LAUSR

The paper by Luke et al. published in this issue of JARG is bound to heat up the debate about freezing embryos (frozen embryo transfer, FET, versus transfer of fresh embryos) during in vitro fertilization. The practice of IVF already has moved towards greater use of FET, in part to reduce complications associated with ovarian hyperstimulation and in part to accommodate pre-implantation genetic screening (PGS). In theory, transferring embryos Bafter the fresh cycle^ could allow the endometrium to Brecover^ from stimulation and result in implantation within a more Bnatural^ hormonal milieu, i.e., one without the high levels of estrogen and progesterone used for stimulation. Some IVF clinics have jumped on these theoretical and practical advantages and now advocate using only FET [11]. The evidence base for transfer of frozen rather than fresh embryos, however, is more inchoate. There have been a number of observational studies that indicate FETs, compared with fresh embryo transfers, are less frequently associated with pregnancy complications, such as preterm birth, antepartum hemorrhage, perinatal mortality, and low birth weight [7, 8]. Studies relying on observational data, however, are susceptible to substantial bias if important confounders are not adequately measured or controlled, e.g., the indication for the IVF or parental socio-economic differences. There have been several registered randomized studies that soon could provide valuable information and are less susceptible to some of these potential biases because of the random assignment. Among the few trials with published results, there also has been controversy even in outcomes as basic as the implantation. For example, the pregnancy rate after a freezeall policy has increased by as much as 30% in some studies [2, 4, 13], but not others [14, 15]. Even data from randomized controlled trials, however, are susceptible to potential bias given uncertainty in whether any given cycle results in a birth and the frequent need for multiple treatments before birth [5]. Moreover, there are very few data on long-term outcomes for either the child or mother. Recognized disadvantages of freezing embryos include inconvenience to patients because of delaying pregnancy and potentially increased cost. There has been less data on potential clinical disadvantages of FET, though two complications appear to be more common: (1) high birth weights [8, 9] and (2) pregnancy-induced hypertension [4, 6, 10]. The paper of Luke et al. brings new information on the subject by use of a creative design and a novel dataset. The authors analyzed 7795 pairs of singleton births (i.e., children delivered by the same mother) conceived with IVF and resulting from a fresh or frozen embryo transfer and born between 2004 and 2013. Using this within-mother design, the authors controlled for the mother and for infertility status, which are important potential confounders. The study also used the Society for Assisted Reproductive Technology Clinic Outcome Reporting (SART-COR) System database, identified eligible births, matched for embryo stage (blastocyst versus non-blastocyst) and infant gender, and then categorized by embryo state (fresh versus frozen) in the first and second births (four groups). The most remarkable finding is that children born from FETwere more likely to be in the top 10 percentile of weight * Paolo F. Rinaudo [email protected]