Scientists reveal dangers of older fathers

Scientists reveal dangers of older fathers
By Laura Donnelly, Health Correspondent
Last Updated: 10:18PM BST 31/05/2008
Children are almost twice as likely to die before adulthood if they have a father over 45, research has shown.
A mass study found that deaths of children fathered by over-45s occurred at almost twice the rate of those fathered by men aged between 25 and 30.

Scientists believe that children of older fathers are more likely to suffer particular congenital defects as well as autism, schizophrenia and epilepsy. The study was the first of its kind of such magnitude in the West, and researchers believe the findings are linked to the declining quality of sperm as men age.

A total of 100,000 children born between 1980 and 1996 were examined, of whom 830 have so far died before they reached 18, the majority when they were less than a year old.



The deaths of many of the children of the older fathers were related to congenital defects such as problems of the heart and spine, which increase the risk of infant mortality. But there were also higher rates of accidental death, which the researchers believe might be explained by the increased likelihood of suffering from autism, epilepsy or schizophrenia.

Most research into older parents has, until now, focused on the risks passed on by older mothers. But the new study, published in the European Journal of Epidemiology, was adjusted to take account of maternal age and socio-economic differences.

The research also found higher death rates among children of the youngest fathers, especially those below the age of 19. However, the study said these differences were explained by the risks of teenage motherhood and poorer diet and lifestyle.

Previous research using the same data found that older men were four times as likely to father a child with Down's syndrome, while other studies have found that the genetic quality of sperm deteriorates as men age.

More than 75,000 babies in Britain are born to fathers aged 40 and over each year, or more than one in 10 of all births. This includes more than 6,000 born to fathers aged 50 or over. The average age of fathering a child in this country is 32.

Dr Allan Pacey, senior lecturer in andrology – the medical specialty dealing with male reproduction – at the University of Sheffield, said: "A lot of people know that there are risks for the child that come from having an older mother, but children of older fathers also carry an increased risk. These sorts of results provide another good reason to have children early, when possible."

Dr Pacey, who is secretary of the British Fertility Society, said scientists were unsure exactly what impact the ageing process had on the quality of sperm, making it impossible to detect defects before conception.

Dr Jin Liang Zhu, from the Danish Epidemiology Science Centre, which carried out the research, said: "The risks of older fatherhood can be very profound, and it is not something that people are always aware of."
The mother's age still has the bigger impact on child health, however. About one in 900 babies born to women under 30 have Down's syndrome – a figure which reaches one in 100 by the age of 40. The number of over-40s giving birth in Britain each year has doubled in the past decade to 16,000. The risk of miscarriage rises sharply with age.

Spontaneous Mutations are they due to Older Paternal Age

Spontaneous Mutations Rife in Non-Familial Schizophrenia
Non-Hereditary Genetic Variations May Help Explain Illness’s Evolutionary Staying Power

People with schizophrenia (http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml) from families with no history of the illness were found to harbor eight times more spontaneous mutations — most in pathways affecting brain development — than healthy controls, in a study supported in part the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH). By contrast, no spontaneous mutations were found in people with schizophrenia who had family histories of the illness.

"Our findings strongly suggest that rare, spontaneous mutations likely contribute to vulnerability in cases of schizophrenia from previously unaffected families," said Maria Karayiorgou, M.D., of Columbia University, who led the research team. "This may also shed light on why the illness has frustrated efforts to implicate gene variants with major effects, and seems to defy natural selection by persisting in the population even though relatively few of those affected have children."

Karayiorgou and her colleagues report on their whole genome study online in Nature Genetics, May 30, 2008.

"Such abnormal deletions or duplications of genetic material are increasingly being implicated in schizophrenia and autism (http://www.nimh.nih.gov/science-news/2008/autism-gene-scans-converge-on-two-suspect-sites-two-types-of-genetic-risk.shtml)," explained NIMH Director Thomas R. Insel, M.D. "Now we have a dramatic demonstration that genetic vulnerabilities for these illnesses may not be inherited from parents, at least in the sense that these vulnerabilities were not present in the parental genome. This line of research holds promise for improved treatments — and perhaps someday even prevention — of developmental brain disorders."

Although it's known that genetics plays a major role in the transmission of both autism and schizophrenia, most cases are sporadic rather than familial.

Echoing findings of another recent study (http://www.nimh.nih.gov/science-news/2008/rates-of-rare-mutations-soar-three-to-four-times-higher-in-schizophrenia.shtml), Karayiorgou and her colleagues determined that most of the suspect mutations were not random, but found in genes and pathways involved in brain development. However, whether a mutation was spontaneous or inherited was not determined for most of the subjects included in the earlier study.

To pinpoint the sources of the glitches, the researchers in the new study compared genetic data from 369 subjects with data from their biological parents — in a total sample of 1,077 individuals drawn from the European ancestry Afrikaner population in South Africa. Including parental genes makes it possible to definitively determine what’s inherited.

Scans of each person's genome detected the spontaneous mutations in 15 of 152 individuals (10 percent) with non-familial schizophrenia, and only in two of 159 people (1 percent) without the illness — the eight-fold difference. Such sporadic cases were only 1.5 times more likely than controls to harbor inherited mutations.

The researchers also found three deletions of genetic material at a site on chromosome 22 previously implicated in schizophrenia, confirming it as the only known recurrent such mutation linked to schizophrenia. In addition to NIMH, the current study also cites support from the NIH’s National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Eye Institute, and the Lieber Center for Schizophrenia Research at Columbia University.

The National Institute of Mental Health (NIMH) mission is to reduce the burden of mental and behavioral disorders through research on mind, brain, and behavior. More information is available at the NIMH website, http://www.nimh.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.


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Reference:
Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat Genet. 2008 May 30. [Epub ahead of print] PMID: 18488028

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Why Has Francis Collins Not Warned About the Paternal Age Effect?

Chief geneticist steps down
Collins credited with setting stage for medical progress
By Jonathan D. Rockoff | Sun reporter
May 29, 2008 WASHINGTON - The government's leading geneticist announced yesterday that he is stepping down after 15 years spent paving the way for the growing role that DNA will play in medical care.

As director of the National Human Genome Research Institute, Dr. Francis S. Collins led the successful effort to sequence the human genome and helped secure a new law, signed just last week, barring discrimination based on genetic information. He also shepherded significant advances in understanding the genetic causes of common diseases, while attempting to reassure a public concerned about the ethical implications of the fast-moving developments.

"He has put us where we can now move from the genome to health - to use the fruits of the human genome project to improve the health of American citizens," said Dr. Joe Leigh Simpson, president of the American College of Medical Genetics.

Collins, 58, is known as a top-notch scientist who can translate complicated details into ordinary language, a government official equally adept on C-SPAN and Comedy Central's Colbert Report. As head of the genome institute, he pushed for various projects, including the sequencing of the human genome, initially viewed as time-consuming and costly, with a relentless and ultimately accurate optimism about their prospects.

Fewer Boys Born In Industrialized Nations

Fewer Boys Born In Industrialized Nations
A review of birth rates from several industrialized nations shows that the number of male births has declined significantly in the past few decades. Researchers say this change may be tied to increases in male reproductive health problems.
Researchers from the World Resources Institute in Washington, DC, looked at data from Denmark, the Netherlands, Canada and the US, and found similar declines in the sex ratio, or the number of male births per female births, in these countries. For example, from 1970-1990 in the US, the reported decline of 1 male birth per 1,000 births resulted in 38,000 fewer male births. And in Canada, the decline of 2.2 male births per 1,000 births resulted in 8,600 fewer boys being born during the same period.
"Such small changes... can have profound implications for large populations, where hundreds of thousands or millions of births occur each year," write Devra Lee Davis and fellow researchers in The Journal of the American Medical Association.
The investigators explain that several factors influence whether a fetus, which starts out female, becomes male. Exposure to hormones, older age of fathers, use of fertility drugs, hepatitis and non-Hodgkin's lymphoma may all reduce the proportion of male fetuses. Workplace and environmental factors such as "...exposure to smelting operations, pesticides, inorganic borates, lead, solvents, (and) alcohol" have also been linked to reduced male populations.
In addition to the concerns about the reduced male birth rates, Davis and colleagues note that disorders of the male reproductive tract, such as hypospadias (an abnormality of the penis where the urethra opens on the underside rather than at the tip) and cryptorchidism (a condition where the testes don't descend normally) are becoming more common. The researchers suggest there is a link, and theorize that prenatal exposures may affect men's overall health and development.
The authors call for additional studies about birth rates by state, region and nation. "The potential repercussions of conditions that may alter the ratio of the sexes at birth should be considered a matter of utmost concern," they write.
SOURCE: The Journal of the American Medical Association

[Congenital malformations in children born after IVF]

Harefuah. 2005 Dec;144(12):852-8, 910.
Links
[Congenital malformations in children born after IVF]
[Article in Hebrew]
Hellmann O, Bentov Y.
Physical Therapy Department, Faculty of Health Science, Ben-Gurion University, Beer Sheva. hellmann@walla.co.il
BACKGROUND: Major congenital malformations are a leading cause of perinatal morbidity and mortality. Congenital malformations are caused by three factors: genetic, environmental or multifactorial, all of which are present in the context of artificial reproductive techniques. FINDINGS: In 1999 Bergh et al. conducted a retrospective study, which included all the children born following IVF treatment in Sweden. The relative risk found was RR = 1.39 [95% CI 1.25-1.54] and there was no stratification for maternal age and parity. In 2002 Hansen et al. conducted a well-established retrospective study in Western Australia. When only term singletons were included in the study, the OR found was OR = 2.1 [1.4-3.2] in the IVF group and OR = 2.2 [1.2-4] in the ICSI group. Results were stratified for maternal age, parity and offspring sex. A meta-analysis of 19 studies found a relative risk of 1.29 for major malformations among IVF pregnancies. DISCUSSION: Explanations for the increased risk of fetal malformations could be divided into three categories: first, the characteristics of the infertile population which include many risk factors: older age, lower parity, chronic diseases and infertility itself. Second, the techniques used to treat infertility are not physiologic. Third, the characteristics of the pregnancy achieved: the incidence of high-order pregnancies is much greater and this fact exposes the offspring to other risk factors such as preterm birth and low birth weight. CONCLUSIONS: Major advances in reproductive techniques offered hope for many couples, but they were also the reason for much concern regarding the outcome of the awaited offspring. The recent studies seem to justify some of those doubts.

Growth and schizophrenia: aetiology, epidemiology and epigenetics.

1: Novartis Found Symp. 2008;289:196-203; discussion 203-7, 238-40.
Growth and schizophrenia: aetiology, epidemiology and epigenetics.
Malaspina D, Perrin M, Kleinhaus KR, Opler M, Harlap S.
Department of Psychiatry, New York University School ofMedicine, New York, NY 10016, USA.
There is a strong genetic component for schizophrenia risk, but it is unclear how the illness is maintained in the population given the significantly reduced fertility of those with the disorder. One possibility is that new mutations occur in schizophrenia vulnerability genes. If so, then those with schizophrenia may have older fathers, since advancing paternal age is the major source of new mutations in humans. We found that paternal age at conception is a robust risk factor for schizophrenia, explaining perhaps a quarter of all cases. The predisposing genetic events appear to occur stochastically in proportion to advancing paternal age, and the possible mechanisms include de novo point mutations or defective epigenetic regulation of paternal genes. The risk might also be related to paternal toxic exposures, nutritional deficiencies, suboptimal DNA repair enzymes or other factors that influence the fidelity of genetic information in the constantly replicating male germ line. We propose that de novo genetic alterations in the paternal germline cause an independent and common variant of schizophrenia and that abnormal methylation of paternally imprinted genes could be the mechanism. These findings suggest exciting new

Births to women over age 40 soaring, and so is birth rate,Older Fathers Cause Autism Rates to Soar etc.

Births to women over age 40 soaring, and so is birth rate
By ANNE CONSTABLE The Santa Fe New Mexican
Article Launched: 05/18/2008 11:30:17 AM MDT


SANTA FE, N.M.—Barton Bond is looking forward to coaching his son's football team. His wife, Joyce, can't wait to sew Halloween costumes when their children are old enough to go trick-or-treating.
The Bonds sound like typical new parents, but they're not.

They've been married 32 years, but have no other children. Barton has retired from one job and now teaches part-time at Central New Mexico Community College. Joyce is just two and a half years away from retirement from her job as marketing manager for the city of Santa Fe.

Last July, she gave birth to triplets, Jayci Clare, Dallas Witt and Marie Patrice.

At a time when most people their age would be looking forward to being grandparents, they are feeding, changing and burping their merry trio.

At 53, Joyce is part of a new, growing demographic. Births to women over age 40 are soaring and so is the birth rate.

In obstetrical terms, a woman of 35 is considered to have reached "advanced maternal age." And a woman over 40, well, she might be scaling 13,000-foot peaks or swimming laps three times a week, but her eggs are senior citizens. Her biological clock has virtually stopped.

A woman's fertility starts to decline around age


27. According to the American Fertility Association, the chance she will get pregnant is 20-to-30 percent per cycle until her 30s and by age 40 falls to 5 percent.
But many women are lengthening their childbearing years through assisted reproductive technologies such as fertility treatments, egg donation and in vitro fertilization, in which egg cells are fertilized by sperm outside the woman's womb and then implanted in her uterus.

In 1995 and 2006, for example, the number of babies born to women 40 to 44 grew from 67,250 to 105,476. And the number of babies born to women older than that increased from 2,727 to 6,958, according to the federal Centers for Disease Control's National Vital Statistics System.

The birth rate of the women 40 to 44 grew by 45 percent in that time, and the birth rate for the oldest group doubled.

More babies are born to women having their first child over age 40 as well. The number of these births increased from 20,096 in 2000 to 24,284 in 2006.

"There's a lot more you can do. The biologic clock has changed," said Jim Thompson, a fertility specialist with the Center for Reproductive Medicine in Albuquerque.

Women in their late 40s and even their early 50s can have babies using donor eggs or embryos so long as they have a healthy uterus, Thompson said.

Artificial insemination and in vitro fertilization become less efficient, however, because of the declining quality of a woman's eggs, he said. Women in their mid-40s have a 60 percent chance of getting pregnant with an egg donor, compared to 1 or 2 percent with their own eggs.

Pregnancy carries a higher risk among older women who are more likely to experience complications such as pregnancy-induced hypertension, high blood pressure, placental separation and low birth weight.

"That being said," Thompson said, "most women do fine in their mid- to late 40s, even their early 50s."

The Bonds' living room in their home is full of baby equipment. Jayci and Dallas are swaying back and forth in their swings. Marie is bobbing in a walker. Nobody is crying.

"We're running out of room," said Joyce as she surveyed the multiple pieces of baby equipment.

Her mother was 45 when Joyce was born. "I loved having an older mother. I felt that my brother and I (who is six years older than Joyce) kept Mom and Dad young," she said.

But Joyce and Barton, who is 55, "didn't suddenly sit down at the kitchen table and say, 'Let's have babies in our 50s.'"

Our data revealed a higher mortality in offspring of fathers aged 45 years or more that lasted into adulthood

Journal Article
Paternal age and mortality in children.
Zhu JL, Vestergaard M, Madsen KM, Olsen J. Eur J Epidemiol 2008; ePub(ePub): ePub.
Affiliation: The Danish Epidemiology Science Centre, University of Aarhus, Vennelyst Boulevard 6, 8000, Aarhus C, Denmark, zjl@soci.au.dk.
DOI: 10.1007/s10654-008-9253-3 What is this?
(Copyright © 2008, Springer Science+Business Media)
Background: Since paternal age correlates with some diseases that have a high case-fatality, a paternal age effect on offspring's survival is expected but unsettled. We examined the association between paternal age and mortality in children in a large population-based cohort taking maternal age and socioeconomic factors into account. Methods: From the Danish Fertility Database (1980-1996), we identified 102,879 couples and their firstborn singleton children. Information on childhood death (N = 831) was obtained by linking the cohort to the nationwide register on cause of death (1980-1998). Results: We observed a U-shaped association between paternal age and the overall mortality rate in children up to 18 years of age. Adjustment for maternal age and other confounders reduced the mortality rate ratio (MRR) for children of younger fathers but not for children of older fathers. Compared with children of fathers aged between 25 and 29 years, the adjusted MRR was 1.77 (95% confidence interval 1.28-2.45) for children of fathers aged between 45 and 49 years and 1.59 (1.03-2.46) for children of fathers aged 50 years or more. The cause-specific MRRs were highest for congenital malformations [2.35 (1.42-3.88)] and injury or poisoning [3.43 (1.49-7.92)] for children of fathers aged 45 years or more. Conclusion: Our data revealed a higher mortality in offspring of fathers aged 45 years or more that lasted into adulthood. This adds to the cumulating evidence on adverse effects of advanced paternal age in procreation.

The pros and cons of being an older dad

Dr Miriam

Todays health topic: Todays health topic: The pros and cons of being an older dad
7/05/2008
"It's 28 years since Les Dennis held his last baby (son Philip, by his first wife Lynne). And judging by his tired demeanour, looking after 13-day-old Eleanor Grace has been a bit of a jolt.

A month ago, the 53-year-old comedian said he felt the happiest and most contented he'd ever been. But snapped earlier this week at a north London cafe, with baby Eleanor and fiancee Claire Nicholson, he looked totally worn out.

Some would argue that few men of Les's age have the energy to deal with a new baby. But there are now more older dads than ever - the average age of dads in the UK has increased from 29 to 32 since 1980.

But before becoming an older dad, here are a few points to weigh up first..

Reduced fertility

It's not just women whose fertility falls with age. In the US, tests on 100 healthy men aged 22 to 80 found that by the time a man is 40, 60 per cent of his sperm is unhealthy or abnormal compared to 25 per cent of that of a 22-year-old.

Lifespan

Although we're living longer than ever, the later you become a dad, the less likely you are to still be around into your offspring's middle age.

Health consequences

Babies of older dads are at greater risk of:

Autism-a 2006 US study reported that men aged 40 and over have a two-and-a-half times greater risk of fathering an autistic child than those under 30.

Schizophrenia - one in six cases of schizophrenia may have been due to having a father aged over 30, according to research published in the BMJ, and involving more than 700,000 people.

Alzheimer's - in a study involving more than 200 people with Alzheimer's, researchers at Munich University found that children born to older dads had a slightly higher risk of developing the condition.

The theory is that as we age, damage builds up in our DNA and this is passed on to a child. So the older the dad, the more time there has been for DNA damage to accumulate.
The upside

But it's not all doom and gloom. Research has also established that older dads tend to be more nurturing, affectionate and gentle.

One theory is that the calm approach of older dads is thought to be due to a drop in their testosterone levels And studies show that older dads are three times more likely to share in nappy changing, feeding, bath times, story reading and bedtimes.

Sure enough, Les showed his caring side when he interrupted his brunch with Claire to walk around the restaurant with Eleanor.

This is also good news for little Eleanor because many respected studies have shown that the children of involved dads do well in life - they have more confidence, higher self-esteem, greater sense of security and are better able to cope with stress."

"It is also recognized that paternal age is increased among affected children."

Nat Rev Genet. 2008 May;9(5):341-55. Links
Advances in autism genetics: on the threshold of a new neurobiology.Abrahams BS, Geschwind DH.
Neurology Department, and Semel Institute for Neuroscience and Behaviour, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1769 USA. brett.abrahams@gmail.com

Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.

PMID: 18414403 [PubMed - in process]