Unexplained infertility is frustrating for couples and their doctors. Without a clear reason why a woman is having trouble becoming pregnant, it is difficult to choose a treatment that has a high rate of success but doesn’t increase the chances of a high-risk multiple pregnancy. A study published today in The New England Journal of Medicine compared three drugs commonly used to treat unexplained infertility. Unfortunately, there was no clear winner.
Infertility is defined as the inability to become pregnant after about a year of appropriate and well-timed efforts. Infertility affects about 10% of women ages 15 to 44. For those desiring a child, the inability to become pregnant can be devastating, and the drive to seek treatment is understandable. The usual first step along that path is a detailed evaluation of the couple. Almost half the time, when an issue is identified, it is with the male partner, usually a problem with his sperm. Sometimes we discover a woman has blocked fallopian tubes (so eggs can’t be fertilized and travel to the uterus) or abnormalities of the uterine cavity, such as fibroids (which may prevent a fertilized egg from implanting).
But in 15-20% of cases, no reason is identified — so-called “unexplained infertility.”
Many with unexplained infertility will become pregnant on their own simply with more time. But for those reluctant to just wait, a first step is to try using medicines to push the ovaries to mature more than just one egg (this is called ovulation induction). With more eggs available for fertilization per cycle, the hope is that at least one will result in a pregnancy. This therapy is simpler and much less expensive than in vitro fertilization (IVF). Cost is an important issue because finances can be a huge barrier to infertility treatment. Very few states mandate that insurance plans provide coverage for IVF, which can easily run more than $10,000 for each cycle, or “try.”
But every time you drive the ovaries to produce more eggs, you run the risk of “super-ovulation,” or making many eggs available for fertilization. This in turn means you run the risk of a “multiple pregnancy” — twins, triplets, and beyond. For couples desperate to build a family, more babies may sound like hitting the jackpot. But multiple pregnancies are the biggest risk of infertility treatments, and arguably should be counted as failures rather than successes. These pregnancies — even with “just” twins — mean the babies are more likely to be born prematurely and the mothers are more likely to experience complications. Both these situations can be serious and have long-term consequences.
So which drugs are best at meeting the goals of infertility treatment — that is, achieving a pregnancy with one baby? In this study, a national network of investigators looked at how the drug letrozole compared with two standard drugs to stimulate ovulation. Letrozole works to stimulate ovulation through a different path than traditional fertility medications.
Investigators assigned cver a thousand couples with unexplained infertility to as many as four rounds of treatment with either letrozole or one of two “standard treatments”: gonadotropin (Menopur is one brand name) or clomiphene (Clomid is a common brand name). The results: live birth rates were lower in the women who took letrozole (19%) as compared with gonadotropin (32%), but were statistically similar to clomiphene (23%). On the other hand, rates of multiple pregnancies (all twins and triplets in this study) were higher in the gonadotropin group (all the triplets in were in this treatment group) than in the letrozole and clomiphene groups (which had about the same rate).
Hardly a home run for those who were hoping letrozole would be the answer. Over all, the numbers indicate that for couples with unexplained infertility, these alternatives to IVF may help them achieve a pregnancy — but success is hardly a sure thing. The drugs that bring a higher chance of pregnancy, also bring a greater chance that pregnancy will be a high-risk one.
While disappointing, the results argue for more work to optimize fertility therapies. A very important part of this work — whether we’re talking about ovulation induction or IVF — are continued efforts to reduce the unsatisfactorily high rate of multiple pregnancies that current treatment options carry. Until we have answers, judicious therapy means appropriately limiting the doses of ovulation induction drugs, and in the case of IVF, limiting the number of embryos transferred. That means doctors need to help patients make wise decisions, especially when there is more than one embryo available for transfer.
The true and heartfelt goal of couples and their doctors isn’t just a pregnancy, but a pregnancy with a good outcome—a healthy mom and a healthy baby. Here, more does not translate into better.