less than or equal to 7%.
In prespecified sensitivity analyses, the association of TSH and FT4 or thyroid function
test abnormalities with gestational hypertension, preeclampsia or its composite outcome
did not differ according to the gestational age at blood sampling, parity or TPO antibody
status (appendix pp 12-13). Out of all subsequent stratified analyses (selected based on P
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for interaction ≤0.15), those with a clinically relevant point estimate indicated a higher risk
of preeclampsia for high TSH and a higher risk of the composite outcome of gestational
hypertension or preeclampsia especially towards later pregnancy (e.g., 24 weeks vs 12
weeks), but these analyses lacked adequate statistical power (appendix p 22).
DISCUSSION
In this individual participant data meta-analysis, maternal subclinical hypothyroidism was
associated with a higher risk of preeclampsia. Additionally, both subclinical hypothyroidism
and overt hyperthyroidism during pregnancy were associated with a higher risk of the
composite outcome of gestational hypertension or preeclampsia. In contrast, there was no
association of subclinical hyperthyroidism, isolated hypothyroxinemia, or TPO antibody
positivity with any of the studied outcomes. Additionally, both a higher and lower maternal
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TSH concentration were associated with a higher risk of preeclampsia in a dose-dependent

manner.
This study shows that subclinical hypothyroidism was associated with a higher risk of
preeclampsia. Various mechanisms, which can be extrapolated from experimental studies
on the effects of thyroid hormones on vascular function and placental formation, could
explain how a (relative) lack of thyroid hormones, as is likely reflected by subclinical
hypothyroidism, might influence the development of pregnancy-induced hypertension.
Hypothyroidism has been associated with endothelial cell dysfunction likely secondary
to decreased production of vasoactive substances (e.g., nitric oxide) which leads to
impaired vasorelaxation, increased sympathetic tone, and vascular resistance and finally
hypertension.18,20,39,40 Critical processes during placental formation, such as decidual cell
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migration and angiogenesis are regulated by inflammatory mediators (e.g., interleukin-10,

leptin, and nitric oxide synthase 2) and at least in part influenced by thyroid hormones.41–43
Consequently, conditions with a low thyroid hormone availability may result in an
inadequate anti-inflammatory environment in the developing placenta and therefore in
placental vascularity disturbances, which have been associated with adverse pregnancy
outcomes such as preeclampsia and miscarriage.16
Alternatively, it may be that the association of subclinical hypothyroidism with preeclampsia

is due to reverse causation. One of the major pathophysiological mechanisms that underlies
preeclampsia is excessive release of antiangiogenic proteins, most notably soluble FMS-like
tyrosine kinase-1 (sFlt1) from the placenta into the maternal circulation.44 Interestingly,
one longitudinal study showed that the increase in the serum sFlt1 concentration was
associated with an increase in the serum TSH concentrations and a higher risk of subclinical
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hypothyroidism45 and similar results were obtained in a cross sectional study.46 As such,
rather than subclinical hypothyroidism increasing the risk of preeclampsia, it may be that the
anti-angiogenic profile that arises already in early stages of preeclampsia adversely affects
thyroid gland vascularization, as demonstrated in animal studies.47 Further evidence in favor
of reverse causation is the lack of any signal that levothyroxine treatment of subclinical
hypothyroidism reduces the risk of preeclampsia,48–51 while potential overtreatment of
women with a normal thyroid function could increase the risk of preeclampsia.48 Further
studies on these underlying mechanisms are required to understand the clinical relevance of
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slight thyroid hypofunction as a risk factor or marker of preeclampsia.
Previous studies examining the associations of overt hyperthyroidism with hypertensive

disorders of pregnancy identified conflicting results. This may be because of heterogeneity
in study design and definitions of thyroid function test abnormalities.15,23,24,26–28,52–55 In
the current study, we identified that overt hyperthyroidism was associated with a higher
risk of a composite outcome of gestational hypertension or preeclampsia. Hyperthyroidism
contributes to endothelial cell dysfunction through impairment of protective mechanisms
against endothelial damage, such as tissue plasminogen activator and plasminogen activator
inhibitor secretion, regulation of interleukin-18 and soluble vascular cell adhesion molecule
1 (VCAM-1).17,19,56 Higher FT4 concentrations in early pregnancy have been associated
with higher vascular resistance in both the maternal and fetal placental compartment, which
may induce adverse pregnancy outcomes.57 Additionally, the association of hyperthyroidism
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with hypertensive disorders of pregnancy could in part be related to dysregulation of

placental deiodinases, which activate or deactivate thyroid hormones in local tissues
(placental deiodinases type 1 [DIO1] and type 2 [DIO2] convert T4 to T3 whereas
placental deiodinase type 3 [DIO3] inactivates T4).16 It has been suggested that since
both hypothyroidism and hyperthyroidism are risk factors for preeclampsia, the existence
of divergent molecular mechanisms of placental deiodinase dysregulation in preeclampsia
could be implied.16 Future clinical studies could assess this possibility, for example by
assessing the association of maternal FT3 or the FT4/FT3 ratio with gestational hypertension
and preeclampsia.16
The higher risk of preeclampsia in women with overt hyperthyroidism identified in this
study may depend on the underlying etiology. Overt hyperthyroidism during pregnancy
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(gestational hyperthyroidism) is often transient and caused by an early pregnancy,

physiological increase in human chorionic gonadotropin (hCG), which stimulates thyroid
hormone production through its affinity for the TSH receptor.58,59 Overt hyperthyroidism
can also be caused by underlying thyroid pathology such as Graves’ disease or toxic
adenoma.58,59 It has been reported that women with both high FT4 and high hCG
concentrations do not have a higher risk of developing preeclampsia, whereas women
with a high FT4 concentration despite a low hCG have a 3.4 to 4.9-fold higher risk of
preeclampsia.60 On the other hand, a higher hCG concentration during early pregnancy in
the absence of hyperthyroidism, has been associated with a higher risk of preeclampsia.61
These findings suggest that according to the etiology of hyperthyroidism during pregnancy,
there may be different mechanisms underlying the higher risk of preeclampsia. More
studies are required to further elucidate the pathophysiologic mechanisms underlying the
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relationships of thyroid function test abnormalities with hypertensive disorders of pregnancy.
In the current study, we also identified that pregnant women with the lowest and highest
concentrations of TSH had a higher risk of preeclampsia, even within the reference range.
The current findings indicate that women with a TSH concentration in the middle of the
TSH reference range have the lowest risk of preeclampsia. Given the lack of clinical trials
on the effects of different levothyroxine treatment targets on adverse pregnancy outcomes,
optimal TSH treatment targets can only be extrapolated from observational studies. In
line with other observational studies62,63, our data indicate that an optimal TSH treatment
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target could be in the middle of the reference range, which highlights the relevance of
follow-up of thyroid function tests during pregnancy in women treated with levothyroxine
to avoid under- or overtreatment. It has been described that hyperthyroidism in otherwise
healthy women or those overtreated with levothyroxine (e.g., iatrogenic hyperthyroidism
or treatment for a gestational TSH 2.5–4.0 mIU/L, especially in TPO antibody negative
women) was associated with a higher risk of preeclampsia, preterm delivery, gestational
diabetes, small for gestational age, attention-deficit/hyperactivity disorder and behavioral
problems.48,64 Additional studies that assess how the changes in thyroid function in patients
on pharmacological therapy during pregnancy could be translated to clinical benefits or
harms are needed.
Finally, we did not identify any association of TPO antibody positivity with any of
the outcomes assessed, which is consistent with results from previous studies 10,28,54,65
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Furthermore, studies in specific subgroups that did not meet the inclusion criteria for the
current study, such as women with previous pregnancy losses, showed similar results.66
A synergistically higher risk of TPO antibody positivity with thyroid function test
abnormalities and preeclampsia67 as well as other adverse pregnancy outcomes68–70 has
been previously described. However, in the current study we did not identify any evidence of
a synergistic risk between TPO antibody positivity and high TSH.
This study included 19 prospective, population-based birth cohorts from 12 countries with
detailed data on thyroid function tests in early pregnancy, adverse pregnancy outcomes
and potential confounding factors. The analysis of individual participant data allowed
standardization of thyroid function test abnormalities and consistent statistical analyses
across cohorts. One of the main limitations of this study derives from the observational
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nature of the studies included in this meta-analysis, such as residual or unmeasured

confounding. Our inability to include all the published cohorts in our analyses due to
data-sharing regulations and restrictions, lack of interest or failure to obtain a response from
contact authors, and publication date during or after conducting the statistical analyses for
the current study may have affected our results. The nature of individual participant data
meta-analysis, requiring extensive time to coordinate data sharing, prohibited an updated
search strategy. Also, the use of Firth bias reduction method in case of near or complete
separation in smaller cohorts may have produced hyperinflated estimates when the 2-step
approach was used; this may account for the discrepant results as regards the association of
subclinical hyperthyroidism with preeclampsia. Finally, we were unable to include personal
or familial history of hypertensive gestational disorders as part of our exclusion criteria,
and to assess the differential risk of frequently used subcategories of hypertensive disorders
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of pregnancy based on the gestational age at the time of onset (i.e., early vs late), which
may have influenced the identification of a clinically meaningful difference in the effects of
thyroid function test abnormalities across gestation or new insights into the pathophysiology
underlying thyroid hormones and hypertensive disorders of pregnancy.71,72
In conclusion, this individual participant data meta-analysis shows that subclinical

hypothyroidism during pregnancy was associated with a higher risk of preeclampsia, and
that there was a U-shaped association of TSH with preeclampsia. These findings add
to the total body of evidence on the risk of adverse maternofetal outcomes of thyroid
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dysfunction during pregnancy and indirectly informs on the optimal TSH treatment target in
women treated with levothyroxine during pregnancy, which needs to be assessed in future
interventional studies.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
SM was supported by the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco
Settlement Proceeds Act of 2000, and by the United States Department of Veterans Affairs Health Services
Research & Development Service of the VA Office of Research and Development, under Merit review award
number 1I21HX003268-01A1. UFR’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
Author Manuscript
National Cancer Institute of the National Institutes of Health under 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 №
121031100288-5, governmental research topic № 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 United States Government. Cohort-specific grants appear in appendix pp 23-24.
Funding
Arkansas Biosciences Institute and Netherlands Organization for Scientific Research (grant 401.16.020).
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RESEARCH IN CONTEXT
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Evidence before this study

Adequate maternal thyroid function during pregnancy is important for an uncomplicated
pregnancy. Some studies indicate that thyroid function test abnormalities are associated
with hypertensive disorders of pregnancy, but there is considerable heterogeneity and
inconsistency in the results. We searched MEDLINE (Ovid), Embase, Scopus, and
the Cochrane Database of Systematic Reviews up to December 27, 2019, and we
collected data on serum thyroid function tests and antibodies status during pregnancy
and gestational hypertension and/or preeclampsia from prospective cohort studies,
including treatment-naive pregnant women. There were no individual participant data
meta-analyses about this topic identified with our search strategies.
Added value of this study

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This individual participant data meta-analysis showed that subclinical hypothyroidism

and overt hyperthyroidism are associated with a higher risk of the composite outcome
of gestational hypertension or preeclampsia. We also identified that both a higher and a
lower thyroid-stimulating hormone (TSH) concentration were associated with a higher
risk of preeclampsia.
Implications of all the available evidence

These findings imply that optimal TSH treatment target could be in the middle of the
reference range, which highlights the relevance of follow-up of thyroid function tests
during pregnancy in women treated with levothyroxine to avoid under- or overtreatment.
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Figure 1.
Flowchart of the study and participant selections
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Figure 2.
Association of thyroid function test abnormalities with gestational hypertension and
preeclampsia
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Figure 3.
Association of thyroid-stimulating hormone (TSH) concentrations with gestational
hypertension (HTN) and preeclampsia
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Figure 4.
Association of free thyroxine (FT4) concentrations with gestational hypertension (HTN) and
preeclampsia
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Table 1.
Characteristics of total study population (n=46528)

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No. of participants / Total No. (%) Median (95% range)
Maternal demographics
Age, years 46017 29.1 (5.2)a
Gestational age at blood sampling, weeks 46262 12.5 (7.0–39.7)
Body mass index 32665 23.8 (4.4)a
Parity
0 23759/43202 55.0
1 13279/43202 30.7
2 4036/43202 9.3
≥3 2128/43202 4.9
Smoking status
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Nonsmoker or past smoker 39949/45081 88.6

Current smoker 5132/45081 11.4
Educational level
Primary school 10471/33655 31.1
High school 11495/33655 34.2
College or higher education 11689/33655 34.7
Maternal thyroid function tests

Thyrotropin, mIU/L 45877 1.29 (0.11–4.56)
Free thyroxine, ng/dL 45930 1.01 (0.56–1.73)b
Thyroid peroxidase antibody positivity 3005/39736 7.6
Outcomes
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Preeclampsia 809/38147 2.1

Gestational hypertension 1717/43082 4.0
Composite outcome c 1963/34973 5.6
a
Expressed as mean (SD)
b
pmol/L: 13.1 (7.2–22.3)
c
Refers to either studies with data on both preeclampsia and gestational hypertension or studies that did not report individually on gestational
hypertension and preeclampsia. Studies with data only on preeclampsia or gestational hypertension are not included here.
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Association of maternal thyroid function with gestational

Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA.

Rigshospitalet, Copenhagen, Denmark.

Josep Trueta Hospital, Girona, Spain.

28.Pompeu Fabra University, Barcelona, Spain.

34.Faculty of Nursing and Chiropody, Universitat de València, Valencia, Spain.

43.Medical School, University of Western Australia, Crawley, Western Australia, Australia.

44.School of Medicine, University of Glasgow, Glasgow, United Kingdom.

Interpretation—Subclinical hypothyroidism during pregnancy was associated with a higher risk

The group of pregnancy-induced hypertensive disorders includes gestational hypertension,

yet fully elucidated.

Adequate maternal thyroid function during pregnancy is important for an uncomplicated

thyroid function test abnormalities with gestational hypertension and preeclampsia.

PARTICIPANTS AND METHODS

Search strategy and selection criteria

hypertension, preeclampsia, or both (appendix pp 2–3). Additionally, open invitations were

Primary and secondary outcomes

Role of the funding source

preeclampsia were only counted once for the composite outcome.

There was no association of TPO antibody positivity, as compared to TPO antibody

TSH concentration were associated with a higher risk of preeclampsia in a dose-dependent

migration and angiogenesis are regulated by inflammatory mediators (e.g., interleukin-10,

Alternatively, it may be that the association of subclinical hypothyroidism with preeclampsia

slight thyroid hypofunction as a risk factor or marker of preeclampsia.

Previous studies examining the associations of overt hyperthyroidism with hypertensive

with hypertensive disorders of pregnancy could in part be related to dysregulation of

(gestational hyperthyroidism) is often transient and caused by an early pregnancy,

relationships of thyroid function test abnormalities with hypertensive disorders of pregnancy.

nature of the studies included in this meta-analysis, such as residual or unmeasured

In conclusion, this individual participant data meta-analysis shows that subclinical

review. Hum Reprod Update 2011; 17(5): 605–19. [PubMed: 21622978]

comprehensive reviewdagger. Biol Reprod 2020; 102(1): 8–17. [PubMed: 31494673]

(Oxf) 2018; 88(5): 728–34. [PubMed: 29453792]

147(6): 803–16. [PubMed: 24534949]

pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective

Evidence before this study

Added value of this study

This individual participant data meta-analysis showed that subclinical hypothyroidism

Implications of all the available evidence

Characteristics of total study population (n=46528)

No. of participants / Total No. (%) Median (95% range)

Nonsmoker or past smoker 39949/45081 88.6

Maternal thyroid function tests

Preeclampsia 809/38147 2.1

Composite outcome c 1963/34973 5.6

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