THE MALE BIOLOGICAL CLOCK:

New study shows connection between father's age and Down syndrome According to the study’s author, Harry Fisch, M.D., director of the male reproductive center at Columbia Medical Center and associate professor of urology at Columbia University College of Physicians and Surgeons, older men who have children with older women may be at increased risk of having babies with Down syndrome (clinically called trisomy 21 — for its trademark extra 21st chromosome, creating three where there should be a pair). The most common genetic abnormality in babies of older mothers, Down syndrome occurs in 1 out of 800 to 1,000 births, according to the federal Centers for Disease Control and Prevention. The Columbia study is the largest data set ever examined: 3,419 cases of Down syndrome babies born in New York State between 1983-1997, to mothers over age 35, using data from the New York State Department of Health Congenital Malformation Registry, the report says. During the 15-year period, Dr. Fisch points out, “There’s a marked increase in the number of men and women over 30 having children." In 1983, 7 percent of all births were to women over 35; in 1997, it was 17 percent. There was a 111 percent increase in the number of mothers 35 years and older, and a 60 percent increase in the number of 35-plus-year-old fathers during the decade-and-a-half period. While various studies of Down syndrome have been conducted in recent years, this is the first to show clear evidence that advanced paternal age plays a role in the incidence of Down syndrome, when combined with advanced maternal age, according to the report, which appears in the June 2003 issue of the Journal of Urology. “In younger women, for whom maternal age was not a risk factor for Down syndrome, there was no paternal effect,” Dr. Fisch explains. But as the age of the mother increased, the impact of the father’s age on Down syndrome rose significantly, showing its greatest effect in couples older than 40 years, where the risk of Down syndrome was six times the rate in couples younger than 35 years, Dr. Fisch says. The group with the largest percent increase in parental age during the 15 years was men and women over 40, Dr. Fisch says. “As a fertility doctor, I’m asked every day by older couples, ‘Are we at higher risk of having genetic problems?’ That’s why I did this study,” says Dr. Fisch, adding that the results may represent “a new paradigm for other genetic abnormalities in children of older fathers. The findings are really dramatic.” And not unexpected, fertility experts say. “We know that sperm count goes down in a man with age; we know that there is often an increase in abnormal sperm with age. There have been a number of prior studies that have basically proved equivocal results. But no one has ever tied it up as nicely as this in terms of a disease state,” says Susan Benoff, M.D., director of the Fertility Research Laboratories at the North Shore–Long Island Jewish Research Institute in Manhasset, N.Y., and an expert in “unexplained” male infertility. “The paradigm shift, with the idea that with age, normal looking sperm might be accumulating defects that could lead to chromosomal abnormalities in the offspring, makes a lot of sense,” Dr. Benoff says. “The fact that for the first time someone’s looking at the relationship between male age, female age and problems in the offspring, I think is very, very important,”

Both male-female factors play key role in fertility problems, data shows Our ever-evolving society is a key factor in this paradigm shift, medical experts say. “It’s a well-known recent phenomenon that the maternal age at first birth and subsequent birth is increasing,” says Mark Ehrenpreis, M.D., a Forest Hills urologist and an assistant professor at New York Medical College. “I’ll see a couple with teenage kids, for example, and now they want more children. Or I’ll see a man in his mid-40s who’s remarried, and his new wife wants kids.” Dr. Ehrenpreis says he typically won’t see a couple until they’ve had an infertile relationship for at least six to 12 months. “I feel that infertility is a couple’s issue, and both the male and the female should be seen by a competent physician during the evaluation process." It’s not only a woman’s problem, he contends. “One of the things that has struck me all along is how under-served the man is overall,” Dr. Benoff says. “You’re always looking at female factors when you’re talking about infertility. We know that there are problems in the male — this just points it out.” However, Gerald Matthews, M.D., chief of the section of male reproductive urology at New York Medical College and an expert in male sexual dysfunction, cautions: “These data don’t necessarily support that male age in and of itself is an independent factor in the risk of Down syndrome. It’s only in combination with an older female partner.” Couples where the male partner is over 40 and the female is under 35 shouldn’t be alarmed that their risk is greater, he says, because male age is not an independent variable. “I’ve always viewed fertility problems as a couples’ phenomenon,” Dr. Matthews adds. “It takes two. It takes a man and a woman to initiate a pregnancy, and viewing this as a problem with men or a problem with women overlooks the broader picture.” While young couples can also face fertility issues, these increase significantly for older couples. “Today, folks are delaying marriage and delaying families for any number of reasons, but certainly the average age of folks looking to be parents is increasing to a much greater extent as compared to even just a couple of generations ago,” Dr. Matthews points out. “We know clearly that as couples do get older, there are increasing risks with pregnancy, increasing risks of genetic abnormalities, and increasing difficulty in getting pregnant in the first place.”

Advanced paternal age associated with other genetic abnormalities The Columbia study, Dr. Fisch says, “takes a lot of the blame away from women, as well as the feelings of guilt many women experience when they have children with genetic abnormalities." The medical community, he says, is beginning to realize that the concept that men can be older and have children without any regard is wrong. "We need to shift our focus of research to see how men are actually affecting a woman’s health, at least as it pertains to genetic abnormalities. I’m sure we need to study it all over to confirm this, and I think we need more and more research into this field. It’s a topic that has not been touched, and I call it a public health concern.” While the study focused on Down syndrome, its author acknowledges there could be many other smaller genetic problems associated with advanced paternal age — learning disabilities, for example. "We now realize that babies born to older couples may be at higher risk of genetic abnormalities than we ever thought. There are consequences to waiting longer to have children, for men as well as women. This study may give us a clue that we may be doing this to ourselves,” Dr. Fisch says. The environment may be a factor as well, says Dr. Benoff, who is interested in the role of the environment on male infertility. In a recent study of the semen of 140 men whose partners were undergoing in vitro fertilization, she found a “convincing link” between high seminal lead levels and male infertility. While lead exposure is an occupational factor for men who work as painters, plumbers or landscapers, behavior such as smoking, drinking alcohol and failing to exercise also affect lead levels. Lead is just “one of the potential environmental exposures that could cause infertility,” Dr. Benoff says. And is there an interaction between these environmental toxins and the male Biological Clock? “We don’t know yet,” Dr. Benoff concedes. “If a man is older, might he be more susceptible to a level of lead that might not affect a younger man? Well, that’s a possibility, but we haven’t studied it yet.” Clearly, Dr. Fisch stresses, older couples need to be aware that they are at a higher risk of having children with some problems, "and they have to deal with the situation as it arises. "But," he says, "as a doctor, I know that preventive medicine is always best, and people need to be aware when they’re younger that these issues do exist.”

Study: Increased Health Risks Seen for Babies Born Via Assisted Reproduction Techniques

By Barbra Williams Cosentino, R.N., C.S.W. Significant advances in infertility treatments have brought untold joy to the thousands of couples who have finally been able to attain their dream of becoming parents. However, new research reveals that there may be a downside to the widespread use of these treatments. According to a study published in a recent issue of the Journal of Medical Genetics, children who are conceived through assisted reproductive techniques (ART) such as in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) are up to four times more likely to suffer from a rare genetic disorder known as Beckwith-Wiedemann syndrome (BWS), which usually affects between two and five children in 100,000. In the study of 149 children with the disorder, six of the youngsters — or 4 percent — had been conceived via assisted conception methods, a number that was significantly higher than expected. BWS is a syndrome manifested by overgrowth (increased birth weight, height and head circumference), omphalocele (failure of the abdominal wall to properly close over the internal organs), macroglossia (enlarged tongue), low blood sugar and asymmetric enlargement of body parts. Other distinctive features of children with the disorder include earlobe creases with pits, or low set ears, large prominent eyes, a ridge in the forehead, an enlarged fontanelle (soft spot), and undescended testicles. Babies born with BWS tend to have early bone maturation and accelerated growth in the 90 percent or above percentile; cardiovascular abnormalities are seen in approximately 15 percent of patients. (Puberty and sexual maturation tend to occur around the normal time, and the abnormally fast growth rates seen in younger children begins to normalize in adolescence). The incidence of BWS is approximately equal in males and females. It is generally accepted to be a genetic disorder, with the gene for the syndrome located on the short arm of chromosome 11, near a gene that has a major impact on fetal growth. The condition results from aberrations in the genes which undergo imprinting, a process which leads to certain genes acting differently depending on whether they are inherited from the mother's or father's side. Dr. Wolf Reik, a developmental geneticist at the Babraham Institute in Cambridge, England, who conducted the recent study, notes that imprinting normally occurs when the sperm or egg is produced, and that ART appears to interfere with the normal imprinting process. The activity of the paternal imprinted genes is increased while the maternal genes (which normally regulate fetal growth) are deactivated, thereby increasing the risk that the child will develop the syndrome. Infants born with BWS are frequently born with hypoglycemia (low blood sugar). Although mild mental retardation has been reported as a possible complication of BWS, it appears that this may be due to uncontrolled low blood sugar during infancy, rather than as a result of a congenital malformation of nervous tissue. Early diagnosis of hypoglycemia and treatment with intravenous glucose can enhance the likelihood of normal cognitive development, and, in fact, the majority of youngsters with the disorder are of average or above intelligence. BWS may be considered as a possible diagnosis if abdominal abnormalities are detected as a result of ultrasound testing conducted during the prenatal period or if polyhydramnios (excessive amniotic fluid) is present. Perinatal BWS is associated with a relatively high incidence of prematurity; some studies reveal that approximately 50 percent of babies with the disorder are born between the 30th and the 38th week of pregnancy. Prematurity, along with congestive heart failure, sleep apnea, and infantile respiratory distress syndrome contribute to an infant mortality rate, which may be as high as 21 percent. When BWS is suspected in a newborn, a variety of tests (including bone X-rays, ultrasound or X-rays of the abdomen, MRI scans, blood tests and chromosome studies) may be performed to help confirm the diagnosis. Lab results may show evidence of hypothyroidism, low calcium levels, abnormally high numbers of red blood cells, and high blood cholesterol and insulin levels. Recognition of BWS is important not only because of the need for early stabilization of blood sugar, but also because patients with the disorder need careful monitoring since they are at an increased risk of developing certain types of cancers. According to a previous study published in the journal Clinical Pediatrics, the prognosis for long-term survival of BWS babies is favorable as long as neonatal complications such as apnea, seizures, low blood sugar, and respiratory and feeding problems are addressed. (Infants with the disorder may have trouble feeding, sleeping and breathing due to the presence of an enlarged tongue). Because almost 10 percent of patients with BWS develop malignant tumors (particularly Wilm's tumor of the kidney, adrenal carcinomas and liver cancer), long-term survival is also dependent on the early detection and treatment of these tumors. Michael R. DeBaun, M.D., M.P.H., a pediatric oncologist at St. Louis Children's Hospital and principal investigator for the BWS Registry, points out that although the majority of children who develop Wilm's tumor do so before their fourth birthday, it can develop in youngsters up to 7 or 8 years of age. Dr. DeBaun recommends a screening protocol that includes frequent ultrasound exams of the kidney and liver, and monitoring AFP (alpha-feta protein) levels, which tend to rise in children with cancer of the liver. Pediatric pathologist Bruce Beckwith, M.D., of the Beckwith-Wiedemann Support Network medical advisory board, has been conducting longitudinal studies following youngsters with the disorder that bears his name for the past 25 years. Dr. Beckwith reports (online at Beckwith-Wiedemann Syndrome Family Forum; www.geocities.com/beckwith_wiedemann) that the majority of adolescents or adults who were diagnosed with the disorder as children have grown up to be normal in appearance. Many of the features that appear distinctive in early childhood, such as the large tongue, tend to diminish in time, he says. The three points he emphasizes to parents of newly-diagnosed cases are straightforward and reassuring: — The usual complications of BWS can usually be anticipated and can almost always be successfully managed. • The older they become, the more normal they become. • Most affected offspring have the disorder in such a subtle form that it does not alter their quality of life. Study Finds More Incidence of Eye Cancer in In-Vitro Babies Another study reported in a recent issue of the British medical journal, Lancet, suggests that babies born after in-vitro fertilization are between five and seven times more likely to suffer from retinoblastoma, an eye cancer which usually leads to blindness. The Dutch findings were tentative, but significant, because they were reported very soon after the discovery of the higher risk of Beckwith-Wiedemann syndrome for children born after IVF. David Ben Ezra, M.D., of the Hadassah Hebrew University Hospital in Jerusalem, states that the increased risk of retinoblastoma appears "unprecedented and alarming" and emphasizes the need for a heightened awareness of other possible problems, coupled with close follow-up of those children conceived through assisted reproductive techniques. Researchers further speculate that babies created through cloning would also have an increased risk of developing Beckwith-Wiedemann syndrome because, similar to assisted reproductive techniques, cloning methodologies interfere with the imprinting process which controls the activity of certain genes involved in the growth of the fetus.