To become a father at 52 is unusual. To become a mother at 52 is to defy nature. Alan and Deirdre, both 52, don't want to let many of their friends and colleagues in on their secret yet, in case something goes wrong. But they are doing everything in their power to have a baby. They have the money, and they have the will. Deirdre, a trim, athletic researcher at a medical school in Connecticut, has three adult children from a previous marriage; Alan, a college English professor, has never had kids. "I always wanted children," he says. "Three years ago, when I found this woman I loved who was my own age, I thought, 'Well, that's one dream I'll have to relinquish.'"
Deirdre had already gone through menopause. By supplying the correct amounts of estrogen and progesterone via hormone therapy, it is relatively easy to make the uterus of a postmenopausal woman hospitable to a fetus. But even then, the chance of a woman Deirdre’s age getting pregnant with her own eggs is nonexistent. So doctors suggested the couple consider implanting a donor egg fertilized with Alan’s sperm. Egg donation is no longer considered cutting-edge medicine, but using the procedure to impregnate a woman over 50 is. Still, Alan and Deirdre were overjoyed. “I thought, ‘Isn’t science great?’ ” Alan says.
In a few weeks, Machelle Seibel, a reproductive endocrinologist at the Fertility Center of New England, will mix the eggs of a much younger woman with Alan’s sperm and introduce the resulting embryos to Deirdre’s uterus. Her chances of giving birth will then rocket from less than 1 percent to 50 percent. “I would have considered doing this even if I hadn’t remarried,” Deirdre says with a lopsided grin. “The idea of having another child at this stage is compelling.”
Not that Deirdre and Alan are unaware of the problems of being older parents. They worry about how they’ll function with little sleep—“although I needed a lot of sleep even when I was in college,” Alan says—and they are concerned that they might not be around to see their child come of age. If Deirdre gets pregnant, they plan to move to the Midwest to be near Alan’s four brothers and sisters. “As a hedge against possible early death, we want our child to be surrounded by as much family as possible,” Alan says.
Deirdre’s three children, all in their twenties, are trying to be supportive. But they’re skeptical. “Independently they came to me and said they thought it would be weird to be their age and have parents in their late seventies,” Deirdre says. “But I look at it like this: Our definition of ‘family’ has expanded. Now there are gay and adoptive and single-parent families who’ve used assisted technology. So although an ‘older-parent family’ is what we’ll be, it’s only one of several variations.”
Twenty-two years after the world’s first test-tube baby was conceived through in vitro fertilization, science is giving men and women—at least those who can afford the steep medical fees—increasing flexibility to alter the seasons of their lives. Infertility treatments once considered revolutionary are now commonplace: If a man has a low sperm count, sperm cells can be retrieved from a testicle for direct injection into an egg’s cytoplasm. If the shell of an egg has hardened because of age, doctors can hatch it in the lab and then implant it on the uterine wall. If a woman has stopped producing eggs, she can avail herself of drugs to induce ovulation, as well as donor eggs or donor embryos. These days, the science of assisted reproductive technology is advancing at such a rapid rate that laboratory researchers say it will soon be medically possible for even a centenarian to give birth. But such tinkering with the biological clock begs a commonsense question: How old is too old to have a baby? And this seemingly straightforward question trickles into a cascade of other questions: How old is too old for parents? For children? For society?
When it comes to treating women for infertility, the American Society for Reproductive Medicine would like to draw its line in the sand at menopause. “Around 50, that’s when reproductive processes have physiologically stopped, and therefore the intervention and treatment by physicians should also stop,” says Robert Stillman, a former member of the society’s board of directors. “Infertility is a medical disorder, affected by the reproductive life span. Just as we wouldn’t consider inducing a prepubescent individual to conceive—although we could—we shouldn’t induce pregnancy in someone who’s gone through menopause.”
In recent years, an increasing number of women have chosen to spend more time building a career, or looking for the right mate, before having children. Some have been shocked to belatedly discover there is no denying a fact of nature. Without any scientific intervention, childbearing is out of the question for most women by the time they reach their early forties. Between the ages of 35 and 40, fertility tapers off, and after 43 it pretty much plummets off the cliff. That is because something about the aging process upsets the process of meiosis, the nuclear division of the ovum or sperm in which chromosomes are reduced to half their original number. Sex cells do not divide properly, and there are too many or too few chromosomes in the egg or sperm.
For women in their mid-forties, there is a dramatic increase in the risk that their eggs will have the wrong number of chromosomes after ovulation. Hence the difficulty in getting, and staying, pregnant. And unlike a man, whose sperm supply is constantly renewing itself, a woman is born with all the eggs she’ll ever have. In fact, ovaries start aging before a woman’s birth. A 20-week-old fetus has about 7 million eggs. Eighteen weeks later, at birth, that number has been decimated to less than 2 million. Even though the eggs remain unused throughout childhood, by puberty the egg supply has dropped to 400,000—less than 6 percent of what the child started with. By menopause, the egg larder is close to empty.
Even when an older mother manages to get pregnant, she and her baby face additional medical hurdles. With mothers over 35, there is a greater risk of hypertension and diabetes for themselves, and likely a greater risk of juvenile diabetes for the children. A 1995 Swedish study found that women born to mothers age 45 or older had a slightly higher chance of developing breast cancer than women born to younger mothers. Most well known is the increased risk of certain chromosomal abnormalities such as Down’s syndrome, in which there is an extra set of genes in each cell.
Studies suggest that being the child of an older father also carries risk. Because older sperm tend to have more chromosomal mutations—ranging in seriousness from harmless to lethal—there is among older fathers a higher rate of kids born with certain rare tumors, neural-tube defects, congenital cataracts, and upper limb defects. Curiously, there’s also a higher rate of homosexual children born to older dads.
While men experience some decline in the number of sperm, motility, and morphology—the number of normal sperm—after age 40, it’s generally not enough to prevent them from becoming fathers. There are typically 150 to 300 million sperm released in one ejaculation. Even if the number drops by 50 percent, there are still pretty good odds there will be some keepers.
And now, technology has advanced to the point where even men with extremely poor sperm quality can father children. With intracytoplasmic sperm injection, an embryologist can inject a single sperm into the cytoplasm of an egg with a microscopic needle while bypassing the normal cascade of chemical reactions necessary for fertilization.
The procedure, which has only been around since 1992, is a primary reason for the speed-of-light development of fertility treatment for aging would-be parents—because it’s not only sperm that can be injected into the egg. The processes of microinjection and micromanipulation of egg and sperm are making a wider array of new treatments possible.
DOUBLE TROUBLE:
Since the advent of in vitro fertilization two decades ago, there has been an explosion in the number of multiple births, particularly among women over 40. Statistics released last September by the Centers for Disease Control reveal a 52 percent increase overall in twin births between 1980 and 1997. Among women between 40 and 44, the increase in the number of twins born was 63 percent, and among women between 45 and 49 it was a staggering 1,000 percent.
The ages of the mothers had less effect on the health or survival of the infants than the pregnancy complications generally associated with multiple births. For example, the risk of a very low birth weight is eight times higher for twins than for single births. The ultimate impact of multiple births on the lives of older parents is immeasurable. “Keeping up with two kids instead of one is a real challenge,” says Machelle Seibel. “The increase in energy required is exponential rather than additive.”
For example, embryologist Jacques Cohen, scientific director at the Institute for Reproductive Medicine and Science of Saint Barnabas in Livingston, New Jersey, has developed a procedure called cytoplasmic transfer that shows promise for assisting women approaching their early forties who either can’t get pregnant through in vitro fertilization or have embryos of such poor quality they don’t survive. Doctors take the cytoplasm of a youthful and healthy egg—containing not the dna but the proteins and enzymes for healthy cell growth—and inject it into the problematic egg to boost its quality. Possible health risks with the procedure have not yet been conclusively studied and there are troubling ethical questions. (See “Can a Baby Have Three Parents?” page 66.) But out of 26 attempts, the technique has resulted in 12 live births.
Jamie Grifo, director of New York University’s reproductive endocrinology unit, is further refining another technique to assist women between 42 and 45, whose chances of having a child with their own eggs hover around 5 percent. He takes an older woman’s egg and extracts the nucleus, which contains the dna. Then he removes the nucleus from the donor egg of a much younger woman and in its place microinjects the genetic material of the older woman. The procedure, attempted on two women last year, resulted in fertilized embryos but not babies. Grifo and his team went back to the lab, perfecting the process on mice. The result: baby mice.
Grifo’s groundbreaking work could provide the answer women like Alison Carlson are looking for. Carlson is a golden girl: blond, sunny, a former professional tennis coach in San Francisco. When she got married last year to a younger man and started trying to get pregnant at 42, she assumed she’d succeed quickly. “I was an athlete,” she says. “I felt the normal rules wouldn’t apply to me.” At first it seemed she would be right. In her initial round of in vitro fertilization, Carlson produced an impressive 27 eggs, and 25 were fertilized: “I was a champ.” She got pregnant but quickly miscarried. Forty-five percent of women over 40 do, usually because of chromosomal abnormalities in their eggs. “Suddenly I felt like I should buy one of these T-shirts that say ‘I Can’t Believe I Forgot to Have Children.’” Carlson says that when she tried again, she failed to get pregnant at all.
Intellectually, Carlson knows the problem is age, but emotionally she cannot accept it. Like so many men and women over 40 who begin fertility treatments, she feels pressure to keep trying. “I’m embarrassed because, first, I felt I was being so arrogant,” she says. “Like, here we all are, a bunch of baby boomers who went to college in the second wave of feminism, dedicated to having important careers before having babies, and then paying gobs of money so science can give us what we want. I’m appalled at my own sense of entitlement.”
Given the anguish many aging baby boomers now experience trying to get pregnant, it’s hard to fathom that the future holds no less than the end of infertility. Doctors recently discovered how to freeze a woman’s eggs when she’s young and then thaw them when she’s ready to get pregnant. A woman could finish college and graduate school, launch a career, and then start a family with eggs she parked on ice at age 18.
Banking individual eggs is just the beginning. Recently Kutluk Oktay, the chief of reproductive endocrinology and infertility at New York Methodist Hospital in Brooklyn, has been experimenting with freezing and transplanting swatches of ovarian tissue. Each bit of tissue contains thousands of immature follicle eggs. While individual, already-developed eggs die easily when frozen, immature follicle eggs embedded in the ovarian tissue fare a lot better. Oktay has already tried the technique on a 30-year-old dancer from Arizona who’d had her first ovary removed at 17 because of cysts but had the foresight to have her second ovary frozen. Last fall, Oktay sewed 80 small pieces of the tissue back into her pelvis and revived her menstrual cycle. The woman is not trying to conceive. But Oktay’s colleague, Roger Gosden, now reproductive biology research director of McGill University’s Royal Victoria Hospital in Montreal, has removed the ovaries of sheep, frozen them, thawed them, sutured them back in the sheep—and gotten lambs aplenty.
Of course cryopreservation will not help those whose eggs are already sitting on the porch in little rocking chairs. But researchers have found ways to keep old eggs alive. Jon Tilly, the director of the Vincent Center for Reproductive Biology at Massachusetts General Hospital in Boston, has been studying genetically altered mice to better understand the process of apoptosis, or natural cell death. Cells are programmed to die: Fifty or sixty genes, maybe more, regulate their expiration. One specifically involved in the death of immature eggs in the ovaries is known as the bax gene. When Tilly and his researchers studied mice that lacked the bax gene, they found that 24-month-old females—the equivalent of 80- to 100-year-old humans—still have functioning, estrogen-producing ovaries.
“We were pretty amazed,” says Tilly. “And the bax gene has a precise counterpart in humans that appears to be responsible for the decimation of eggs during menopause.” Silencing of one of the “cell death” genes may be the first step in finding treatments to help woman delay menopause or avoid the health problems—osteoporosis, heart disease—associated with the cessation of estrogen production. Tilly also believes that in the not-wildly-distant future the ability to suppress the bax gene in women’s ovaries may prolong their fertility too. He is quick to add, however, that even though the old female mice with newly viable eggs were allowed to cavort with young, studly mice, they did not produce offspring. This is because older mice lose the capacity to excrete adequate levels of two hormones: one that stimulates egg follicles to grow and mature and another that causes the ripened egg to be released from the ovary into the reproductive tract.
Another approach to ending infertility involves beating the numbers game. What if a woman had an unlimited number of eggs? This may someday be possible if researchers can get somatic cells—that is, cells from anywhere in the body—to act like sex cells. Normal cells are diploid, with 46 chromosomes—23 from one’s father and 23 from one’s mother. The gonads (testicles and ovaries) divide the chromosomes to create haploid cells, namely spermatozoa and eggs. As the eggs age, most suffer from aneuploidy, the uneven division of the chromosomes. Anything other than 23 sets of chromosomes makes the egg either entirely unviable, or viable but resulting in abnormalities like Down’s syndrome. It is not that the eggs, in their undeveloped state, are abnormal; it’s that something about the machinery of meiosis—the chromosomal division at ovulation—goes awry as women age. The key to fixing this problem is to make faux eggs—normal body cells that behave like eggs by undergoing meiosis. Thus, anyone 18 to 100 would have an unlimited supply of easily harvested “sex cells.”
This is exactly what Cohen and some other researchers are working on now. Bioethicists balk, because the process sounds like a kissing cousin to cloning. But it’s not. The resulting cell has half its mother’s chromosomes and, when united with sperm, could be expected to create a bona fide, half-his, half-hers human. The catch is that the parents could theoretically be 100 or more years old. “This is going to involve some major discussions about what’s clinically acceptable and what’s socially acceptable,” Cohen says.
Of course, even if they have all the financial resources in the world, most couples past the age of retirement probably won’t want to start raising children. “This won’t be some huge public policy issue,” says Arthur Caplan, director of the University of Pennsylvania’s Center for Bioethics. “It’s not like you’ll see all these people running from nursing homes to birthing centers.” But, Caplan adds, the very fact that 50-year-old mothers and fathers could become relatively commonplace raises another issue. “One of the ethical questions becomes: What’s in the best interest of the child? And the answer is simple: It’s good not to be an orphan. A good, loving environment requires one parent.
So if a father is 20 and a mother 80, that’s not a problem. If the father is 60 and the mother 40, well, one should think about the implications of depriving a child of grandparents. It’s not morally reprehensible, but it’s an issue. Now, if both parents are in their sixties”—as was the case in 1996 with Arceli Keh, the 63-year-old Filipino who gave birth after lying about her age to her fertility specialists in California—“that’s a problem.”
Contemplating their own untimely demise won’t deter truly determined older parent wanna-bes, like Eileen and Charles Volz of Millbury, Massachusetts. Eileen, a certified public accountant, was 42 and had just married Charles, a digital commerce executive, in 1992 when she was diagnosed with breast cancer. Radiation and chemotherapy put her into immediate menopause, but she overcame the cancer. Four years passed before she and her husband heard about egg donation. “People thought we were a little nuts,” says Charles Volz. “I mean, I already had three children, and she had survived breast cancer—why should we tempt fate?”
One look at their son, C.J., answers the question. On her first try at Machelle Seibel’s clinic, she got pregnant with a donor egg and had C.J. at 48. “I never for a moment felt he wasn’t mine,” Eileen says. “Genetics is the smallest part of being a mother.”
Eileen Volz is now 50; her husband is 48. They tried a second round of egg donation, which failed, but they are contemplating a third. Sure they’ll be collecting Social Security by the time C.J. is ready to head off to college. But Charles Volz speaks for older parents everywhere when he offers this Pollyannaish view of his midlife adventure: “It’s not a problem at all. Hey, I’m going to live forever.”
Perhaps the biggest question for science and society will not be answered for a number of years, until the first generation of children born to older parents through assisted reproductive technology enters their teenage years: What happens when children nature did not intend to create become adults? Already there are some troubling questions about the 20,000 children conceived throughout the world by intracytoplasmic sperm injection. Aggressively injecting a sperm into an egg manually has been found to change a whole sequence of molecular events in fertilization; for example, the dna packaged in the head of the sperm unravels more slowly than in normal fertilization, throwing off the timing of the process. Scientists worry that although there hasn’t been an obvious increase in birth defects so far, sex chromosome abnormalities may show up when the children reach puberty. One 1998 study in Belgium showed that of 1,082 prenatal tests on intracytoplasmic sperm injection pregnancies, one in 120 had sex chromosome abnormalities, as compared to a general population figure of one in 500 pregnancies.
“Fertility is a unique field in some respects,” says Massachusetts General’s Jon Tilly. “In most fields of scientific inquiry, most of the problems are worked out in animal models. But here, technology is moving so fast, and people are so desperate for answers, that work on humans is paralleling work on animals. That may be turn out to be good, because we are accelerating the application of our knowledge. But it may be bad, because we don’t know what’s safe. We don’t know about unforeseen problems. There may be reasons the body is not designed to be reproducing after its early forties.”
