Risk of Birth Defects Linked to Father’s Age

For years, many prospective parents--and doctors, as well--have blithely assumed that if birth defects occur when an older couple has a baby, it’s most likely because of the woman’s advancing age.

And there’s some truth to this. The risk of mental retardation because of Down syndrome, for instance, clearly rises with advancing maternal age--from one in 1,000 at age 29 to one in 100 births at age 40. Other diseases in which a child inherits an extra copy of a particular chromosome are also linked to older maternal age.

But increasingly, scientists are discovering that by focusing almost exclusively on mothers-to-be, they may have been barking up the wrong genome. A man, or more accurately, his sperm, also has a biological clock. And its ticking can be just as spooky as a woman’s, perhaps even more so because it’s virtually impossible to do prenatal tests to pick up all the possible mutations in sperm.

“There’s always been this myth that fathers can be fathers until they die, and that would be fine. It’s always the mother who had to be young,” says Eric Vilain, a geneticist and pediatrician at UCLA. But that’s because the risks associated with advancing paternal age have been routinely underestimated, he says.

Comparing Men in Their 40s and Those in Their 20s

“It always strikes me as odd that when we see a woman with her husband, we talk about advanced maternal age, even when the husband may be 10 or 15 years older than she is,” adds Joan Stoler, a clinical geneticist at Massachusetts General Hospital. “There are problems as men get older, too, and it seems ironic that these are rarely addressed.”

In fact, the risk of new mutations (those that haven’t shown up in a family before) is four to five times greater for fathers age 45 and older than for those age 20 to 25, according to the American College of Medical Genetics. And the risk goes up linearly with time.

For the population as a whole, the average age of a father at the time of conception is still a relatively youthful 27. But it’s tough to know precisely how many men older than 40 are fathering children because birth certificates often list only the age of the mother, notes T.J. Mathews, a demographer at the National Center for Health Statistics. You can’t infer the age of the father from that of the mother since many men marry younger women, either the first time around or when they start a new family after divorce.

The latest and most dramatic evidence of the risks of late fatherhood came in April when Columbia University researchers published results from a large study in Israel.

Study Is Pegged to Schizophrenic Children

Led by Dolores Malaspina, a Columbia psychiatrist, the team correlated the birth records of nearly 88,000 people born in Jerusalem between 1964 and 1976 with records from the Israel Psychiatric Registry. They found that men between the ages of 45 and 49 were twice as likely as those younger than 25 to have children with schizophrenia, and men who were 50 or older, had three times the risk. Overall, they found that advancing paternal age accounted for as many as one in every four cases of schizophrenia.

The huge sample enabled researchers to separate maternal from paternal age, says Susan Harlap, a co-author and an obstetrician-gynecologist at New York University. In some other studies, she says, researchers couldn’t do that and hence, gave too much weight to maternal age as a risk factor for particular problems.

Over the years, geneticists have linked a number of other diseases to advancing paternal age, including achondroplasia (dwarfism), Marfan’s syndrome (which can lead to fatal rupture of a major blood vessel) and Apert’s syndrome (malformation of the skull, hands and feet).

Retinoblastoma (an eye cancer), neurofibromatosis (fleshy growths of abnormal nerve tissue) and some types of prostate cancer have also been linked with advancing paternal age. And some diseases caused by genes on the X-chromosome, among them hemophilia, Duchenne muscular dystrophy and Hunter syndrome, have been linked to advanced age not of a child’s father but of his maternal grandfather. (In these cases, an older man passes on a defective gene on the X chromosome to his daughter, who, like Queen Victoria, becomes an unaffected carrier who can pass the disease to her sons.)

For certain diseases caused by new mutations that have not occurred in a family before, the odds are seven to 10 times greater that the mutation has occurred in the father’s rather than the mother’s DNA, says Victor McKusick, professor of medical genetics at Johns Hopkins University.

And there’s a good reason for this: In men, sperm cells are constantly dividing, which provides ample opportunity for tiny mistakes--mutations--to occur as the DNA is copied.

By contrast, when a baby girl is born, her tiny ovaries are full of eggs that are almost mature. The eggs just sit there--not dividing--in a kind of suspended animation for years. Once a woman hits puberty and starts ovulating, the result each month is one egg that completes a cell division, the final stage of egg maturation. The egg is then released into the Fallopian tubes, where it may be fertilized by incoming sperm.

Because a woman’s eggs are so quiescent for so long, “there’s very little chance for things to get messed up,” notes James Crow, emeritus professor of genetics at the University of Wisconsin.

How Defects Are Carried by Women

When genetic accidents do occur in a woman, though, they are big ones--typically an extra copy of a whole chromosome. Researchers do not know why the odds of “trisomy,” (an extra chromosome) increase as a woman ages. But when the fetus gets an extra copy of chromosome 21, the result is Down syndrome. With an extra copy of 13 or 18, the result is severe mental retardation and birth defects; with an extra copy of the X chromosome, the result is Klinefelter’s syndrome, in which males are usually infertile.

And there are undoubtedly more instances of trisomy than most people realize because lethal abnormalities often trigger spontaneous miscarriages. “If you do chromosome studies of the products of miscarriage, a high percentage have chromosome damage,” notes Dr. Wayne Grody, director of the DNA diagnostics laboratory at UCLA.

Glitches Are Harder to Detect in Sperm

With men, the biology is quite different because the testes keep producing new sperm cells throughout a man’s life. “There are more chances in a male for things to go wrong because there are more cell divisions,” Crow says. By age 15, sperm cells have undergone roughly 35 cell divisions. By age 20, it’s 150; by 40, it’s 610, and by 50, 840--hundreds of opportunities, in other words, for tiny glitches in DNA copying that result in “point mutations,” or defects in a single gene.

Even single gene defects can have large consequences. In Marfan’s syndrome, for instance, connective tissues in the eyes, bones and blood vessels might be affected. Some people with Marfan’s go undiagnosed until, like Olympic volleyball star Flo Hyman, they die suddenly when a major blood vessel called the aorta ruptures.

And knowing which gene is at fault can be a mixed blessing. In 1994, for instance, when the gene for achondroplasia, a type of dwarfism, was discovered, some hailed it a breakthrough because it meant genetic testing was now possible. But others feared it could lead to further stigmatizing of dwarfism as a “defect” rather than a variation from the average.

Still, many couples would like to be able to test a fetus to see if it carries any of the potential genetic defects associated with rising paternal age, “but there’s no good way to test,” says Michelle Fox, a genetic counselor at UCLA.

In women, amniocentesis and chorionic villus sampling, both of which are somewhat invasive, can detect whole-chromosome abnormalities such as Down syndrome.

And many women who get pregnant in their late 30s or later do have their fetuses tested.

But it’s much more difficult to test for genetic problems linked to aging sperm because there aren’t enough probes to test all the possible single-gene defects. If an older man has already had one child with a syndrome linked to advanced paternal age, however, doctors can sometimes test a subsequent fetus for that same defect if the gene is known.

With so much uncertainty, the best advice for couples in which an older man wants to be a father is to ask a genetics counselor if it makes sense to get a series of ultrasounds of the fetus. This approach is controversial because not all genetic defects show up on ultrasound, and some that do may become visible only late in pregnancy.

And for women seeking to get pregnant through sperm donation? The best advice is to ask for a donor age 40 or younger.

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Judy Foreman, a fellow in medical ethics at Harvard Medical School, can be reached at foremanj@brandeis.edu. Her column appears occasionally in Health. For a more complete list of diseases linked to advancing paternal age, go to https://www.ncbi.nlm.nih.gov/omim.https://