Effect of advanced paternal age on fertility and pregnancy
- Isiah D Harris, MD, MSc
Isiah D Harris, MD, MSc
- Department of Obstetrics and Gynecology
- Center for Reproductive Health
- Santa Clara Medical Center/Kaiser Permanente
Women are generally aware of the reproductive issues related to advanced maternal age, typically defined as 35 years of age or older on the estimated date of confinement. These issues include higher risks of infertility, fetal aneuploidy, gestational diabetes, preeclampsia, and stillbirth . (See "Effect of advanced age on fertility and pregnancy in women".)
Although reproductive concerns related to advanced paternal age are less well defined, this topic reviews the available data . Additional information on age and fertility can be found elsewhere. (See "Optimizing natural fertility in couples planning pregnancy" and "Management of pregnancy in women of advanced age" and "Fertility preserving options for women of advancing age".)
The probability of conception is primarily dependent upon maternal age, and to a lesser extent, paternal age. In contrast to oogenesis, which appears to be limited to the fetus in humans, spermatogenesis continues even in elderly men. Since the adult male's germ cells have passed through more mitotic replications than the adult female's germ cells, there is a greater opportunity for error. Increasing age has been associated with more breaks in sperm DNA, loss of apoptosis, and a higher frequency of point mutations [3,4]. (See "Male reproductive physiology".)
A review on the association between male age and semen quality compared 30-year-old men to 50-year-old men and found decreases in semen volume (3 to 22 percent), sperm motility (3 to 37 percent), and percent of normal sperm (4 to 18 percent), but not sperm concentration, with age . Similar findings were noted in a subsequent series that evaluated men age 22 to 80 years . However, standard sperm parameters do not correlate perfectly with fertilizing capacity and achievement of pregnancy.
Studies have consistently shown that increasing male age is associated with an increased time to pregnancy and decreased pregnancy rates [7-10]. However, only a few studies have examined these outcomes adjusted for female age.
- Leuzzi RA, Scoles KS. Preconception counseling for the primary care physician. Med Clin North Am 1996; 80:337.
- Thacker PD. Biological clock ticks for men, too: genetic defects linked to sperm of older fathers. JAMA 2004; 291:1683.
- Singh NP, Muller CH, Berger RE. Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertil Steril 2003; 80:1420.
- Glaser RL, Broman KW, Schulman RL, et al. The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm. Am J Hum Genet 2003; 73:939.
- Kidd SA, Eskenazi B, Wyrobek AJ. Effects of male age on semen quality and fertility: a review of the literature. Fertil Steril 2001; 75:237.
- Eskenazi B, Wyrobek AJ, Sloter E, et al. The association of age and semen quality in healthy men. Hum Reprod 2003; 18:447.
- Hassan MA, Killick SR. Effect of male age on fertility: evidence for the decline in male fertility with increasing age. Fertil Steril 2003; 79 Suppl 3:1520.
- Klonoff-Cohen HS, Natarajan L. The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer. Am J Obstet Gynecol 2004; 191:507.
- de La Rochebrochard E, Thonneau P. Paternal age >or=40 years: an important risk factor for infertility. Am J Obstet Gynecol 2003; 189:901.
- de La Rochebrochard E, de Mouzon J, Thépot F, et al. Fathers over 40 and increased failure to conceive: the lessons of in vitro fertilization in France. Fertil Steril 2006; 85:1420.
- Ford WC, North K, Taylor H, et al. Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. The ALSPAC Study Team (Avon Longitudinal Study of Pregnancy and Childhood). Hum Reprod 2000; 15:1703.
- Mathieu C, Ecochard R, Bied V, et al. Cumulative conception rate following intrauterine artificial insemination with husband's spermatozoa: influence of husband's age. Hum Reprod 1995; 10:1090.
- Dain L, Auslander R, Dirnfeld M. The effect of paternal age on assisted reproduction outcome. Fertil Steril 2011; 95:1.
- Frattarelli JL, Miller KA, Miller BT, et al. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles. Fertil Steril 2008; 90:97.
- Luna M, Finkler E, Barritt J, et al. Paternal age and assisted reproductive technology outcome in ovum recipients. Fertil Steril 2009; 92:1772.
- Paulson RJ, Milligan RC, Sokol RZ. The lack of influence of age on male fertility. Am J Obstet Gynecol 2001; 184:818.
- Bellver J, Garrido N, Remohí J, et al. Influence of paternal age on assisted reproduction outcome. Reprod Biomed Online 2008; 17:595.
- Whitcomb BW, Turzanski-Fortner R, Richter KS, et al. Contribution of male age to outcomes in assisted reproductive technologies. Fertil Steril 2011; 95:147.
- Beguería R, García D, Obradors A, et al. Paternal age and assisted reproductive outcomes in ICSI donor oocytes: is there an effect of older fathers? Hum Reprod 2014; 29:2114.
- Wu Y, Kang X, Zheng H, et al. Effect of Paternal Age on Reproductive Outcomes of In Vitro Fertilization. PLoS One 2015; 10:e0135734.
- Weinstein M, Stark M. Behavioral and biological determinants of fecundability. Ann N Y Acad Sci 1994; 709:128.
- Rosen RC, Wing R, Schneider S, Gendrano N 3rd. Epidemiology of erectile dysfunction: the role of medical comorbidities and lifestyle factors. Urol Clin North Am 2005; 32:403.
- Sartorius GA, Nieschlag E. Paternal age and reproduction. Hum Reprod Update 2010; 16:65.
- Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151:54.
- Araujo AB, Mohr BA, McKinlay JB. Changes in sexual function in middle-aged and older men: longitudinal data from the Massachusetts Male Aging Study. J Am Geriatr Soc 2004; 52:1502.
- Auroux M. [Age of the father and development]. Contracept Fertil Sex 1993; 21:382.
- Tarín JJ, Brines J, Cano A. Long-term effects of delayed parenthood. Hum Reprod 1998; 13:2371.
- Martin RH, Rademaker AW. The effect of age on the frequency of sperm chromosomal abnormalities in normal men. Am J Hum Genet 1987; 41:484.
- Sartorelli EM, Mazzucatto LF, de Pina-Neto JM. Effect of paternal age on human sperm chromosomes. Fertil Steril 2001; 76:1119.
- Friedman JM. Genetic disease in the offspring of older fathers. Obstet Gynecol 1981; 57:745.
- McIntosh GC, Olshan AF, Baird PA. Paternal age and the risk of birth defects in offspring. Epidemiology 1995; 6:282.
- Olshan AF, Schnitzer PG, Baird PA. Paternal age and the risk of congenital heart defects. Teratology 1994; 50:80.
- Olson JM, Breslow NE, Beckwith JB. Wilms' tumour and parental age: a report from the National Wilms' Tumour Study. Br J Cancer 1993; 67:813.
- Zhu JL, Madsen KM, Vestergaard M, et al. Paternal age and congenital malformations. Hum Reprod 2005; 20:3173.
- Lian ZH, Zack MM, Erickson JD. Paternal age and the occurrence of birth defects. Am J Hum Genet 1986; 39:648.
- Urhoj SK, Mortensen LH, Andersen AN. Advanced paternal age and risk of musculoskeletal congenital anomalies in offspring. Birth Defects Res B Dev Reprod Toxicol 2015; :273.
- Yang Q, Wen SW, Leader A, et al. Paternal age and birth defects: how strong is the association? Hum Reprod 2007; 22:696.
- Saha S, Barnett AG, Foldi C, et al. Advanced paternal age is associated with impaired neurocognitive outcomes during infancy and childhood. PLoS Med 2009; 6:e40.
- Malaspina D, Harlap S, Fennig S, et al. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 2001; 58:361.
- Sipos A, Rasmussen F, Harrison G, et al. Paternal age and schizophrenia: a population based cohort study. BMJ 2004; 329:1070.
- Tsuchiya KJ, Takagai S, Kawai M, et al. Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population. Schizophr Res 2005; 76:337.
- Perrin MC, Brown AS, Malaspina D. Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia. Schizophr Bull 2007; 33:1270.
- Reichenberg A, Gross R, Weiser M, et al. Advancing paternal age and autism. Arch Gen Psychiatry 2006; 63:1026.
- Tsuchiya KJ, Matsumoto K, Miyachi T, et al. Paternal age at birth and high-functioning autistic-spectrum disorder in offspring. Br J Psychiatry 2008; 193:316.
- Durkin MS, Maenner MJ, Newschaffer CJ, et al. Advanced parental age and the risk of autism spectrum disorder. Am J Epidemiol 2008; 168:1268.
- Croen LA, Najjar DV, Fireman B, Grether JK. Maternal and paternal age and risk of autism spectrum disorders. Arch Pediatr Adolesc Med 2007; 161:334.
- Lauritsen MB, Pedersen CB, Mortensen PB. Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. J Child Psychol Psychiatry 2005; 46:963.
- Jayasekara R, Street J. Parental age and parity in dyslexic boys. J Biosoc Sci 1978; 10:255.
- American College of Obstetricians and Gynecologists. Advanced paternal age. ACOG Committee Opinion #189. American College of Obstetricians and Gynecologists; Washington, DC 1997.
- Erickson JD. Paternal age and Down syndrome. Am J Hum Genet 1979; 31:489.
- Stene J, Fischer G, Stene E, et al. Paternal age effect in Down's syndrome. Ann Hum Genet 1977; 40:299.
- Roth MP, Feingold J, Baumgarten A, et al. Reexamination of paternal age effect in Down's syndrome. Hum Genet 1983; 63:149.
- Hook EB, Regal RR. A search for a paternal-age effect upon cases of 47, +21 in which the extra chromosome is of paternal origin. Am J Hum Genet 1984; 36:413.
- Sloter E, Nath J, Eskenazi B, Wyrobek AJ. Effects of male age on the frequencies of germinal and heritable chromosomal abnormalities in humans and rodents. Fertil Steril 2004; 81:925.
- De Souza E, Morris JK, EUROCAT Working Group. Case-control analysis of paternal age and trisomic anomalies. Arch Dis Child 2010; 95:893.
- Yip BH, Pawitan Y, Czene K. Parental age and risk of childhood cancers: a population-based cohort study from Sweden. Int J Epidemiol 2006; 35:1495.
- Hatch M, Kline J, Levin B, et al. Paternal age and trisomy among spontaneous abortions. Hum Genet 1990; 85:355.
- de la Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study. Hum Reprod 2002; 17:1649.
- Slama R, Werwatz A, Boutou O, et al. Does male age affect the risk of spontaneous abortion? An approach using semiparametric regression. Am J Epidemiol 2003; 157:815.
- Slama R, Bouyer J, Windham G, et al. Influence of paternal age on the risk of spontaneous abortion. Am J Epidemiol 2005; 161:816.
- Nybo Andersen AM, Hansen KD, Andersen PK, Davey Smith G. Advanced paternal age and risk of fetal death: a cohort study. Am J Epidemiol 2004; 160:1214.
- Gallardo E, Simón C, Levy M, et al. Effect of age on sperm fertility potential: oocyte donation as a model. Fertil Steril 1996; 66:260.
- Practice Committee of the American Society for Reproductive Medicine. Aging and infertility in women: a committee opinion. Fertil Steril 2002; 78:215.
- Olshan AF, Ananth CV, Savitz DA. Intrauterine growth retardation as an endpoint in mutation epidemiology: an evaluation based on paternal age. Mutat Res 1995; 344:89.
- Shah PS, Knowledge Synthesis Group on determinants of preterm/low birthweight births. Paternal factors and low birthweight, preterm, and small for gestational age births: a systematic review. Am J Obstet Gynecol 2010; 202:103.
- Resseguie LJ. Paternal age, stillbirths and mutation. Ann Hum Genet 1976; 40:213.
- Yerushalmy, J. Age of father and survival of offspring. Hum Biol 1939; 11:342.
- Woolf, CM. Stillbirths and paternal age. Obstet Gynecol 1965; 26:1.
- Selvin S, Garfinkel J. Paternal age, maternal age and birth order and the risk of a fetal loss. Hum Biol 1976; 48:223.
- Astolfi P, De Pasquale A, Zonta LA. Late paternity and stillbirth risk. Hum Reprod 2004; 19:2497.
- Chen XK, Wen SW, Krewski D, et al. Paternal age and adverse birth outcomes: teenager or 40+, who is at risk? Hum Reprod 2008; 23:1290.
- Urhoj SK, Jespersen LN, Nissen M, et al. Advanced paternal age and mortality of offspring under 5 years of age: a register-based cohort study. Hum Reprod 2014; 29:343.
- SEMEN QUALITY
- Sexual function and coital frequency
- AUTOSOMAL DOMINANT DISEASE
- CONGENITAL ANOMALIES AND DISEASES
- NEURODEVELOPMENT OF OFFSPRING
- Cognitive ability
- Autism spectrum disorder
- X LINKED DISEASE
- IMPACT ON PREGNANCY
- Preconception counseling
- Fetal growth restriction, preterm birth, and stillbirth
- SUMMARY AND RECOMMENDATIONS