(Source: Shi et al. Transfer of Fresh versus Frozen Embryos in Ovulatory Women. N Engl J Med 2018.)
A 34-year-old woman and her husband visit their family medicine physician with questions about getting pregnant. Three years ago, they had an ectopic pregnancy and have been trying, unsuccessfully, to get pregnant since then. The woman is healthy with normal menstrual periods. She says, “We’re both nurses and have read a lot about IVF. We want to try it. Is it best to implant fresh or frozen embryos?”
Over the past 4 decades, infertility testing and assisted reproductive technologies, such as in vitro fertilization (IVF), have become more effective and accessible. The likelihood of having a baby with IVF has increased with the use of gonadotropin for controlled ovarian stimulation to retrieve more oocytes and cryopreservation of embryos for use in additional cycles. Some studies have demonstrated slightly higher pregnancy rates with frozen-embryo compared to fresh-embryo transfer, particularly in women with infertility due to polycystic ovary syndrome (PCOS). Because frozen-embryo transfer can be timed to avoid the supraphysiologic condition after ovarian stimulation — particularly in women with PCOS — it might provide a more favorable intrauterine environment for embryo implantation. However, questions remain about whether frozen-embryo transfer improves pregnancy outcomes in infertile women without PCOS.
Two multicenter randomized controlled studies compared outcomes associated with frozen- or fresh-embryo transfer in women without PCOS. The study by Shi et al. included about 2150 women who were undergoing their first IVF cycle and the study by Vuong et al. included nearly 800 women who were undergoing a first or second IVF cycle. In both studies, the women were randomized to receive a maximum of two fresh or frozen embryos.
Neither study found a significant difference in the rate of live births between the frozen- and fresh-embryo groups (48.7% vs. 50.2% and 33.8% vs. 31.5%, respectively). In addition, the study by Shi et al. found no significant between-group differences in rates of implantation, obstetrical and perinatal complications, low birthweight, congenital anomalies, or neonatal mortality. However, the frozen-embryo group had a significantly lower risk of moderate or severe ovarian hyperstimulation syndrome (0.6% vs. 2.0%). Although no significant differences were reported in overall pregnancy loss, a post-hoc analysis showed that second-trimester pregnancy loss was significantly lower in the frozen-embryo group (1.5% vs. 4.7%). The study by Vuong et al. found no significant between-group differences in rates of ectopic pregnancy, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome in the primary cycle, or pregnancy complications. However, the frozen-embryo group had a longer median time to pregnancy (3.6 vs. 2.2 months) and a higher proportion of singleton babies with birthweight below the 10th percentile.
Returning to the couple’s questions, the family physician can explain that their infertility could be due to problems in the fallopian tubes associated with the ectopic pregnancy, sperm issues, or other causes. The physician should refer the couple to a fertility specialist who can perform a full workup to determine the cause of infertility and assist with the fertility procedures that are most likely to be successful. This may include IVF, for which recent studies have found similar rates of success with frozen- and fresh-embryo transfer for couples like them. The physician should also encourage them to make an appointment for primary care follow-up.
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Karen is a 2017-2018 NEJM Editorial Fellow, Clinical Professor at UC Berkeley-UCSF Joint Medical Program and UC Berkeley School of Public Health, researcher on children’s nutrition and oral health, and member of American Academy of Pediatrics.