Should women receive luteal support following natural cycle frozen embryo transfer? A systematic review and meta-analysis

Background: Spontaneous ovulation during a natural menstrual cycle is frequently used for timing frozen embryo transfer (FET). Nevertheless, it remains unclear whether or not women should receive luteal phase support (LPS) following natural cycle frozen embryo transfer (NC-FET). Objective and Rationale: The aim of this systematic review and meta-analysis was to study whether the administration of LPS improves the reproductive outcome following NC-FET. Search Methods: We conducted a systematic search of the literature published in Medline/PubMed, Embase and the Cochrane Library, from January 2000 until December 2020. We included all original English, peer-reviewed articles, irrespective of the study design. The search strategy included keywords related to NC-FET and luteal phase support. Studies reporting the results of artificial or stimulated FET cycles were excluded. Outcomes: Our systematic search generated 416 records. After screening, eight studies were included in the review and seven studies were included in the meta-analysis. Two studies (n = 858) used hCG and six studies (n = 1507) used progesterone for luteal support. Four studies were randomised controlled trials (RCTs), whereas the other four were historic cohort studies. In a meta-analysis using a random effects model, hCG administration for LPS did not increase the clinical pregnancy rate (CPR) (two studies, odds ratio (OR) 0.85, 95% CI 0.64-1.14). On the other hand, progesterone LPS was associated with a higher CPR (five studies, OR 1.48, 95% CI 1.14-1.94), and a higher live birth rate (LBR) (three studies, OR 1.67, 95% CI 1.19-2.36). The association between progesterone LPS and the LBR remained significant after excluding non-randomised studies. Wider Implications: The available evidence indicates that progesterone administration for LPS is beneficial following NC-FET. There is no evidence to support the administration of hCG for LPS in these cases. Additional large RCTs are necessary to improve the quality of evidence and validate our findings.