P–409 Comparison of the incidence of ectopic pregnancies in fresh versus frozen embryo transfers in IVF/ICSI cycles: a meta-analysis of Randomized Controlled Trials (RCT)
Authors: Scaglione P , Marino A , Gullo S , Volpes A , Sammartano F , Allegra A 
Published: August 2021

Abstract

Study question
Is the incidence of ectopic pregnancy (EP) increased in fresh compared with frozen embryo transfer (ET)?

Summary answer
The fresh ET is not associated with an increase of the incidence of EP in comparison with frozen ET.

What is known already
EP represents the first cause of mortality in the first trimester of pregnancy. Assisted reproductive technologies (ART) are associated with an increased EP risk. The reasons of this effect are inadequately explained and may be associated with variables patients-related as tubal diseases and ART-related as the number of embryos transferred, the depth of insertion of the catheter tip during ET and the supraphysiological estradiol levels during ovarian stimulation affecting endometrial receptivity and tubal function. The role of this last factor seems to be corroborated by higher incidence of EP in fresh versus frozen ET, as highlighted by some retrospective studies.

Study design, size, duration
A meta-analysis, based on PubMed, Cochrane CENTRAL, EMBASE, was conducted to estimate and compare the EP rate in fresh versus frozen-thawed ET. Following PICOS, inclusion criteria were: Population, patients undergoing IVF/ICSI; Intervention, fresh ET; Comparison, frozen/thawed ET; Outcome, EP (primary one), clinical/ongoing pregnancy and live birth rates (secondary ones). Study design: RCT.

Participants/materials, setting, methods
Electronic and manual search, conducted from 1990 to 2020, yielded 269 studies. Two researchers reviewed the studies independently, excluding 247 and 16 studies after the first and second screening. The outcome data from the 6 included studies were combined using a Mantel–Haenszel model and applying the random effects models. The dichotomous data results of each study were expressed as risk ratio (RR) with 95% confidence intervals (CI). Heterogeneity was evaluated using the I2 statistic.

Main results and the role of chance
The six studies included in the present review comprise in total 6,675 participants, 3,320 undergoing frozen ET and 3,355 fresh ET (Ferraretti et al., 1999; Chen et al., 2016; Le et al., 2018; Shi et al., 2018; Wei et al., 2019; Stormlund et al., 2020).
Preliminary analyses excluded interaction between covariates, defining intervention/control groups and outcome. In particular, the incidence of tubal infertility was comparable between the two groups. Risk ratio of EP ranged from 0.03 (Ferraretti et al., 1999) to 2.77 (Shi et al., 2018). The level of heterogeneity (I2) between studies was 42% and it was considered as moderate. EP incidence resulted not significantly different in fresh ET [56/1,703 pregnancies] compared with frozen ET [44/1,799 pregnancies] (RR = 0.450, 95% CI 0.13–1.81, p = 0.29; I2=42%).
Analysis of the secondary outcomes was conducted on 5 studies; results showed that clinical pregnancy rate was not significantly different between fresh (0.52) and frozen ET (0.56) (RR = 1.11; 95% CI = 0.93–1.34); at the same manner, the ongoing pregnancy rate (RR = 1.11; 95%CI=0.91–1.37; 0.46 vs 0.49 for fresh and frozen, respectively) and the live birth rate (RR = 0.93; 95%CI=0.60–1.44; 0.47 vs 0.49 for fresh and frozen, respectively) resulted not significantly different between the two groups.

Limitations, reasons for caution
The EP incidence was not the primary outcome of the included RCTs. This could have determined a sample size not calibrated for the analysis of the primary outcome of the present meta-analysis.
Wider implications of the findings: This meta-analysis indicates that EP incidence is similar between fresh and frozen ET. The possible role on EP risk of the supraphysiological estradiol levels during ovarian stimulation should be reconsidered. Based on these results, the choice of a frozen ET should not derive by the presumed reduction of EP risk.

Trial registration number
Not applicable