Ethnic Differences in Preterm Birth Risks fo r Pregnan t Wom en w ith Thyroid Dys func tion o r Au toimm unity: A Meta-analysis＊

LI M in, WANG Shao Wei, WU Feng Li, SHI Jin, YU Pu Lin,#, PENG Xiu Ling, and SUN Liang

1. Department of Gynecology and Obstetrics, Beijing Hospital, National Center of Gerontology, Beijing 100730, China; 2. Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing 100730, China; 3. Department of Gynecology and Obstetrics, Morin Dawa Daur Autonomous Banner Hospital, Hulunbuir 162850, Inner Mongolia Autonomous Region, China

Ethnic Differences in Preterm Birth Risks fo r Pregnan t Wom en w ith Thyroid Dys func tion o r Au toimm unity: A Meta-analysis＊

LI M in1, WANG Shao Wei1, WU Feng Li1, SHI Jin2, YU Pu Lin2,#, PENG Xiu Ling3, and SUN Liang2

1. Department of Gynecology and Obstetrics, Beijing Hospital, National Center of Gerontology, Beijing 100730, China; 2. Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing 100730, China; 3. Department of Gynecology and Obstetrics, Morin Dawa Daur Autonomous Banner Hospital, Hulunbuir 162850, Inner Mongolia Autonomous Region, China

ObjectiveAbnormal maternal thyroid function is associated w ith preterm birth. However, this association stays dubious in relevant individual studies for ethnic difference reasons and lack of direct supporting data. This study aimed to evaluate the relationship between preterm birth and thyroid dysfunction or autoimmunity based on ethnic differences.

MethodsRelevant studies were identified through searches of MEDLINE, Excerpta Medica, Wan Fang, China Biological Medicine disc, and China National Know ledge Infrastructure from inception to June 15, 2016. Original articles in which an incidence or prevalence of thyroid dysfunction or autoimmunity before second trimester of pregnancy could be extracted were included.

ResultsThirty-two unique studies were included for the final meta-analysis. Patients involved were divided into two groups: Group 1 (G1) and Group 2 (G2) comprising of Asian and Caucasian populations, respectively. Positive thyroid antibodies were associated with the occurrence of preterm birth in both G1 [odds ratio (OR): 3.62, 95% confidence interval (CI): 2.83-4.65] and G2 (OR: 1.35, 95% CI: 1.17-1.56); hypothyroidism, only in G2 (OR: 1.20, CI: 1.09-1.33); and subclinical hypothyroidism or hypothyroxinem ia, in neither group.

ConclusionThyroid autoimmunity may be a more favorable factor leading to preterm birth among pregnant women of different ethnicities, compared with thyroid dysfunction.

Thyroid; Hypothyroidism; Autoimmunity; Preterm birth; Ethnicity

www.besjournal.com (full text)CN: 11-2816/QCopyright ?2016 by China CDC

INTRODUCTION

P reterm birth, occurring in 6%-12% of pregnancy, is defined as the birth of a child prior to 37 weeks of gestation[1-2]. It is the leading cause of neonatal mortality, responsible for 75% of neonatal deaths with no congenital anomalie[1-2]. Preterm birth is also associated w ith perinatal complications, such as congenital neurologic disability, and psychiatric, metabolic, cardiovascular, and renal diseases[1,3]. To address this problem, numerous works have been conducted over the last decades, yet there is still no great prospect of early prediction and prevention of preterm delivery[4].

As the fetus does not yet produce its own thyroid hormones, adequate functioning of the maternal thyroid is confirmed to be particularly important for the development of the fetal brain during the first trimester[5-6]. Thyroid dysfunction and thyroid autoimmunity are relatively common in women at reproductive age, affecting 2%-3% and5%-15% of pregnant women, respectively[6-7]. Both thyroid dysfunction and thyroid autoimmunity are associated with adverse pregnancy outcomes[6,8]. However, over the last 20 years, conflicting results published on alteration of diagnostic criteria of thyroid function tests make the exact prevalence of thyroid diseases in pregnant women and its relationship with preterm labor even more unclear[5,9-10].

A number of studies have shown that inter-individual differences in thyroid hormone levels may, at least partially, be explained by ethnic background[11-12]. Only a few studies analyzed the ethnic differences of thyroid function tests during pregnancy[13-14]. La'ulu et al.[14-15]and other authors[13,16]reported that the reference range values for thyroid parameters may differ among Asians, white, black, and Hispanic Americans, and even in different subgroups of Caucasians. These ethnic differences between different populations emphasize the significance of calculating populationspecific reference ranges for TSH during pregnancy, suggesting that the risk of preterm birth should be estimated in the same ethnic population. Therefore, this study aimed to conduct a meta-analysis to analyze the risk of preterm birth for pregnant women with thyroid dysfunction or thyroid autoimmunity based on ethnic variety by including data from random ized controlled trials (RCTs) and cohort studies.

METHODS

Search Strategy

Relevant studies were identified through searches of MEDLINE, Excerpta Medica, Wan Fang, China Biological Medicine disc, and China National Know ledge Infrastructure from inception to June 15, 2016. Search criteria used were related to thyroid dysfunction, thyroid autoimmunity, and preterm birth. The following search terms were used: subclinical hypothyroidism, hypothyroidism, thyroiditis, thyroid peroxidase, thyrotropin, thyrotropin receptor antibody,thyroid-stimulatingimmunoglobulin, thyroid m icrosomal antibodies, thyroid dysfunction, hypothyroxinem ia, thyroid diseases, pregnancy, pregnancy outcome, immature and premature labor, premature delivery, preterm birth, cohort analysis, longitudinal study, prospective study, retrospective study, follow up, and case-control study. The language lim itation for the initial search was set to include only Chinese and English. RCTs, cohort studies, and case-control studies were included.

Study Selection

The criteria for inclusion were (1) pregnant women w ith overt hypothyroidism, subclinical hypothyroidism, hypothyroxinem ia, and positive thyroid autoantibody; (2) preterm birth outcome; (3) assessment of thyroid function before second trimester of pregnancy; (4) articles in English or Chinese; and (5) same ethnic population being more than 80% of all patients. The criteria for exclusion were (1) poor quality studies; (2) articles from the same cohort studies (only the newest were included); and (3) subjects with cardiovascular or rheumatic diseases.

Quality Evaluation

Studies were judged on scientific quality accordingtotheCONSORTandSTROBE statements[17]. Study quality assessment was performed based on the NewcastleOttawa scale for cohort studies[17](http://www.ohri.ca/programs/ clinicalepidem iology/oxford. asp).

Data Extraction

The procedure was performed independently by two reviewers (L. M, W. FL). Articles included for full text screening were compared during a consensus meeting. In case of disagreement, a third reviewer (W. SW) was consulted for the decision on inclusion or exclusion for full-text evaluation.

Statistical Analysis

In each study, incidence of thyroid dysfunction or thyroid autoimmunity compared to that of controls was expressed both as odds ratios (OR) w ith the corresponding 95% confidence intervals (CI). Review Manager software version 5.2 was used to perform the meta-analyses. Statistical heterogeneity was evaluated using the I2test[17], with I2＞50% represents moderate to substantial heterogeneity, in which case random-effects models were used to pool summary estimates[17]. Funnel plots present the publication bias. Begg's and Egger's tests were performed to assess publication bias quantitatively. All statistical analyses were conducted using STATA 12.0 software (Stata Corp, College Station, TX, USA). A two-sided P＜0.05 was considered statistically significant.

RESULTS

Literature Search

A total of 3,520 articles were selected from thesearch results for critical appraisal. After elim ination of duplicate and irrelevant studies, 32 unique studies consistent w ith the inclusion criteria, including 4 Chinese and 28 English, were finally included (Figure 1). Of the 32 articles in this systematic review, 13 reported on hypothyroidism[16,18-26,31,33,41], 18 on subclinical hypothyroidism[16,18-19,22-24,26-34,46-48], 4 on hypothyroxinem ia[18,23,27,29], and 18 on thyroid antibodies[16,18-19,27,32,45]. All 32 cohort studies exhibited low risk of bias for selection and NOS score more than 7. Among these studies, 1 article is RCT; 23, prospective cohort studies; 6, retrospective cohort studies, and 2, case-control studies.

Study Characteristics

The characteristics of the articles included are reported in Table 1. The studies were conducted in different ethnicities, such as Caucasians or white, Hispanic, African Americans, and Asians. Given that there were no studies on African American and Hispanic, patients in the involved studies were divided into two groups, namely, Group 1 (G1, Asians) and Group 2 (G2, Caucasians). The size of the cohorts ranged from 306 to 223,512 (total 579,692). There were 42,804 cumulative preterm birth cases.

Effect of Overt Hypothyroidism on Preterm Birth by Ethnic Groups

Table 1. Characteristics and Quality Features of the 32 Studies Included in the Systematic Review of the Association between Thyroid Dysfunction and Preterm Birth

Continued

Data from 13 articles reporting 5,140 patients w ith overt hypothyroidism and 450,576 controls could be included in the meta-analysis and showed an increased risk of preterm delivery (OR: 1.25, 95% CI: 1.04-1.51, P=0.02; Figure 2). The studyin G2 showed a significant association between overt hypothyroidism and preterm birth (OR: 1.20, 95% CI: 1.08-1.32, P=0.0004; Figure 2). By contrast, no significant difference was observed in G1 (OR: 1.68, 95% CI: 0.64-4.38, P=0.29; Figure 2).

Effect of Subclinical Hypothyroidism on Preterm Birth by Ethnic Groups

There were 66,647 individual data from 18 studies, including 3,192 pregnant women w ith subclinical hypothyroidism and 63,455 controls. Difference in the risk of preterm birth was not observed between patients w ith subclinical hypothyroidism and euthyroid controls in both ethnic groups [G1 (OR: 1.37, 95% CI: 0.98-1.92, P=0.06; Figure 3); G2 (OR: 1.23, 95% CI: 0.96-1.57, P=0.10; Figure 3)].

Effect of Hypothyroxinem ia on Preterm Birth by Ethnic Groups

Fourstudieswereinvestigatedfor hypothyroxinem ia, including 653 pregnant women w ith hypothyroxinem ia and 31,847 controls. The relation between hypothyroxinem ia and preterm birth was investigated in one study of G1. The study reported no difference between patients and controls (G1, OR: 0.57, 95% CI: 0.08-4.28, P=0.58). Meta-analysis on three studies of G2 resulted in a pooled OR of 1.48 and 95% CI of 0.96-2.28 (P=0.07; Figure 4). No association between hypothyroxinem ia and preterm birth was observed in G2.

Effect of Thyroid Autoimmunity on Preterm Birth by Ethnic Groups

Eighteen studies, including 4,182 pregnant women with positive antibodies and 42,733 healthy controls, were investigated for thyroid autoimmunity. Metaanalysis revealed an increased risk of preterm birth in patients, with positive thyroid antibodies, of both G1 (OR: 2.85, 95% CI: 1.68-4.85, P=0.0001; Figure 5) and G2 (OR: 1.44, 95% CI: 1.06-1.95, P=0.02; Figure 5).

Publication Bias

Funnel plots present the publication bias (data not shown). Begg's and Egger's tests were performed to assess publication bias quantitatively. No evidence of publication bias was found in the sensitivity testing of every subgroup analysis (Table 2).

Table 2. Publication bias of Each Subgroup

DISCUSSION

The present meta-analysis provides clear evidence for a relationship between the presence of thyroid dysfunction or autoimmunity and preterm birth in different ethnic groups.

The presence of thyroid antibodies was significantly related to the occurrence of preterm birth, compared with the absence of antibodies.

Association between preterm birth and patients w ithsubclinicalhypothyroidismor hypothyroixinem ia was not observed in both ethnic groups. High TSH level or low free T4 level alone seemed to not necessarily increase the risk of preterm birth. An increased risk of preterm birth was only observed in the other ethnic group w ith hypothyroidism. No evidence was found for a relationship between hypothyroidism and preterm birth in Asians. Asians were less susceptible to high TSH level, compared w ith Caucasians. Considering lim ited data available on preterm birth in Asians w ith hypothyroxinem ia, the role of hypothyroxinem ia in preterm delivery needs further investigation.

Positive thyroid antibodies were associated with an increased risk of preterm birth in both ethnic groups. Moreover, preterm delivery may occur more frequently in Asians with positive thyroid antibodies, w ith a 2.85 fold higher risk. These results showed that thyroid autoimmunity may be a key factor for increased risk of preterm delivery among different ethnicities. Although not all individual studies involved reported this association, meta-analysis was conclusive on this point, show ing the additional value of pooled studies compared with individual studies. Several hypotheses exist on the causality between thyroid autoimmunity and obstetric complications. First, thyroid antibodies could be associated w ith a subtle decrease of thyroid function or m ight reflect a generalized activation of the immune system and specifically a deregulated activity of the immune system at the fetal-maternal interface[9,49]. Because pregnancy represents an inflammatory process with a shift in the regulation of cytokine networks w ithin the local placentaldecidual environment, a deregulation of the local inflammatory processes can be associated w ith m iscarriage and premature delivery[5,9,50]. Supporting our results, a recent meta-analysis showed that maternal thyroid autoimmunity increases by twofold the risk of preterm delivery for women w ith biochem ically normal thyroid function[49]. Second, theautoimmunityincreasestheriskof hypothyroidism, ow ing to the chronic lymphocytic thyroiditis that is associated w ith the presence of thyroid antibodies. The thyroid then may fail to respond adequately to the increased demand for thyroid hormone during pregnancy. Thus, a high prevalence of thyroid antibodies is reasonable amongwomenwithovertorsubclinical hypothyroidism (e.g., 25% in Stagnaro-Green et al.[41], 32% in Korevaar et al.[18], and 50% in Mannisto[19].

This meta-analysis has several lim itations. As previously mentioned, the studies used different inclusion criteria for the patients and different cutoff levels for TSH, fT4, and antibodies (Table 1). This lim itation should be considered when using the results for clinical application. Meanwhile, the fact that the diagnoses are made based on ICD-9 coding instead of the specific criteria of blood test results is a lim itation of some studies w ith large sample size[23-24]. Moreover, the differences of the first-time collection of maternal serum samples may partially contribute to the lim itations. Although we used random-effectsmodelstoperformthe meta-analyses of the pooled data in case of heterogeneity while the majority of data showed a very sim ilar trend, some degree of population heterogeneity cannot be excluded. In addition, the affected subjects had a large difference (10.8% vs. 89.2% in weight, and the ORs are 1.68 in Asians and 1.20 in Caucasians); therefore, these differences may be caused by statistical power (Figure 2).

We conclude that pregnant women with hypothyroidism and thyroid autoimmunity may have an increased risk of preterm birth in different ethnic groups. Thyroid autoimmunity may be a more favorable factor leading to preterm birth among pregnant women of different ethnicities, compared w ith thyroid dysfunction. The association of subgroups of thyroid antibodies with preterm birth should be further investigated in the future studies.

CONFLICT OF INTEREST

The authors declare no competing financial interests.

ACKNOWLEDGMENTS

The authors thank Prof. LI Hua Tian for her critical revisions during manuscript drafting.

AUTHOR CONTRIBUTION

LI M in: Data management, Manuscript w riting

WANGShaoWei:Datamanagement, Manuscript editing

WU Feng Li: Data collection

SHI Jin: Data analysis

YU Pu Lin: Project development, Manuscript editing

PENG Xiu Ling: Data collection

Accepted: October 1, 2016

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Biomed Environ Sci, 2016; 29(10): 724-73310.3967/bes2016.097ISSN: 0895-3988

*This study was funded by the National Natural Science Foundation of China (Grant No. 81302277).

#Correspondence should be addressed to YU Pu Lin, Tel: 86-134-88806089, Fax: 86-10-85136220, E-mail: pulin_yu@163.com

Biographical note of the LI Min, female, born in 1973, MD, majoring in pregnancy w ith thyroid diseases, Obstetric complications.

March 11, 2016;