Multiple-Birth Rates Lower With Letrozole Than Gonadotropin

Pam Harrison

September 24, 2015

Ovarian stimulation with letrozole, an aromatase inhibitor, results in significantly fewer multiple gestations compared with gonadotropin among couples with unexplained infertility, according to a large-scale randomized trial. However, the rate of multiple gestations was not significantly different between letrozole and clomiphene, researchers report in an article published in the September 24 issue of the New England Journal of Medicine.

Michael Diamond, MD, from Georgia Regents University in Augusta, and colleagues also found that pregnancy rates with letrozole were significantly lower than rates achieved with standard therapy with either gonadotropin or clomiphene (P = .003) or gonadotropin alone (P < .0010), but not with clomiphene alone (P = .10).

After treatment with up to four cycles of gonadotropin, clinical pregnancies, as reflected by fetal heart activity, occurred in 35.5% of cycles compared with 28.3% of cycles when women were treated with clomiphene and 22.4% of cycles when ovarian stimulation was induced by letrozole.

Live birth rates were also higher, at 32.2% after administration of gonadotropin compared with 23.3% after clomiphene administration (P = .02 compared with gonadotropin) and 18.7% after administration after letrozole (P < .001 compared with gonadotropin).

Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole at 13%, or 9 of 67 pregnancies, did not differ significantly from the multiple gestation rate after both gonadotropin and clomiphene stimulation, at 22% (42 of 192 pregnancies) and 9% (8 of 85 pregnancies), respectively, but it was lower than the 32% multiple gestation rate compared with gonadotropin alone. Furthermore, all multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twins and 10 triplet gestations.

"[E]mpirical ovarian stimulation (with clomiphene or particularly with gonadotropin) is frequently complicated by the ovarian hyperstimulation syndrome and by multiple gestations, with an increased risk of preterm birth and associated neonatal morbidity and costs," the authors write.

They add, "the use of letrozole for ovarian stimulation resulted in significantly reduced rates of ongoing clinical pregnancy and live births, but not of multiple gestations, as compared with a combined group receiving standard therapy (gonadotropin or clomiphene), but the two comparators had different effects on these outcomes."

Testing Letrozole in a Trial

The authors note that letrozole has been used successfully to stimulate ovulation in women with polycystic ovarian syndrome, and several reports suggest it is also useful in couples with unexplained infertility. To formally test that possibility, the Assessment of Multiple Intrauterine Gestations for Ovarian Stimulation (AMIGOS) clinical trial was conducted by the National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network at 12 clinical sites throughout the United States.

Women between 18 and 40 years of age with regular menses and a normal uterine cavity with at least one patent fallopian tube were enrolled, together with their male partner. The male partner was required to have a semen specimen of at least 5 million sperm/mL.

Women received gonadotropin (Menopur, Ferring Pharmaceuticals), given subcutaneously, or clomiphene or letrozole, both given orally. Treatment was initiated on days 3, 4, or 5 of the menstrual cycle, and ovarian stimulation was given for up to four treatment cycles, along with intrauterine insemination (IUI). Women who conceived were followed through pregnancy and delivery.

Of 900 couples who were randomly assigned to a treatment group, 746 couples completed the study. "There was no significant difference in the time to conception among the three groups," the investigators observe. "Among the women who conceived, there was no significant difference among groups in the incidence of clinical pregnancy."

However, when the three individual treatment groups were compared, the incidence of multiple clinical pregnancy was significantly higher after treatment with gonadotropin than with either clomiphene or letrozole (P = .001).

The rate of pregnancy loss among established pregnancies did not differ according to the treatment group, at 36.4% for gonadotropin, 29.2% with clomiphene, and 30.6% with letrozole. More than 90% of the pregnancy losses occurred in the first trimester, the authors note.

Live-Born Infants

A total of 272 infants were live-born, the investigators add. "As anticipated, the mean gestational age at delivery decreased with an increasing number of fetuses," at 38.6 weeks for singletons; 35.3 weeks for twins, and 34.2 weeks for triplets (P < .001).

Among singletons, the mean birth weight did not differ significantly among the three treatment groups. Moreover, there were no observed differences between groups in the frequencies of congenital anomalies or major fetal and neonatal complications, the authors observe. The most common neonatal complications in all groups were jaundice, respiratory distress syndrome, and intrauterine growth restriction.

Similarly, the frequency of individual serious adverse maternal events or serious adverse fetal or neonatal events did not differ significantly among the three treatment groups, although the cumulative incidence of serious adverse events was more common in the gonadotropin group than in the other two groups (P = .009).

Usual First Step

Asked to comment on the study, Owen Davis, MD, president-elect of the American Society for Reproductive Medicine, told Medscape Medical News that ovulation induction is typically the first step couples with unexplained infertility take to enhance chances of conceiving.

"The traditional flow has been to start with clomiphene, which is a time-tried and true agent. You take it orally for 5 days, and it has a fairly low rate of multiple gestations, at a twin rate of about 8% in younger women," Dr Davis explained.

Gonadotropins, in contrast, need to be injected, and they are much more expensive than clomiphene.

Moreover, the gonadotropins have a much higher rate of multiple births, including twins and triplets, because they are much more potent stimulators of the ovaries than clomiphene.

"In most cases, if you are not doing in vitro fertilization, you start with clomiphene IUI for anywhere from 3 to 6 cycles, and then if that doesn't work, and you don't want to go to [in vitro fertilization], you might then escalate to using the gonadotropins, which we know is more successful than clomiphene," Dr Davis explained. Letrozole has come down the pike more recently as being an oral alternative to clomiphene, he added.

"I think what the study really showed us is what we already know which is multiple birth rates are lower with clomiphene or letrozole than with gonadotropin, and the pregnancy rates with letrozole IUI vs clomiphene IUI are at least noninferior to clomiphene," Dr Davis said.

At the same time, Dr Davis observed that the live birth rate per cycle was actually 19% higher with clomiphene IUI. "This didn't reach statistical significance in the study, which raises the question as to whether the study was adequately powered to look at this specific question," he noted.

Dr Davis also pointed out that it was generally felt that ovarian stimulation using letrozole led to fewer twins than clomiphene, and indeed, that was one of the reasons why this study was done. "This study does not confirm this belief," Dr Davis said. "And in fact, it shows that the level of risk for multiple births seems to be very similar between the two agents.

The study was supported by grants from the National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Several coauthors reports receiving financial, grant, or other support or personal fees from one or more of the following companies: AbbVie, Bayer, EMD Serono, Advanced Reproductive Care, Roche Diagnostics, Ferring International Pharmascience Center US, Euroscreen, Clarus Therapeutics, Takeda, AstraZeneca, Merck, and Menogenix. The other authors and Dr Davis have disclosed no relevant financial relationships.

N Engl J Med. 2015;373:1230-1240. Full text

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