Golden Genius Garden

Some fertility clinics embrace new, gentler methods

Cairo Medical Group Prepared by Mr.AHNAF & Mr.J.saito

Nichola Grant underwent five in-vitro fertilization attempts the traditional way. First came weeks of daily hormone shots to stimulate egg production, which painfully bloated her ovaries and stomach. Then doctors inserted a needle through her vaginal wall to remove the eggs -- up to 20 at a time, she says -- 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 Ms. Grant, a 34-year-old nurse in Queens, N.Y. She went to Manhattan fertility doctor John Zhang. 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," she says. "It's no comparison."

Dr. Zhang doesn't claim his method leads to higher pregnancy rates, but he does assert that Ms. Grant's story represents 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 Zhang method and others like it, while supported only by preliminary evidence, are fueling debate in a fast-growing business. Women in the U.S. 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 Debora Spar, a Harvard Business School professor who studies the fertility industry.

"If you take too much fertility drugs, you make too many useless eggs," says Dr. Zhang, a native of China who completed his residency at the New York University School of Medicine.

"A lot of people realize we're overdoing it," adds George Inge, a doctor at the Center for Reproductive Medicine in Mobile, Ala. "We've got to come out with ways so women are not so beat down."

Mainstream fertility doctors remain 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," says William Gibbons, president of the Society for Assisted Reproductive Technology. Removing only a handful of eggs, these doctors say, 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 treatments typically have 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 a natural trigger of ovulation, when eggs are discharged from the ovaries. Once that happened, doctors 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, says Bart Fauser, chairman of reproductive medicine at the University Medical Center in Utrecht, the Netherlands. Today, he estimates the average in the U.S. is 15 to 20 eggs. Other U.S. 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 of hormones under this approach can be dangerous. One of the most serious complications is ovarian hyperstimulation 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 cases of OHSS rose to one in 421 patients from one in 1,445. The review was published in the journal Human Reproduction in 1999.

One patient who contracted OHSS was Mary Piragas of Old Forge, Pa. At 34, Ms. Piragas was undergoing her second IVF attempt with fertility doctor Jennifer Gell. After the typical hormone regime, Dr. Gell harvested 24 eggs and implanted two embryos in July 2005, medical records show.

The next day Ms. Piragas started to feel nauseated and her stomach began to bloat. Dr. Gell, she says, told her she had "a little bit of hyperstimulation" that would "work itself out." But then, Ms. Piragas says, the bloating got worse and it was "really scaring me."

Dr. Gell admitted her to a hospital, where doctors drained about seven liters of fluid over two days from her abdominal cavity with a needle. Ms. Piragas says she couldn't walk for a few days because her hips, legs and feet were enlarged. Her ovaries were so swollen that they were at risk of twisting and losing their blood supply, Ms. Piragas says Dr. Gell told her. It wasn't until January that her ovaries returned to normal size. However, the fertility treatment made her pregnant, and last week she gave birth to twins.

Dr. Gell says that confidentiality rules prevent her from discussing Ms. Piragas's case. She adds that in seven years of practice only two of her patients have contracted severe OHSS.

Dr. Gell says she has tried a milder approach, "but unfortunately, being aggressive the patients get pregnant more." Many of her patients aren't wealthy and some have mortgaged their homes to pay for IVF. "The pressure is there that they are paying for this and what they want is to get pregnant. So in that situation you might push somebody a little bit higher," she says. "I know that at times I am treating more aggressively."

Dr. Zhang questions whether harvesting more eggs really means a higher likelihood of pregnancy. He thinks 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 Dr. Zhang's clinic, where he performs about 700 IVF treatments a year, the vast majority of patients get what he calls "oral therapy IVF." He doesn't use agonist hormones and gives his patients an egg-making stimulant called Clomid, 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. He supplements the Clomid with no more than three injections of the more powerful egg-making hormones, instead of 25 or so as is typical.

Clomid is cheap and available as a generic, reducing the overall cost of an IVF cycle, Dr. Zhang says. He says he charges $4,800 for a typical cycle, while the average in New York is $9,000. He still has to insert a needle to remove the eggs, but he says a local anesthetic usually suffices because ovaries are less swollen with the oral treatment. On average, Dr. Zhang extracts between three to five eggs.

According to Dr. Zhang, preliminary 2005 statistics from his center show that 38 percent of women under 37 who have eggs harvested with his method go on to have a pregnancy. He says this is comparable to conventional IVF, where U.S. national figures from 2003 for that age group show a live-birth rate of 38 percent. For women older than 38, Dr. Zhang says his pregnancy rate is 19 percent, also similar to the national average for that age group. The Kato Ladies Clinic in Japan, which developed the Clomid-based method that Dr. Zhang is using and has performed thousands of the oral IVF procedures, also reports pregnancy rates similar to the Japanese average. Dr. Zhang and the Kato clinic haven't published their data.

Evidence supporting the milder approach comes from Austrian researchers, who published results in 2002 from a randomized clinical trial that compared a Clomid-based 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 authors wrote in the journal Fertility and Sterility 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 led by Dr. Fauser 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 egg stimulation has begun. Like Dr. Zhang's method, 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 patients 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," Dr. Fauser says. "It's going to be hard for the scientific community to deny this." He presented the results at a meeting of the European Society of Human Reproduction and Embryology last June and has submitted them for publication in a medical journal.

Dr. Fauser argues that more-aggressive hormone treatments, while producing more eggs, might lead to eggs of lower quality. A separate randomized trial of 82 women by Dr. Fauser and other Dutch doctors found that eggs from women receiving milder hormone treatments 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. Zev Rosenwaks, a fertility specialist at Cornell University, says there's little evidence that making women produce many eggs diminishes the quality of the eggs.

Dr. Gibbons, 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.