Cover Stories: Making Babies

By Philip Elmer-DeWitt

Couched in a halo of nutrient cells, an egg smaller than the dot on an i drifts slowly down a Fallopian tube, one of a pair of narrow passages that lead from a woman's ovaries to her womb. Like a beacon guiding ships at night, the egg sends forth a calling signal. A convoy of sperm -- the remnants of an armada that was once a couple of hundred million strong -- sails into view, their long tails thrashing vigorously. Lured by the chemical signal, several hundred of the most energetic swimmers close in on the egg, their narrow tips unleashing a carefully timed sequence of biochemical salvos. One substance dissolves the jelly-like veil surrounding the egg. Another softens the egg's tough outer shell, preparing it for penetration. In the last moments before conception, a few dozen sperm race to break through the final barricade.

One and only one succeeds. The instant it tunnels its way past the egg's outer layer, an electric charge fires across the membrane and a signal from the sperm causes the eggshell to snap shut, blocking entry to any remaining contenders. The successful seed then releases its tightly coiled package of DNA, which fuses with the egg's own DNA and sets in motion a series of genetic events that culminate, nine months later, in the birth of a new human being.

That is how it is supposed to work. And for hundreds of thousands of years, without anyone knowing quite how or why, it has worked -- well enough to perpetuate the species, populate the planet and bring the joy and responsibility of children to countless generations of parents.

But what if it doesn't work? What if egg meets sperm and nothing happens? Human sexual reproduction, as couples even before Sarah and Abraham have known, can be a heartbreakingly unreliable process. Even under the best of circumstances -- a fertile couple having intercourse at the optimum moment in the woman's cycle -- it fails 3 times out of 4. When conditions are less than ideal -- when the woman is over 35, for example, or the man's sperm is defective or in short supply -- the odds lengthen dramatically.

America today is in the midst of an infertility epidemic, the unforeseen consequence of a variety of historical and socioeconomic trends. The advent of the Pill, the women's movement and an economy that pushes women into the workplace during their most fertile years have led many members of the baby- boom generation to wait so long to have children that they are in danger of waiting forever. This same generation was also party to the sexual revolution, and that too has taken a toll. With exposure to more sex partners came a sharp rise in sexually transmitted diseases and other infections that can impair fertility. In addition, tens of thousands of women now in their 30s and 40s were born with malformed reproductive systems as a result of their mothers' use of the drug DES (diethylstilbestrol), which was widely prescribed in the 1940s and '50s to prevent miscarriage.

Taken together, more than 1 in 12 U.S. couples has difficulty conceiving -- a number that is as high as 1 in 7 for couples in the thirtysomething years. And given the size of that age group, there have never been as many people looking for help. The number of doctor visits for fertility problems nearly tripled between 1968 and 1984. Last year more than a million new patients sought treatment, six times as many people as were treated for lung cancer and 10 times the number of reported cases of AIDS.

The sad fact is that half the people who seek assistance never overcome their infertility. But there is real hope for even the most difficult cases. Through a series of remarkable advances, scientists have opened a new window on the mysteries of fertilization that shows for the first time not only how the process works but also what can be done when it doesn't. Doctors today can manipulate virtually every aspect of the reproductive cycle, from artificially ripening eggs in the ovary to inserting individual sperm directly into the egg's inner membrane. Now researchers at several U.S. clinics are pushing the scientific envelope even further, screening embryos for genetic defects in the lab before placing them in their mothers' wombs.

The result is a reproductive revolution: an explosion of new techniques for overcoming infertility and an unprecedented rush by would-be parents to take advantage of them. Thirteen years after the birth of the first test-tube baby, Louise Brown, in England, in vitro fertilization (IVF) has not only reset the biological clock for thousands of patients -- and produced some 10,000 babies in the U.S. alone -- but spawned a host of new procedures, like GIFT, ZIFT, microinjection and zona drilling, that offer even greater promise. Today, using the new technology, an infertile couple in their mid-30s has as good a chance of getting pregnant artificially as a pair of fertile teenagers having unprotected sex at any random moment the old-fashioned way.

Families can be pieced together with borrowed sperm, borrowed eggs and borrowed wombs. Women are having babies long after their prime childbearing year -- even after menopause. In yet another twist, Arlette Schweitzer, 42, of Aberdeen, S. Dak., is expected to give birth to her own twin grandchildren next month, having served as a surrogate for her daughter Christa, who was born without a uterus. "Next to Christa, I'm the happiest woman in the world," says Schweitzer. "We feel so blessed."

The brave new technologies stir up conflicting feelings, breeding hope and despair where once there was resignation. The high price of in vitro * treatments (ranging from $6,000 to more than $50,000 per live birth) means that only the rich and well-insured can afford them. Patients who have undergone round after round say it is like riding an emotional roller coaster; you never know when you are going to run into a brick wall and have your heart broken.

The new techniques have also given birth to once unimaginable ethical dilemmas. Do sperm and egg donors have a claim on their biological offspring, and vice versa? Do embryos, frozen or thawed, have a constitutional right to life? How much manipulation of genetic material will society be willing to permit? "Technology makes us look at our most cherished conceptions of who we are and what we want to be," says Dr. Kenneth Ryan, a professor of reproductive biology at Harvard Medical School. "People have to decide what kind of society they want to live in."

But all these issues pale before the newly revealed miracle of fertilization, an event so dizzyingly complex that researchers say the more they know, the more they wonder that it works as often as it does. The actual merger of egg and sperm turns out to be one of the most straightforward steps in the process -- and the easiest to duplicate in a test tube. The events that occur before and after that union, scientists say, are where the real troubles lie.

The long road to conception actually begins seven months before a woman is born, when microscopic eggs start to form in the buds that will become her ovaries. Unlike the testicles of a man, which continuously churn out sperm at the prodigious rate of 1,000 per sec. (30 billion a year), the ovaries never produce any new eggs. The eggs a woman is born with -- usually about 2 million -- are all she will ever have. By puberty, normal degeneration will have reduced that number to about 400,000. When the woman exhausts the supply, her ovaries will virtually shut down, an event she experiences as menopause.

The limited supply of eggs is believed to be a chief reason that fertility decreases with age. Each month, starting at puberty, hundreds of eggs begin the maturation process. One of them, growing in a fluid-filled sac called the follicle, quickly establishes itself as the first among equals. In a normal cycle, only that single egg will be released to the Fallopian tubes for possible fertilization. About 1,000 more will wither away and disappear. So although a woman may have 400,000 eggs to start with, the number she can effectively use is closer to 400.

To make matters worse for the aging female, the eggs that remain in her ovaries get older and less fertile with each passing year. Recent studies of egg donation provide strong evidence that it is the age of the eggs, and not the age of the reproductive system, that causes fertility to decline sharply after age 40: older women who receive eggs from younger women get pregnant at rates comparable to the age of the egg donor, not the age of the recipient.

None of this is to say that men do not play a role in infertility. On the contrary, the sperm of the human male is notoriously prone to defects. A typical sample is riddled with "pinheaded" sperm, which lack a full complement of DNA, two-headed freaks, and sperm that cannot swim a straight line. Urologists estimate that when a couple experiences infertility, so- called male factors are just as likely to be responsible as female ones. But because of the way sperm are manufactured, assembly-line fashion in the factory of the testes, not much can be done to change either their quality or rate of production (although scientists have developed some extraordinary new procedures to help deficient sperm accomplish their mission). Even the varicocelectomy, a widely prescribed operation that enhances sperm production by removing a varicose vein in the scrotum, seems from recent studies to have little effect on a couple's ability to conceive.

The sequence of events by which eggs mature and ovulate, by contrast, lends itself to all kinds of tinkering. Every step in that process is controlled by hormones, and much of the infertility work done in the '60s and '70s involved finding which hormones were out of balance and how to adjust them. A woman whose ovaries do not release their eggs properly, for example, might be given human chorionic gonadotropin, which triggers ovulation. A woman who tends to miscarry may be given progesterone, which helps soften the uterine lining to make it more receptive.

A widely used drug called Pergonal (menotropin), which for years was derived from the urine of postmenopausal Italian nuns, is rich in the hormone that stimulates eggs to develop and form follicles. This follicle-stimulating hormone usually allows only one egg to reach full maturity, but when administered in huge doses it can trick the ovaries into producing more than a dozen mature eggs in a single cycle. This abundance of eggs is key to most assisted-reproduction techniques. By fertilizing large numbers of eggs and selecting the healthiest embryos, fertility specialists maximize the odds of achieving a successful pregnancy.

Hormone treatments can cover a multiple of symptoms. But there are any number of problems that don't respond to hormone therapy. A woman's Fallopian tubes may be blocked or rendered inoperative by scarring from pelvic infections, sexually transmitted diseases or bits of tissue leaking out of the uterus, a condition called endometriosis. A man may have too few sperm that can make the long journey, or his sperm may lack specific enzymes needed to clear the passage to the egg. Some couples learn late in the game that they are incompatible at a cellular level. A woman can be allergic to her husband's sperm; her antibodies may destroy her partner's seeds before they get a chance to be sown.

There are treatments for each of these conditions. Blocked Fallopian tubes can be freed or cleared of obstructions by a variety of operations, ranging from laser-beam surgery to inflating a tiny balloon within the clogged passage. Men with extremely low sperm counts can be helped toward fatherhood by artificial insemination, which puts what sperm they have directly into the cervix, or by microinjection, which puts a single sperm right into the egg. And for couples with sperm-allergy problems, a procedure known as sperm washing strips the sperm of some of the chemical antigens that trigger the allergic reaction.

But most of these treatments have been supplanted by the family of techniques known as in vitro fertilization. The beauty and power of IVF are that it allows doctors to take many key events in reproduction out of the body, where they are subject to the vagaries of human biology, and perform them in vitro, "in glass." By removing mature eggs from the ovaries, mixing them with sperm in a Petri dish and reintroducing the resulting embryos directly into the uterus, doctors can bypass most of the important barriers to fertility, from low sperm counts to nonfunctioning Fallopian tubes.

The status of IVF has undergone a striking transformation in the past decade. It used to be considered an option of last resort; with success rates running below 5%, most doctors put couples through the full gamut of conventional therapies before turning to IVF. Today a couple in their 30s with undiagnosed infertility is likely to be told to skip invasive tests and exploratory surgeries and go straight to in vitro or related technologies. Streamlined procedures and lowered costs are part of the reason. But it was the development of two variations on the basic IVF procedure -- GIFT and ZIFT -- and the impressive success rates they have produced that have made believers of most doctors.

The major sticking point of the original procedure, it turned out, was that the embryos just wouldn't stick. Helped by hormone treatments, a woman might produce dozens of eggs each cycle. Her husband's sperm might fertilize 10 of them. But for reasons that remained mysterious, the embryos simply refused to take root -- or implant -- on the walls of the uterus. Even the best-run clinics were getting success rates not much higher than 15% to 20% just five years ago.

Scientists now know that implantation is one of the most difficult hurdles in the human reproductive system. It is estimated that even among perfectly fertile couples, as many as one-third of all pregnancies are lost, before anyone knows they have begun, because the embryos fail to implant in the uterus wall. Only in the past few years have researchers begun to understand why this is so.

A key breakthrough came in the mid-1980s at Dr. Ricardo Asch's laboratory at the University of Texas at San Antonio. Asch was trying to find a simpler way to do IVF, one that would not require the skills of an embryologist, when he hit upon the procedure he called gamete intra-Fallopian transfer, or GIFT. Rather than attempting fertilization in a Petri dish, he simply loaded the sperm and eggs (known to biologists as gametes) into a fine pipette and inserted them into the Fallopian tube, where he hoped they would take care of business by themselves. Not only did they fertilize, but they implanted as well -- at a much higher rate than he expected.

Scientists attribute the implantation rates of GIFT to the way in which the fertilized embryo enters the uterus. In IVF the embryo is squirted, rather violently, into a reproductive tract that has been pretty roughly treated, first by various hormone treatments, then by the egg-retrieval procedure. In GIFT, by contrast, the embryo drifts quietly into the uterus, much as it would naturally. To further improve the success rates, Asch's researchers tried fertilizing the egg in a lab dish and then placing the pre-embryo, or zygote, directly into the Fallopian tube -- a procedure known as ZIFT (zygote intra- Fallopian transfer).

The results were startling. Using GIFT and ZIFT, clinics were soon reporting + implantation rates two to three times as high as those achieved in their own IVF facilities. Among couples for whom sperm quality is not a factor, a single cycle of GIFT or ZIFT at Asch's clinic can result in pregnancy 40% to 50% of the time. A healthy, fertile couple trying to conceive naturally in any given month has about a 25% success rate.

The latest clue in the mystery of implantation was hit upon by scientists working on a completely different problem: lazy sperm. Some sperm lack the ability to penetrate the egg's outer membrane, or zona pellucida, often as a result of old testicular injuries or early exposure to toxic chemicals. Several methods have been devised to give these sperm a boost, including microinjection (the sperm is inserted directly into the egg by means of a microscopic needle) and partial zona drilling (a tiny hole is made in the egg's protective shell).

It was while working with patients with severe sperm deficiencies that researchers noticed something surprising. Eggs whose shells had been poked open were doing a much better job of sticking to the uterus wall. In a trial performed by Dr. Jacques Cohen, one of the scientists who developed the PZD procedure, embryos successfully lodged in the womb at a rate more than five times the national average for IVF. "I was so excited I couldn't sleep at night," says Cohen. Apparently eggs with a hole in their outer membrane somehow benefit from that hole. Cohen theorizes that embryos that don't implant may be having trouble "hatching" through the shell that housed the original egg. The tiny hole Cohen makes to help the sperm get in may be helping the embryo get out -- and may suggest a method for helping increase implantation rates across the board.

In April scientists from Israel and the U.S reported a new finding that may offer yet another way to help infertile couples. It had long been assumed that there was no communication between egg and sperm until they collided in the Fallopian tube. But by closely watching the behavior of sperm in test tubes containing the fluid from an egg's follicular sac, an interesting effect was observed. A small number of sperm seemed to change their swimming patterns in response to chemicals secreted by the egg or cells around the egg.

It was not a dramatic effect, and not all eggs emitted even this weak chemical signal. But when the researchers correlated the results, they discovered a startling pattern: only eggs that emitted the "come hither" message were successfully fertilized. "This indicated to us that attraction may indeed be a key process in fertilization," says Michael Eisenbach at Israel's Weizmann Institute of Science. Now Eisenbach is trying to find out whether this phenomenon could be exploited to help treat the most stubborn infertility cases.

Scientists in South Korea are on the verge of a breakthrough in a procedure doctors have been dreaming about for some time: the freezing and storage of unfertilized eggs. Sperm and embryos are regularly frozen for later use, but not eggs, which quickly lose their viability when manipulated outside the body. But Dr. Kwang Yul Cha, an endocrinologist at Cha Women's Hospital in Seoul, reports that his team has produced two pregnancies from eggs matured not in an ovary but in a Petri dish -- a major step in the eventual perfection of egg freezing. Many scientists expect that the procedure will be available within the next few years.

That could be a godsend for a young woman facing surgery or chemotherapy that would destroy the functioning of her ovaries. Such a woman would have the option of putting her healthy eggs on ice for future use. That option might also appeal to, say, a professional woman inclined to postpone childbearing. Theoretically, at least, she could store her best, grade-A eggs during her most fertile years and pull them out of the deep freezer at a later age should she run into trouble conceiving. Not everyone, though, would approve this use of an expensive technology.

Even more provocative is a new area of research that combines the techniques of in vitro fertilization with the latest advances in genetic screening. Abnormalities like sickle-cell anemia or cystic fibrosis are present in the genetic code from the moment of conception. Since embryos in their earliest stages are fairly forgiving -- they can lose a cell or two without impairing their subsequent development -- it is theoretically possible to remove a cell from, say, a 16-cell embryo, test it for a suspected defect, and get the answer before that embryo is inserted into the uterus for implantation.

Embryologists at several U.S. labs are doing just that. Doctors at Chicago's Illinois Masonic Medical Center have screened embryos from 15 couples who have a known risk of carrying such diseases as Tay-Sachs, a rare, crippling condition that often results in death by age four. Last week doctors at Cornell Medical Center began clinical studies on embryos at risk for cystic fibrosis.

These experiments are sure to arouse protests. Today most in vitro clinics are very careful never to purposely destroy viable embryos. Even when couples agree to freeze embryos, they are required to sign an agreement specifying what will happen to any embryos they don't need: they can be donated to couples that can't produce their own or donated to research. But the premise of pre-embryotic genetic testing is that defective embryos will be destroyed. If the problem is a debilitating disease like Tay-Sachs, this may be justifiable. But what if couples choose to reject embryos whose only offense is that they are of the wrong sex? "You're dealing with human tissues from a human body," says Lynne Lawrence, at the American Fertility Society. "Like sex, it tends to cut near and dear to people's hearts and raises a red flag."

Society has just begun to wrestle with the financial burden of assisted reproduction. "It takes courage and cash," says Dr. Georgeanna Jones, whose work with her husband, Dr. Howard Jones, in Norfolk, Va., produced the first IVF baby in the U.S. A single in vitro cycle can cost $6,000 to $8,000, a burden most medical plans are not eager to share. Nine states have passed laws requiring insurance companies to cover the cost of infertility treatments, but resistance in the remaining states is strong. The question, says Leroy Walters, at Georgetown University's Kennedy Institute of Ethics, is "to what extent society has a responsibility to assist couples that are infertile." In Walters' opinion, society should pay for the diagnosis of the problem, "but beyond that, given the cost, I'd place the financial responsibility on the couples themselves." It may, for instance, be more in society's interest to encourage intractably infertile couples to adopt.

The Federal Government has tried to steer clear of infertility issues. Under pressure from right-to-life lobbies, it quietly cut funds for in vitro research in 1980, despite a Health Department study that called such a ban "neither justifiable nor wise." Last fall Congress appropriated $3 million for three contraceptive centers and five infertility centers. But because of the government's ban on funding IVF research, the scientists haven't been able to begin their work. "Britain and Australia are surpassing us in research because of the restraints we face in this country," says Harvard's Ryan. "The U.S. government has created a moral vacuum."

And where there is a moral vacuum, there are lawsuits. Around the country, a number of bizarre court cases have cropped up as a result of ambiguities in the rules governing the new technologies. In one peculiar case, a wealthy couple died in a plane accident, leaving two frozen embryos as their only direct heirs; a court decided that the embryos could not inherit the estate. In a case that is still pending, a divorced Tennessee couple are battling over whether the woman has the right to make use of frozen embryos created while the couple were still married.

Making matters more confusing for consumers is the fact that success rates among the nation's 225 IVF centers vary wildly -- from zero for new ones to 40% and better at some of the top clinics. And infertility specialists are not always what they claim to be. Some obstetricians print INFERTILITY on their business cards on the strength of three-month residency training programs. "They pick up infertility because it's easier than delivering babies at 3 a.m.," scoffs Dr. Richard Marrs, who headed the ethics committee of the American Fertility Society.

Horror stories abound. It is not unusual for a poorly trained physician to schedule advanced infertility treatments -- even surgery -- on a woman without first checking her partner's sperm count. A lawsuit is pending against a physician in Torrance, Calif., who is accused of duping patients into believing he was performing in vitro fertilization when he wasn't even collecting eggs. Consumers are advised to seek guidance from either the American Fertility Society, based in Birmingham, or Resolve, a national infertility organization with headquarters in Somerville, Mass. "You need to be a careful consumer," warns Dr. Arthur Wisot, a Redondo Beach, Calif., infertility specialist. "If you're going to invest all your life's hopes and dreams, you should at least check out the qualifications of the medical group."

Pamela and Jonathan Loew know about investing all their hopes and dreams in achieving pregnancy. The Los Angeles couple went through a five-year effort that included hormone treatment, artificial insemination, an ectopic pregnancy, sperm washing and finally GIFT. "Intellectually you know it's a medical problem," says Pamela, "but emotionally you can't get it out of your mind that you're not like a normal woman."

When Pamela and Jonathan learned during a Las Vegas vacation that their first GIFT procedure had failed, they sat together in a rental car and cried. . "It was pretty devastating," recalls Pam. When Jonathan got a call telling him that their second GIFT attempt was successful and that his wife was at long last pregnant, he was incredulous: "I couldn't believe that after five years we had finally hit the jackpot."

Today the passage of time has dulled the pain. Little Alexandra is 17 months old, and her parents are thinking about having a second child. They still have 12 frozen embryos saved from their second GIFT procedure, and during the next few months those embryos will be thawed and inserted, a few at a time. But whether it works or not is of much less moment to Pamela and Jonathan now than it would have been two years earlier. As baby Alex sits in the living room, engrossed in a music video playing on the VCR, they know full well that they are already ahead of the game.

With reporting by Ann Blackman/Washington, Barbara Dolan/Norfolk and Jeanne McDowell/Los Angeles