In vitro fertilization (IVF): Where are we now?

The world's first birth from in vitro fertilization (IVF) occurred in 1978 (Fauser in 1971 Bob Edwards (who, along with Patrick Steptoe, performed the first successful IVF cycle in 1978) predicted that there would “probably be demand for thousands of babies born by this means every year” (Edwards in 2015 alone there were 231,936 ART cycles performed in the United States (Centers for Disease Control and Prevention, 2017). From its inception, ethical issues have surrounded the field of ART. In the early days, questions of eugenics, genetic testing of embryos, and the discarding of human embryos drew the objections of the religious institutions (Edwards currently questions surrounding the production of human embryonic stem cells, gene editing technology, and mitochondrial transfer (or so-called three-parent IVF) continue to raise ethical questions in the field (Harper et al., 2018). However, perhaps the most challenging question for the young but burgeoning field is that of the long-term safety of IVF in terms of outcomes for the resulting children. This issue of Birth Defects Research Reviews provides an overview of some of the current research in the field of ART, focusing on birth outcomes and means to improve the safety of IVF and the health of IVF offspring. Many of the authors are physicians practicing ART/IVF on a regular basis. Although studies to date have overall been reassuring as to the long-term health of children born following ART, there is a small but significant increase in birth defects and differences in markers of cardiovascular and metabolic health noted in some large studies (Boulet et al., 2016; Fauser et al., 2014). Whether these differences are a result of the fertility procedures themselves or other factors, such as infertility itself, is still a matter of debate, although there are several proposed mechanisms for how ART may influence in-utero development. Patil provides an overview of the incidence of congenital cardiac defects following IVF and potential mechanisms for the observed increase. Multiple gestation is a known complication of IVF, the result of transferring more than one embryo at a time to the uterus in attempt to improve the efficiency of an IVF cycle. However, multiple pregnancies (including twins and less frequently triplets), are inherently more high-risk than singleton pregnancies and result in higher rates of preterm delivery and complications related to prematurity. There are several methods being currently used and investigated to improve embryo selection, the ability to choose the single best embryo to transfer in an IVF cycle, to improve IVF success rates while reducing twin pregnancy. Neal and Werner discuss preimplantation genetic screening (PGS), a means of selecting embryos based on testing the chromosomal makeup of the preimplantation embryo. Aparicio-Ruiz, Romany, and Meseguer report on time-lapse microscopy, a noninvasive means of embryo selection that relies on dynamic assessments of embryo morphology to select the embryo most likely to result in a successful pregnancy. Another relatively new ART development has been the increasing use of cryopreservation to freeze and store extra embryos for later transfer. When first developed, IVF involved transferring fresh embryos in the same menstrual cycle as they were retrieved from a woman's oocytes (Fauser & Edwards, 2005). However, with the emergence of technologies such as vitrification, rapid freezing in liquid nitrogen, embryos are increasingly being frozen after the initial culture stage and stored until transfer at a later date. Van Heertum and Weinerman discuss how the uterine environment in a fresh IVF cycle (following hormonal stimulation to induce multiple mature eggs) may be contributing to the differences in birth outcomes observed following IVF and the role embryo freezing may play in preventing these negative outcomes by allowing time for the uterine environment to normalize. However, the effect of frozen embryo transfer itself on the offspring has not been fully established. Bernsten and Pinborg review the association between frozen embryo transfer and large for gestational age babies, providing potential mechanisms for this association. As the oldest children born following IVF are now in their late 30's, significant research remains to be done to establish the long-term safety of ART. However, as the reviews in this current issue discuss, there are methods to modify IVF practices today to focus on improving the safety of ART procedures to optimize birth outcomes, particularly by reducing multiple gestation and paying close attention to the intrauterine environment. As the field is only 40 years old, there will likely be significant advances in the future that will continue to make IVF a safe and effective option for couples who need ART to conceive. None