Frozen Embryos Tied to Higher Live Birth Rates in PCOS

Veronica Hackethal, MD

August 11, 2016

Women with polycystic ovarian syndrome (PCOS) may have greater success with in vitro fertilization (IVF), in terms of live birth rates, with frozen rather than fresh embryo transfer, according to results published in the August 11 issue of the New England Journal of Medicine.

"[I]n a randomized trial involving infertile women with the [PCOS], we found that frozen-embryo transfer resulted in a higher frequency of live births than fresh-embryo transfer, a difference that was attributed to a lower rate of pregnancy loss," write first author Zi-Jiang Shen, MD, from Shandong University, Jinan, China, and colleagues. "Women in the frozen-embryo group also had a lower frequency of the ovarian hyperstimulation syndrome but a higher frequency of preeclampsia."

Although many IVF clinics may prefer transferring fresh embryos, some research suggests that transferring frozen embryos may improve live birth rates. Past research has also suggested frozen embryo transfer may decrease rates of ovarian hyperstimulation syndrome and pregnancy complications in women with PCOS, which confers a higher risk for such problems.

Recent years have witnessed improved rates of pregnancy and live birth rates after frozen embryo transfer, perhaps related to the use of vitrification, a rapid freezing procedure that eliminates ice crystal formation often found with slower freezing techniques.

The trial took place at 14 reproductive medical centers in China between June 2013 and July 2015. Researchers randomly assigned 1508 women aged 20 to 34 years with PCOS and infertility to either fresh- or frozen-embryo transfer. All women were starting their first IVF cycle, conducted according to a standard protocol. Embryos developed for 3 days in culture, after which time researchers performed embryo transfer.

Frozen embryo transfer yielded a higher live birth rate compared with fresh embryo transfer (49.3% vs 42.0%, respectively; rate ratio, 1.17; 95% confidence interval [CI], 1.05 - 1.31; P = .004). After adjusting for study site and baseline characteristics, the live birth rate remained higher in the frozen embryo group compared with in the fresh embryo group.

Frozen embryo transfer was also linked to less pregnancy loss (22.0% vs 32.7%; rate ratio, 0.67; 95% CI, 0.54 - 0.83; P < .001) and less ovarian hyperstimulation syndrome (1.3% vs 7.1%; rate ratio, 0.19; 95% CI, 0.10 - 0.37; P < 0.001) than the fresh embryo group.

In contrast, the frozen embryo group had a higher rate of preeclampsia (4.4% vs. 1.4%; rate ratio, 3.12; 95% CI, 1.26 - 7.73; P = .009) than the fresh embryo group.

There were no significant differences in neonatal complications, including congenital anomalies. However, the frozen embryo group experienced more neonatal death (two stillbirths and five neonatal deaths) compared with none in the fresh embryo group (P = .50 and P = .06, respectively).

"The potential excess of neonatal death, owing primarily to prematurity, in the frozen-embryo group warrants attention," the authors write, while pointing out that the results were of borderline significance and could be a result of chance. Some studies have suggested higher risk for perinatal death after frozen embryo transfer, whereas others have suggested lower risk.

Although the study could not evaluate underlying mechanisms, the authors hypothesize that frozen embryo transfer allows for a "fresh start" by allowing time for ovarian recovery, as well as shedding and regeneration of the endometrial lining. Also, compared with frozen cycles, fresh cycles have higher estradiol levels, which have been linked to increased risk for ovarian hyperstimulation syndrome and pregnancy loss.

The results provide "reassurance" about the success of vitrification and show that both frozen and fresh embryo transfer yield "respectable" live birth rates, writes Christo Coutifaris, MD, PhD, from the University of Pennsylvania, Philadelphia, in a linked editorial.

"A strength of this report, as compared with previous studies that have addressed the freeze-only approach, is its focus on the rate of live birth as the primary outcome, a standard that should be applied in the evaluation of any fertility-related treatment," he points out.

That is, clinical pregnancy rate per cycle is usually used to measure the success rate of clinics, but live birth rate may be a better indicator of IVF success.

He also points out that the study used 3-day-old embryos and included women with PCOS, so results may not apply to normal-risk women who undergo 5-day-old embryo transfer, which is the standard.

Dr Coutifaris also weighed the potential benefits and drawbacks of frozen embryo transfer, including increased financial costs, emotional costs of waiting to become pregnant, physiological costs of additional hormone injections, and more office visits.

"In high-risk women, such as those with the [PCOS], a freeze-only approach to minimize the risk of the ovarian hyperstimulation syndrome may outweigh the costs," he concludes.

"[I]n women with a sufficient number of good-quality embryos who are at low risk for complications or implantation failure owing to embryo–endometrial dyssynchrony, it may be reasonable to continue to recommend fresh-embryo transfer as available."

One coauthor reports grant support and/or personal fees the following: Ferring, AstraZeneca, Euroscreen, Takeda, Clarus Therapeutics, Sprout Pharmaceuticals, Kindex, Bayer. Dr Coutifaris reports grant support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and personal fees from the American Society for Reproductive Medicine.

N Engl J Med. 2016;375:523-533, 577-579. Article abstract, Editorial extract

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