The impact of advanced paternal age on prematurity and birth weight: a systematic review and meta-analysis

Introduction

Background

Changing patterns in education, increased life expectancy, shifts in women’s roles in society, delayed marriage, and the popularization of assisted reproductive technologies are key factors associated with late reproductive patterns, which are linked to higher risks of adverse reproductive outcomes (1,2). A study examining the population of England and Wales revealed that over a 10-year period, there was a decrease in trends for younger paternal age and an increase in fatherhood at ages over 35, with a 15% rise in paternal age rates observed between 1993 and 2003 (3). Similarly, data from the United States showed increases of 9%, 14%, 16%, and 8% in paternity rates among men aged 35–39, 40–44, 45–49, and 50 years or older, respectively, over a 10-year period up to 2013 (4). These epidemiological trends align with the transformation of the demographic pyramid, where population aging is accompanied by delayed parenthood (5). This global trend in fatherhood has demonstrated impacts on perinatal health, raising concerns that biological aging may not align with recent behavioural changes and modern lifestyle patterns (6).

Rationale and knowledge gap

Prematurity (gestational age <37 weeks) and low birth weight are common challenges and represent major causes of childhood morbidity and mortality worldwide (7). Numerous studies have demonstrated that advanced maternal age is associated not only with decreased fertility but also with a range of perinatal complications widely documented in the scientific literature. These include stillbirths, preterm births, spontaneous abortion, congenital anomalies, macrosomia, large-for-gestational-age infants, and increased rates of caesarean deliveries (8-11). In contrast, the impacts of potential genetic mutations in sperm associated with advanced paternal age (APA) remain less conclusive. This uncertainty arises from inconsistencies in defining APA and conflicting results regarding its effects on a wide range of outcomes, spanning from perinatal life to adulthood (1,3). Several complications linked to this reproductive trend have been investigated, including leukaemia in offspring (12), autism (13), schizophrenia (14), bipolar disorder (15), Down syndrome (16), achondroplasia (17), and musculoskeletal disorders such as thanatophoric dysplasia, osteogenesis imperfecta, and other types of birth defects (18).

Several aetiologies have been proposed to explain the impact of APA on prematurity, low birth weight, and other birth outcomes (19). Epigenetic and genetic changes are frequently cited as primary contributors, including chromosomal aneuploidies, loss of DNA integrity, telomere shortening, de novo or spontaneous mutations, and DNA fragmentation. These paternal genetic alterations are intrinsically linked to placentation issues and consequent fetal growth restriction (20-23). Although studies have established correlations between APA and specific outcomes, other reviews challenge these associations for various reasons. Firstly, there is no universal definition of APA (2,24).

Secondly, different studies often yield conflicting results regarding these outcomes. For instance, a study conducted by Bu et al. in 2023 analysed a large North American population of over 17 million individuals over 5 years and observed that APA was associated with an increased risk of preterm birth and low birth weight deliveries (25). In contrast, the seminal study by Abel et al. in 2002 found no statistically significant odds ratios (ORs) for any paternal age groups when assessing low birth weight and preterm birth in Caucasian and North American populations (26). Additionally, beyond the controversies surrounding paternal aging, various confounding factors, such as inconsistent assessments of maternal age and variations in paternal ethnicity, complicate the ability to draw definitive conclusions. Thus, the topic remains under debate and highlights the need for a comprehensive synthesis of current evidence.

Objective

This systematic review and meta-analysis aim to further explore this debate. We will properly analyse the recently published studies to assess the clear information regarding the APA and its outcomes on preterm deliveries and low birth weight. We present this article in accordance with the PRISMA reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-25-117/rc).

Methods

Protocol and registration

This review and meta-analysis were performed with unwavering adherence to the recommendations of the Cochrane Collaboration (25) and registered on the International Prospective Register of Systematic Reviews – PROSPERO (https://www.crd.york.ac.uk/, accessed on January 10th, 2025) under registration number CRD42025636811.

Eligibility criteria

Studies were considered eligible for inclusion if they satisfied the following conditions: (I) They provide cases of preterm birth age correlated with the paternal age; (II) They provide the value of low birth weight (<2,500 g) correlated with the paternal age; (III) The control group consisted of men between 18 and 34 years old. Exclusion criteria included case reports, reviews, opinion pieces, animal studies, guidelines, in vitro experiments, studies without reported results and studies with overlapping populations. Furthermore, only published studies in the English language were considered eligible for inclusion.

Search strategy and data extraction

A systematic search for published studies across multiple databases was conducted, including PubMed, Scopus, Web of Science, and Cochrane, in July 2024. A supplementary search was conducted in December 2025. We customized search terms for each database using specific syntax rules and Medical Subject Headings (MeSH), employing Boolean connectors (OR, AND) to combine terms. The detailed search strategy, including the specific terms used, is provided in Table S1. The study is not based upon clinical study or patient data.

The search strategy was carried out by two authors, A.B.A.B. and I.C.A.L. In order to find additional studies, we screened abstracts, examined the reference list of included articles and conducted systematic reviews of the literature. Studies identified from databases and article references were imported into Zotero (version 6.0.36) to remove duplicates and subsequently managed using reference management software Rayyan (version 1.1).

Two authors, L.M.V. and I.C.A.L., independently screened the titles and abstracts of identified articles, and they independently extracted data based on predefined search criteria. In cases of discrepancies between reviewers, a third author, A.B.A.B., made the final decision. The extracted baseline characteristics from the included articles included the authors, study design, year of publication, total number of births and maternal and paternal ages. One article for which the full text could not be obtained was excluded from the analysis (Table S2).

Endpoints

Our objective was to investigate the impact of APA on prematurity and low birth weight. Specifically, we examined infant births with complete paternal age data, either restricted to mothers younger than 30 years or based on adjusted ORs. The study compared outcomes between infants whose fathers were 35 or older and those whose fathers were younger than 35. The primary outcomes assessed were (I) prematurity, defined as a gestational age of less than 37 weeks, and (II) low birth weight, defined as less than 2,500 g.

Risk of bias assessment

The assessment of the quality of each observational study was conducted using the Newcastle-Ottawa Scale (NOS) (27), a tool specifically designed for non-randomized studies and cohort studies. Each study underwent scrutiny across three domains: the selection of exposed cohorts; comparability regarding key confounding factors and outcome assessment, including the duration and adequacy of follow-up. Studies that received scores between 0 and 7 points were deemed lower quality or lacking robustness, whereas those with scores ranging from 8 to 9 points were considered high-quality assessments (27). The evaluations were independently conducted by two reviewers (A.B.N.S. and L.M.V.), ensuring the highest level of objectivity and reducing the potential for bias. Any discrepancies between the reviewers’ assessments and issues related to the conceptual framework of the intervention or methodological and statistical concerns were resolved through consensus. Contour-enhanced funnel plots

were visually examined to explore the potential for publication bias. Sensitivity analysis was conducted using a funnel plot and leave-one-out to analyse the symmetry of all outcomes and risk of publication bias.

Statistical analysis

Baseline characteristics of the sample were pooled to evaluate their influence on the outcome. The reported binary outcome of interest and its OR was calculated with 95% confidence intervals (CIs) using a fixed-effect model for endpoints with I²<25% and considered relevant when P value <0.05. In contrast, the DerSimonian and Laird random-effects model was used for significant heterogeneity outcomes. Heterogeneity and effect size variability were assessed using the I² and Tau² statistics. All statistical analyses were carried out using R statistical software, version 4.2.3 (R Foundation for Statistical Computing). The robustness of the results was assessed through sensitivity analyses, including visual inspection of funnel plots and a leave-one-out approach, to evaluate the symmetry and stability of the effect estimates across all outcomes.

Results

Study selection and baseline characteristics

According to the PRISMA flow diagram (Figure 1), our systematic search identified 4,497 studies on databases and five studies from citation searching. After removing duplicates and screening titles or abstracts, 34 full-text manuscripts were subjected to a comprehensive review based on predefined inclusion and exclusion criteria. Ultimately, 22 studies met the criteria for inclusion in the analysis. Table 1 provides an overview of the studies included in the analysis, which consists of three prospective observational studies and 19 retrospective studies. The total number of births reported across these studies is 74,428,755. The findings indicate a diverse range of maternal ages, primarily concentrated in the 20–45-year bracket, while paternal ages vary from 17 to 64 years and older. Studies that considered mothers over the age of 29 adjusted for this confounding factor, as detailed in Table 1. Additionally, paternal age categories differed among studies, as outlined in Table 1. Consequently, not all studies were included in the meta-analyses concerning prematurity and birth weight.

Figure 1 PRISMA diagrams of included studies.

Two studies, by Astolfi et al. (30) and Basso and Wilcox (31), featured two control groups of mothers: one group aged 20–24 and the other aged 25–29. As a result, data from these studies were included twice.

Given the challenges in categorizing paternal age, an analysis was conducted for fathers older than 35 years, focusing on the risks of prematurity (births under 37 weeks) and low birth weight. The age categories for fathers included in this analysis are specified in parentheses next to each study name.

Risk of prematurity under 37 weeks

Regarding the risk of prematurity before 37 weeks’ gestation, seven studies (28,30,32,33,39,41,43) assessed outcomes in offspring of fathers aged 35–39 years. No statistically significant association was observed in this age group (OR: 1.04; 95% CI: 1.00–1.09; P=0.078; I²=90.2%; Figure 2A). In contrast, prematurity outcomes were reported in six studies for paternal age groups 40–44 years (28,30,32,39,41,43), 45–49 years (30,32,36,39,41,43) and >50 years (30,32,36,39,41,43). In all three age categories, a statistically significant association was identified, indicating an increased risk of prematurity with advancing paternal age. Specifically, paternal age 40–44 years was associated with an OR of 1.11 (95% CI: 1.03–1.19; P=0.004; I²=92.6%; Figure 2B), paternal age 45–49 years with an OR of 1.15 (95% CI: 1.05–1.27; P=0.002; I²=89.1%; Figure 2C), and paternal age >50 years with an OR of 1.16 (95% CI: 1.03–1.30; P=0.012, I²=83.7%; Figure 2D).

Figure 2 Risk of prematurity under 37 weeks. (A) Fathers aged 35–39 years; (B) fathers aged 40–44 years; (C) fathers aged 45–49 years; (D) fathers aged ≥50 years. CI, confidence interval; OR, odds ratio.

Overall risk of prematurity among fathers over 35 years

The overall analysis of prematurity among offspring of fathers aged >35 years included 12 studies (25,26,28,30-33,36,38,39,41,43). The studies by Huanco-Apaza et al. (29), Goisis et al. (34), Hurley et al. (35), Mayo et al. (37), Tamura et al. (40), and Yin et al. (42) were excluded from the analysis because their results were not reported as ORs. The pooled analysis demonstrated a statistically significant association, indicating an increased risk of prematurity in offspring of fathers aged >35 years (OR: 1.11; 95% CI: 1.07–1.14; P<0.001; I²=95.9%; Figure 3).

Figure 3 Overall risk of prematurity under 37 weeks among fathers ≥35 years. CI, confidence interval; OR, odds ratio.

Overall risk of low birth weight among fathers over 35 years

For the analysis of low birth weight (characterized by a birth weight of less than 2.5 kg), among children of fathers aged >35 years, data from 12 studies (19,25,26,28,32,33,36,38,39,41,44,45) were included in the pooled analysis (Figure 4). The studies by Huanco-Apaza et al. (29), Goisis et al. (34), Hurley et al. (35), Tamura et al. (40), and Sabas et al. (46) were excluded because their results were not reported as ORs. The meta-analysis demonstrated a statistically significant association, indicating an increased risk of low birth weight in offspring of fathers aged >35 years (OR: 1.11; 95% CI: 1.06–1.17; P<0.001; I²=95.1%; Figure 4).

Figure 4 Overall risk of low birth weight among fathers ≥35 years. CI, confidence interval; OR, odds ratio.

Sensitivity analysis

To assess the robustness of findings related to low birth weight and prematurity categories, a leave-one-out sensitivity analysis was performed.

For the 35–39 age group, exclusion of individual studies did not significantly alter the results, as seen in Figure S1A. The pooled estimates remained close to the null value across iterations, with CIs frequently including 1, indicating that the lack of statistical significance was not driven by any single study.

In contrast, for the age groups 40–44 and 45–49, leave-one-out sensitivity analyses demonstrated that the pooled effect estimates were robust to the exclusion of any individual study (Figure S1B and Figure 1C, respectively). Across all iterations, ORs consistently remained above unity and statistically significant, indicating that the observed associations were not driven by a single influential study.

For the age group >50 years, leave-one-out sensitivity analysis showed that when the study by Khandwala et al. (36) or the study by Wang et al. (41) is excluded, the result is no longer significant (P=0.067 and P=0.059, respectively) (Figure S1D).

In the overall analysis including parents aged 35 years and older, leave-one-out sensitivity analysis showed highly consistent pooled ORs across all iterations, ranging from 1.10 to 1.11, with all estimates remaining statistically significant (P<0.001) (Figure S1E). No individual study substantially influenced the overall effect size.

Similarly, for the low-birth-weight outcome, leave-one-out sensitivity analysis also demonstrated stability of the pooled effect estimates (Figure S2). ORs remained statistically significant across all iterations (P<0.001), and exclusion of individual comparisons did not affect the magnitude of the association.

Assessment of publication bias and small-study effects was performed across all categories using funnel plot analysis (Figures S3,S4). Visual inspection of the funnel plots consistently showed symmetric distributions of effect estimates around the pooled effects, with a small number of studies located outside the funnel across analyses, for all age categories on prematurity (Figure S3A-S3E) and low birth weight (Figure S4). This pattern is consistent with underlying clinical or methodological differences between studies rather than directional publication bias or small-study effects. Formal evaluation using Egger’s regression test for the overall analysis of prematurity in parents aged 35 years or older and low birth weight analysis did not indicate statistically significant funnel plot asymmetry (t=0.75, df=43, P=0.456; Figure S3E; t=0.72, df=27, P=0.478, Figure S4). Egger’s regression test was not performed for other categories because they included fewer than 10 studies.

Quality assessment

Using the Newcastle-Ottawa Scale (27), as shown in Table S3, most included cohort studies demonstrated high methodological quality, with 14 studies achieving the maximum score of nine points. Eight studies received lower scores (7–8 points) due to specific methodological limitations. Huanco-Apaza et al. (29) and Olshan et al. (39) scored seven points, primarily because of limited comparability, as these studies did not adequately adjust for key confounding variables. Basso and Wilcox (31), Chung et al. (44), Hurley et al. (35), Reichman and Teitler (19), Sabas et al. (46), and Zhu et al. (43) scored eight points, mainly due to incomplete adjustment for additional confounders or lack of clarity regarding outcome assessment or follow-up adequacy. Despite these limitations, all studies met the core selection criteria, including representativeness of the exposed cohort, reliable ascertainment of exposure, and confirmation that outcomes were not present at baseline, supporting the overall robustness of the evidence base.

Discussion

Key findings

By synthesizing current evidence, this systematic review and meta-analysis thoroughly examine how APA influences preterm birth and low birth weight, thereby expanding upon the existing knowledge explored in previous reviews on this topic (7).

Regarding preterm birth, significant associations were observed for fathers aged 40–44 years (OR 1.11; 95% CI: 1.03 to 1.19; P=0.004, I²=92.6%), 45–49 years (OR 1.15; 95% CI: 1.05 to 1.27; P=0.002, I²=89.1%), and ≥50 years (OR 1.16; 95% CI: 1.03 to 1.30; P=0.012, I²=83.7%). No significant association was found for fathers aged 35–39 years (P=0.078). When data were synthesized across all fathers aged ≥35 years, a significant association with preterm birth before 37 weeks of gestation was observed (OR 1.11; 95% CI: 1.07 to 1.14; P<0.001, I²=95.9%; Figure 3). In contrast to the previous meta-analysis (7), which did not evaluate preterm birth using aggregated paternal age categories, our findings indicate that APA is associated with an increased risk of prematurity, with risk progressively increasing across older age groups.

For low birth weight, despite substantial heterogeneity among the 12 included studies, an increased risk was observed among children of fathers aged ≥35 years (OR 1.11; 95% CI: 1.06 to 1.17; P<0.001, I²=95.1%; Figure 4). These results contrast with those of the earlier meta-analysis (7), which included fewer studies and did not identify a significant association between APA and low birth weight. Overall, our findings support an association between APA and an increased risk of low birth weight.

Strengths and limitations

There are several limitations to this meta-analysis. First, all included studies were observational, which are inherently subject to residual confounding and potential bias. To address this, study quality was systematically assessed using the NOS, allowing for a structured evaluation of selection, comparability, and outcome assessment across studies.

Second, there was substantial variability in how individual studies adjusted for confounders. While some studies controlled for key factors such as smoking, education level, socioeconomic status, and parity, others applied more limited adjustment strategies. To mitigate this issue, we prioritized the extraction of minimally adjusted ORs, with preference given to models adjusted solely for maternal age, in order to enhance comparability across studies.

Third, several potentially relevant studies identified in the systematic review could not be included in the quantitative synthesis because results were not reported as ORs or lacked sufficient data to calculate effect estimates. This limitation reflects a broader issue in the literature, where inconsistent reporting of effect measures restricts evidence synthesis and may influence pooled estimates. Additionally, heterogeneity in paternal age categorization, reference groups, and outcome definitions across studies further limited direct comparability.

Finally, although sensitivity analyses—including leave-one-out procedures and funnel plot assessments—were conducted to evaluate the robustness of the findings and identify influential studies, the overall heterogeneity remained high. This suggests that unmeasured or inconsistently measured factors may still play a role in the observed associations.

Despite these limitations, this meta-analysis provides a comprehensive and updated synthesis of the association between APA and adverse birth outcomes. The inclusion of a large number of studies encompassing a wide total population enhances statistical power, while the incorporation of diverse geographic and demographic settings improves the generalizability of the findings. Importantly, this work highlights critical methodological gaps in the existing literature and underscores the need for standardized reporting and analytic approaches in future research on paternal age and perinatal outcomes.

Comparison with similar research

Previous reviews on this topic (7) have examined a smaller set of studies, including six articles on low birth weight and seven on preterm birth. Our current analysis incorporated 18 articles for preterm birth and 17 articles for low birth weight, extending the existing knowledge by synthesizing more data and exploring specific age categories. This approach offers a more nuanced understanding of the associations between paternal age and these adverse pregnancy outcomes.

Explanations of findings

Several factors could explain these findings. One of them is the decline in sperm quality, particularly in terms of total and progressive motility, as well as changes in morphology and DNA integrity with advancing paternal age (21,22). This could result in sperm with alterations that negatively impact fetal health, potentially contributing to preterm birth. However, further studies are needed to confirm this correlation. Additionally, the literature has shown that there are significant changes in the architecture of the male gamete during spermatogenesis, including the replacement of histones by protamines, which directly impacts epigenetic expression (47). Epigenetic changes associated with APA in semen have been linked to altered placental imprinted gene expression and growth (48), which in turn affects placental implantation and, consequently, potentially leads to adverse fetal outcomes (49). This impact could help explain the correlation observed in our meta-analysis between fathers over the age of 35 and preterm birth.

Implications and actions needed

The substantial heterogeneity observed among the included studies highlights important methodological gaps in the current literature and underscores the need for more rigorous and standardized research approaches. Future studies should adopt harmonized adjustment strategies, including consistent control for key maternal factors (such as maternal age, parity, comorbidities, and assisted reproductive technologies), paternal characteristics (including socioeconomic status, health conditions, and lifestyle factors), and pregnancy-related variables. The use of clearly defined paternal age categories would also improve comparability across studies.

From a clinical and public health perspective, the findings of this review suggest that paternal age should be more consistently considered in perinatal research and risk assessment frameworks. Although the observed associations vary across outcomes and studies, the potential influence of APA on birth outcomes has implications for preconception counselling and reproductive planning. Integrating paternal age into future guidelines and surveillance systems may contribute to a more comprehensive understanding of parental age-related risks and support evidence-based decision-making.

Conclusions

This meta-analysis evaluated the impact of APA on preterm birth and low birth weight. A significant association was observed between paternal age over 35 years and preterm birth before 37 weeks of gestation, with a progressive increase in risk across older age categories (40–44, 45–49, and ≥50 years). Additionally, offspring of fathers aged over 35 years showed a significantly higher risk of low birth weight. These findings contrast with previous meta-analyses and suggest that APA is an independent risk factor for adverse perinatal outcomes, with a dose-response pattern for prematurity. Future research should prioritize standardized definitions of paternal age categories, consistent adjustment strategies and reporting of effect estimates as ORs to enable robust evidence synthesis.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-25-117/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-25-117/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-25-117/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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