Influence of paternal age on perinatal outcomes

doi:10.1016/j.ajog.2017.07.034

American Journal of Obstetrics and Gynecology

Volume 217, Issue 5, November 2017, Pages 566.e1-566.e6

The abstract for this study was presented as a poster at the Scientific Meeting of the American Society for Reproductive Medicine, Salt Lake City, UT, Oct. 15-19, 2016.

https://doi.org/10.1016/j.ajog.2017.07.034 Get rights and content

Background

There is an increasing trend to delay childbearing to advanced parental age. Increased risks of advanced maternal age and assisted reproductive technologies are widely accepted. There are limited data regarding advanced paternal age. To adequately counsel patients on risk, more research regarding advanced paternal age is necessary.

Objective

We sought to determine the influence of paternal age on perinatal outcomes, and to assess whether this influence differs between pregnancies achieved spontaneously and those achieved with assisted reproductive technology.

Study Design

A population-based retrospective cohort study of all live births in Ohio from 2006 through 2012 was completed. Data were evaluated to determine if advanced paternal age is associated with an increased risk of adverse outcomes in pregnancies. The analysis was stratified by status of utilization of assisted reproductive technology. Generalized linear regression models assessed the association of paternal age on pregnancy complications in assisted reproductive technology and spontaneously conceived pregnancies, after adjusting for maternal age, race, multifetal gestation, and Medicaid status, using Stata software (Stata, Release 12; StataCorp, College Station, TX).

Results

Paternal age was documented in 82.2% of 1,034,552 live births in Ohio during the 7-year study period. Paternal age ranged from 12-87 years, with a median of 30 (interquartile range, 26-35) years. Maternal age ranged from 11-62 years, with a median of 27 (interquartile range, 22-31) years. The use of assisted reproductive technology in live births increased as paternal age increased: 0.1% <30 years vs 2.5% >60 years, P < .001. After accounting for maternal age and other confounding risk factors, increased paternal age was not associated with a significant increase in the rate of preeclampsia, preterm birth, fetal growth restriction, congenital anomaly, genetic disorder, or neonatal intensive care unit admission. The influence of paternal age on pregnancy outcomes was similar in pregnancies achieved with and without assisted reproductive technology.

Conclusion

Older paternal age does not appear to pose an independent risk of adverse perinatal outcomes, in pregnancies achieved either with or without assisted reproductive technology. However, small effect sizes such as very small risk increases or decreases may not be detectable despite the large sample size in this study of >830,000 births.

Introduction

There is an increasing trend to delay childbearing to advanced parental age, mother and father alike. The associated risks of advanced maternal age, generally defined ≥35 years of age, are well studied. Increased maternal age is associated with increased miscarriage rate, obstetric complications, and perinatal mortality and is associated with decreased success when using assisted reproductive technologies (ART).1, 2 Less is known regarding the risks associated with advanced paternal age and pregnancy outcomes. Some studies have shown that advanced paternal age has effects on sperm quality, miscarriage rates, infant birthweights, and childhood/adult illnesses.1, 3, 4, 5, 6, 7, 8 Nonetheless, 1 study published in 2008 by Chen et al⁹ found that advanced paternal age is not associated with adverse birth outcomes.

As parental ages increase, more couples may turn to ART for aid in achieving pregnancy. ART itself is associated with increased perinatal risks including prematurity, low birthweight, and multiple gestations.¹⁰ However, there is a paucity of data evaluating the impact of advanced paternal age on the risks associated with ART pregnancies. A review of 10 articles published in 2011 found that there is insufficient evidence to determine if paternal age has a negative impact on ART outcomes.¹ The outcomes evaluated included fertilization rate, pregnancy rate, miscarriage rate, and live birth rate. Only 4 of the studies reviewed evaluated live birth rate with 2 of the studies finding no significant difference and 2 studies with a decreased chance of live birth with advanced paternal age.¹ A study published in 2014 found no increased risk for prematurity, low birthweight, or small for gestational age in pregnancies achieved with ART at older paternal age.¹¹ After a thorough review of the literature, we found a limited amount of research evaluating advanced paternal age and perinatal outcomes in pregnancies achieved with ART.

The aim of this study was to utilize a large population-based data source to assess whether advanced paternal age poses independent increased perinatal risks, and assess whether those risks differ in pregnancies achieved by ART or spontaneously without ART.

Section snippets

Materials and Methods

A population-based retrospective cohort study of all live births in Ohio from 2006 through 2012 was performed to quantify the influence of advanced paternal age on pregnancy complications. Study approval was obtained from the Ohio Department of Health Institutional Review Board and a deidentified data set extracted from live birth certificates was provided for this analysis. This study was exempt from review by the institutional review board at the University of Cincinnati, Cincinnati, OH.

The

Results

Paternal age was documented in approximately 82.2% of 1,034,552 live births in Ohio from 2006 through 2012. A total of 833,727 births were included in the study after excluding those without a paternal age recorded and limiting to the first birth of multifetal gestations. Approximately 3.7% of the births (3118) were achieved with ART compared to 830,609 non-ART births. Paternal age ranged from 12-87 years, with a median of 30 (interquartile range, 26-35) years. Maternal age ranged from 11-62

Comment

As couples delay childbearing, the question of the effects of older age gain importance. Advanced maternal age is well defined with understood risks and implications; however, this is not true for advanced paternal age. There is no widely accepted definition of advanced paternal age and the consequences of pregnancies achieved at advanced paternal age are not well understood. Also, with advanced parental age, couples are more likely to utilize ART, which has risks of its own. Our study

References (16)

L. Dain et al.
The effect of paternal age on assisted reproduction outcome
Fertil Steril
(2011)
R. Ramasamy et al.
Male biological clock: a critical analysis of advanced paternal age
Fertil Steril
(2015)
G.R. Alexander et al.
A United States national reference for fetal growth
Obstet Gynecol
(1996)
B.B. Luke et al.
Validation of infertility treatment and assisted reproductive technology use on the birth certificate in eight states
Am J Obstet Gynecol
(2016)
A.M. Valent et al.
Gestational age-specific neonatal morbidity among pregnancies complicated by advanced maternal age: a population-based retrospective cohort study
J Matern Neonatal Med
(2016)
R. Sharma et al.
Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring
Reprod Biol Endocrinol
(2015)
E. de la Rochebrochard et al.
Paternal age and maternal age are risk factors for miscarriage; results of a multicenter European study
Hum Reprod
(2002)
K. Kleinhaus et al.
Paternal age and spontaneous abortion
Obstet Gynecol
(2006)

There are more references available in the full text version of this article.

Cited by (35)

Paternal age and first trimester placental size and growth: The Rotterdam Periconceptional Cohort
2024, Placenta
Despite a noticeable trend of delayed fatherhood, less is known about the impact of paternal age on the paternally programmed placenta. We hypothesize that paternal aging affects seminal quality and as such induces ageing-related epigenetic alterations that influence placental growth. Our main aim is to investigate associations between paternal age and first trimester (vascular) placental growth trajectories.
Pregnant women were enrolled before 10 weeks of gestation in the Rotterdam Periconceptional Cohort (Predict study). Placental volumes (PV) and utero-placental vascular volumes (uPVV) were measured at 7, 9, and 11 weeks gestation. Associations between paternal age and PV and uPVV were investigated using linear mixed models and the maximum likelihood ratio test to test non-linear relationships. We adjusted for gestational age, fetal sex, parental smoking and maternal age, BMI, education and parity, and stratified for conception mode.
From 808 pregnancies we obtained 1313 PV and from 183 pregnancies 345 uPVV measurements. We show no associations between paternal age and PV (p = 0.934) and uPVV (p = 0.489) in our total population or in pregnancies conceived naturally (PV p = 0.166; uPVV p = 0.446) and after IVF/ICSI (PV p = 0.909; uPVV p = 0.749). For example, PV was 0.9% smaller (95% CI -5.7%—7.1%) in fathers aged 40 compared to 30 years old at 9 weeks gestation in the total study population.
We are not demonstrating a significant impact of paternal age on first trimester placental growth in a tertiary care population. Given the trend of increasing paternal age, our study should be repeated in the general population.
Paternal age does not jeopardize the live birth rate and perinatal outcomes after in vitro fertilization: an analysis based on 56,113 frozen embryo transfer cycles
2024, American Journal of Obstetrics and Gynecology
The global trend of delaying childbearing has led to an increasing number of couples seeking in vitro fertilization. The adverse effects of advanced maternal age on pregnancy and perinatal outcomes are well documented, regardless of the conception method. In addition, advanced paternal age may contribute to poor reproductive potential because of high levels of sperm DNA fragmentation. However, it remains challenging to guide older men regarding the effect of paternal age on pregnancy and birth outcomes in the field of assisted reproduction.
This study aimed to investigate the association of paternal age with live birth and perinatal outcomes following in vitro fertilization-frozen embryo transfer.
A retrospective study was performed at a university-affiliated fertility center, involving women who were younger than 36 years and had undergone frozen embryo transfer from January 2011 to June 2021. Subjects were categorized into 6 groups based on paternal age: <25, 25 to 29, 30 to 34, 35 to 39, 40 to 44, and ≥45 years. A generalized estimating equation logistic regression model was used to account for the clustered nature of data and to adjust for confounders. Paternal age between 25 and 29 years served as the reference group in the logistic regression models.
A total of 56,113 cycles who met the inclusion criteria were included in the final analysis. On unadjusted analyses, the reproductive outcome parameters showed a considerable decline with increasing male age. The live birth rate decreased from 47.9% for men aged 25 to 29 years to 40.3% among men aged ≥40 years. Similarly, the clinical pregnancy rate decreased from 54.4% in the reference group to 47.8% in the ≥40 years age group. Conversely, the miscarriage rate increased as male age increased, from 10.2% among men aged 25 to 29 years to 13.5% among men aged ≥45 years. However, the differences in the reproductive outcomes mentioned above were no longer significant in the multivariable models. Compared with the younger controls, advanced paternal age was not associated with a lower chance of live birth (males aged 40–44 years: adjusted odds ratio, 0.94; 95% confidence interval, 0.85–1.04; males aged ≥45 years: adjusted odds ratio, 0.93; 95% confidence interval, 0.79–1.10). In addition, the rates of clinical pregnancy (males aged 40–44 years: adjusted odds ratio, 0.95; 95% confidence interval, 0.85–1.05; males aged ≥45 years: adjusted odds ratio, 0.94; 95% confidence interval, 0.79–1.12) and miscarriage (males aged 40–44 years: adjusted odds ratio, 1.05; 95% confidence interval, 0.85–1.31; males aged ≥45 years: adjusted odds ratio, 1.07; 95% confidence interval, 0.77–1.50) were comparable between the reference and advanced paternal age groups. Furthermore, men in the youngest age group (<25 years) did not have worse pregnancy outcomes than those in the reference group. Regarding perinatal outcomes, there was no difference among the study cohorts in terms of preterm birth, low birthweight, macrosomia, small for gestational age, and large for gestational age, both in the unadjusted and confounder-adjusted models.
This study did not demonstrate a significant association between paternal age and live birth and perinatal outcomes after in vitro fertilization-frozen embryo transfer when the female partners were younger than 36 years. With the global trend toward delaying childbirth, our findings provide useful information for counseling patients that increasing paternal age may not adversely affect pregnancy and perinatal outcomes in assisted reproduction.
Association between paternal age and subtypes of preterm birth: a retrospective study
2022, Reproductive BioMedicine Online
Is advanced paternal age (APA) associated with preterm birth overall and with the subtypes of preterm birth?
A total of 66,167 pregnancies were included. Linear regression and logistic regression models were used to analyse the association between paternal age and subtypes of preterm birth.
APA was associated with a higher risk of preterm birth (35–44 years: odds ratio [OR] 1.16 [1.04–1.28], P = 0.006; >44 years: OR 1.40 [1.10–1.78], P = 0.007) and very early preterm birth (VPTB; <34 weeks) (35–44 years: OR 1.46 [1.17–1.81], P = 0.002; >44 years: OR 1.65 [1.01–2.69], P = 0.045). The increased risk of preterm birth was mostly associated with preterm birth with premature rupture of membranes (PROM-PTB) (35–44 years: OR 1.23 [1.03–1.48], P = 0.021) and medically induced preterm birth (MI-PTB) (>44 years: OR 1.55 [1.12–2.15], P = 0.008). For women who carried a male fetus, having the father in the 35- to 44-year-old group carried a 1.29-fold risk of PROM-PTB (OR 1.29 [1.02–1.63], P = 0.031) and a 1.26-fold risk of MI-PTB (OR 1.26 [1.04–1.52], P = 0.017). There was no evidence of a higher risk of PROM-PTB among women carrying a female fetus, but there was a 1.67-fold higher risk of MI-PTB for the 45-or-older paternal age group (OR 1.67 [1.04–2.67], P = 0.035).
These results suggest that APA is associated with a higher risk of preterm birth and VPTB, mainly related to PROM-PTB and MI-PTB. The study also indicates a fetal sex-specific association between APA and a higher risk of PROM-PTB for male fetuses.
Influence of paternal age on assisted reproductive technology cycles and perinatal outcomes
2021, Fertility and Sterility
To characterize paternal age among assisted reproductive technology (ART) cycles performed in the United States and to evaluate the influence of paternal age on ART cycles and perinatal outcomes.
Retrospective cohort.
Not applicable.
All reported fresh, nondonor, noncancelled in vitro fertilization (IVF) cycles performed in 2017.
Not applicable.
The primary outcomes were intrauterine pregnancy, live birth (≥20 weeks), and miscarriage (<20 weeks) per cycle start and per embryo transfer. The secondary outcomes were full-term live birth (≥37 weeks) among singleton and twin gestations. Modified Poisson regression was performed to estimate associations between paternal age and cycle and perinatal outcomes, overall and stratified by maternal age.
Among 77,209 fresh nondonor, noncancelled IVF cycles, the average paternal age was 37.8 ± 6.3 years and the average maternal age was 35.5 ± 4.6 years. Compared with paternal age ≤45 years, paternal age ≥46 years was associated with a lower likelihood of pregnancy per cycle (adjusted risk ratio [aRR] 0.81; 95% confidence interval [CI] 0.76–0.87) and per transfer (aRR 0.85; 95% CI 0.81–0.90), as well as a lower likelihood of live birth per cycle (aRR 0.76; 95% CI 0.72–0.84) and per transfer (aRR 0.82; 95% CI 0.77–0.88) after controlling for maternal age and other confounders. When restricted to women aged <35 years, there were no significant differences in the rates of live birth or miscarriage among couples in which the men were aged ≤45 years compared with those aged ≥46 years.
Compared with paternal age ≤45 years, paternal age ≥46 years is associated with a lower likelihood of pregnancy and live birth among couples undergoing IVF. The negative effect of paternal age is most notable among women aged ≥35 years, likely because maternal age is a stronger predictor of ART outcome.
Influencia de la edad paterna en los ciclos de reproducción asistida y resultados perinatales.
Caracterizar la edad paterna en los ciclos de reproducción asistida (ART) realizados en los Estados Unidos y evaluar la influencia de la edad paterna en los ciclos de ART y los resultados perinatales.
Cohorte retrospectiva.
No aplicable.
Todos los ciclos de fecundación in vitro (IVF) reportados como frescos, no donantes y no cancelados realizados en 2017.
No aplicable.
Los resultados primarios fueron embarazo intrauterino, nacidos vivos (≥20 semanas) y aborto espontáneo (<20 semanas) por inicio de ciclo y por transferencia de embriones. Los resultados secundarios fueron los nacidos vivos a término (≥37 semanas) entre las gestaciones gemelares y únicas. Se realizó una regresión de Poisson modificada para estimar las asociaciones entre la edad paterna y el ciclo y los resultados perinatales, en general y estratificados por edad materna.
Entre los 77,209 ciclos de IVF frescos, no donantes y no cancelados, el promedio de edad paterna fue 37.8 ± 6.3 años y el promedio de edad materna fue 35.5 ± 4.6 años. En comparación con la edad paterna ≤ 45 años, la edad paterna ≥ 46 años fue asociada con una menor probabilidad de embarazo por ciclo (ratio de riesgo ajustado [aRR] 0.81; intervalo de confianza [CI] del 95% 0.76-0.87) y por transferencia (aRR 0.85; 95% CI 0.81-0.90), así como una menor probabilidad de nacidos vivos por ciclo (aRR 0.76; 95% CI 0.72-0.84) y transferencia (aRR 0.82; 95% CI 0.77-088) después de controlar por edad materna y otros factores de confusión. Cuando se restringió a mujeres < 35 años, no hubo diferencias significativas en las tasas de nacidos vivos o abortos espontáneos entre las parejas en las cuales los hombres tenían una edad ≤ 45 años comparado con aquellos con edad ≥ 46 años.
Comparado con la edad paterna ≤ 45 años, la edad paterna ≥ 46 años está asociada con una menor probabilidad de embarazo y nacidos vivos entre parejas sometidas a FIV. El efecto negativo de la edad paterna es más notable entre las mujeres ≥ 35 años, probablemente porque la edad materna es un predictor fuerte de resultado de ART.
ART, IVF, edad paterna.
Got daddy issues? Fathers impact on perinatal outcomes
2020, Seminars in Perinatology
Citation Excerpt :
Similar trends occurred with post-neonatal mortality (death between 28 days to a year of age).28 Surprisingly, there was no association with paternal age and preterm delivery.7,29 However, less paternal education was related to risk of preterm birth.29,30
Mothers’ genetics as well as their environment, behaviors, and social determinants of health are all important factors influencing short and long term childhood outcomes. There is an emerging body of literature investigating the extent to which fathers also contribute to their offspring's future health. We review fathers’ impact on short term birth outcomes, longer term health, and neurodevelopment to emphasize the inter-relatedness of individual paternal traits. Factors that are linked to offspring outcomes include paternal demographics, race, stress, marriage and support, mental health, and the baseline health and behaviors of fathers. Several methodologic issues exist in current research such as maternal report of paternal information. Mechanisms proposed regarding paternal effect on progeny health range from genetic to reduction of stress of mothers through support. These are varied, possibly inter-related, and difficult to isolate as a single etiology. Future initiatives need to support fathers to allow them to support their families.
Associations of parental ages at childbirth with healthy aging among women
2019, Maturitas
Citation Excerpt :
Older paternal age has been associated with increased risk of non-Hodgkin’s Lymphoma among women [12], obesity in adulthood [14], psychiatric morbidities in childhood and adolescence [4], and mortality [10]. Furthermore, older paternal age has been associated with increased risk of low birthweight and premature birth in some studies [15], whereas others have observed no associations of paternal age with adverse birth outcomes [16]. Unlike other studies, we examined an older, healthier cohort of women ages 65–79 years at baseline who had already survived many earlier negative outcomes that may be associated with delayed parental age.
To examine associations of parental ages at childbirth with healthy survival to age 90 years among older women.
This study included a racially and ethnically diverse sub-cohort of 8,983 postmenopausal women from the larger Women’s Health Initiative population, recruited during 1993–1998 and followed for up to 25 years through 2018.
The outcome was categorized as: 1) healthy survival, defined as survival to age 90 without major morbidities (coronary heart disease, stroke, diabetes, cancer, or hip fracture) or mobility disability; 2) usual survival, defined as survival to age 90 without healthy aging (reference category); or 3) death before age 90. Women reported their own and their parents’ birth years, and parental ages at childbirth were calculated and categorized as <25, 25–29, 30–34, or ≥35 years.
Women were aged on average 71.3 (standard deviation 2.7; range 65–79) years at baseline. There was no significant association of maternal age at childbirth with healthy survival to age 90 or death before age 90. Women born to fathers aged ≥35 compared with 30–34 years at their births were more likely to achieve healthy than usual survival (OR, 1.15; 95% CI, 1.00–1.32). There was no association of paternal age at childbirth with death before age 90.
Findings suggest that being born to older fathers was associated with healthy survival to age 90 among women who had survived to ages 65–79 years at study baseline. There was no association of maternal age at childbirth with healthy survival to age 90 among these older women.

View all citing articles on Scopus

: This work was supported by the Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, and March of Dimes Grant 22-FY14-470 for the March of Dimes Prematurity Research Center Ohio Collaborative.

: The authors report no conflict of interest. This study includes data provided by the Ohio Department of Health, which should not be considered an endorsement of this study or its conclusions.

: Cite this article as: Hurley EG, DeFranco EA. Influence of paternal age on perinatal outcomes. Am J Obstet Gynecol 2017;217:566.e1-6.

View full text

Original ResearchGynecologyInfluence of paternal age on perinatal outcomes

Background

Objective

Study Design

Results

Conclusion

Introduction

Section snippets

Materials and Methods

Results

Comment

Fertil Steril

Fertil Steril

Obstet Gynecol

Am J Obstet Gynecol

Gestational age-specific neonatal morbidity among pregnancies complicated by advanced maternal age: a population-based retrospective cohort study

J Matern Neonatal Med

Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring

Reprod Biol Endocrinol

Paternal age and maternal age are risk factors for miscarriage; results of a multicenter European study

Hum Reprod

Paternal age and spontaneous abortion

Obstet Gynecol

Original Research
Gynecology
Influence of paternal age on perinatal outcomes