Brief description of patient problem/setting (summarize the case very briefly):
Advanced maternal age and its potential complications in pregnancy is well-studied. In fact, clinical guidelines list any female over 35 years old to be considered a high-risk pregnancy. However, advanced paternal age and its potential links to pregnancy complications remains grossly unexplored. Global trends show that individuals are waiting longer to have children, so it is important to understand potential complications of advanced age of either parent—be it male or female—not only to prevent poor perinatal outcomes but also to guide clinical guidelines and education in family planning.
Search Question:
Do infants born to fathers of advanced paternal age, defined as 40 years or older, have an increased risk of pregnancy/perinatal complications?
Question Type: What kind of question is this?
☒Etiology ☐Screening ☐Diagnosis
☒Prognosis ☐Treatment ☐Harms
What other types of study might you include if meta-analyses or systematic reviews are not available?
Systematic Review
Meta Analyses
RCT
Cohort Studies (Prospective / Retrospective)
Case-Control Series
RCTs would be the highest available level of evidence excluding systematic reviews and/or meta-analysis; however, it would be difficult and unethical to purposely expose infants to the risk of poor pregnancy outcomes stratified by paternal age. Because this is a question of prognosis/etiology, cohort studies, especially retrospective ones, and case-control series would provide the most ethical, empirically sound method to analyze causation and future risk of poor outcomes.
Retrospective cohorts contain relevant clinical information used to gain more insight into correlation and causation of interventions like advanced paternal age without exposing participants to potential harm; because I am exploring the association of poor pregnancy outcomes with advanced paternal age, I would not want to risk using a study design which could expose new individuals to the likelihood of infantile morbidity/mortality. Retrospective cohorts do have faults. Clinical sites, demographics, geography, patient personality, and even documentation methods are not uniform between research teams, so findings may be skewed when comparing gained information to the general population. However, we must use the best available evidence to understand the correlation/causation of paternal age and pregnancy outcomes to better guide clinical practice/guidelines of family planning and paternal counseling.
PICO search terms:
| P | I | C | O |
| Infants | Advanced paternal age | Fathers younger than 40 | Pregnancy/perinatal outcomes |
| Neonates | Fathers over 40 | Younger fathers | Birth weight |
| Perinatal | Older fathers | Apgar score | |
| Newborns | Preterm birth | ||
| Miscarriages and/or stillbirth |
Search tools and strategy used:
| Database | Search Terms | Filters | Results |
| PubMed | Paternal age and pregnancy | Last yearClinical TrialsReview | 16 |
| Cochrane Library | Paternal age and pregnancy outcomes | Reviews | 0 |
| TRIP Database | Advanced paternal age and pregnancy | Systematic ReviewsUSA | 6 |
| Google Scholar | Advanced paternal age and pregnancy outcomes | Last five years | 17,400 |
| NEJM | Advanced paternal age and pregnancy | Reviews | 28 |
Current research < 5 years with a high level of evidence in the form of systematic reviews, meta-analyses, and/or RCTs were preferred. Some databases offered no results, like Cochrane, which was disappointing, but others, like Google Scholar, offered numerous results. It was difficult to sort through the results, as many were related to advanced maternal age and pregnancy outcomes while few mentioned paternal age and its association with pregnancy outcomes. Though I found the studies on advanced maternal age interesting, they did not fit my study criteria as the mother is less than 35 years old so I excluded studies listing those parameters. Many of the listed results were also dated over 5 years, which I also excluded so as to keep my research current. Some retrospective cohort studies were initially relevant, but I later excluded them because the data was gathered from 1960-1980–years in which the clinical guidelines were not applicable to current practice.
Additionally there were many results that mentioned advanced paternal age and its effect on fertility. In fact, many, if not most, results were related to these terms. Though related, I am specifically interested in how advanced paternal age influences fetal pregnancy outcomes. Some studies were based in other countries which I felt comfortable including because they had the highest level of evidence and were current. I did include some literature reviews in addition to those articles with higher levels of evidence because they included current APA guidelines in addition to suggestions regarding clinical practice, such as the need for paternal age counseling in family planning discussions.
| 1. Systematic Review of Literature Brandt JS, Cruz Ithier MA, Rosen T, Ashkinadze E. Advanced paternal age, infertility, and reproductive risks: A review of the literature. Prenatal Diagnosis. 2019;39:81–87. https://doi.org/10.1002/pd.5402 advanced paternal age, infertility, and reproductive risks literature review.pdf |
| ABSTRACTAdvanced paternal age (APA) is associated with infertility and other reproductive risks. Studies looking at APA and outcomes have used different paternal age cut‐offs, which has complicated systematic evaluations of reproductive risk associated with paternal aging. This review of the literature suggests that the impact of paternal aging on adverse reproductive outcomes is small, but significant. Studies suggest the incidence of paternal age effect disorders attributed to de novo autosomal dominant mutations is less than 0.5%. Other risks associated with APA include infertility, miscarriage, birth defects, poor neurodevelopmental outcomes, and childhood cancer. Although the increasing prevalence of APA has mirrored the rise in maternal age, this topic has not received similar attention. In this review, we summarize the available literature on the reproductive risks associated with APA to provide a framework for comprehensive genetic counseling and evidence‐based management of APA pregnancies. |
| I chose this literature review as it summarizes the reproductive risks of advanced paternal age and pregnancies and it suggests guidelines from empirical-based research. I chose this because advanced paternal age isn’t well studied as advanced maternal age. In fact, there isn’t a stratified definition of what advanced paternal age is– American College of Obstetrics and Gynecology (ACOG), the National Society of Genetic Counselors, and the International Society of Prenatal Diagnosis (ISPD), have not published formal practice guidelines on this topic. The guidelines directly addresses my PICO question and also includes additional information regarding advanced paternal age such as the rates of autism! |
| 2. Retrospective, Population Based Cohort Y.S. Khandwala, V.L. Baker, G.M. Shaw, D.K. Stevenson, Y. Lu, M.L. Eisenberg. Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: BMJ (2018), 10.1136/bmj.k4372. https://www.bmj.com/content/363/bmj.k4372.longPMID: 30381468 PMCID: PMC6207919 DOI: 10.1136/bmj.k4372 Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States- population based cohort study.pdf |
| OBJECTIVETo evaluate the impact of advanced paternal age on maternal and perinatal outcomes in the United States. METHODS40, 529, 905 documented live births between 2007 and 2016 in the US. Primary perinatal outcomes were gestational age, birth weight, Apgar score at five minutes, admission to a neonatal intensive care unit, need for postpartum antibiotics, and seizures. Primary maternal outcomes were gestational diabetes and pre-eclampsia. Secondary outcome was the number of preventable perinatal events. In this retrospective cohort analysis, we drew on data published by the National Vital Statistics System, a federal data sharing programme provided by the Centers for Disease Control and Prevention and the National Center for Health Statistics. Through contracts with individual vital registration systems within each state, the National Center for Health Statistics compiles data on live births from birth certificates and permits distribution of these statistics for medical research purposes. Standard birth certificates contain self reported parental demographics such as age, race, and education as well as pregnancy and birth outcomes, which are documented by healthcare providers. All births occurring within the US since 1985 are captured by this system RESULTSHigher paternal age was associated with an increased risk of premature birth, low birth weight, and low Apgar score. After adjustment for maternal age, infants born to fathers aged 45 years or older had 14% higher odds of premature birth (odds ratio 1.14, 95% confidence interval 1.13 to 1.15), independent of gestational age, and 18% higher odds of seizures (1.18, 0.97 to 1.44) compared with infants of fathers aged 25 to 34 years. The odds of gestational diabetes was 34% higher (1.34, 1.29 to 1.38) in mothers with the oldest partners. 13.2% (95% confidence interval 12.5% to 13.9%) of premature births and 18.2% (17.5% to 18.9%) of gestational diabetes in births associated with older fathers were estimated to be attributable to advanced paternal age. CONCLUSIONAdvanced paternal age is associated with negative effects on both mothers and offspring. Given the relatively low prevalence of advanced paternal age in the US, population level impacts are currently modest. Nevertheless, as advanced paternal age has doubled in the US over the past generation, further investigation is warranted of the impact on birth outcomes and public health. When faced with vaccine hesitancy, public health authorities are looking for effective strategies to address this issue. In this paper, the findings of 15 published literature reviews or meta-analysis that have examined the effectiveness of different interventions to reduce vaccine hesitancy and/or to enhance vaccine acceptance are presented and discussed. From the literature, there is no strong evidence to recommend any specific intervention to address vaccine hesitancy/refusal. The reviewed studies included interventions with diverse content and approaches that were implemented in different settings and targeted various populations. Few interventions were directly targeted to vaccine hesitant individuals. Given the paucity of information on effective strategies to address vaccine hesitancy, when interventions are implemented, planning a rigorous evaluation of their impact on vaccine hesitancy/vaccine acceptance will be essential. |
| I decided to include this because it directly addresses my clinical question and was published exclusively in the US over a long period of time, which can be directly applicable to clinical practice. I liked this study because it included a large population size (n=, 40, 529, 905), was relatively recent (2018). It is a retrospective cohort study, so it does have the same empirical status for evidence as meta-analysis or systematic review, but I found it to be sufficient as level II evidence due to its large population size and longitudinal study design. |
| 3. Retrospective CohortAlio, A. P., Salihu, H. M., McIntosh, C., August, E. M., Weldeselasse, H., Sanchez, E., & Mbah, A. K. (2012). The Effect of Paternal Age on Fetal Birth Outcomes. American Journal of Men’s Health, 427–435. https://doi.org/10.1177/1557988312440718PMID: 22564913 DOI: 10.1177/1557988312440718https://journals.sagepub.com/doi/pdf/10.1177/1557988312440718 The Effect of Paternal Age on Fetal Birth Outcomes.pdf |
| AbstractResearch investigating the role of paternal age in adverse birth outcomes is limited. This population-based retrospective cohort study used the Missouri maternally linked data set from 1989 to 2005 to assess whether paternal age affects fetal birth outcomes: low birth weight (LBW), preterm birth (PTB), stillbirth, and small size for gestational age (SGA). We examined these outcomes among infants across seven paternal age-groups (<20, 20-24, 25-29, 30-34, 35-39, 40-45, and >45 years) using the generalized estimating equation framework. Compared with infants born to younger fathers (25-29 years), infants born to fathers aged 40 to 45 years had a 24% increased risk of stillbirth but a reduced risk of SGA. A 48% increased risk of late stillbirth was observed in infants born to advanced paternal age (>45 years). Moreover, advanced paternal age (>45 years) was observed to result in a 19%, 13%, and 29% greater risk for LBW, PTB, and VPTB (very preterm birth) infants, respectively. Infants born to fathers aged 30 to 39 years had a lower risk of LBW, PTB, and SGA, whereas those born to fathers aged 24 years or younger had an elevated likelihood of experiencing these same adverse outcomes. These findings demonstrate that paternal age influences birth outcomes and warrants further investigation. |
| This retrospective cohort study was included due to a few different factors: it looked at a period of over 16 years, and answered my question as it specifically looked at preterm birth, low birth weights. This study was geographically limited to Missouri, but did have a large sample size of 755, 344 patients between 1989-2005, which addresses issues of confounding factors. In using a predetermined population data set, selection bias is also decreased. I also liked this study because it addressed external, maternal factors like socioeconomic status, marital status, and race with statistical analysis; however, this information on fathers was not recorded. This article, because of this inclusion, has a higher level of applicability to the general population but is less specific with the inclusion of fathers of all ages. |
| 4. Retrospective CohortXi-Kuan Chen, Shi Wu Wen, Daniel Krewski, Nathalie Fleming, Qiuying Yang, Mark C. Walker, Paternal age and adverse birth outcomes: teenager or 40+, who is at risk?, Human Reproduction, Volume 23, Issue 6, June 2008, Pages 1290–1296, https://doi.org/10.1093/humrep/dem403PMID: 18256111 DOI: 10.1093/humrep/dem403https://academic.oup.com/humrep/article/23/6/1290/585429 Paternal age and adverse birth outcomes- teenager or 40þ, who is at risk?.pdf |
| BACKGROUNDMost previous studies on the effect of paternal age have focused on the association of advanced paternal age with congenital anomalies. The objective of this study was to determine whether paternal age is associated with the risk of adverse birth outcomes, independent of maternal confounders. METHODS:We carried out a retrospective cohort study of 2 614 966 live singletons born to married, nulliparous women aged 20–29 years between 1995 and 2000 in the USA. Multiple logistic regressions were applied to estimate the independent effect of paternal age on adverse birth outcomes RESULTS:Compared with infants born to fathers aged 20–29 years, infants fathered by teenagers (<20 years old) had an increased risk of preterm birth [odds ratio (OR) = 1.15, 95% confidence interval (CI): 1.10, 1.20], low birth weight (OR = 1.13, 95% CI: 1.08, 1.19), small-for-gestational-age births (OR = 1.17, 95% CI: 1.13, 1.22), low Apgar score (OR = 1.13, 95% CI: 1.01, 1.27), neonatal mortality (OR = 1.22, 95% CI: 1.01, 1.49) and post-neonatal mortality (OR = 1.41, 95% CI: 1.09, 1.82). Advanced paternal age (≥40 years) was not associated with the risk of adverse birth outcomes. CONCLUSION:Teenage fathers carry an increased risk of adverse birth outcomes that is independent of maternal confounders, whereas advanced paternal age is not an independent risk factor for adverse birth outcomes. |
| I ultimately included this article because it also addressed my clinical question. As a retrospective cohort, it does have a lower level of evidence vs meta-analysis/literature review. However, it has an extremely large population size of 2 614 966 and was retrieved data from all 50 states using the National Center for Health Statistics, which it estimates that 99% of live births are included-making it more applicable to the general population. I included it because it ultimately came to a different clinical conclusion than the other articles do. I suspect that this different conclusion is because the article is old, from 2008, so the clinical conclusions are probably outdated vs the others. It also only included data from 1995-2000, which is not as long as other studies. |
| Author (Date) | Level of Evidence | Sample/Setting | Outcomes | Key Findings | Limitations and Biases |
| Brandt et al(2019) | Literature review | Prospective CohortN=603 women wanting to become pregnant Population case control. Prospective study n= 630 women 18-55 years with most recent pregnancy ending in first trimester abortion Prospective study based in California n=5,121 women Retrospective cohort of 17,000 intrauterine insemination cycles Large US based retrospective cohort and US based population study of randomly selected births in cities over 200k in population from years 1998-2000. N=4621. | Miscarriage rates, rates of spontaneous abortions, birth weight, Apgar score | Advanced paternal age over 35 associated with increased miscarriage and/or spontaneous abortions rates In men older than 35 years old, there is a 1.26 x increased risk vs men < 35 even when controlling for maternal age. (95% CI, 1-1.6). APA linked with miscarriage rate of 32.4% of fathers over 35 had rates of miscarriage vs those younger than 35 with a rate of 13.4% (P<0.001). Advanced paternal age over 35 and Apgar scoring results are inconclusive, No association was found in advanced paternal age and decreased Apgar scores in one study, while the US based urban study showed an increased rate of low birth rate in white fathers over 35 at P<.001 CI: 95%, 1.7, (0.9, 3.3). A Danish cohort study showed that increased risk of low Apgar scores at 1 and 5 minutes in advanced age over 45 years. Advanced paternal age over 45 linked to lower birth weights. APA 35-44 and low birth weight association uncertain. The population based sample of 4,621 births found fathers over 35 to have a 90% increased risk for lower birth rates. . | Outdated/Time Limited ResearchSome of the research was taken in a specific time frame from which obstetric practices may have changed which could alter results. Selection Bias:These studies relied heavily on retrospective data, meaning that the outcome was first known then followed which could create selection bias. Flawed Study Design: Some of the studies included maternal demographics but did not include information on the fathers SES/race/education which have been shown to be associated with poor pregnancy outcomes in mothers, which may apply to fathers as well. |
| Khandwala et al., (2016) | Retrospective population based cohort | 40,529,905 live births from 2007-2016 based in the United States to gestational full term | Primary:Gestational Age, weight, Apgar score at 5 min, admission to NICU, need for postpartum antibiotics, seizures, maternal gestational diabetes Secondary:Number of preventable poor outcomes | Advanced paternal age over 45 linked to higher rates of premature birth even after adjusting for maternal age. Infants born to fathers aged 45 years or older had 14% higher odds of premature birth (odds ratio 1.14, 95% confidence interval 1.13 to 1.15) vs those with fathers under 34. 13.2% (95% confidence interval 12.5% to 13.9%) of premature births estimated to be attributable to advanced paternal age. Advanced paternal age over 45 linked to higher rates of seizures.Infants born to fathers aged 45 years or older had 18% higher odds of seizures (1.18, 0.97 to 1.44) Advanced paternal age linked to higher levels of gestational diabetes. The odds of gestational diabetes was 34% higher (1.34, 1.29 to 1.38) in mothers with the oldest partners. 18.2% (17.5% to 18.9%) of gestational diabetes in births associated with older fathers were estimated to be attributable to advanced paternal age | Long Time SpanThis data searched all live births of 9 years which lowers the risk of bias. Confounding BiasBecause this study pooled all live births from 2007-2016, annual fluctuations in pregnancy outcomes is reduced further reducing the risk of confounding bias. Selection BiasOnly full term pregnancies were included. One strength of this study’s selection was an almost even ratio of male: female offspring. Reporting BiasThe system used relies on birth certificate data originating from self-reported information. |
| Alio et al., (2012) | Population based retrospective cohort | Missouri population based retrospective cohort of 755, 334 women singleton births from 1989-2005. | Pre-term labor, Apgar score, | Advanced paternal age over 45 linked to lower birth weights. APA 35-44 and low birth weight association uncertain. Missouri population based retrospective cohort of 755, 334 showed that fathers over 45 years old had a 19% increase in low birth weight (AOR = 1.19, 95% CI = 1.09-1.29) vs fathers aged less than 30 controlling for other external factors Advanced paternal age over 45 linked to PTL.Missouri population based retrospective cohort of 755, 334 showed that fathers over 45 years old had a13% increase in PTL (AOR = 1.13, 95% CI = 1.05-1.22) and a 29% increase in very PTL ((AOR = 1.29, 95% CI = 1.15-1.44) vs fathers aged less than 30. | Selection BiasThis study was limited geographically to the Missouri area which decreases the likelihood of it being applicable to the generalized population Long Time SpanThis data searched all live births of 10 years which lowers the risk of bias. |
| Chen et al., (2008) | Retrospective Cohort | 2,614, 966 live singletons born to married, nulliparous women aged 20–29 years between 1995 and 2000 in the USA | Very low birth weight, very preterm delivery, preterm delivery, preterm delivery, small for gestational age birth, less than 4 Apgar score at 5 minutes, fetal distress, neonatal death | Advanced paternal age was not associated with increased risk of adverse birth outcomes. | Confounding FactorsA strength of this study was that it had a large variation in fathers’ age divided by groups was compared to a limited maternal age group. Reporting BiasLMP was self-reported in this study which may skew the data for correct gestational ages and birth weights. Outdated ResearchThis research is older than 10 years, so that it may be outdated and not clinical applicable to today’s population. |
Brandt et al., (2019):
As a systematic review of the literature, this article has a relatively low level of evidence with a total of over 1,000 total patients included throughout various trials. It includes some information that is very current as it was published in 2019. This article found that advanced paternal age over 35 years was associated with a small, but significantly increased risk of spontaneous abortions and or miscarriage rates, but that APGAR score information remained inconclusive.
Khandwala et al., (2016):
This article was a retrospective population based cohort with a study population n=40, 452, 905 of live births from the years 2007-2016 in the US. As a retrospective population based cohort, this study ranked much higher than the literature review posted above. Retrospective cohort studies rank just below meta analysis and RCTs concerning empirical levels of evidence. The conclusions from this study state that infants born to men over 45 have higher rates of premature birth in addition to gestational diabetes and infantile seizures. I’d argue that the level of evidence for this study should rank amoungst the highest for any retrospective cohort included in this study due to its long time span and its very large population size.
Alio et al., (2012):
This article was another population based, retrospective cohort only including of 755, 334 females over the time span of 1989-2005. It’s long time-span gives it a higher level of evidence with lower bias, but would rank lowest concerning any of the included articles due to its very small geographic population located in Missouri only. As a retrospective cohort, it would rank lower than any RCT or meta-analysis, and does rank higher than the first article, but would fall below Brandt et al., (2019)and Chen et al., (2008). This article finds that advanced paternal age over 45 is significantly linked with lower birth weights, but information on children from men between the ages of 35-44 remains inconclusive. However, APA over 45 was significantly linked with higher rates of pre term labor.
Chen et al., (2008):
The final article is another retrospective cohort which studies n= 2,614, 966
nulliparious women aged 20-29 throughout the United States between 1995-2000. I would argue that this study is the 2ndranking retrospective cohort solely based on the number of women included and 5 year time span. This was the only study which did not find statistically significant links between advanced paternal age and poor birth outcomes. However, I would argue that this study has two major flaws: maternal age has increased since 2000, making some of this data potentially irrelevant and that this study also included self reported LMP, which is at risk for reporting bias.
Overarching Conclusions:
PTL and APA over 45 are positively linked. Alio et al., (2012) and Khandwala et al., (2016)’s results show a positive link between PTL and APA over 45—demonstrating a high level of evidence for the association between these two factors. Concerning other birth outcomes, statistically significant evidence is inconclusive. However, both Brandt et al., (2019)andAlio et al., (2012) conclude that advanced paternal age over 45 are linked with lower APGAR scores at birth. However, both of these studies rank low on empirical evidence; more studies are necessary to intangibly demonstrate this link. Brandt et al., (2019) was the only study in which linked APA over 45 with higher rates of spontaneous miscarriages and/or abortions, while Chen et al., (2008) found no such link.
What is the clinical “bottom line” derived from these articles in answer to your question?
After reviewing the available data and assessing it for its current application, the clinical bottom line derived from the articles significantly suggests that with advanced paternal age at or greater than 45 years is at increased risk of pregnancy complications of preterm labor. Inconclusive evidence suggests that APA over 45 may be linked with higher rates of miscarriage, low birth weight, low Apgar scores and stillbirths across 3 of the 4 articles. The clinical bottom line suggests that any couple, including the couple above, should be referred to a genetic counselor in cases of advanced paternal age over 45 years old as there is evidence that advanced paternal age does in fact increase the risk of poor pregnancy outcomes. I would even argue that men over 35 should also be referred to genetic conseling, due to the inconclusive findings of Alio et al., (2012) suggesting that men between 35-44 could also increase the risk of PTL.There is a drastic need for more RCTs and/or systematic reviews on this subject using objective, rather than subjective, levels of measurement including but not limited to: LMP, EGA, etc.
