Risk Factors for Thyroid Function Test Abnormalities During Pregnancy: A Systematic Review of the Literature to Validate Current Risk Factors and Identify Novel Ones

Abstract

Background:

International guidelines recommend that the indication to perform thyroid function testing during pregnancy is based on the presence of risk factors for thyroid function test abnormalities. However, the discriminative ability of currently recommended risk factors is questionable. To inform on an update of the American Thyroid Association Guidelines for the Diagnosis and Management of Thyroid Disease in Preconception, Pregnancy, and the Postpartum, we aimed to systematically review the literature to evaluate evidence for current risk factors and potential novel ones for thyroid function test abnormalities in pregnancy.

Methods:

A systematic literature search was performed on Embase, Medline Ovid, and the Cochrane Library from inception to October 17, 2024, to identify articles on the associations of any candidate variables with thyroid function test abnormalities, thyroid antibody positivity, or results of continuous thyroid function tests in pregnancy. Additional records were identified through citation searching. Study quality was assessed using the Newcastle-Ottawa Scale. We summarized the results using a narrative synthesis.

Results:

A total of 81 articles were included, describing 36 candidate variables. Thyroid antibody positivity was associated with a higher risk of overt or subclinical hypothyroidism compared with antibody negativity (absolute risks: 2.4–7.0% vs. 0.1–0.2% for overt hypothyroidism and 1.9–29.0% vs. 2.0–5.7% for subclinical hypothyroidism). In cases of iodine deficiency, sufficiency, and intake above pregnancy requirements or excess, the absolute risks for subclinical hypothyroidism were 2.2–42.6%, 1.42–16.0%, and 3.8–24.3%, respectively. A limited number of studies were available for history of autoimmune diseases, family history of thyroid disease, symptoms of hypothyroidism, and history of pregnancy loss, preterm delivery, or infertility. There was little or no association of current risk factors with isolated hypothyroxinemia or (subclinical) hyperthyroidism. We did not identify novel risk factors for thyroid function test abnormalities.

Conclusions:

Evidence for most currently recommended risk factors remains limited and heterogeneous, and no novel risk factor was identified. While risk factors can help guide thyroid function testing in pregnancy, a clinical risk assessment cannot be replaced. Future studies are needed to detect novel risk factors that can improve the accuracy and efficiency of identifying pregnant women at high risk of thyroid function test abnormalities, in particular, overt hypothyroidism.

Introduction

Adequate thyroid hormone availability is important for a healthy pregnancy and optimal fetal growth and development.¹ Overt and subclinical hypothyroidism are present in about 0.4% and 3.2% of pregnancies, and overt and subclinical hyperthyroidism in about 0.9% and 1.4% of pregnancies.² When left untreated, especially overt but also subclinical hypothyroidism are associated with adverse pregnancy and child outcomes, including pregnancy loss, abnormal fetal growth, preterm delivery, gestational diabetes mellitus, pre-eclampsia, and suboptimal offspring neurodevelopment.^{3

–11} To mitigate these risks, levothyroxine therapy is recommended for pregnancies complicated by overt hypothyroidism and most cases of subclinical hypothyroidism.¹² To help identify pregnant women at high risk of thyroid function test abnormalities, the 2017 guidelines of the American Thyroid Association (ATA) recommend using a set of risk factors to guide thyroid function testing.¹² However, accurately identifying high-risk women remains a challenge.

The vast majority of women presenting with a thyroid function test abnormality during pregnancy are asymptomatic, and not all current risk factors for identifying high-risk populations have a good discriminative ability.^2,13,14 With the use of the risk factors recommended in the 2017 ATA guidelines, 55–78% of pregnant women would be considered high-risk and could undergo thyroid testing, while the detection rates were only 75–85% and 54–59% for overt and subclinical hypothyroidism, respectively.^12,15

–18 Moreover, in multiple studies, there was no difference in the prevalence of overt and/or subclinical hypothyroidism between the high- and low-risk groups, further verifying a lack of discriminative ability.^15
–17 In a recent individual participant data (IPD) meta-analysis, it was shown that various current risk factors with a high prevalence (e.g., maternal age >30 years, parity ≥2, and body mass index [BMI] >40 kg/m²) are poor screening factors for thyroid function test abnormalities, indicating their limited effectiveness in guiding indications for thyroid function testing.² The identification of pregnant women at high risk of thyroid function test abnormalities could be improved with an evidence-based reevaluation of currently recommended risk factors and the addition of novel risk factors with a potentially better discriminative ability and differential absolute risks of clinical significance for thyroid function test abnormalities. However, there is currently no up-to-date overview of relevant risk factors.

As initiated by the ATA Task Force for the Guidelines for the Diagnosis and Management of Thyroid Disease in Preconception, Pregnancy, and the Postpartum, this study was performed to systematically review the literature to summarize evidence on the risk factors currently recommended in the 2017 ATA guidelines and to identify potential novel risk factors for thyroid function test abnormalities in pregnancy.

Methods

This systematic review was reported following the procedures of Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.¹⁹

To identify studies for inclusion, we conducted a systematic literature search for articles on the associations of any candidate variables with thyroid function test abnormalities, thyroid antibody positivity, or results of continuous thyroid function tests in pregnancy, published from database inception to September 26, 2022, without language restrictions, using Embase, Medline Ovid, and the Cochrane Library. The primary outcomes of this review were thyroid function test abnormalities, including overt hypothyroidism, subclinical hypothyroidism, isolated hypothyroxinemia, subclinical hyperthyroidism, and overt hyperthyroidism. Secondary outcomes included thyroid antibody positivity and continuous thyroid function tests. A candidate variable was considered as a potential risk factor if there were both statistically significant relative measures of the association and differential absolute risks for the primary outcomes.²⁰ An update of the literature search was performed on October 17, 2024, and relevant data were retrieved and added to the review. A detailed search strategy can be found in Supplementary Tables S1 and S2. There were also additional relevant studies added through citation searching. Possible studies for inclusion were divided among specific working group members of the Guideline Task Force (T.I.M.K., A.M.L., S.B., C.D., E.K.A., S.M.), and titles and abstracts were independently assessed for suitability in duplicate. Full-text screening was independently performed by two reviewers (Y.L. and T.I.M.K.), and any disagreement was resolved by discussion with a third reviewer (A.M.L.).

We included both observational studies and randomized controlled trials. Studies were excluded if the full text was unavailable, there was a lack of information on thyroid hormone measurements, or they were not written in English. Studies whose populations overlapped with those of another study that had a larger sample size (including meta-analyses) were excluded unless they contributed distinct candidate variables not examined by the larger study, in which case they were retained for those specific variables only. Studies using a fixed upper limit of 2.5 or 3.0 mU/L for TSH or retrieving data only based on diagnosis code (e.g., International Statistical Classification of Diseases and Related Health Problems, 10th Revision [ICD-10]) to define overt or subclinical hypothyroidism were excluded from the main study, but were outlined in Supplementary Tables S3 and S4 for specific candidate variables in case of sparse data availability for a risk factor and as a benchmark utility for future studies.

Data extraction was performed by Y.L., and extracted data were organized into frequency tables for different types of thyroid function test abnormalities, thyroid antibody positivity, and continuous thyroid function tests. If a composite outcome was reported, such as elevated or suppressed TSH without regard to FT4, which therefore included both overt and subclinical thyroid dysfunction, it was assigned to the largest category (subclinical hypothyroidism or subclinical hyperthyroidism) to ensure optimal data availability. Data on effect estimates (e.g., odds ratio [OR], relative risk [RR], regression coefficient) as well as absolute risks were extracted if these were reported in the articles. If not provided, and if data permitted, relative risks were manually calculated using MedCalc Software, and absolute risks were estimated based on the frequency or percentage.²¹

Quality assessment of included studies was performed by Y.L. using the Newcastle-Ottawa Scale, a risk of bias assessment tool for cohort and case-control studies and in a modified version for cross-sectional studies.^22
–24 Cohort or case-control studies were scored out of a maximum of 9 points across three main categories (selection, comparability, and ascertainment of exposure/outcome) with a total score of ≥7, 4–6, or ≤3 indicative of a high, medium, or low quality of evidence, respectively.²³ Cross-sectional studies were scored out of a maximum of 10 points across three main categories (selection, comparability, and ascertainment of outcome) with a total score of ≥8, 4–7, or ≤3 indicative of a high, medium, or low quality of evidence, respectively.²⁴

Due to the small number of eligible studies per risk factor and heterogeneous definitions of exposures/outcomes, we were not able to perform a meta-analysis. Instead, we have provided a narrative synthesis of the extracted data. We placed greater emphasis on overt and subclinical hypothyroidism, as there are established treatment recommendations for both conditions during pregnancy, whereas there is no therapeutic indication for either isolated hypothyroxinemia or non-Graves’ hyperthyroidism.¹²

Results

After excluding duplicates, the literature search yielded 1686 records. Following title and abstract screening, 130 full-text articles were assessed, 79 of which were included. Two additional articles were retrieved as a result of citation searching. In total, 81 articles were included in the systematic review (Fig. 1).^{2,13,18,25

–102} We identified 36 candidate variables, of which 11 are currently recommended in the 2017 ATA guidelines, and 25 are not addressed by the 2017 ATA guidelines but were explored for the associations with thyroid function test abnormalities in our literature search (Table 1). For other currently recommended risk factors, including presence of a goiter, history of head or neck radiation, prior thyroid surgery, the use of amiodarone or lithium, and recent administration of iodinated radiological contrast, we did not identify any study assessing them.¹²

FIG. 1.

PRISMA flowchart. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1.

Number of Articles Assessing Potential Risk Factors for Thyroid Function Test Abnormalities, Results of Thyroid Function Tests, and Thyroid Antibody Positivity in Pregnancy

Candidate variable	Overt hypothyroidism (n)	Subclinical hypothyroidism (n)	Isolated hypothyroxinemia (n)	Subclinical hyperthyroidism (n)	Overt hyperthyroidism (n)	Thyroid function tests (n)	Thyroid antibody positivity (n)
Demographics
Maternal age	1	7	7	4	1	10	4
BMI	3	3	6	3	1	9	4
Smoking	2	4	2	3	1	7	2
Alcohol		1					1
Physical activity		1
Education	2	3	2	2	1	5	1
Race/ethnicity		3	1	2		5	5
Geographic area		1	2				1
Gestational characteristics
Parity	1	3	4	2	1	6	4
Gravidity			1				1
IVF	1	1	1	1	1	1
Twin pregnancy	2	2	2	2	2	3	1
Gestational age at blood sampling	4	8	6	5	3	13	7
Thyroid antibody positivity	2	10	4	4	1	13
Symptoms of thyroid disease	1	2					1
Thyroid volume			1			1	1
Season of enrollment							1
History of diseases
Personal history of autoimmunity		1
Family history of thyroid disease		2	1	3	1		2
History of pregnancy loss		3	2	1			3
History of preterm delivery							1
History of infertility		1					1
History of abnormal uterine bleeding		1
History of pre-eclampsia		1
Dietary determinants
Iodine	4	12	11	2	2	18	10
Vitamin D			1			1
Weekly egg consumption						1
Weekly seafood consumption			1			1	1
Non-thyroidal serum markers
hCG	1	1	1	1	1	1	1
PAPP-A						1	1
sFlt1		1	1		1	3	1
PlGF		1	1		1	2	1
Tg						1
Iron	1	2	3	1		6	2
Hemoglobin			1			2
Air pollutants and EDCs		2	2			16	5

BMI, body mass index; EDC, endocrine disrupting chemical; hCG, human chorionic gonadotropin; IVF, in vitro fertilization; PAPP-A, pregnancy associated plasma protein A; PlGF, placental growth factor; sFlt1, soluble FMS-like tyrosine kinase-1; Tg, thyroglobulin.

The details of the 13 studies assessing overt hypothyroidism are described in Table 2,^{2,13,36,44,51,54,57,63,81,83,85,92,97} 37 studies assessing subclinical hypothyroidism in Table 3,^{2,13,18,29,36,39,42,44
–46,51,54,57
–59,61,63,64,67,68,72
–74,76,78,80

–87,91,92,95,97} 26 studies assessing isolated hypothyroxinemia in Supplementary Table S5,^{2,26,28,35,36,42
–44,46,48,50,51,54,57
–59,63,65,67,69,74,81,83,86,92,97} 14 studies assessing subclinical hyperthyroidism in Supplementary Table S6,^{2,27
–29,36,42,44,57,76,78,81,84,87,97} 9 studies assessing overt hyperthyroidism in Supplementary Table S7,^{2,27,36,44,57,59,63,74,97} 57 studies assessing results of thyroid function tests in Supplementary Table S8,^{2,25,30,32,33,36

–43,45,47

–53,55,56,59

–64,66,68

–71,73
–75,77,79,80,83

–86,88
–90,92
–94,96

–102} and 31 studies assessing thyroid antibody positivity in Supplementary Table S9.^{26,31,34,36,45

–51,54,55,58,60,62,63,66,69,73,74,78,83,84,88,89,92,93,96,98,99}

Table 2.

Candidate Risk Factors for Overt Hypothyroidism

Risk factor	Author, year, study type, geographic area, N of pregnant women^[ref]	Definition of exposure	Definition of comparator	Thyroid function tests	Absolute risk^a	Effect estimate (95% CI)
Maternal age	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	Age (years)	N/A	Trimester-specific reference intervals	From ∼0.4% to 0.6% for maternal age from 20 to 40 years	aOR 1.02 (1.00, 1.05)
BMI	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	BMI (kg/m²)	N/A	Trimester-specific reference intervals	From ∼0.5% to 0.8% for BMI from 20 to 40 kg/m²	aOR 1.03 (1.01, 1.06)^b
	Refaat et al., 2021, cross-sectional study, Saudi Arabia, 810⁸¹	BMI (kg/m²)	N/A	TSH: 4.0 or 4.2 μIU/mL fixed limit; FT4: reference interval from another population	N/A	aOR 1.11 (0.97, 1.27)
	Han et al., 2015, cross-sectional study, China, 6303⁵¹	<18.5 kg/m²	18.5–24.9 kg/m²	Trimester-specific reference intervals	0.2% vs. 0.9%	OR 0.25 (0.06, 1.02)
		25.0–29.9 kg/m²			2.0% vs. 0.9%	OR 2.20 (1.23, 3.93)^b
		≥30.0 kg/m²			3.3% vs. 0.9%	OR 3.70 (1.12, 12.2)^b
Smoking	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	Active smoking	Non-smoking	Trimester-specific reference intervals	∼0.5% vs. 0.5%	aOR 1.11 (0.73, 1.70)
	Refaat et al., 2021, cross-sectional study, Saudi Arabia, 810⁸¹	Active smoking	Non-smokers	TSH: 4.0 or 4.2 μIU/mL fixed limit; FT4: reference interval from another population	8.8% vs. 6.1%	OR 1.48 (0.42, 5.16)
		Passive smoking	Non-smokers		5.1% vs. 6.1%	OR 0.82 (0.44, 1.52)
Education	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	Medium: ISCED 3–4	Low: ISCED 0–2	Trimester-specific reference intervals	∼0.4% vs. 0.5%	aOR 0.83 (0.58, 1.18)
		High: ISCED 5–8	Low: ISCED 0–2	Trimester-specific reference intervals	∼0.3% vs. 0.5%	aOR 0.68 (0.44, 1.05)
	Refaat et al., 2021, cross-sectional study, Saudi Arabia, 810⁸¹	Primary education	University	TSH: 4.0 or 4.2 μIU/mL fixed limit; FT4: reference interval from another population	15.3% vs. 0.6%	aOR 44.1 (5.82, 334)^b
		Secondary education	University		7.6% vs. 0.6%	aOR 11.2 (1.70, 74.1)^b
Parity	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	1	0	Trimester-specific reference intervals	∼0.5% vs. 0.5%	aOR 1.00 (0.74, 1.37)
		2			∼0.4% vs. 0.5%	aOR 0.88 (0.54, 1.37)
		≥3			∼0.6% vs. 0.5%	aOR 1.21 (0.72, 2.05)
IVF	Osinga et al., 2024, individual participant data meta-analysis, Multiple, 65,559²	Pregnancy through IVF	Natural pregnancy	Trimester-specific reference intervals	∼0.5% vs. 1.0%	aOR 1.90 (0.69, 5.23)
Twin pregnancy	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	Twin pregnancy	Singleton pregnancy	Trimester-specific reference intervals	∼0.5% vs. 0.3%	aOR 0.45 (0.06, 3.01)
	Chen et al., 2021, prospective cohort study, China, 48,042³⁶	Twin pregnancy	Singleton pregnancy	Trimester-specific reference intervals in early pregnancy	1.8% vs. 0.3%	aOR 1.95 (0.70, 5.42)
		Twin pregnancy	Singleton pregnancy	Trimester-specific reference intervals in late pregnancy	1.3% vs. 0.2%	aOR 2.83 (0.67, 11.9)
Gestational age at blood sampling	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	Gestational age (week)	N/A	Trimester-specific reference intervals	From ∼0.9% to 0.1% for gestational weeks from 6 to 36	aOR 0.93 (0.90, 0.97)^b
	Etemadi et al., 2020, cross-sectional study, Iran, 1080⁴⁴	Second trimester	First trimester	Trimester-specific reference intervals	1.36% vs. 2.66%	OR 0.50 (0.17, 1.49)
	Etemadi et al., 2020, cross-sectional study, Iran, 1080⁴⁴	Third trimester	First trimester	Trimester-specific reference intervals	0.96% vs. 2.66%	OR 0.35 (0.10, 1.30)
	Refaat et al., 2021, cross-sectional study, Saudi Arabia, 810⁸¹	Second trimester	First trimester	TSH: 4.0 or 4.2 μIU/mL fixed limit; FT4: reference interval from another population	3% vs. 2.6%	aOR 0.94 (0.20, 4.32)
		Third trimester	First trimester		11.8% vs. 2.6%	aOR 5.81 (1.41, 24.0)^b
	Li et al., 2023, prospective cohort study, China, 1540⁶³	First, second trimester		Trimester-specific reference intervals	0.5%, 0.1%, respectively	N/A
Thyroid antibody positivity	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	TPOAb positivity	TPOAb negativity	Trimester-specific reference intervals	∼4.2% vs. 0.2%	aOR 24.2 (18.5, 31.6)^b
		Isolated TgAb positivity, isolated TPOAb positivity, combined TPOAb and TgAb positivity	TPOAb and TgAb negativity	Trimester-specific reference intervals	∼0.1%, 2.4%, 3.8%, and 7.0% for combined antibody negativity, isolated TgAb positivity, isolated TPOAb positivity, and combined antibody positivity, respectively	Positive association^b
	Sun et al., 2020, cross-sectional study, China, 7073⁸⁵	Isolated TPOAb positivity: >34 IU/mL	TPOAb and TgAb negativity	Cohort-specific reference intervals	N/A	aOR 14.6 (5.99, 35.8)^b
		Isolated TgAb positivity: >115 IU/mL			N/A	aOR 7.83 (3.25, 19.0)^b
		Combined TPOAb and TgAb positivity			N/A	aOR 44.7 (23.5, 85.1)^b
Symptoms of thyroid disease	Pop et al., 2017, prospective cohort study, Netherlands, 2198¹³	High hypothyroid symptom scores (>1 SD > mean)	Low hypothyroid symptom scores	Cohort-specific reference intervals	0.3% vs. 0.8%	RR 0.40 (0.05, 3.10)
Iodine	Refaat et al., 2021, cross-sectional study, Saudi Arabia, 810⁸¹	24-h UIC (μg/L)	N/A	TSH: 4.0 or 4.2 μIU/mL fixed limit; FT4: reference interval from another population	N/A	aOR 0.98 (0.97, 1.00)^b
		Non-iodized salt intake	Iodized salt intake		14.2% vs. 2.2%	aOR 9.15 (2.78, 30.2)^b
		No iodine supplement	Iodine supplement		11.0% vs. 1.2%	aOR 6.79 (1.42, 32.5)^b
	Wang et al., 2022, cross-sectional study, China, 1264⁹²	UIC <100 µg/L	UIC 150–249 µg/L	Reference intervals from national guidelines	1.6% vs. 0.9%	OR 1.79 (0.50, 6.40)
		UIC 100-149 µg/L			1.3% vs. 0.9%	OR 1.46 (0.36, 5.89)
		UIC ≥250 µg/L			1.4% vs. 0.9%	OR 1.50 (0.27, 8.26)
		UIC <100 µg/L		TSH: 4.0 mU/L fixed limit; FT4: reference interval from national guidelines	1.1% vs. 0.5%	OR 2.39 (0.43, 13.1)
		UIC 100-149 µg/L			0.3% vs. 0.5%	OR 0.73 (0.07, 8.05)
		UIC ≥250 µg/L			0.7% vs. 0.5%	OR 1.49 (0.13, 16.6)
	Shi et al., 2015, cross-sectional study, China, 7190⁸³	UIC <100 g/L	UIC 150–249 g/L	Cohort-specific reference intervals	1.5% vs. 0.7%	No association
		UIC 100–149 g/L			0.8% vs. 0.7%	No association
		UIC 250–500 g/L			1.2% vs. 0.7%	No association
		UIC ≥500 g/L			0.9% vs. 0.7%	No association
	Ji et al., 2023, cross-sectional study, China, 912⁵⁴	SIC <10%	SIC 10-90%	Trimester-specific reference intervals	N/A	OR 1.28 (0.16, 10.5)
	Ji et al., 2023, cross-sectional study, China, 912⁵⁴	SIC <10%	SIC 10-90%	Trimester-specific reference intervals	N/A	aOR 1.31 (0.16, 10.8)
hCG	Korevaar et al., 2017, prospective cohort study, Netherlands, 5435⁵⁷	hCG (IU/L)	N/A	Trimester-specific reference intervals	From ∼0.9% to 0.6% for hCG concentrations from 25,000 to 150,000 IU/L	No association
Iron	Yu et al., 2015, cross-sectional study, China, 3340⁹⁷	Negative values of TBI, sTfR >4.4 mg/L, or SF <12 µg/L	Iron adequacy	Trimester-specific reference intervals	1.2% vs. 0.3%	OR 3.82 (0.48, 30.2)

Gray background, manual calculation based on provided data.

Exposure group vs. comparator group.

Significant relative risk with p-value <0.05.

aOR, adjusted odds ratio; CI, confidence interval; FT4, free thyroxine; ISCED, International Standard Classification of Education; N/A, not applicable; OR, odds ratio; RR, rate ratio; SD, standard deviation; SF, serum ferritin; SIC, serum iodine concentration; sTfR, serum transferrin receptor; TBI, total body iron; TgAb, thyroglobulin antibodies; TPOAb, thyroid peroxidase antibody; TSH, thyroid stimulating hormone; UIC, urine iodine concentration.

Table 3.

Candidate Risk Factors for Subclinical Hypothyroidism

Risk factor	Author, year, study type, geographic area, N of pregnant women^[ref]	Definition of exposure	Definition of comparator	Thyroid function tests	Absolute risk^a	Effect estimate (95% CI)
Maternal age	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	Age (years)	N/A	Trimester-specific reference intervals	From ∼3.3% to 4.8% for maternal age from 20 to 40 years	aOR 1.02 (1.01, 1.03)^b
	Corcino et al., 2019, prospective cohort study, Brazil, 243³⁹	Age (year)	N/A	Cohort-specific reference intervals	N/A	aOR 0.8 (0.7, 1.0)
	Potlukova et al., 2012, cross-sectional study, Czech Republic, 5223⁷⁶	Age (year)	N/A	TSH elevation: trimester-specific reference interval	N/A	No association
		≥30 years	<30 years	TSH elevation: trimester-specific reference interval	5.5% vs. 5.8%	OR 0.96 (0.75, 1.23)
	Dieguez et al., 2016, cross-sectional study, Spain, 2509⁴²	≥30 years	<30 years	Raised TSH: reference interval from another population	5.0% vs. 6.6%	OR 0.72 (0.50, 1.06)
	Quinn et al., 2005, cross-sectional study, Russian Federation, 1588⁷⁸	≥30 years	<30 years	Abnormal TSH: trimester-specific reference interval	8.48% vs. 5.56%	OR 1.57 (1.02, 2.42)^b
	Etemadi et al., 2020, cross-sectional study, Iran, 1080⁴⁴	≥30 years	<30 years	Trimester-specific reference intervals	N/A	aOR 1.2 (0.7, 2.12)
	Vaidya et al., 2007, prospective cohort study, United Kingdom, 1560⁸⁷	>35 years	≤35 years	Raised TSH: manufacturer’s reference interval	N/A	RR 1.4 (0.7, 2.8)
BMI	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	BMI (kg/m²)	N/A	Trimester-specific reference intervals	From ∼3.8% to 3.8% for BMI from 20 to 40 kg/m²	aOR 1.00 (0.99, 1.01)
	Refaat et al., 2021, cross-sectional study, Saudi Arabia, 810⁸¹	BMI (kg/m²)	N/A	TSH: 4.0 or 4.2 μIU/mL fixed limit; FT4: reference interval from another population	N/A	aOR 1.00 (0.90, 1.11)
	Han et al., 2015, cross-sectional study, China, 6303⁵¹	<18.5 kg/m²	18.5-24.9 kg/m²	Trimester-specific reference intervals	3.3% vs. 3.1%	OR 1.08 (0.72, 1.62)
		25.0–29.9 kg/m²			3.3% vs. 3.1%	OR 1.06 (0.69, 1.61)
		≥30.0 kg/m²			7.8% vs. 3.1%	OR 2.64 (1.20, 5.80)^b
Smoking	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	Active smoking	Non-smoking	Trimester-specific reference intervals	∼2.6% vs. 3.8%	aOR 0.70 (0.58, 0.80)^b
	Vaidya et al., 2007, prospective cohort study, United Kingdom, 1560⁸⁷	Smoking during pregnancy	Non-smoking	Raised TSH: manufacturer’s reference interval	1.2% vs. 3.2%	RR 0.4 (0.25, 0.6)^b
		Smoking (all smokers)	Non-smoking	Raised TSH: manufacturer’s reference interval	N/A	RR 1.0 (0.8, 1.2)
	Corcino et al., 2019, prospective cohort study, Brazil, 243³⁹	Smoking	Non-smoking	Cohort-specific reference intervals	25.0% vs. 4.3%	aOR not adjusted for thyroid antibodies 213 (7.2, 6000)^b
		Smoking	Non-smoking	Cohort-specific reference intervals	25.0% vs. 4.3%	aOR adjusted for thyroid antibodies 215 (5.4, 8500)^b
	Refaat et al., 2021, cross-sectional study, Saudi Arabia, 810⁸¹	Active smoking	Non-smoking	TSH: 4.0 or 4.2 μIU/mL fixed limit; FT4: reference interval from another population	8.8% vs. 21.0%	OR 0.36 (0.11, 1.22)
		Passive smoking	Non-smoking		20.4% vs. 21.0%	OR 0.96 (0.68, 1.36)
Alcohol	Yang et al., 2023, case-control study, China, 126⁹⁵	Alcohol consumption ≥1 day a month	No alcohol consumption	Reference intervals from national guidelines	38.1% vs. 32.4%^c	OR 1.29 (0.49, 3.39)
Physical activity	Yang et al., 2023, case-control study, China, 126⁹⁵	Exercise ≥1 day a week	No exercise	Reference intervals from national guidelines	33.7% vs. 32.5%^c	OR 1.06 (0.48, 2.35)
Education	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	Medium: ISCED 3–4	Low: ISCED 0–2	Trimester-specific reference intervals	∼3.0% vs. 3.5%	aOR 0.92 (0.78, 1.07)
		High: ISCED 5–8	Low: ISCED 0–2	Trimester-specific reference intervals	∼3.8% vs. 3.5%	aOR 1.09 (0.91, 1.29)
	Yang et al., 2023, case-control study, China, 126⁹⁵	College degree	Senior high school and below	Reference intervals from national guidelines	32% vs. 16.7%^c	OR 2.35 (0.23, 23.6)
	Yang et al., 2023, case-control study, China, 126⁹⁵	Bachelor’s degree and above	Senior high school and below	Reference intervals from national guidelines	34.7% vs. 16.7%^c	OR 2.66 (0.30, 23.7)
	Refaat et al., 2021, cross-sectional study, Saudi Arabia, 810⁸¹	Primary education	University	TSH: 4.0 or 4.2 μIU/mL fixed limit; FT4: reference interval from another population	42.7% vs. 7.6%	aOR 7.93 (2.41, 26.1)^b
		Secondary education	University		24.8% vs. 7.6%	aOR 2.41 (0.94, 6.23)
Race/ethnicity	Vaidya et al., 2007, prospective cohort study, United Kingdom, 1560⁸⁷	South Asian	White	Raised TSH: manufacturer’s reference interval	N/A	RR 2.8 (1.6, 4.6)^b
	Korevaar et al., 2016, prospective cohort study, Netherlands, 9767⁵⁸	Other Western	Dutch	Elevated TSH: cohort-specific reference interval	N/A	OR 0.87 (0.60, 1.28)
		Other Western				aOR 0.88 (0.60, 1.28)
		Moroccan				OR 0.40 (0.22, 0.73)^b
		Moroccan				aOR 0.40 (0.22, 0.76)^b
		Surinamese				OR 0.37 (0.20, 0.66)^b
		Surinamese				aOR 0.38 (0.21, 0.69)^b
		Turkish				OR 0.76 (0.48, 1.19)
		Turkish				aOR 0.82 (0.50, 1.33)
		Asian				OR 1.49 (0.92, 2.42)
		Asian				aOR 1.49 (0.91, 2.43)
		Other non-Western				OR 0.56 (0.39, 0.81)^b
		Other non-Western				aOR 0.57 (0.39, 0.83)^b
	Sletner et al., 2021, prospective cohort study, Norway, 785⁸⁴	South Asia	Europe	TSH: 4.0 mU/L fixed limit; FT4: manufacturer’s reference interval	14.2% vs. 4.1%	OR 3.84 (2.00, 7.39)^b
		East Asia			0% vs. 4.1%	N/A
		Middle East			4.7% vs. 4.1%	OR 1.15 (0.44, 3.03)
		Sub-Saharan Africa			5.4% vs. 4.1%	OR 1.31 (0.37, 4.69)
Geographic area	Etemadi et al., 2020, cross-sectional study, Iran, 1080⁴⁴	Rural area	Urban area	Trimester-specific reference intervals	N/A	aOR 0.93 (0.57, 1.53)
Parity	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	1	0	Trimester-specific reference intervals	∼3.2% vs. 3.9%	aOR 0.84 (0.75, 0.94)^b
		2			∼3.7% vs. 3.9%	aOR 0.94 (0.80, 1.11)
		≥3			∼3.2% vs. 3.9%	aOR 0.84 (0.68, 1.05)
	Vaidya et al., 2007, prospective cohort study, United Kingdom, 1560⁸⁷	Previous pregnancy	No previous pregnancy	Raised TSH: manufacturer’s reference interval	N/A	RR 0.9 (0.7, 1.1)
	Etemadi et al., 2020, cross-sectional study, Iran, 1080⁴⁴	Multiparity	Nulliparity	Trimester-specific reference intervals	N/A	aOR 0.9 (0.6, 1.6)
IVF	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	Pregnancy through IVF	Natural pregnancy	Trimester-specific reference intervals	∼3.7% vs. 3.8%	aOR 0.91 (0.55, 1.52)
Twin pregnancy	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	Twin pregnancy	Singleton pregnancy	Trimester-specific reference intervals	∼2.2% vs. 3.8%	aOR 0.60 (0.30, 1.22)
	Chen et al., 2021, prospective cohort study, China, 48,042³⁶	Twin pregnancy	Singleton pregnancy	Trimester-specific reference intervals in early pregnancy	0.7% vs. 2.5%	aOR 0.27 (0.13, 0.54)^b
		Twin pregnancy	Singleton pregnancy	Trimester-specific reference intervals in late pregnancy	8.2% vs. 2.2%	aOR 4.05 (3.21, 5.11)^b
Gestational age at blood sampling	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	Gestational age (week)	N/A	Trimester-specific reference intervals	From ∼4.5% to 1.8% for gestational weeks from 6 to 36	Nonlienarly negative association^b
	Etemadi et al., 2020, cross-sectional study, Iran, 1080⁴⁴	Second trimester	First trimester	Trimester-specific reference intervals	7.05% vs. 9.04%	aOR 0.82 (0.47, 1.4)
	Etemadi et al., 2020, cross-sectional study, Iran, 1080⁴⁴	Third trimester	First trimester	Trimester-specific reference intervals	8.31% vs. 9.04%	aOR 0.9 (0.5, 1.7)
	Okoli et al., 2024, cross-sectional study, Nigeria, 318⁷²	Second trimester	First trimester	Trimester-specific reference intervals	1.9% vs. 7.5%	OR 0.25 (0.05, 1.19)
	Okoli et al., 2024, cross-sectional study, Nigeria, 318⁷²	Third trimester	First trimester	Trimester-specific reference intervals	1.9% vs. 7.5%	OR 0.25 (0.05, 1.22)
	Refaat et al., 2021, cross-sectional study, Saudi Arabia, 810⁸¹	Second trimester	First trimester	TSH: 4.0 or 4.2 μIU/mL fixed limit; FT4: reference interval from another population	18.9% vs. 8.9%	aOR 2.75 (1.08, 21.0)^b
		Third trimester	First trimester		32.9% vs. 8.9%	aOR 7.43 (2.65, 20.8)^b
	Quinn et al., 2005, cross-sectional study, Russian Federation, 1588⁷⁸	Second trimester	First trimester	Abnormal TSH: trimester-specific reference interval	3.7% vs. 5.7%	OR 0.64 (0.36, 1.14)
		Third trimester	First trimester	Abnormal TSH: trimester-specific reference interval	2.7% vs. 5.7%	OR 0.46 (0.23, 0.89)^b
	Rebagliato et al., 2010, prospective cohort study, Spain, 1844⁸⁰	12–13 weeks	<12 weeks	Raised TSH: cohort-specific reference interval	6.6% vs. 3.4%	OR 1.99 (0.90, 4.37)
		≥14 weeks	<12 weeks	Raised TSH: cohort-specific reference interval	5.5% vs. 3.4%	OR 1.64 (0.69, 3.87)
	Teng et al., 2018, retrospective cohort study, China, 723⁸⁶	First, second, and third trimester		Trimester-specific reference intervals	1.6%, 2.2%, and 2.3%, respectively	N/A
	Li et al., 2023, prospective cohort study, China, 1540⁶³	First, second, and third trimester		Trimester-specific reference intervals	1.4%, 2.1%, and 1.2%, respectively	N/A
Thyroid antibody positivity	Osinga et al., 2024, individual participant data meta-analysis, multiple, 65,559²	TPOAb positivity	TPOAb negativity	Trimester-specific reference intervals	∼17.6% vs. 2.2%	aOR 8.42 (7.60, 9.32)^b
		Isolated TgAb positivity, Isolated TPOAb positivity, combined TPOAb and TgAb positivity	TPOAb and TgAb negativity	Trimester-specific reference intervals	∼2.2%, 8.1%, 14.2%, and 20.0% for combined antibody negativity, isolated TgAb positivity, isolated TPOAb positivity, and combined antibody positivity, respectively	Positive association^b
	Ollero et al., 2019, prospective cohort study, Spain, 300⁷³	Positive thyroid autoimmunity	Negative thyroid autoimmunity	High TSH: 4 mIU/L fixed limit	1.9% vs. 2%	OR 0.93 (0.11, 8.13)
	Gallas et al., 2002, prospective cohort study, Netherlands, 82 women with diabetes mellitus type 1⁴⁵	TPOAb >100 kU/L	TPOAb negativity	Manufacturer’s reference intervals	N/A	No association
	Corcino et al., 2019, prospective cohort study, Brazil, 243³⁹	TPOAb ≥34 IU/mL and/or TgAb ≥115 IU/mL	TPOAb and TgAb negativity	Cohort-specific reference intervals	23.8% vs. 3.2%	aOR 7.2 (0.9, 56.2)
	Etemadi et al., 2020, cross-sectional study, Iran, 1080⁴⁴	TPOAb >35 IU/mL	TPOAb negativity	Trimester-specific reference intervals	N/A	aOR 2.56 (1.34, 4.86)^b
	Vaidya et al., 2007, prospective cohort study, United Kingdom, 1560⁸⁷	TPOAb positivity: a reactive pattern detected at a final dilution of 1 in 1600 or greater	TPOAb negativity	Raised TSH: manufacturer’s reference interval	N/A	RR 8.4 (4.6, 15.3)^b
	Wang et al., 2017, case-control study, China, 219⁹¹	TPOAb >35 IU/L	TPOAb negativity	Reference intervals from national guidelines	60.7% vs. 34.8%^c	OR 2.89 (1.60, 5.24)^b
	Wang et al., 2017, case-control study, China, 219⁹¹	TgAb >20 IU/L	TgAb negativity	Reference intervals from national guidelines	65.6% vs. 36.1%^c	OR 3.37 (1.93, 5.89)^b
	Sun et al., 2020, cross-sectional study, China, 7073⁸⁵	Isolated TPOAb positivity: >34 IU/mL	TPOAb and TgAb negativity	Cohort-specific reference intervals	N/A	aOR 4.36 (2.59, 7.32)^b
		Isolated TgAb positivity: >115 IU/mL				aOR 2.86 (1.84, 4.44)^b
		Combined TPOAb and TgAb positivity				aOR 6.26 (4.29, 9.13)^b
	Sletner et al., 2021, prospective cohort study, Norway, 785⁸⁴	TPOAb >60 kU/L	TPOAb negativity	TSH: 4.0 mU/L fixed limit; FT4: manufacturer’s reference interval	29.0% vs. 5.7%	OR 6.76 (2.94, 15.6)^b
	Andersen et al., 2022, prospective cohort study, Denmark, 14,030²⁹	TPOAb ≥95th percentile	TPOAb < limit of detection	Trimester-specific reference intervals	25.4% vs. 3.3%	RR 7.66 (6.54, 8.97)^b
		TgAb ≥95th percentile	TgAb < limit of detection	Trimester-specific reference intervals	21.1% vs. 3.0%	RR 7.12 (6.12, 8.28)^b
Symptoms of thyroid disease	Pop et al., 2017, prospective cohort study, Netherlands, 2198¹³	High hypothyroid symptom scores (>1 SD > mean)	Low hypothyroid symptom scores	Cohort-specific reference intervals	1.3% vs. 3.5%	RR 0.36 (0.13, 0.98)^b
	Goel et al., 2012, prospective cohort study, India, 1005¹⁸	Fatigue	No fatigue	Trimester-specific reference intervals	3.19% vs. 3.65%	OR 0.87 (0.42, 1.81)
		Cold intolerance	No cold intolerance		8.33% vs. 3.36%	OR 2.61 (0.59, 11.6)
		Constipation	No constipation		3.81% vs. 3.39%	OR 1.13 (0.50, 2.53)
		Depression	No depression		8.0% vs. 3.36%	OR 2.50 (0.56, 11.1)
		Muscle weakness	No muscle weakness		0 vs. 3.53%	N/A
		Muscle cramps	No muscle cramps		2.85% vs. 3.70%	OR 0.76 (0.33, 1.77)
		Hoarseness of voice	No hoarseness of voice		0 vs. 3.52%	N/A
		Excessive weight gain (normotensive)	No excessive weight gain (normotensive)		19.4% vs. 2.96%	OR 7.86 (2.99, 20.7)^b
		Galactorrhea	No galactorrhea		2.94% vs. 3.55%	OR 0.82 (0.25, 2.74)
		Goiter	No goiter		16.7% vs. 3.40%	OR 5.68 (0.65, 50.0)
Personal history of autoimmunity	Vaidya et al., 2007, prospective cohort study, United Kingdom, 1560⁸⁷	Personal history of type 1 diabetes and other autoimmune disorders	No personal history of autoimmunity	Raised TSH: manufacturer’s reference interval	N/A	RR 4.8 (1.3, 18.2)^b
Family history of thyroid disease	Goel et al., 2012, prospective cohort study, India, 1005¹⁸	Family history of thyroid disorders	No family history of thyroid disorders	Trimester-specific reference intervals	9.1% vs. 3.4%	OR 2.88 (0.65, 12.9)
Family history of thyroid disease	Vaidya et al., 2007, prospective cohort study, United Kingdom, 1560⁸⁷	Family history (in first and second degree relatives) of thyroid disorders	No family history of thyroid disorders	Raised TSH: manufacturer’s reference interval	N/A	RR 3.4 (1.8, 6.2)^b
History of pregnancy loss	Goel et al., 2012, prospective cohort study, India, 1005¹⁸	Previous preterm or recurrent abortions	No history of abortions	Trimester-specific reference intervals	8.6% vs. 3.3%	OR 2.75 (0.80, 9.48)
	Vaidya et al., 2007, prospective cohort study, United Kingdom, 1560⁸⁷	History of miscarriage	No history of miscarriage	Raised TSH: manufacturer’s reference interval	N/A	RR 1.3 (1.1, 1.6)^b
	Korevaar et al., 2016, prospective cohort study, Netherlands, 9767⁵⁸	Medical history of miscarriage or stillborn	No medical history of miscarriage or stillborn	Elevated TSH: cohort-specific reference interval	N/A	OR 1.03 (0.77, 1.37)
		Medical history of miscarriage or stillborn	No medical history of miscarriage or stillborn	Elevated TSH: cohort-specific reference interval	N/A	aOR 1.02 (0.76, 1.37)
History of infertility	Goel et al., 2012, prospective cohort study, India, 1005¹⁸	History of infertility	No history of infertility	Trimester-specific reference intervals	7.3% vs. 3.1%	OR 2.44 (0.98, 6.08)
History of abnormal uterine bleeding	Goel et al., 2012, prospective cohort study, India, 1005¹⁸	History of abnormal uterine bleeding	No history of abnormal uterine bleeding	Trimester-specific reference intervals	5.3% vs. 3.3%	OR 1.64 (0.56, 4.77)
History of pre-eclampsia	Levine et al., 2009, nested case-control study and prospective cohort study, United States and Norway, 141 pregnant women with pre-eclampsia, 141 normotensive controls, and 7121 women after pregnancy⁶¹	Pre-eclampsia	Normotension	High TSH (measured before delivery): manufacturer’s reference interval	24% vs. 14%	aOR 2.2 (1.1, 4.4)^b
		History of pre-eclampsia in first pregnancy in women with ≥1 pregnancies	No pre-eclampsia in first pregnancy	High TSH (measured >20 years after pregnancy): cohort-specific reference interval	10.7% vs. 5.9%	aOR 1.7 (1.1, 2.5)^b
		History of pre-eclampsia in first or second pregnancy in women with ≥2 pregnancies	No pre-eclampsia in first pregnancy or second pregnancy		8.2% vs. 6.0%	aOR 1.3 (0.9, 2.1)
		History of pre-eclampsia in first and second pregnancy in women with ≥2 pregnancies	No pre-eclampsia in first pregnancy or second pregnancy		16.0% vs. 6.0%	aOR 2.5 (0.9, 7.5)
Iodine	Sang et al., 2012, cross-sectional study, China, 384⁸²	UIC >250 μg/L	UIC 150–250 μg/liter	Trimester-specific reference intervals	N/A	OR 6.20 (1.10, 35.1)^b
	Wang et al., 2017, case-control study, China, 219⁹¹	UIC ≥250 μg/L	UIC 150–249 μg/L	Reference intervals from national guidelines	73.7% vs. 41.1%^c	OR 4.01 (1.70, 9.48)^b
		UIC 51–149 μg/L			52.6% vs. 41.1%^c	OR 1.59 (0.86, 2.95)
		UIC ≤ 50 μg/L			53.8% vs. 41.1%^c	OR 1.67 (0.51, 5.47)
	Corcino et al., 2019, prospective cohort study, Brazil, 243³⁹	Any UIC ≥500 μg/l + median UIC ≥250 μg/L	UIC 150–249 μg/L	Cohort-specific reference intervals	N/A	aOR not adjusted for thyroid antibodies 6.6 (1.2, 37.4)^b
		Any UIC ≥500 μg/l + median UIC ≥250 μg/L	UIC 150–249 μg/L	Cohort-specific reference intervals	N/A	aOR adjusted for thyroid antibodies 3.7 (0.6, 25.4)
	Wang et al., 2022, cross-sectional study, China, 1264⁹²	UIC <100 μg/L	UIC 150–249 μg/L	Reference intervals from national guidelines	42.6% vs. 16.0%	aOR 2.47 (1.22, 5.71)^b
		UIC 100-149 μg/L			16.7% vs. 16.0%	aOR 1.02 (0.44, 2.45)
		UIC ≥250 μg/L			24.3% vs. 16.0%	aOR 1.50 (0.59, 3.92)
		UIC <100 μg/L		TSH: 4.0 mU/L fixed limit; FT4: reference interval from national guidelines	23.4% vs. 5.3%	aOR 5.22 (1.73, 6.09)^b
		UIC 100-149 μg/L			11.1% vs. 5.3%	aOR 1.85 (0.56, 6.16)
		UIC ≥250 μg/L			13.5% vs. 5.3%	aOR 2.72 (0.71, 5.24)
	Okoli et al., 2024, cross-sectional study, Nigeria, 318⁷²	UIC <150 μg/L	UIC 150–249 μg/L	Trimester-specific reference intervals	32% vs. 1.42%	OR 46.2 (12.2, 175)^b
	Shi et al., 2015, cross-sectional study, China, 7190⁸³	UIC <100 g/L	UIC 150–249 g/L	Cohort-specific reference intervals	3.0% vs. 2.4%	aOR 1.14 (0.75, 1.74)
		UIC 100–149 g/L			2.2% vs. 2.4%	aOR 0.94 (0.62, 1.42)
		UIC 250–500 g/L			4.2% vs. 2.4%	aOR 1.72 (1.13, 2.61)^b
		UIC ≥500 g/L			5.7% vs. 2.4%	aOR 2.17 (1.13, 4.19)^b
	Rebagliato et al., 2010, prospective cohort study, Spain, 1844⁸⁰	UIC 50–99 μg/L	UIC <50 μg/L	Raised TSH: cohort-specific reference interval	6.4% vs. 4.4%	aOR 1.39 (0.55, 3.53)
		UIC 100–149 μg/L			5.9% vs. 4.4%	aOR 1.20 (0.46, 3.11)
		UIC 150–249 μg/L			7.6% vs. 4.4%	aOR 1.55 (0.62, 3.89)
		UIC ≥250 μg/L			3.8% vs. 4.4%	aOR 0.69 (0.25, 1.91)
		Iodized salt consumption	No iodized salt consumption		5.7% vs. 6.3%	aOR 0.85 (0.56, 1.29)
		Iodine intake from diet ≥160 μg/day	Iodine intake from diet <160 μg/day		5.8% vs. 6.4%	aOR 1.04 (0.70, 1.55)
		Iodine intake from supplements 100–199 μg/day	Iodine intake from supplements 0–99 μg/day		6.7% vs. 4.9%	aOR 1.47 (0.78, 2.79)
		Iodine intake from supplements ≥200 μg/day	Iodine intake from supplements 0–99 μg/day		7.5% vs. 4.9%	aOR 2.51 (1.16, 5.43)^b
		Iodine intake from supplements ≥200 μg/day	Iodine intake from supplements 0–99 μg/day	Raised TSH: 4 μU/mL fixed limit	N/A	aOR 2.6 (0.85, 7.88)
	Refaat et al., 2021, cross-sectional study, Saudi Arabia, 810⁸¹	24-h UIC (μg/L)	N/A	TSH: 4.0 or 4.2 μIU/mL fixed limit; FT4: reference interval from another population	N/A	aOR 0.99 (0.98, 1.0)^b
		Non-iodized salt intake	Iodized salt intake		44.6% vs. 8.9%	aOR 9.80 (4.07, 23.6)^b
		No iodine supplement	Iodine supplement		35.5% vs. 6.6%	aOR 6.59 (2.29, 19.0)^b
	Moleti et al., 2008, prospective cohort study, Italy, 100 TPOAb negative pregnant women⁶⁸	Iodized salt use <24 months	Iodized salt use ≥24 months	Trimester-specific reference intervals	36.8% vs. 6.4%	RR 5.7 (2.03, 16.1)^b
	Moleti et al., 2011, prospective cohort study, Italy, 433 TPOAb negative pregnant women⁶⁷	Prenatal preparations containing 150 μg of iodine from early pregnancy	Neither taking iodine supplements nor using iodized salt	Raised TSH: trimester-specific reference interval	26.1% vs. 29.4%	OR 0.85 (0.53, 1.38)
		Regularly used (>2 years) iodized salt prior to becoming pregnant	Neither taking iodine supplements nor using iodized salt	Raised TSH: trimester-specific reference interval	15.2% vs. 29.4%	OR 0.43 (0.23, 0.81)^b
	Pan et al., 2019, cross-sectional study, China, 1099⁷⁴	SIC >138.5 μg/L (>90th percentile)	SIC ≤138.5 μg/L (≤90th percentile)	Reference intervals from national guidelines	N/A	OR 0.65 (0.08, 4.96)
	Pan et al., 2019, cross-sectional study, China, 1099⁷⁴	SIC >138.5 μg/L (>90th percentile)	SIC ≤138.5 μg/L (≤90th percentile)	Reference intervals from national guidelines	N/A	aOR 0.70 (0.09, 5.56)
	Ji et al., 2023, cross-sectional study, China, 912⁵⁴	SIC <10%	SIC 10-90%	Trimester-specific reference intervals	N/A	OR 1.38 (0.31, 6.21)
		SIC <10%				aOR 1.36 (0.30, 6.18)
		SIC >90%				OR 0.63 (0.08, 4.87)
		SIC >90%				aOR 0.58 (0.07, 4.47)
hCG	Korevaar et al., 2017, prospective cohort study, Netherlands, 5435⁵⁷	hCG (IU/L)	N/A	Trimester-specific reference intervals	From ∼6.8% to 2.8% for hCG concentrations from 25,000 to 150,000 IU/L	No association
sFlt1	Korevaar et al., 2015, prospective cohort study, Netherlands, 5517⁵⁹	sFlt1 (ng/mL)	N/A	Trimester-specific reference intervals	From ∼3.8% to 9.0% for sFlt1 concentrations from 5 to 30 ng/ml	No association
		>95th percentile	≤95th percentile		N/A	aOR 1.85 (1.04, 3.29)^b
		>97.5th percentile	≤97.5th percentile		N/A	aOR 2.37 (1.16, 4.83)^b
PlGF	Korevaar et al., 2015, prospective cohort study, Netherlands, 5517⁵⁹	PlGF (pg/mL)	N/A	Trimester-specific reference intervals	From ∼7.6% to 1.6% for PlGF concentrations from 10 to 400 pg/ml	No association
		>95th percentile	≤95th percentile		N/A	aOR 0.75 (0.32, 1.79)
		>97.5th percentile	≤97.5th percentile		N/A	aOR 1.01 (0.36, 2.85)
Iron	Yu et al., 2015, cross-sectional study, China, 3340⁹⁷	Negative values of TBI, sTfR >4.4 mg/L, or SF <12 μg/L	Iron adequacy	Trimester-specific reference intervals	2.3% vs. 3.1%	OR 0.74 (0.18, 3.06)
	Li et al., 2023, retrospective cohort study, China, 781⁶⁴	SF Quartile 2	SF Quartile 1	TSH: 4 mIU/l fixed limit	N/A	OR 1.21 (0.61, 2.44)
		SF Quartile 2				aOR 1.18 (0.59, 2.39)
		SF Quartile 3				OR 0.61 (0.27, 1.38)
		SF Quartile 3				aOR 0.63 (0.28, 1.44)
		SF Quartile 4				OR 0.36 (0.14, 0.93)^b
		SF Quartile 4				aOR 0.37 (0.14, 0.96)^b
Air pollutants and EDC	Ghassabian et al., 2019, prospective cohort study, multiple, 9931⁴⁶	NO₂ (10 μg/m³)	N/A	High TSH: cohort-specific reference interval	N/A	OR 1.02 (0.94, 1.12)
		NO₂ (10 μg/m³)				aOR 1.02 (0.94, 1.12)
		NO _x (20 μg/m³)				OR 1.00 (0.94, 1.06)
		NO _x (20 μg/m³)				aOR 0.99 (0.93, 1.06)
		PM_2.5 (5 μg/m³)				OR 1.16 (0.94, 1.45)
		PM_2.5 (5 μg/m³)				aOR 1.14 (0.88, 1.48)
		PM₁₀ (10 μg/m³)				OR 1.16 (0.87, 1.55)
		PM₁₀ (10 μg/m³)				aOR 1.17 (0.87, 1.58)
		PM_2.5-10 (5 μg/m³)				OR 1.12 (0.84, 1.50)
		PM_2.5-10 (5 μg/m³)				aOR 1.18 (0.88, 1.57)
		PM_2.5 absorbance (10⁻⁵ × m⁻¹)				OR 1.10 (0.96, 1.26)
		PM_2.5 absorbance (10⁻⁵ × m⁻¹)				aOR 1.10 (0.95, 1.26)
	Yang et al., 2023, case-control study, China, 126⁹⁵	MEHP (μg/L)	N/A	Reference intervals from national guidelines	N/A	OR 1.54 (0.87, 2.73)
		MEHP (μg/L)				aOR 1.69 (0.87, 3.28)
		MEHHP (μg/L)				OR 1.43 (0.90, 2.26)
		MEHHP (μg/L)				aOR 1.61 (0.92, 2.82)
		MEOHP (μg/L)				OR 1.59 (0.98, 2.60)
		MEOHP (μg/L)				aOR 1.81 (1.02, 3.22)^b
		MECPP (μg/L)				OR 1.67 (0.97, 2.88)
		MECPP (μg/L)				aOR 1.89 (1.01, 3.60)^b
		MBP (μg/L)				OR 1.32 (0.82, 2.13)
		MBP (μg/L)				aOR 1.25 (0.71, 2.19)
		MiBP (μg/L)				OR 1.51 (0.88, 2.59)
		MiBP (μg/L)				aOR 1.49 (0.80, 2.78)
		MEP (μg/L)				OR 1.43 (1.08, 1.90)^b
		MEP (μg/L)				aOR 1.42 (1.03, 1.95)^b
		MMP (μg/L)				OR 0.93 (0.78, 1.12)
		MMP (μg/L)				aOR 0.91 (0.74, 1.13)
		ΣDEHP (μmol/L)				OR 1.69 (0.95, 2.99)
		ΣDEHP (μmol/L)				aOR 1.92 (1.01, 3.78)^b
		ΣDBP (μmol/L)				OR 1.41 (0.84, 2.34)
		ΣDBP (μmol/L)				aOR 1.34 (0.73, 2.45)
		ΣLMWP (μmol/L)				OR 1.59 (0.93, 2.73)
		ΣLMWP (μmol/L)				aOR 1.55 (0.82, 2.94)
		ΣPAE (μmol/L)				OR 1.71 (0.95, 3.07)
		ΣPAE (μmol/L)				aOR 1.76 (0.88, 3.53)

Gray background, manual calculation based on provided data.

Exposure group vs. comparator group.

Significant relative risk with p-value <0.05.

Prevalence = N _{subclinical hypothyroidism}/(N _{subclinical hypothyroidism} + N _euthyroidism).

DBP, di-n-butyl phthalate; DEHP, di-(2-ethylhexyl) phthalate; LMWP, low molecular weight phthalate; MBP, monobutyl phthalate; MECPP, mono-(2-ethyl-5-carboxypentyl) phthalate; MEHP, mono-(2-ethylhexyl) phthalate; MEHHP, mono-(2-ethyl-5-hydroxyhexyl) phthalate; MEOHP, mono-(2-ethyl-5-oxohexyl) phthalate; MEP, monoethyl phthalate; MiBP, mono-isobutyl phthalate; MMP, monomethyl phthalate; NO₂, nitrogen dioxide; NO _x , nitrogen oxides; PAE, phthalate acid ester; PM, particulate matter.

In the quality assessment, 52/54 cohort studies, 3/3 case-control studies, and 16/23 cross-sectional studies were considered high quality (Supplementary Tables S10, S11 and S12). We also included one IPD meta-analysis. Since there is no specific quality assessment tool for IPD meta-analysis, we considered the included IPD meta-analysis high quality because it was conducted with a predefined protocol and registration, a comprehensive search strategy and study selection, a clear data acquisition, a homogeneous and standardized data analysis, a satisfactory technique for assessing risk of bias in individual studies, and a large sample size.

Overt hypothyroidism

Regarding the currently recommended risk factors, there was no association of maternal age,² parity,² or hypothyroid symptom scores¹³ with overt hypothyroidism. TPOAb and/or thyroglobulin antibody (TgAb) positivity was associated with a higher risk of overt hypothyroidism as compared with thyroid antibody negativity.^2,85 The absolute risks for overt hypothyroidism were 2.4–7.0% and 0.1–0.2% for thyroid antibody positivity and negativity, respectively. Higher BMI was overall associated with a higher risk of overt hypothyroidism, while the absolute risk difference for overt hypothyroidism was relatively small according to an IPD meta-analysis (approximately 0.3% for BMI from 20 to 40 kg/m²).^2,51,81 There was only limited evidence to indicate an association of iodine status with the risk of overt hypothyroidism (1/4 studies; adjusted OR for 24-hour urinary iodine concentration [UIC], 0.98; 95% confidence interval [CI], 0.97, 1.00).^54,81,83,92

As for potential novel risk factors, there was no association of smoking,^2,81 in vitro fertilization (IVF),² twin pregnancy,^2,36 iron deficiency,⁹⁷ or human chorionic gonadotropin (hCG) level⁵⁷ with overt hypothyroidism. One cross-sectional study applying a smaller sample size and a TSH fixed upper limit of 4.0 mU/L indicated a positive association of gestational age at blood sampling and a negative association of maternal education levels with the risk of overt hypothyroidism.⁸¹ However, an IPD meta-analysis using trimester-specific reference intervals for thyroid function indicated a negative association of gestational age at blood sampling and no association of maternal education levels with the risk of overt hypothyroidism.²

Subclinical hypothyroidism

Regarding the currently recommended risk factors, there was no association of history of infertility with subclinical hypothyroidism.¹⁸ Pregnant women with TPOAb and/or TgAb positivity (7/10 studies),^{2,29,39,44,45,73,84,85,87,91} iodine deficiency (2/5 studies),^{72,80,83,91,92} or iodine intake above pregnancy requirements or excess (4/6 studies)^{39,80,82,83,91,92} tended to have a higher risk of subclinical hypothyroidism. The absolute risks for subclinical hypothyroidism were 1.9–29.0% and 2.0–5.7% (60.7–65.6% and 34.8–36.1% in one outlying case-control study) in cases of thyroid antibody positivity and negativity, respectively. As for iodine deficiency, sufficiency, and intake above pregnancy requirements or excess, the absolute risks for subclinical hypothyroidism were 2.2–42.6%, 1.42–16.0%, and 3.8–24.3% (52.6–53.8%, 41.1%, and 73.7% in one outlying case-control study), respectively. We identified a positive association of personal history of type 1 diabetes and other autoimmune disorders with the risk of subclinical hypothyroidism (RR, 4.8; CI, 1.3, 18.2).⁸⁷ There was a negative association of hypothyroid symptom scores with the risk of subclinical hypothyroidism (RR, 0.36; CI, 0.13, 0.98),¹³ while excessive weight gain was associated with a higher risk of subclinical hypothyroidism (OR, 7.86; CI, 2.99, 20.7).¹⁸ There was only limited evidence to indicate an association of maternal age (2/7 studies),^{2,39,42,44,76,78,87} BMI (1/3 studies),^2,51,81 parity (1/3 studies),^2,44,87 family history of thyroid disease (1/2 studies),^18,87 and history of pregnancy loss (1/3 studies)^18,58,87 with the risk of subclinical hypothyroidism, with the absolute risk differences <5.0% for subclinical hypothyroidism (except 5.7% and 5.3% in case of family history of thyroid disease and history of pregnancy loss, respectively) from a baseline absolute risk of 3–7%.

As for potential novel risk factors, there was no association of alcohol consumption,⁹⁵ physical activity,⁹⁵ IVF,² geographic area,⁴⁴ history of abnormal uterine bleeding,¹⁸ hCG,⁵⁷ soluble FMS-like tyrosine kinase 1 (sFlt1),⁵⁹ placental growth factor (PlGF),⁵⁹ or air pollutants⁴⁶ with subclinical hypothyroidism. Pregnant women with pre-eclampsia tended to have an elevated predelivery TSH (absolute risk difference: 10%), and history of pre-eclampsia was associated with an elevated TSH measured years after pregnancy (absolute risk difference: 4.8%).⁶¹ In two studies, smoking was associated with a lower risk of subclinical hypothyroidism,^2,87 while there were different associations in the other two studies with relatively small sample sizes.^39,81 There was only limited evidence to support a positive association of maternal education levels (1/3 studies)^2,81,95 or exposure to phthalates⁹⁵ with the risk of subclinical hypothyroidism, as well as a negative association of blood iron levels (1/2 studies)^64,97 with the risk of subclinical hypothyroidism. There was no convincing overall association of twin pregnancy^2,36 or gestational age at blood sampling^{2,44,63,72,78,80,81,86} with subclinical hypothyroidism. The absolute risks for subclinical hypothyroidism varied from 4.1% to 14.2% across different ethnicities, but no clear, generalizable pattern could be extracted.^58,84,87

Isolated hypothyroxinemia

Regarding the currently recommended risk factors, there was no association of family history of thyroid disease or history of pregnancy loss with isolated hypothyroxinemia.^28,58 Pregnant women with higher maternal age (4/7 studies),^{2,42,44,48,65,69,86} higher BMI (4/6 studies),^{2,48,51,65,69,81} or higher parity (3/4 studies)^2,44,48,65 tended to have a higher risk of isolated hypothyroxinemia. In an IPD meta-analysis, the absolute risk differences for isolated hypothyroxinemia were approximately 1.6%, 3.1%, and <1.0% for maternal age from 20 to 40 years, BMI from 20 to 40 kg/m², and parity, respectively. There was only limited evidence to indicate a positive association of TPOAb and/or TgAb positivity (1/4 studies, absolute risk difference 0.9–6.9%),^2,26,28,44 iodine intake above pregnancy requirements or excess (1/3 studies, absolute risk difference 1.0–2.7%),^50,83,92 and iodine deficiency (2/5 studies, absolute risk difference 0.2–12.4%)^{43,50,63,83,92} with the risk of isolated hypothyroxinemia.

As for potential novel risk factors, there was no association of IVF,² vitamin D,⁶⁵ perfluorinated acids,³⁵ or weekly seafood consumption⁴⁸ with isolated hypothyroxinemia. We identified that twin pregnancy^2,36 and iron deficiency or anemia^65,69,97 were associated with a higher risk of isolated hypothyroxinemia. The absolute risks for isolated hypothyroxinemia were 3.3–4.7% and 2.0–2.2% for twin and singleton pregnancy, respectively; 2.1–24% for iron deficiency or anemia, and 1.5–14% for adequate iron status. We also identified a negative association of maternal education levels with isolated hypothyroxinemia, and the absolute risks for isolated hypothyroxinemia were 1.4–8.1%, 1.4–6.4%, and 1.1–1.7% in cases of low, medium, and high education, respectively.^2,81 Two studies indicated that greater gestational age at blood sampling was associated with a higher risk with isolated hypothyroxinemia,^2,44 but there was no association in another two studies with relatively small sample sizes.^50,81 There was only limited evidence to support a positive association of smoking (1/2 studies),^2,81 gravidity,⁶⁵ sFlt1,⁵⁹ PlGF,⁵⁹ and PM_2.5 ⁴⁶ with the risk of isolated hypothyroxinemia, as well as a negative association of thyroid volume,⁴⁸ hCG⁵⁷ with the risk of isolated hypothyroxinemia. There was a difference in the risks of isolated hypothyroxinemia across different ethnicities and different geographic areas, but no clear, generalizable pattern could be extracted.^44,50,58

Subclinical hyperthyroidism

Regarding the currently recommended risk factors, there was no association of maternal age,^2,42,76,87 family history of thyroid disease,^27,28,87 history of pregnancy loss,⁸⁷ or iodine status^28,81 with subclinical hyperthyroidism. We identified a positive association of parity with subclinical hyperthyroidism, whereas the absolute risk difference between multiparity and nulliparity for subclinical hyperthyroidism was <2.0%.^2,87 A cross-sectional study with a smaller sample size indicated that higher BMI was associated with a higher risk of subclinical hyperthyroidism.⁸¹ However, an IPD meta-analysis indicated a negative association of BMI with subclinical hyperthyroidism (absolute risks for subclinical hyperthyroidism from approximately 1.3% to 0.8% for BMI from 20 to 40 kg/m²).² There was no convincing overall association of TPOAb and/or TgAb positivity with the risk of subclinical hyperthyroidism.^2,29,84,87

As for potential novel risk factors, there was no association of IVF,² maternal education levels,^2,81 or iron deficiency⁹⁷ with subclinical hyperthyroidism. We identified that twin pregnancy was associated with a higher risk of subclinical hyperthyroidism.^2,36 The absolute risks for subclinical hyperthyroidism were 3.0–7.2% and 1.2–2.2% in cases of twin pregnancy and singleton pregnancy, respectively. There was no convincing overall association of gestational age at blood sampling with the risk of subclinical hyperthyroidism.^{2,27,44,78,81} There was only limited evidence to support a positive association of hCG with the risk of subclinical hyperthyroidism.⁵⁷ The absolute risks for subclinical hyperthyroidism varied from 1.7% to 11.9% across different ethnicities, but no clear, generalizable pattern could be extracted.^84,87

Overt hyperthyroidism

Regarding the currently recommended risk factors, there was no association of maternal age² or family history of thyroid disease²⁷ with overt hyperthyroidism. We identified that serum iodine concentration (but not UIC) was positively associated with the risk of overt hyperthyroidism.^63,74 There was only limited evidence to indicate an association of BMI,² parity,² and TPOAb and/or TgAb positivity² with the risk of overt hyperthyroidism, whereas the absolute risk differences for overt hyperthyroidism were <1.0% for these risk factors.

As for potential novel risk factors, there was no association of IVF,² sFlt1,⁵⁹ or PlGF⁵⁹ with overt hyperthyroidism. We identified that a twin pregnancy was associated with a higher risk of overt hyperthyroidism.^2,36 The absolute risks for overt hyperthyroidism were 5.7–8.5% and 0.5–1.3% in cases of twin pregnancy and singleton pregnancy, respectively. There was only limited evidence to support a positive association of maternal education levels² and hCG⁵⁷ with the risk of overt hyperthyroidism, as well as a negative association of smoking,² gestational age at blood sampling (1/2 studies),^2,44 and maternal education levels² with the risk of overt hyperthyroidism.

Thyroid function tests

Higher BMI (3/4 studies)^2,30,69,84 and TPOAb and/or TgAb positivity (5/5 studies)^{2,53,56,75,84} were associated with a higher TSH, while higher parity (2/2 studies)^2,84 was associated with a lower TSH. Higher maternal age (3/5 studies),^{2,42,69,84,97} higher BMI (5/6 studies),^{2,30,48,53,69,84} and TPOAb and/or TgAb positivity (3/5 studies)^{2,53,56,75,84} were associated with a lower FT4. There was no convincing overall association of maternal age^2,42,69,84 or UIC^{56,60,69,80,84} with TSH concentrations. Similarly, there was no convincing overall association of UIC^{33,56,60,69,75,84,86} or parity^2,84 with FT4 concentrations.

As for potential novel determinants, greater gestational age at blood sampling (2/2 studies)^2,84 was associated with a higher TSH, while smoking (3/4 studies),^2,30,41,69 a twin pregnancy (3/3 studies),^2,32,36 higher levels of blood iron measurements (serum ferritin [SF], total body iron stores [TBI], soluble transferrin receptor [sTfR], hemoglobin; 4/5 studies)^{52,53,69,88,97} were associated with a lower TSH. A twin pregnancy (2/3 studies)^2,32,36 and higher levels of blood iron measurements (SF, TBI, hemoglobin; 4/5 studies)^{52,53,69,86,97} were associated with a higher FT4, while smoking (3/4 studies)^2,30,41,69 and a greater gestational age at blood sampling (3/4 studies)^2,53,84,97 were associated with a lower FT4. There was only limited evidence to support that maternal education levels² and pregnancy associated plasma protein-A⁶⁶ were positively associated with TSH concentrations, or that vitamin D,⁹⁰ thyroglobulin (Tg),⁷⁰ and thyroid volume⁴⁸ were negatively associated with TSH concentrations; IVF,² vitamin D,⁹⁰ Tg,⁷⁰ and thyroid volume⁴⁸ were positively associated with FT4 concentrations. There was no convincing overall association of sFlt1 or PlGF with TSH and FT4 concentrations.^59,61,66

Thyroid antibody positivity

Pregnant women with a family history of thyroid disease (2/2 studies),^26,73 iodine deficiency (3/5 studies),^{50,60,83,92,98} or iron deficiency (2/2 studies)^49,88 had a higher risk of TPOAb and/or TgAb positivity. The absolute risks for TPOAb and/or TgAb positivity were 18.5–22.8% and 8.1–16.5% for women with and without family history of thyroid diseases, respectively; 0.9–14.8% and 5.3–10.1% (19.3% and 20.6% in one outlying cross-sectional study) for iodine deficiency and sufficiency, respectively; and 3.1–6.0% and 10.0–22.1% for iron deficiency and sufficiency, respectively. We identified a negative association of gestational age at blood sampling with TPOAb positivity (4/5 studies).^{47,50,58,69,78} There was only limited evidence to support a positive association of BMI (1/4 studies),^48,51,58,88 gravidity,⁹⁹ iodine intake above pregnancy requirements or excess (1/5 studies),^{50,60,83,92,98} and thyroid volume⁴⁸ with the risk of TPOAb and/or TgAb positivity, as well as a negative association of parity (1/4 studies)^45,48,58,73 with the risk of TPOAb and/or TgAb positivity. We did not identify an association of alcohol consumption,⁹⁹ geographic area,⁵⁰ or symptoms of thyroid disease²⁶ with the risk of TPOAb positivity. There was no convincing overall association of smoking^58,99 or maternal age^48,58,78,88 with TPOAb positivity. The absolute risks for thyroid antibody positivity varied from 3% to 29.9% and from 10.3% to 12.3% across different ethnicities^{31,58,84,89,99} and different seasons of enrollment,⁹⁹ respectively, but no clear, generalizable pattern could be extracted.

Discussion

In this study, we systematically searched the literature and reviewed 81 studies to assess the association of 36 candidate variables with thyroid function test abnormalities, thyroid antibody positivity, and the results of continuous thyroid function tests in pregnancy. Out of all risk factors currently recommended in the 2017 ATA guidelines,¹² we found that thyroid antibody positivity remains the most relevant risk factor for both overt and subclinical hypothyroidism. Additionally, we found iodine deficiency, personal history of type 1 diabetes or other autoimmune disorders, and family history of thyroid disease were associated with a higher risk of subclinical hypothyroidism during pregnancy, albeit limited to a few studies. There was a negligible or no convincing overall association of currently recommended risk factors with isolated hypothyroxinemia, subclinical hyperthyroidism, or overt hyperthyroidism. The differentiation capacity of other risk factors currently recommended for thyroid function testing in pregnancy was either absent or relatively small.

For the majority of characteristics that are currently considered risk factors for thyroid function test abnormalities during pregnancy, we identified not only large differences in data availability between risk factors, but also large differences in how that data altogether would support that these risk factors are associated with a significant risk of thyroid function test abnormalities during pregnancy. For example, there was ample data on maternal age, BMI, and parity from heterogeneous, small single-center studies. However, with a homogeneous method and a large sample size, results from a recent IPD meta-analysis suggest that while these characteristics may reach a statistically significant association, there is a relatively small difference in the absolute risks for either (subclinical) hypothyroidism or (subclinical) hyperthyroidism (<2.0%).² Consequently, their relevance in guiding thyroid function testing in pregnancy appears limited. For other currently recommended risk factors, evidence remains scant and/or inconsistent. For example, we identified only one study assessing personal history of autoimmune disease, which indicated a higher risk of subclinical hypothyroidism.⁸⁷ Similarly, there was only one study on the history of infertility indicating no association with subclinical hypothyroidism.¹⁸ Moreover, results on subclinical hypothyroidism in relation to symptoms of thyroid disease, family history of thyroid disease, and history of pregnancy loss were inconsistent.^13,18,58,87 The inconsistent findings could be due to discrepancies in study populations and different methods of defining reference intervals for maternal thyroid function. Given the limited and/or inconsistent evidence, it is difficult to determine whether these risk factors would be efficient to indicate thyroid function testing. Utilizing risk factors without robust evidence may increase the likelihood of unnecessary thyroid function testing, overdiagnosis, and overtreatment. Therefore, more studies are needed to evaluate current and/or promising risk factors before they can be integrated into clinical guidelines for thyroid function testing in pregnancy.

TPOAb positivity is the most important risk factor for (subclinical) hypothyroidism during pregnancy and is currently used to guide the decision-making for thyroid function follow-up.^1,12 We purposefully added the data on this well-known risk factor as a benchmark of clinical significance, and the absolute risk difference for overt hypothyroidism (∼4.0%) was considerably higher than many of other characteristics except gestational age at blood sampling and maternal education levels studied in a cross-sectional study with a relatively small sample size.^2,81 On the other hand, TgAbs also reflect thyroid autoimmunity, and studies indicate higher TSH concentrations and a higher risk of (subclinical) hypothyroidism in women with isolated TgAb positivity.^2,103,104 While TPOAbs remain the preferred marker to identify thyroid autoimmunity and those at high risk of hypothyroidism, a TgAb measurement may be worth consideration in TPOAb negative women susceptible to autoimmune thyroiditis (e.g., women with a family history of thyroid disease and/or iodine deficiency) who also have a high-normal TSH concentration.

Iodine plays a critical role in thyroid physiology, and iodine deficiency is a known risk factor for gestational hypothyroidism.¹⁰⁵ Consistent with this, we observed in several studies that there was a higher risk of overt or subclinical hypothyroidism in women with iodine deficiency or who lacked iodine supplementation during pregnancy.^68,72,81,92 Interestingly, iodine intake above pregnancy requirements or excess was also associated with a higher risk of subclinical hypothyroidism,^39,82,83,91 possibly due to the Wolff–Chaikoff effect or due to increased thyroid autoimmunity.¹⁰⁶ While living in a severely iodine-deficient area is already recommended as an indication for thyroid function testing, living in an area with high iodine exposure or having been recently exposed to iodinated contrast or other sources of excessive iodine may also pose a reasonable indication for thyroid function testing. However, the evidence on iodine intake above pregnancy requirements or excess remains limited and more studies on pregnant women are required to better quantify the risks.

Other potential risk factors, such as iron deficiency, twin pregnancy, ethnicity, and history of pre-eclampsia, are not included in the current ATA guidelines.¹² First, we identified a higher risk of isolated hypothyroxinemia in women with iron deficiency.^65,69,97 Additionally, in a recent systematic review there was a higher risk of TPOAb positivity in iron deficient women.¹⁰⁷ Neither of these biochemical abnormalities are an indication for levothyroxine treatment, suggesting that iron deficiency is not a relevant thyroid function testing indication during pregnancy.¹² Second, we identified that a twin pregnancy was associated with a higher risk of overt or subclinical hyperthyroidism and isolated hypothyroxinemia.^2,36 This could be explained by a higher concentration of hCG, which stimulates the production of thyroid hormones, and more overt physiological changes that may lower thyroid hormone availability in twin pregnancies (e.g., a greater increase in thyroxine binding globulin, placental type 3 deiodinase expression, and the consumption of thyroid hormone by the fetuses) as compared with singleton pregnancies.^108

–111 The association of twin pregnancy with overt or subclinical hyperthyroidism was more apparent during early pregnancy than late pregnancy, which is compatible with the hCG peak at the end of the first trimester, suggesting a biochemical but likely physiological hyperthyroidism related to the increase of hCG.^2,36,108,109 Accordingly, a transient gestational hCG-induced thyrotoxicosis does not warrant the use of antithyroid drugs, implicating limited value of twin pregnancy added to thyroid function testing indication.¹² Third, some studies reported relevant differences in the absolute risks (>10%) for subclinical hypothyroidism, subclinical hyperthyroidism, and thyroid antibody positivity according to national or ethnic background.^31,84 However, given the locality-specific diversity in national/ethnic backgrounds and the complexity in ethnic identities, it is difficult to draw distinct patterns which would support routine thyroid function testing.¹¹² Fourth, women with history of pre-eclampsia were found to have a higher risk of elevated TSH concentrations after pregnancy, and the onset of pre-eclampsia seemed to be associated with a higher predelivery TSH as well, which may be caused by antiangiogenic effects on the thyroid gland by placental factors.^59,61 These data suggest that further research is warranted to clarify the association between history of pre-eclampsia with the risk of thyroid function test abnormalities in subsequent pregnancies.

In addition, we could not identify any study in pregnant women on several risk factors known to increase the risk of thyroid dysfunction in non-pregnant populations such as prior thyroid surgery, history of head or neck radiation, and the use of specific medications (e.g., amiodarone, lithium, recent administration of iodinated radiological contrast).¹² Despite the lack of pregnancy-specific data, these risk factors should still be considered as indications for thyroid function testing given their intuitive and well-established risk patterns outside of pregnancy. Nonetheless, quantification of the associated risks could prove meaningful for future risk models and patient counseling.

In this systematic review, we provide an extensive overview of studies on potential risk factors for thyroid function test abnormalities during pregnancy. We initially assessed the potential of a candidate variable to be considered as a risk factor based on statistical significance and relative effect measures. However, our study remains subjective to some extent as the true relevance of any potential risk factor depends on the clinically significant increase in absolute risk and discriminative ability, which should be decided upon by following, for example, the Delphi method.¹¹³ In addition, the heterogeneity in study populations, definitions of thyroid function test abnormalities, and iodine status across regions made it difficult to compare studies or draw consistent conclusions about most risk factors. Discrepancies in definitions of exposures/outcomes also precluded us from performing a meta-analysis. Furthermore, included studies which used alternative approaches to define reference intervals (e.g., a TSH fixed upper limit of 4.0 mU/L and nonpregnancy reference intervals), as compared with population-based trimester-specific reference intervals, were more likely to over- and under-diagnose thyroid function test abnormalities in pregnancy, limiting interpretability of the results.¹¹⁴

Our study primarily focused on individual risk factors, whereas the co-occurrence and interaction of multiple risk factors may provide a more comprehensive understanding of the development and assessment of thyroid function test abnormalities. In an IPD meta-analysis, maternal age, BMI, smoking status, parity, and gestational age at blood sampling were used to construct receiver operator characteristic curves for overt and subclinical hypothyroidism.² With area under the curve values ranging from 0.58 to 0.63, the combined model offered only modest discriminative performance, suggesting that combining individual risk factors did not lead to satisfactory discriminative abilities and further studies to optimize risk factor models are needed.

This systematic review presents a comprehensive overview of risk factors for thyroid function test abnormalities during pregnancy. On the one hand, thyroid autoimmunity, particularly TPOAb positivity, and iodine deficiency were relevant risk factors for (subclinical) hypothyroidism. On the other hand, several currently recommended risk factors, including age, BMI, and parity, were associated with only small differences in the absolute risk for thyroid function test abnormalities, and should be reconsidered for guiding indications for thyroid function testing in pregnant women. Future studies are needed to focus research on key risk factors using consistent definitions. Given the need for improvement in current thyroid function test indications, clinical risk assessment remains essential in medical practice. Additionally, exploring novel risk factors is needed to improve the identification of pregnant women at high risk of thyroid function test abnormalities.

Footnotes

Acknowledgment

The authors would like to thank Ms. Reese S. Braam from Erasmus University Medical Center for her help in double-checking the quality of included studies and data extraction.

Authors’ Contributions

T.I.M.K. contributed to the conceptualization and design of the systematic review. T.I.M.K. designed the search strategy and supervised the study. T.I.M.K., A.M.L., S.B., C.D., E.K.A., S.M., and Y.L. screened and selected the articles. Y.L., J.A.J.O., and T.I.M.K. contributed to the data acquisition, analysis, and interpretation. Y.L. wrote the original draft, and all authors reviewed, revised, and approved the final version of the article. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Author Disclosure Statement

The authors have nothing to disclose.

Funding Information

This study is funded by a Vidi grant (016.176.331) from the Netherlands Organization for Scientific Research (RPP), by a clinical fellowship from ZonMw, project number 90700412 (RPP) and by the ATHENA project, funded under the European Union’s Horizon 2020 Program for research, technological development and demonstration, grant agreement no. 825161. Y.L. received a scholarship from the China Scholarship Council. The funders had no role in study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit the article for publication.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

Supplementary Table S5

Supplementary Table S6

Supplementary Table S7

Supplementary Table S8

Supplementary Table S9

Supplementary Table S10

Supplementary Table S11

Supplementary Table S12

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