Effect of levothyroxine supplementation on pregnancy loss and preterm birth in women with subclinical hypothyroidism and thyroid autoimmunity: a systematic review and meta-analysis

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.