Gentler IVF method fuels debate

Patient underwent five invitro fertilization attempts the traditional way. First came weeks of daily hormone shots to stimulate egg production, which painfully bloated her ovaries and stomach. The doctors inserted a needle through her vaginal wall to remove the eggs – up at 20 a time – from her ovaries. On three occasions fertilized eggs were put back in her womb but failed to lead to a baby. That was enough discomfort for patient, a 34-year-old nurse in Queens, New York. She went to a Manhattan fertility doctor. There were barely any shots – mostly pills – and he removed just three eggs. He implanted one in the womb, and she delivered a baby boy in January. "It was so easy. It’s no comparison."

Doctor doesn’t claim his method leads to higher pregnancy rates, but he does assert that patient story represent what’s wrong with standard operating procedure at fertility clinics. He says the fertility profession is too concerned with drawing lots of eggs from women. The result, he believes, is more pain, a higher risk of complications and a success rate little improved over gentler approaches. The doctor’s method and other like it, while supported only by preliminary evidence, are fueling debate in a fast-growing business. Women in the US underwent more than 120,000 in-vitro fertilization procedures in 2003, nearly double the figure in 1996, according to federal-government data. Americans spend nearly $3 billion a year on IVF, according to a Harvard Business School professor who studies that fertility industry.

If you take too much fertility drugs, you make too many useless eggs. A lot of people realize they’re overdoing it. They’ve got to come out with ways so women are not so beat down. Mainstream fertility remains skeptical of applying the milder approach for most women. The more eggs, the more embryos; the more embryos, the better the chance of getting a normal embryo. Removing only a handful of eggs, this leaves no margin for error and may force women to come back for another expensive and emotionally draining treatment.

In-vitro fertilization has come a long way from its first successful attempt in 1978. Through the 1980s, only about 15 percent of women who tried the technology got pregnant. Today’s treatment is typically having a 30 percent to 40 percent chance of resulting in pregnancy. The jump is largely due to the introduction of more aggressive hormone treatments that let doctors harvest multiple eggs. Normally, women in their fertile years produce one mature egg a month. An ovary releases the egg into the fallopian tube, where it can be fertilized. From the early days of IVF, doctors injected man-made hormones to stimulate the ovaries to produce extra eggs. But the injections often backfired because the overload of eggs served as natural trigger of ovulation, when eggs are discharged from the ovaries. Once that happened, they lost their chance to harvest the eggs for fertilization.

In the late 1980s, a breakthrough came along: new "agonist" hormones that in effect told the body to ignore all the extra eggs. Having injected agonists, doctors could follow up with high doses of the egg-stimulating hormones over a longer period. They could harvest as many as two dozen eggs, without worrying that a sudden ovulation would thwart the process. Before agonists, the average IVF treatment yielded six to eight eggs. Today, the average in the US is 15 to 20 eggs. Other US authorities put the figure at 10 to 15.

With extra eggs, mainstream fertility doctors believe they have a higher probability of producing a good embryo. What’s more, women can put aside any leftover embryos for another implantation, should one be necessary. But the higher doses or hormones under this approach can be dangerous. One of the most serious complications is ovarian hyper stimulation syndrome, or OHSS, a potentially fatal condition in which ovarian tissue leaks fluid into the body cavity. This makes the blood thicker and increases the risk of stroke. Mild OHSS, which brings discomfort but doesn’t require hospitalization, occurs in up to 35 percent of IVF cycles. Moderate to severe forms take place in up to 6 percent of cycles.

A review of thousands of IVF cycles done in Israel showed that after the use of agonists began, the number of severe case of OHSS rose to one in 421 patients from one in 1,445. The review was published in the journal Human Reproduction in 1999. They question whether harvesting more eggs really means a higher likelihood of pregnancy. Doctors may be deceived when they see women who produce lots of eggs get pregnant time after time. Perhaps it isn’t the number of eggs that makes the difference. It could be that these women had healthy ovaries and eggs to begin with, and would enjoy high success rates even if they weren’t stimulated to produce so many eggs.

At doctors clinic, where they perform about 700 IVF treatments a year, the vast majority of patients get what they call "oral therapy IVF." They did not use agonist hormones and gives his patients an egg-making stimulant in pill form. The drug was widely used in the early days of IVF but was largely abandoned once newer hormones came on the scene. They supplement with no more than three injections of the more powerful egg-making hormones, instead of 25 or so as is typical. Preliminary 2005 statistics from center show that 38 percent of women under 37 who have eggs harvested with method to go on to have a pregnancy. This is comparable to conventional IVF, where US national figures from 2003 for that age group show a live-birth rate of 38 percent. For women older than 38, pregnancy rate is 19 percent, also similar to the national average for that age group. The Clinic in Japan, which develops the method that has performed thousands of the oral IVF procedures, also reports pregnancy rates similar to the Japanese average.

Evidence supporting the milder approach comes from Austrian researchers, who published results in 2002 from a randomized clinical trial that compared a treatment with conventional IVF. The trial of 294 women found pregnancy rates in both groups to be similar: 35 percent in the mild hormone group and 29 percent in the conventional IVF group. The Journal Fertility and Sterility shows that the milder treatment involved fewer shots, cost less and led to fewer complications in patients. They recommended the treatment as a first option for women undergoing IVF.

In the Netherlands, a group is carrying out a larger randomized trial comparing conventional IVF with another approach based on milder stimulation and fewer eggs. This approach uses drugs to block sudden ovulation, but the drugs are different from the ones used in conventional IVF and they are given only after eggs stimulation has begun. This treatment is relatively short and involves fewer total injections. In the Dutch study, women receiving the mild hormone treatment have only a single embryo implanted in their wombs, while those receiving conventional treatment receive two embryos. Preliminary results from the trial of 410 patient’s show that within a year 56 percent of women in the mild hormone group became pregnant versus 58 percent in the stronger hormone group.

It’s time for a paradigm shift. It’s going to be hard for the scientific community to deny this. They presented the results at a meeting of the European Society of Human Reproduction and Embryology last June and have submitted them for publication in a medical journal. The more-aggressive hormone treatments, while producing more eggs, might lead to eggs of lower quality. A separate randomized trial of 82 women and other Dutch doctors found that eggs from women receiving milder hormone treatment had on average more normal chromosomes than eggs from women who underwent conventional IVF. A 1997 study from the University of Arizona found similar results.

The data so far are too limited to persuade those who use conventional IVF. A fertility specialist at Cornell University says there’s a little evidence that making women produce many eggs diminishes the quality of the eggs. The president of the fertility doctors’ society says he disagrees with the depiction of conventional doctors as "blasting" women with drugs to extract a maximum number of eggs. He says good doctors already minimize the dose of drugs for patients who are sensitive to them, and he disputes the notion that the current standard is too aggressive for the majority of cases.