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Subclinical hypothyroidism and thyroid autoimmunity in recurrent pregnancy loss: a systematic review and meta-analysis

      Objective

      To determine whether overt/subclinical hypothyroidism and/or thyroid autoimmunity is associated with recurrent pregnancy loss (RPL) and whether treatment improves outcomes.

      Design

      Systematic review and meta-analysis.

      Setting

      University obstetrics and gynecology departments.

      Patient(s)

      Women with RPL and overt/subclinical hypothyroidism, and/or thyroid autoimmunity.

      Intervention(s)

      None.

      Main Outcome Measure(s)

      Associations between RPL and overt/subclinical hypothyroidism and/or thyroid autoimmunity and any effects of treatment.

      Result(s)

      After our review of articles from PubMed, EMBASE, Web of Science, and CENTRAL, we found two interventional studies in which levothyroxine did not improve the subsequent live-birth rate in women with subclinical hypothyroidism with or without thyroid antibodies. A meta-analysis of five studies revealed the prevalence of subclinical hypothyroidism in RPL to be 12.9% (95% confidence interval [CI], 0%–35.2%). A meta-analysis of 17 studies revealed a statistically significant association between RPL and thyroid autoimmunity (odds ratio 1.94; 95% CI, 1.43–2.64). However, a randomized study suggested that levothyroxine does not benefit euthyroid women with thyroid autoimmunity.

      Conclusion(s)

      Based on the limited observational studies available, no association exists between RPL and subclinical hypothyroidism, nor does levothyroxine improve subsequent pregnancy outcomes. An association exists between RPL and thyroid autoimmunity, but levothyroxine does not improve subsequent pregnancy outcomes. Women with RPL should be screened/treated for overt thyroid disease but not thyroid autoimmunity. Thyroid antibody screening is not supported by the published studies, and further randomized studies are needed. No recommendation regarding the treatment of subclinical hypothyroidism can be made at this time; prospective and randomized studies are urgently needed.
      Hipotiroidismo subclínico y autoinmunidad tiroidea en pérdida gestacional recurrente: una revisión sistemática y meta-análisis

      Objetivo

      Determinar si el hipotiroidismo clínico/subclínico y/o la autoinmunidad tiroidea están asociados con pérdida gestacional recurrente (RPL) y si su tratamiento mejora los resultados.

      Diseño

      Revisión sistemática y meta-análisis.

      Escenario

      departamentos universitarios de Obstetricia y Ginecología.

      Paciente(s)

      Mujeres con RPL e hipotiroidismo clínico o subclínico y/o autoinmunidad tiroidea.

      Intervención(es)

      ninguna.

      Medida de resultado principal(es)

      Asociaciones entre RPL e hipotiroidismo clínico o subclínico y/o autoinmunidad tiroidea y algún efecto de su tratamiento.

      Resultado(s)

      después de revisar artículos de PubMed, EMBASE, Web of Science y CENTRAL, encontramos dos estudios de intervención en los cuales la levotiroxina no mejoró la tasa de recién nacido vivo en mujeres con hipotiroidismo subclínico con o sin anticuerpos tiroideos. Un meta-análisis de 5 estudios reveló que la prevalencia de hipotiroidismo subclínico en RPL era del 12,9% (95% intervalo de confianza (CI), 0%-35.2%). Un meta-análisis de 17 estudios reveló una asociación estadísticamente significativa entre RPL y autoinmunidad tiroidea (odds ratio 1.94; 95% CI, 1.43-2.64). Sin embargo, un estudio aleatorizado sugirió que la levotiroxina no beneficia a mujeres eutiroideas con autoinmunidad tiroidea.

      Conclusión(es)

      basado en los estudios observacionales disponibles, no existe asociación entre RPL e hipotiroidismo subclínico, ni la levotiroxina mejora los resultados de la gestación subsecuente. Existe una asociación entre RPL y autoinmunidad tiroidea, pero la levotiroxina no mejora los resultados de la gestación subsecuente. Las mujeres con RPL deben ser valoradas y tratadas por enfermedad tiroidea clínica pero no por autoinmunidad tiroidea. El screening de anticuerpos anti tiroideos no se justifica en los estudios publicados y se necesitan más estudios aleatorizados. No pueden hacerse recomendaciones respecto al tratamiento de hipotiroidismo subclínico en este momento; se necesitan de forma urgente, estudios prospectivos aleatorizados.

      Key Words

      Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/55100-28284
      Recurrent pregnancy loss (RPL) is a devastating reproductive problem. Random numerical chromosome errors, such as trisomy, monosomy, and polyploidy, are the most common cause of miscarriage in the first 10 weeks of gestation, accounting for nearly half of cases (
      • Stephenson M.D.
      • Awartani K.A.
      • Robinson W.P.
      Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study.
      ). Excluding such “explained” miscarriages, RPL is associated with endocrinopathies, immunological, anatomical, and inherited genetic factors (
      • Stephenson M.D.
      Frequency of factors associated with habitual abortion in 197 couples.
      ).
      Normal thyroid function is known to be important for reproduction. Nearly one-quarter of overt hypothyroid women report menstrual disturbances (
      • Krassas G.E.
      Thyroid disease and female reproduction.
      ). Maternal thyroid function is also known to be important for normal embryonic and fetal development, especially neurodevelopment (
      • De Escobar G.M.
      • Obregón M.J.
      • del Rey F.E.
      Maternal thyroid hormones early in pregnancy and fetal brain development.
      ). It is thus intuitive that thyroid dysfunction may be associated with pregnancy loss.
      In 1990, Stagnaro-Green et al. (
      • Stagnaro-Green A.
      • Roman S.H.
      • Cobin R.H.
      • el-Harazy E.
      • Alvarez-Marfany M.
      • Davies T.F.
      Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies.
      ) reported an association between thyroid autoimmunity, defined as positive titers of thyroid peroxidase antibodies (TPOAb) and/or thyroglobulin antibodies and miscarriage. In addition, many observational studies have linked both overt hypothyroidism—defined as an elevated thyroid-stimulating hormone (TSH) and low free thyroxine—and subclinical hypothyroidism—defined as elevated TSH levels and normal free thyroxine—to pregnancy loss (
      • Abalovich M.
      • Gutierrez S.
      • Alcaraz G.
      • Maccallini G.
      • Garcia A.
      • Levalle O.
      Overt and subclinical hypothyroidism complicating pregnancy.
      ,
      • Benhadi N.
      • Wiersinga W.M.
      • Reitsma J.B.
      • Vrijkotte T.G.M.
      • Bonsel G.J.
      Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death.
      ,
      • Taylor P.N.
      • Minassian C.
      • Rehman A.
      • Iqbal A.
      • Draman M.S.
      • Hamilton W.
      • et al.
      TSH levels and risk of miscarriage in women on long-term levothyroxine: a community-based study.
      ,
      • Wang S.
      • Teng W.P.
      • Li J.X.
      • Wang W.W.
      • Shan Z.Y.
      Effects of maternal subclinical hypothyroidism on obstetrical outcomes during early pregnancy.
      ). However, what constitutes an elevated level of TSH is controversial at present, with newer guidelines suggesting that an upper limit of 4.0 mIU/L should be considered diagnostic compared with the previous guideline of 2.5 mIU/L (
      • Alexander E.K.
      • Pearce E.N.
      • Brent G.A.
      • Brown R.S.
      • Chen H.
      • Dosiou C.
      • et al.
      2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum.
      ).
      The American Society for Reproductive Medicine (ASRM) defines RPL as two or more clinical pregnancy losses (
      American Society for Reproductive Medicine
      Evaluation and treatment of recurrent pregnancy loss: a committee opinion.
      ). The European Society of Human Reproduction and Embryology (ESHRE) defines RPL as two or more pregnancy losses at any gestational age, with the exclusion of ectopic and molar pregnancies (
      • Bender Atik R.
      • Christiansen O.B.
      • Elson J.
      • Kolte A.M.
      • Lewis S.
      • Middeldorp S.
      • et al.
      ESHRE guideline: recurrent pregnancy loss.
      ). Recurrent miscarriage is defined by the Royal College of Obstetricians and Gynaecologists (RCOG) as three or more consecutive pregnancy losses before 24 weeks’ gestation (
      Royal College of Obstetricians and Gynaecologists
      Recurrent Miscarriage, Investigation and Treatment of Couples (Green-top Guideline No. 17).
      ), so recurrent miscarriage could be considered a more strictly defined subset of RPL.
      Given that overt thyroid disease is associated with miscarriage, it is reasonable to question whether subclinical hypothyroidism and thyroid autoimmunity could be associated with RPL. This review will systematically evaluate eligible studies in RPL in which subclinical hypothyroidism and/or thyroid autoimmunity was assessed as well as whether intervention improved subsequent pregnancy outcomes. The evidence from this review will be placed in the context of current clinical practice recommendations from ASRM, ESHRE, and the RCOG. Presently, ASRM (2012) recommends that an evaluation for RPL include TSH, but thyroid antibodies are not mentioned (
      American Society for Reproductive Medicine
      Evaluation and treatment of recurrent pregnancy loss: a committee opinion.
      ). ESHRE (2018) recommends that an evaluation for RPL include both TSH and TPOAbs (
      • Bender Atik R.
      • Christiansen O.B.
      • Elson J.
      • Kolte A.M.
      • Lewis S.
      • Middeldorp S.
      • et al.
      ESHRE guideline: recurrent pregnancy loss.
      ). The RCOG (2011) recommends evaluation for RPL but does not include specifics on thyroid screening (
      Royal College of Obstetricians and Gynaecologists
      Recurrent Miscarriage, Investigation and Treatment of Couples (Green-top Guideline No. 17).
      ).
      There is universal agreement that overt hypothyroidism should be treated, but management of subclinical hypothyroidism and/or thyroid autoimmunity in RPL remains controversial. Neither ASRM nor the RCOG make a clear recommendation for the treatment of subclinical hypothyroidism in RPL (
      American Society for Reproductive Medicine
      Evaluation and treatment of recurrent pregnancy loss: a committee opinion.
      ,
      Royal College of Obstetricians and Gynaecologists
      Recurrent Miscarriage, Investigation and Treatment of Couples (Green-top Guideline No. 17).
      ), ESHRE states that treatment of subclinical hypothyroidism may reduce the rate of miscarriage, but the decision to treat should be weighed against the potential risks of treatment (
      • Bender Atik R.
      • Christiansen O.B.
      • Elson J.
      • Kolte A.M.
      • Lewis S.
      • Middeldorp S.
      • et al.
      ESHRE guideline: recurrent pregnancy loss.
      ). In isolated thyroid autoimmunity, ESHRE states there is not enough evidence to support treatment outside of clinical trials (
      • Bender Atik R.
      • Christiansen O.B.
      • Elson J.
      • Kolte A.M.
      • Lewis S.
      • Middeldorp S.
      • et al.
      ESHRE guideline: recurrent pregnancy loss.
      ). Neither ASRM nor the RCOG recommend treatment of thyroid autoimmunity in women with a history of RPL (
      American Society for Reproductive Medicine
      Evaluation and treatment of recurrent pregnancy loss: a committee opinion.
      ,
      Royal College of Obstetricians and Gynaecologists
      Recurrent Miscarriage, Investigation and Treatment of Couples (Green-top Guideline No. 17).
      ). This systematic review and meta-analysis will evaluate the eligible published studies on overt or subclinical hypothyroidism or thyroid autoimmunity in women with a history of RPL, and will summarize the ongoing clinical trials that are assessing whether levothyroxine is of benefit for the treatment of subclinical hypothyroidism and/or thyroid autoimmunity in RPL.

      Materials and methods

      This study was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement (
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ). The protocol for this review was registered with PROSPERO under registration number CRD42018110340. As a systematic review and meta-analysis is classified as nonhuman subjects research, no institutional review board approval was required. The PubMed, EMBASE, Web of Science, and CENTRAL databases were searched from inception to September 10, 2018, or inception to 2019 if exact date ranges were not available, to identify studies involving thyroid dysfunction in women with a history of RPL. The search query included the following terms: “thyroid antibodies” OR “thyroid antibodies in pregnancy” OR “thyroid antibody positive” OR “thyroid antibody levels” OR “thyroid peroxidase antibodies” OR “thyroglobulin antibodies” OR “thyroid peroxidase antibody” OR “thyroglobulin antibody” OR “thyroid autoantibodies” AND “pregnancy” OR “hypothyroidism” OR “subclinical hypothyroidism” OR “thyroid autoimmunity” OR “Thyroid autoantibodies” OR “Thyroid peroxidase antibodies” OR “thyroglobulin antibodies” AND “recurrent pregnancy loss” OR “recurrent miscarriage” OR “habitual abortion” OR “recurrent spontaneous abortion” OR “recurrent abortion.” All studies were imported into RefWorks 2.0 (ProQuest, Ann Arbor, MI), and duplicate studies were removed electronically and manually.
      Titles and abstracts of articles were reviewed by two authors (A.D. and J.M.), and the relevant articles were selected for full-text review. Only English-language articles were included. Case studies, review articles, and systematic reviews were excluded. The inclusion criteria consisted of women with RPL, as defined in the respective studies, and either hypothyroidism (overt or subclinical) and/or thyroid autoimmunity, as defined in the respective studies. Backward-citation chasing was performed on all selected articles to avoid missing relevant citations. The final list of included studies was reviewed by all authors.
      Data extraction was performed by two authors (A.D. and J.M.), including study size, study design, and definitions of RPL, hypothyroidism, and/or thyroid autoimmunity, and results. The corresponding author of one study was contacted for additional information regarding the definition of RPL used in the study.
      Bias assessment was performed using the Newcastle Ottawa Score for case-control and cohort studies (
      • Wells G.A.
      • Shea B.
      • O’Connell D.
      • Peterson J.
      • Welch V.
      • Losos M.
      • Tugwell P.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute, 2000.
      ). A modified version by Herzog et al. (
      • Herzog R.
      • Álvarez-Pasquin M.J.
      • Díaz C.
      • Del Barrio J.L.
      • Estrada J.M.
      • Gil Á.
      Are healthcare workers’ intentions to vaccinate related to their knowledge, beliefs and attitudes? A systematic review.
      ) was used for cross-sectional studies. An abbreviated version of the Newcastle Ottawa Score system for cohort studies was used for case series studies that omitted the scoring elements for control subjects. Randomized controlled trials were evaluated with the revised Cochrane risk of bias for randomized trials (RoB2) tool (
      • Higgins J.
      • Savović J.
      • Page M.J.
      • Sterne J.
      A revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Cochrane Collaboration, 2020.
      ).
      Meta-analysis was performed on studies with data available that compared the prevalence of thyroid autoimmunity in women with RPL to non-RPL controls to calculate an odds ratio (OR), as well as on studies giving the prevalence of subclinical hypothyroidism in women with RPL to yield a pooled prevalence. Analysis was performed using the MetaXL version 5.3 (Epigear International) add-in for Microsoft Excel 2016 version 16.0.9330.2124. To account for study heterogeneity, the MetaXL inverse heterogeneity model was used; in this model, weighting for each study is determined based on the study’s heterogeneity.

      Results

      From the primary literature search, 2,498 articles were identified. Both manually and electronically, 1,011 duplicate citations were identified and removed. From the remaining 1,487 studies, 1,418 studies were excluded after review of the titles and/or abstracts. Sixty-nine studies were selected for full-text review, of which 29 were excluded, as listed in Supplemental Table 1 (available online). Backward-citation chasing yielded an additional three citations. During the preparation of this article, a randomized controlled trial was published, for a total of 44 eligible studies. A flowchart for the study selection strategy can be found in Supplemental Figure 1 (available online). Details for the 44 eligible studies are included in Table 1, Table 2, Table 3 and Supplemental Tables 2–3 (available online). Summaries of bias assessment are listed in Supplemental Tables 4–8 (available online).
      Table 1Studies examining the association between subclinical hypothyroidism and recurrent pregnancy loss.
      StudyStudy designNRPL definitionSCH definitionTime of thyroid testingResultP value/OR
      Bernardi et al. 2013 (
      • Bernardi L.A.
      • Cohen R.N.
      • Stephenson M.D.
      Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss.
      )
      Observational cohort-control180≥2 Pregnancy losses <10 weeks’ sizeTSH >2.5 and fT4 between 0.9 and 1.7 ng/dLBefore pregnancySCH prevalence 19%; SCH cumulative LBR 69% vs. euthyroid cumulative LBR 74%P=.57
      Liu et al. 2015 (
      • Liu Y.
      • Liu Y.
      • Zhang S.
      • Chen H.
      • Liu M.
      • Zhang J.
      Etiology of spontaneous abortion before and after the demonstration of embryonic cardiac activity in women with recurrent spontaneous abortion.
      )
      Case series232≥2 First-trimester clinical pregnancy lossesTSH >2.5 but <10 mIU/L and “normal” fT3 and fT4 (not defined)First trimesterSCH prevalence 16%NA
      Triggianese et al. 2016 (
      • Triggianese P.
      • Perricone C.
      • Conigliaro P.
      • Chimenti M.S.
      • Perricone R.
      • De Carolis C.
      Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure.
      )
      Case control210≥2 Consecutive pregnancy losses <20 weeks’ gestationTSH >2.5 and fT4 between 8.5 and 20 pg/mL or abnormal TRH testNonpregnantSCH prevalence 63% in primary RPL and 60% in secondary RPL vs. 27% non-RPLPrevalence of SCH in RPL vs. non-RPL, P<.0001
      van Dijk et al. 2016 (
      • Van Dijk M.M.
      • Vissenberg R.
      • Bisschop P.H.
      • Dawood F.
      • van Wely M.
      • Goddijn M.
      • et al.
      Is subclinical hypothyroidism associated with lower live birth rates in women who have experienced unexplained recurrent miscarriage?.
      )
      Observational cohort838≥2 Pregnancy losses <20 weeks’ gestationTSH >97.5th percentile (4.5 mIU/L) and TT4 between 2.5th and 97.5th percentiles (71–140 nmol/L)Not statedSCH prevalence 2%; SCH cumulative LBR 45% vs. euthyroid cumulative LBR 52%; SCH PR 65% vs. euthyroid PR 69%; SCH MR1 35% vs. euthyroid MR1 28%Cumulative LBR SCH vs. euthyroid, OR 0.69 (0.28-1.71); PR SCH vs. euthyroid, OR 0.82 (0.32–2.10); MR1 SCH vs. euthyroid, OR 1.43 (0.56–3.68)
      Uchida et al. 2017 (
      • Uchida S.
      • Maruyama T.
      • Kagami M.
      • Miki F.
      • Hihara H.
      • Katakura S.
      • et al.
      Impact of borderline-subclinical hypothyroidism on subsequent pregnancy outcome in women with unexplained recurrent pregnancy loss.
      )
      Retrospective cohort317“Unexplained RPL,” ≥2 pregnancy lossesTSH >2.5 but <4.5 mIU/L and “normal” fT4 (not defined)Not statedSCH mean number of prior miscarriages 2.6 vs. euthyroid mean number of prior miscarriages 2.5; SCH MR2 29% vs. euthyroid MR2 18%Mean number of prior miscarriages SCH vs. euthyroid, P=.357; MR2 SCH vs. euthyroid, P=.16
      Note: fT3 = free triiodothyronine; fT4 = free thyroxine; LBR = live-birth rate; OR = odds ratio; MR1 = miscarriage rate, defined as pregnancy losses <20 weeks of gestation; MR2 = miscarriage rate, defined as pregnancy losses <22 weeks of gestation; NA = not applicable; PR = pregnancy rate, defined as pregnancies continuing >12 weeks of gestation; RPL = recurrent pregnancy loss; SCH = subclinical hypothyroidism; TRH = thyrotropin releasing hormone; TSH = thyroid-stimulating hormone; TT4 = total thyroxine.
      Table 2Intervention studies on subclinical hypothyroidism and/or thyroid autoimmunity in recurrent pregnancy loss.
      StudyStudy designNRPL definitionInterventionTiming and doseResult
      SCH
       Bernardi et al. 2013 (
      • Bernardi L.A.
      • Cohen R.N.
      • Stephenson M.D.
      Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss.
      )
      Observational cohort-control180≥2 Pregnancy losses of <10 weeks’ sizeLevothyroxineStarted before pregnancy or <6 weeks’ gestation; dosage titrated to maintain TSH ≤2.5 mIU/LSCH-treated cumulative LBR 71% (17/24) vs. SCH-nontreated cumulative LBR 67% (10/15), P=1.00
      TAI
       Yan et al. 2012 (
      • Yan J.
      • Sripada S.
      • Saravelos S.H.
      • Chen Z.J.
      • Egner W.
      • Li T.C.
      Thyroid peroxidase antibody in women with unexplained recurrent miscarriage: prevalence, prognostic value, and response to empirical thyroxine therapy.
      )
      Retrospective cohort4963 Nonconsecutive miscarriages <20 weeks’ gestationLevothyroxine50 μg QD starting at ≤6 weeks’ gestation, continued throughout pregnancyTAI-treated LBR 53% (9/17) vs. TAI-nontreated LBR 58% (21/36), P>.05
       Mosaddegh et al. 2012 (
      • Mosaddegh M.H.
      • Ghasemi N.
      • Jahaninejad T.
      • Mohsenifar F.
      • Aflatoonian A.
      Treatment of recurrent pregnancy loss by levothyroxine in women with high anti-TPO antibody.
      )
      Observational cross-sectional452 Nonconsecutive miscarriagesLevothyroxine25–100 μg QD started before pregnancy, continued throughout pregnancyTAI-treated ongoing pregnancy 83% (29/35) vs. TAI-nontreated OP 0% (0/3)
       Vissenberg et al. 2016 (
      • Vissenberg R.
      • Fliers E.
      • van der Post J.A.
      • van Wely M.
      • Bisschop P.H.
      • Goddijn M.
      Live-birth rate in euthyroid women with recurrent miscarriage and thyroid peroxidase antibodies.
      )
      Retrospective cohort2022 Nonconsecutive miscarriages <20 weeks’ gestationLevothyroxineStarted before pregnancy; unknown doseTAI-treated LBR 60% (6/10) vs. TAI negative 51% (89/174), P=.50
       Dhillon-Smith et al. 2019 (
      • Dhillon-Smith R.
      • Middleton L.J.
      • Sunner K.K.
      • Cheed V.
      • Baker K.
      • Farrell-Carver S.
      • et al.
      Levothyroxine in women with thyroid peroxidase antibodies before conception.
      )
      Randomized controlled trial1963 Nonconsecutive miscarriagesLevothyroxine50 μg QD started before pregnancy, continued throughout pregnancyTAI-treated LBR 36% (34/94) vs. TAI-placebo 35% (36/102), RR 1.04 (0.72–1.51)
       Kiprov et al. 1996 (
      • Kiprov D.D.
      • Nachtigall R.D.
      • Weaver R.C.
      • Jacobson A.
      • Main E.K.
      • Garovoy M.R.
      The use of intravenous immunoglobulin in recurrent pregnancy loss associated with combined alloimmune and autoimmune abnormalities.
      )
      Case series243 Nonconsecutive miscarriagesIVIG200–250 mg/kg each mo before and/or in pregnancy; stopped at 8 months’ gestationTAI-IVIG treated LBR 88% (21/24)
       Vaquero et al. 2000 (
      • Vaquero E.
      • Lazzarin N.
      • De Carolis C.
      • Valensise H.
      • Moretti C.
      • Ramanini C.
      Mild thyroid abnormalities and recurrent spontaneous abortion: diagnostic and therapeutical approach.
      )
      Case series272 Nonconsecutive first-trimester miscarriagesIVIG or thyroid extract0.5 g/kg on 2 consecutive days, monthly from 5–32 weeks’ pregnancy, or 66 mg (11 mg T3 and 38 mg T4)TAI-IVIG treated LBR 55% (6/11) vs. TAI-thyroid extract treated 81% (13/16)
      SCH + TAI
       Lata et al. 2013 (
      • Lata K.
      • Dutta P.
      • Sridhar S.
      • Rohilla M.
      • Srinivasan A.
      • Prashad G.R.
      • et al.
      Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage: a case-control study.
      )
      Case control1002 Consecutive miscarriagesLevothyroxine25 μg QD titrated according to TSH at time of recruitment, before or during pregnancyNo difference in MR in SCH/TPOAb-treated vs. TPOAb-only (data not reported), P=.23
      Note: An ongoing pregnancy is ≥20 weeks’ gestation. IVIG = intravenous immunoglobulin; LBR = live-birth rate; MR = miscarriage rate; OP = ongoing pregnancy; QD = daily; RPL = recurrent pregnancy loss; RR = risk ratio; SCH = subclinical hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TAI = thyroid autoimmunity; TPOAb = thyroid peroxidase antibodies; TSH = thyroid-stimulating hormone.
      Table 3Studies examining the association between thyroid autoimmunity and recurrent pregnancy loss.
      StudyStudy designNRPL definitionAntibodies includedThyroid statusResultsP value/OR
      Association found
       Bussen and Steck 1995 (
      • Bussen S.
      • Steck T.
      Thyroid autoantibodies in euthyroid non-pregnant women with recurrent spontaneous abortions.
      )
      Case control22≥3 Consecutive miscarriagesTPO or Tg AbsUnknownRPL TAI prevalence 36% (8/22) vs. 9% (2/22) nulligravid vs. 4.5% (1/22) multigravida non-RPLTAI prevalence RPL vs. nulligravids, P=.03; TAI prevalence RPL vs. multigravids, P=.009
       Roberts et al. 1996 (
      • Roberts J.
      • Jenkins C.
      • Wilson R.
      • Pearson C.
      • Franklin I.A.
      • MacLean M.A.
      • et al.
      Recurrent miscarriage is associated with increased numbers of CD5/20 positive lymphocytes and an increased incidence of thyroid antibodies.
      )
      Cross sectional11≥3 Consecutive miscarriages and no live childrenTPO or Tg AbsEuthyroid: TSH <5 mIU/L and fT4 55–158 nmol/LRPL TAI prevalence 36% (4/11) vs. 0 nonpregnant vs. 0 non-RPL women in first trimester vs. 0 women “experiencing miscarriage” vs. 20% (2/11) women presenting for terminationTAI prevalence RPL vs. all other non-RPL groups, P<.01
       Bussen and Steck 1997 (
      • Bussen S.S.
      • Steck T.
      Thyroid antibodies and their relation to antithrombin antibodies, anticardiolipin antibodies and lupus anticoagulant in women with recurrent spontaneous abortions (antithyroid, anticardiolipin and antithrombin autoantibodies and lupus anticoagulant in habitual aborters).
      )
      Case control28≥3 Consecutive miscarriagesTPO or Tg AbsEuthyroid: not definedRPL TAI prevalence 39% (11/28) vs. 7% (2/28) multigravida without RPL/endocrine dysfunctionTAI prevalence RPL vs. non-RPL, P<.01
       Kutteh et al. 1999 (
      • Kutteh W.H.
      • Yetman D.L.
      • Carr A.C.
      • Beck L.A.
      • Scott R.T.
      Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing assisted reproduction.
      )
      Case control700≥2 Consecutive miscarriagesTPO or Tg AbsUnknownRPL TAI prevalence 23% (158/700) vs. 15% (29/200) non-RPLTAI prevalence RPL vs. non-RPL, P=.01
       Mavragani et al. 1999 (
      • Mavragani C.P.
      • Ioannidis J.P.
      • Tzioufas A.G.
      • Hantoumi I.E.
      • Moutsopoulos H.M.
      Recurrent pregnancy loss and autoantibody profile in autoimmune diseases.
      )
      Case control12≥2 Miscarriages in the first or second trimesterTPO or Tg AbsUnknownSignificant association between Tg Abs and RPL, but not between TPO Abs and RPL (exact prevalences not reported)Tg Ab prevalence RPL vs. non-RPL, P=.03; TPO Abs prevalence RPL vs. non-RPL, P=.14
       Dendrinos et al. 2000 (
      • Dendrinos S.
      • Papasteriades C.
      • Tarassi K.
      • Christodoulakos G.
      • Prasinos G.
      • Creatsas G.
      Thyroid autoimmunity in patients with recurrent spontaneous miscarriages.
      )
      Case control30≥3 Consecutive miscarriagesTPO or Tg AbsEuthyroid: TSH 0.5–4.6 mIU/LRPL TAI prevalence 37% (11/30) vs. 13% (2/15) non-RPLTAI prevalence RPL vs. non-RPL, P<.05
       Mecacci et al. 2000 (
      • Mecacci F.
      • Parretti E.
      • Cioni R.
      • Lucchetti R.
      • Magrini A.
      • La Torre P.
      • et al.
      Thyroid autoimmunity and its association with non-organ-specific antibodies and subclinical alterations of thyroid function in women with a history of pregnancy loss or preeclampsia.
      )
      Case control138≥2 Pregnancy losses in the first trimesterTPO or Tg AbsUnknownRPL TAI prevalence 38% (11/29) vs. 15% (10/69) non-RPLTAI prevalence RPL vs. non-RPL, P<.02
       Bagis et al. 2001 (
      • Bagis T.
      • Gokcel A.
      • Saygili E.S.
      Autoimmune thyroid disease in pregnancy and the postpartum period: relationship to spontaneous abortion.
      )
      Prospective cohort108≥3 MiscarriagesTPO or Tg AbsUnknownTAI RPL prevalence 11% (12/108) vs. 3% (24/768) without TAIRPL prevalence TAI vs. no TAI, P<.0001
       Marai et al. 2004 (
      • Marai I.
      • Carp H.
      • Shai S.
      • Shabo R.
      • Fishman G.
      • Shoenfeld Y.
      Autoantibody panel screening in recurrent miscarriages.
      )
      Case control38≥3 Consecutive miscarriagesTPO or Tg AbsUnknownRPL TAI prevalence 21% (8/38) vs. 0 (0/20) non-RPLTAI prevalence RPL vs. non-RPL, P=.01
       Iravani et al. 2008 (
      • Iravani A.T.
      • Saeedi M.M.
      • Pakravesh J.
      • Hamidi S.
      • Abbasi M.
      Thyroid autoimmunity and recurrent spontaneous abortion in Iran: a case-control study.
      )
      Case control641≥3 Consecutive miscarriagesTPO or Tg AbsEuthyroid: TSH 0.4–4.0 mIU/L and fT4 4.5–10.9 μg/dLRPL TAI prevalence 25% (157/541) vs. 13% (34/269) non-RPLTAI prevalence RPL vs. non-RPL, P<.001
       Fouda et al. 2011 (
      • Fouda E.D.
      • Badr G.A.
      • Fata A.
      • Hadad M.
      • Alrayes M.
      Thyroid autoantibodies as a marker of immunologic disorder in women with unexplained recurrent spontaneous abortion.
      )
      Cross sectional50≥ 3 Consecutive miscarriages <20 weeks’ gestationTPO or Tg AbsEuthyroid: normal fT3, fT4, and TSH (ranges not provided)RPL TPO Abs prevalence 68% (34/50) vs. 45% (9/20) non-RPL, RPL Tg Abs prevalence 58% (29/50) vs. 15% (3/20) non-RPL; only Tg Abs associated with RPLTPO Abs prevalence RPL vs. non-RPL, P=.176; Tg Abs prevalence RPL vs. non-RPL, P=.02
       Ticconi et al. 2011 (
      • Ticconi C.
      • Giuliani E.
      • Veglia M.
      • Pietropolli A.
      • Piccione E.
      • Di Simone N.
      Thyroid autoimmunity and recurrent miscarriage.
      )
      Case control160≥2 Consecutive miscarriagesTPO or Tg AbsUnknownRPL TAI prevalence 29% (46/160) vs. 13% (13/100) non-RPL, primary RPL TAI prevalence 28% (31/111) vs. 31% (15/49), secondary RPL, 2 prior miscarriages, TAI prevalence 23% (21/92) vs. 37% (25/68) >3 prior miscarriagesTAI prevalence RPL vs. non-RPL, P<.05; TAI prevalence primary RPL vs. secondary RPL, P>.05; TAI prevalence 2 prior miscarriages vs. >3 prior miscarriages, P>.05
       Lakshmi et al. 2016 (
      • Lakshmi G.
      • Hema N.S.
      • Sarma P.S.
      Prevalence of thyroid autoantibodies as determinant of recurrent pregnancy loss a hospital based study.
      )
      Case control73≥3 MiscarriagesTPO AbsUnknownRPL TAI prevalence 60.3% (44/73) vs. 44% (92/209) non-RPLTAI prevalence RPL vs. non-RPL, P=.017
       Mumusoglu et al. 2016 (
      • Mumusoglu S.
      • Beksac M.S.
      • Ekiz A.
      • Ozdemir P.
      • Hascelik G.
      Does the presence of autoantibodies without autoimmune diseases and hereditary thrombophilia have an effect on recurrent pregnancy loss?.
      )
      Retrospective cohort119≥2 MiscarriagesTPO or Tg AbsUnknownTAI RPL prevalence 30% vs. 18% TAI negative (exact numbers NA), but only Tg Abs associated with RPL, not TPO AbsRPL prevalence TAI vs. TAI negative, P=.013
      No association found
       Tulppala et al. 1993 (
      • Tulppala M.
      • Palosuo T.
      • Ramsay T.
      • Miettinen A.
      • Salonen R.
      • Ylikorkala O.
      A prospective study of 63 couples with a history of recurrent spontaneous abortion: contributing factors and outcome of subsequent pregnancies.
      )
      Prospective cohort60≥3 Consecutive miscarriagesTPO or Tg AbsUnknownRPL TAI prevalence 17% (10/60) vs. 17% (10/60) non-RPLNot reported
       Pratt et al. 1993 (
      • Pratt D.
      • Novotny M.
      • Kaberlein G.
      • Dudkiewicz A.
      • Gleicher N.
      Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss.
      )
      Case control45≥3 Consecutive first or second trimester miscarriagesTPO or Tg AbsUnknownRPL TAI prevalence 31% (14/45) vs. 19% (19/100) “apparently normal” blood donorsTAI prevalence RPL vs. non-RPL, P>.05
       Esplin et al. 1998 (
      • Esplin M.S.
      • Branch D.W.
      • Silver R.
      • Stagnaro-Green A.
      Thyroid autoantibodies are not associated with recurrent pregnancy loss.
      )
      Case control74≥3 MiscarriagesTPO or Tg AbsUnknownRPL TAI prevalence 29% (22/74) vs. 37% (28/75) non-RPLTAI prevalence RPL vs. non-RPL, P>.05
       Shoenfeld et al. 2006 (
      • Shoenfeld Y.
      • Carp H.J.A.
      • Molina V.
      • Blank M.
      • Cervera R.
      • Balasch J.
      • et al.
      Autoantibodies and prediction of reproductive failure.
      )
      Case control109≥3 Consecutive miscarriagesTPO or Tg AbsUnknownNo association between RPL and TAI (exact data NA)Not reported
       Ashrafi et al. 2007 (
      • Ashrafi M.
      • Yazdi R.S.
      • Madani T.
      • Bazrafshan A.
      Anti-thyroid peroxidase and risk of recurrent spontaneous abortion.
      )
      Case control58≥2 Consecutive miscarriages and ≤1 prior live birthTPO AbsUnknownRPL TAI prevalence 21% (12/58) vs. 14% (8/58) non-RPLTAI prevalence RPL vs. non-RPL, P>.05
       Feki et al. 2008 (
      • Feki M.
      • Omar S.
      • Menif O.
      • Tanfous N.B.
      • Slimane H.
      • Zouari F.
      • et al.
      Thyroid disorders in pregnancy: frequency and association with selected diseases and obstetrical complications in Tunisian women.
      )
      Cross sectional99≥2 Consecutive miscarriages from 5–26 weeks’ gestationTPO AbsUnknownTAI RPL prevalence 4% (4/99) vs. 5.2% (74/1,420) without TAIRPL prevalence TAI vs. no TAI, P=.61
       Roye-Green et al. 2011 (
      • Roye-Green K.
      • Frederick J.
      • Wharfe G.
      • Choo-Kang E.
      • DaCosta V.
      • Fletcher H.
      • et al.
      Antiphospholipid and other autoantibodies in a cohort of habitual aborters and healthy multiparous women in Jamaica.
      )
      Case control50≥2 Consecutive miscarriagesTPO or Tg AbsUnknownRPL TAI prevalence 2% (1/50) vs. 1% (2/135) non-RPLNot reported
       Yan et al. 2012 (
      • Yan J.
      • Sripada S.
      • Saravelos S.H.
      • Chen Z.J.
      • Egner W.
      • Li T.C.
      Thyroid peroxidase antibody in women with unexplained recurrent miscarriage: prevalence, prognostic value, and response to empirical thyroxine therapy.
      )
      Retrospective cohort496≥3 Miscarriages <20 weeks’ gestationTPO AbsUnknownUnexplained RPL TAI prevalence 11% (53/496) vs. 12% (26/220) explained RPLUnexplained RPL prevalence TAI vs. explained RPL, P>.05
       Motak-Pochrzest and Malinowski 2013 (
      • Motak-Pochrzest H.
      • Malinowski A.
      The occurrence of immunological disturbances in patients with recurrent miscarriage (RM) of unknown etiology.
      )
      Case control155≥ 3 Consecutive miscarriages <22 weeks’ gestationTPO or Tg AbsEuthyroid: TSH 0.27–4.2 mIU/LUnexplained RPL TAI prevalence 22% (34/155) vs. 16% (8/50) non-RPLTAI prevalence unexplained RPL vs. non-RPL, P=.37
       Triggianese et al. 2016 (
      • Triggianese P.
      • Perricone C.
      • Conigliaro P.
      • Chimenti M.S.
      • Perricone R.
      • De Carolis C.
      Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure.
      )
      Case control210≥2 Consecutive miscarriages <20 weeks’ gestationTPO or Tg AbsUnknownPrimary RPL TAI prevalence 20% (29/145), secondary RPL TAI prevalence 26% (17/65) vs. 20% (9/45) non-RPLPrimary RPL prevalence TAI vs. non-RPL, P>.05; secondary RPL prevalence TAI vs. non-RPL, P>.05
       Meena et al. 2016 (
      • Meena M.
      • Chopra S.
      • Jain V.
      • Aggarwal N.
      The effect of anti-thyroid peroxidase antibodies on pregnancy outcomes in euthyroid women.
      )
      Prospective cohort40≥2 Consecutive miscarriagesTPO AbsEuthyroid: TSH 0.2–4.2 mIU/LTAI RPL prevalence 20% (8/40) vs. 12.5% (5/40) without TAITAI prevalence RPL vs. no TAI, P=.367
       Cueva et al. 2018 (
      • Cueva S.
      • Burks C.
      • McQueen D.
      • Barkoff M.S.
      • Stephenson M.D.
      Maternal antithyroid antibodies and euploid miscarriage in women with recurrent early pregnancy loss.
      )
      Retrospective cohort74≥2 Miscarriages <10 weeks’ gestationTPO or Tg AbsUnknownRPL euploid miscarriage TAI prevalence 42% (5/12) vs. 56% (28/50) euploid miscarriage without TAIPresence of TAI RPL euploid miscarriage vs. no TAI, P>.05
      Note: Abs = antibodies; fT3 = free triiodothyronine; fT4 = free thyroxine; NA = not available; OR = odds ratio; RPL = recurrent pregnancy loss; TAI = thyroid autoimmunity; Tg = thyroglobulin; TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone.

       Overt Hypothyroidism and RPL

       Question: Is overt hypothyroidism associated with RPL?

      No studies examining the potential associations between overt hypothyroidism and RPL were identified in this systematic review.

       Question: Does treatment improve pregnancy outcomes in women with RPL who have overt hypothyroidism?

      No studies examining whether treating overt hypothyroidism in women with RPL improves pregnancy outcomes were identified in this systematic review.

       Discussion

      No studies explicitly examining overt hypothyroidism in women with RPL have been published. However, given the wide range of adverse impacts that have been linked to overt hypothyroidism in pregnancy and the universally accepted recommendations for treatment (
      • Alexander E.K.
      • Pearce E.N.
      • Brent G.A.
      • Brown R.S.
      • Chen H.
      • Dosiou C.
      • et al.
      2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum.
      ,
      American College of Obstetricians and Gynecologists
      Practice Bulletin No. 148: Thyroid disease in pregnancy.
      ), such studies would be unethical to conduct at this point. Although treatment of overt hypothyroidism is not known to have beneficial impacts on pregnancy outcomes in women with RPL specifically, treatment must nevertheless be given to all women found to have overt hypothyroidism.

       Subclinical Hypothyroidism and RPL

       Question: Is subclinical hypothyroidism associated with RPL?

      Five eligible studies addressed whether subclinical hypothyroidism is associated with RPL (
      • Bernardi L.A.
      • Cohen R.N.
      • Stephenson M.D.
      Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss.
      ,
      • Liu Y.
      • Liu Y.
      • Zhang S.
      • Chen H.
      • Liu M.
      • Zhang J.
      Etiology of spontaneous abortion before and after the demonstration of embryonic cardiac activity in women with recurrent spontaneous abortion.
      ,
      • Triggianese P.
      • Perricone C.
      • Conigliaro P.
      • Chimenti M.S.
      • Perricone R.
      • De Carolis C.
      Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure.
      ,
      • Van Dijk M.M.
      • Vissenberg R.
      • Bisschop P.H.
      • Dawood F.
      • van Wely M.
      • Goddijn M.
      • et al.
      Is subclinical hypothyroidism associated with lower live birth rates in women who have experienced unexplained recurrent miscarriage?.
      ,
      • Uchida S.
      • Maruyama T.
      • Kagami M.
      • Miki F.
      • Hihara H.
      • Katakura S.
      • et al.
      Impact of borderline-subclinical hypothyroidism on subsequent pregnancy outcome in women with unexplained recurrent pregnancy loss.
      ). Descriptions of each study, including their definitions of RPL and subclinical hypothyroidism, and their results are shown in Table 1. A meta-analysis of the prevalence of subclinical hypothyroidism in women with RPL was conducted from these five studies, and the pooled prevalence was calculated to be 12.6% (95% confidence interval [CI], 0%–35.2%; I2 99%).

       Question: Does treatment with levothyroxine improve subsequent pregnancy outcomes in women with a history of RPL who have subclinical hypothyroidism?

      One study reported on subsequent pregnancy outcomes after treatment with levothyroxine in women with RPL who had subclinical hypothyroidism (
      • Bernardi L.A.
      • Cohen R.N.
      • Stephenson M.D.
      Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss.
      ), as shown in Table 2. The definition of RPL as well as the dose and timing of levothyroxine administration and the results are included in the table.

       Discussion

      Liu et al. (
      • Liu Y.
      • Liu Y.
      • Zhang S.
      • Chen H.
      • Liu M.
      • Zhang J.
      Etiology of spontaneous abortion before and after the demonstration of embryonic cardiac activity in women with recurrent spontaneous abortion.
      ) reported that the prevalence of subclinical hypothyroidism in women with RPL was 16%, but there was no control group for comparison. Of the remaining four studies, three found no association between subclinical hypothyroidism and RPL (
      • Bernardi L.A.
      • Cohen R.N.
      • Stephenson M.D.
      Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss.
      ,
      • Van Dijk M.M.
      • Vissenberg R.
      • Bisschop P.H.
      • Dawood F.
      • van Wely M.
      • Goddijn M.
      • et al.
      Is subclinical hypothyroidism associated with lower live birth rates in women who have experienced unexplained recurrent miscarriage?.
      ,
      • Uchida S.
      • Maruyama T.
      • Kagami M.
      • Miki F.
      • Hihara H.
      • Katakura S.
      • et al.
      Impact of borderline-subclinical hypothyroidism on subsequent pregnancy outcome in women with unexplained recurrent pregnancy loss.
      ). However, Triggianese et al. (
      • Triggianese P.
      • Perricone C.
      • Conigliaro P.
      • Chimenti M.S.
      • Perricone R.
      • De Carolis C.
      Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure.
      ) did find a significant association. The three studies reporting no association between subclinical hypothyroidism and RPL used definitions of RPL that do not require consecutive pregnancy losses; the study by Triggianese et al. (
      • Triggianese P.
      • Perricone C.
      • Conigliaro P.
      • Chimenti M.S.
      • Perricone R.
      • De Carolis C.
      Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure.
      ) does require consecutive losses. This difference may account for the differing results.
      The prevalence of subclinical hypothyroidism in pregnancy is approximately 3.5%, and the prevalence in the general nonpregnant population (men and women) is approximately 4.3% (
      • Dong A.C.
      • Stagnaro-Green A.
      Differences in diagnostic criteria mask the true prevalence of thyroid disease in pregnancy: a systematic review and meta-analysis.
      ,
      • Hollowell J.G.
      • Staehling N.W.
      • Flanders W.D.
      • Hannon W.H.
      • Gunter E.W.
      • Spencer C.A.
      • et al.
      Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III).
      ). Based on our meta-analysis, it is unclear whether women with RPL have a higher prevalence of subclinical hypothyroidism compared with those without RPL. Our meta-analysis found the prevalence of subclinical hypothyroidism in women with RPL to be 12.9%, but the heterogeneity between studies was extremely high and the 95% CI was very wide; therefore, the calculated prevalence is questionable. Thus, there remains a great need for further research on this topic.
      As stated earlier, the current evidence suggests no association between subclinical hypothyroidism and RPL when RPL is defined by nonconsecutive pregnancy losses. Consequently, treating subclinical hypothyroidism is unlikely to improve pregnancy outcomes in these women. This statement is supported by the results of Bernardi et al. (
      • Bernardi L.A.
      • Cohen R.N.
      • Stephenson M.D.
      Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss.
      ), who documented no difference in live-birth rates between women with subclinical hypothyroidism and those with RPL who did or did not receive levothyroxine.
      However, the study by Triggianese et al. (
      • Triggianese P.
      • Perricone C.
      • Conigliaro P.
      • Chimenti M.S.
      • Perricone R.
      • De Carolis C.
      Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure.
      ) suggests that there may be an association between subclinical hypothyroidism and consecutive RPL. Biologically, this is plausible, as increasing numbers of consecutive pregnancy losses would imply pathology that is consistently present and impactful, such as thyroid dysfunction, as opposed to random chromosome errors or implantation on a uterine septum. It may be helpful to stratify future studies based on RPL definitions that comprise consecutive versus nonconsecutive losses to resolve whether an association exists between subclinical hypothyroidism and these forms of RPL.
      There is currently one randomized control trial, the Chinese Recurrent Pregnancy Loss and Thyroid Disease Study, registered in the United States Clinical Trials Registry (ClinicalTrials.gov ID: NCT03106935) that is evaluating whether Chinese women with RPL would have improved pregnancy outcomes with levothyroxine intervention. This study defines RPL as two or more first-trimester pregnancy losses, and subclinical hypothyroidism is defined as testing positive for thyroid antibodies with a TSH above 2.5 mIU/L but below the upper limit of the pregnancy-specific reference range or testing negative for thyroid antibodies with TSH levels greater than the lower limit of the pregnancy-specific reference range but below 10.0 mIU/L. The study’s primary outcomes include gestational age at delivery, birth weight, and APGAR score at birth. The secondary outcomes include clinical pregnancy rates, ongoing pregnancy at 12 weeks, and miscarriage. The study was anticipated to have been completed by June 2018, but it had not been published at the time of this article’s writing, and attempts to contact the principal investigator were unsuccessful.

       Thyroid Autoimmunity and RPL

       Question: Is thyroid autoimmunity associated with RPL?

      Twenty-six eligible studies addressed whether thyroid autoimmunity is associated with RPL (
      • Triggianese P.
      • Perricone C.
      • Conigliaro P.
      • Chimenti M.S.
      • Perricone R.
      • De Carolis C.
      Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure.
      ,
      • Bussen S.
      • Steck T.
      Thyroid autoantibodies in euthyroid non-pregnant women with recurrent spontaneous abortions.
      ,
      • Roberts J.
      • Jenkins C.
      • Wilson R.
      • Pearson C.
      • Franklin I.A.
      • MacLean M.A.
      • et al.
      Recurrent miscarriage is associated with increased numbers of CD5/20 positive lymphocytes and an increased incidence of thyroid antibodies.
      ,
      • Bussen S.S.
      • Steck T.
      Thyroid antibodies and their relation to antithrombin antibodies, anticardiolipin antibodies and lupus anticoagulant in women with recurrent spontaneous abortions (antithyroid, anticardiolipin and antithrombin autoantibodies and lupus anticoagulant in habitual aborters).
      ,
      • Kutteh W.H.
      • Yetman D.L.
      • Carr A.C.
      • Beck L.A.
      • Scott R.T.
      Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing assisted reproduction.
      ,
      • Mavragani C.P.
      • Ioannidis J.P.
      • Tzioufas A.G.
      • Hantoumi I.E.
      • Moutsopoulos H.M.
      Recurrent pregnancy loss and autoantibody profile in autoimmune diseases.
      ,
      • Dendrinos S.
      • Papasteriades C.
      • Tarassi K.
      • Christodoulakos G.
      • Prasinos G.
      • Creatsas G.
      Thyroid autoimmunity in patients with recurrent spontaneous miscarriages.
      ,
      • Mecacci F.
      • Parretti E.
      • Cioni R.
      • Lucchetti R.
      • Magrini A.
      • La Torre P.
      • et al.
      Thyroid autoimmunity and its association with non-organ-specific antibodies and subclinical alterations of thyroid function in women with a history of pregnancy loss or preeclampsia.
      ,
      • Bagis T.
      • Gokcel A.
      • Saygili E.S.
      Autoimmune thyroid disease in pregnancy and the postpartum period: relationship to spontaneous abortion.
      ,
      • Marai I.
      • Carp H.
      • Shai S.
      • Shabo R.
      • Fishman G.
      • Shoenfeld Y.
      Autoantibody panel screening in recurrent miscarriages.
      ,
      • Iravani A.T.
      • Saeedi M.M.
      • Pakravesh J.
      • Hamidi S.
      • Abbasi M.
      Thyroid autoimmunity and recurrent spontaneous abortion in Iran: a case-control study.
      ,
      • Ticconi C.
      • Giuliani E.
      • Veglia M.
      • Pietropolli A.
      • Piccione E.
      • Di Simone N.
      Thyroid autoimmunity and recurrent miscarriage.
      ,
      • Tulppala M.
      • Palosuo T.
      • Ramsay T.
      • Miettinen A.
      • Salonen R.
      • Ylikorkala O.
      A prospective study of 63 couples with a history of recurrent spontaneous abortion: contributing factors and outcome of subsequent pregnancies.
      ,
      • Pratt D.
      • Novotny M.
      • Kaberlein G.
      • Dudkiewicz A.
      • Gleicher N.
      Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss.
      ,
      • Esplin M.S.
      • Branch D.W.
      • Silver R.
      • Stagnaro-Green A.
      Thyroid autoantibodies are not associated with recurrent pregnancy loss.
      ,
      • Shoenfeld Y.
      • Carp H.J.A.
      • Molina V.
      • Blank M.
      • Cervera R.
      • Balasch J.
      • et al.
      Autoantibodies and prediction of reproductive failure.
      ,
      • Feki M.
      • Omar S.
      • Menif O.
      • Tanfous N.B.
      • Slimane H.
      • Zouari F.
      • et al.
      Thyroid disorders in pregnancy: frequency and association with selected diseases and obstetrical complications in Tunisian women.
      ,
      • Roye-Green K.
      • Frederick J.
      • Wharfe G.
      • Choo-Kang E.
      • DaCosta V.
      • Fletcher H.
      • et al.
      Antiphospholipid and other autoantibodies in a cohort of habitual aborters and healthy multiparous women in Jamaica.
      ,
      • Yan J.
      • Sripada S.
      • Saravelos S.H.
      • Chen Z.J.
      • Egner W.
      • Li T.C.
      Thyroid peroxidase antibody in women with unexplained recurrent miscarriage: prevalence, prognostic value, and response to empirical thyroxine therapy.
      ,
      • Meena M.
      • Chopra S.
      • Jain V.
      • Aggarwal N.
      The effect of anti-thyroid peroxidase antibodies on pregnancy outcomes in euthyroid women.
      ,
      • Cueva S.
      • Burks C.
      • McQueen D.
      • Barkoff M.S.
      • Stephenson M.D.
      Maternal antithyroid antibodies and euploid miscarriage in women with recurrent early pregnancy loss.
      ,
      • Fouda E.D.
      • Badr G.A.
      • Fata A.
      • Hadad M.
      • Alrayes M.
      Thyroid autoantibodies as a marker of immunologic disorder in women with unexplained recurrent spontaneous abortion.
      ,
      • Lakshmi G.
      • Hema N.S.
      • Sarma P.S.
      Prevalence of thyroid autoantibodies as determinant of recurrent pregnancy loss a hospital based study.
      ,
      • Motak-Pochrzest H.
      • Malinowski A.
      The occurrence of immunological disturbances in patients with recurrent miscarriage (RM) of unknown etiology.
      ,
      • Mumusoglu S.
      • Beksac M.S.
      • Ekiz A.
      • Ozdemir P.
      • Hascelik G.
      Does the presence of autoantibodies without autoimmune diseases and hereditary thrombophilia have an effect on recurrent pregnancy loss?.
      ,
      • Ashrafi M.
      • Yazdi R.S.
      • Madani T.
      • Bazrafshan A.
      Anti-thyroid peroxidase and risk of recurrent spontaneous abortion.
      ). Table 3 includes descriptions of each study, including their definitions of RPL as well as thyroid autoimmunity, thyroid status, and results. Fourteen of the 26 studies showed a statistically significant association between thyroid autoimmunity and RPL (
      • Bussen S.
      • Steck T.
      Thyroid autoantibodies in euthyroid non-pregnant women with recurrent spontaneous abortions.
      ,
      • Roberts J.
      • Jenkins C.
      • Wilson R.
      • Pearson C.
      • Franklin I.A.
      • MacLean M.A.
      • et al.
      Recurrent miscarriage is associated with increased numbers of CD5/20 positive lymphocytes and an increased incidence of thyroid antibodies.
      ,
      • Bussen S.S.
      • Steck T.
      Thyroid antibodies and their relation to antithrombin antibodies, anticardiolipin antibodies and lupus anticoagulant in women with recurrent spontaneous abortions (antithyroid, anticardiolipin and antithrombin autoantibodies and lupus anticoagulant in habitual aborters).
      ,
      • Kutteh W.H.
      • Yetman D.L.
      • Carr A.C.
      • Beck L.A.
      • Scott R.T.
      Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing assisted reproduction.
      ,
      • Mavragani C.P.
      • Ioannidis J.P.
      • Tzioufas A.G.
      • Hantoumi I.E.
      • Moutsopoulos H.M.
      Recurrent pregnancy loss and autoantibody profile in autoimmune diseases.
      ,
      • Dendrinos S.
      • Papasteriades C.
      • Tarassi K.
      • Christodoulakos G.
      • Prasinos G.
      • Creatsas G.
      Thyroid autoimmunity in patients with recurrent spontaneous miscarriages.
      ,
      • Mecacci F.
      • Parretti E.
      • Cioni R.
      • Lucchetti R.
      • Magrini A.
      • La Torre P.
      • et al.
      Thyroid autoimmunity and its association with non-organ-specific antibodies and subclinical alterations of thyroid function in women with a history of pregnancy loss or preeclampsia.
      ,
      • Bagis T.
      • Gokcel A.
      • Saygili E.S.
      Autoimmune thyroid disease in pregnancy and the postpartum period: relationship to spontaneous abortion.
      ,
      • Marai I.
      • Carp H.
      • Shai S.
      • Shabo R.
      • Fishman G.
      • Shoenfeld Y.
      Autoantibody panel screening in recurrent miscarriages.
      ,
      • Iravani A.T.
      • Saeedi M.M.
      • Pakravesh J.
      • Hamidi S.
      • Abbasi M.
      Thyroid autoimmunity and recurrent spontaneous abortion in Iran: a case-control study.
      ,
      • Ticconi C.
      • Giuliani E.
      • Veglia M.
      • Pietropolli A.
      • Piccione E.
      • Di Simone N.
      Thyroid autoimmunity and recurrent miscarriage.
      ,
      • Fouda E.D.
      • Badr G.A.
      • Fata A.
      • Hadad M.
      • Alrayes M.
      Thyroid autoantibodies as a marker of immunologic disorder in women with unexplained recurrent spontaneous abortion.
      ,
      • Lakshmi G.
      • Hema N.S.
      • Sarma P.S.
      Prevalence of thyroid autoantibodies as determinant of recurrent pregnancy loss a hospital based study.
      ,
      • Mumusoglu S.
      • Beksac M.S.
      • Ekiz A.
      • Ozdemir P.
      • Hascelik G.
      Does the presence of autoantibodies without autoimmune diseases and hereditary thrombophilia have an effect on recurrent pregnancy loss?.
      ), whereas 12 studies showed no association (
      • Triggianese P.
      • Perricone C.
      • Conigliaro P.
      • Chimenti M.S.
      • Perricone R.
      • De Carolis C.
      Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure.
      ,
      • Tulppala M.
      • Palosuo T.
      • Ramsay T.
      • Miettinen A.
      • Salonen R.
      • Ylikorkala O.
      A prospective study of 63 couples with a history of recurrent spontaneous abortion: contributing factors and outcome of subsequent pregnancies.
      ,
      • Pratt D.
      • Novotny M.
      • Kaberlein G.
      • Dudkiewicz A.
      • Gleicher N.
      Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss.
      ,
      • Esplin M.S.
      • Branch D.W.
      • Silver R.
      • Stagnaro-Green A.
      Thyroid autoantibodies are not associated with recurrent pregnancy loss.
      ,
      • Shoenfeld Y.
      • Carp H.J.A.
      • Molina V.
      • Blank M.
      • Cervera R.
      • Balasch J.
      • et al.
      Autoantibodies and prediction of reproductive failure.
      ,
      • Feki M.
      • Omar S.
      • Menif O.
      • Tanfous N.B.
      • Slimane H.
      • Zouari F.
      • et al.
      Thyroid disorders in pregnancy: frequency and association with selected diseases and obstetrical complications in Tunisian women.
      ,
      • Roye-Green K.
      • Frederick J.
      • Wharfe G.
      • Choo-Kang E.
      • DaCosta V.
      • Fletcher H.
      • et al.
      Antiphospholipid and other autoantibodies in a cohort of habitual aborters and healthy multiparous women in Jamaica.
      ,
      • Yan J.
      • Sripada S.
      • Saravelos S.H.
      • Chen Z.J.
      • Egner W.
      • Li T.C.
      Thyroid peroxidase antibody in women with unexplained recurrent miscarriage: prevalence, prognostic value, and response to empirical thyroxine therapy.
      ,
      • Meena M.
      • Chopra S.
      • Jain V.
      • Aggarwal N.
      The effect of anti-thyroid peroxidase antibodies on pregnancy outcomes in euthyroid women.
      ,
      • Cueva S.
      • Burks C.
      • McQueen D.
      • Barkoff M.S.
      • Stephenson M.D.
      Maternal antithyroid antibodies and euploid miscarriage in women with recurrent early pregnancy loss.
      ,
      • Motak-Pochrzest H.
      • Malinowski A.
      The occurrence of immunological disturbances in patients with recurrent miscarriage (RM) of unknown etiology.
      ,
      • Ashrafi M.
      • Yazdi R.S.
      • Madani T.
      • Bazrafshan A.
      Anti-thyroid peroxidase and risk of recurrent spontaneous abortion.
      ).
      Meta-analysis of the 17 studies that provided data comparing the prevalence of thyroid autoimmunity in a cohort of women with RPL to those without RPL revealed a statistically significant association between thyroid autoimmunity and RPL (OR 1.94; 95% CI, 1.43–2.64) (
      • Bussen S.
      • Steck T.
      Thyroid autoantibodies in euthyroid non-pregnant women with recurrent spontaneous abortions.
      ,
      • Kutteh W.H.
      • Yetman D.L.
      • Carr A.C.
      • Beck L.A.
      • Scott R.T.
      Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing assisted reproduction.
      ,
      • Dendrinos S.
      • Papasteriades C.
      • Tarassi K.
      • Christodoulakos G.
      • Prasinos G.
      • Creatsas G.
      Thyroid autoimmunity in patients with recurrent spontaneous miscarriages.
      ,
      • Mecacci F.
      • Parretti E.
      • Cioni R.
      • Lucchetti R.
      • Magrini A.
      • La Torre P.
      • et al.
      Thyroid autoimmunity and its association with non-organ-specific antibodies and subclinical alterations of thyroid function in women with a history of pregnancy loss or preeclampsia.
      ,
      • Bagis T.
      • Gokcel A.
      • Saygili E.S.
      Autoimmune thyroid disease in pregnancy and the postpartum period: relationship to spontaneous abortion.
      ,
      • Iravani A.T.
      • Saeedi M.M.
      • Pakravesh J.
      • Hamidi S.
      • Abbasi M.
      Thyroid autoimmunity and recurrent spontaneous abortion in Iran: a case-control study.
      ,
      • Ticconi C.
      • Giuliani E.
      • Veglia M.
      • Pietropolli A.
      • Piccione E.
      • Di Simone N.
      Thyroid autoimmunity and recurrent miscarriage.
      ,
      • Tulppala M.
      • Palosuo T.
      • Ramsay T.
      • Miettinen A.
      • Salonen R.
      • Ylikorkala O.
      A prospective study of 63 couples with a history of recurrent spontaneous abortion: contributing factors and outcome of subsequent pregnancies.
      ,
      • Pratt D.
      • Novotny M.
      • Kaberlein G.
      • Dudkiewicz A.
      • Gleicher N.
      Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss.
      ,
      • Esplin M.S.
      • Branch D.W.
      • Silver R.
      • Stagnaro-Green A.
      Thyroid autoantibodies are not associated with recurrent pregnancy loss.
      ,
      • Roye-Green K.
      • Frederick J.
      • Wharfe G.
      • Choo-Kang E.
      • DaCosta V.
      • Fletcher H.
      • et al.
      Antiphospholipid and other autoantibodies in a cohort of habitual aborters and healthy multiparous women in Jamaica.
      ,
      • Lakshmi G.
      • Hema N.S.
      • Sarma P.S.
      Prevalence of thyroid autoantibodies as determinant of recurrent pregnancy loss a hospital based study.
      ,
      • Motak-Pochrzest H.
      • Malinowski A.
      The occurrence of immunological disturbances in patients with recurrent miscarriage (RM) of unknown etiology.
      ,
      • Ashrafi M.
      • Yazdi R.S.
      • Madani T.
      • Bazrafshan A.
      Anti-thyroid peroxidase and risk of recurrent spontaneous abortion.
      ,
      • Lata K.
      • Dutta P.
      • Sridhar S.
      • Rohilla M.
      • Srinivasan A.
      • Prashad G.R.
      • et al.
      Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage: a case-control study.
      ). A forest plot for these 17 studies is presented in Figure 1. Sensitivity analyses were performed that considered only studies that had entirely euthyroid RPL cohorts, excluding the one study that only examined TPOAb as opposed to both TPOAb and thyroglobulin antibodies, and excluding the studies with fewer than 30 and fewer than 40 participants with RPL. None of these analyses changed the statistical significance or magnitude of the results (data not shown).
      Figure thumbnail gr1
      Figure 1Forest plot of 17 studies examining the association between thyroid autoimmunity and recurrent pregnancy loss. Results are presented as odds ratios with 95% confidence intervals. Weighting of studies was done based on study heterogeneity.

       Question: Does thyroid autoimmunity predict future pregnancy outcomes in women with RPL?

      Six studies have been published on the predictive value of thyroid autoimmunity on the prognosis of future pregnancies of women with RPL (
      • Lata K.
      • Dutta P.
      • Sridhar S.
      • Rohilla M.
      • Srinivasan A.
      • Prashad G.R.
      • et al.
      Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage: a case-control study.
      ,
      • Singh A.
      • Dantas Z.N.
      • Stone S.C.
      • Asch R.H.
      Presence of thyroid antibodies in early reproductive failure: biochemical versus clinical pregnancies.
      ,
      • Rushworth F.H.
      • Backos M.
      • Rai R.
      • Chilcott I.T.
      • Baxter N.
      • Regan L.
      Prospective pregnancy outcome in untreated recurrent miscarriers with thyroid autoantibodies.
      ,
      • Pratt D.E.
      • Kaberlein G.
      • Dudkiewicz A.
      • Karande V.
      • Gleicher N.
      The association of antithyroid antibodies in euthyroid nonpregnant women with recurrent first trimester abortions in the next pregnancy.
      ,
      • Wilson R.
      • Ling H.
      • MacLean M.A.
      • Mooney J.
      • Kinnane D.
      • McKillop J.H.
      • et al.
      Thyroid antibody titer and avidity in patients with recurrent miscarriage.
      ,
      • Vissenberg R.
      • Fliers E.
      • van der Post J.A.
      • van Wely M.
      • Bisschop P.H.
      • Goddijn M.
      Live-birth rate in euthyroid women with recurrent miscarriage and thyroid peroxidase antibodies.
      ), as shown in Supplemental Table 2. Three studies reported no association between thyroid autoimmunity and future risk of pregnancy loss in women with RPL (
      • Lata K.
      • Dutta P.
      • Sridhar S.
      • Rohilla M.
      • Srinivasan A.
      • Prashad G.R.
      • et al.
      Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage: a case-control study.
      ,
      • Singh A.
      • Dantas Z.N.
      • Stone S.C.
      • Asch R.H.
      Presence of thyroid antibodies in early reproductive failure: biochemical versus clinical pregnancies.
      ,
      • Rushworth F.H.
      • Backos M.
      • Rai R.
      • Chilcott I.T.
      • Baxter N.
      • Regan L.
      Prospective pregnancy outcome in untreated recurrent miscarriers with thyroid autoantibodies.
      ). However, three other studies reported that thyroid autoimmunity, mainly TPOAb positivity, is associated with worse outcomes in future pregnancies in women with RPL (
      • Pratt D.E.
      • Kaberlein G.
      • Dudkiewicz A.
      • Karande V.
      • Gleicher N.
      The association of antithyroid antibodies in euthyroid nonpregnant women with recurrent first trimester abortions in the next pregnancy.
      ,
      • Wilson R.
      • Ling H.
      • MacLean M.A.
      • Mooney J.
      • Kinnane D.
      • McKillop J.H.
      • et al.
      Thyroid antibody titer and avidity in patients with recurrent miscarriage.
      ,
      • Vissenberg R.
      • Fliers E.
      • van der Post J.A.
      • van Wely M.
      • Bisschop P.H.
      • Goddijn M.
      Live-birth rate in euthyroid women with recurrent miscarriage and thyroid peroxidase antibodies.
      ).

       Question: What are potential mechanisms by which thyroid autoimmunity might impact RPL?

      Two studies have been published examining the potential mechanisms of action for how thyroid antibodies may cause miscarriage in women with RPL (
      • Lazzarin N.
      • Moretti C.
      • De Felice G.
      • Vaquero E.
      • Manfellotto D.
      Further evidence on the role of thyroid autoimmunity in women with recurrent miscarriage.
      ,
      • Mariee N.G.
      • Tuckerman E.
      • Laird S.
      • Li T.C.
      The correlation of autoantibodies and uNK cells in women with reproductive failure.
      ). Lazzarin et al. (
      • Lazzarin N.
      • Moretti C.
      • De Felice G.
      • Vaquero E.
      • Manfellotto D.
      Further evidence on the role of thyroid autoimmunity in women with recurrent miscarriage.
      ) published a cross-sectional study reporting that 30 of 46 (65%) euthyroid, Italian women with RPL—defined as two or more consecutive first-trimester pregnancy losses—who tested positive for either TPO or thyroglobulin antibodies had abnormal responses to thyroid-releasing hormone (TRH), possibly indicating some level of subtle thyroid dysfunction despite otherwise normal thyroid function tests.
      Mariee et al. (
      • Mariee N.G.
      • Tuckerman E.
      • Laird S.
      • Li T.C.
      The correlation of autoantibodies and uNK cells in women with reproductive failure.
      ) published a prospective cohort study that assessed uterine natural killer (NK) cells in 42 English women with a history of RPL, defined as three or more consecutive first-trimester pregnancy losses. Thyroid status was not presented. The mean proportion of uterine NK cells was 7.1% in women who tested positive for TPO antibodies, compared with 10.6% in those who tested negative (P>.05).

       Question: Is there an association between thyroid autoimmunity and antiphospholipid antibodies in women with RPL?

      Four studies have been published evaluating whether there is an association between antiphospholipid antibodies and thyroid antibodies in women with RPL (
      • Bussen S.S.
      • Steck T.
      Thyroid antibodies and their relation to antithrombin antibodies, anticardiolipin antibodies and lupus anticoagulant in women with recurrent spontaneous abortions (antithyroid, anticardiolipin and antithrombin autoantibodies and lupus anticoagulant in habitual aborters).
      ,
      • Mecacci F.
      • Parretti E.
      • Cioni R.
      • Lucchetti R.
      • Magrini A.
      • La Torre P.
      • et al.
      Thyroid autoimmunity and its association with non-organ-specific antibodies and subclinical alterations of thyroid function in women with a history of pregnancy loss or preeclampsia.
      ,
      • De Carolis C.
      • Greco E.
      • Guarino M.D.
      • Perricone C.
      • Dal Lago A.
      • Giacomelli R.
      • et al.
      Anti-thyroid antibodies and antiphospholipid syndrome: evidence of reduced fecundity and of poor pregnancy outcome in recurrent spontaneous aborters.
      ,
      • Promberger R.
      • Walch K.
      • Seemann R.
      • Pils S.
      • Ott J.
      A retrospective study on the association between thyroid autoantibodies with beta2-glycoprotein and cardiolipin antibodies in recurrent miscarriage.
      ), as shown in Supplemental Table 3.

       Question: Does treatment with levothyroxine improve subsequent pregnancy outcomes in women with a history of RPL who have thyroid autoimmunity?

      Four studies have examined the use of levothyroxine for thyroid autoimmunity in women with RPL (
      • Yan J.
      • Sripada S.
      • Saravelos S.H.
      • Chen Z.J.
      • Egner W.
      • Li T.C.
      Thyroid peroxidase antibody in women with unexplained recurrent miscarriage: prevalence, prognostic value, and response to empirical thyroxine therapy.
      ,
      • Vissenberg R.
      • Fliers E.
      • van der Post J.A.
      • van Wely M.
      • Bisschop P.H.
      • Goddijn M.
      Live-birth rate in euthyroid women with recurrent miscarriage and thyroid peroxidase antibodies.
      ,
      • Mosaddegh M.H.
      • Ghasemi N.
      • Jahaninejad T.
      • Mohsenifar F.
      • Aflatoonian A.
      Treatment of recurrent pregnancy loss by levothyroxine in women with high anti-TPO antibody.
      ,
      • Dhillon-Smith R.
      • Middleton L.J.
      • Sunner K.K.
      • Cheed V.
      • Baker K.
      • Farrell-Carver S.
      • et al.
      Levothyroxine in women with thyroid peroxidase antibodies before conception.
      ) as shown in Table 2.

       Question: Does treatment with intravenous immunoglobulin improve subsequent pregnancy outcomes in women with a history of RPL who have thyroid autoimmunity?

      Two published case-series studies have examined the use of intravenous immunoglobulin (IVIG) in women with a history of RPL who tested positive for thyroid antibodies (
      • Kiprov D.D.
      • Nachtigall R.D.
      • Weaver R.C.
      • Jacobson A.
      • Main E.K.
      • Garovoy M.R.
      The use of intravenous immunoglobulin in recurrent pregnancy loss associated with combined alloimmune and autoimmune abnormalities.
      ,
      • Vaquero E.
      • Lazzarin N.
      • De Carolis C.
      • Valensise H.
      • Moretti C.
      • Ramanini C.
      Mild thyroid abnormalities and recurrent spontaneous abortion: diagnostic and therapeutical approach.
      ), as shown in Table 2.

       Discussion

      Studies examining the association between thyroid autoimmunity and RPL have yielded mixed results, with 14 studies reporting statistically significant associations and 12 studies reporting no association. This is likely due to differences in the definitions used to define RPL, as well as the presence of confounding factors that may also be associated with RPL such as antiphospholipid antibodies. Our meta-analysis, however, did demonstrate a statistically significant association between thyroid autoimmunity and RPL.
      Differences in thyroid status may also result in effect modification of thyroid autoimmunity on RPL. Seven studies in our present review analyzed only women with euthyroid thyroid autoimmunity. Of these, only the studies by Meena et al. (
      • Meena M.
      • Chopra S.
      • Jain V.
      • Aggarwal N.
      The effect of anti-thyroid peroxidase antibodies on pregnancy outcomes in euthyroid women.
      ) and Motak-Pochrzest and Malinowski (
      • Motak-Pochrzest H.
      • Malinowski A.
      The occurrence of immunological disturbances in patients with recurrent miscarriage (RM) of unknown etiology.
      ) reported no association between RPL and thyroid autoimmunity; the remaining five did show a statistically significant association. In our own meta-analysis, in a sensitivity analysis that excluded studies that did not have an entirely euthyroid cohort, the association between thyroid autoimmunity and RPL remained statistically significant; however, the study by Meena et al. (
      • Meena M.
      • Chopra S.
      • Jain V.
      • Aggarwal N.
      The effect of anti-thyroid peroxidase antibodies on pregnancy outcomes in euthyroid women.
      ) was not included in our analysis because the design was not suitable for comparison. Thus, when considering studies that included only euthyroid patients, the evidence in our present review supports an association between thyroid autoimmunity in euthyroid women with RPL.
      Additionally, the majority of studies included in this review (14 out of 26) show an association between thyroid autoimmunity and RPL, regardless of thyroid status. The two studies involving the largest RPL cohorts, Kutteh et al. (
      • Kutteh W.H.
      • Yetman D.L.
      • Carr A.C.
      • Beck L.A.
      • Scott R.T.
      Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing assisted reproduction.
      ) and Iravani et al. (
      • Iravani A.T.
      • Saeedi M.M.
      • Pakravesh J.
      • Hamidi S.
      • Abbasi M.
      Thyroid autoimmunity and recurrent spontaneous abortion in Iran: a case-control study.
      ), comprising of 700 and 641 women with history of RPL respectively, both showed a statistically significant association between thyroid autoimmunity and RPL. The largest study that did not show an association was performed by Yan et al. (
      • Yan J.
      • Sripada S.
      • Saravelos S.H.
      • Chen Z.J.
      • Egner W.
      • Li T.C.
      Thyroid peroxidase antibody in women with unexplained recurrent miscarriage: prevalence, prognostic value, and response to empirical thyroxine therapy.
      ), involving 496 women with a history of unexplained RPL. The comparison group in this study was 220 women with known causes of RPL; however, finding the presence of a potential cause of RPL in a woman does not necessarily exclude the presence or contribution of other causes.
      Recurrent pregnancy loss has many potential confounding risk factors. Thyroid autoimmunity’s influence on RPL can thus be difficult to assess. Antiphospholipid antibodies, one of the most well-studied factors associated with RPL, could reasonably confound or result in effect-modification in studies on thyroid autoimmunity. However, only Promberger et al. (
      • Promberger R.
      • Walch K.
      • Seemann R.
      • Pils S.
      • Ott J.
      A retrospective study on the association between thyroid autoantibodies with beta2-glycoprotein and cardiolipin antibodies in recurrent miscarriage.
      ) reported a statistically significant association between RPL and markers of antiphospholipid antibodies, while the remaining three did not (
      • Bussen S.S.
      • Steck T.
      Thyroid antibodies and their relation to antithrombin antibodies, anticardiolipin antibodies and lupus anticoagulant in women with recurrent spontaneous abortions (antithyroid, anticardiolipin and antithrombin autoantibodies and lupus anticoagulant in habitual aborters).
      ,
      • Mecacci F.
      • Parretti E.
      • Cioni R.
      • Lucchetti R.
      • Magrini A.
      • La Torre P.
      • et al.
      Thyroid autoimmunity and its association with non-organ-specific antibodies and subclinical alterations of thyroid function in women with a history of pregnancy loss or preeclampsia.
      ,
      • De Carolis C.
      • Greco E.
      • Guarino M.D.
      • Perricone C.
      • Dal Lago A.
      • Giacomelli R.
      • et al.
      Anti-thyroid antibodies and antiphospholipid syndrome: evidence of reduced fecundity and of poor pregnancy outcome in recurrent spontaneous aborters.
      ). The latter group includes the study by De Carolis et al. (
      • De Carolis C.
      • Greco E.
      • Guarino M.D.
      • Perricone C.
      • Dal Lago A.
      • Giacomelli R.
      • et al.
      Anti-thyroid antibodies and antiphospholipid syndrome: evidence of reduced fecundity and of poor pregnancy outcome in recurrent spontaneous aborters.
      ), which was specifically designed to study the effects of thyroid autoimmunity in women with and without antiphospholipid syndrome. Thus, as a whole, the available evidence supports an association between thyroid autoimmunity and RPL that is independent of antiphospholipid antibodies.
      However, the mechanism for the association between RPL and thyroid autoimmunity is unclear, with the study by Lazzarin et al. (
      • Lazzarin N.
      • Moretti C.
      • De Felice G.
      • Vaquero E.
      • Manfellotto D.
      Further evidence on the role of thyroid autoimmunity in women with recurrent miscarriage.
      ) suggesting that thyroid autoimmunity is a marker for subtle thyroid dysfunction. However, the apparent lack of an association between subclinical hypothyroidism and RPL would seem to refute this. Others have suggested a more general immunological mechanism involving NK cells, although this is refuted in the study by Mariee et al. (
      • Mariee N.G.
      • Tuckerman E.
      • Laird S.
      • Li T.C.
      The correlation of autoantibodies and uNK cells in women with reproductive failure.
      ).
      Whether or not the presence of thyroid autoimmunity suggests a higher likelihood of subsequent miscarriages also remains unclear. Although it has yet to be proven, the fact that thyroid autoimmunity has been solidly linked to an increased risk of miscarriage in the general non-RPL population makes it intuitive that the same should be true for women with RPL (
      • De Leo S.
      • Pearce E.N.
      Autoimmune thyroid disease during pregnancy.
      ). As a whole, the studies performed on this topic in women with RPL have suffered from a lack of power. Additional prospective studies focused on large cohorts of women with a history of RPL will be needed to definitively prove whether thyroid autoimmunity is predictive of future negative pregnancy outcomes.
      In terms of the use of levothyroxine for thyroid autoimmunity in the setting of RPL, three of the four studies showed no benefit of treatment (
      • Yan J.
      • Sripada S.
      • Saravelos S.H.
      • Chen Z.J.
      • Egner W.
      • Li T.C.
      Thyroid peroxidase antibody in women with unexplained recurrent miscarriage: prevalence, prognostic value, and response to empirical thyroxine therapy.
      ,
      • Vissenberg R.
      • Fliers E.
      • van der Post J.A.
      • van Wely M.
      • Bisschop P.H.
      • Goddijn M.
      Live-birth rate in euthyroid women with recurrent miscarriage and thyroid peroxidase antibodies.
      ,
      • Dhillon-Smith R.
      • Middleton L.J.
      • Sunner K.K.
      • Cheed V.
      • Baker K.
      • Farrell-Carver S.
      • et al.
      Levothyroxine in women with thyroid peroxidase antibodies before conception.
      ). Of particular note are the recently reported results from the multicenter, randomized, double-blind, controlled Thyroid Antibodies and Levothyroxine (TABLET) study, which showed no benefit of low-dose (50 μg) levothyroxine started before pregnancy in euthyroid women with infertility or any history of miscarriage with thyroid peroxidase antibodies; these results held when considering women with RPL as well, though the study was not adequately powered for this outcome (
      • Dhillon-Smith R.
      • Middleton L.J.
      • Sunner K.K.
      • Cheed V.
      • Baker K.
      • Farrell-Carver S.
      • et al.
      Levothyroxine in women with thyroid peroxidase antibodies before conception.
      ). By contrast, Mosaddegh et al. (
      • Mosaddegh M.H.
      • Ghasemi N.
      • Jahaninejad T.
      • Mohsenifar F.
      • Aflatoonian A.
      Treatment of recurrent pregnancy loss by levothyroxine in women with high anti-TPO antibody.
      ) did report a higher rate of ongoing pregnancy in women with thyroid autoimmunity who were treated with levothyroxine; however, the primary reported outcome was pregnancies that continued beyond 20 weeks’ gestation as opposed to live birth. They also reported a statistically significant decrease in TPOAb titer in women who received treatment, but this may have been due to the higher rate of pregnancy in the treated women, as TPO antibody titers are known to decrease in pregnancy (
      • Mosaddegh M.H.
      • Ghasemi N.
      • Jahaninejad T.
      • Mohsenifar F.
      • Aflatoonian A.
      Treatment of recurrent pregnancy loss by levothyroxine in women with high anti-TPO antibody.
      ,
      • De Leo S.
      • Pearce E.N.
      Autoimmune thyroid disease during pregnancy.
      ). Thus, the strongest evidence available at this time suggests that there is no benefit to low-dose levothyroxine supplementation in RPL women with euthyroid thyroid autoimmunity. The currently ongoing T4-Life trial has a similar design and intervention, but it is specific to women with RPL and will help to prove or disprove this finding.
      The evidence for the use of IVIG in women with RPL and thyroid autoimmunity is low quality, consisting only of case-series reports. The uncontrolled study designs and the large number of women with confounding autoimmune conditions make interpretation of these studies difficult. Vaquero et al. (
      • Vaquero E.
      • Lazzarin N.
      • De Carolis C.
      • Valensise H.
      • Moretti C.
      • Ramanini C.
      Mild thyroid abnormalities and recurrent spontaneous abortion: diagnostic and therapeutical approach.
      ) reported the superiority of thyroid extract to IVIG. Thyroid extract is no longer considered a standard treatment for thyroid supplementation; however, this finding would suggest that if treatment does in fact benefit thyroid autoimmunity-positive women with RPL, levothyroxine would be superior to IVIG, given the similar mechanism of actions of levothyroxine and thyroid extract. Thus, IVIG should not be used in these women, and future research should continue to focus on levothyroxine.
      There is currently one ongoing randomized clinical trial, the aforementioned T4-Life study (EudraCT Number: 2011-001820-39), and one prospective cohort study, the Thyroid Autoimmunity and Reproductive Failure in Danish Women study (ClinicalTrials.gov ID NCT02912442), examining thyroid autoimmunity in women with RPL. They are registered either in the United States Clinical Trials Registry or the European Union Clinical Trials Registry.
      The T4-Life Study is a multicenter, randomized, double-blind, placebo-controlled trial investigating whether levothyroxine treatment of euthyroid, Dutch women with RPL, defined as two or more pregnancy losses before 20 weeks’ gestational age, who have tested positive for thyroid antibodies, will impact live-birth rates (
      • Vissenberg R.
      • van Dijk M.M.
      • Fliers E.
      • van der Post J.A.M.
      • van Wely M.
      • Bloemenkamp K.W.M.
      • et al.
      Effect of levothyroxine on live birth rate in euthyroid women with recurrent miscarriage and TPO antibodies (T4-LIFE study).
      ). The secondary outcomes will include ongoing pregnancy at 12 weeks, miscarriage, preterm delivery, adverse events, time to conception, and infant survival at 28 days. The women are being randomized before conception, and the levothyroxine dose depends on body weight and TSH concentration. Both the treatment and placebo arms will continue treatment from randomization to the end of pregnancy or after 2 years without a pregnancy.
      The Thyroid Autoimmunity and Reproductive Failure in Danish Women study is a prospective cohort study that is estimated to be completed in December 2020, which will include Dutch women with infertility and/or RPL (not defined in the registry). The study is investigating the potential mechanisms and associations between thyroid autoimmunity and these patient populations.
      The results of both these studies will provide further clarity on the associations between thyroid autoimmunity and RPL, and whether treatment is of benefit.

       Concurrent Subclinical Hypothyroidism and Thyroid Autoimmunity and RPL

       Question: Does treatment with levothyroxine improve subsequent pregnancy outcomes in women with a history of RPL who have both subclinical hypothyroidism and thyroid autoimmunity as opposed to treatment of thyroid autoimmunity alone?

      One study has examined whether treatment of combined subclinical hypothyroidism and thyroid autoimmunity in women with RPL results in improved pregnancy outcomes compared with treating thyroid autoimmunity alone (
      • Lata K.
      • Dutta P.
      • Sridhar S.
      • Rohilla M.
      • Srinivasan A.
      • Prashad G.R.
      • et al.
      Thyroid autoimmunity and obstetric outcomes in women with recurrent miscarriage: a case-control study.
      ), as shown in Table 2.

       Discussion

      The American Thyroid Association recommends treatment of combined subclinical hypothyroidism and thyroid autoimmunity in the general pregnant population based on an increased risk of adverse pregnancy outcomes (
      • Alexander E.K.
      • Pearce E.N.
      • Brent G.A.
      • Brown R.S.
      • Chen H.
      • Dosiou C.
      • et al.
      2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum.
      ). However, based on a single study in the RPL population, there is no added benefit to treating combined subclinical hypothyroidism and thyroid autoimmunity as compared to treating thyroid autoimmunity alone. Thus, given that there appears to be no benefit in treating thyroid autoimmunity in women with RPL, treatment of combined subclinical hypothyroidism and thyroid autoimmunity cannot be recommended based on the currently available evidence. However, further research is needed on this topic before definitive conclusions can be drawn.

      Conclusion

      Currently published observational studies suggest no association between subclinical hypothyroidism RPL, defined by nonconsecutive pregnancy losses; however, an association may exist between consecutive RPL and subclinical hypothyroidism—this requires further investigation. Treatment of subclinical hypothyroidism, with or without concurrent thyroid autoimmunity, is not supported by the observational studies to date. Prospective and randomized trials are urgently needed to determine whether levothyroxine is of benefit to women with RPL who are found to have subclinical hypothyroidism. Without these types of studies, no recommendation can be made for or against the treatment of subclinical hypothyroidism in women with RPL at this time.
      The available evidence and our own meta-analysis support an association between thyroid autoimmunity and RPL. However, whether thyroid antibodies predict future pregnancy outcomes remains unclear. Furthermore, treatment with either levothyroxine or IVIG of euthyroid women with a history of RPL who have thyroid antibodies does not appear to increase the subsequent live-birth rate. Thus, evaluation of thyroid antibodies in women with RPL is not supported by the published studies to date.
      The evaluation of women with RPL should include TSH screening with reflex free thyroxine if the TSH is abnormal, but not thyroid antibody screening. Women with RPL should be treated for overt hypothyroidism, but not thyroid autoimmunity at this time. Further studies, preferably randomized controlled trials, are urgently needed to further assess thyroid autoimmunity in RPL. No recommendation for or against the treatment of subclinical hypothyroidism in women with RPL can be made at this time. Again, further studies are urgently needed.

      Appendix

      Figure thumbnail fx1
      Supplemental Figure 1PRISMA flowchart depicting article selection strategy.

      Supplementary data

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