Paternal Age Past 44 is Particularly Dangerous For Female Offspring

Science 4 July 1997:
Vol. 277. no. 5322, pp. 17 - 21
DOI: 10.1126/science.277.5322.17b
Prev | Table of Contents | Next

Letters
When Fatherhood Should Stop?
Constance Holden's piece "The perils of late-age procreation" (Random Samples, 6 June, p. 1503), about our recent finding that daughters of older fathers live shorter lives, has stimulated us to return to this problem and to reanalyze the data for different ranges of paternal ages at reproduction.

Our previous analysis, based on a multiple linear regression model, has demonstrated that in the range of paternal ages of 35 to 55 years, the mean loss in daughters' life span is 0.16 ± 0.06 years per each additional year of paternal age (sample size, n = 2159; Student's test, t = 2.43; P = 0.02). It turned out, however, that for the subgroup of younger fathers (35 to 45 years) the mean loss of daughters' life span is small (0.02 ± 0.12 years per each additional year of paternal age) and statistically insignificant (n = 1651; t = 0.16; P = 0.87), while for older fathers (45 to 55 years) this loss is particularly high (0.48 ± 0.21 years per each additional year of paternal age) and significant (n = 598; t = 2.34; P = 0.02).

These results are consistent with the general conclusion of James Crow on the nonlinear accelerating increase of mutation rates with paternal age (1) and could decrease the anxiety among the majority of fathers who reproduce before 45 years.


Leonid A. Gavrilov
A. N. Belozersky Institute,
Moscow State University,
Moscow 119899, Russia,
E-mail: leonid@gavrilov.genebee.msu.su
Natalia S. Gavrilova
Institute for Systems Analysis,
Russian Academy of Sciences,
Moscow 117312, Russia

REFERENCES
J. Crow, J. Environ. Mol. Mutagenesis 21, 122 (1993); J. Exp. Clin. Immunogenet. 12, 121 (1995).

That said, the perfect compromise would be to try to complete your family before both partners reach the age of 35.

March 23, 2009

Do older men have less intelligent children?
New research suggests the older your father is when you are born, the lower your IQ, so how late is too late?Dr Mark Porter
New research suggesting that the age of your father influences your IQ - the older he was when you were born, the worse you are likely to fare when tested - is the latest addition to growing evidence that it is not just maternal age that matters when it comes to starting a family. The longer a couple delay, the poorer the outcome for all concerned. But how late is too late?

Back in the early Nineties, about a quarter of children were fathered by men over the age of 35; today it is closer to half, at least for married couples, who still account for the majority (just) of children born in the UK, with the average first-time mother and father now being aged 30 and 32 respectively.

There are lots of reasons why couples are waiting longer, but career and financial pressures feature highly - a trend likely to have been exacerbated by the current economic climate. But while there are obvious benefits to having more mature parents, these have to be offset against the medical implications - and there are many.

For women the main hurdle is declining fertility. While it is technically possible to conceive naturally right up until your last period, female fertility wanes dramatically after the age of 35, and by the time most women reach their late forties they are technically infertile.

Related Links
Biological clock strikes for men too - at 35
Children of older fathers at risk of autism
The problems of being an older mum
A healthy couple in their twenties have a 25 to 30 per cent chance of conceiving each month. This falls to between 10 and 25 per cent when the woman is in her mid-thirties, and has plummeted to less than 5 per cent by the time she is in her early forties. What's more, nearly half of those who do manage to conceive at this age will miscarry within the first three months.

Much of this decline is due to genetic damage inflicted on a woman's eggs by a combination of environmental factors, such as toxins in the diet and natural background radiation. Women are born with a finite supply of eggs, and a 40-year-old egg is harder to fertilise and nurture than a 20-year-old one.

Tradition has it that advancing years do not have such a detrimental effect on men, who, unlike women, manufacture fresh sperm throughout their lives. But they are not actually manufactured from scratch, and the basic template that matures into a fully grown sperm is, like a woman's eggs, as old as the man - so male fertility wanes, too.

The fall starts to become significant when a man reaches his early forties, meaning that it takes longer to conceive, irrespective of the age of the would-be mother. When they are successful, the woman is also more likely to miscarry if her partner is over 40.

The effect of age on the risk of congenital abnormalities appears to be shared between the parents, too. The best known example in women is the link with Down's syndrome. If a woman is in her late twenties, the risk of her child having Down's is about 1 in 1,000. By the age of 35 it increases to 1 in 270, and by 40 it is closer to 1 in 100.

But less marked genetic mutations are thought to be a problem in older fathers as well, and the implications can be just as serious. Children born to men aged over 35 are more likely to have a cleft lip or palate, congenital heart defects, and to develop some forms of cancer, including leukaemia (a 50 per cent increase) and brain tumours (25 per cent increase).

There is also evidence of a link between paternal age and the chances of a child going on to develop autism, dyslexia or schizophrenia - the link with the last of these being particularly strong. Experts estimate that the trend towards delayed fatherhood could account for as many as 10 per cent of new cases of schizophrenia diagnosed each year.

But let's not be overly pessimistic. Torture statistics enough and they will tell you anything. In fact, the vast majority of older mums and dads will have trouble-free pregnancies and perfectly healthy children. Leaving it later may increase the risk of a range of complications - but a 50 per cent increase on a tiny risk is still only a tiny risk. And the medical implications need to be offset against the social and emotional benefits of bringing up a child in a more stable environment.

That said, the perfect compromise would be to try to complete your family before both partners reach the age of 35. It's a feat that my parents managed with ease - they were just 20 and 21 when they had me, which, statistically, means that I will probably live for ever.

The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood

Offspring of Older Fathers May Have Subtle Neurocognitive Impairments


Laurie Barclay, MD


March 18, 2009 — The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood, according to the results of a study reported in the March 10 issue of PLoS Medicine.

"Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia, as well as with dyslexia and reduced intelligence," write Sukanta Saha, from Queensland Centre for Mental Health Research, The Park Centre for Mental Health, in Richlands, Australia, and colleagues. "The aim of this study was to examine the relationship between paternal age and performance on neurocognitive measures during infancy and childhood."

The study sample consisted of 33,437 singleton children enrolled in the US Collaborative Perinatal Project. At ages 8 months, 4 years, and 7 years, these children underwent testing with the Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children (WISC), and Wide Range Achievement Test. The primary analyses evaluated the association between neurocognitive measures and paternal or maternal age, after adjustment for potential confounding factors.

On all the neurocognitive measures, except for the Bayley Motor score, advanced paternal age correlated significantly with poorer scores. At all 3 ages tested, the findings were broadly consistent in direction and effect size. In contrast, there was an association between advanced maternal age and generally better scores on these same tests.

"The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood," the study authors write. "In light of secular trends related to delayed fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny."

Limitations of this study include nonrandom sample attrition and missing data that could affect the generalizability of the results; cohort members born in the United States during the 1960s, limiting generalizability to more contemporary cohorts; and neurocognitive outcomes only determined until age 7 years.

"While most of the neurocognitive differences were small at the individual level, these could have important implications from a public health perspective," the study authors conclude.

The study authors have disclosed no relevant financial relationships.

PLoS Med. 2009;6:e40.

“It turns out the optimal age for being a mother is the same as the optimal age for being a father. The fact that men can stay fertile longer is a dif

Vital Signs
Lower I.Q. Scores Among Children of Older Fathers


By RONI CARYN RABIN
Published: March 9, 2009
Children of older fathers scored lower than offspring of younger dads on I.Q. tests and a range of other cognitive measures at eight months, four years and seven years of age, according to a new study that adds to a growing body of evidence suggesting there are risks to postponing fatherhood.
The study is the first to show that children of older fathers don’t perform as well on cognitive tests at very young ages. Although the differences in scores were slight and usually just off by a few points on average, researchers called the findings “unexpectedly startling."
“The older the dads were, the slightly worse the children were doing,” said Dr. John J. McGrath, the paper’s senior author and a professor of psychiatry at the Queensland Brain Institute in Brisbane, Australia. “The findings fit in a straight line, suggesting there may be some steady beat of mutations happening in the dad’s sperm.”
Earlier studies have found a higher incidence of schizophrenia and autism among offspring of men who were in their mid- to late 40s or older when they had children. A study published in 2005 reported that 16- and 17-year-olds with older fathers scored lower on non-verbal I.Q. tests, as did the offspring of teenage fathers.
The new study, published on Monday in the journal PLoS Medicine, re-analyzed data from the Collaborative Perinatal Project, which gathered information from pregnant women seen at 12 university clinics in the United States between 1959 and 1965.
The researchers analyzed the scores of 33,437 babies resulting from these pregnancies. They had been tested at regular intervals on a variety of measurements of cognitive skills, including thinking and reasoning, concentration, memory, understanding, speaking and reading, as well as on motor skills.
Regardless of their mothers’ ages, children whose fathers were 50 years old had lower scores on all of the measures, except for those assessing physical coordination, than those whose fathers were 20, the researchers found. And the older the fathers, the more likely the children were to have lower scores, they found.
By contrast, children with older mothers generally performed higher on the cognitive measures, a finding that is in line with most other studies, suggesting these children may benefit from more nurturing home environments associated with the generally higher income and education levels of older mothers, researchers said.
“I think there has been a bit of a cultural bias against even looking at this issue, but finally people are willing to entertain this,” said Dr. Dolores Malaspina, professor of psychiatry at New York University Medical Center, who authored the studies finding an increased risk for schizophrenia among children of older fathers, as well as studies that found lower non-verbal I.Q. scores among teens with older dads.
“It turns out the optimal age for being a mother is the same as the optimal age for being a father. The fact that men can stay fertile longer is a different issue."

Children of older fathers perform less well in intelligence tests during infancy
Press release from PLoS Medicine
Children of older fathers perform less well in a range of cognitive tests during infancy and early childhood, according to a study published this week in the open-access journal PLoS Medicine. In contrast, the study finds that children with older mothers gain higher scores in the same tests – designed to measure the ability to think and reason, including concentration, learning, memory, speaking and reading skills.
The age at which men and women are having children is increasing in the developed world, but whilst the "biological clock" – the effect of increasing maternal age on reduced fertility – is widely-discussed, the consequences of increased paternal age are not as well known. Recent evidence demonstrates a link between older fathers and specific health problems in their children, including birth deformities and cancer, as well as neuropsychiatric conditions such as autism and schizophrenia. This new study by John McGrath, of the Queensland Brain Institute, University of Queensland in Australia, and colleagues, investigates the link between a father's age and their child's general cognitive ability, by reanalyzing an existing dataset of 33,437 children born between 1959 and 1965 in the United States. This data formed part of the US Collaborative Perinatal Project (CPP), which tested each child in the dataset at 8 months, 4 years and 7 years of age with a number of widely-used intelligence scales – including assessments of sensory discrimination and hand-eye coordination, conceptual and physical coordination, and at 7 years reading, spelling and arithmetic ability.
Crucially in their reanalysis of this dataset, McGrath and colleagues adjusted their study to take into account socio-economic factors. They used two models: one that focused on physical factors including the parents' age, and a second that indexed social factors such as maternal and paternal education and family income. They found that the older the father, the more likely the child was to have lower scores on the various tests used by the CPP – with the exception of one measure of physical coordination. The researchers also grouped the children by their mother's age and found that in contrast, the older the mother the higher the scores of the child in the cognitive tests.
Previous researchers have suggested that the children of older mothers may perform better because they experience a more nurturing home environment; if this is the case, this study suggests that children of older fathers do not necessarily experience the same benefit. The researchers advance several hypotheses as possibilities to explain the association between advanced paternal age and children's cognitive ability, including genetic and social arguments. Unlike a woman's eggs – which are formed when she herself is in the womb – a man's sperm accumulates over his lifetime, which previous studies have suggested can mean increased incidence of mutations in the sperm at an older age. However, as emphasized in an expert commentary on the findings by Mary Cannon (Royal College of Surgeons in Ireland) – who was uninvolved with the study – genetic and social factors can operate in conjunction. "New explanatory models are needed that can encompass socio-cultural and interpersonal factors as well as biological variables", she argues. Given the trend towards older maternal and paternal ages in the developing world, policy-makers may want to consider promoting an awareness of the risks to children that this study associates with delayed fatherhood.

Men also hear biological clock: study

Men also hear biological clock: study
March 10, 2009 - 1:04AM
The biological clock ticks just as loudly for Australian men, new research shows.
Scientists at the University of Queensland (UQ) have found children born to older men perform poorer on intelligence tests.
Professor John McGrath analysed data from 33,000 children born and raised across the United States and the results were "startling", he says.
"It's long been known that the age of the mother is important, we've been concerned about the risk of Downs Syndrome," says Prof McGrath, from the university's Queensland Brain Institute.
"Now we need to change our position on that ... we are getting more evidence of the age of the father being just as important."
The study took in fathers aged as young as 14 and as old as 66.
Their children underwent cognitive tests at age eight months, four years and seven years, and those born to older dads generally fared worse.
Prof McGrath said it added weight to earlier studies showing children of older dads also faced a heightened risk of schizophrenia and autism.
No single age was found as a time of heightened risk for men having children, but a "general decline across the age range" was observed.
Prof McGrath thinks sperm health could explain the deterioration.
"We are concerned that older men accumulate more mutations in the developing sperm cells," he says.
"These mistakes then pile up and increase the risks of problems in the children, and it is possible that these mistakes will carry on into the next generation."
Paradoxically, when the study looked at the cognitive results of children born to older mums it produced the opposite result.
"Offspring of older women do better in similar tests, but this is usually put down to socio-economic status of women," Prof McGrath says.
The research involved a new analysis of data collected for the Collaborative Perinatal Project, one of the largest studies of children in the US, and it is published in medical journal PLoS Medicine.

Bravo James Watson co-discoverer of DNA structure for making the connection between paternal age and schizophrenia with his son Rufus

The Sunday Times
March 8, 2009
Not too bright? Now the blame is on your old man
Jonathan Leake, Science Editor

CHILDREN with older fathers seem to perform worse in intelligence tests, according to a study due out this week.
They tended to obtain significantly lower scores in a variety of cognitive tests than those born to younger fathers, researchers have found.
The results could be controversial. Until recent years it had been thought that it was a mother’s age that had most impact on the health and abilities of children. The father’s age, by contrast, was thought to be much less important.
The research, led by John McGrath, of the Queensland Brain Institute at the University of Queensland in Australia, suggests such ideas need rethinking.
“The offspring of older fathers show subtle impairments on tests of neurocognitive ability during infancy and childhood,” he said. “In light of the trends to delay fatherhood, the clinical implications and the mechanisms underlying these findings warrant closer scrutiny.”
Other research has shown linkage between advanced paternal age (men over 35) and an increased risk of neurodevelopmental disorders, such as autism and schizophrenia, as well as dyslexia. Such findings prompted James Watson, co-discoverer of the structure of DNA, to speak of his concern. His son Rufus suffers from schizophrenia and as more is uncovered about its causes Watson has publicly questioned if he is to blame. “I worry that I was 42 with Rufus,” he says. “I read that the frequency of schizophrenia goes up with the age of both parents.”
The tests, designed to measure the ability to think and reason, also generated a second startling finding — that children with older mothers gain higher intelligence scores.
McGrath analysed data on 33,437 Americans born between 1959 and 1965. All were tested at eight months, four years and seven. The data set, despite its age, remains one of the best resources. McGrath also used advanced statistical techniques to remove environmental influences.
For McGrath one of the key questions is the underlying biological mechanisms. One idea is that as men age the cells that produce sperm suffer increasing numbers of mutations, which are passed on to an offspring.
Why, though, would children born to older mothers tend to have higher intelligence? McGrath suggests this is because women’s eggs are formed when they are still in the womb and so their DNA is protected from mutation until they are used.

1: Geriatrics. 2009 Jan;64(1):14-7.
The aging male and his biological clock.
Fisch H.
Department of Urology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York, NY.
Couples are waiting longer to have children, and advances in reproductive technology are allowing older men and women to consider having children. The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome. The age-related changes associated with the male biological clock affect sperm quality, fertility, hormone levels, libido, erectile function, and a host of non-reproductive physiological issues. This article focuses on the potentially adverse effects of the male biological clock on fertility in older men. Advanced paternal age increases the risk for spontaneous abortion as well as genetic abnormalities in offspring due to multiple factors, including DNA damage from abnormal apoptosis and reactive oxygen species. Increased paternal age is also associated with a decrease in semen volume, percentage of normal sperm, and sperm motility. Older men considering parenthood should have a thorough history and physical examination focused on their sexual and reproductive capacity. Such examination should entail disclosure of any sexual dysfunction and the use of medications, drugs, or lifestyle factors that might impair fertility or sexual response. Older men should also be counseled regarding the effects of paternal age on spermatogenesis and pregnancy.
PMID: 19256577 [PubMed - in process]