The association between the presence of genetic disease in the offspring and the paternal age: A systematic review La asociación

Objective: To determine the association between the presence of gene-tic disease in the offspring and the paternal age. Methods: We carried out a systematic review in: Medline (Ovid), EM-BASE, The Cochrane Central Register of Controlled Trials (CENTRAL), from encompassing the full catalogue up until October 2022. We included RCTs, Cohort, case-control and cross-sectional studies. Every study was evaluated according to eligibility criteria. Meta-analysis was not possible given the clinical and methodological heterogeneity. Results: We identified 502 studies through the database search. Forty-five studies were selected for data collection and were included in the qualitative analysis. In this systematic review we did not find associations with anomalies such as Trisomy 18, Obsessive Compulsive Disorder, Tourette syndrome, schizoaffective disorder, adverse peri-natal outcomes, hematologic disturbances, microcephaly, hydrocephalus, gastrointestinal disturbances, cleft lip with or without cleft palate, cleft palate, and genitourinary disturbances. In contrast, we found a tendency of association between older fathers and psychiatric disorders (schizophrenia, autism, bipolar disorder syndrome, intellectual disability), nervous system cancer and overall musculoskeletal congenital anomalies. Conclusion: There is a tendency of association among the advanced paternal age and an increased number of birth defects regarding some specific conditions.


Introduction
According to the National Human Genome Re- veloped countries. (1)(2)(3) Postponing pregnancy comes with several consequences, especially for the offspring.
The negative impact of advanced maternal age on reproductive outcomes has been widely studied and is well documented. It has been linked to decrease in fertility rates, increase in miscarriage rates, pregnancy complications, congenital anomalies, and perinatal mortality. (1,4,5) Just as maternal age is of concern, paternal age, independently from the former, should also be a topic of interest. Even if it is still not as clear, advanced paternal age has an important correlation to negative outcomes both for the pregnancy, and for the newborn. (6)(7)(8)(9) Some evidence points out a negative effect of father aging on embryo development beyond the cleavage stage. Besides, advanced paternal age correlates with an increased risk of pregnancy loss, and newborn disorders such as monogenic diseases, autosomal dominant diseases, neuropsychiatric and neurocognitive disorders, and even augmented cancer risk. (6,10) Most of the available studies are retrospective, and there is a considerable heterogeneity among them. The principal issue being that not even an age threshold has been established yet. Some propose >34 years, others >40 years, others >45 years, and so on. (6) It is mandatory to elucidate the exact consequences of paternal advanced age on pregnancy and the offspring, mainly for couple counseling regarding postponing childbearing. (1) Then, we aimed to determine the association of specific outcomes in the offspring and the paternal age.

Methods
We conducted this study according to the (MeSh), Entree language, and related text words.

Collection of data
We first examined on a title/abstract level, and then, retrieved the complete articles. We reviewed the full-text studies with a pre-specified inclusion and exclusion criteria. Then, we collected data using a standardized format, which contained the study design, participants, variables, comparisons, and results. We confirmed the data entry and verified the information for greater accuracy. We solved disagreements by consensus between two researchers.

Synthesis of the results
We could not perform Meta-analysis given the clinical and methodological heterogeneity presented in the studies.

Studies selection
We identified 502 studies through the search. After excluding duplicates, we included 44 records in the qualitative analysis ( Figure 1).

Characteristics of Included studies
We included 47 records in Table 1:

Characteristics of the excluded studies
The studies excluded treated different topics or had a different study design.

1) Wilms Tumor
We found three studies about Wilms tumor. (26,39,40) Only one of them found an increased risk for fathers >55 years, compared to those <20 years, with an OR of 2.1. (39)

2) Down Syndrome
Various studies focused on Down Syndrome. (15,17,27,41) Two of them found no association between the two variables. (31,42) One of them, found an increasing adjusted relative risk for Down syndrome with increasing paternal age.  (43) that found that fathers 41 years and older, independent of the mother's age, had a strongly increased risk for having offspring with Down syndrome. They found a significant increased risk when associated with higher mother's age (p=0.03).
In British Columbia Registry for Handicapped Children, authors found that the mean paternal age was about half a year greater than the entire population of live births after controlling for maternal age (p=0.05). They encountered an increase of 1.024-fold for each year of paternal age, after adjusting for maternal age. (44) Another study found that the prevalence of Down syndrome increased with increasing paternal age at a statistically significant level (p=0.05). They also found that, when children with Down's syndrome were excluded from the study, the association was slightly reduced. (27) One of the studies reviewed the association of mother, father, and maternal grandmother's age, with Down Syndrome incidence. They found that the effect of age of mother and father was smaller than the effect of maternal grandmother age. Nonetheless, for every year of father's age, there was a significant (p<0.001) relation with Down Syndrome. (28) The estimated odds ratio for Down syndrome associated with a 10-year increase in paternal age was 1.13, 95%CI (0.85 to 1.52).
Authors concluded that there was no association between paternal age and Down syndrome.
Nevertheless, the estimated effect is much smaller than the effect of maternal age. (29)

3) Trisomy 18
Only one of the included studies, evaluated the relationship of Trisomy 18 and paternal age. (11) There was an OR for paternal age >45 of 1.90 (95% CI: 0.83 to 4.41). So, they concluded that Trisomy 18 was not related to paternal age.

4) Retinitis Pigmentosa
Also, only one of the studies studied the association between Retinitis Pigmentosa and father's age (46). They found that, for the clinically related late onset-mild sporadic form, the mean paternal age differs from the general population (p<0.001). The paternal age was not higher in other types.

5) Hematologic malignancies
We found four studies regarding hematologic malignancies. One of them, (23)  significantly decreased among offspring to the oldest parents.
Another one did not find a significant relationship between circulatory malformations, and advanced paternal age. (27) One of the studies, (26)

6) Mental and neurocognitive disorders
Nine studies analyzed the association between paternal advanced age, and mental and neurocognitive disorders. (22,46) One of them found that advanced paternal age was associated with a wide range of cognitive dysfunctions. (47) Even though, after multivariate analyses, the only significant difference was the age at onset.
Another one studied the association between parental age and bipolar disorder. (46) After adjusting for confusing factors, offspring of fathers aged ≥50 years had 2.8-fold increased odds of bipolar disorder, as compared to those with fathers aged 30-34 years. The odds were also increased in fathers aged 20-24 years. All these findings were statistically significant.
One of them found that the offspring of older parents had increased risk compared with those of parents aged 25 to 29 years for a mental health disorder. (22) Nonetheless, when particular disorders were analyzed, the relationship changed. The older fathers increased the risk of schizophrenia, mental retardation, and autism spectrum disorders. In contrast, those from young fathers increased the risk of substance abuse, hyperkinetic disorders, and mental retardation.
One of the studies found schizophrenia associated with advanced paternal age. (32) There was a persistent risk for paternal age >50 years, after controlling for socioeconomic factors and family psychiatric history.
Another study found a direct correlation with educational length. (48) Conscripts born from fathers aged >40 years had a higher proportion of schizophrenia spectrum disorder and psychiatric admissions among their siblings.
One study showed that patients with schizophrenia, and also patients with other mental disorders, manifested a statistically significant higher paternal age, compared to controls. (17) They concluded that there seems to be a higher risk for the development of schizophrenia in offspring from advanced age fathers.
Another one found a significant association between intellectual disability risk and paternal age. (16) Both mild and severe cases demonstrated a significant association with advanced paternal age.
One study reported that offspring from younger fathers had no increased risk of Tourette syndrome and chronic tic disorder, in contrast with the previous studies. (12) Also, another study reported that each ad- of Tourette disorder by 9.1%. (35) Nonetheless, this was a nonsignificant finding.

7) Neurofibromatosis
Three studies evaluated the association between neurofibromatosis and advanced paternal age. (21,25,36) One of them reported increased risk of non-familial neurofibromatosis for offspring of fathers aged 35-39 years, and ≥40 years (significantly higher). (21) Another study found a significant difference between the mean paternal age at birth of Neurofibromatosis 1 sporadic cases. (25) Another one found no association among these fathers of patients with Sporadic Neurofibromatosis 1 and control subjects (p=0.07).
There was no change when adjusted for socioeconomic status or maternal age. (36)

8) Other musculoskeletal diseases
Eight more studies discussed the relationship between advanced paternal age, and other musculoskeletal diseases. One of them found that for non-familial phakomatoses, other than neurofibromatosis 1, the risk estimate for offspring of fathers aged ≥40 years was higher, but non-statistically significant. Also, they found that paternal age was not associated with familial phakomatoses. (21) Another one studied achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta. (34)  Another study, found that the prevalence of syndromes of multiple systems increased with increasing paternal age, and, to a lesser extent, for malformations of extremities. (27) One study, described that fathers in the highest quintile of paternal age for the general population had a statistically significant higher relative risk to have a child with sporadic OI compared with fathers in the lowest quintile. (52) Another one, found that there was no statistical difference between the ages of the fathers for non-inherited achondroplasia compared to the controls. (33) Another study reported slightly higher significant risk for musculoskeletal congenital anomalies per 10-year increase in paternal age. (49)   years, and older, the excess risk was 38%, 45%, and 42%, respectively. They also studied the relationship between paternal age and other subgroups: facial appearance, short stature, extremities, early overgrowth, Marfan, and other skeletal changes. They found a similar risk in these specific subgroups to those found for syndromic musculoskeletal congenital anomalies; however, in the specific subgroups short stature, extremities, and marfan.

The Clinical Epidemiology of Skeletal
Dysplasia in South America found that mean parental ages had higher values in cases than controls. (24) However, logistic regression showed paternal age higher than 39-year as a statistically significant risk factor for osteochondrodysplasias, regardless of maternal age.
They found that, except for autosomal recessive osteochondrodysplasias and for lethal osteogenesis imperfecta, for which paternal age was not different from controls, a significant association with paternal age was found for achondroplasia, thanatophoric dysplasia, non-lethal osteogenesis imperfecta, and all the other autosomal dominant osteochondrodysplasias.

9) Embryo aneuploidies
Five studies analyzed the relationship between embryo aneuploidies and paternal age. One of them found that embryo aneuploidy was significantly greater for all men aged >40 years when compared to men <34 years (p <0.001) when using donor eggs. (18) They reported that no significant difference in embryo aneuploidy was seen between groups of men aged 40-44, 45-60, and 60 and older.
Another one evaluated the effect of paternal age in embryos. (37) Authors found that controlling for donor oocyte age, there was no significant association between male part-   9% (p 0.15). (49) The last one found that male partner age was not significantly associated with aneuploidy rate at any age. (50)

10) Perinatal complications
Only one study reviewed the relationship between perinatal complications and paternal age. (14) They reported that the frequency of perinatal complications was higher in the youngest (<30 years) and oldest ( ≥60 years) paternal age groups. They reported that adjustment for maternal age resulted in null independent influence of paternal age on adverse pregnancy outcomes. That is so, they concluded that the observed influence of paternal age was attributable primarily to concordant similar extremes of maternal age. Of note, the use of assisted reproductive technology in live births significantly increased as paternal age increased with 0.1% of pregnancies achieved with assisted reproductive technology when paternal age was <30 compared to 2.5% when >60 years of age (p <0.001). They also noted that after accounting for the confounding influences of maternal age, race, Medicaid status and multifetal gestation, increased paternal age was not associated with a significant increase in the rate of pre-eclampsia, preterm birth, fetal growth restriction, congenital anomaly, genetic disorder or neonatal intensive care admission with analyses stratified by use of assisted reproductive technology.

11) Cancer
Three studies described different cancer incidences and their relationship with advanced father's age. The biggest one which we previously mentioned reported that there was an increased risk of cancer overall and leukemias, for older maternal and paternal age without mutual adjustment. (13)  Another one which studied brain tumors, found that parental age was not associated with brain tumors overall. (51) The third one already mentioned that paternal age was not associated with the risk of developing retinoblastoma, irrespective of maternal age. (26) Also, they found no significant paternal age effects in childhood central nervous system cancer, before adjust- between paternal age and Non-Hodgkin lymphoma, or Wilms tumor.

12) Other congenital malformations
There were two studies about various congenital malformations and its relationship with paternal age. One of them found that for neural tube defects in general, meaning: anencephaly and/or spina bifida, there was an overall trend of increasing risk with increasing paternal age. (30) They reported that risk increased for each age group category above referent group (25)(26)(27)(28)(29) years), except for men in the 45-49 years category. A similar pattern was reported for both anencephaly and spina bifida, individually.
They found that cataracts also showed a trend of increasing risk, except for the 45-49-yearold group. The analysis of microcephaly, hydrocephalus, tracheoesophageal fistula, atresia of the large intestine, anomalies of the diaphragm, cleft palate, cleft lip with or without cleft palate, hypospadias, atresia of the urethra, found some elevated odds ratios for age categories over 29 years, but the estimates did not follow a monotonic pattern. In addition, they reported that many estimates were imprecise, as reflected in the wide confidence intervals. They found no consistent association with older paternal age and pyloric stenosis, obstructive renal defects, cystic kidney, Hirschsprung's disease, or renal agenesis. Interestingly, they also found that several defects showed an association with younger paternal age (<20 years). As we already said before, they found a strong association The other one reported that there were no differences in the prevalence of congenital malformations in different paternal age groups. (27) However, they observed that prevalence of syndromes of multiple systems increased with increasing paternal age, and, to a lesser extent, for malformations of extremities. When children with Down's syndrome were excluded, the association between paternal age and syndromes of multiple systems was slightly reduced.

Discussion
Nowadays, given the tremendous changes in health, social, and most of all, cultural scenarios, delaying childbearing has become a widespread phenomenon, mainly among developed countries. (1)(2)(3) Postponing pregnancy comes with several consequences, especially for the offspring.
Just as maternal age is of concern, paternal age, independently from the former, should also be a topic of interest. Even if it is still not as clear, advanced paternal age has been correlated to negative outcomes both for the pregnancy, and for the newborn. (6)(7)(8)(9) One of the most important things is that there is no obvious cut-off point beyond which paternal age should be considered as 'advanced'; that is, a dose-dependent model is proposed instead. (53,54) The main biological hypothesis proposed to explain the effects of advanced paternal age is called the "copy error". (55,56)  showing that several conditions due to new, dominant mutations, are associated with older paternal age. (57) However, some new data has indicated that a simple copy error model may not be a primary mechanism underlying some conditions. (56) It is also reasonable to suggest that advanced paternal age may be associated with an adverse psychosocial environment for the offspring, such as unwanted pregnancy, and that older fathers may have certain personality traits that would result in an increased age of parenthood. (58) The reason that an important paternal age effect is found for some conditions re-  (36,59) Another proposed hypothesis is based on the variation in the susceptibility of specific genes to copy errors, the existence of a maternal effect. It proposes that the paternal age effect is not of the same magnitude for all autosomal dominant mutations and may even not exist at all for some conditions. (36) Some studies have reported conflicting results for paternal age and birth defects, but they often evaluated only a single defect or a small group of defects, or they included a limited study size.
We found no statistically significant association between advanced paternal age and anomalies such as Trisomy   Regarding neurofibromatosis, there is evidence that the majority of de novo NF1 and NF2 mutations are of paternal origin. (60,61) Also, a paternal age effect for this disease, specially sporadic NF1, has been reported consistently, although the age difference has not always been statistically significant. (36,62) The literature shows the increase of both mean paternal age and age difference of the parents in dominant retinitis pigmentosa (38.8 + 4.7 years) as compared with the mean age of fathers in the general population (29.1 years, p < 0.001). (63) Since the 80's, advanced parental age has been proposed to constitute a generic risk factor for the development of any mental disorder. (64) Nonetheless, the evidence also found an increased risk for younger fathers. However, there are only a few studies that examined the effect of paternal age across different diagnostic categories simultaneously. (64)(65)(66) Of note, we found that the association between paternal age and mental disorders, followed a U shape, meaning that there was a higher incidence for older, but also, younger fathers offspring. For instance, for schizophrenia, we found an increased incidence for fathers ≥40 years, and ≤20 years. The literature strongly supports our findings. (32,(67)(68)(69)(70)(71) For instance, one meta-analysis concluded that higher paternal age doubles or triples the risk for schizophrenia in the offspring of men above 40 years of age but also of fathers younger than 25 years old. (72) Another meta-analysis suggested that parental age >55 years constitutes a risk, (73) while a third one reported that both parental ages <20 and >35 constitute a risk factor. (74) Neural tube defects are also well studied.
For some of them there is strong evidence supporting a direct association between paternal age and incidence of illness, while there is conflicting information about others. Data conflict on whether there is a relation between paternal age and defects such as hydrocephalus and oral clefts. (30) We found something similar for schizophrenia, for neural tube defects combined.
The risk was higher for <20 years-old fathers too. The same pattern was seen for anencepha-  (76) in 1973 that fathers of patients with sporadic bilateral retinoblastoma are more than 1.2 years older, than fathers of the general population, while fathers of sporadic unilateral retinoblastoma patients do not differ in average age from fathers in the general population. (39) Down syndrome is one of the most studied conditions and the evidence is conflicting.
Some studies report a positive association, (30,77) while some others find no significant effect. (8) The same was found in this study. We also found no consensus for Down syndrome. Some studies reported no significant relationship while others reported a significant increased risk for fathers ≥41 years old, or >50 years old.
Of note, the same U shape as for mental disorders, was found for this disease. The incidence was higher for <20 and 25-29 year-old-father offspring too.

Strengths and limitations
This is the first systematic review that seeks an association between paternal age and genetic diseases. This type of review can provide valuable information for future decision making for couples considering childbearing.

Conclusions
We found a tendency of association between older fathers and psychiatric disorders (schizophrenia, autism, bipolar disorder syndrome, intellectual disability), nervous system cancer and musculoskeletal congenital anomalies.
In contrast, we did not find associations