Progression of Gestational Subclinical Hypothyroidism and Hypothyroxinemia to Overt Hypothyroidism After Pregnancy: Pooled Analysis of Data from Two Randomized Controlled Trials

Abstract

Background:

To examine the incidence of overt hypothyroidism 1 and 5 years after pregnancies where screening before 21 weeks identified subclinical hypothyroidism (SH) or hypothyroxinemia (HT).

Methods:

Secondary analysis of two multicenter treatment trials for either SH or HT diagnosed between 8 and 20 weeks gestation. Current analyses focus only on individuals randomized to the placebo groups in the two parallel studies. SH was diagnosed with thyrotropin (TSH) ≥4.0 mU/L and normal free T4 (fT4) (0.86–1.9 ng/dL). HT was diagnosed with normal TSH (0.08–3.99 mU/L) but fT4 <0.86 ng/dL. Serum from initial testing was stored for later thyroid peroxidase (TPO) antibody assay; results were not returned for clinical management. At 1 and 5 years after delivery, participants were asked whether they had either been diagnosed with or were being treated for a thyroid condition. Maternal serum was collected at these visits and thyroid function measured. Subsequent overt hypothyroidism was defined as TSH ≥4.0 mU/L with fT4 <0.86 ng/dL.

Results:

Data for 1- and 5-year follow-up were available in 307 of the 338 participants with SH and 229 of the 261 with HT. Subsequent hypothyroidism was more common both at year 1 (13.4% vs. 3.1%, p < 0.001) and year 5 (15.6% vs. 2.6%, p < 0.001) for participants with SH compared with those with HT. This progression was more common in individuals with TSH values >10 mIU/mL. Baseline TPO level >50 IU/mL in participants with SH was associated with higher rates of hypothyroidism at year 1 (26.7% vs. 6.5%, odds ratio [OR] = 5.3 [confidence interval (CI) 2.6–10.7]) and year 5 (30.5% vs. 7.5%, OR = 5.4 [CI: 2.8–10.6]) compared with those with TPO levels ≤50 IU/mL. For participants with HT, no differences in overt hypothyroidism were seen at 1 year related to baseline TPO level >50 IU/mL (1/10 (10%) vs. 6/218 (2.8%), OR = 3.9 [CI: 0.43–36.1]), but more participants with TPO levels >50 IU/mL developed hypothyroidism by year 5 (2/10 (20%) vs. 4/218 (1.8%), OR = 13.4 [CI: 2.1–84.1]).

Conclusion:

SH is associated with higher rates of overt hypothyroidism or thyroid replacement therapy within 5 years of delivery than is HT when these conditions are diagnosed in the first half of pregnancy.

Introduction

During pregnancy, normal maternal thyroid function is required for optimal maternal and perinatal outcomes. Both hypothyroidism and hyperthyroidism are associated with adverse pregnancy outcomes.¹ In addition, untreated maternal hypothyroidism is associated with an increased risk of infant neurodevelopmental delay.² Diagnosis of overt and subclinical thyroid disorders is based on abnormal thyroid function tests. For example, subclinical hypothyroidism (SH) and hypothyroxinemia (HT) are diagnosed by an elevated thyrotropin (TSH) and normal free thyroxine (fT4) values for the former (SH) and low free T4 and normal TSH values for the latter (HT).

While diagnosing and treating overt thyroid disorders in pregnancy is associated with improved short- and long-term maternal and neonatal outcomes, the benefit of treating subclinical conditions (SH and HT) in pregnancy is controversial. The Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network (NICHD MFMU Network) conducted two parallel placebo-controlled trials of thyroxine replacement during pregnancy in women with SH and HT and found no difference in pregnancy outcomes or offspring neurocognitive testing.³ Thus, the American College of Obstetricians and Gynecologists currently recommends against universal screening and treatment of SH and HT during pregnancy.¹

Thyroid disease is more common in women than in men,⁴ and various aspects of the disease spectrum vary by sex.⁵ Several studies have reported progression rates of SH to overt hypothyroidism in women.^6,7 However, these reported outcomes have enrolled women across extended age spans, many of whom have been peri- or postmenopausal and have not focused on women’s long-term outcomes with subclinical thyroid dysfunction (SH and HT) diagnosed during pregnancy. In this study, we report longitudinal follow-up of participants in the two aforementioned NICHD MFMU Network trials to evaluate the frequency of progression of ST and HT identified during pregnancy to overt hypothyroidism and to assess whether the presence of thyroid peroxidase (TPO) antibodies is associated with more frequent progression to overt hypothyroidism.

Materials and Methods

This is a secondary analysis of two multicenter randomized placebo-controlled trials of thyroxine therapy for subclinical hypothyroid disorders diagnosed in pregnancy.³ The trials were conducted in 15 centers and 33 participating hospitals within the NICHD MFMU Network. The parent protocols were approved by the institutional review boards at each center, and informed written consent was obtained from all participants.

People with singleton pregnancies were screened prior to 21 weeks’ gestation. SH was considered present in people with TSH ≥4.0 mU/L and free T4 in the normal range (0.86–1.9 ng/dL). HT was considered present in people with normal TSH (0.08–3.99 mU/L), but T4 <0.86 ng/dL. Individuals with singleton nonanomalous pregnancies and who were diagnosed with SH or HT were eligible for the primary trials. Exclusion criteria for both trials included a history of thyroid cancer or current thyroid disease (overt hypothyroidism or hyperthyroidism) requiring medication, concurrent serious medical illness, planned delivery at a nonparticipating hospital, inability to commit to a 5-year follow-up protocol, and participation in any interventional study that might influence maternal or perinatal outcomes. Participation in the parent trials in a previous pregnancy was an additional exclusion criterion. Participants had monthly TSH assessments during pregnancy, and levothyroxine dosage was adjusted to attain a normal TSH or fT4 level (depending on the trial), with sham adjustments for placebo.

At enrollment in the parent study, serum was collected and stored for later TPO antibody assay. These results were not available for clinical management.

Although the parent trials showed no effect with treatment on any child neurodevelopmental outcomes, the current analyses were limited only to those persons randomized to the placebo groups in the parent trials.

Participating people were evaluated at 1 and 5 years after delivery, including assessment by interview whether they had been diagnosed with, or were currently being treated for, a thyroid condition. Maternal serum was obtained at both the 1- and 5-year visits and stored for subsequent thyroid hormone and antibody analyses. Samples were stored at –80°C until batch was analyzed at the conclusion of the study.

The primary outcome for this study was the diagnosis of maternal hypothyroidism at either the 1 and 5 year follow-up visits. Hypothyroidism was defined either by a maternal history of concurrent thyroid replacement therapy or by a TSH ≥4.0 mU/L and fT4 <0.86 ng/dL on the stored maternal serum samples.

Sample analysis techniques/location

The serum samples of consenting pregnant people were analyzed at a centralized laboratory (University of Minnesota). TSH limit of detection was 0.001 μIU/mL, and the interassay coefficient of variation (CV) ranged from 4.01% to 4.19%. There was no significant cross-reactivity with human chorionic gonadotropin levels up to 200,000 mU/mL. The lower limit of detection for fT4 assays was 0.1 ng/dL, and the interassay CV ranged from 4.34% to 5.77%. Cross-reactivity with l-triiodothyronine (1 mg/dL), diiodotyrosine (100 mg/dL), and monoiodotyrosine (100 mg/dL) did not exceed 0.02%. TPO antibodies were detected by chemiluminescent antibody assays. TPO antibodies in the parent study were considered elevated if >50 IU/mL.

Statistical analysis

Categorical variables were analyzed using the chi-square test, or Fisher’s exact test and continuous variables were compared using the Wilcoxon test. The primary outcome was the presence of hypothyroidism at either the 1- or 5-year follow-up visit. Logistic regression was used to examine the association of baseline thyroid status (SH or HT), TPO, baseline maternal age, gestational age at randomization, and insurance payor status with this outcome. A nominal two-tailed p value <0.05 was considered significant. Imputation for missing data was not performed. No adjustment was made for multiple comparisons. All analyses were performed using SAS 9.4 statistical software (SAS Institute Inc., Cary, NC).

Results

A total of 599 participants were randomized to placebo in the two parent trials. Data were available for analysis in 307 of 338 participants with SH and 229 of 261 with HT with follow-up at both year 1 and year 5. Baseline characteristics of the two populations are presented in Table 1. Data on family history of thyroid disease were not collected in the parent studies. Distribution by criteria for the diagnosis of hypothyroidism at the time of the research visits are presented in Table 2. Three individuals were diagnosed with hyperthyroidism at the 1-year visit, two in the SH group and one in the HT group. At the 5-year visit, four individuals in each group were diagnosed with hyperthyroidism.

Table 1.

Baseline Characteristics of the Subclinical Hypothyroidism and Hypothyroxinemia Placebo Populations

Characteristic	SH (placebo population)	HT (placebo population)
Maternal race/ethnicity			<0.001
Hispanic	165 (53.8)	−105 (45.9)
Non-Hispanic Caucasian	−107 (34.9)	−63 (27.5)
Non-Hispanic African American	−24 (7.8)	−59 (25.8)
Other	−11 (3.6)	−2 (0.9)
Maternal age (mean ± SD)	27.3 (5.7)	28.3 (5.7)	0.04
Payor status			0.54
Gov. assisted	169 (55.1)	136 (59.4)
Private	94 (30.6)	66 (28.8)
Self-pay	44 (14.3)	27 (11.8)
TSH level at randomization (mean ± SD)	5.0 (2.6)	1.5 (0.8)	<0.001
Preterm delivery (%)	29 (9.5)	11 (4.8)	0.04
Newborn sex			0.20
Male	−160 (52%)	−132 (57.6)
Female	−147 (47.9)	−97 (42.4)
Newborn birthweight (mean ± SD)	3345.4 (551.6)	3399.9 (522.5)	0.47

HT, hypothyroxinemia; SD, standard deviation; SH, subclinical hypothyroidism; TSH, thyrotropin.

Table 2.

Diagnosis of Thyroid Condition by Stratum^a at the 1- and 5-Year Research Visit

	S-Stratum	H-Stratum	p value
Year 1 (%)	41/307 (13.4%)	7/229 (3.1%)	<0.001
Prior diagnosis of hypothyroidism^b	N = 16	N = 2
Diagnosis based on research serum test	N = 25	N = 5
(On treatment for hypothyroidism)^c	N = 14	N = 1
Year 5 (%)	48/307 (15.6%)	6/229 (2.6%)	<0.001
Prior diagnosis of hypothyroidism^b	N = 39	N = 5
Diagnosis based on research serum test	N = 9	N = 1
(On treatment for hypothyroidism)^c	N = 31	N = 4
Year 1 or year 5 (%)	71/307 (23.1%)	11/229 (4.8%)	<0.001

H-Stratum, hypothyroxinemia; S-Stratum, subclinical hypothyroidism.

Mother diagnosed with thyroid condition since delivery or last study visit (participant report).

Not included in research visit diagnosis totals.

Subsequent development of hypothyroidism was more common at year 1 and year 5 for participants with SH than for those with HT (Table 2). This progression was more common in individuals with TSH values >10 μIU/mL (Table 3). Of note, masked subsequent thyroid function testing was performed as part of the parent protocols. Of individuals treated with placebo in the SH group 53% (161/304) had at least one normal TSH assessment in the second half of pregnancy. In the HT group 62% (140/227) individuals had at least one normal fT4 assessment in the second half of pregnancy.

Table 3.

Association in Untreated Subclinical Hypothyroidism Diagnosed Prior to 20 Weeks Gestation Between Screening Thyrotropin and Subsequent Overt Hypothyroidism or Receipt of Thyroid Replacement Therapy at 1 Year, 5 Years, and the Outcome at Either 1 or 5 Years

	TSH >10 µIU/mL	TSH ≤10 µIU/mL	p value
Overt hypothyroidism or thyroid replacement therapy—year 1	−4/11 (36%)	37/296 (12.5%)	0.045
Overt hypothyroidism or thyroid replacement therapy—year 5	8/11 (72.7%)	40/296 (13.5%)	<0.001
Overt hypothyroidism or thyroid replacement therapy—year 1 or 5	10/11 (90.9%)	61/296 (20.6%)	<0.001

The majority (25/41 at the 1-year visit) of the individuals diagnosed with SH during their index pregnancy and who were found to have progressed to overt hypothyroidism were not diagnosed clinically, but only at the time of the research analyses.

Compared with people with SH and baseline TPO concentrations ≤50 IU/mL, those who had a baseline TPO level >50 IU/mL were more likely to be diagnosed with hypothyroidism at year 1 (28/105 (26.7%) vs. 13/201 (6.5%), odds ratio (OR) = 5.3 [confidence interval (CI): 2.6–10.7]) and at year 5 (32/105 (30.5%) vs. 15/201 (7.5%), OR = 5.4 [CI: 2.8–10.6]) (Table 4). However, among people with HT, a baseline TPO level >50 IU/mL was not associated with an increased rate of overt hypothyroidism only at 5 years (2/10 (20%) vs. 4/218 (1.8%), OR = 13.4 [CI: 2.1–84.1]) (Table 4). In multivariable regression analysis of the combined groups, TPO >50 was associated with higher rates of hypothyroidism at either year 1 or 5 (OR = 7.16 [CI: 4.09–12.56]). Baseline SH was also associated with higher rates of hypothyroidism at year 1 or 5 than HT (OR = 2.85 [CI: 1.38–5.90]). There was no effect on progression of thyroid disease based on maternal age, payor status, or gestational age at randomization (Table 5).

Table 4.

Baseline Thyroid Peroxidase Status and Thyroid Diagnosis in the Parent Studies³ (at the 1- and 5-Year Research Visits)

	TPO >50 IU/mL	TPO <50 IU/mL	p value
SH-Stratum
Year 1	28/105 (26.7%)	13/201 (6.5%)	<0.001
Year 5	32/105 (30.5%)	15/201 (7.5%)	<0.001
HT-Stratum
Year 1	1/10 (10%)	6/218 (2.8%)	0.27
Year 5	2/10 (20%)	4/218 (1.8%)	0.02

HT-Stratum, hypothyroxinemia; SH-Stratum, subclinical hypothyroidism; TPO, thyroid peroxidase antibody.

Table 5.

Outcome: Diagnosis of Thyroid Condition Year 1 or 5

	Adjusted OR	[CI]	p value
Baseline TPO >50 IU/mL	7.16	[4.09, 12.56]	<0.001
S-Stratum vs. H-Stratum	2.85	[1.38, 5.90]	0.005
GA at randomization (weeks)	1.00	[0.91, 1.09]	0.98
Maternal age (years)	1.00	[0.95, 1.05]	0.97
Private vs. public insurance or self-pay	1.42	[0.78, 2.60]	0.25

Logistic regression model included baseline TPO adjusted for baseline characteristics of thyroid status, maternal age, type of insurance, and GA at randomization.

CI, confidence interval; GA, gestational age; OR, odds ratio.

Discussion

Over the course of 5 years following their index deliveries, we prospectively evaluated thyroid function studies in a large cohort of pregnant individuals between 8 and 20 weeks gestation diagnosed with SH or HT and who were not treated during their pregnancy. We found that, within 5 years postpartum, progression to overt hypothyroidism or thyroid replacement therapy was more common in individuals with SH than in those with HT. Much of this progression occurred in the first year and was not diagnosed via clinical encounters. Individuals diagnosed with HT in the first half of pregnancy were more likely to progress to overt hypothyroidism or thyroid replacement therapy if their TSH values were >10 μIU/mL. In addition, TPO antibody levels >50 IU/mL at baseline in pregnancy were associated with this progression.

Our study is the largest cohort of pregnant individuals diagnosed with subclinical thyroid testing abnormalities followed across 5 years for progression to clinical hypothyroidism (N = 536). However, several previous reports warrant discussion. Li and colleagues⁸ followed a cohort of pregnant individuals in China with SH following delivery. Of their 216 individuals in their study, 84 (38.9%) were clinically hypothyroid at 7–19 months (median = 11 months) postpartum. Of interest, they noted a significant correlation between the gestational age at the time of diagnosis and the likelihood of subsequent postpartum hypothyroidism. We did not see a similar correlation in our population, perhaps because their population had universal thyroid hormone testing performed at 11–13, 24–28, and 34 weeks gestation, whereas none of the institutions participating in our parent studies performed such universal screening.⁹ Participants in our parent studies were screened for thyroid function from 8 weeks 0 days through 20 weeks 6 days gestation.⁹

Neelaveni and colleagues¹⁰ performed a retrospective cohort study in which 467 pregnant women in India, also diagnosed with SH during pregnancy, were assessed two years postpartum, at which time 83 (17.8%) had developed hypothyroidism. Shields and colleagues¹¹ followed a small cohort of women diagnosed with SH in pregnancy to 5 years postpartum and found that 16 of 65 (24.6%) had elevated TSH levels. The aforementioned studies provide some background for comparison of our follow-up results for individuals diagnosed with SH during the first half of pregnancy. However, we are not aware of any long-term follow-up reports (of 5 years or longer) on individuals diagnosed with HT during the first half of pregnancy.

We found a significantly higher likelihood of clinically apparent subsequent hypothyroidism in participants of both parent trials who had elevated TPO antibodies. These findings are consistent with previous follow-up studies of pregnant people diagnosed with SH or HT in whom these antibodies were measured at initial diagnosis.¹² Data exist associating the presence of TPO antibodies in SH with a higher risk for subsequent cardiovascular disease.¹³ Unfortunately, maternal cardiovascular disease was not evaluated at the parent study 1- or 5-year visits. Likewise, although reported in larger population-based studies,¹³ we found no association between subsequent hypothyroidism and maternal age or payor status. This is likely the result of both our sample size and the fact that our follow-up was limited to 5 years after delivery.

Our study has several strengths. Study data were derived from a nationally representative population, and the data were prospectively collected by trained, certified research personnel. We had 5-year follow-up on a high proportion of the subjects (92%) who participated in the parent studies. All assays were performed centrally, and all included participants who had thyroid function measured at the follow-up visits. Limitations of our study include the lack of thyroid function assessments, including TPO antibody status, before pregnancy, during the immediate puerperium, or at follow-up visits. In addition, we have no comparison group of women with normal thyroid function testing but positive TPO antibodies, the latter being a group that could demonstrate the association of TPO antibodies alone. Likewise, we have only single assessments at each study time point, raising the possibility of both false-positive (subsequent normal testing) and false-negative (subsequent abnormal testing) results.¹⁴ In addition, our findings are limited to pregnant people diagnosed with SH or HT during the first half of pregnancy and cannot be extrapolated to nonpregnant individuals. Because we do not have any preconception thyroid testing results on parent study participants, we cannot exclude the possibility that some participants might have had overt hypothyroidism prior to conception that was masked by the physiological effect of Human Chorionic Gonadotropin (HCG). Finally, a small proportion of individuals in both groups were receiving thyroid replacement at the time of follow-up study visits. We do not know if these individuals had abnormal thyroid function testing or whether they were treated presumptively either because of symptoms or because of participation in the parent studies.

It should also be noted that this report is a secondary analysis of data from two completed clinical trials, which thereby precludes any ability to adjust their entry criteria. In both parent studies a TSH value of 4.0 mIU/mL was designated as the diagnostic threshold for both SH (≥4.0 mIU/mL) and HT (<4.0 mIU/mL). This value is slightly lower than the 4.5 mIU/mL threshold currently recommended by the United States Preventive Services Task Force.¹⁴ TSH levels are known to decrease in the first trimester and also to vary with age between various racial and ethnic groups.¹⁵ TSH levels are also known to fluctuate during nonthyroidal illnesses, with certain medication exposures, and both with time of day and time of the year.⁷ As a result, the sensitivity and specificity of the population screening for both parent studies were less than perfect which, in turn, may have further limited the generalizability of our findings to specific populations.

In conclusion, SH is associated with higher rates of overt hypothyroidism or thyroid replacement therapy within 5 years of delivery than is HT when these conditions are diagnosed in the first half of pregnancy.

Footnotes

Acknowledgments

The authors thank Lisa Moseley, R.N., B.S.N. and Gail Mallett, R.N., B.S.N., C.C.R.C. for protocol development and coordination between clinical research centers; Barbara Jones-Binns, J.D., M.P.H., for protocol and data management, overall coordination, and quality control; and Elizabeth A. Thom, Ph.D., Yoram Sorokin, M.D., and Catherine Y. Spong, M.D. for protocol development and oversight. In addition to the authors, other members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network are as follows: The University of Utah Health Sciences Center, Salt Lake City, UT—K. Hill, A. Sowles, S. Timothy, P. Reed (deceased, Intermountain Healthcare), E. S. Esplin (Intermountain Healthcare); University of Texas Southwestern Medical Center, Dallas, TX—L. Moseley, J. Price, C. Melton, M. Garcia, J. Gerald, M. Santillan; University of Pittsburgh, Pittsburgh, PA—M. Cotroneo, D. DeAngelis, M. Luce, R. Kennedy, D. Nowinski; University of Alabama at Birmingham, Birmingham, AL—S. Harris, F. Biasini, M. Parks, J. Grant, C. Lee, A. Todd, K. Domnanovich, W. Andrews; Wayne State University, Detroit, MI—N. Hauff, Y. Sorokin, L. Goldston, D. Driscoll; The Ohio State University, Columbus, OH—F. Johnson, J. Iams, S. Wylie, R. Devlin, B. Selegue, C. Latimer, J. Bauer; Brown University, Providence, Rhode Island—D. Allard, T. Leach, V. Watson, B. Hughes; Columbia University, New York, NY—S. Bousleiman, V. Carmona, A. Zygmunt, Y. Williams (Drexel University), M. Grant (Drexel University), C. Kitto (Christiana Care Health Systems), B. Higley (Christiana Care Health Systems), M. Falk (St. Peter’s University Hospital), L. Padovano (St. Peter’s University Hospital); University of Texas Medical Branch, Galveston, TX—A. Salazar, A. Acosta, K. Smith, G. Hankins, S. Jain, M. Munn, L. Pacheco; MetroHealth Medical Center-Case Western Reserve University, Cleveland, OH—C. Milluzzi, B. Nielsen, W. Dalton, H. Cozart, E. Chien; The University of Texas Health Science Center at Houston, McGovern Medical School-Children’s Memorial Hermann Hospital, Houston, TX—F. Ortiz, S. Blackwell, B. Rech, M. Hutchinson, P. Givens; University of North Carolina at Chapel Hill, Chapel Hill, NC—K. Clark, S. Timlin, K. Dorman, E. Campos, H. Byers, S. Brody (WakeMed Health & Hospitals); Northwestern University, Chicago, IL—G. Mallett, M. Ramos-Brinson, M. Weissbourd (Lurie Children’s Hospital), M. Dinsmoor (NorthShore University HealthSystem), K. Paychek (NorthShore University HealthSystem), P. Campbell; Oregon Health & Science University, Portland, OR—M. Rincon, J. Tolosa, L. Pereira, P. Blasco, S. Saxton, K. Beach, J. Snyder; George Washington University Biostatistics Center, Washington, DC—E.A. Thom (deceased), B. Jones-Binns; National Institute of Neurological Disorders and Stroke, Bethesda, MD—D.G. Hirtz; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD—C. Spong, S. Tolivaisa; MFMU Network Steering Committee Chair (Medical University of South Carolina, Charleston, SC)—J.P. VanDorsten, M.D.

Authors’ Contributions

Conception and design of the study: M.W.V. and A.M.P. Acquisition, analysis, or interpretation of data: M.W.V., L.M., B.M.C., A.M.P., U.M.R., R.J.W., J.M.T., G.R.S., A.T.N.T., D.J.R., B.M.S., M.M.C., B.M.M., and S.N.C. Drafting the work and revising: M.W.V. and L.M. Final approval of the article: M.W.V., L.M., B.M.C., A.M.P., U.M.R., R.J.W., J.M.T., G.R.S., A.T.N.T., D.J.R., B.M.S., M.M.C., B.M.M., and S.N.C.

Author Disclosure Statement

None of the authors have any competing financial interests.

Funding Information

The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD34208, HD34116, HD40512, HD27917, HD40485, HD40560, HD53097, HD27869, HD40500, HD40545, HD27915, HD40544, HD53118, HD21410, and HD36801], the National Institute of Neurological Disorders and Stroke, and the National Institutes of Health’s National Center for Advancing Translational Sciences [UL1TR001070]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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