Down-Syndrome Screening: A One-Parent Test for a Two-Parent Risk

The standard first-trimester screen for Down syndrome, called the combined test, uses three numbers in an algorithm to assess the chance that the fetus has the genetic disorder: markers from the mother’s blood; ultrasound measurements of the fetus’s nuchal fold, an area of tissue at the back of the neck; and the mother’s age.

This last one is perhaps the most well-known risk factor among parents and parents-to-be—it’s common knowledge that as a woman’s age increases, so does her chance of having a baby with a genetic abnormality. Down syndrome occurs when the egg contains an extra copy of chromosome 21. This kind of error is more likely to happen in older eggs, due in part to the decay of proteins within the egg over time.

Here’s what the algorithm doesn’t account for: Extra genetic material can also attach itself to chromosome 21 in the sperm. Scientists agree that Down syndrome can be attributed to the father in 5 to 10 percent of cases, and some believe that number may be as high as 20 percent. As men age, their risk of fathering a child with Down syndrome may increase—the older the man, the more likely that the process of spermatogenesis, or sperm production will go awry, leading to sperm that contain errors like an extra chromosome. In 2003, a study examining New York State health records found that for parents over 40, paternal contribution to Down syndrome could be as high as 50 percent.

“For genetic abnormalities, it’s not just a woman’s problem anymore,” says Harry Fisch, a professor of urology at Weill Cornell Medical College and the study’s lead author. “The fact that couples are waiting longer to have children makes this very significant.”

But the combined test takes only maternal age into consideration, in part because paternal age hasn’t yet been studied enough for it to be accurately used as a risk factor. A father’s age has long been recognized as a factor in relatively rare genetic conditions like Klinefelter syndrome and achondroplasia, or dwarfism—but it’s only in the last 15 years or so that it’s started to receive more research attention, as studies have shown that it may also play a role in better-known conditions like autism and schizophrenia.

“The question is, why aren’t more people looking into this? There’s still much more interest in maternal issues than paternal issues. It takes a long time for a paradigm shift in the way we think,” Fisch says.

While women who have children at age 35 or older are considered to be of “advanced maternal age,” the medical community has yet to define “advanced paternal age,” according to the geneticists Helga Toriello and Jeanne Meck, who co-authored a guideline for genetic counseling for older fathers. “Some studies look at [men] over 40, some over 50, some over 35,” Toriello says. Though research suggests that the paternal-age effect is most significant for fathers over 40, younger fathers may also face an increased risk, possibly because spermatogenesis in very young fathers is more likely to result in the same mutations seen in older fathers. A recent study suggests that a 20-year-old father doubles the chance of Down syndrome as compared to one who’s 40.

But until more is known about the effect of paternal age, it’s difficult to know the true accuracy of the current combined test for Down syndrome. A woman who’s 49 has a one-in-nine chance of having a baby with Down syndrome—but the test doesn’t account for fluctuations in that number based on whether her partner is 24 or 64. And because women often partner with men older than they are, it’s also not clear now much paternal age may have already silently influenced the risk that the combined test assigns to each additional year of a mother’s life.

“You would need to take those 49-year-old women and those that have a 20-something-year-old partner and those that have a 30-year-old partner [and so on] and see what the differences might be,” Toriello says. Fisch’s study comes the closest, but no one has replicated that study with a bigger sample size.

The most accurate risk assessment would take both the maternal and paternal contribution into account, adjusted for the combined age of the mother and the father. “It’s not a maternal issue, it’s not a paternal issue. It’s a parental issue,” Fisch says. “It’s no longer one or the other.”

“The bottom line is that we don’t have a good direction for how to counsel for the effect of paternal age on the mother’s risk,” says Toriello. And the medical professionals who conduct screening tests and interpret the results for patients may not understand the role of paternal age, either. “I think there’s a lot of ignorance in the field,” says Meck. “A lot of OBGYNs don’t understand a lot about prenatal screening. The physicians don’t have the time and they don’t have the full range of knowledge. Those offices that do the best are the ones that have genetic counselors in them.”

But in recent years, some doctors have begun to abandon the combined test and other invasive screening techniques in favor of a newer, noninvasive prenatal test, which uses placental cells floating in the mother’s blood to check for chromosomal abnormalities in the fetus. As this type of testing becomes more widely available, age-based risk assessments may become outmoded. Noninvasive prenatal testing is more accurate than the combined test—with a 93  percent detection rate, as opposed to 82 to 87 percent—and can be performed as early as 10 weeks into pregnancy. Most importantly, noninvasive prenatal testing, which doesn’t rely on any algorithm to assess risk, takes both maternal and paternal age out of the picture. (In the U.S., noninvasive prenatal testing may be offered as an alternative to the combined test, though it may not be covered by insurance.)

Still, outdated beliefs about the egg and the sperm persist in standard clinical practices like the combined test for Down syndrome. When a screening test takes only maternal age into account, it creates the false impression that only maternal age matters for genetic abnormalities—that a woman’s eggs go bad over time, as if they were sitting on a supermarket shelf, while a man continues to produce fresh, robust sperm into old age.

Research has contradicted that idea, showing that while men do produce sperm into old age, their sperm carries more mutations and there’s less of it. “There are a lot of changes that compromise spermatogenesis,” says Patricia Hunt, a reproductive biologist at Washington State University. “It’s like a machine that gets rusty with age.”

In the meantime, scientists are only beginning to understand the effect of paternal age on sperm. “I think we’re just at the tip of the iceberg,” Fisch says. “We have no idea what other paternal-age effects there are.”