OBJECTIVES: We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers together with reference checking and contact with study authors and experts in the field to identify studies. We searched for all published and unpublished randomised controlled trials (RCTs) comparing
thyroxine with no treatment or placebo, without language restrictions, from inception to 8 April 2019, and in consultation with the Cochrane CGF Information Specialist.
SELECTION CRITERIA: We included women undergoing assisted reproduction treatment, meaning both in vitro fertilisation and intracytoplasmic sperm injection, with a history of
subfertility and with subclinical
hypothyroidism or with euthyroid ATD. We excluded women with a previously known clinical
hypothyroidism or already taking
thyroxine or tri-iodothyronine. RCTs compared
thyroxine (
levothyroxine) with either placebo or no treatment.
DATA COLLECTION AND ANALYSIS: 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.
AUTHORS' CONCLUSIONS: We could draw no clear conclusions in this systematic review due to the very low to low quality of the evidence reported.