Paternal age effect
Encyclopedia
The paternal age effect can refer to the statistical relationships of: (1) a man's age to sperm
and semen
abnormalities; (2) a man's age to his fertility
; (3) a man's age to adverse pregnancy outcomes in his female partner (including miscarriage
and fetal death
); (4) a father's age at the birth of his offspring on the probability of an adverse birth outcome (such as low birthweight); or (5) a father's age at the birth of his offspring on the probability that the offspring will have a health-related condition (e.g., decreased intelligence
), a specific disease (e.g., autism spectrum disorder, bipolar disorder
, Down syndrome
, and schizophrenia
), or an increased risk of mortality.
The genetic quality of sperm, as well as its volume and motility, all typically decrease with age. Scientists have formulated at least two hypotheses to explain how paternal age might cause health effects.
, a German physician, was the first person to hypothesize that non-inherited cases of achondroplasia
could be more common in last-born children than in children born earlier to the same set of parents. Although Weinberg "made no distinction between paternal age, maternal age and birth order
" in his hypothesis, by 1953 the term "paternal age effect" had occurred in the medical literature on achondroplasia.
Scientific interest in paternal age effects increased in the late 20th and early 21st centuries because the average paternal age increased in countries such as the United Kingdom, Australia, and Germany, and because birth rates for fathers aged 30–54 years have risen between 1980 and 2006 in the United States. Possible reasons for the increases in average paternal age include increasing life expectancy and increasing rates of divorce and remarriage. Despite recent increases in average paternal age, however, the oldest father documented in the medical literature was born in 1840: George Isaac Hughes was 94 years old at the time of the birth of his son by his second wife, a 1935 article in the Journal of the American Medical Association
stated that his fertility "has been definitely and affirmatively checked up medically," and he fathered a daughter in 1936 at age 96.
A study of semen samples from 66 men published in 2003 demonstrated a correlation of increasing age with more DNA damage, less apoptosis
, and lower sperm motility. In 2006-2007 studies of sperm, age was again associated with DNA damage.
A study of semen samples from 100 men published in 2010 found low-level germline mosaicism
in one third of infertile men, with increased incidence with advancing age.
, for couples in which the men are oligozoospermic, the chance of pregnancy decreased 5% for each year of paternal age, while no effect on age was seen in normozoospermic men.
, and fetal death (which includes both miscarriage and stillbirth). In addition, one 2002 study linked paternal age with pre-eclampsia
, a complication of pregnancy that can be associated with adverse health outcomes for both the pregnant woman and the fetus.
published in 2010 of 10 studies published in 1972-2008 concluded that the relationship of the risk of low birthweight in infants with paternal age is "saucer-shaped"; that is, the highest risks occur at low and at high paternal ages. Compared with a paternal age of 25–28 years as a reference group, the odds ratio for low birthweight was approximately 1.1 at a paternal age of 20 and approximately 1.2 at a paternal age of 50. There was no association of paternal age with preterm births or with small for gestational age
births.
In a 2008 retrospective cohort study of 2,614,966 births, a paternal age of 40 years or greater was not associated with neonatal death ("death of a live birth within 28 days") or post-neonatal death ("death of a live birth between 28–364 days of age") compared with a paternal age of 20–29 years. However, the risks of neonatal mortality and post-neonatal mortality were elevated for infants whose fathers were less than 20 years old.
, noting that five studies found a positive relationship, two found no relationship, and one found a negative relationship. Because some cases of Alzheimer's are related to genetics, the researchers performed a case-control study that examined 154 people: 52 had Alzheimer's with a low probability of having a major gene for Alzheimer's ("low MGAD"), 52 had Alzheimer's disease with a high probability of having a major gene for Alzheimer's disease ("high MGAD"), and 50 were age- and sex-matched controls. The mean age at onset in the two Alzheimer's groups was 66.6 years. The mean age of fathers of the "low MGAD" group was significantly higher than the mean age of fathers of people in the other two groups, which the researchers interpreted as evidence that increased paternal age is a risk factor for Alzheimer's not associated with a major gene. However, two studies published in 1997 and 2000 failed to find a relationship between paternal age and Alzheimer's.
, with an odds ratio of 1.12. The authors noted that adjustment or cross-stratification by maternal age may either reduce the association of paternal age and breast cancer, or cause the association to disappear entirely. A 1999 study from Sweden noted a risk ratio of 1.09 for each 10-year increment in paternal age for childhood brain cancer
when adjusted for maternal age, but there was no association of paternal age with childhood leukemia. One 2002 study suggested that advanced paternal age is a risk factor for acute lymphoblastic leukemia
. Analyses of cases of multiple endocrine neoplasia
types 2A and 2B found that the mutations associated with the disease occur only on the paternally-derived chromosome, and that the mean paternal age of cases is higher than the mean paternal age of the population.
and paternal age. Of these, Blom et al. (1989), Patterson et al. (1994), and Bock et al. (1994) were described as not finding an association, and Wadsworth et al. (1997) was described as finding a decreased risk with older paternal age. The literature from 1998 onwards continues to show inconsistent results:
analyzed data for 727 children in 150 families and found no paternal age effect for the risk of Down syndrome
after controlling for the maternal age effect. Largely based on a 2003 paper by Fisch et al. that found a paternal age effect only "in association with a maternal age of 35 years and older", a 2009 review of the literature subsequent to Penrose's paper concludes that "a paternal-age effect exists, but is very small in comparison to maternal-age effect in Down syndrome prevalence".
or decreased learning capacity of unknown aetiology" was thought to be associated with increased paternal age. In 2005, Malaspina and colleagues detected an "inverted U-shaped relationship" between paternal age and intelligence quotient
s (IQs) in 44,175 people from Israel. There was a peak at paternal ages of 25-44; fathers younger than 25 and older than 44 tended to have children with lower IQs. Malaspina et al. also reviewed the literature and found that "at least a half dozen other studies ... have demonstrated significant associations between paternal age and human intelligence."
A 2009 study by Saha et al. examined 33,437 children at 8 months, 4 years, and 7 years. The researchers found that paternal age was associated with poorer scores in almost all neurocognitive
tests used, but that maternal age was associated with better scores on the same tests. An editorial accompanying the paper by Saha et al. emphasized the importance of controlling for socioeconomic status
in studies of paternal age and intelligence. A 2010 paper from Spain provided further evidence that average paternal age is elevated in cases of mental retardation.
and 24,194 matched controls found a risk of 2.00 if the fathers were 51–55 years old versus 21–25 years old; however, two subsequent studies did not confirm the association.
and paternal age include:
notes that there is no standard definition of "advanced paternal age." Although the College recommends obstetric ultrasonography
at 18–20 weeks gestation in cases of advanced paternal age "to evaluate fetal growth and development," it notes that this procedure "is unlikely to detect many of the conditions of interest." Bray et al.. (2006) expressed an opinion that any adverse effects of advanced paternal age "should be weighed up against potential social advantages for children born to older fathers who are more likely to have progressed in their career and to have achieved financial security."
Sperm
The term sperm is derived from the Greek word sperma and refers to the male reproductive cells. In the types of sexual reproduction known as anisogamy and oogamy, there is a marked difference in the size of the gametes with the smaller one being termed the "male" or sperm cell...
and semen
Semen
Semen is an organic fluid, also known as seminal fluid, that may contain spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...
abnormalities; (2) a man's age to his fertility
Fertility
Fertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...
; (3) a man's age to adverse pregnancy outcomes in his female partner (including miscarriage
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
and fetal death
Perinatal mortality
Perinatal mortality , also perinatal death, refers to the death of a fetus or neonate and is the basis to calculate the perinatal mortality rate. Variations in the precise definition of the perinatal mortality exist specifically concerning the issue of inclusion or exclusion of early fetal and...
); (4) a father's age at the birth of his offspring on the probability of an adverse birth outcome (such as low birthweight); or (5) a father's age at the birth of his offspring on the probability that the offspring will have a health-related condition (e.g., decreased intelligence
Intelligence
Intelligence has been defined in different ways, including the abilities for abstract thought, understanding, communication, reasoning, learning, planning, emotional intelligence and problem solving....
), a specific disease (e.g., autism spectrum disorder, bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, Down syndrome
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
, and schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
), or an increased risk of mortality.
The genetic quality of sperm, as well as its volume and motility, all typically decrease with age. Scientists have formulated at least two hypotheses to explain how paternal age might cause health effects.
History
In 1912, Wilhelm WeinbergWilhelm Weinberg
Dr Wilhelm Weinberg was a German half-Jewish physician and obstetrician-gynecologist, practicing in Stuttgart, who in a 1908 paper Dr Wilhelm Weinberg (Stuttgart, December 25, 1862 – Tübingen, November 27, 1937) was a German half-Jewish physician and obstetrician-gynecologist, practicing in...
, a German physician, was the first person to hypothesize that non-inherited cases of achondroplasia
Achondroplasia
Achondroplasia dwarfism occurs as a sporadic mutation in approximately 85% of cases or may be inherited in an autosomal dominant genetic disorder that is a common cause of dwarfism...
could be more common in last-born children than in children born earlier to the same set of parents. Although Weinberg "made no distinction between paternal age, maternal age and birth order
Birth order
Birth order is defined as a person's rank by age among his or her siblings. Birth order is often believed to have a profound and lasting effect on psychological development...
" in his hypothesis, by 1953 the term "paternal age effect" had occurred in the medical literature on achondroplasia.
Scientific interest in paternal age effects increased in the late 20th and early 21st centuries because the average paternal age increased in countries such as the United Kingdom, Australia, and Germany, and because birth rates for fathers aged 30–54 years have risen between 1980 and 2006 in the United States. Possible reasons for the increases in average paternal age include increasing life expectancy and increasing rates of divorce and remarriage. Despite recent increases in average paternal age, however, the oldest father documented in the medical literature was born in 1840: George Isaac Hughes was 94 years old at the time of the birth of his son by his second wife, a 1935 article in the Journal of the American Medical Association
Journal of the American Medical Association
The Journal of the American Medical Association is a weekly, peer-reviewed, medical journal, published by the American Medical Association. Beginning in July 2011, the editor in chief will be Howard C. Bauchner, vice chairman of pediatrics at Boston University’s School of Medicine, replacing ...
stated that his fertility "has been definitely and affirmatively checked up medically," and he fathered a daughter in 1936 at age 96.
Semen and sperm abnormalities
A 2001 review by Kidd et al. examined 1980-1999 scientific literature on variation in semen quality and fertility by male age. It concluded that older men had lower semen volume, lower sperm motility, and a decreased percent of normal sperm. The same researchers participated in a 2003 study that showed decreased semen volume and sperm motility with age.A study of semen samples from 66 men published in 2003 demonstrated a correlation of increasing age with more DNA damage, less apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, and lower sperm motility. In 2006-2007 studies of sperm, age was again associated with DNA damage.
A study of semen samples from 100 men published in 2010 found low-level germline mosaicism
Germline Mosaicism
Germline mosaicism, also known as gonadal mosaicism, is a condition in which the precursor cells to ova and spermatazoa are a mixture of two or more genetically different cell lines....
in one third of infertile men, with increased incidence with advancing age.
Fertility
A review of the literature by Kidd et al. (2001) determined that older men had decreased pregnancy rates, increased time to pregnancy, and increased subfecundity (i.e., infertility of a couple at a given point in time). In contrast, in 2001 a study detected "no association between male age and the fertilization rate of donated oocytes in vitro, pregnancy rates, or live birth rates"; however, subsequent studies examining how well older men's sperm can fertilize donated eggs have been "contradictory." A 2002 study of 782 couples did find decreased fertility for older men; in specific, 35-39 year old women whose male partners were the same age had a probability of pregnancy under certain conditions of 0.29, but if the male partner was five years older the probability decreased to 0.18. In a study of 1,024 couples undergoing ICSIIntracytoplasmic sperm injection
Intracytoplasmic sperm injection is an in vitro fertilization procedure in which a single sperm is injected directly into an egg.-Indications:...
, for couples in which the men are oligozoospermic, the chance of pregnancy decreased 5% for each year of paternal age, while no effect on age was seen in normozoospermic men.
Adverse pregnancy outcomes and pre-eclampsia
Studies published between 2002 and 2008 have been consistent in associating advanced paternal age with miscarriage (spontaneous abortion), stillbirthStillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...
, and fetal death (which includes both miscarriage and stillbirth). In addition, one 2002 study linked paternal age with pre-eclampsia
Pre-eclampsia
Pre-eclampsia or preeclampsia is a medical condition in which hypertension arises in pregnancy in association with significant amounts of protein in the urine....
, a complication of pregnancy that can be associated with adverse health outcomes for both the pregnant woman and the fetus.
Adverse birth outcomes
A systematic reviewSystematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
published in 2010 of 10 studies published in 1972-2008 concluded that the relationship of the risk of low birthweight in infants with paternal age is "saucer-shaped"; that is, the highest risks occur at low and at high paternal ages. Compared with a paternal age of 25–28 years as a reference group, the odds ratio for low birthweight was approximately 1.1 at a paternal age of 20 and approximately 1.2 at a paternal age of 50. There was no association of paternal age with preterm births or with small for gestational age
Small for gestational age
Small for gestational age babies are those who are smaller in size than normal for the baby's sex and gestational age, most commonly defined as a weight below the 10th percentile for the gestational age.-Terminology:...
births.
In a 2008 retrospective cohort study of 2,614,966 births, a paternal age of 40 years or greater was not associated with neonatal death ("death of a live birth within 28 days") or post-neonatal death ("death of a live birth between 28–364 days of age") compared with a paternal age of 20–29 years. However, the risks of neonatal mortality and post-neonatal mortality were elevated for infants whose fathers were less than 20 years old.
Notable conditions and diseases
Evidence for a paternal age effect in a number of conditions and diseases includes the following.Alzheimer's disease
Bertram and colleagues reviewed the 1982-1995 literature on paternal age and Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, noting that five studies found a positive relationship, two found no relationship, and one found a negative relationship. Because some cases of Alzheimer's are related to genetics, the researchers performed a case-control study that examined 154 people: 52 had Alzheimer's with a low probability of having a major gene for Alzheimer's ("low MGAD"), 52 had Alzheimer's disease with a high probability of having a major gene for Alzheimer's disease ("high MGAD"), and 50 were age- and sex-matched controls. The mean age at onset in the two Alzheimer's groups was 66.6 years. The mean age of fathers of the "low MGAD" group was significantly higher than the mean age of fathers of people in the other two groups, which the researchers interpreted as evidence that increased paternal age is a risk factor for Alzheimer's not associated with a major gene. However, two studies published in 1997 and 2000 failed to find a relationship between paternal age and Alzheimer's.
Autism spectrum disorder
Most studies examining autism spectrum disorder (ASD) and advanced paternal age have demonstrated a statistically significant association between the two, but some have not:- A 2004 study from Australia compared 465 cases of ASD with 1,313 random population-based controls. The mean paternal age was significantly higher for cases than for controls (31.74 vs. 30.31 years); in a logistic regressionLogistic regressionIn statistics, logistic regression is used for prediction of the probability of occurrence of an event by fitting data to a logit function logistic curve. It is a generalized linear model used for binomial regression...
, however, paternal age was not significant. - A nested case-control studyNested case-control studyA nested case control study is a variation of a case-cohort study in which only a subset of controls from the cohort are compared to the incident cases. In a case-cohort study, all incident cases in the cohort are compared to a random subset of participants who do not develop the disease of interest...
from Denmark by Larsson et al. published in 2005 involved 698 children with a diagnosis of autism and 17,450 controls. In an adjusted model including only perinatal factors, advanced paternal age was significantly associated with autism; however, in an adjusted model including perinatal factors, parental psychiatric history, and socioeconomic characteristics, advanced paternal age did not reach statistical significance. - Another Danish study from 2005 followed 943,664 children less than 10 years old. Between 1994 and 2001, 818 of the children developed autism, and those whose fathers were 35 years or older had a risk of autism of 1.39 compared to those whose fathers were 25–29 years old.
- A matched, population-based case–control study from Denmark included 473 cases and 4,730 controls. In an unadjusted (crude) analysis published in 2006, the odds ratio for paternal age of >35 versus 25–29 years was statistically significant at 1.3, but an adjusted odds ratio of 1.2 did not reach statistical significance.
- Reichenberg et al. (2006) examined a cohort of 132,271 Israeli people, of whom 110 had been diagnosed with ASD. They stated that people with fathers 30–39 years old were 1.62 times as likely, and people with fathers 40 years or older were 5.75 times as likely, to have ASD compared with people with fathers younger than 30 years old, controlling for year of birth, socioeconomic status, and maternal age.
- Comparing 593 children with ASD with 132,251 other births in the Kaiser PermanenteKaiser PermanenteKaiser Permanente is an integrated managed care consortium, based in Oakland, California, United States, founded in 1945 by industrialist Henry J. Kaiser and physician Sidney Garfield...
health maintenance organizationHealth maintenance organizationA health maintenance organization is an organization that provides managed care for health insurance contracts in the United States as a liaison with health care providers...
system in Northern California between 1995 and 1999, researchers found that paternal age was significantly and independently associated with risk for "autistic disorder... [and] Asperger disorder or pervasive developmental disorder not otherwise specified." - Durkin et al. (2008) used a case-cohort study design with data from the Centers for Disease Control and PreventionCenters for Disease Control and PreventionThe Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
; 253,347 children were in the cohort, of which 1,251 children with ASD were the cases. Paternal age of 40 years or greater was significantly and independently associated with risk of ASD, with an adjusted odds ratio of 1.4 versus a paternal age of 25–29 years. - King et al. (2009) used California birth data from 1992 through 2000 and autism data to 2006. They determined that the risk of paternal age varied by birth cohort and was inflated if data are pooled across multiple birth cohorts.
- In a 2009 analysis of California birth data from 1989 through 2002 and autism data to 2006, an increase of 10 years in paternal age was associated with a 22% increase in risk for autism. The association between paternal age and autism was significant in most of the birth years studied (1989 and 1993–2002)
- A 2010 study of California birth data from 1996 to 2000 and autism data to 2006 examined geographic clusters of autism. Within the clusters, the researchers found a correlation between paternal age and autism, but the correlation was much weaker than that between parental education and autism.
- A 2010 study of California birth data from 1990 to 1999 and autism data through 2006 revealed that "autism risk was associated with advancing paternal age primarily among mothers <30."
Bipolar disorder
Frans et al. (2008) considered 13,428 Swedish cases of bipolar disorder and 67,140 controls, and found an increased risk for bipolar disorder for people whose fathers were older than 24 years than those whose fathers were 20–24 years old at birth. The risks increased with increasing age of the father, with even stronger associations when the analyses were limited to cases who developed bipolar disorder before the age of 20 years. A 2010 cohort study also using Swedish data was consistent with the findings of Frans et al..Cancers
In a systematic review and meta-analysis of 10 studies published between October 1, 1980 and June 21, 2007, researchers claimed that paternal age was associated with an increased risk of breast cancerBreast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, with an odds ratio of 1.12. The authors noted that adjustment or cross-stratification by maternal age may either reduce the association of paternal age and breast cancer, or cause the association to disappear entirely. A 1999 study from Sweden noted a risk ratio of 1.09 for each 10-year increment in paternal age for childhood brain cancer
Brain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
when adjusted for maternal age, but there was no association of paternal age with childhood leukemia. One 2002 study suggested that advanced paternal age is a risk factor for acute lymphoblastic leukemia
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts.Malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone...
. Analyses of cases of multiple endocrine neoplasia
Multiple endocrine neoplasia
The term multiple endocrine neoplasia encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign...
types 2A and 2B found that the mutations associated with the disease occur only on the paternally-derived chromosome, and that the mean paternal age of cases is higher than the mean paternal age of the population.
Diabetes mellitus
Prior to 1998, four studies had been published concerning a possible association between diabetes mellitus type 1Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
and paternal age. Of these, Blom et al. (1989), Patterson et al. (1994), and Bock et al. (1994) were described as not finding an association, and Wadsworth et al. (1997) was described as finding a decreased risk with older paternal age. The literature from 1998 onwards continues to show inconsistent results:
- In a case-control study conducted in TaipeiTaipeiTaipei City is the capital of the Republic of China and the central city of the largest metropolitan area of Taiwan. Situated at the northern tip of the island, Taipei is located on the Tamsui River, and is about 25 km southwest of Keelung, its port on the Pacific Ocean...
and published in 1998, a multiple logistic regression found an odds ratio of 0.33 for paternal ages 30–39 versus paternal ages <30, while the risk for paternal ages 40 and above was not significantly different from the risk for paternal ages <30. - In 1999, Rami et al. published the results of a population-based case-control study from Austria with 114 cases of type 1 diabetes and 495 matched controls. The mean paternal age of cases was 31.7 years, which was significantly higher than the mean paternal age of controls of 30.1 years.
- A 1999 Danish case-control study detected no association between paternal age and risk of type 1 diabetes.
- In a prospective study from the United Kingdom, Bingley et al. noted increasing relative risks for type 1 diabetes in childhood in each paternal age group 20 years and older versus paternal age less than 20; for example, in the multivariate analysis the relative risk for 40-45 year old fathers was 1.57.
- A Norwegian study of 2001 found no association with paternal age after adjustment for maternal age.
- In a 2005 study set in Northern Ireland, paternal age or 35 years or more was associated with a relative risk of 1.52 compared with a paternal age of less than 25 years.
Down syndrome
In 1933, Lionel PenroseLionel Penrose
Lionel Sharples Penrose, FRS was a British psychiatrist, medical geneticist, mathematician and chess theorist, who carried out pioneering work on the genetics of mental retardation. He was educated at the Quaker Leighton Park School and St...
analyzed data for 727 children in 150 families and found no paternal age effect for the risk of Down syndrome
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
after controlling for the maternal age effect. Largely based on a 2003 paper by Fisch et al. that found a paternal age effect only "in association with a maternal age of 35 years and older", a 2009 review of the literature subsequent to Penrose's paper concludes that "a paternal-age effect exists, but is very small in comparison to maternal-age effect in Down syndrome prevalence".
Mental retardation and decreased intelligence
By 1998, "mental retardationMental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
or decreased learning capacity of unknown aetiology" was thought to be associated with increased paternal age. In 2005, Malaspina and colleagues detected an "inverted U-shaped relationship" between paternal age and intelligence quotient
Intelligence quotient
An intelligence quotient, or IQ, is a score derived from one of several different standardized tests designed to assess intelligence. When modern IQ tests are constructed, the mean score within an age group is set to 100 and the standard deviation to 15...
s (IQs) in 44,175 people from Israel. There was a peak at paternal ages of 25-44; fathers younger than 25 and older than 44 tended to have children with lower IQs. Malaspina et al. also reviewed the literature and found that "at least a half dozen other studies ... have demonstrated significant associations between paternal age and human intelligence."
A 2009 study by Saha et al. examined 33,437 children at 8 months, 4 years, and 7 years. The researchers found that paternal age was associated with poorer scores in almost all neurocognitive
Neurocognitive
Neurocognitive is a term used to describe cognitive functions closely linked to the function of particular areas, neural pathways, or cortical networks in the brain substrate layers of neurological matrix at the cellular molecular level...
tests used, but that maternal age was associated with better scores on the same tests. An editorial accompanying the paper by Saha et al. emphasized the importance of controlling for socioeconomic status
Socioeconomic status
Socioeconomic status is an economic and sociological combined total measure of a person's work experience and of an individual's or family’s economic and social position in relation to others, based on income, education, and occupation...
in studies of paternal age and intelligence. A 2010 paper from Spain provided further evidence that average paternal age is elevated in cases of mental retardation.
Multiple sclerosis
A 2004 case-control study performed in Sweden involving 4,443 people with multiple sclerosisMultiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
and 24,194 matched controls found a risk of 2.00 if the fathers were 51–55 years old versus 21–25 years old; however, two subsequent studies did not confirm the association.
Schizophrenia
Studies examining schizophreniaSchizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and paternal age include:
- In a cohort of 87,907 people born in Jerusalem in 1964-1976 and followed through 1997, Malaspina et al. (2001) calculated relative riskRelative riskIn statistics and mathematical epidemiology, relative risk is the risk of an event relative to exposure. Relative risk is a ratio of the probability of the event occurring in the exposed group versus a non-exposed group....
s for individuals' being diagnosed with schizophrenia given their fathers' ages at their births, controlling for maternal age and other factors. Compared with people whose fathers were younger than 25 years, the relative risk was 2.02 if a person's father was 45–49 years old and 2.96 if a person's father was 50 years or older. As noted in the newsmedia, the authors claimed that over 26% of the 658 schizophrenia cases could be attributed to paternal age. - A study published in 2004 by Sipos and colleagues found an association between paternal age and hospitalization for schizophrenia in persons with no family history of schizophrenia; the hazard ratioHazard ratioIn survival analysis, the hazard ratio is the ratio of the hazard rates corresponding to the conditions described by two sets of explanatory variables. For example, in a drug study, the treated population may die at twice the rate per unit time as the control population. The hazard ratio would be...
was 1.60 for each 10 year increase in paternal age. The cohort included 712,014 Swedish people, of whom 639 (0.09%) had been admitted with a diagnosis of schizophrenia after follow-up for a mean of nine years. - A 2009 meta-analysis was performed that included Malaspina et al.. (2001) and nine 1958-2008 studies with comparable available data. It concluded that paternal age was associated with schizophrenia "primarily among offspring of fathers ages 55 and over" and that "compared with other known risk factors for schizophrenia, advanced paternal age appears to be intermediate in magnitude."
- A 2010 case-control study from Spain using age as a continuous (not categorical) variable and using Bonferroni correctionBonferroni correctionIn statistics, the Bonferroni correction is a method used to counteract the problem of multiple comparisons. It was developed and introduced by Italian mathematician Carlo Emilio Bonferroni...
failed to find a higher paternal age in persons with diagnoses corresponding to ICD-10 codes for schizophrenia, schizotypal and delusional disorders.
Other conditions and diseases correlated with paternal age
- AchondroplasiaAchondroplasiaAchondroplasia dwarfism occurs as a sporadic mutation in approximately 85% of cases or may be inherited in an autosomal dominant genetic disorder that is a common cause of dwarfism...
and chondrodystrophyChondrodystrophyChondrodystrophy refers to a skeletal disorder caused by one of myriad genetic mutations that can affect the development of cartilage.... - AcrodysostosisAcrodysostosisAcrodysostosis also known as Arkless-Graham syndrome or Maroteaux-Malamut syndrome is a rare congenital malformation syndrome which involves shortening of the interphalangeal joints of the hands and feet, mental deficiency in approximately 90% of affected children, and peculiar facies...
- AniridiaAniridiaAniridia is the absence of the iris. Aniridia usually involves both eyes. It can be congenital or caused by a penetrant injury. Isolated aniridia is a congenital disorder which is not limited to a defect in iris development, but is a panocular condition with macular and optic nerve hypoplasia,...
- Apert syndromeApert syndromeApert syndrome is a form of acrocephalosyndactyly, a congenital disorder characterized by malformations of the skull, face, hands and feet. It is classified as a branchial arch syndrome, affecting the first branchial arch, the precursor of the maxilla and mandible...
- Basal cell nevus syndromeNevoid basal cell carcinoma syndromeNevoid basal cell carcinoma syndrome , also known as basal cell nevus syndrome, multiple basal cell carcinoma syndrome, Gorlin syndrome, and Gorlin–Goltz syndrome, is an inherited medical condition involving defects within multiple body systems such as the skin, nervous system, eyes, endocrine...
- CataractCataractA cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light...
s - Cerebral palsyCerebral palsyCerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
, athetoid/dystonic - CHARGE syndromeCHARGE syndromeCHARGE syndrome , is a syndrome caused by a genetic disorder. It was first described in 1979.In 1981, the term "CHARGE" came into use as an acronym for the set of unusual congenital features seen in a number of newborn children...
- Cleft palate
- Cleidocranial dysostosisCleidocranial dysostosisCleidocranial dysostosis, also called Cleidocranial dysplasia, is a hereditary congenital disorder due to haploinsufficiency caused by mutations in the CBFA1 gene also called Runx2, located on the short arm of chromosome 6....
- Costello syndromeCostello syndromeCostello syndrome, also called faciocutaneoskeletal syndrome or FCS syndrome, is a rare genetic disorder that affects many parts of the body. It is characterized by delayed development and mental retardation, distinctive facial features, unusually flexible joints, and loose folds of extra skin,...
- CraniosynostosisCraniosynostosisCraniosynostosis is a condition in which one or more of the fibrous sutures in an infant skull prematurely fuses by ossification, thereby changing the growth pattern of the skull...
- Crouzon syndromeCrouzon syndromeCrouzon syndrome is a genetic disorder known as a branchial arch syndrome. Specifically, this syndrome affects the first branchial arch, which is the precursor of the maxilla and mandible...
- Diaphragmatic herniaDiaphragmatic herniaDiaphragmatic hernia is a defect or hole in the diaphragm that allows the abdominal contents to move into the chest cavity. Treatment is usually surgical.The following types of diaphragmatic hernia exist:* Congenital diaphragmatic hernia** Morgagni's hernia...
- Duchenne muscular dystrophyDuchenne muscular dystrophyDuchenne muscular dystrophy is a recessive X-linked form of muscular dystrophy, which results in muscle degeneration, difficulty walking, breathing, and death. The incidence is 1 in 3,000 boys. Females and males are affected, though females are rarely affected and are more often carriers...
- ExostosesExostosisAn exostosis is the formation of new bone on the surface of a bone. Exostoses can cause chronic pain ranging from mild to debilitatingly severe, depending on where they are located and what shape they are....
, multiple - Extremities: congenital malformations in general, and reduction defects of the upper limb in specific
- Fibrodysplasia ossificans progressivaFibrodysplasia ossificans progressivaFibrodysplasia ossificans progressiva , sometimes referred to as Stone Man Syndrome, is an extremely rare disease of the connective tissue. A mutation of the body's repair mechanism causes fibrous tissue to be ossified when damaged. In many cases, injuries can cause joints to become permanently...
- Heart: atrial septal defectAtrial septal defectAtrial septal defect is a form of congenital heart defect that enables blood flow between the left and right atria via the interatrial septum. The interatrial septum is the tissue that divides the right and left atria...
s, ventricular septal defectVentricular septal defectA ventricular septal defect is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart.The ventricular septum consists of an inferior muscular and superior membranous portion and is extensively innervated with conducting cardiomyocytes.The membranous...
s, pulmonary valve stenosisPulmonary valve stenosisPulmonary valve stenosis is a heart valve disorder in which outflow of blood from the right ventricle of the heart is obstructed at the level of the pulmonic valve. This results in the reduction of flow of blood to the lungs. Valvular pulmonic stenosis accounts for 80% of right ventricular outflow...
, right ventricular outflow tract obstruction - HemangiomaHemangiomaA hemangioma of infancy is a benign self-involuting tumor of endothelial cells, the cells that line blood vessels. It usually appears during the first weeks of life and sometimes resolves by age 10. In more severe case hemangioma may have permanency, if not treated by a physician...
- HemiplegiaHemiplegiaHemiplegia /he.mə.pliː.dʒiə/ is total paralysis of the arm, leg, and trunk on the same side of the body. Hemiplegia is more severe than hemiparesis, wherein one half of the body has less marked weakness....
- Hemophilia A
- HydrocephalusHydrocephalusHydrocephalus , also known as "water in the brain," is a medical condition in which there is an abnormal accumulation of cerebrospinal fluid in the ventricles, or cavities, of the brain. This may cause increased intracranial pressure inside the skull and progressive enlargement of the head,...
- Klinefelter's syndromeKlinefelter's syndromeKlinefelter syndrome, 46/47, XXY, or XXY syndrome is a condition in which human males have an extra X chromosome. While females have an XX chromosomal makeup, and males an XY, affected individuals have at least two X chromosomes and at least one Y chromosome...
- Lesch-Nyhan syndromeLesch-Nyhan syndromeLesch–Nyhan syndrome , also known as Nyhan's syndrome, Kelley-Seegmiller syndrome and Juvenile gout, is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase , produced by mutations in the HPRT gene located on X chromosome. LNS affects about...
- Marfan syndromeMarfan syndromeMarfan syndrome is a genetic disorder of the connective tissue. People with Marfan's tend to be unusually tall, with long limbs and long, thin fingers....
- Nasal aplasiaAplasiaAplasia is defined in general as "defective development or congenital absence of an organ or tissue." In the field of hematology, the term refers to "incomplete, retarded, or defective development, or cessation of the usual regenerative process."-Examples:*Acquired pure red cell aplasia*Aplasia...
- Neural tube defects
- Oculodentodigital syndrome
- Osteogenesis imperfectaOsteogenesis imperfectaOsteogenesis imperfecta is a genetic bone disorder. People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen...
type IIA - Pfeiffer syndromePfeiffer syndromePfeiffer syndrome is a rare genetic disorder characterized by the premature fusion of certain bones of the skull , which prevents further growth of the skull and affects the shape of the head and face...
- Polycystic kidney diseasePolycystic kidney diseaseAutosomal dominant polycystic kidney disease is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels...
- Polyposis coli
- Preauricular cystPreauricular sinus and cystA preauricular sinus or cyst A preauricular sinus or cyst A preauricular sinus or cyst (also known as a "Congenital auricular fistula," "Congenital preauricular fistula," "Ear pit", and "Preauricular cyst"...
- ProgeriaProgeriaProgeria is an extremely rare genetic condition wherein symptoms resembling aspects of aging are manifested at an early age. The word progeria comes from the Greek words "pro" , meaning "before", and "géras" , meaning "old age"...
- Psychotic disordersPsychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
- von Recklinghausen neurofibromatosisNeurofibromatosis type INeurofibromatosis type I , formerly known as von Recklinghausen disease after the researcher who first documented the disorder, is a human genetic disorder. It is possibly the most common inherited disorder caused by a single gene...
- Retinitis pigmentosaRetinitis pigmentosaRetinitis pigmentosa is a group of genetic eye conditions that leads to incurable blindness. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some...
- RetinoblastomaRetinoblastomaRetinoblastoma is a rapidly developing cancer that develops in the cells of retina, the light-detecting tissue of the eye. In the developed world, Rb has one of the best cure rates of all childhood cancers , with more than nine out of every ten sufferers surviving into...
, bilateral - Situs inversusSitus inversusSitus inversus is a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions. The normal arrangement is known as situs solitus...
- Soto's basal cell nevus
- Syndromes of multiple systems (including Down syndrome)
- Thanatophoric dysplasiaThanatophoric dysplasiaThanatophoric dysplasia is a severe skeletal disorder characterized by extremely short limbs and folds of extra skin on the arms and legs.-Symptoms:Infants with this condition have disproportionately short arms and legs with extra folds of skin...
- Treacher-Collins Syndrome
- Tuberous sclerosisTuberous sclerosisTuberous sclerosis or tuberous sclerosis complex is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioral...
- Urethral stenosisMeatal stenosisUrethral meatal stenosis or urethral stricture is a narrowing of the opening of the urethra at the external meatus , thus constricting the opening through which urine leaves the body from the urinary bladder....
- Waardenburg syndromeWaardenburg syndromeWaardenburg syndrome Waardenburg syndrome Waardenburg syndrome (also Waardenburg Shah Syndrome, Waardenburg-Klein syndrome, Mende's syndrome II, Van der Hoeve-Halbertsma-Waardenburg syndrome, Ptosis-Epicanthus syndrome, Van der Hoeve-Halbertsma-Gualdi syndrome, Waardenburg type Pierpont,[5] Van...
- Wilms' tumorWilms' tumorWilms' tumor or nephroblastoma is cancer of the kidneys that typically occurs in children, rarely in adults.Its common name is an eponym, referring to Dr. Max Wilms, the German surgeon who first described this kind of tumor....
Mortality of offspring
A 2008 paper from Denmark found a higher overall mortality rate for children (i.e., mortality rate up to age 18) of older fathers versus younger fathers. The relative mortality rates were especially high for certain conditions; for example, for congenital malformations and injury/poisoning, the adjusted mortality rate ratios were 2.35 and 3.43 respectively for children of fathers aged 45 years or more compared with children of fathers aged 25–29 years.Pathophysiology
At least two hypothesized chains of causality exist whereby increased paternal age may lead to health effects:- Genetic mutations: In contrast to oogenesisOogenesisOogenesis, ovogenesis or oögenesis is the creation of an ovum . It is the female form of gametogenesis. The male equivalent is spermatogenesis...
, which involves 22 mitoticMitosisMitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
divisions prior to birth and 2 meioticMeiosisMeiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
divisions after birth, spermatogenesisSpermatogenesisSpermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
involves 30 mitotic divisions prior to puberty, and 4 mitotic and 2 meiotic divisions after puberty. Advanced paternal age may therefore lead to "copy error" in replication or the accumulation of mutagenMutagenIn genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...
s, thereby leading to de novoDe novoIn general usage, de novo is a Latin expression meaning "from the beginning," "afresh," "anew," "beginning again." It is used in:* De novo transcriptome assembly, the method of creating a transcriptome without a reference genome...
mutations in sperm DNA. - EpigeneticEpigeneticsIn biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...
processes such as parental imprinting could explain the association between paternal age and schizophrenia.
Clinical implications
The American College of Medical GeneticsAmerican College of Medical Genetics
The American College of Medical Genetics is an organization composed of biochemical, clinical, cytogenetic, medical and molecular geneticists, genetic counselors and other health care professionals committed to the practice of medical genetics....
notes that there is no standard definition of "advanced paternal age." Although the College recommends obstetric ultrasonography
Obstetric ultrasonography
Obstetric sonography is the application of medical ultrasonography to obstetrics, in which sonography is used to visualize the embryo or foetus in its mother's uterus...
at 18–20 weeks gestation in cases of advanced paternal age "to evaluate fetal growth and development," it notes that this procedure "is unlikely to detect many of the conditions of interest." Bray et al.. (2006) expressed an opinion that any adverse effects of advanced paternal age "should be weighed up against potential social advantages for children born to older fathers who are more likely to have progressed in their career and to have achieved financial security."
Further reading
- Gavrilov, L.A., Gavrilova, N.S. Human longevity and parental age at conception. In: J.-M.Robine, T.B.L. Kirkwood, M. Allard (eds.) Sex and Longevity: Sexuality, Gender, Reproduction, Parenthood, Berlin, Heidelberg: Springer-Verlag, 2000, 7-31.
- Gavrilov, L.A., Gavrilova, N.S. Parental age at conception and offspring longevity. Reviews in Clinical Gerontology, 1997, 7: 5-12.
- Gavrilov, L.A., Gavrilova, N.S. When Fatherhood Should Stop? Letter. Science, 1997, 277(5322): 17-18.