More than a dozen years after fertility specialists learned to turn all-but-sterile men into fathers, scientists are awaiting answers to a looming question: What about the sons?
The first few babies born using a process that transformed male infertility by allowing doctors to use sperm from men with impossibly low counts and other problems are now turning 15. An even larger crop of so-called “ICSI babies,” children conceived with the help of intracytoplasmic sperm injection and in vitro fertilization, or IVF, are just approaching adolescence.
For the daughters born to these dads, there appears to be little problem. Research suggests that, in general, techniques such as IVF and ICSI are safe and effective, although some scientists say there's not enough data to be sure. One of the central concerns centers on the possibility of chromosomal abnormalities leading to male infertility.
As puberty kicks in, scientists believe they may start to see sons who’ve inherited the problems of their fathers, an issue that many couples may not have considered in their quest to have children.
“This is the generation we’ve created,” said Dr. Tommaso Falcone, who chairs the obstetrics and gynecology department at the Cleveland Clinic and directs the Reproductive Endocrinology Research Laboratory. “We may have tens of thousands of boys born with infertility.”
Genetic fallout for ICSI sons is still a largely unexplored issue in the field of infertility, which affects an estimated one in eight couples in the United States, or about 7.3 million people, according to RESOLVE, a national infertility group. Up to 40 percent of cases are attributed to problems with the man, including damaged sperm, low sperm or no sperm at all.
Of the more than 52,000 babies born using IVF in the U.S. each year, between 8,000 and 9,000 are the offspring of male factor fathers, according to Falcone.
“We tell parents there could be a genetic cost to this,” he said.
Basic facts about infertility are fueling scientists' concerns. In women, infertility is most often caused by a physical problem such as blocked fallopian tubes or scar tissue caused by endometriosis, issues that aren't likely to be inherited by their daughters . When IVF was pioneered three decades ago, it solved many of those problems by providing a way to get the sperm and egg together outside the woman.
In men, however, it's not so clear cut. Doctors don't know what causes infertility in about half the cases, but think that many men's infertility problems may be rooted in their genes.
Last year, Danish researchers reported that levels of the male sex hormone testosterone were lower in baby boys produced through ICSI than in those conceived naturally. Until more boys mature, however, they can't be certain if that will hold true in older kids or what form other problems might take.
The whole issue raises the science-fiction prospect of a society in which many men can’t father children naturally. According to one estimate in the journal Nature Genetics, if even half of affected men used ICSI to have kids, the incidence of severe male factor infertility could double nationwide within seven generations.
But it also raises more practical questions for the families of the boys who might be affected: How do they feel about transmitting the struggles of infertility to their sons? And what do they tell the kids about the birds and the bees?
“The puberty talk is usually: ‘You can get someone pregnant,’” Falcone said. “But with these boys, you can't.”
No different than getting glasses, dad says
At least one father of a boy born after using ICSI said he’s not worried, even if he did pass on a genetic trigger for infertility, because there are increasingly successful treatments to deal with it.
“The basic feeling I have is that it’s like eyeglasses now,” said the father, a 41-year-old professor at a well-known eastern university, who has two ICSI children, a son, 6, and a daughter, 4. “Generations ago, if you had bad eyesight, it was a problem. Now, it’s just not anymore.”
The father agreed to discuss his son’s future fertility only anonymously because it’s such a sensitive issue. “I don’t want his girlfriend googling him when he’s 13 and finding out his father’s infertile,” he said.
The professor and his wife turned to ICSI nearly a decade ago after trying unsuccessfully to become pregnant for more than a year. Tests showed that he had a sperm count far below the 20 million per milliliter necessary for normal conception.
“It was in the 100s or the single digits. I don’t think they count that low,” he said. “But all it takes is one.”
Indeed, his wife got pregnant on the first cycle with their son, using ICSI, the procedure that snags a single live sperm and injects it directly into the center of a human egg. The technique even produced embryos to spare. They froze four and, three years later, conceived their daughter from the same batch.
“The whole process of treating infertility is no big deal in the grand scheme of things,” he said.
In the early-to-mid 1990s, scientists developed the ICSI technique. The first babies were born in 1993; many more have followed.
In general, between 70 percent and 85 percent of eggs are fertilized in an ICSI procedure, resulting in a pregnancy and birth rate of about 43 percent. The New England couple was fortunate in their experience, but the dad said by the time his son requires treatment, if he does, the success rate likely will be much higher.
Even now, ICSI is now used in 62 percent of all IVF cases and in 86 percent of male factor infertility cases, according to 2006 statistics, the latest available, from the Society for Assisted Reproductive Technology.
Specialists worry, however, that some sons and even grandsons may inherit genetic problems, such as the microdeletion of a gene on the Y chromosome; troubles with androgen receptors that help regulate certain sex characteristics; or congenital problems, such as the absence of the vas deferens, the tube that connects the testes with the urethra.
Little research exists about the potential problems, primarily because the children haven’t been mature enough to test. Once enough boys begin producing sperm and agree to be studied, scientists say they'll learn more.
Unknown problems worry docs
In the meantime, they worry about problems that remain undetected, said Dr. Pasquale Patrizio, director of the Yale Fertility Center.
“We are helping men to have a baby, but we don’t know why they don’t make sperm,” he said.
Parents considering treatment might benefit from a session with a genetic counselor to talk about their child’s future fertility, among other issues, noted Steven Keiles, president-elect of the National Society of Genetic Counselors. Early analysis can flag potential problems that parents might not have considered.
"I'm not so sure people think that far ahead," Keiles said.
Other specialists caution, however, that parents who use ICSI and IVF shouldn’t worry that the procedures will result in a child with an abnormality.
“We wind up having these discussions and people suddenly panic and wonder what they’ve done,” said Dr. Howard Zacur, director of the Division of Reproductive Endocrinology and Infertility at the Johns Hopkins University School of Medicine.
Nor should parents imagine that specialists are seeking to create their next generation of customers.
"I can't even remotely think that way," said Zacur. "You're really trying to help a couple. You're really giving them a chance to have a child."
Still, it is important that parents understand the real risk that genetic problems — including infertility — may be inherited and consider every option, warns Art Caplan, director of the Center for Bioethics at the University of Pennsylvania and an msnbc.com columnist.
"It is true that future fertility techniques may well be able to help a sterile or near-sterile child reproduce but that may be an outcome that parents do not want to risk and they may instead turn to a known-to-be-fertile sperm donor," he said. "I think every program using ICSI should disclose this possible set of risks and offer alternatives including anonymous or identified sperm donation."
Specialists and parents say there are no rules about when — and if — to tell a child about potential fertility problems. Like all information about the circumstances of conception and birth, it depends on the age and maturity of the kid.
Although it would be possible to test the boys' sperm count when they reach adolescence, few doctors now recommend that. Zacur said he doesn't even advise routine screening for certain root causes of infertility in his male patients because the tests can be expensive and inconclusive — and they don't alter the final treatment.
The professor father of the ICSI boy said he likely won’t tell his son about potential problems until he’s grown and facing questions of fatherhood. And it certainly won’t be part of early adolescent discussions of sex.
“I just don’t see any reason to burden him with this concern,” the dad said. “If you know about it, you alter your behavior.”
When he does divulge the news, he’ll likely remind his son — and his daughter — that any problems likely can be corrected through the technology and medicine that created their family.
“I do sometimes imagine have how sad it would have been to have been born in an earlier era,” he said. “There are an awful lot of people who wouldn’t have been around without this.”