For women who take fertility drugs, the risk of having them work "too well" -- resulting in a multiple birth -- is small and declining, but it's not zero.
The latest spectacular reminder of that risk is Patti Frustaci, the 30-year-old English teacher who gave birth to seven premature babies on May 21 in Orange, Calif. One of the septuplets was stillborn, and another died less than three days later. The others -- all weighing less than 1 pound, 13 ounces at birth -- remained hospitalized Monday, two of them in critical condition.
Frustaci became pregnant after taking Pergonal (generic name: menotropins), a potent fertility drug that contains ovary-stimulating hormones normally produced by the pituitary gland. Pergonal was developed 20 years ago from the urine of postmenopausal women, which is rich in these hormones.
Sometimes called the "big gun" of fertility drugs, Pergonal is used mainly as a last resort by couples for whom other, less expensive and less risky means of increasing fertility have failed. The number of women in the United States who have taken Pergonal is estimated at fewer than 10,000.
"It's a relatively small part of even an infertility specialist's practice," says Dr. Robert Stillman, director of the division of reproductive endocrinology and fertility at the George Washington University Medical Center.
Infertility has many causes. About one third of the time, it is due to male factors, such as abnormalities in the production or mobility of sperm. The most common cause of female infertility is scarred or blocked fallopian tubes, preventing the egg from reaching the uterus.
In about 20 percent of cases, infertility is traced to hormonal failure resulting in erratic ovulation or no ovulation at all. The ovaries either fail to produce a mature egg or fail to release it for possible fertilization by sperm. This is the type of infertility most often treated with drugs.
The drug most commonly used to stimulate ovulation is Clomid (generic name: clomiphene citrate), taken in pill form. Clomid helps regulate the complex system of hormonal signals between the pituitary gland and the ovaries which is necessary for ovulation.
"Clomid stimulates the pituitary gland to produce more hormones and to produce them in the right proportion to stimulate the ovary to function normally," says Dr. Safa Rifka, a fertility specialist at the Reproductive and Infertility Center at Georgetown University and the Columbia Hospital for Women.
About 70 percent of the carefully screened infertile women who take Clomid ovulate, Rifka says, and between 40 and 50 percent become pregnant.
Clomid also boosts the chance of a multiple birth from about 1.2 percent to between 6 and 8 percent. Almost all of the multiple births in women taking Clomid are twins. The miscarriage rate is 15 percent, about the same as in the normal population.
Unlike Clomid, which indirectly stimulates the ovaries by signaling the pituitary to produce hormones, Pergonal actually contains the hormones. It is given in daily injections, followed by careful monitoring of the estrogen levels in the blood. When estrogen levels are high enough -- usually within a week or two -- the woman is given an injection of another hormone called HCG, which induces ovulation within 36 hours.
More than half of the women who take Pergonal become pregnant. "For a woman whose pituitary gland is incapable of sending the proper signals to ovulate," says Rifka, "Pergonal is a savior."
But there are risks. In the early days after its introduction 20 years ago, Pergonal caused several deaths in women whose ovaries were overstimulated, grew to near-grapefruit size and burst, causing internal bleeding.
More sophisticated monitoring, including ultrasound pictures called sonograms and measurement of estrogen levels in the blood, have reduced the risk of damaging the ovaries to "way less than 1 percent," Rifka says.
Pergonal is also expensive. A typical course of treatment, including daily doses of the drug and daily blood tests to monitor its progress, can run between $500 and $1,000 a week.
And the rate of multiple gestation jumps to 20 percent in women who take Pergonal. Most of those multiple births are twins or triplets, but in rare instances Pergonal triggers "superovulation" that can lead to five or more fetuses in a single womb.
The risk of a multiple birth can be reduced, but not eliminated, by careful monitoring.
"Human reproduction is really designed for the single pregnancy," says Dr. Allan B. Weingold, chairman of the department of obstetrics and gynecology at GW Medical Center.
"There isn't a single complication in obstetrics that doesn't occur with greater frequency in multiple births. The more babies you have, the more likely they [complications] are to occur, and earlier."
Weingold delivered a set of quintuplets two years ago, born to Pamela and Daniel Pisner of Olney, Md.
Multiple births, Weingold says, entail three major risks to mother and babies:
* Premature labor. The Frustaci septuplets in California were born at 28 weeks -- 12 weeks premature. The Pisner quintuplets, who all survived, were only eight weeks premature. Babies born prematurely, particularly if their birth weight is very low, have a much higher rate of illness and death.
* Nutritional problems. With multiple gestation, there are simply fewer nutrients available to both the mother and the fetuses. That can cause growth retardation, stillbirth or early death in the newborn. The average baby born at 28 weeks weighs about 1,000 grams (2 pounds, 3 ounces); the California septuplets averaged just over half that.
* Maternal complications. Multiple gestation poses many risks to the mother, the most important of which is pregnancy-induced high blood pressure. In many cases, the mother must be hospitalized and bedridden for weeks to permit careful monitoring and reduce the chance of premature labor. Delivery, of course, is almost always by cesarean section.
"The key point," says GW's Weingold, "is that with all our abilities to make the diagnosis and with all the technology available, it's still a major, major obstetrical complication with a very poor prognosis for the babies and signficant risk to the mother.
"It's critical that when we give these drugs, they be monitored extremely closely so this kind of thing can be avoided."
A sonogram taken six or eight weeks after conception usually shows how many gestation sacs are in the uterus, alerting patient and doctors to the possibility of multiple births.
Although quintuplets and even higher-multiple births are usually associated with use of fertility drugs, perhaps the most remarkable case of quintuplets -- the Dionne quints -- occurred in 1934, long before Pergonal was even developed.
The Dionne quints were born in a cabin in rural Canada. A country doctor and a midwife swaddled them in cotton sheets and old napkins and covered them with oven-warmed blankets. Their first feedings consisted of warm water laced with corn syrup and drops of rum, before milk could be obtained from nursing mothers in the region. No incubators were available for three days, no oxygen tank for a week.
Yet the Dionne quints survived.
"It's sobering," says Weingold of the Dionne case, noting that the Pisner quints were delivered and cared for by a medical team of 30, plus all the high-tech equipment a modern medical center can provide. "It kind of humbles you."
In the past seven years, Rifka says, only two women treated with Pergonal at Georgetown's Reproductive and Infertility Center have produced more than four fetuses at once. One had five; the other, six. Both chose to abort. In subsequent pregnancies, one produced twins and the other, triplets.
How do such women react to the news that they are going to have a multiple birth?
"The ones who have twins or triplets, they are ecstatic," Rifka says. "If you are an infertile woman trying to get pregnant for 10 years, and suddenly you have two kids, this is a jackpot.
"More than three, it's very difficult and risky."