Advanced paternal age is associated with an increased risk for high-functioning autistic-spectrum disorder.

The British Journal of Psychiatry (2008) 193: 316-321. doi: 10.1192/bjp.bp.107.045120
© 2008 The Royal College of Psychiatrists



Paternal age at birth and high-functioning autistic-spectrum disorder in offspring
Kenji J. Tsuchiya, MD, PhD
Osaka Hamamatsu Joint Research Center for Child Mental Development, and Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Kaori Matsumoto, MA and Taishi Miyachi, MD, PhD

Osaka Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan

Masatsugu Tsujii, PhD

Osaka Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, and Faculty of Sociology, Chukyo University, Nagoya, Japan

Kazuhiko Nakamura, MD, PhD, Shu Takagai, MD, PhD, Masayoshi Kawai, MD, PhD, Atsuko Yagi, MD, PhD, Kimie Iwaki, MD and Shiro Suda, MD, PhD

Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Genichi Sugihara, MD, PhD

Osaka Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan

Yasuhide Iwata, MD, PhD

Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Hideo Matsuzaki, MD, PhD

Osaka Hamamatsu Joint Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan

Yoshimoto Sekine, MD, PhD and Katsuaki Suzuki, MD, PhD

Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Toshirou Sugiyama, MD, PhD

Aichi Children's Health and Medical Center, Obu, Japan

Norio Mori, MD, PhD

Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

Nori Takei, MD, PhD, MSc

Osaka Hamamatsu Joint Research Center for Child Mental Development and Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan, and Division of Psychological Medicine, Institute of Psychiatry, London, UK

Correspondence: Nori Takei, Osaka Hamamatsu Joint Research Center for Child Mental Development (OHJRC–CMD), Hamamatsu University School of Medicine, Handayama 1 Higashiku, Hamamatsu 431-3192, Japan. Email: ntakei@hama-med.ac.jp

Declaration of interest

None. Funding detailed in Acknowledgements.

Background

Previous studies have reported the association between advanced paternal age at birth and the risk of autistic-spectrum disorder in offspring, including offspring with intellectual disability.

Aims

To test whether an association between advanced paternal age at birth is found in offspring with high-functioning autistic-spectrum disorder (i.e. offspring without intellectual disability).

Method

A case–control study was conducted in Japan. The participants consisted of individuals with full-scale IQ70, with a DSM–IV autistic disorder or related diagnosis. Unrelated healthy volunteers were recruited as controls. Parental ages were divided into tertiles (i.e. three age classes). Odds ratios and 95% confidence intervals were estimated using logistic regression analyses, with an adjustment for age, gender and birth order.

Results

Eighty-four individuals with autistic-spectrum disorder but without intellectual disability and 208 healthy controls were enrolled. Increased paternal, but not maternal, age was associated with an elevated risk of high-functioning autistic-spectrum disorder. A one-level advance in paternal age class corresponded to a 1.8-fold increase in risk, after adjustment for covariates.

Conclusions

Advanced paternal age is associated with an increased risk for high-functioning autistic-spectrum disorder.




Related articles in BJP:


Highlights of this issue
Kimberlie Dean
BJP 2008 193: A14. [Full Text]

Children whose fathers were over 33 were 1.8 times more likely to have autism than those fathers were under 29.

Father age link to autism in children
Older fathers are almost twice as likely to have autistic children as younger men, research has found.

By Rebecca Smith, Medical Editor
Last Updated: 12:31AM BST 01 Oct 2008

A small study of children with autism spectrum disorder, the umbrella term for a range of similar conditions, found they were more likely to have been fathered by men over the age of 33.

There was no link with the condition and the mother's age, the Japanese study found.

The research involved 84 children with high-functioning autism spectrum disorders, meaning they had the social impairments of the condition but had normal intelligence, and 208 children without the disorder.

Children whose fathers were over 33 were 1.8 times more likely to have autism than those fathers were under 29. Men who fathered children between the age of 29 and 32 were 30 per cent more likely to have an autistic child.

The research is published in the British Journal of Psychiatry.

This is the first study to explore the effect of paternal age on the risk of high-functioning autistic spectrum disorder. Its findings correspond with previous studies which have shown a link between older fathers and a low IQ in children.

Benet Middleton, director of communications at The National Autistic Society, said: "The causes of autism are still being investigated. Many experts believe that the pattern of behaviour from which autism is diagnosed may not result from a single cause. Autism affects around one in 100 people in the UK and does not solely affect children of older parents.

"Members of the NAS are made up of parents of children from a variety of ages and backgrounds; in addition there is evidence to suggest that complex genetic factors are responsible for some forms of autism."

Some experts have argued that the measles, mumps and rubella vaccination is linked to the development of autism but this has been widely discredited and other studies have failed to find any link.

Radio waves from cellphones damage sperm, study says

Radio waves from cellphones damage sperm, study says
11:50 AM, September 19, 2008
Attention male cellphone users of reproductive age: Take that phone out of your pocket. Information published today suggests that the radio-frequency energy released by cellphones decreases sperm quality in men.

Last year, researchers from the Cleveland Clinic released a study showing that men who used their cellphones for more than four hours a day had significantly lower sperm quality than men who used their phones for less time. That study, however, did not reveal what might be causing this association. The new study by the same research group, published online today in Fertility & Sterility, took sperm samples from 32 men and divided the samples into two parts for a test group and a control group. The test group specimens were placed an inch from a 850 MHz cellphone that was in talk mode. Measurements taken after the one-hour exposure showed that the sperm exposed to the cellphone contained higher levels of harmful free radicals and a decreased amount of protective antioxidants compared with the unexposed sperm. These factors caused a decline in the sperm's function and motility and in the overall health of the sperm. However, there was no significant difference in damage to the DNA of the exposed cells.
For now, the amount of radio-frequency energy released from cellphones is considered safe. But there are looming questions about the long-term and heavy use of cellphones. Links between brain cancer and cellphones have been suggested, for example. And a recent study found a link between women who used a cellphone in pregnancy and later behavior problems in their children. See this recent L.A. Times Health section story on cellphones and the risk of disease.

Further studies are needed to determine if the results seen in the laboratory sperm samples hold true in men. Many men put their phones in a trouser pocket when using a hands-free device. In the lab, the sperm and cellphone were placed side-by-side. But in real life, the phone and the male reproductive organs are separated by several layers of tissue. Still, men who are planning a family may want to play it safe and keep the active phone a safe distance from their reproductive parts.

"Since many people are now using hands-free sets with their cellphones for various health and safety reasons, it's important that we continue studying this topic to gain a better understanding of the true impact these devices are having on every part of the body," said Dr. Edmund Sabanegh, director of the Center for Male Fertility for the Glickman Urological and Kidney Institute at the Cleveland Clinic.

-- Shari Roan

Photo: More people than ever are using hands-free phone devices or headsets and placing their phones on a belt or in a pocket. Credit: Annie Wells /Los Angeles Times

A Biological Clock for Dads Too Affects Offspring

A Biological Clock for Dads Too
Tuesday, Sep. 09, 2008 By ELIZABETH HOWTON
Turns out women aren't the only ones with an expiration date on their fertility. An emerging body of research is showing that men, too, have a "biological clock."



Not only do men become less fecund as they age, but their fertility begins to decline relatively early — around age 24, six years or so before women's. Historically, infertility has been seen as a female issue, as has the increased risk of Down syndrome and other birth defects, but studies now also link higher rates of autism, schizophrenia and Down syndrome in children born to older fathers. A recent paper by researchers at Sweden's Karolinska Institute found that the risk of bipolar disorder in children increased with paternal age, particularly in children born to men age 55 or older.

It used to be that "if you had hair on your chest, it was your wife's problem," says Barry Behr, an associate professor of obstetrics and gynecology at the Stanford Medical School and director of Stanford's in vitro fertilization laboratory. Even now, he said, though about half of infertility cases are caused by male factors, such as low sperm count or motility, there are many more tests to evaluate a woman's fertility than a man's.

To some degree, that bias is rooted in biology. Women are born with as many eggs as they'll ever have — about a million. That number steadily diminishes, and "the best eggs are ovulated first," Behr says. The ones that remain — after age 35 or so, on average — are vulnerable to toxins, radiation and other insults that may degrade their quality and viability.

By contrast, men make new sperm about every 90 days, Behr says, so the logic has been that there should not be that much difference between a young man's sperm and an old man's. Indeed, men as old as 94 have been known to father children.

Still, the research suggests it gets harder with age. A French study published in the current issue of Reproductive BioMedicine Online found that in couples undergoing infertility treatment, the father's age had as much effect as the mother's on rates of pregnancy and miscarriage — the older either parent was, the less likely they were to get pregnant, and the more likely to miscarry. Other studies have found similar trends: on average, it will take longer than a year to conceive for 8% of couples in which the man is younger than 25; that percentage nearly doubles, to 15%, in couples with men 35 or older. Data have also suggested that couples whose partners are the same age, or in which the man is younger than the woman, are more likely to conceive within a year, compared with couples in which men are at least five years older than their partners.

There are many possible explanations for the decline in male fertility, from a decrease in the number of sperm and their motility, to lower testosterone levels, to the effects of other age-related diseases such as diabetes, which is associated with erectile dysfunction and lower levels of testosterone. But researchers think that genetic factors may be behind the link between paternal age and risk of bipolar disorder and other psychiatric disorders, like autism and schizophrenia, whose origins are increasingly being attributed to DNA. Although sperm may be no more than 90 days old, the cells that make sperm may be subject to increasing DNA mutations as men age, affecting the quality of the sperm they produce.

In the Swedish study, published Sept. 1 in the Archives of General Psychiatry, researchers found that risk of developing bipolar disorder began to increase in children born to fathers around age 40. The highest risk, however, occurred in men 55 and older; their offspring were 37% more likely to develop the disorder than children born to men in their 20s. Children of older men were also twice as likely to develop early-onset disease — before age 20 — which studies suggest has a strong genetic component.

What does all this mean for would-be older dads? While women are used to seeing grim statistics about their decreasing chances of achieving pregnancy and the increasing risks of Down syndrome as they age, men have typically believed they had all the time in the world. Perhaps now, men in the mid-30s will start sharing the same "now or never" pressure to conceive that women have long endured.

When older men father children, Behr says, the traditional response has been to "pat them on the back and buy them a beer." He has seen patients that he felt were too old to become fathers, but "plenty of people make decisions about parenthood that I wouldn't," he says. "Our responsibility is to educate patients with the facts, and they decide."

Bipolar Disorder Tied to Age of Fathers

Bipolar Disorder Tied to Age of Fathers

By NICHOLAS BAKALAR
Published: September 8, 2008
The older a man is, the more likely he is to father children who develop bipolar disorder as adults, a large Swedish study reports.



Get Health News From The New York Times » Previous studies have found an association between paternal age and both autism and schizophrenia, but this is the first time a connection with bipolar illness has been suggested. The study appears in the September issue of The Archives of General Psychiatry.

The researchers examined highly accurate Swedish government health records of more than seven million people with known biological parents to find 13,428 with bipolar disorder diagnosed at two or more separate hospital admissions. They matched each case with five controls, people of the same age and sex but without bipolar illness. They divided the fathers into five-year age categories beginning at 20.

After statistically adjusting for the age of the mother, family history of psychotic disorders, education level and other factors, they found consistently increasing risk as fathers aged. The highest risk was in fathers 55 and older. For mothers, after adjusting for the father’s age, they found a statistically significant increase in only the 35 to 39 age group.

“It’s a strong study from a methodological standpoint,” said Dr. Alan Brown, an associate professor of psychiatry at Columbia who was not involved in the study. “National registries are very important because you’re less likely to get bias and you can generalize findings across a whole country.”

David Glahn, an associate professor of psychiatry at Yale, also uninvolved in the work, agreed. “The methodology is very strong,” he said. “The statistics done here are all first-rate.”

There is a possible biological explanation for the phenomenon, the authors write. The older a man is, the more often his sperm cells have replicated, and the more replications, the greater the chance for DNA copying errors. These are random changes, called de novo mutations, that are not inherited. Women are born with a complete supply of eggs that do not replicate as they age. The finding of only a small effect of mother’s age on the incidence of bipolar illness in the offspring is consistent with this idea.

Emma M. Frans, a doctoral student in epidemiology at the Karolinska Institute and the lead author of the study, said in a phone interview that the findings applied to adult offspring only, not children. Bipolar illness is a rare disease in any age group; in community samples the prevalence varies from 0.4 percent to 1.6 percent of the population. Still, the risk of bipolar disease in the offspring of the oldest fathers was 35 percent higher than for those of the youngest, and the association was even stronger in the small number of cases in the study diagnosed before age 20.

Dr. Dolores Malaspina, a professor of psychiatry at New York University who has studied schizophrenia in the offspring of older fathers, called the new study “very important,” but added: “The vast majority of children of any fathers will not get bipolar illness. At the level of the whole population, it may be important, but for the individual father it’s a small risk.”

1: Reprod Biomed Online. 2008 Sep;17(3):392-7.Effect of maternal and paternal age on pregnancy and miscarriage rates after intrauterine insemination.Belloc S, Cohen-Bacrie P, Benkhalifa M, Cohen-Bacrie M, De Mouzon J, Hazout A, Ménézo Y.
Laboratoire d'Eylau, 55 rue Saint Didier, 75116 Paris, France; Unité AMP Eylau La Muette, 46-48 rue Nicolo 75116, Paris, France; Unité AMP Eylau Cherest, 5 Rue Pierre Cherest 92200 Neuilly sur Seine, France.

More than 17,000 intrauterine insemination (lUI) cycles were analysed retrospectively with respect to outcome according to differing aetiologies of infertility. The quantity and motility of spermatozoa in the final preparation used for insemination had a positive effect on the outcome, as classically observed in the past. It was found that advanced maternal age had a negative effect on the pregnancy rate and was associated with increased miscarriage rate. More interestingly, an exactly parallel effect was found for paternal age. The impact of increased age on necrospermia and sperm DNA structure is discussed as a probable direct cause of this paternal effect.

PMID: 18765010 [PubMed - in process]