Experimental in vitro fertility option may be safer, cheaper

Knight Ridder Newspapers

(KRT)

PHILADELPHIA - Last June, after a week of fertility-drug shots, Christine Mozes' ovaries went into overdrive, literally bursting with eggs ripening in their watery sacs.

If she were to have taken the full course of drugs, her hyperstimulated ovaries could have triggered life-threatening breathing problems, kidney failure, and blood clots.

George Taliadouros, her avuncular physician at Delaware Valley Institute of Fertility and Genetics in Marlton, N.J., cut off the treatment she needed to get pregnant.

"He said, `We just can't do this,'" recalled Mozes, 37.

Her plight was one of the most common and vexing in infertility treatment. Like an estimated three million U.S. women, she has polycystic ovarian syndrome, a hormonal disorder that disrupts ovulation. It's a leading cause of female infertility - but it makes infertility treatment extremely risky because the ovaries can easily be overstimulated.

The good news is that this reproductive double whammy is promoting the development of technology that may someday reduce the complications and cost of all high-tech baby-making. Instead of removing fully mature eggs from the ovaries and promptly fertilizing them, physicians remove immature eggs, ripen them in a lab dish, then add sperm. With this approach, the woman requires only three days of fertility drugs to gently stimulate her ovaries - compared with up to two weeks under the conventional method.

Lab-dish or in vitro egg maturation - IVM for short - is experimental, and has produced only about 300 babies worldwide, too few to firmly establish its safety.

Even so, for Mozes and her husband, John, it was a godsend. She is now four months pregnant.

"This is just overwhelming," she said. "It was great because I only needed three days of shots. And no misery."

In vitro egg maturation is not really new. In 1994, Australian researchers reported the first birth after IVM in a patient with polycystic ovaries.

Since then, conventional in vitro fertilization - uniting a mature egg and sperm in a dish, growing embryos, then implanting some in the uterus - has become increasingly successful. About two million IVF babies have been born worldwide. But IVM remains a challenge.

Human eggs - the largest cells in the body - are constantly changing, from the moment a woman is born with more than a million of them, until puberty, when about 300,000 remain, through menopause, when the supply is gone.

During each monthly menstrual cycle, one egg becomes dominant, accumulates fluid in its sac, and breaks out. About 34 hours before it escapes, the egg gets a hormonal signal to jettison half the chromosomes in its nucleus - just in case a sperm comes along to replace the lost genetic material.

Scientists have long struggled to make eggs perform this nuclear split, called "meiosis," in a lab dish instead of an ovary. But even when they succeeded, the eggs resisted fertilization because their outer membranes had hardened; sperm just bounced off. When eggs did manage to fertilize, the embryos usually died soon afterward.

On the encouraging side, studies have found that when IVM works, babies are healthy and develop normally.

"The principle behind this is great. It has potential and promise," said Christos Coutifaris, head of the University of Pennsylvania's IVF program. "But it's still experimental."

Danish researchers have led the way in developing better chemical solutions to nurture egg maturation. In November, Denmark-based Medicult became the first company to win FDA approval of its IVM culturing medium.

That medium is now being used by eight U.S. infertility clinics, including Delaware Valley Institute. A clinic in Florida and another in Illinois have each achieved a single IVM pregnancy, although one patient miscarried, according to Medicult and the clinics.

The new method may increase laboratory costs, as embryologist Jennifer Macdonald must closely monitor the eggs during their 32-hour sojourn in the culture medium. Fertilization also is a bit more expensive; to overcome the hardened-membrane problem, the egg is carefully punctured and a single sperm is injected.

Still, experts believe that maturing eggs outside the body could dramatically cut costs because the woman's ovaries would need minimal stimulation and she would need fewer ultrasounds and blood tests. Taliadouros estimates patients would need $900 worth of fertility drugs, instead of $5,000.

If science usurps yet another small but critical step in the creation of life, could abnormalities or defects turn up?

"We worry about that," he said. "But right now, we're doing it for patients for whom Nature doesn't do it better."

Women such as Mozes.

She didn't know she had polycystic ovarian syndrome until she first tried to get pregnant about eight years ago.

The syndrome, which affects an estimated 6 percent of women of childbearing age, is a complex set of metabolic and hormonal malfunctions that can vary in severity and symptoms. Basically, the ovary doesn't make all the hormones needed for eggs to fully mature. Even though eggs may start to grow and accumulate fluid, they remain trapped and eventually die in their sacs, turning into fibrous cysts. Without the release of an egg, the menstrual cycle is irregular or missing - the hallmark symptom.

Mozes, a child-welfare administrator, often missed periods. But then, so did her mother and sisters, and they had no apparent fertility problems.

When Mozes couldn't get pregnant, she and her husband resorted to in vitro fertilization. They succeeded on their very first try - daughter Riley is now 4 ¹/₂ - but the fertility drugs made Mozes extremely ill.

Her ovaries ballooned, causing fluids to shift from her blood vessels into her belly and chest. That erroneously signaled her kidneys to stop making urine, which made the swelling even worse. Even after the drug treatment was over, and 30 eggs had been removed from her ovaries, she spent a week in bed, massively bloated, short of breath, with severe abdominal pain and nausea.

And that bout of hyperstimulation was not nearly as severe as what she was headed for last summer, when her treatment was halted.

Although deaths are rare, severe hyperstimulation can cause strokes and other long-term complications.

Some patients can endure the treatment if drug doses are reduced or briefly interrupted, but it's a dicey balancing act.

"If you give too little medication, the patient may not respond," Taliadouros said. "Give too much, the patient hyperstimulates."

In Denmark, Anne Lis Mikkelsen, an IVM pioneer at Herlev University Hospital's fertility clinic, has been offering IVM not only to polycystic patients, but also to couples in which the man has fertility problems.

Pregnancy rates of 24 percent per IVM attempt - one out of every four patients - have been achieved, she wrote in a journal article in May.

Others say the technology has a long way to go. But it's only a matter of time.

In vitro egg maturation "is not ready for prime time. But you have to start somewhere," said Carolyn Coulam, a reproductive endocrinologist at the Rinehart Center for Reproductive Medicine in Chicago.

"I think it is the wave of the future."

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(c) 2006, The Philadelphia Inquirer. Distributed by Knight Ridder/Tribune News Service.