TY - JOUR
AU - Tang,, Li
AB - Abstract BACKGROUND Subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes such as pregnancy loss and preterm birth. However, the ability of levothyroxine (LT4) supplementation to attenuate the risks of these outcomes remains controversial. OBJECTIVE AND RATIONALE This systematic review and meta-analysis was conducted to determine the effect of LT4 supplementation on pregnancy loss rate (PLR) and preterm birth rate (PBR) among pregnant women with SCH and TAI. SEARCH METHODS A systematic literature search of the PubMed, EMBASE, Web of Science and Cochrane Controlled Trials Register databases and Clinicaltrials.gov was performed to identify all relevant English studies published up to April 2018. The following terms were used for the search: [subclinical hypothyroidism OR thyroid autoimmunity OR thyroperoxidase antibody (TPO-Ab) OR thyroglobulin antibodies (Tg-Ab)] AND (levothyroxine OR euthyrox) AND [pregnancy outcome OR miscarriage OR abortion OR pregnancy loss OR preterm birth OR premature delivery OR early labo(u)r]. The reference lists of the relevant publications were also manually searched for related studies. Published manuscripts were included if they reported data on pregnancy loss, preterm birth or both. We separately analysed the pooled effects of LT4 supplementation on PLR and PBR in women with SCH and TAI. OUTCOMES Overall, 13 eligible studies including 7970 women were included in the meta-analysis. Eight and five of these studies were randomized controlled trials (RCTs) and retrospective studies, respectively. The pooled results indicated that LT4 supplementation significantly decreased the PLR [relative risk (RR) = 0.56, 95% confidence interval (CI): 0.42–0.75, I2 = 1%, 12 studies] and PBR (RR = 0.68, 95% CI: 0.51–0.91, I2 = 21%, eight studies) in women with SCH and/or TAI. We further found that LT4 supplementation significantly decreased the risk of pregnancy loss (RR = 0.43, 95% CI: 0.26–0.72, P = 0.001, I2 = 0%) but not of preterm birth (RR = 0.67, 95% CI: 0.41–1.12, P = 0.13, I2 = 0%) in women with SCH. Furthermore, LT4 supplementation significantly decreased the risks of both pregnancy loss (RR = 0.63, 95% CI: 0.45–0.89, P = 0.009, I2 = 0%) and preterm birth (RR = 0.68 95% CI: 0.48–0.98, P = 0.04, I2 = 46%) in women with TAI. These results were consistent when only RCTs were included in the analysis. Further, in women with SCH, LT4 supplementation reduced the risk of pregnancy loss in pregnancies achieved by assisted reproduction (RR = 0.27, 95% CI: 0.14–0.52, P < 0.001, I2 = 14%) but not in naturally conceived pregnancies (RR = 0.60, 95% CI: 0.28–1.30, P = 0.13, I2 = 0%). By contrast, in women with TAI, LT4 supplementation reduced the risks of both pregnancy loss (RR = 0.61, 95% CI: 0.39–0.96, P = 0.03, I2 = 0%) and preterm birth (RR = 0.49, 95% CI: 0.30–0.79, P = 0.003, I2 = 0%) in naturally conceived pregnancies but not in pregnancies achieved by assisted reproduction (RR = 0.68, 95% CI: 0.40–1.15, P = 0.15, I2 = 0% for pregnancy loss and RR = 1.20, 95% CI: 0.68–2.13, P = 0.53, I2 not applicable for preterm birth). WIDER IMPLICATIONS This meta-analysis confirmed the beneficial effects of LT4 supplementation, namely the reduced risks of pregnancy loss and preterm birth, among pregnant women with SCH and/or TAI. The different effects of LT4 supplementation on naturally conceived pregnancies and pregnancies achieved by assisted reproduction in women with SCH and/or TAI suggest that these women should be managed separately. Due to the limited number of studies included in this meta-analysis, especially in the subgroup analysis, further large RCTs and fundamental studies are warranted to confirm the conclusions and better clarify the molecular mechanism underlying these associations. subclinical hypothyroidism, thyroid autoimmunity, levothyroxine, pregnancy loss, preterm birth, naturally conceived pregnancy, assisted reproduction Introduction Subclinical hypothyroidism (SCH) is defined as an elevated serum thyrotropin (TSH) level with normal serum thyroxine (T4) level and affects 3–8% of women of childbearing age (Karmisholt et al., 2008; Maraka et al., 2016a). International guidelines advocate the use of population-based reference ranges of TSH during pregnancy; however, if these ranges are unavailable, the recommended upper reference limit for TSH is 2.5 mIU/L during the first trimester and 3.0 mIU/L during the second and third trimesters (Stagnaro-Green et al., 2011). Based on these criteria, SCH is estimated to affect up to 14–15% of pregnancies in developed countries (Blatt et al., 2012; Aguayo et al., 2013). Thyroid autoimmunity (TAI) refers to the presence of antibodies to thyroperoxidase (TPO-Abs) or thyroglobulin (Tg-Abs) and is the main cause of hypothyroidism among women of childbearing age (Vissenberg et al., 2015). Many studies (Rushworth et al., 2000; Haddow et al., 2010; Sen et al., 2014; Maraka et al., 2016b) and meta-analyses (Thangaratinam et al., 2011; van den Boogaard et al., 2011; Busnelli et al., 2016; Zhang et al., 2017b) have demonstrated that SCH and TAI during pregnancy increase the risks of adverse pregnancy outcomes, including pre-eclampsia, placental abruption, miscarriage, preterm birth and neonatal mortality, among women with pregnancies conceived naturally or by ART. Although SCH and TAI are regarded as subtle deficiencies in thyroid function, a small alteration in the thyroxine level during pregnancy, albeit within the normal range, was found to be negatively associated with gestational diabetes mellitus and pre-eclampsia (Zhang et al., 2017a). In such cases, levothyroxine (LT4) supplementation may theoretically reduce the risks of these adverse pregnancy outcomes. However, the effect of LT4 supplementation on these outcomes in women with SCH or TAI remains controversial. Some studies have found that LT4 supplementation significantly decreases the risks of both pregnancy loss and preterm birth (Negro et al., 2006; Nazarpour et al., 2017), whereas others have suggested beneficial effects on either pregnancy loss (Lepoutre et al., 2012) or preterm birth (Nazarpour et al., 2018). Some other studies have observed no effect on pregnancy loss or preterm birth (Negro et al., 2016; Maraka et al., 2016b). Notably, all of the above-mentioned studies focused on naturally conceived pregnancies in women with SCH or TAI. Further, some investigations have reported the beneficial effects of LT4 supplementation on infertile women undergoing IVF /ICSI. In one retrospective study, TAI-positive women undergoing IVF did not benefit from LT4 supplementation in terms of pregnancy outcomes (Revelli et al., 2009). Consistent with that finding, LT4 supplementation showed no significant beneficial effects on clinical pregnancy, live birth or miscarriage rates in a small randomized controlled trial (RCT) (Negro et al., 2005). Nevertheless, two other RCTs found that LT4 supplementation improved fertilization and live birth rates while reducing the miscarriage rate (Abdel Rahman et al., 2010; Kim et al., 2011). In 2013, Velkeniers et al. (2013) conducted a systematic review and meta-analysis of the above-mentioned RCTs and found that LT4 supplementation could reduce the miscarriage rate and increase the live birth rate, but has no obvious effect on the clinical pregnancy rate. In 2017, a large RCT found no differences in the live birth and miscarriage rates between the LT4 and control groups in TPO-Ab-positive euthyroid women following IVF (Wang et al., 2017). However, a much lower miscarriage rate was observed in LT4-treated patients (7.3%) than in control patients (16.1%), when only women with a female infertility cause were included in the analysis, although the difference was not significant. Therefore, it is necessary to update the evidence from previous published studies on the role of LT4 supplementation on the risk of pregnancy loss and preterm birth. The combination and analysis of data on this controversial issue may provide useful information for clinical management and counselling of women with SCH and/or TAI. Methods Literature search A systematic search of the PubMed, EMBASE, Web of Science and Cochrane Controlled Trials Register databases and Clinicaltrails.gov was performed to identify all relevant studies published up to 28 April 2018. The search was limited to human studies published in English. The following terms were used to search the databases: [subclinical hypothyroidism OR thyroid autoimmunity OR thyroperoxidase antibody (TPO-Ab) OR thyroglobulin antibodies (Tg-Ab)] AND (levothyroxine OR euthyrox) AND [pregnancy outcome OR miscarriage OR abortion OR pregnancy loss OR preterm birth OR preterm delivery OR premature delivery OR early labo(u)r]. The reference lists of the relevant publications were also manually searched for related studies. Two researchers (Z.Z. and M.R.) independently completed the literature search and identified the eligible studies. Conflicting decisions were resolved by consensus with a third researcher (F.Z.). Study selection Studies were included if they: (i) comprised LT4-treated pregnant women with SCH or TPO-Ab positivity without overt thyroid dysfunction as subjects; (ii) compared pregnancy outcomes between LT4-treated and untreated/placebo-treated women; and (iii) included data for the outcomes of pregnancy loss, preterm birth or both. Studies were excluded if they: (i) were published as an abstract, letter to the editor, case report or review and (ii) failed to provide sufficient data for analysis. In the included studies, clinical pregnancies were diagnosed by ultrasound visualization of foetal cardiac activity. Pregnancy loss is generally defined as miscarriage occurring before 20 weeks of gestation or stillbirth occurring at or after 20 weeks of gestation (Zegers-Hochschild et al., 2009; de Jong et al., 2013). However, pregnancy loss was defined differently across different potentially eligible studies as pregnancy loss during the first 13, 20, 22 or 28 weeks or other gestational ages. We enroled all studies that included data on miscarriage and stillbirth provided that the pregnancy outcomes had a good comparability in terms of gestational age. The pregnancy loss rate (PLR) was calculated as the number of pregnancy losses per clinical pregnancy. The preterm birth rate (PBR) was defined as the number of live neonate deliveries before 37 weeks of gestation per clinical pregnancy. Data extraction Two reviewers (M.R. and Z.Z.) independently extracted the following types of data from the included articles: first author, year of publication, country, study design, patient characteristics, age, BMI, thyroid status reference values, thyroid status, thyroid hormone (TH) values and interventions. The pregnancy outcomes of pregnancy loss and preterm birth were recorded and expressed as the numbers of events in the LT4-treated and untreated control groups. The corresponding author was contacted for more information if the data presented in the article were inadequate for analysis. Quality assessment of included studies Retrospective studies were subjected to the Newcastle–Ottawa Quality Assessment Scale (NOS) for quality assessment (Stang, 2010). The NOS evaluates study quality based on three aspects: the selection of participants, comparability of study groups and ascertainment of the outcomes of interest. A score of 6–9 suggests a high level of quality and low risk of bias. Discrepancies in the scores were resolved by consensus. For the RCTs, the Cochrane risk of bias tool was used to evaluate the study quality based on randomization, blinding of the outcome assessment, completeness of the outcome assessment, selective reporting and other bias (Rao et al., 2018). Each domain was categorized as low, high or unclear. Statistical analysis All analyses were performed using Review Manager software version 5.2 (The Cochrane Collaboration) and R software with the metafor package (version 3.4.0; The R Project for Statistical Computing). A standard meta-analytic method was used to compare the included studies, and the relative risk (RR), which was used to describe the effect size, and the corresponding 95% CI were used to express the combined results. The degree of heterogeneity was also measured using the I2 statistic, with values of <25%, 25–50% and >50% indicating low, moderate and high heterogeneity, respectively (Rao et al., 2018). A fixed effects model was used when I2 was < 50%; otherwise, the random effects model was used. Inter-study variance was evaluated by calculating Tau2, which represents the estimated standard deviation of the underlying effects across studies. The level of statistical significance was set at P < 0.05. If a study varied significantly in terms of methodology or findings from all other included studies, we performed a sensitivity analysis excluding those studies from the meta-analysis. We also separately analysed the pooled effects of LT4 supplementation on patients with SCH and TAI. We subsequently performed a subgroup analysis to further analyse the effects of LT4 supplementation on pregnancy outcomes based on the following aspects: (i) study design (RCT or not) and (ii) type of pregnancy (naturally conceived pregnancy or pregnancy achieved by ART). Results Literature search The literature search initially yielded 1021 articles from databases and another eight studies through manual search. After removing duplicate studies and reviewing the titles and abstracts, 34 full-text articles were screened and assessed for eligibility. Thereafter, another 21 studies were excluded because the two groups compared in them were not LT4-treated and untreated/placebo-treated groups (n = 9) or they did not provide data about the PLR or PBR (n = 12). Finally, 13 full-text articles were included in the meta-analysis, as shown in Fig. 1. Figure 1 View largeDownload slide PRISMA flow chart. Figure 1 View largeDownload slide PRISMA flow chart. Characteristics of included studies Overall, 13 relevant studies including a total of 7970 patients were published between 2005 and 2018 and were conducted in Italy (Negro et al., 2006, 2016; Revelli et al., 2009), Egypt (Abdel Rahman et al., 2010), South Korea (Kim et al., 2011), China (Wang et al., 2012, 2017), USA (Maraka et al., 2016b, 2017), Iran (Nazarpour et al., 2017, 2018) and Belgium (Lepoutre et al., 2012). Eight studies were RCTs (Negro et al., 2005, 2006, 2016; Abdel Rahman et al., 2010; Kim et al., 2011; Nazarpour et al., 2017, 2018; Wang et al., 2017), and the remaining five were retrospective studies (Revelli et al., 2009; Lepoutre et al., 2012; Wang et al., 2012; Maraka et al., 2016b, 2017). Women in five studies underwent IVF/ICSI and had been diagnosed with thyroid disorders prior to IVF/ICSI. In these studies, LT4 was administered before initiating IVF/ICSI cycles and was maintained throughout the pregnancy (Negro et al., 2005; Revelli et al., 2009; Abdel Rahman et al., 2010; Kim et al., 2011; Wang et al., 2017). Another eight studies focused on pregnant women who had been diagnosed with SCH/TAI during pregnancy and received LT4 supplementation throughout the pregnancy. All included studies reported data on pregnancy loss. In the studies by Lepoutre et al. (2012) and Wang et al. (2012), pregnancy loss was defined as early miscarriage occurring before 13 weeks of gestation. In another three studies, pregnancy loss was described as miscarriage before 20, 21 or 22 weeks of gestation (Negro et al., 2006, 2016; Kim et al., 2011). Nazarpour (2017, 2018) defined pregnancy loss as miscarriage before 20 weeks of gestation and as stillbirth thereafter. In the study by Wang et al. (2017), pregnancy loss was described as miscarriage before 28 weeks of gestation. In the remaining studies, pregnancy loss was not described in detail. Six and seven of the included studies focused on women with SCH and TAI, respectively. Nine studies reported data on preterm births (Negro et al., 2006, 2016; Lepoutre et al., 2012; Wang et al., 2012, 2017; Maraka et al., 2016b, 2017; Nazarpour et al., 2017, 2018); four and five of these studies focused on women with SCH and TAI, respectively. The LT4 supplementation protocols varied across studies, with five studies using fixed doses (Negro et al., 2005; Revelli et al., 2009; Abdel Rahman et al., 2010; Kim et al., 2011; Nazarpour et al., 2018) and six using individually adjusted doses (Negro et al., 2006, 2016; Lepoutre et al., 2012; Wang et al., 2012, 2017; Nazarpour et al., 2017). In the remaining studies, the doses were not described in detail (Maraka et al., 2016b, 2017). Details of the trial characteristics were collected and are presented in Table 1. Table I Characteristics of included studies. Study Country Study design Patients Age (years) Reference values for thyroid status Negro et al. (2005) Italy RCT 86 TPO-Ab positive infertile women undergoing IVF/ICSI Treated group:29.2 ± 4; Placebo: 30.1 ± 5 TSH 0.27–4.2 mIU/L, fT4 9.3–18.0 ng/L (12–33.5 pmol/L), TPO-Ab 0–100 kIU/L Negro et al. (2006) Italy RCT 115 TPO-Ab positive pregnant women For all patients: 30 ± 6 TSH 0.27–4.2 mU/L; fT4 9.3–18.0 ng/L; TPO-Ab < 100 IU/mL Revelli et al. (2009) Italy Retrospective 93 TPO-Ab/Tg-Ab positive infertile women undergoing IVF Treated group: 35.1 ± 4.1; Placebo: 37.0 ± 3.5 TPO-Ab 0–40 IU/mL; Tg-Ab 0–35 IU/mL Abdel Rahman et al. (2010) Egypt RCT 70 infertile women with SCH undergoing ICSI Treated group:31.2 ± 4.7; Placebo: 30 ± 4.3 TSH 0.27–4.2 mIU/L, fT3 2.56–4.4 pg/mL, fT4 0.9–2.59 ng/dL Kim et al. (2011) South Korea RCT 64 infertile women with SCH undergoing IVF/ICSI Treated group:36.0 ± 2.4; Placebo: 36.1 ± 2.2 TSH 0.27–4.0 mIU/L fT4 0.9–2.59 ng/dL Lepoutre et al. (2012) Belgium Retrospective 96 TPO-Ab positive pregnant women Treat group:31.5 ± 5.5; Control group: 32.5 ± 5.3 TSH 0.2–3.5 mIU/L; fT4 0.6–1.4 ng/dL; TPO-Ab < 9 IU/mL Wang et al. (2012) China Retrospective 196 pregnant women with SCH For all patients:19 to 45 years old TSH 0.13–2.5 mIU/L, 12 Pmol/L≤ FT4 < 23.34 pmol/L for the first trimester Maraka et al. (2016b) USA Retrospective 366 pregnant women with SCH Treated group:30 ± 5.2; Control: 30 ± 4.5 TSH ≤2.5 mIU/L for the first trimester; ≤3 mIU/L for the second and third trimesters. Negro et al. (2016) Italy RCT 393 TPO-Ab positive pregnant women Treated group:28.9 ± 5.2; Control: 31.3 ± 5.2 TSH 0.30–3.6 mIU/L; TPO-Ab ≤16 IU/mL Maraka et al. (2017) USA Retrospective 5394 pregnant women with SCH Treated group:31.7 ± 4.7; Control: 29.9 ± 5.1 TSH 2.5–10.0 mIU/L for the first trimester Nazarpour (2017) Iran RCT 131 TPO-Ab positive pregnant women Treat group:26.6 ± 5.8; Control group: 27.0 ± 4.7 TSH 0.1–2.5 μIU/mL; FT4I 1–4.5; TPO < 50 IU/mL Wang et al. (2017) China RCT 600 TPO-Ab positive infertile women undergoing IVF Treated group: 31.3 ± 3.9; Placebo: 31.7 ± 3.8 TSH 0.5–4.78 mIU/L TPO-Ab 0–60 IU/mL Nazarpour (2018) Iran RCT 366 pregnant women with SCH, negative for TPO-Ab Treat group:27.0 ± 5.3; Control group: 26.9 ± 4.7 TSH 0.1–2.5 mIU/L; FT4I 1–4.5; TPO-Ab < 50 IU/mL Study Country Study design Patients Age (years) Reference values for thyroid status Negro et al. (2005) Italy RCT 86 TPO-Ab positive infertile women undergoing IVF/ICSI Treated group:29.2 ± 4; Placebo: 30.1 ± 5 TSH 0.27–4.2 mIU/L, fT4 9.3–18.0 ng/L (12–33.5 pmol/L), TPO-Ab 0–100 kIU/L Negro et al. (2006) Italy RCT 115 TPO-Ab positive pregnant women For all patients: 30 ± 6 TSH 0.27–4.2 mU/L; fT4 9.3–18.0 ng/L; TPO-Ab < 100 IU/mL Revelli et al. (2009) Italy Retrospective 93 TPO-Ab/Tg-Ab positive infertile women undergoing IVF Treated group: 35.1 ± 4.1; Placebo: 37.0 ± 3.5 TPO-Ab 0–40 IU/mL; Tg-Ab 0–35 IU/mL Abdel Rahman et al. (2010) Egypt RCT 70 infertile women with SCH undergoing ICSI Treated group:31.2 ± 4.7; Placebo: 30 ± 4.3 TSH 0.27–4.2 mIU/L, fT3 2.56–4.4 pg/mL, fT4 0.9–2.59 ng/dL Kim et al. (2011) South Korea RCT 64 infertile women with SCH undergoing IVF/ICSI Treated group:36.0 ± 2.4; Placebo: 36.1 ± 2.2 TSH 0.27–4.0 mIU/L fT4 0.9–2.59 ng/dL Lepoutre et al. (2012) Belgium Retrospective 96 TPO-Ab positive pregnant women Treat group:31.5 ± 5.5; Control group: 32.5 ± 5.3 TSH 0.2–3.5 mIU/L; fT4 0.6–1.4 ng/dL; TPO-Ab < 9 IU/mL Wang et al. (2012) China Retrospective 196 pregnant women with SCH For all patients:19 to 45 years old TSH 0.13–2.5 mIU/L, 12 Pmol/L≤ FT4 < 23.34 pmol/L for the first trimester Maraka et al. (2016b) USA Retrospective 366 pregnant women with SCH Treated group:30 ± 5.2; Control: 30 ± 4.5 TSH ≤2.5 mIU/L for the first trimester; ≤3 mIU/L for the second and third trimesters. Negro et al. (2016) Italy RCT 393 TPO-Ab positive pregnant women Treated group:28.9 ± 5.2; Control: 31.3 ± 5.2 TSH 0.30–3.6 mIU/L; TPO-Ab ≤16 IU/mL Maraka et al. (2017) USA Retrospective 5394 pregnant women with SCH Treated group:31.7 ± 4.7; Control: 29.9 ± 5.1 TSH 2.5–10.0 mIU/L for the first trimester Nazarpour (2017) Iran RCT 131 TPO-Ab positive pregnant women Treat group:26.6 ± 5.8; Control group: 27.0 ± 4.7 TSH 0.1–2.5 μIU/mL; FT4I 1–4.5; TPO < 50 IU/mL Wang et al. (2017) China RCT 600 TPO-Ab positive infertile women undergoing IVF Treated group: 31.3 ± 3.9; Placebo: 31.7 ± 3.8 TSH 0.5–4.78 mIU/L TPO-Ab 0–60 IU/mL Nazarpour (2018) Iran RCT 366 pregnant women with SCH, negative for TPO-Ab Treat group:27.0 ± 5.3; Control group: 26.9 ± 4.7 TSH 0.1–2.5 mIU/L; FT4I 1–4.5; TPO-Ab < 50 IU/mL Study Thyroid status and thyroid hormone values in patients Intervention Pregnancy outcomes Negro et al. (2005) For all patients: TPO-Ab (+). TSH and fT4 within normal range. Treated group: TSH 1.9 ± 0.7 mIU/L before treatment, fT4 11.2 ± 1.8 ng/L before treatment; TSH 1.1 ± 0.3 mIU/L after treatment, fT4 14.1 ± 2.5 ng/L after treatment; Control group: TSH 1.7 ± 0.7 mIU/L, fT4 11.7 ± 2.1 ng/L. Patients in treated group underwent LT4 1 μg/kg/day treatment, one month before ART, this treatment was maintained throughout pregnancy. PLR Negro et al. (2006) For all patients: TPO-Ab (+). Treated group: TSH 1.6 ± 0.5 mIU/L; control group: TSH 1.7 ± 0.4 mIU/L. fT4 level was not clearly provided. Patients received LT4 0.5 μg/kg/day if they had TSH < 1.0 μIU/mL, 0.75 μg/kg/day for TSH 1.0–2.0 μIU/mL, and a 1 μg/kg/day dose for TSH > 2.0 μIU/mL or a TPOAb titre exceeding 1500 IU/mL; dosages were maintained throughout gestation. PLR, PBR Revelli et al. (2009) For all patients: TPO-Ab or Tg-Ab (+). TSH and fT4 within normal range. Treated group: TSH 2.1 ± 1.3 mIU/L, fT4 9.9 ± 3.5 pg/mL, fT3 3.0 ± 1.5 pg/mL; control group: TSH 2.0 ± 1.2 mIU/L, fT4 10.6 ± 2.8 pg/mL, fT3 3.1 ± 1.4 pg/mL. Patients in treated group underwent LT4 50 mg/day treatment during IVF, one month before ART, this treatment was maintained throughout pregnancy. Treatments were prescribed by different endocrinologists taking care of the patients’ thyroid conditions without any known selection criteria apart from their personal, clinical experience. PLR Abdel Rahman et al. (2010) For all patients: TSH > 4 mUI/L, fT4 within normal range. Treated group: TSH 4.7 ± 0.5 mIU/L before treatment, fT3 2.85 ± 0.7 ng/L before treatment, fT4 1 ± 0.4 before treatment; Control group: TSH 4.8 ± 0.7 mIU/L, fT3 2.79 ± 0.8 ng/L, fT4 1.04 ± 0.49 ng/L. Patients in treated group underwent LT4 50–100 μg/day, 1 month before ART, this treatment was maintained throughout pregnancy. PLR Kim et al. (2011) For all patients: TSH > 4.5 mUI/L, fT4 within normal range. Treated group: TSH 6.6 ± 1.7 mIU/L before treatment, fT4 1.2 ± 0.2 before treatment; Conttrol group: TSH 6.7 ± 1.8 mIU/L, fT4 1.2 ± 0.2 ng/L. Patients in treated group underwent LT4 50 μg/day, from the first day of controlled ovarian stimulation, this treatment was maintained throughout pregnancy. PLR Lepoutre et al. (2012) Not clearly described. In treatment group: the initial LT4 dose started as soon as TPOAb was detected and TSH > 1 mU/l, and maintained throughout the pregnancy to maintain a TSH level between 1 and 2 mU/L. PLR, PBR Wang et al. (2012) Not clearly described. The initial dose of LT4 depended on the TSH level: Dose for TSH 2.5–5 mIU/L was 50 μg/day; for TSH 5–8 mIU/L was 75 μg/day and TSH > 8 mIU/L was 100 μg/day. The drug dosage was adjusted according to their serum TSH level until delivery. PLR, PBR Maraka et al. (2016b) Treated group: TSH 4.9 ± 1.4 mIU/L; control group: TSH 3.5 ± 0.9 mIU/L. fT4 level was not clearly provided. Not clearly described. PLR, PBR Negro et al. (2016) For all patients: TPO-Ab (+). Treated group: TSH 1.42 ± 0.5 mIU/L; control group: TSH 1.37 ± 0.5 mIU/L. In treatment group: women with a TSH between 0.5 and 1.5 were begun on 0.5 mg/kg/d of LT4, between 1.5 and 2.5 mIU/L were begun on 1 mg/kg/day. In the second trimester, if the TSH > 3.0 or < 0.5 mIU/L, LT4 was increased or decreased by 12.5 mg/kg/d, respectively. In control group, LT4 was given when TSH > 3.0 mIU/L in the second trimester. PLR, PBR Maraka et al. (2017) Baseline of TSH in treated group: 4.8 ± 1.7 mIU/L; in control group: 3.3 ± 0.9 mIU/L. Not clearly described. PLR, PBR Nazarpour (2017) For all patients: TPO-Ab (+). TSH and fT4 in the first trimester [median (percentiles 25–75)]: Treated group: TSH 3.7 (2.8–4.8) μIU/mL, fT4I 2.7 (2.3–3.4); control group: TSH 3.2 (2.1–5.2) μIU/mL, fT4I 2.8 (2.3–3.1). Patients received LT4 0.5 μg/kg/day if they had TSH < 1.0 μIU/mL, 0.75 μg/kg/day for TSH 1.0–2.0 μIU/mL, and a 1 μg/kg/day dose for TSH > 2.0 μIU/mL or a TPOAb titre exceeding 1500 IU/mL; dosages were maintained throughout gestation. PLR, PBR Wang et al. (2017) For all patients: TPO-Ab (+). TSH and fT4 within normal range. Treated group: TSH (mean (interquartile range)), 2.94 (2.04–3.74) mIU/L before treatment, fT4 (mean ± SD), 1.16 ± 0.13 before treatment; Conttrol group:TSH 2.12 (1.5–2.8) mIU/L, fT4 1.19 ± 0.14 ng/L LT4 was supplemented between 2 and 4 weeks before the COS and continued through the end of pregnancy. For individuals with a TSH level ≥ 2.5 mIU/L, the starting dose was 50 μg/day; for those with a TSH level < 2.5 mIU/L, the starting dose was 25 μg/day. For individuals with body weight <50 kg, the starting dose was decreased by 50%. The LT4 dose was titrated to keep the TSH level within 0.1–2.5 mIU/L in the first trimester, 0.2–3.0 mIU/L in the second trimester, and 0.3–3.0 mIU/L in the third trimester. PLR, PBR Nazarpour (2018) TSH and fT4 in the first trimester [median (percentiles 25–75)]: Treated group: TSH 3.7 (2.8–4.8) μIU/mL, fT4I 2.7 (2.3–3.2); control group: TSH 3.6 (2.1–4.2) μIU/mL, fT4I 3.6 (2.9–3.9). Patients were treated with a LT4 morning dose of 1 μg/kg/day, initiated 4–8 days after the first prenatal visit and maintained throughout pregnancy. PBR Study Thyroid status and thyroid hormone values in patients Intervention Pregnancy outcomes Negro et al. (2005) For all patients: TPO-Ab (+). TSH and fT4 within normal range. Treated group: TSH 1.9 ± 0.7 mIU/L before treatment, fT4 11.2 ± 1.8 ng/L before treatment; TSH 1.1 ± 0.3 mIU/L after treatment, fT4 14.1 ± 2.5 ng/L after treatment; Control group: TSH 1.7 ± 0.7 mIU/L, fT4 11.7 ± 2.1 ng/L. Patients in treated group underwent LT4 1 μg/kg/day treatment, one month before ART, this treatment was maintained throughout pregnancy. PLR Negro et al. (2006) For all patients: TPO-Ab (+). Treated group: TSH 1.6 ± 0.5 mIU/L; control group: TSH 1.7 ± 0.4 mIU/L. fT4 level was not clearly provided. Patients received LT4 0.5 μg/kg/day if they had TSH < 1.0 μIU/mL, 0.75 μg/kg/day for TSH 1.0–2.0 μIU/mL, and a 1 μg/kg/day dose for TSH > 2.0 μIU/mL or a TPOAb titre exceeding 1500 IU/mL; dosages were maintained throughout gestation. PLR, PBR Revelli et al. (2009) For all patients: TPO-Ab or Tg-Ab (+). TSH and fT4 within normal range. Treated group: TSH 2.1 ± 1.3 mIU/L, fT4 9.9 ± 3.5 pg/mL, fT3 3.0 ± 1.5 pg/mL; control group: TSH 2.0 ± 1.2 mIU/L, fT4 10.6 ± 2.8 pg/mL, fT3 3.1 ± 1.4 pg/mL. Patients in treated group underwent LT4 50 mg/day treatment during IVF, one month before ART, this treatment was maintained throughout pregnancy. Treatments were prescribed by different endocrinologists taking care of the patients’ thyroid conditions without any known selection criteria apart from their personal, clinical experience. PLR Abdel Rahman et al. (2010) For all patients: TSH > 4 mUI/L, fT4 within normal range. Treated group: TSH 4.7 ± 0.5 mIU/L before treatment, fT3 2.85 ± 0.7 ng/L before treatment, fT4 1 ± 0.4 before treatment; Control group: TSH 4.8 ± 0.7 mIU/L, fT3 2.79 ± 0.8 ng/L, fT4 1.04 ± 0.49 ng/L. Patients in treated group underwent LT4 50–100 μg/day, 1 month before ART, this treatment was maintained throughout pregnancy. PLR Kim et al. (2011) For all patients: TSH > 4.5 mUI/L, fT4 within normal range. Treated group: TSH 6.6 ± 1.7 mIU/L before treatment, fT4 1.2 ± 0.2 before treatment; Conttrol group: TSH 6.7 ± 1.8 mIU/L, fT4 1.2 ± 0.2 ng/L. Patients in treated group underwent LT4 50 μg/day, from the first day of controlled ovarian stimulation, this treatment was maintained throughout pregnancy. PLR Lepoutre et al. (2012) Not clearly described. In treatment group: the initial LT4 dose started as soon as TPOAb was detected and TSH > 1 mU/l, and maintained throughout the pregnancy to maintain a TSH level between 1 and 2 mU/L. PLR, PBR Wang et al. (2012) Not clearly described. The initial dose of LT4 depended on the TSH level: Dose for TSH 2.5–5 mIU/L was 50 μg/day; for TSH 5–8 mIU/L was 75 μg/day and TSH > 8 mIU/L was 100 μg/day. The drug dosage was adjusted according to their serum TSH level until delivery. PLR, PBR Maraka et al. (2016b) Treated group: TSH 4.9 ± 1.4 mIU/L; control group: TSH 3.5 ± 0.9 mIU/L. fT4 level was not clearly provided. Not clearly described. PLR, PBR Negro et al. (2016) For all patients: TPO-Ab (+). Treated group: TSH 1.42 ± 0.5 mIU/L; control group: TSH 1.37 ± 0.5 mIU/L. In treatment group: women with a TSH between 0.5 and 1.5 were begun on 0.5 mg/kg/d of LT4, between 1.5 and 2.5 mIU/L were begun on 1 mg/kg/day. In the second trimester, if the TSH > 3.0 or < 0.5 mIU/L, LT4 was increased or decreased by 12.5 mg/kg/d, respectively. In control group, LT4 was given when TSH > 3.0 mIU/L in the second trimester. PLR, PBR Maraka et al. (2017) Baseline of TSH in treated group: 4.8 ± 1.7 mIU/L; in control group: 3.3 ± 0.9 mIU/L. Not clearly described. PLR, PBR Nazarpour (2017) For all patients: TPO-Ab (+). TSH and fT4 in the first trimester [median (percentiles 25–75)]: Treated group: TSH 3.7 (2.8–4.8) μIU/mL, fT4I 2.7 (2.3–3.4); control group: TSH 3.2 (2.1–5.2) μIU/mL, fT4I 2.8 (2.3–3.1). Patients received LT4 0.5 μg/kg/day if they had TSH < 1.0 μIU/mL, 0.75 μg/kg/day for TSH 1.0–2.0 μIU/mL, and a 1 μg/kg/day dose for TSH > 2.0 μIU/mL or a TPOAb titre exceeding 1500 IU/mL; dosages were maintained throughout gestation. PLR, PBR Wang et al. (2017) For all patients: TPO-Ab (+). TSH and fT4 within normal range. Treated group: TSH (mean (interquartile range)), 2.94 (2.04–3.74) mIU/L before treatment, fT4 (mean ± SD), 1.16 ± 0.13 before treatment; Conttrol group:TSH 2.12 (1.5–2.8) mIU/L, fT4 1.19 ± 0.14 ng/L LT4 was supplemented between 2 and 4 weeks before the COS and continued through the end of pregnancy. For individuals with a TSH level ≥ 2.5 mIU/L, the starting dose was 50 μg/day; for those with a TSH level < 2.5 mIU/L, the starting dose was 25 μg/day. For individuals with body weight <50 kg, the starting dose was decreased by 50%. The LT4 dose was titrated to keep the TSH level within 0.1–2.5 mIU/L in the first trimester, 0.2–3.0 mIU/L in the second trimester, and 0.3–3.0 mIU/L in the third trimester. PLR, PBR Nazarpour (2018) TSH and fT4 in the first trimester [median (percentiles 25–75)]: Treated group: TSH 3.7 (2.8–4.8) μIU/mL, fT4I 2.7 (2.3–3.2); control group: TSH 3.6 (2.1–4.2) μIU/mL, fT4I 3.6 (2.9–3.9). Patients were treated with a LT4 morning dose of 1 μg/kg/day, initiated 4–8 days after the first prenatal visit and maintained throughout pregnancy. PBR RCT, randomized controlled trial; TSH, thyrotropin; T3, Triiodothyronine; fT3, free T3; T4, thyroxine; fT4, free thyroxine; FT4I, free thyroxine index; TPO-Ab, antithyroperoxidase antibody; LT4, levothyroxine; SCH, subclinical hypothyroidism; PLR, pregnancy loss rate; PBR, preterm birth rate. Table I Characteristics of included studies. Study Country Study design Patients Age (years) Reference values for thyroid status Negro et al. (2005) Italy RCT 86 TPO-Ab positive infertile women undergoing IVF/ICSI Treated group:29.2 ± 4; Placebo: 30.1 ± 5 TSH 0.27–4.2 mIU/L, fT4 9.3–18.0 ng/L (12–33.5 pmol/L), TPO-Ab 0–100 kIU/L Negro et al. (2006) Italy RCT 115 TPO-Ab positive pregnant women For all patients: 30 ± 6 TSH 0.27–4.2 mU/L; fT4 9.3–18.0 ng/L; TPO-Ab < 100 IU/mL Revelli et al. (2009) Italy Retrospective 93 TPO-Ab/Tg-Ab positive infertile women undergoing IVF Treated group: 35.1 ± 4.1; Placebo: 37.0 ± 3.5 TPO-Ab 0–40 IU/mL; Tg-Ab 0–35 IU/mL Abdel Rahman et al. (2010) Egypt RCT 70 infertile women with SCH undergoing ICSI Treated group:31.2 ± 4.7; Placebo: 30 ± 4.3 TSH 0.27–4.2 mIU/L, fT3 2.56–4.4 pg/mL, fT4 0.9–2.59 ng/dL Kim et al. (2011) South Korea RCT 64 infertile women with SCH undergoing IVF/ICSI Treated group:36.0 ± 2.4; Placebo: 36.1 ± 2.2 TSH 0.27–4.0 mIU/L fT4 0.9–2.59 ng/dL Lepoutre et al. (2012) Belgium Retrospective 96 TPO-Ab positive pregnant women Treat group:31.5 ± 5.5; Control group: 32.5 ± 5.3 TSH 0.2–3.5 mIU/L; fT4 0.6–1.4 ng/dL; TPO-Ab < 9 IU/mL Wang et al. (2012) China Retrospective 196 pregnant women with SCH For all patients:19 to 45 years old TSH 0.13–2.5 mIU/L, 12 Pmol/L≤ FT4 < 23.34 pmol/L for the first trimester Maraka et al. (2016b) USA Retrospective 366 pregnant women with SCH Treated group:30 ± 5.2; Control: 30 ± 4.5 TSH ≤2.5 mIU/L for the first trimester; ≤3 mIU/L for the second and third trimesters. Negro et al. (2016) Italy RCT 393 TPO-Ab positive pregnant women Treated group:28.9 ± 5.2; Control: 31.3 ± 5.2 TSH 0.30–3.6 mIU/L; TPO-Ab ≤16 IU/mL Maraka et al. (2017) USA Retrospective 5394 pregnant women with SCH Treated group:31.7 ± 4.7; Control: 29.9 ± 5.1 TSH 2.5–10.0 mIU/L for the first trimester Nazarpour (2017) Iran RCT 131 TPO-Ab positive pregnant women Treat group:26.6 ± 5.8; Control group: 27.0 ± 4.7 TSH 0.1–2.5 μIU/mL; FT4I 1–4.5; TPO < 50 IU/mL Wang et al. (2017) China RCT 600 TPO-Ab positive infertile women undergoing IVF Treated group: 31.3 ± 3.9; Placebo: 31.7 ± 3.8 TSH 0.5–4.78 mIU/L TPO-Ab 0–60 IU/mL Nazarpour (2018) Iran RCT 366 pregnant women with SCH, negative for TPO-Ab Treat group:27.0 ± 5.3; Control group: 26.9 ± 4.7 TSH 0.1–2.5 mIU/L; FT4I 1–4.5; TPO-Ab < 50 IU/mL Study Country Study design Patients Age (years) Reference values for thyroid status Negro et al. (2005) Italy RCT 86 TPO-Ab positive infertile women undergoing IVF/ICSI Treated group:29.2 ± 4; Placebo: 30.1 ± 5 TSH 0.27–4.2 mIU/L, fT4 9.3–18.0 ng/L (12–33.5 pmol/L), TPO-Ab 0–100 kIU/L Negro et al. (2006) Italy RCT 115 TPO-Ab positive pregnant women For all patients: 30 ± 6 TSH 0.27–4.2 mU/L; fT4 9.3–18.0 ng/L; TPO-Ab < 100 IU/mL Revelli et al. (2009) Italy Retrospective 93 TPO-Ab/Tg-Ab positive infertile women undergoing IVF Treated group: 35.1 ± 4.1; Placebo: 37.0 ± 3.5 TPO-Ab 0–40 IU/mL; Tg-Ab 0–35 IU/mL Abdel Rahman et al. (2010) Egypt RCT 70 infertile women with SCH undergoing ICSI Treated group:31.2 ± 4.7; Placebo: 30 ± 4.3 TSH 0.27–4.2 mIU/L, fT3 2.56–4.4 pg/mL, fT4 0.9–2.59 ng/dL Kim et al. (2011) South Korea RCT 64 infertile women with SCH undergoing IVF/ICSI Treated group:36.0 ± 2.4; Placebo: 36.1 ± 2.2 TSH 0.27–4.0 mIU/L fT4 0.9–2.59 ng/dL Lepoutre et al. (2012) Belgium Retrospective 96 TPO-Ab positive pregnant women Treat group:31.5 ± 5.5; Control group: 32.5 ± 5.3 TSH 0.2–3.5 mIU/L; fT4 0.6–1.4 ng/dL; TPO-Ab < 9 IU/mL Wang et al. (2012) China Retrospective 196 pregnant women with SCH For all patients:19 to 45 years old TSH 0.13–2.5 mIU/L, 12 Pmol/L≤ FT4 < 23.34 pmol/L for the first trimester Maraka et al. (2016b) USA Retrospective 366 pregnant women with SCH Treated group:30 ± 5.2; Control: 30 ± 4.5 TSH ≤2.5 mIU/L for the first trimester; ≤3 mIU/L for the second and third trimesters. Negro et al. (2016) Italy RCT 393 TPO-Ab positive pregnant women Treated group:28.9 ± 5.2; Control: 31.3 ± 5.2 TSH 0.30–3.6 mIU/L; TPO-Ab ≤16 IU/mL Maraka et al. (2017) USA Retrospective 5394 pregnant women with SCH Treated group:31.7 ± 4.7; Control: 29.9 ± 5.1 TSH 2.5–10.0 mIU/L for the first trimester Nazarpour (2017) Iran RCT 131 TPO-Ab positive pregnant women Treat group:26.6 ± 5.8; Control group: 27.0 ± 4.7 TSH 0.1–2.5 μIU/mL; FT4I 1–4.5; TPO < 50 IU/mL Wang et al. (2017) China RCT 600 TPO-Ab positive infertile women undergoing IVF Treated group: 31.3 ± 3.9; Placebo: 31.7 ± 3.8 TSH 0.5–4.78 mIU/L TPO-Ab 0–60 IU/mL Nazarpour (2018) Iran RCT 366 pregnant women with SCH, negative for TPO-Ab Treat group:27.0 ± 5.3; Control group: 26.9 ± 4.7 TSH 0.1–2.5 mIU/L; FT4I 1–4.5; TPO-Ab < 50 IU/mL Study Thyroid status and thyroid hormone values in patients Intervention Pregnancy outcomes Negro et al. (2005) For all patients: TPO-Ab (+). TSH and fT4 within normal range. Treated group: TSH 1.9 ± 0.7 mIU/L before treatment, fT4 11.2 ± 1.8 ng/L before treatment; TSH 1.1 ± 0.3 mIU/L after treatment, fT4 14.1 ± 2.5 ng/L after treatment; Control group: TSH 1.7 ± 0.7 mIU/L, fT4 11.7 ± 2.1 ng/L. Patients in treated group underwent LT4 1 μg/kg/day treatment, one month before ART, this treatment was maintained throughout pregnancy. PLR Negro et al. (2006) For all patients: TPO-Ab (+). Treated group: TSH 1.6 ± 0.5 mIU/L; control group: TSH 1.7 ± 0.4 mIU/L. fT4 level was not clearly provided. Patients received LT4 0.5 μg/kg/day if they had TSH < 1.0 μIU/mL, 0.75 μg/kg/day for TSH 1.0–2.0 μIU/mL, and a 1 μg/kg/day dose for TSH > 2.0 μIU/mL or a TPOAb titre exceeding 1500 IU/mL; dosages were maintained throughout gestation. PLR, PBR Revelli et al. (2009) For all patients: TPO-Ab or Tg-Ab (+). TSH and fT4 within normal range. Treated group: TSH 2.1 ± 1.3 mIU/L, fT4 9.9 ± 3.5 pg/mL, fT3 3.0 ± 1.5 pg/mL; control group: TSH 2.0 ± 1.2 mIU/L, fT4 10.6 ± 2.8 pg/mL, fT3 3.1 ± 1.4 pg/mL. Patients in treated group underwent LT4 50 mg/day treatment during IVF, one month before ART, this treatment was maintained throughout pregnancy. Treatments were prescribed by different endocrinologists taking care of the patients’ thyroid conditions without any known selection criteria apart from their personal, clinical experience. PLR Abdel Rahman et al. (2010) For all patients: TSH > 4 mUI/L, fT4 within normal range. Treated group: TSH 4.7 ± 0.5 mIU/L before treatment, fT3 2.85 ± 0.7 ng/L before treatment, fT4 1 ± 0.4 before treatment; Control group: TSH 4.8 ± 0.7 mIU/L, fT3 2.79 ± 0.8 ng/L, fT4 1.04 ± 0.49 ng/L. Patients in treated group underwent LT4 50–100 μg/day, 1 month before ART, this treatment was maintained throughout pregnancy. PLR Kim et al. (2011) For all patients: TSH > 4.5 mUI/L, fT4 within normal range. Treated group: TSH 6.6 ± 1.7 mIU/L before treatment, fT4 1.2 ± 0.2 before treatment; Conttrol group: TSH 6.7 ± 1.8 mIU/L, fT4 1.2 ± 0.2 ng/L. Patients in treated group underwent LT4 50 μg/day, from the first day of controlled ovarian stimulation, this treatment was maintained throughout pregnancy. PLR Lepoutre et al. (2012) Not clearly described. In treatment group: the initial LT4 dose started as soon as TPOAb was detected and TSH > 1 mU/l, and maintained throughout the pregnancy to maintain a TSH level between 1 and 2 mU/L. PLR, PBR Wang et al. (2012) Not clearly described. The initial dose of LT4 depended on the TSH level: Dose for TSH 2.5–5 mIU/L was 50 μg/day; for TSH 5–8 mIU/L was 75 μg/day and TSH > 8 mIU/L was 100 μg/day. The drug dosage was adjusted according to their serum TSH level until delivery. PLR, PBR Maraka et al. (2016b) Treated group: TSH 4.9 ± 1.4 mIU/L; control group: TSH 3.5 ± 0.9 mIU/L. fT4 level was not clearly provided. Not clearly described. PLR, PBR Negro et al. (2016) For all patients: TPO-Ab (+). Treated group: TSH 1.42 ± 0.5 mIU/L; control group: TSH 1.37 ± 0.5 mIU/L. In treatment group: women with a TSH between 0.5 and 1.5 were begun on 0.5 mg/kg/d of LT4, between 1.5 and 2.5 mIU/L were begun on 1 mg/kg/day. In the second trimester, if the TSH > 3.0 or < 0.5 mIU/L, LT4 was increased or decreased by 12.5 mg/kg/d, respectively. In control group, LT4 was given when TSH > 3.0 mIU/L in the second trimester. PLR, PBR Maraka et al. (2017) Baseline of TSH in treated group: 4.8 ± 1.7 mIU/L; in control group: 3.3 ± 0.9 mIU/L. Not clearly described. PLR, PBR Nazarpour (2017) For all patients: TPO-Ab (+). TSH and fT4 in the first trimester [median (percentiles 25–75)]: Treated group: TSH 3.7 (2.8–4.8) μIU/mL, fT4I 2.7 (2.3–3.4); control group: TSH 3.2 (2.1–5.2) μIU/mL, fT4I 2.8 (2.3–3.1). Patients received LT4 0.5 μg/kg/day if they had TSH < 1.0 μIU/mL, 0.75 μg/kg/day for TSH 1.0–2.0 μIU/mL, and a 1 μg/kg/day dose for TSH > 2.0 μIU/mL or a TPOAb titre exceeding 1500 IU/mL; dosages were maintained throughout gestation. PLR, PBR Wang et al. (2017) For all patients: TPO-Ab (+). TSH and fT4 within normal range. Treated group: TSH (mean (interquartile range)), 2.94 (2.04–3.74) mIU/L before treatment, fT4 (mean ± SD), 1.16 ± 0.13 before treatment; Conttrol group:TSH 2.12 (1.5–2.8) mIU/L, fT4 1.19 ± 0.14 ng/L LT4 was supplemented between 2 and 4 weeks before the COS and continued through the end of pregnancy. For individuals with a TSH level ≥ 2.5 mIU/L, the starting dose was 50 μg/day; for those with a TSH level < 2.5 mIU/L, the starting dose was 25 μg/day. For individuals with body weight <50 kg, the starting dose was decreased by 50%. The LT4 dose was titrated to keep the TSH level within 0.1–2.5 mIU/L in the first trimester, 0.2–3.0 mIU/L in the second trimester, and 0.3–3.0 mIU/L in the third trimester. PLR, PBR Nazarpour (2018) TSH and fT4 in the first trimester [median (percentiles 25–75)]: Treated group: TSH 3.7 (2.8–4.8) μIU/mL, fT4I 2.7 (2.3–3.2); control group: TSH 3.6 (2.1–4.2) μIU/mL, fT4I 3.6 (2.9–3.9). Patients were treated with a LT4 morning dose of 1 μg/kg/day, initiated 4–8 days after the first prenatal visit and maintained throughout pregnancy. PBR Study Thyroid status and thyroid hormone values in patients Intervention Pregnancy outcomes Negro et al. (2005) For all patients: TPO-Ab (+). TSH and fT4 within normal range. Treated group: TSH 1.9 ± 0.7 mIU/L before treatment, fT4 11.2 ± 1.8 ng/L before treatment; TSH 1.1 ± 0.3 mIU/L after treatment, fT4 14.1 ± 2.5 ng/L after treatment; Control group: TSH 1.7 ± 0.7 mIU/L, fT4 11.7 ± 2.1 ng/L. Patients in treated group underwent LT4 1 μg/kg/day treatment, one month before ART, this treatment was maintained throughout pregnancy. PLR Negro et al. (2006) For all patients: TPO-Ab (+). Treated group: TSH 1.6 ± 0.5 mIU/L; control group: TSH 1.7 ± 0.4 mIU/L. fT4 level was not clearly provided. Patients received LT4 0.5 μg/kg/day if they had TSH < 1.0 μIU/mL, 0.75 μg/kg/day for TSH 1.0–2.0 μIU/mL, and a 1 μg/kg/day dose for TSH > 2.0 μIU/mL or a TPOAb titre exceeding 1500 IU/mL; dosages were maintained throughout gestation. PLR, PBR Revelli et al. (2009) For all patients: TPO-Ab or Tg-Ab (+). TSH and fT4 within normal range. Treated group: TSH 2.1 ± 1.3 mIU/L, fT4 9.9 ± 3.5 pg/mL, fT3 3.0 ± 1.5 pg/mL; control group: TSH 2.0 ± 1.2 mIU/L, fT4 10.6 ± 2.8 pg/mL, fT3 3.1 ± 1.4 pg/mL. Patients in treated group underwent LT4 50 mg/day treatment during IVF, one month before ART, this treatment was maintained throughout pregnancy. Treatments were prescribed by different endocrinologists taking care of the patients’ thyroid conditions without any known selection criteria apart from their personal, clinical experience. PLR Abdel Rahman et al. (2010) For all patients: TSH > 4 mUI/L, fT4 within normal range. Treated group: TSH 4.7 ± 0.5 mIU/L before treatment, fT3 2.85 ± 0.7 ng/L before treatment, fT4 1 ± 0.4 before treatment; Control group: TSH 4.8 ± 0.7 mIU/L, fT3 2.79 ± 0.8 ng/L, fT4 1.04 ± 0.49 ng/L. Patients in treated group underwent LT4 50–100 μg/day, 1 month before ART, this treatment was maintained throughout pregnancy. PLR Kim et al. (2011) For all patients: TSH > 4.5 mUI/L, fT4 within normal range. Treated group: TSH 6.6 ± 1.7 mIU/L before treatment, fT4 1.2 ± 0.2 before treatment; Conttrol group: TSH 6.7 ± 1.8 mIU/L, fT4 1.2 ± 0.2 ng/L. Patients in treated group underwent LT4 50 μg/day, from the first day of controlled ovarian stimulation, this treatment was maintained throughout pregnancy. PLR Lepoutre et al. (2012) Not clearly described. In treatment group: the initial LT4 dose started as soon as TPOAb was detected and TSH > 1 mU/l, and maintained throughout the pregnancy to maintain a TSH level between 1 and 2 mU/L. PLR, PBR Wang et al. (2012) Not clearly described. The initial dose of LT4 depended on the TSH level: Dose for TSH 2.5–5 mIU/L was 50 μg/day; for TSH 5–8 mIU/L was 75 μg/day and TSH > 8 mIU/L was 100 μg/day. The drug dosage was adjusted according to their serum TSH level until delivery. PLR, PBR Maraka et al. (2016b) Treated group: TSH 4.9 ± 1.4 mIU/L; control group: TSH 3.5 ± 0.9 mIU/L. fT4 level was not clearly provided. Not clearly described. PLR, PBR Negro et al. (2016) For all patients: TPO-Ab (+). Treated group: TSH 1.42 ± 0.5 mIU/L; control group: TSH 1.37 ± 0.5 mIU/L. In treatment group: women with a TSH between 0.5 and 1.5 were begun on 0.5 mg/kg/d of LT4, between 1.5 and 2.5 mIU/L were begun on 1 mg/kg/day. In the second trimester, if the TSH > 3.0 or < 0.5 mIU/L, LT4 was increased or decreased by 12.5 mg/kg/d, respectively. In control group, LT4 was given when TSH > 3.0 mIU/L in the second trimester. PLR, PBR Maraka et al. (2017) Baseline of TSH in treated group: 4.8 ± 1.7 mIU/L; in control group: 3.3 ± 0.9 mIU/L. Not clearly described. PLR, PBR Nazarpour (2017) For all patients: TPO-Ab (+). TSH and fT4 in the first trimester [median (percentiles 25–75)]: Treated group: TSH 3.7 (2.8–4.8) μIU/mL, fT4I 2.7 (2.3–3.4); control group: TSH 3.2 (2.1–5.2) μIU/mL, fT4I 2.8 (2.3–3.1). Patients received LT4 0.5 μg/kg/day if they had TSH < 1.0 μIU/mL, 0.75 μg/kg/day for TSH 1.0–2.0 μIU/mL, and a 1 μg/kg/day dose for TSH > 2.0 μIU/mL or a TPOAb titre exceeding 1500 IU/mL; dosages were maintained throughout gestation. PLR, PBR Wang et al. (2017) For all patients: TPO-Ab (+). TSH and fT4 within normal range. Treated group: TSH (mean (interquartile range)), 2.94 (2.04–3.74) mIU/L before treatment, fT4 (mean ± SD), 1.16 ± 0.13 before treatment; Conttrol group:TSH 2.12 (1.5–2.8) mIU/L, fT4 1.19 ± 0.14 ng/L LT4 was supplemented between 2 and 4 weeks before the COS and continued through the end of pregnancy. For individuals with a TSH level ≥ 2.5 mIU/L, the starting dose was 50 μg/day; for those with a TSH level < 2.5 mIU/L, the starting dose was 25 μg/day. For individuals with body weight <50 kg, the starting dose was decreased by 50%. The LT4 dose was titrated to keep the TSH level within 0.1–2.5 mIU/L in the first trimester, 0.2–3.0 mIU/L in the second trimester, and 0.3–3.0 mIU/L in the third trimester. PLR, PBR Nazarpour (2018) TSH and fT4 in the first trimester [median (percentiles 25–75)]: Treated group: TSH 3.7 (2.8–4.8) μIU/mL, fT4I 2.7 (2.3–3.2); control group: TSH 3.6 (2.1–4.2) μIU/mL, fT4I 3.6 (2.9–3.9). Patients were treated with a LT4 morning dose of 1 μg/kg/day, initiated 4–8 days after the first prenatal visit and maintained throughout pregnancy. PBR RCT, randomized controlled trial; TSH, thyrotropin; T3, Triiodothyronine; fT3, free T3; T4, thyroxine; fT4, free thyroxine; FT4I, free thyroxine index; TPO-Ab, antithyroperoxidase antibody; LT4, levothyroxine; SCH, subclinical hypothyroidism; PLR, pregnancy loss rate; PBR, preterm birth rate. Quality assessment As shown in Supplemental Table S1, the retrospective studies received NOS scores of 6–8, suggesting a low risk of bias. However, in the study by Wang et al. (2012), the mean age of patients was significantly higher in the LT4-treated group than in the control group (30.4 vs 27.7 years), and other critical confounders, such as BMI and history of other endocrine diseases, were not described. The study by Maraka et al. (2017) was a population-based retrospective study in which patients’ age distribution and baseline TSH levels were not matched, and thus, a sensitivity analysis was performed including and excluding this study. Furthermore, all included RCTs exhibited a low risk of bias in the domains of random sequence generation, blinding of participants and personnel, blinding of outcome assessments, incomplete outcome data and selective reporting (Supplemental Fig. S1). However, two studies by Nazarpour et al. (2017, 2018) showed a high risk of bias in terms of allocation concealment. The risks of other biases in the four of the included RCTs were unclear (Negro et al., 2005; Abdel Rahman et al., 2010; Kim et al., 2011; Wang et al., 2017) because all of them focused on infertile women undergoing IVF/ICSI. In these studies, pregnancy outcomes might have been affected by various factors such as the causes of infertility, use of ovarian stimulation and laboratory technology. Overall effects of LT4 supplementation on PLR in women with SCH and/or TAI Of the 13 studies that reported data on pregnancy loss, six focused on women with SCH (Abdel Rahman et al., 2010; Kim et al., 2011; Wang et al., 2012; Maraka et al., 2016b, 2017; Nazarpour et al., 2018) and seven focused on women with TAI (Negro et al., 2005, 2006, 2016; Revelli et al., 2009; Lepoutre et al., 2012; Nazarpour et al., 2017; Wang et al., 2017). We first combined all of these studies and found that compared with placebo/no treatment, LT4 supplementation significantly decreased the PLR (RR = 0.69, 95% CI: 0.58–0.82, I2 = 14%; fixed effects model) in women with SCH and/or TAI (Fig. 2A). The meta-analysis excluding the study by Maraka et al. (2017) resulted in a pooled RR of 0.56 (95% CI: 0.42–0.75), which was similar to that of the meta-analysis including the study by Maraka et al. (2017) (Fig. 2B); however, the heterogeneity decreased from 14 to 1%. Figure 2 View largeDownload slide Forest plot presenting the overall effects of LT4 supplementation on PLR in women with SCH and/or TAI. Overall effects of LT4 supplementation on PLR in women with SCH and/or TAI when including (A) and excluding (B) the study by Maraka et al. (2017). LT4, levothyroxine; SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; PLR, pregnancy loss rate; CI, confidence interval. Figure 2 View largeDownload slide Forest plot presenting the overall effects of LT4 supplementation on PLR in women with SCH and/or TAI. Overall effects of LT4 supplementation on PLR in women with SCH and/or TAI when including (A) and excluding (B) the study by Maraka et al. (2017). LT4, levothyroxine; SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; PLR, pregnancy loss rate; CI, confidence interval. Overall effects of LT4 supplementation on PBR in women with SCH and/or TAI Of the nine studies that reported data on PBR, four focused on women with SCH (Wang et al., 2012; Maraka et al., 2016b, 2017; Nazarpour et al., 2018) and the remaining five focused on women with TAI (Negro et al., 2006, 2016; Lepoutre et al., 2012; Nazarpour et al., 2017; Wang et al., 2017). The combination of all these studies showed that LT4 supplementation was not significantly associated with a decreased risk of preterm birth (RR = 0.75, 95% CI: 0.50–1.11, I2 = 57%; random effects model) (Fig. 3A). However, on excluding the study by Maraka et al. (2017), LT4 supplementation was found to significantly decrease the PBR compared with placebo/no treatment (RR = 0.68, 95% CI: 0.51–0.91, I2 = 21%; fixed effects model) (Fig. 3B). The degree of heterogeneity declined from high to low on excluding the study by Maraka et al. (2017), indicating that this study was heterogeneous with other studies. Therefore, this study was not included in the following subgroup analysis. Figure 3 View largeDownload slide Forest plot presenting the overall effects of LT4 supplementation on PBR in women with SCH and/or TAI. Overall effects of LT4 supplementation on PBR in women with SCH and/or TAI when including (A) and excluding (B) the study by Maraka et al. (2017). LT4, levothyroxine; SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; PBR, preterm birth rate. Figure 3 View largeDownload slide Forest plot presenting the overall effects of LT4 supplementation on PBR in women with SCH and/or TAI. Overall effects of LT4 supplementation on PBR in women with SCH and/or TAI when including (A) and excluding (B) the study by Maraka et al. (2017). LT4, levothyroxine; SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; PBR, preterm birth rate. Effect of LT4 supplementation on PLR in women with SCH Five studies reported the effects of LT4 supplementation on PLR in women with SCH. The meta-analysis revealed a significant decrease in the risk of pregnancy loss (RR = 0.43, 95% CI: 0.26–0.72) with LT4 supplementation, with no heterogeneity (I2 = 0%) (Fig. 4A). The two RCTs by Kim et al. (2011) and Abdel Rahman et al. (2010) focused on infertile women undergoing IVF/ICSI; therefore, the subgroup analysis revealed a significant decrease in the PLR among women undergoing IVF/ICSI (RR = 0.27, 95% CI: 0.14–0.52). The subgroup analysis of RCTs (Abdel Rahman et al., 2010; Kim et al., 2011; Nazarpour et al., 2018) showed consistent results (RR = 0.27, 95% CI: 0.14–0.52) with the combined effects of both RCTs and retrospective studies, whereas no such effect was observed with non-RCTs and women with naturally conceived pregnancies (both RR = 0.60, 95% CI: 0.28–1.30) (Tables 2 and 3, Fig. 5). Figure 4 View largeDownload slide LT4 supplementation and PLR/PBR in women with SCH and TAI. (A) LT4 supplementation and PLR in patients with SCH; (B) LT4 supplementation and PBR in patients with SCH; (C) LT4 supplementation and PLR in patients with TAI; and (D) LT4 supplementation and PBR in patients with TAI. LT4, levothyroxine; SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; PLR, pregnancy loss rate; PBR, preterm birth rate. Figure 4 View largeDownload slide LT4 supplementation and PLR/PBR in women with SCH and TAI. (A) LT4 supplementation and PLR in patients with SCH; (B) LT4 supplementation and PBR in patients with SCH; (C) LT4 supplementation and PLR in patients with TAI; and (D) LT4 supplementation and PBR in patients with TAI. LT4, levothyroxine; SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; PLR, pregnancy loss rate; PBR, preterm birth rate. Table II Subgroup analysis for the effect of LT4 supplementation on PLR and PBR, according to study design. Subgroup No. of studies No. of women Effect model Effect size (RR, 95% CI) I2 Psubgroup SCH and PLR 5 1062 Fixed 0.43 (0.26, 0.72) 0  RCTs 3 500 Fixed 0.27 (0.14, 0.52) 14  Non-RCTs 2 562 Fixed 0.60 (0.28, 1.30) 0 0.001 TAI and PLR 7 1514 Random 0.63 (0.45, 0.89) 0  RCTs 5 1325 Random 0.68 (0.48, 0.97) 0  Non-RCTs 2 189 Random 0.36 (0.02, 5.47) 60 0.02 SCH and PBR 3 928 Fixed 0.67 (0.41, 1.12) 0  RCTs 1 366 Fixed 0.86 (0.47, 1.55) N/A  Non-RCTs 2 562 Fixed 0.44 (0.17, 1.13) 0 0.13 TAI and PBR 5 1335 Random 0.68 (0.48, 0.98) 46  RCTs 4 1239 Random 0.61 (0.32, 1.14) 59  Non-RCTs 1 96 Random 0.71 (0.17, 3.04) N/A 0.10 Subgroup No. of studies No. of women Effect model Effect size (RR, 95% CI) I2 Psubgroup SCH and PLR 5 1062 Fixed 0.43 (0.26, 0.72) 0  RCTs 3 500 Fixed 0.27 (0.14, 0.52) 14  Non-RCTs 2 562 Fixed 0.60 (0.28, 1.30) 0 0.001 TAI and PLR 7 1514 Random 0.63 (0.45, 0.89) 0  RCTs 5 1325 Random 0.68 (0.48, 0.97) 0  Non-RCTs 2 189 Random 0.36 (0.02, 5.47) 60 0.02 SCH and PBR 3 928 Fixed 0.67 (0.41, 1.12) 0  RCTs 1 366 Fixed 0.86 (0.47, 1.55) N/A  Non-RCTs 2 562 Fixed 0.44 (0.17, 1.13) 0 0.13 TAI and PBR 5 1335 Random 0.68 (0.48, 0.98) 46  RCTs 4 1239 Random 0.61 (0.32, 1.14) 59  Non-RCTs 1 96 Random 0.71 (0.17, 3.04) N/A 0.10 SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; RCT, randomized controlled trial; PLR, pregnancy loss rate; PBR, preterm birth rate; RR, risk ratio; N/A, not applicable. Significant associations are printed bold. View Large Table II Subgroup analysis for the effect of LT4 supplementation on PLR and PBR, according to study design. Subgroup No. of studies No. of women Effect model Effect size (RR, 95% CI) I2 Psubgroup SCH and PLR 5 1062 Fixed 0.43 (0.26, 0.72) 0  RCTs 3 500 Fixed 0.27 (0.14, 0.52) 14  Non-RCTs 2 562 Fixed 0.60 (0.28, 1.30) 0 0.001 TAI and PLR 7 1514 Random 0.63 (0.45, 0.89) 0  RCTs 5 1325 Random 0.68 (0.48, 0.97) 0  Non-RCTs 2 189 Random 0.36 (0.02, 5.47) 60 0.02 SCH and PBR 3 928 Fixed 0.67 (0.41, 1.12) 0  RCTs 1 366 Fixed 0.86 (0.47, 1.55) N/A  Non-RCTs 2 562 Fixed 0.44 (0.17, 1.13) 0 0.13 TAI and PBR 5 1335 Random 0.68 (0.48, 0.98) 46  RCTs 4 1239 Random 0.61 (0.32, 1.14) 59  Non-RCTs 1 96 Random 0.71 (0.17, 3.04) N/A 0.10 Subgroup No. of studies No. of women Effect model Effect size (RR, 95% CI) I2 Psubgroup SCH and PLR 5 1062 Fixed 0.43 (0.26, 0.72) 0  RCTs 3 500 Fixed 0.27 (0.14, 0.52) 14  Non-RCTs 2 562 Fixed 0.60 (0.28, 1.30) 0 0.001 TAI and PLR 7 1514 Random 0.63 (0.45, 0.89) 0  RCTs 5 1325 Random 0.68 (0.48, 0.97) 0  Non-RCTs 2 189 Random 0.36 (0.02, 5.47) 60 0.02 SCH and PBR 3 928 Fixed 0.67 (0.41, 1.12) 0  RCTs 1 366 Fixed 0.86 (0.47, 1.55) N/A  Non-RCTs 2 562 Fixed 0.44 (0.17, 1.13) 0 0.13 TAI and PBR 5 1335 Random 0.68 (0.48, 0.98) 46  RCTs 4 1239 Random 0.61 (0.32, 1.14) 59  Non-RCTs 1 96 Random 0.71 (0.17, 3.04) N/A 0.10 SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; RCT, randomized controlled trial; PLR, pregnancy loss rate; PBR, preterm birth rate; RR, risk ratio; N/A, not applicable. Significant associations are printed bold. View Large Table III Subgroup analysis for the effect of LT4 supplementation on PLR and PBR, according to patients’ characteristics. Subgroup No. of studies No. of women Effect model Effect size (RR, 95% CI) I2 Psubgroup SCH and PLR 5 1062 Fixed 0.43 (0.26, 0.72) 0  ART pregnancy 2 134 Fixed 0.27 (0.14, 0.52) 14  Spontaneous pregnancy 3 928 Fixed 0.60 (0.28, 1.30) 0 0.001 TAI and PLR 7 1514 Fixed 0.63 (0.45, 0.89) 0  ART pregnancy 3 779 Fixed 0.68 (0.40, 1.15) 0  Spontaneous pregnancy 4 735 Fixed 0.61 (0.39, 0.96) 31 0.009 SCH and PBR 3 928 Fixed 0.67 (0.41, 1.12) 0  ART pregnancy 0 0 N/A N/A N/A  Spontaneous pregnancy 3 928 Fixed 0.67 (0.41, 1.12) 0 0.13 TAI and PBR 5 1335 Fixed 0.68 (0.48, 0.98) 46  ART pregnancy 1 600 Fixed 1.20 (0.68, 2.13) N/A  Spontaneous pregnancy 4 735 Fixed 0.49 (0.30, 0.79) 0 0.04 Subgroup No. of studies No. of women Effect model Effect size (RR, 95% CI) I2 Psubgroup SCH and PLR 5 1062 Fixed 0.43 (0.26, 0.72) 0  ART pregnancy 2 134 Fixed 0.27 (0.14, 0.52) 14  Spontaneous pregnancy 3 928 Fixed 0.60 (0.28, 1.30) 0 0.001 TAI and PLR 7 1514 Fixed 0.63 (0.45, 0.89) 0  ART pregnancy 3 779 Fixed 0.68 (0.40, 1.15) 0  Spontaneous pregnancy 4 735 Fixed 0.61 (0.39, 0.96) 31 0.009 SCH and PBR 3 928 Fixed 0.67 (0.41, 1.12) 0  ART pregnancy 0 0 N/A N/A N/A  Spontaneous pregnancy 3 928 Fixed 0.67 (0.41, 1.12) 0 0.13 TAI and PBR 5 1335 Fixed 0.68 (0.48, 0.98) 46  ART pregnancy 1 600 Fixed 1.20 (0.68, 2.13) N/A  Spontaneous pregnancy 4 735 Fixed 0.49 (0.30, 0.79) 0 0.04 SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; PLR, pregnancy loss rate; PBR, preterm birth rate; RR, risk ratio; CI, confidence interval; ART, assisted reproductive technology; N/A, not applicable. Significant associations are printed bold. View Large Table III Subgroup analysis for the effect of LT4 supplementation on PLR and PBR, according to patients’ characteristics. Subgroup No. of studies No. of women Effect model Effect size (RR, 95% CI) I2 Psubgroup SCH and PLR 5 1062 Fixed 0.43 (0.26, 0.72) 0  ART pregnancy 2 134 Fixed 0.27 (0.14, 0.52) 14  Spontaneous pregnancy 3 928 Fixed 0.60 (0.28, 1.30) 0 0.001 TAI and PLR 7 1514 Fixed 0.63 (0.45, 0.89) 0  ART pregnancy 3 779 Fixed 0.68 (0.40, 1.15) 0  Spontaneous pregnancy 4 735 Fixed 0.61 (0.39, 0.96) 31 0.009 SCH and PBR 3 928 Fixed 0.67 (0.41, 1.12) 0  ART pregnancy 0 0 N/A N/A N/A  Spontaneous pregnancy 3 928 Fixed 0.67 (0.41, 1.12) 0 0.13 TAI and PBR 5 1335 Fixed 0.68 (0.48, 0.98) 46  ART pregnancy 1 600 Fixed 1.20 (0.68, 2.13) N/A  Spontaneous pregnancy 4 735 Fixed 0.49 (0.30, 0.79) 0 0.04 Subgroup No. of studies No. of women Effect model Effect size (RR, 95% CI) I2 Psubgroup SCH and PLR 5 1062 Fixed 0.43 (0.26, 0.72) 0  ART pregnancy 2 134 Fixed 0.27 (0.14, 0.52) 14  Spontaneous pregnancy 3 928 Fixed 0.60 (0.28, 1.30) 0 0.001 TAI and PLR 7 1514 Fixed 0.63 (0.45, 0.89) 0  ART pregnancy 3 779 Fixed 0.68 (0.40, 1.15) 0  Spontaneous pregnancy 4 735 Fixed 0.61 (0.39, 0.96) 31 0.009 SCH and PBR 3 928 Fixed 0.67 (0.41, 1.12) 0  ART pregnancy 0 0 N/A N/A N/A  Spontaneous pregnancy 3 928 Fixed 0.67 (0.41, 1.12) 0 0.13 TAI and PBR 5 1335 Fixed 0.68 (0.48, 0.98) 46  ART pregnancy 1 600 Fixed 1.20 (0.68, 2.13) N/A  Spontaneous pregnancy 4 735 Fixed 0.49 (0.30, 0.79) 0 0.04 SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; PLR, pregnancy loss rate; PBR, preterm birth rate; RR, risk ratio; CI, confidence interval; ART, assisted reproductive technology; N/A, not applicable. Significant associations are printed bold. View Large Figure 5 View largeDownload slide Summary of the meta-analysis results. Effect size is expressed as [RR (95% CI)]. LT4, levothyroxine; SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; RR, relative risk. Figure 5 View largeDownload slide Summary of the meta-analysis results. Effect size is expressed as [RR (95% CI)]. LT4, levothyroxine; SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; RR, relative risk. Effect of LT4 supplementation on PBR in women with SCH Only three studies investigated the association between LT4 supplementation and PBR in patients with SCH (Wang et al., 2012; Maraka et al., 2016b; Nazarpour et al., 2018). The pooled results revealed no beneficial effect of LT4 supplementation on the risk of preterm birth (RR = 0.67, 95% CI: 0.41–1.12, I2 = 0%) (Fig. 4B). Further subgroup analyses also indicated no beneficial effect on PBR in the RCT (RR = 0.86, 95% CI: 0.47–1.55) or non-RCTs (RR = 0.44, 95% CI: 0.17–1.13). In addition, no conclusions could be drawn regarding the effects of LT4 supplementation on PBR in patients undergoing IVF as all of the studies focused on women with naturally conceived pregnancies (Tables 2 and 3, Fig. 5). Effect of LT4 supplementation on PLR in women with TAI Seven studies reported data on the association between LT4 supplementation and PLR in patients with TAI. The combined results of all these studies revealed a significant effect of LT4 supplementation on the PLR, with a pooled RR of 0.63 (95% CI: 0.45–0.89, I2 = 0%; fixed effects model) (Fig. 4C). This pooled result did not change when any of the included studies were removed from the meta-analysis. In the subgroup analysis, the pooled results from five RCTs (Negro et al., 2005, 2006, 2016; Nazarpour et al., 2017; Wang et al., 2017) were consistent with the overall results (RR = 0.68, 95% CI: 0.48–0.97, I2 = 0%), whereas the pooled results from non-RCTs (Revelli et al., 2009; Lepoutre et al., 2012) suggested no beneficial effects of LT4 supplementation on PLR (RR = 0.36, 95% CI: 0.02–5.47, I2 = 60%). The combination of the four studies that focused on naturally conceived pregnancies (Negro et al., 2006, 2016; Lepoutre et al., 2012; Nazarpour et al., 2017) revealed a significant improvement in the PLR with LT4 supplementation (RR = 0.61, 95% CI: 0.39–0.96, I2 = 31%), whereas no such improvement was observed in studies that focused on patients undergoing IVF/ICSI (Negro et al., 2005; Revelli et al., 2009; Wang et al., 2017) (RR = 0.68, 95% CI: 0.40–1.15, I2 = 0%) (Tables 2 and 3, Fig. 5). Effect of LT4 supplementation on PBR in women with TAI Five studies reported data on the association between LT4 supplementation and preterm births in patients with TAI. The pooled effects revealed a significantly decreased risk of preterm birth among women treated with LT4 compared with that among untreated women (RR = 0.68 95% CI: 0.48–0.98, I2 = 46%; fixed effects model) (Fig. 4D). However, the subgroup analyses of RCTs (RR = 0.61, 95% CI: 0.32–1.14; I2 = 59%) and non-RCTs (RR = 0.71, 95% CI: 0.17–3.04) revealed no such decrease in the risk. Further, a decreased risk of preterm birth was observed among patients with naturally conceived pregnancies (RR = 0.49, 95% CI: 0.30–0.79, I2 = 0%) but not among those undergoing IVF/ICSI (RR = 1.20, 95% CI: 0.68–2.13, I2 not applicable) (Tables 2 and 3, Fig. 5). Discussion Principle findings In this systematic review and meta-analysis, we found beneficial effects of LT4 supplementation on the risks of pregnancy loss and preterm birth among pregnant women with SCH and/or TAI. Further analysis suggested that LT4 supplementation may reduce the risk of pregnancy loss in pregnant women with SCH or TAI and the risk of preterm birth in pregnant women with TAI but not in those with SCH. The subgroup analysis further indicated an association between LT4 supplementation and decreased odds of pregnancy loss in pregnancies achieved by ART, but not in naturally conceived pregnancies, among women with SCH. By contrast, LT4 seems to reduce the risks of pregnancy loss and preterm birth in naturally conceived pregnancies, but not in pregnancies achieved by ART, among patients with TAI. As these subgroup analyses were based on a limited number of studies, further research is needed to draw firm conclusions. LT4 supplementation and PLR in women with SCH and/or TAI In 2012, Vissenberg et al. (2012) meta-analysed the effect of LT4 intervention on miscarriage rate in pregnant women with TAI reported in three studies (Negro et al., 2005, 2006; Revelli et al., 2009) and found no beneficial effect of LT4. However, in the present meta-analysis, we included more recently published studies and found a 31% relative risk reduction in pregnancy loss by LT4 supplementation among pregnant women with SCH and/or TAI compared with that by no treatment/placebo. All included studies were carefully reviewed and assessed for the quality. The study by Maraka et al. (2017) was a large retrospective study including 5405 pregnant women in the US and provided data on pregnancy loss and preterm birth. We noted that the patients’ age distribution was significantly different between LT4 supplementation and control groups, with a higher percentage of younger women ( < 25 years old) in the control group than in the LT4 supplementation group. This may inevitably affect the pregnancy outcomes such as pregnancy loss and preterm birth because there is a higher risk of these adverse outcomes in women with increased age (Frederiksen et al., 2018; Sheen et al., 2018). In addition, the proportion of patients with baseline TSH levels of 2.5–4.0 mIU/L was significantly lower in the LT4 supplementation group (39.1%) than in the control group (84.7%), indicating that the patients in these two groups had different thyroid dysfunction levels. Furthermore, the percentage of patients with a history of thyroid disease was also different between these two groups. These confounders may cause bias with respect to pregnancy outcomes between the groups. Therefore, this meta-analysis was repeated without this study in the sensitivity analysis. The inclusion and exclusion of this study produced similar results with regard to pregnancy loss and both showed an obvious decrease in heterogeneity, but the exclusion of this study produced a large effect on the pooled outcome of preterm birth. Thus, we did not include this study in the subsequent subgroup analysis. Based on the limited data available, LT4 was found to reduce the risk of pregnancy loss by 57 and 37% in women with SCH and TAI, respectively. These results were further confirmed by the subgroup analysis of RCTs alone. Subgroup analysis revealed that LT4 supplementation was associated with decreased PLR in pregnancies achieved by ART, but not in naturally conceived pregnancies, among women with SCH (Fig. 5). This result was supported by a very large cohort study (n = 184,611) in China, the authors of which showed that preconception TSH elevation even within the normal non-pregnant range (2.50–4.29 mIU/L) was associated with increased risks of a series of adverse pregnancy outcomes, including pregnancy loss and preterm birth (Chen et al., 2017), indicating that improving thyroid function before conception may improve pregnancy outcomes. This result of subgroup analysis was based on two small sample-sized RCTs (Abdel Rahman et al., 2010; Kim et al., 2011) in which PLR was significantly lower in LT4-treated patients than in control patients. The following aspects may account for the different effects of LT4 between patients who conceived naturally and those who conceived by ART. First, the decrease in PLR in women with SCH who conceived by ART may be due to the beneficial effect of LT4 on oocyte and embryo quality (Aghajanova et al., 2011; Vissenberg et al., 2015). Second, pregnancy loss that occurred in infertile patients was more accurately recorded because these women were possibly more concerned about pregnancy outcomes and therefore were more adherent to follow-up. In addition, the first prenatal visit of some naturally pregnant women (Nazarpour et al., 2017, 2018) may have occurred after the gestational ages during which miscarriages most commonly occur (de Jong et al., 2013). Third, ovarian stimulation with exogenous gonadotropins was found to promote the development of mild hypothyroidism due to high oestradiol levels (Poppe et al., 2004; Benaglia et al., 2014; Hammond et al., 2015). This may also suggest a worse thyroid status in pregnant women who conceived by IVF/ICSI. Thus, women undergoing IVF/ICSI need careful monitoring of thyroid function, and women diagnosed with SCH should receive LT4 supplementation at the earliest possibly time-point, ideally before conception (Velasco and Taylor, 2018). In contrast to women with SCH, women with TAI who conceived naturally, but not those who conceived by ART, benefited from LT4 with respect to reduced pregnancy loss (Fig. 5). Considering that the incidence of pregnancy loss was usually higher in pregnancies achieved by ART in infertile women than in naturally conceived pregnancies (Liu and Rosenwaks, 1991; Wang et al., 2004; Bahceci and Ulug, 2005), it is possible that TAI had a lower contribution to pregnancy loss in naturally conceived pregnancies than in pregnancies achieved by ART, leading to a relatively weaker effect of LT4 on pregnancy loss in pregnancies conceived through ART. Notably, the number of studies in each subgroup was very limited, although the heterogeneity was low to moderate (I2 ranged from 0 to 46%). The results regarding the differential effects of LT4 between pregnancies achieved by ART and naturally conceived pregnancies need to be interpreted with caution. Future large RCTs are warranted to confirm these results. LT4 supplementation and PBR in women with SCH and/or TAI Preterm birth is still one of the most prevalent and morbid perinatal complications and is currently the leading cause of neonatal death. In 2011, Thangaratinam et al. (2011) conducted a meta-analysis of five studies and concluded that the presence of thyroid autoantibodies doubles the risk of preterm birth. Korevaar et al. (2013, 2018) published two large cohort studies (n = 11212 and 5971, respectively) that confirmed the adverse effect of TPO-Ab positivity on pregnancy outcome with respect to preterm birth. In this meta-analysis, a significant decrease in the risk of preterm birth by LT4 supplementation was found in patients with SCH and/or TAI. Patients with SCH who conceived naturally may not show a reduction in preterm birth due to LT4 supplementation (Fig. 5). The study by Wang (2017) was a large RCT (n = 600) and also the only study that reported PBR in patients with TAI undergoing IVF/ICSI. The authors reported no significant reduction in the PBR by LT4 supplementation, which is in contrast to the results for naturally conceiving women with TAI who were likely to exhibit reduced PBR due to LT4 supplementation. Because the pathogenesis of preterm birth caused by SCH and/or TAI remains largely unknown, a clear explanation for these differences in the PBRs was difficult. In our included studies, 70 preterm births occurred among 718 patients with naturally conceived pregnancies (four studies) (Negro et al., 2006, 2016; Lepoutre et al., 2012; Nazarpour et al., 2017), whereas 38 preterm births occurred among 206 patients with pregnancies achieved by ART (one study) (Wang et al., 2017), suggesting a much higher PBR in pregnancies achieved by ART than in naturally conceived pregnancies. This conclusion is supported by many recently published meta-analyses (McDonald et al., 2009; Pandey et al., 2012; Cavoretto et al., 2018). The aetiology of infertility and the treatment were also reported as risk factors for preterm birth (Wisborg et al., 2010; Cavoretto et al., 2018). Therefore, we hypothesized that SCH and/or TAI contributed as only a part of the causes of preterm birth in pregnancies achieved by ART, whereas in naturally conceived pregnancies, SCH and/or TAI may be the main or the only cause of preterm birth. This may at least partially explain why women who conceived naturally, but not those who conceived by ART, benefited from LT4 supplementation in terms of PBR. To date, no study regarding the effect of LT4 on PBR in women with SCH undergoing ART has been published. Future studies in this regard are warranted. Biological interpretation of the evidence Both SCH and TAI are recognized as mild thyroid dysfunctions and may reflect a relative lower thyroid functional capacity that can become apparent during states of increased demand for TH synthesis, such as early pregnancy, even though free thyroxin (fT4) is in the normal range; thus, SCH and TAI were sometimes combined together for data analysis (Velkeniers et al., 2013; Chai et al., 2014). Although similar in terms of the deficiency in thyroid function, SCH and TAI may have different patterns of influence on pregnancy outcomes, as shown in Fig. 6. Figure 6 View largeDownload slide Potential mechanisms of action of SCH/TAI in increased risks of pregnancy loss and preterm birth. Both SCH and TAI represent a mild deficiency in thyroid functional capacity that may lead to pregnancy loss and preterm birth by reducing oocyte and embryo quality, by affecting placentation and placental function, affecting luteogenesis and CL function or impairing thyroidal response to hCG. SCH/TAI may also increase the risk of other obstetric complications, such as pre-eclampsia, PPROM and FGR, leading to pregnancy loss and preterm birth. These risks could be reduced by LT4 supplementation. In addition, TAI is related to a systemic immune disorder, and patients with TAI may also suffer from other connective tissue diseases. TAI may also be involved in the regulation of cytokine networks within the local placental–decidual environment. These mechanisms may also be involved in pregnancy loss and preterm birth in women with TAI. LT4, levothyroxine; SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; IL, interleukin; VEGF, vascular endothelial growth factor; PIGF, placental growth factor; CL, corpus luteum; COX-II, cyclooxygenase II; FGR, foetal growth restriction; PPROM, preterm premature rupture of membranes. Figure 6 View largeDownload slide Potential mechanisms of action of SCH/TAI in increased risks of pregnancy loss and preterm birth. Both SCH and TAI represent a mild deficiency in thyroid functional capacity that may lead to pregnancy loss and preterm birth by reducing oocyte and embryo quality, by affecting placentation and placental function, affecting luteogenesis and CL function or impairing thyroidal response to hCG. SCH/TAI may also increase the risk of other obstetric complications, such as pre-eclampsia, PPROM and FGR, leading to pregnancy loss and preterm birth. These risks could be reduced by LT4 supplementation. In addition, TAI is related to a systemic immune disorder, and patients with TAI may also suffer from other connective tissue diseases. TAI may also be involved in the regulation of cytokine networks within the local placental–decidual environment. These mechanisms may also be involved in pregnancy loss and preterm birth in women with TAI. LT4, levothyroxine; SCH, subclinical hypothyroidism; TAI, thyroid autoimmunity; IL, interleukin; VEGF, vascular endothelial growth factor; PIGF, placental growth factor; CL, corpus luteum; COX-II, cyclooxygenase II; FGR, foetal growth restriction; PPROM, preterm premature rupture of membranes. SCH/TAI and pregnancy loss The pathophysiological mechanism of pregnancy loss caused by SCH/TAI is largely unknown. However, several hypotheses based on available studies may be proposed. First, patients with SCH and TAI have a poor oocyte and embryo quality. TSH and thyroid receptors are expressed in granulosa cells and oocytes and likely influence granulosa cell survival, steroidogenesis and oocyte maturation (De Silva, 1994; Wakim et al., 1994; Aghajanova et al., 2009; Colicchia et al., 2014), although this has not been clearly clarified. TSH elevation is reported to be a significant predictor of fertilization failure in women undergoing IVF/ICSI (Cramer et al., 2003) and can lead to a hypothyroid state, which may result in dysfunction of granulosa cells, thereby reducing oocyte quality and subsequent embryo quality (Kim et al., 2011). Few studies have linked the presence of TPO-Abs with lower fertilization rates and embryo quality (Monteleone et al., 2011; Andrisani et al., 2018), but to date, only associations have been reported and studies exploring the pathophysiology are lacking. Compared with no treatment, a timely supplementation of LT4 significantly improved the embryo quality (Bernal et al., 1999; Kim et al., 2011), thus improving adverse pregnancy outcomes, because a poorer embryo quality has been reported to be associated with a higher miscarriage rate (Zhu et al., 2014; Akamine et al., 2018) in ART cycles. Second, SCH and TAI may influence placental function. TH transporters and receptors are expressed in the trophoblast cells (Loubiere et al., 2010; Aghajanova et al., 2011; Patel et al., 2012), and optimal TH concentrations are necessary to ensure appropriate placentation (Krassas et al., 2010). TH plays a vital role in regulating the invasive potential of extravillous trophoblasts into the decidua and the angiogenesis of maternal and foetal placental vessels (Oki et al., 2004) by regulating a series of growth factors and cytokines, such as angiopoietin 2, vascular endothelial growth factor (VEGF) A, interleukin 6 (IL-6), IL-8, IL-10 and tumour necrosis factor alpha (Cartwright et al., 2010; Pitman et al., 2013; Vasilopoulou et al., 2014). Clearly, changes in placental vascularity are the causes of many obstetric complications, including pregnancy loss and preterm birth (Wormald et al., 1989; Kovo et al., 2011; Odibo et al., 2014). In addition, the subtle deficiency in TH levels in SCH and TAI may affect the placental secretion of progesterone (P4) and human placental lactogen (Maruo et al., 1991; Vissenberg et al., 2015), which play critical roles in maintaining pregnancy (Stephanou and Handwerger, 1995). TPO-Abs may diffuse through the placental barrier during pregnancy (Seror et al., 2014; Vissenberg et al., 2015). Pregnant women with TAI were found to have a high uterine artery pulsatility index, suggesting a defective placentation (Beneventi et al., 2015). However, no published study has reported direct evidence suggesting that TPO-Abs affect placental function (Vissenberg et al., 2015). Third, SCH and TAI may affect luteogenesis and corpora luteum (CL) function. Animal studies have indicated that the presence of an adequate level of circulating TH is needed to support CL formation and normal function (Jiang et al., 2001; Hapon et al., 2007). Hypothyroidism reduced the proliferation, apoptosis and expression of angiogenic factors in the CL of pregnant rats (Silva et al., 2014); thus, hypothyroidism may be involved in the impairment of CL function. TH receptor isoforms have been found in the CL during pregnancy and postpartum, identifying this gland as a TH target during gestation. TH receptor expression is modulated in the CL in accordance with the regulation of P4 metabolism (Navas et al., 2014). However, no direct evidence has shown the changes in P4 levels among pregnant women with SCH and/or TAI. In addition, TAI may be considered as a manifestation of general autoimmunity. The prevalence of connective tissue diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome, anti-phospholipid syndrome, systemic sclerosis and undefined connective tissue disease, was much higher in pregnant women with TAI than in those without TAI (Beneventi et al., 2015, 2016). Many studies have established the association between these connective tissue diseases and increased risks of adverse pregnancy outcomes, such as pregnancy loss, pre-eclampsia, foetal growth restriction and preterm birth (Spinillo et al., 2008, 2012, 2016a, 2016b, 2017; Beneventi et al., 2012). The prevalence of connective tissue diseases among pregnant women is up to 2.5–3.7% during the first trimester (Spinillo et al., 2012, 2016b), but unfortunately, these diseases usually remain unrecognized until screening is performed during pregnancy or an adverse pregnancy event occurs (Spinillo et al., 2012, 2016b). Furthermore, pregnancy itself is an inflammatory process, which involves a shift in the regulation of cytokine networks within the local placental and decidual environment (Redman and Sargent, 2005). Evidence suggests that TAI is closely related to inflammatory dysregulation (Colin et al., 2004), which may be associated with miscarriage and premature birth (Challis et al., 2009). Therefore, thyroid antibodies could possible act as non-specific markers of autoimmune disease and may not be directly linked to the cause of actual miscarriage (De Leo and Pearce, 2018). SCH/TAI and preterm birth Very few studies have attempted to address the pathophysiological mechanism of preterm birth caused by SCH and/or TAI. We propose the following hypotheses that may help, at least in part, to explain the mechanism. First, patients with TAI may have an impaired response to thyroidal stimulation by hCG. During early pregnancy, hCG stimulates the TSH receptor, leading to an increase in concentrations of fT4 and a subsequent decrease in concentrations of TSH (Korevaar et al., 2017a). A recent study demonstrated that TPO-Ab-positive women have an impaired response to thyroidal stimulation by hCG (Korevaar et al., 2017b). Consequently, such women with a lower thyroidal response to hCG stimulation have a higher risk of premature delivery. Second, as mentioned above, SCH and TAI may affect placentation and placental function. Maternal thyroid hormones have a physiological role in early placental development, through regulation of human trophoblast proliferation and invasion (Oki et al., 2004). Inadequate invasion of trophoblast cells may result in abnormal placentation, which is a major risk factor for preterm birth (Kim et al., 2003; Barber et al., 2005). In one rat study, hypothyroidism affected foetal weight by altering the proliferative activity, apoptosis and vascularization of the placenta (Silva et al., 2012), which is one of the important causes of preterm birth (Salafia et al., 1995; Proctor et al., 2009; Apel-Sarid et al., 2010; Kovo et al., 2011). Changes in placental vascularity inevitably affect foetal growth, which is also associated with preterm birth (Lackman et al., 2001; Partap et al., 2016). Another potential mechanism would be the systemic immune disorder in patients with TAI, as we addressed above. Many patients with TAI also suffer from connective tissue diseases, such as rheumatoid arthritis and systemic lupus erythematosus, which have been suggested to be associated with an increased risk of preterm birth (Beneventi et al., 2012; Spinillo et al., 2012, 2016a, 2016b). The last and the most important factor is the increased risk of other obstetric complications that are involved in preterm birth in patients with SCH and/or TAI. Several studies have established the associations of SCH/TAI with increased risks of preterm premature rupture of membranes (Cleary-Goldman et al., 2008; Korevaar et al., 2013, 2017c), pre-eclampsia (Feldthusen et al., 2014; Saki et al., 2015; Zhang et al., 2017a) and intrauterine growth restriction (Chen et al., 2014; Monier et al., 2017; Johns et al., 2018). In 2013, Korevaar et al.’s study (2013) on 5971 pregnant women provided evidence suggesting that both TAI and SCH are associated with an increased risk of preterm birth occurring both before and after 32 weeks of gestation. However, these associations were not supported by some other studies (Negro et al., 2006; Mannisto et al., 2010; Plowden et al., 2017). Because these associations remain controversial, a comprehensive review and quantification of the available data, if possible, would be helpful to draw a relatively firm conclusion. If the associations are accurate, the preterm birth caused by SCH and/or TAI would be mediated mainly by the occurrence of the above-mentioned obstetric complications, which have been shown to be associated with preterm birth (Bukowski et al., 2001; Morken et al., 2006; Carreno et al., 2011; Severi et al., 2012). All of the potential mechanisms proposed above were based on a limited number of available studies. Some of the associations have not yet been evidenced. Thus, further studies are warranted to confirm the associations and elaborate the underlying molecular mechanisms. Strengths and limitations The strength of this meta-analysis is that it included a comprehensive literature search with all available data to obtain relatively firm evidence. Of the 13 included studies, 10 were published after 2010, suggesting a minor effect of publication years on the data combination. However, this meta-analysis had some limitations. First, the data analysis included a limited number of eligible studies. This would have decreased the power of evidence when the subgroup analysis was performed. Because only one to five studies were combined for analysis in each subgroup, further population-based RCTs are needed to confirm our results. Second, the definition of pregnancy loss in the included studies varied, which may have induced reporting bias. Third, all included studies except one (Maraka et al., 2016b) reported data on overall preterm birth but not on very preterm birth ( < 32 weeks) and late preterm birth (32–36+6 weeks) separately; therefore, a separate analysis of the improvement in the PBR was not possible. However, these two conditions differ largely in terms of causes and consequences. Another limitation is that we had no access to the individual participant data, which could have allowed us to minimize the heterogeneity between studies. Furthermore, the enroled studies differed in terms of the methodology and the normal ranges of thyroid function test results, as shown in Table 1. Although LT4 supplementation was maintained throughout pregnancy in the treatment arms of all studies, the starting time varied. More importantly, the studies differed in terms of the LT4 dose, as shown in Table 1. In three of the included studies (Kim et al., 2011; Maraka et al., 2016b; Nazarpour et al., 2017), some women had both SCH and TAI, and this made it very difficult to segregate the results of one condition from the other. Other factors, such as the women’s BMIs and other medical interventions during pregnancy, might also have affected the combined effects and degree of heterogeneity. Another point to be noted is that the combined results might have been affected by the presence of other autoimmune diseases in women with TAI as these diseases are also risk factors for adverse pregnancy outcomes. Clinical and research recommendations The ATA guidelines published in 2017 recommended that subclinical hypothyroid pregnant women with or without TPO-Ab positivity should receive LT4 supplementation to prevent pregnancy loss and preterm birth, but they did not recommend this treatment for euthyroid pregnant women with TAI, except for those with a prior history of pregnancy loss, because of insufficient evidence (Alexander et al., 2017). The results of this present meta-analysis supported the recommendation that LT4 therapy should be administered in pregnant women with SCH, and we propose that TPO-Ab-positive women will also benefit from LT4 supplementation. This suggestion was supported by De Leo et al. (2018) who also recommended treatment with low doses of LT4 to reduce adverse outcomes in pregnant women with TAI, which they follow in their clinical practice. Due to the limited number of studies included in this meta-analysis and inevitable heterogeneity, especially in the subgroup analyses, the conclusions of this study should be further confirmed using large RCTs. RCTs are warranted in the future to evaluate the effect of LT4 supplementation on preterm birth in subclinical hypothyroid women undergoing ART because no such study has yet been published. The study by Wang et al. (2017) was the only trial that reported the effect of LT4 supplementation on preterm birth in patients with TAI undergoing ART, and it revealed no effect in the PBR. Thus, more RCTs are needed to confirm this result. It is essential to evaluate the beneficial effects of LT4 on adverse pregnancy outcomes in patients undergoing ART because it would help in directly evaluating the effects on oocyte and embryo quality. Notably, all included studies involved patients with different aetiology of infertility (male, female, both or an unexplained factor), making it difficult to evaluate the effect of TAI or SCH alone; therefore, future well-designed studies, for example, involving only male factor infertility, will help clarify these issues. In addition, further fundamental research on the effect of TH regulation on the hypothalamic–pituitary–gonadal axis and placental function are needed to better clarify the underlying molecular mechanisms of thyroid dysfunction-related adverse pregnancy outcomes. Conclusions The results of this meta-analysis showed that LT4 supplementation is associated with a decreased risk of pregnancy loss and preterm birth in women with SCH and/or TAI. Further, thyroid function screening prior to ART cycles for infertile women appears necessary because timely LT4 supplementation after SCH diagnosis could decrease the risk of pregnancy loss; however, no such findings were reported for preterm birth. The evidence does not recommend LT4 treatment for naturally conceiving women with SCH. Although LT4 intervention seems to have no improvement in pregnancy loss and preterm birth among women diagnosed with TAI prior to ART cycles, thyroid function should be carefully monitored as ovarian stimulation is associated with decreased thyroid function. By contrast, naturally conceiving women with TAI may benefit from LT4 supplementation. Due to limited number of studies included in this meta-analysis, especially in the subgroup analysis, further large RCTs and fundamental research are warranted to confirm the conclusions obtained in this meta-analysis and better clarify the molecular mechanism underlying these associations. Acknowledgements We want to thank Prof. Ernest Hung-Yu Ng from Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital for his help in revising the article. Authors’ roles M.R., S.Z. and L.T. contributed to the design of the study, M.R., Z.Z. and F.Z. performed the literature search. M.R. and Z.Z. extracted the data. M.R., H.W., R.W. and Y.W. performed the statistical analysis. M.R. and L.T. drafted the article. J.L., Z.Y., C.S. and Z.S. contributed to the interpretation of the results. All authors approved the final draft of the article. Funding Technology & Innovation Team of Reproduction and Genetics from Kunming Medical University (No. CXTD201708), and the Scientific Funding from the First Affiliated Hospital of Kunming Medical University (No. 2017BS008). Conflict of interest None declared. References Abdel Rahman AH , Aly Abbassy H , Abbassy AA . 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Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Effect of levothyroxine supplementation on pregnancy loss and preterm birth in women with subclinical hypothyroidism and thyroid autoimmunity: a systematic review and meta-analysis
JF - Human Reproduction Update
DO - 10.1093/humupd/dmz003
DA - 2019-05-01
UR - https://www.deepdyve.com/lp/oxford-university-press/effect-of-levothyroxine-supplementation-on-pregnancy-loss-and-preterm-Jo5wpgS0Kh
SP - 344
VL - 25
IS - 3
DP - DeepDyve
ER -