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

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.