IVF: Extending Number of Cycles Increases Efficacy

Ricki Lewis, PhD

December 23, 2015

More than four cycles of in vitro fertilization (IVF) can increase the rate of live births for women younger than 42 years, according to results of a study published in the December 22/29 issue of JAMA.

"In some countries, the clinical guidelines limit how many treatment cycles a woman can have, and even in countries where that’s not the case, for example in the US, where there’s lots of private treatment, if you look at national statistics you see that very rarely do women have treatments beyond the third or the fourth," lead author Debbie A. Lawlor, PhD, from the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, United Kingdom, said in a video published on the JAMA Network.

Dr Lawlor and colleagues investigated the extent to which attempting more than four IVF cycles affects the probability of a live birth, defined as an infant born after 24 weeks' gestation that survived at least 1 month. The four-attempt cutoff came from a study from 2001 that found a decline in live-birth rates at that point, but did not include use of intracytoplasmic sperm injection. In addition, older studies counted each embryo transfer as an IVF cycle, even if the embryos resulted from the same ovarian stimulation event. Other changes since that time include improvements in freezing embryos and promotion of single-embryo transfer.

"We were interested in whether the common clinical perception that [for] a couple who have had three or four treatment cycles with IVF [without] a successful live birth, whether...it's very unlikely they will have future success, which is [why] insurance companies and national health services tend to limit treatments to three or four embryo placements," Dr Lawlor also from the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, said in the video.

In the study, an IVF cycle covered ovarian stimulation and all fresh or frozen embryo transfers that followed, using those retrieved oocytes. The researchers designed the study to look at two questions: the chance of a live birth with one ovarian stimulation and oocyte retrieval followed by separate embryo transfers, and the chance of a live birth with repeat ovarian stimulation and oocyte retrievals, counting embryo transfers cumulatively from each cycle, up to a given cycle number.

The researchers used a "prognostic-adjusted estimate" to account for couples who discontinue IVF, bridging the extremes of "optimistic" (the probability of live birth is the same as for women who continue) and "conservative" (the probability of live birth is zero). Optimistic represents discontinuation for nonmedical reasons, such as cost or leaving the United Kingdom; conservative refers to discontinuation because of poor prognosis.

The researchers followed 156,947 women in the United Kingdom who underwent 257,398 IVF cycles between 2003 and 2010, with follow-up until June 2012. The median age at the start of treatment was 35 years, and the median duration of infertility was 4 years.

For all participants, the live-birth rate for the first IVF cycle was 29.5% (95% confidence interval [CI], 29.3% - 29.7%), and it stayed above 20% up to and including the fourth cycle. The cumulative prognosis-adjusted live-birth rate was 65.3% (95% CI, 64.8% - 65.8%) up to the sixth cycle, and it continued to increase up to the ninth cycle.

The results revealed the maternal age effect: For women younger than 40 years using their own oocytes, live-birth rate for the first IVF cycle was 32.3% (95% CI, 32.0% - 32.5%) and remained above 20% up to and including the fourth cycle. Attempting six IVF cycles led to a prognostic-adjusted live-birth rate of 68.4% (95% CI, 67.8% - 68.9%). However, for women aged 40 to 42 years, the live-birth rate for the first IVF cycle was 12.3% (95% CI, 11.8% - 12.8%), and after six cycles, the prognostic-adjusted live-birth rate was 31.5% (95% CI, 29.7% - 33.3%).

For women older than 42 years, all rates within each cycle were less than 4%. The maternal age effect did not appear for women using donor oocytes.

Live-birth rates were lower among women whose partners had untreated infertility, but intracytoplasmic sperm injection or sperm donation erased that effect. The investigation also demonstrated that the number of eggs retrieved after ovarian stimulation in one cycle does not influence the live birth success rate in subsequent cycles. The researchers conclude that the findings "support the efficacy of extending the number of IVF cycles beyond 3 or 4," but point out that repeat IVF is costly and stressful.

A limitation of the study was the assumption behind the prognostic-adjusted estimate from optimistic and conservative estimates. Discontinuation because of poor prognosis was only 3%, but the researchers used 30% to account for variables not analyzed, such as smoking, body mass index, and pretreatment reproductive hormone levels.

In an accompanying editorial, Evan R. Myers, MD, MPH, from the Department of Obstetrics and Gynecology and Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, encourages physicians to share the new findings with couples so that their decisions regarding IVF are informed. He also suggests that the Centers for Disease Control and Prevention's National Assisted Reproductive Technology Surveillance System (NASS), to which clinics must report IVF results, change the way they collect and publish IVF data.

"For policy makers, revising the NASS to allow reporting of outcomes on a per-couple basis (including oocyte donors) would provide significantly more useful information for decision-making purposes," Dr Myers writes.

Dr Nelson has participated in advisory boards for and received speakers' fees from Beckman Coulter, Besins, Ferring, Merck Serono, Merck Sharp & Dohme, and Roche Diagnostic. The other investigators and the editorialist have disclosed no relevant financial relationships.

JAMA. 2015;314:2654-2662 and 2627-2629. Article full text, Editorial extract

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