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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.

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