Abstract: The review included four studies with 820 women. The included studies were of overall low risk of bias. Using GRADE methodology, we assessed the quality of evidence for the primary outcomes of this review to be very low- to low-quality evidence. Evidence was downgraded for imprecision as it was based on single, small trials with wide confidence intervals (CI). We were able to include data from three of the four included studies. In one study of women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies (autoimmune disease), the evidence suggested that thyroxine replacement may have improved live birth rate (RR 2.13, 95% CI 1.07 to 4.21; 1 RCT, n = 64; low-quality evidence) and it may have led to similar miscarriage rates (RR 0.11, 95% CI 0.01 to 1.98; 1 RCT, n = 64; low-quality evidence). The evidence suggested that women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies would have a 25% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 27% and 100%. In women with normal thyroid function and thyroid autoimmunity (euthyroid ATD), treatment with thyroxine replacement compared with placebo or no treatment may have led to similar live birth rates (risk ratio (RR) 1.04, 95% CI 0.83 to 1.29; 2 RCTs, number of participants (n) = 686; I2 = 46%; low-quality evidence) and miscarriage rates (RR 0.83, 95% CI 0.47 to 1.46, 2 RCTs, n = 686, I2 = 0%; low-quality evidence). The evidence suggested that women with normal thyroid function and thyroid autoimmunity would have a 31% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 26% and 40%. Adverse events were rarely reported. One RCT reported 0/32 in the thyroxine replacement group and 1/32 preterm births in the control group in women diagnosed with subclinical hypothyroidism and positive or negative anti-TPO antibodies. One RCT reported 21/300 preterm births in the thyroxine replacement group and 19/300 preterm births in the control group in women diagnosed with positive anti-TPO antibodies. None of the RCTs reported on other maternal pregnancy complications, foetal complications or adverse effects of thyroxine. We could draw no clear conclusions in this systematic review due to the very low to low quality of the evidence reported.

Plain-language summary: Cochrane authors performed a comprehensive literature search of the standard medical databases to 8 April 2019 in consultation with the Cochrane Gynaecology and Fertility Group Information Specialist, for randomised clinical trials (RCTs: clinical studies where people are randomly put into one of two or more treatment groups) investigating the effect of thyroid hormones (levothyroxine) for women diagnosed with ATD or mildly underactive thyroid who were planning to undergo assisted reproduction. Two authors independently selected studies, evaluated them, extracted data and attempted to contact the authors where data were missing. We found four RCTs (with 820 women) that met our inclusion requirements. The thyroid hormones were administered in a range of doses to women diagnosed with mildly underactive thyroid or presence of thyroid antibodies (ATD). In women with mild thyroid hormone imbalance and unknown thyroid autoimmunity status, we were uncertain whether thyroxine replacement had an effect on live birth or miscarriage rates (very low-quality evidence from one study involving 70 women). In women with mildly underactive thyroids (with or without ATD), the evidence suggested that thyroxine replacement may have improved live birth rates (low-quality evidence from one study involving 64 women) and it may have led to similar miscarriage rates (low-quality evidence from one study involving 64 women). The evidence suggested that women with mildly underactive thyroid (with or without ATD) would have a 25% chance of a live birth with placebo or no treatment, and 27% to 100% with thyroxine. In women with ATD and normal thyroid function, treatment with thyroxine replacement compared with placebo or no treatment may have led to similar live birth rates (low-quality evidence from two studies involving 686 women) and miscarriage rates (low quality evidence from two studies involving 686 women). The evidence suggested that women with ATD and normal thyroid function would have a 31% chance of a live birth with placebo or no treatment, and 26% to 40% with thyroxine. Side effects were rarely reported. One study reported none out of 32 preterm births in the thyroxine replacement group and one out of 32 preterm births in the control group in women diagnosed with mildly underactive thyroid (with or without ATD). One study reported 21 out of 300 preterm births in the thyroxine replacement group and 19 out of 300 preterm births in the control group in women diagnosed with ATD and normal thyroid function. None of the studies reported on other maternal pregnancy complications, foetal complications or side effects of thyroxine. The evidence was of very low to low quality. We downgraded the evidence as it was based on single, small trials with widely variable results.