Single oral dose of vitamin D3 supplementation prior to in vitro fertilization and embryo transfer in normal weight women: the SUNDRO randomized controlled trial.

Abstract

BACKGROUND\nImproving in vitro fertilization (IVF) success is an unmet need. Observational studies suggested that women with deficient or insufficient vitamin D have lower chances of success, but whether supplementation improves clinical pregnancy rate is unclear.\n\n\nOBJECTIVE\nTo determine whether oral vitamin D3 supplementation may improve clinical pregnancy in women undergoing an IVF cycle STUDY DESIGN: The SUNDRO trial is a two-centers randomized superiority double-blind placebo controlled trial. Subjects were recruited between October 2016 and January 2019. Participants were women aged 18-39 years with low vitamin D (peripheral 25-hydroxyvitamin D < 30 ng/ml), serum calcium ≥ 10.6 mg/dl, body-mass index (BMI) 18-25 Kg/m2, anti-mullerian hormone (AMH) levels > 0.5 ng/ml, starting their first, second, or third treatment cycle of conventional IVF or intracytoplasmic sperm injection (ICSI). The primary outcome was the cumulative clinical pregnancy rate per cycle. Pregnancies obtained with both fresh or frozen embryo transfers were included. Clinical pregnancy was defined as intrauterine gestational sac with viable fetus. The primary analysis was performed according to the intention to treat principle and could also include natural conceptions. Secondary outcomes included total dose of gonadotropins used, embryological variables (number of oocytes retrieved, number of suitable oocytes retrieved, fertilization rate and rate of top quality embryos) and clinical outcomes (miscarriage rate and live birth rate).\n\n\nRESULTS\n630 women were randomized 2-12 weeks prior to initiate the IVF cycle to receive either a single dose of 600,000 IU of vitamin D3 (n=308) or placebo (n=322). One hundred thirteen (37%) and 130 (40%) women achieved a clinical pregnancy in the treatment and placebo groups, respectively (p=0.37). The risk ratio (RR) of clinical pregnancy in women receiving vitamin D3 was 0.91 (95% confidence interval-CI: 0.75 - 1.11). Compared to placebo, vitamin D3 supplementation did not significantly improve the secondary outcomes. Exploratory subgroup analyses for BMI, age, indication to IVF, ovarian reserve, interval between drug administration and initiation of the cycle and basal levels of 25-hydroxyvitamin D failed to highlight any clinical situation that could benefit from the supplementation.\n\n\nCONCLUSIONS\nIn normal weight women with preserved ovarian reserve and low vitamin D levels undergoing IVF cycles, a single oral dose of 600,000 IU of vitamin D3 does not improve the chances of clinical pregnancy. Although the findings do not support the use of vitamin D3 supplementation to ameliorate IVF success, further studies are required to rule out milder but potentially still interesting benefits as well as exploring the effectiveness of alternative modalities of supplementation.