Fresh vs. frozen embryo transfer: new approach to minimize the limitations of using national surveillance data for clinical research

Abstract

Objective: To assess the benefit of frozen vs. fresh elective single embryo transfer using traditional and novel methods of controlling for confounding.

Design: Retrospective cohort study using data from the National Assisted Reproductive Technology Surveillance System.

Setting: Not applicable.

Patient(s): A total of 44,750 women aged 20-35 years undergoing their first lifetime oocyte retrieval and embryo transfer in 2016-2017, who had ≥4 embryos cryopreserved.

Intervention(s): Fresh elective single embryo transfer and frozen elective single embryo transfer.

Main outcome measure(s): The primary outcome was a singleton live birth. Secondary outcomes included rates of total live birth (singleton plus multiple gestations), twin live birth, clinical intrauterine gestation, total pregnancy loss, biochemical pregnancy, and ectopic pregnancy. Outcomes for infants included gestational age at delivery, birth weight, and being small for gestational age.

Result(s): The eligibility criteria were met by 6,324 fresh and 2,318 frozen cycles. Patients undergoing fresh and frozen transfer had comparable mean age (30.69 [standard deviation {SD} 0.08] years vs. 31.06 [SD 0.08] years) and body mass index (24.76 [SD 0.20] vs. 25.65 [SD 0.15]); however, women in the frozen cohort created more embryos (8.1 [SD 0.12] vs. 6.8 [SD 0.08]). Singleton live birth rates in the fresh vs. frozen groups were 51.4% vs. 48.8% (risk ratio 1.05; 95% confidence interval [CI], 1.00-1.10). After adjustment with a log-linear regression model and propensity score analysis, the difference in singleton live birth rates remained nonsignificant (adjusted risk ratio, 1.05; 95% CI, 0.97-1.14 and 1.02; 95% CI, 0.96-1.08, respectively). A novel dynamical model confirmed inherent fertility (probability of ever achieving a pregnancy) was balanced between groups (odds ratio, 1.23; 95% CI 0.78-1.95]). The per-cycle probability of singleton live birth was not different between groups (odds ratio 1.11 [95% CI 0.94-1.3]).

Conclusion(s): In this retrospective cohort study of fresh vs. frozen elective single embryo transfer, there was no statistically significant difference in singleton live birth rate after adjustment using log-linear models and propensity score analysis. The successful application of a novel dynamical model, which incorporates multiple assisted reproductive technology cycles from the same woman as a surrogate for inherent fertility, offers a novel and complementary perspective for assessing interventions using national surveillance data.

Keywords: Frozen embryo transfer; fresh embryo transfer; modeling; national database; real-world data.

FIGURE 1

Identification of the study population ^a First retrieval: patient’s first in vitro fertilization cycle and oocyte retrieval procedure ^b Nondonor: autologous cycle with patient’s own oocytes ^c Fresh transfer: transfer immediately after ovarian hyperstimulation ^d Frozen transfer: delayed transfer of previously cryopreserved embryo after supraphysiologic hormonal levels induced by ovarian stimulation have resolved. eSET = elective single embryo transfer, PGT = preimplantation genetic testing, ART = assisted reproductive technology, GnRH = gonadotropin-releasing hormone.

FIGURE 2

Forest plot of singleton live birth for elective single embryo and expanded populations. Point estimate >1 favors frozen embryo transfer. The top panel compares the crude risk ratio with those adjusted by the Poisson regression and propensity score matched approaches for both the elective single embryo and expanded populations. The bottom panel displays the per-cycle probability of live birth parameter of the dynamical model (eMethods) which is reported as an odds ratio between frozen/fresh embryo transfer.