Perinatal Outcomes in Blastocyst vs Cleavage Stage Embryo Transfer

The unit of analysis here was a singleton live birth episode resulting from transfer of a fresh blastocyst or cleavage stage ET. As some women had two or more singleton live birth episodes arising from several ETs within the study period, all analyses were conducted under a multilevel framework, which accommodated repeated cycles resulting in livebirths within the same women. In order to account for the dependency between cycles resulting in live birth within women, a population-averaged model using generalized estimating equations was used to explore associations between the exposure groups (blastocyst versus cleavage stage ET) and perinatal outcomes (Hardin and Hilbe, 2003 ) and to estimate 95% CI using robust standard errors that allowed for correlation within women (McCullagh and Nelder, 1989 ). We specified an exchangeable correlation structure, which assumes that the risk of a perinatal adverse event was the same for any live birth within a woman. For the outcomes of preterm birth (preterm birth versus full-term birth), congenital anomaly (yes versus no), and healthy baby status (yes versus no), a robust Poisson regression model was used. For the two birthweight outcome variables (i.e. birthweight coded as low, normal or high, and birthweight adjusted for gestational age coded as SGA, AGA, or LGA), a multinomial logistic regression model was employed since each of these variables had three categories (Chamberlain, 1980 ; Pforr, 2014 ). The association between treatment strategy (blastocyst or cleavage stage ET) and very preterm birth (versus full-term birth) was estimated using multinomial logistic regression (where we also included 32–37 weeks gestation as a nuisance outcome category). Crude risk ratios (RRs), adjusted RRs (aRRs), and 95% CI were calculated. The following factors were considered as confounders: maternal age (years), cause of infertility (i.e. tubal disease, ovulatory disorder, male factor, unexplained), previous pregnancy status (yes/no), treatment type or type of insemination (IVF versus ICSI), number of eggs collected, and year of treatment. The covariates considered for adjustment differed for each of the outcomes and are listed in the footnote under each table. Since ET stage could influence birthweight through its effect on gestational age, gestational age can be considered to be a mediator on the causal pathway from cleavage or blastocyst stage ET to birthweight. Therefore, it was excluded to avoid bias since its inclusion does not allow us to estimate the total direct effect of the stage of ET on birthweight (Wilcox et al., 2011 (link)). In the same way, the number of embryos transferred was considered as a mediator and was excluded from multivariable analyses. Further, congenital anomalies or the underlying cause of congenital anomalies have been linked with iatrogenic preterm birth owing to early induction of labour (Brown, 2009 (link)). In this case, gestational age would be considered a collider rather than a confounder as both ET stage and congenital anomaly can affect gestational age through independent routes. Therefore, gestational age was also excluded from this analysis.