Non-PCOS IVF: Two trials show no benefit with frozen embryo transfer

Contrary to findings in women with polycystic ovary syndrome (PCOS), the transfer of frozen vs. fresh embryos does not lead to significantly higher live birth or ongoing pregnancy rates in women with non-PCOS infertility who undergo in vitro fertilization, according to findings from two randomized trials.

Frozen embryo transfer did, however, result in a lower risk of ovarian hyperstimulation syndrome in one of the trials. In that multicenter study, 2,157 women undergoing their first in vitro fertilization (IVF) cycle were randomized to undergo either fresh embryo transfer or embryo cryopreservation followed by frozen embryo transfer, with up to two cleavage-stage embryos transferred, Yuhua Shi, MD, of Shandong University, Jinan, China, and colleagues reported Jan. 11 in the New England Journal of Medicine. The live birth rate, defined as delivery of a viable neonate at 28 weeks of gestation or greater, was 50.2% and 48.7% in the fresh embryo and frozen embryo groups, respectively (relative risk, 0.97). The rate of ovarian hyperstimulation syndrome was 2.0% and 0.6% in the groups, respectively (RR, 0.32), the investigators reported.

Of note, the rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy did not differ between the groups, but in a post hoc analysis, the rate of second-trimester pregnancy loss was lower with frozen embryo transfer (4.7% vs. 1.5%; RR, 0.33). However, the authors urged caution regarding the latter finding because of the post hoc setting and because the overall rates of pregnancy loss did not differ between the groups.

In the second study, 782 women without PCOS who were undergoing a first or second IVF cycle at a single center were randomized to receive either fresh or frozen embryo transfer with up to two embryos transferred.

After the first complete cycle, the ongoing pregnancy rate – the primary outcome in the study, defined as pregnancy with a detectable heart rate after 12 weeks of gestation – was 34.5% in the fresh embryo group and 36.3% in the frozen embryo group (RR in frozen embryo group, 1.05), Lan N. Vuong, MD, of My Duc Hospital, Ho Chi Minh City, Vietnam, and colleagues reported.

The live birth rates after the first transfer were 31.5% and 33.8%, respectively (risk ratio, 1.07). There also were no differences in rates of implantation or clinical pregnancy, or in rates of ectopic pregnancy, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome in the primary cycle, or pregnancy complications.

The findings of both studies contrast with those from prior studies showing a higher live-birth rate among anovulatory women with PCOS who undergo frozen embryo transfer, compared with those who undergo fresh embryo transfer.

For example, Dr. Shi and associates found in a prior study of women with PCOS that the live birth rate was higher with frozen embryo transfer (42% vs. 49%), and they concluded that this was largely explained by a lower rate of pregnancy loss (N Engl J Med. 2016;375:523-33).

“However, patients with the polycystic ovary syndrome have a different reproductive, metabolic milieu than do other women with infertility; it is characterized by hyperandrogenism and insulin resistance, and these patients typically have a greater ovarian response to gonadotropin stimulation than do ovulatory women undergoing IVF,” they wrote in the current paper.

The findings of the current studies suggest the benefits of frozen vs. fresh embryo transfer, with respect to the primary outcome measures in the studies, do not apply in women with non-PCOS infertility.

Dr. Shi and colleagues speculated that “the difference is due to the unfavorable uterine environment after fresh embryo transfer in women with the polycystic ovary syndrome, as shown by a much lower rate of live birth overall in the previous trial than in the present trial.”

The “altered hormonal milieu” in women with PCOS, along with a need for ovarian stimulation cycle initiation with oral contraceptives or progestin may adversely affect endometrial receptivity after fresh embryo transfer, they explained.

Dr. Vuong and colleagues noted that their findings are not necessarily inconsistent with those reported in women with PCOS, because “the 95% confidence intervals around the risk ratios for live birth that were associated with frozen embryo transfer in our trial overlap with the 95% confidence intervals in that report,” adding that another contributing factor to the different results might be the timing of freezing, which differed in the studies.

They also said that a small difference in the time to conception, which was 1.4 months shorter in the fresh embryo group, could be “a relevant factor for some patients in terms of the overall treatment duration and both the direct and indirect costs of IVF.”

The study by Dr. Shi and associates was supported by grants from the National Key Research and Development Program of China, the Major Program of the National Natural Science Foundation of China, and the State Key Program of the National Natural Science Foundation of China. Dr. Shi reported having no conflicts of interest. One coauthor, Richard S. Legro, MD, reported receiving consulting fees from Ogeda, KinDex Pharmaceuticals, Fractyl Laboratories, Bayer, and AbbVie, and receiving grant support from Ferring Pharmaceuticals. The study by Dr. Vuong and associates was supported by My Duc Hospital. Author disclosures for that study are available with the full text of the article at NEJM.org.

sworcester@frontlinemedcom.com

SOURCES: Shi Y et al. N Engl J Med. 2018;378(2):126-36; Vuong N et al. N Engl J Med. 2018;378(2):137-47.