Revisiting natural cycle frozen embryo transfer: a systematic review and meta-analysis

The optimal endometrial preparation protocol for frozen embryo transfer (FET) remains a subject of ongoing investigation. HRT is the most commonly used approach, but natural cycle (NC) FET has regained attention due to potential improvements in maternal and perinatal outcomes. Despite growing observational evidence supporting NC FET, its adoption is limited by logistical challenges in cycle monitoring and scheduling. Recently, the natural proliferative phase (NPP) FET protocol has been introduced, combining the physiological benefits of a functional corpus luteum with greater scheduling flexibility.

Previous systematic reviews have largely focused on luteal phase support (LPS) or have provided narrative summaries susceptible to selection bias. This systematic review aimed to evaluate the impact of different execution strategies on reproductive outcomes across true-NC and modified-NC and to compare NPP FET with other protocols.

A comprehensive search of MEDLINE, Embase, Global Health, and Cochrane Library was conducted from database inception to 10 November 2024. The search included keywords such as 'frozen embryo transfer', 'natural cycle', 'pregnancy', 'live birth', and 'delivery' with no language or filter restrictions. Reference lists of included studies were screened to identify additional relevant studies.

A total of 70 studies were included: 8 randomized controlled trials (1 with low risk of bias and 7 with some concerns), 16 non-randomized interventional studies (with risk of bias being moderate for 4, serious for 6, and critical for another 6), and 46 observational studies (80.4% of which were good quality) assessing prognostic factors. In true-NC FET, prolonged follicular phases did not adversely affect outcomes. Ovulatory cycles were associated with significantly higher live birth rates (LBRs) than cycles with luteinized unruptured follicle (risk ratio (RR): 1.16, 95% CI: 1.04-1.29, I2 = 0%, three studies, 2907 cycles, very low-certainty evidence). Despite variability in ovulation timing methods, performing FET on serum LH surge +6 to +7 days yielded comparable reproductive outcomes. In modified-NC FET, two observational studies reported similar LBRs when triggering ovulation at follicle diameters between 13 and 22 mm, provided the endometrial thickness was >7 mm and serum progesterone was below 1.5 ng/ml. LPS with vaginal progesterone improved LBRs in true-NC compared to no LPS (RR: 1.43, 95% CI: 1.16-1.78, I2 = 0%, 923 cycles, two studies, moderate-certainty evidence), but showed no benefit in modified-NC FET (RR: 1.04, 95% CI: 0.82-1.32, I2 = 0%, 667 cycles, two studies, moderate-certainty evidence). In NPP FET, a meta-analysis showed higher LBRs compared to HRT FET (RR: 1.25, 95% CI: 1.13-1.38, I2 = 5.36%, 3397 cycles, three studies, very low-certainty evidence).

NC FET protocols are associated with operational constraints. Modified-NC and NPP strategies may balance physiological benefits with scheduling convenience, though high-quality evidence remains limited. Routine LPS improves LBRs in true-NC FET but not in modified-NC. The apparent equivalence of outcomes when hCG is administered across a follicle size range of 13-22 mm suggests a potential 7-day window of scheduling flexibility for modified-NC FET; however, this finding warrants further validation. NPP FET may offer enhanced scheduling convenience without compromising reproductive outcomes, but warrants additional investigation through high-quality trials.

PROSPERO: CRD42023385304.