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      Effect of antithyroid antibodies on women with recurrent miscarriage: A meta‐analysis

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          Abstract

          Problem

          The effect of thyroid autoimmunity (TAI) on the prevalence of recurrent miscarriage (RM) is highly debatable. No meta‐analysis has been published in the past decade to investigate the impact of TAI on women with RM.

          Method of Study

          Systemic literature search was conducted on PubMed, Embase, Cochrane, and Web of Science databases. English language literatures published between 1993 and 2019 were selected. We assessed the relationship between the prevalence of RM and thyroid peroxidase antibodies (TPO‐Ab) or antithyroid antibodies (ATA) and evaluated the thyroid‐stimulating hormone (TSH) level in TPO‐Ab‐positive women with RM. We also observed the treatment effect with levothyroxine (LT4) for RM. Review Manager 5.3 software was used to obtain the pooled odds ratios (OR).

          Results

          Analysis of 22 eligible studies revealed significant association between TPO‐Ab and the prevalence of RM (OR = 1.85; 95% CI, 1.38 to 2.49; P < .001)(n ≥ 3), (OR = 1.82; 95% CI, 1.13 to 2.92; P = .01) (n ≥ 3). Women with ATA + had higher risk of RM (OR = 2.36; 95% CI, 1.71 to 3.25; P < .00001)(n ≥ 3), (OR = 2.34; 95% CI, 1.70 to 3.22; P < .00001)(n ≥ 2). RM women with TPO‐Ab had higher TSH level when compared with those negative for TPO‐Ab (random‐effect SMD = 0.60; 95% CI, 0.31 to 0.90; P < .0001). We also found beneficial effects of LT4 supplementation on the outcome of live birth rate (LBR) among pregnant women with TPO‐Ab (OR = 3.04; 95% CI, 0.69 to 13.36; P = .14).

          Conclusion

          The presence of serum antithyroid antibodies does harms to women and can even lead to recurrent miscarriage; LT4 treatment may have beneficial to RM women.

          Abstract

          This study reveals the association between thyroid autoimmunity and TSH level, the prevalence of RM. And LT4 supplementation may effectively increase live birth rate.

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          Most cited references72

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          Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.

          Patients with serum thyroid-stimulating hormone (TSH) levels outside the reference range and levels of free thyroxine (FT4) and triiodothyronine (T3) within the reference range are common in clinical practice. The necessity for further evaluation, possible treatment, and the urgency of treatment have not been clearly established. To define subclinical thyroid disease, review its epidemiology, recommend an appropriate evaluation, explore the risks and benefits of treatment and consequences of nontreatment, and determine whether population-based screening is warranted. MEDLINE, EMBASE, Biosis, the Agency for Healthcare Research and Quality, National Guideline Clearing House, the Cochrane Database of Systematic Reviews and Controlled Trials Register, and several National Health Services (UK) databases were searched for articles on subclinical thyroid disease published between 1995 and 2002. Articles published before 1995 were recommended by expert consultants. A total of 195 English-language or translated papers were reviewed. Editorials, individual case studies, studies enrolling fewer than 10 patients, and nonsystematic reviews were excluded. Information related to authorship, year of publication, number of subjects, study design, and results were extracted and formed the basis for an evidence report, consisting of tables and summaries of each subject area. The strength of the evidence that untreated subclinical thyroid disease is associated with clinical symptoms and adverse clinical outcomes was assessed and recommendations for clinical practice developed. Data relating the progression of subclinical to overt hypothyroidism were rated as good, but data relating treatment to prevention of progression were inadequate to determine a treatment benefit. Data relating a serum TSH level higher than 10 mIU/L to elevations in serum cholesterol were rated as fair but data relating to benefits of treatment were rated as insufficient. All other associations of symptoms and benefit of treatment were rated as insufficient or absent. Data relating a serum TSH concentration lower than 0.1 mIU/L to the presence of atrial fibrillation and progression to overt hyperthyroidism were rated as good, but no data supported treatment to prevent these outcomes. Data relating restoration of the TSH level to within the reference range with improvements in bone mineral density were rated as fair. Data addressing all other associations of subclinical hyperthyroid disease and adverse clinical outcomes or treatment benefits were rated as insufficient or absent. Subclinical hypothyroid disease in pregnancy is a special case and aggressive case finding and treatment in pregnant women can be justified. Data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few. The consequences of subclinical thyroid disease (serum TSH 0.1-0.45 mIU/L or 4.5-10.0 mIU/L) are minimal and we recommend against routine treatment of patients with TSH levels in these ranges. There is insufficient evidence to support population-based screening. Aggressive case finding is appropriate in pregnant women, women older than 60 years, and others at high risk for thyroid dysfunction.
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            Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications.

            Euthyroid women with autoimmune thyroid disease show impairment of thyroid function during gestation and seem to suffer from a higher rate of obstetrical complications. We sought to determine whether these women suffer from a higher rate of obstetrical complications and whether levothyroxine (LT(4)) treatment exerts beneficial effects. This was a prospective study. The study was conducted in the Department of Obstetrics and Gynecology. A total of 984 pregnant women were studied from November 2002 to October 2004; 11.7% were thyroid peroxidase antibody positive (TPOAb(+)). TPOAb(+) patients were divided into two groups: group A (n = 57) was treated with LT(4), and group B (n = 58) was not treated. The 869 TPOAb(-) patients (group C) served as a normal population control group. Rates of obstetrical complications in treated and untreated groups were measured. At baseline, TPOAb(+) had higher TSH compared with TPOAb(-); TSH remained higher in group B compared with groups A and C throughout gestation. Free T(4) values were lower in group B than groups A and C after 30 wk and after parturition. Groups A and C showed a similar miscarriage rate (3.5 and 2.4%, respectively), which was lower than group B (13.8%) [P < 0.05; relative risk (RR), 1.72; 95% confidence interval (CI), 1.13-2.25; and P < 0.01; RR = 4.95; 95% CI = 2.59-9.48, respectively]. Group B displayed a 22.4% rate of premature deliveries, which was higher than group A (7%) (P < 0.05; RR = 1.66; 95% CI = 1.18-2.34) and group C (8.2%) (P < 0.01; RR = 12.18; 95% CI = 7.93-18.7). Euthyroid pregnant women who are positive for TPOAb develop impaired thyroid function, which is associated with an increased risk of miscarriage and premature deliveries. Substitutive treatment with LT(4) is able to lower the chance of miscarriage and premature delivery.
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              Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence

              Objectives To evaluate the association between thyroid autoantibodies and miscarriage and preterm birth in women with normal thyroid function. To assess the effect of treatment with levothyroxine on pregnancy outcomes in this group of women. Design Systematic review and meta-analysis. Data sources Medline, Embase, Cochrane Library, and SCISEARCH (inception-2011) without any language restrictions. We used a combination of key words to generate two subsets of citations, one indexing thyroid autoantibodies and the other indexing the outcomes of miscarriage and preterm birth. Study selection Studies that evaluated the association between thyroid autoantibodies and pregnancy outcomes were selected in a two stage process. Two reviewers selected studies that met the predefined and explicit criteria regarding population, tests, and outcomes. Data synthesis Odds ratios from individual studies were pooled separately for cohort and case-control studies with the random effects model. Results 30 articles with 31 studies (19 cohort and 12 case-control) involving 12 126 women assessed the association between thyroid autoantibodies and miscarriage. Five studies with 12 566 women evaluated the association with preterm birth. Of the 31 studies evaluating miscarriage, 28 showed a positive association between thyroid autoantibodies and miscarriage. Meta-analysis of the cohort studies showed more than tripling in the odds of miscarriage with the presence of thyroid autoantibodies (odds ratio 3.90, 95% confidence interval 2.48 to 6.12; P<0.001). For case-control studies the odds ratio for miscarriage was 1.80, 1.25 to 2.60; P=0.002). There was a significant doubling in the odds of preterm birth with the presence of thyroid autoantibodies (2.07, 1.17 to 3.68; P=0.01). Two randomised studies evaluated the effect of treatment with levothyroxine on miscarriage. Both showed a fall in miscarriage rates, and meta-analysis showed a significant 52% relative risk reduction in miscarriages with levothyroxine (relative risk 0.48, 0.25 to 0.92; P=0.03). One study reported on the effect of levothyroxine on the rate of preterm birth, and noted a 69% relative risk reduction (0.31, 0.11 to 0.90). Conclusion The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks.
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                Author and article information

                Contributors
                min_jin@zju.edu.cn
                Journal
                Am J Reprod Immunol
                Am. J. Reprod. Immunol
                10.1111/(ISSN)1600-0897
                AJI
                American Journal of Reproductive Immunology
                John Wiley and Sons Inc. (Hoboken )
                1046-7408
                1600-0897
                11 April 2020
                June 2020
                : 83
                : 6 ( doiID: 10.1111/aji.v83.6 )
                : e13238
                Affiliations
                [ 1 ] Second Affiliated Hospital School of Medicine Zhejiang University Hangzhou China
                [ 2 ] Taizhou Women and Children’s Hospital Affiliated to Wenzhou Medical University Taizhou China
                Author notes
                [*] [* ] Correspondence

                Min Jin, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

                Email: min_jin@ 123456zju.edu.cn

                Author information
                https://orcid.org/0000-0003-4860-3508
                https://orcid.org/0000-0002-6360-3058
                Article
                AJI13238
                10.1111/aji.13238
                7317526
                32198952
                a5f8a9b1-def7-425d-9935-aeeff46a65b6
                © 2020 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 December 2019
                : 15 March 2020
                : 16 March 2020
                Page count
                Figures: 7, Tables: 1, Pages: 15, Words: 8451
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81671487
                Categories
                Review Article
                Reviews: Clinical Reproductive Immunology
                Custom metadata
                2.0
                June 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:26.06.2020

                Immunology
                autoimmunity,lt4 treatment,meta‐analysis,recurrent miscarriage,thyroid antibody
                Immunology
                autoimmunity, lt4 treatment, meta‐analysis, recurrent miscarriage, thyroid antibody

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