P-381 A novel natural cycle proliferative phase/progesterone replacement(NC/PR) protocol for endometrial preparation for frozen-thawed embryo transfer(FET) Can it improve pregnancy outcomes : a prospective comparative study
Authors: Varma M , Singh S , Bansal H , Tuli H , Bansal R , Kaur T 
Published: June 2022

Abstract

Study question
Can a novel protocol for endometrial preparation- NC/PR-FET, lead to better pregnancy outcomes than artificial cycle (AC)-FET, with similar ease of cycle monitoring and scheduling?

Summary answer
NC/PR-FET protocol gave comparable clinical pregnancy rates (CPR), significantly less early miscarriage rates (MR) and significantly more live birth rates (LBR) compared to AC-FET protocol.

What is known already
AC-FET is the most common protocol for endometrial preparation due to flexibility, easy monitoring, and high pregnancy rates albeit with evidence of higher obstetrical risks e.g., miscarriage, pre-eclampsia versus NC-FET. This risk could be due to suboptimal hormonal administration in AC-FET leading to impaired endometrial maturation, predecidualization, and altered endometrial function. Studies indicate, estradiol may have a stronger negative effect(versus progesterone) on the endometrial transcriptome. Hence, we studied a novel protocol with NC-estrogen (but with progesterone similar to AC-FET), for better endometrial maturation, predecidualization along with simple monitoring and flexible ET scheduling. Previously, a proof-of-concept case-series has been reported.

Study design, size, duration
The prospective comparative study was conducted at a tertiary center (Jan2019-Dec2021) with 126 patients (both autologous [AO] and donor oocytes [DO]):79 (AC-FET) and 47 (NC/PR-FET) with similar ICSI, vitrification, ET protocols. 2 or 3 Grade A cleavage stage embryos were transferred. CPR, implantation rates(IR), early MR (≤13 weeks, miscarriages/clinical pregnancies) and LBR (≥28 weeks, LBs/ETs) were compared. Serum progesterone was studied on day 5 post-ET. Antenatal care and most deliveries were at the same institute.

Participants/materials, setting, methods
Patients were non-smokers with normal hysteroscopy. In AC-FET, oral estradiol (6-8mg) was initiated from day 1-2 (for 10-17 days). In both groups, when endometrium ≥7mm and S.progesterone&lt;1ng/ml, intramuscular progesterone was initiated(daily till day 4 post-ET, then every 3rd day till week 8). ET was scheduled on day 4 of intramuscular progesterone, and concurrently, vaginal progesterone was added (till week 10). Chi-square, t-tests, and multiple regression was used for statistical analysis and 2-tailed P &lt;.05 indicated statistical significance.

Main results and the role of chance
Mean age and BMI were comparable in NC/PR-FET and AC-FET groups: 34.48±4.69 years vs. 33.58 ± 5.62 years (P =.35) and 26.27 ± 3.62 kg/m2 vs. 27.34 ± 4.61kg/m2 (P =.18) respectively. Similarly, the source of oocytes (%AO) and % singletons were also comparable in NC/PR-FET and AC-FET groups: 57.4% vs. 46.8% (P = .25), and 78.1% vs. 75% (P= .75) respectively. There were 3 ectopic pregnancies overall. The CPRs and IRs were comparable: 68.09% (NC/PR-FET) vs. 60.76% (AC-FET) (P=.41) and 32.30% (NC/PR-FET) vs. 28.96% (AC-FET) (P=.45) respectively.
The early MR was significantly more in AC-FET vs. NC/PR-FET: 29.17% vs. 6.25% (P =.012). Consequently, LBRs were significantly more in NC/PR-FET vs. AC-FET: 59.57% vs. 39.24% (P =.028). After adjusting for age, BMI, AO/DO, this difference remained significant (AOR 2.66; 95% CI 1.21-5.81; P =.014)
Mean serum progesterone was comparable in all patients in both groups: 38.50 ± 13.6ng/ml (NC/PR-FET) vs. 40.98 ± 28.64 ng/ml (AC-FET) (P =.57). Serum progesterone levels were also comparable in patients who were pregnant in both groups: 38.51 ± 14.79 (NC/PR-FET) vs. 42.25 ± 32.63 (AC-FET) (P =.53).Also, in the AC-FET group serum progesterone was comparable in patients who aborted,44.23 ± 31.60 vs. those who didn’t, 41.48 ± 33.44 (P =.79).

Limitations, reasons for caution
This was a single center study. Due to limited sample size, we could not control for many potential confounders (e.g., multiple pregnancies). For the same reason, we could not compare obstetrical risks as a study outcome.

Wider implications of the findings
This study shows significantly better pregnancy outcomes with a novel NC/PR-FET protocol vs. AC-FET. This needs to be validated in larger studies. Since suboptimal hormone administration in AC-FET could be causal factor for pre-eclampsia, larger studies can test if the NC/PR-FET protocol can lead to better obstetrical outcomes.

Trial registration number
not applicable