Department of Genetics and Microbiology A. Buzzati Traverso, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy
1 To whom correspondence should be addressed. Email: astolfi{at}ipvgen.unipv.it
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: delayed childbearing/paternal age/maternal age/pregnancy outcome/risk at birth
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Sporadic cases of some monogenic diseases due to single base substitutions, like achondroplasia, osteogenesis imperfecta, and Apert, Crouzon and Pfeiffer syndromes, have been found to be prevalently of paternal origin, and in some cases a sharply increased incidence with increasing paternal age has been observed (Risch et al., 1987; Carlson et al., 1994
; Moloney et al., 1996
; Bunin et al., 1997
; Wilkin et al., 1998
; Blumsohn et al., 2001
).
The association between paternal ageing and the increase in the incidence of genetic diseases may be explained by the high number of germ cell duplications: if 23 duplications per year are assumed, divisions increase from 150 at the age of 20 years, to 610 at 40 years and to 840 at 50 years (Vogel and Rathenberg, 1975; Drost and Lee, 1995
). In consequence, genetic load in the male germ line is expected to increase for the accumulation of point mutations owing to replication errors and reduced activity of repair enzymes (Crow, 1997
; 2000
), length mutations, strand mispairing in short tandem repeats (Leeflang et al., 1999
; Cummings and Zoghbi, 2000
) and a longer exposure to environmental mutagens (Allen et al., 1995
; Thomas, 1996
).
Harmful mutations, even with mild deleterious effects, might influence monogenic as well as complex polygenic traits so as to affect progeny survival and health. Recently, it has been observed that paternal ageing enhanced the risk of some complex multifactorial pathologies, such as schizophrenia, preeclampsia, Alzheimer's disease and miscarriage (Bertram et al., 1998; Esplin et al., 2001
; Malaspina et al., 2001
; 2002
; de La Rochebrochard and Thonneau, 2002
; Harlap et al., 2002
; Slama et al., 2003
).
The problem of late reproduction has become especially important during the last decade, when socioeconomic and cultural changes have driven Western populations to very low levels of fertility and led to postponement of child bearing to advanced age (Fretts et al., 1995; Gosden and Rutheford, 1995
; Breart, 1997
). Consequently, the evaluation of neonate mortality and morbidity risk in relation to parental ageing has assumed greater relevance from a biological, as well as a sociodemographic and personal, point of view. The importance of delaying childbearing to an advanced age has previously been examined in the Italian population, and the risk of unfavourable pregnancy outcomes has been estimated as a function of maternal ageing (Astolfi et al., 1999
; Astolfi and Zonta, 2002
).
The aim of this paper was to examine the effect of paternal ageing on a complex multifactorial character, stillbirth, after adjustment for maternal age and family education. It is expected that among young mothers who live in highly educated families, where the role of biological and environmental factors on pregnancy impairment may be greatly reduced, the stillbirth risk, possibly associated with late paternity, could be indicative of a genetic component linked to ageing.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Family educational level was coded in two classes: low, corresponding to the present Italian compulsory education of both parents (8 years schooling); and high, corresponding to the secondary school diploma or university degree of at least one parent. It should be noted that a low educational level is usually assumed to be a reliable indicator of unfavourable socioeconomic conditions.
Maternal age was grouped in four classes of 5-year intervals, with the last class grouping mothers 35 years; paternal age was considered in 1-year interval classes, ranging from 20 to 86 years.
Through multiple logistic regression analyses the response variable stillbirth risk [Prob(stillbirth)/Prob(livebirth)] was studied as a linear function of the quantitative variable paternal age (Fi; i = 20, 86), the categorical variables maternal age (Mj; j = 1,4) and family education (Ek; k = 1, 2), and the interactions F*M, F*E, M*E and F*M*E. Models that included paternal age as a linear function showed the best fit in comparison with models including exponential or power functions, which had been fitted to cases of specific disease (Risch et al., 1987; Crow, 1997
; 2000
). Interactions were tested by fitting models with and without each single interaction, and the simplest model was chosen (Clayton and Hills, 1995
).
The critical ages, 35 years for mothers and 40 years for fathers, were used as threshold values to estimate the relative stillbirth risk [odds ratio (OR) (95% CI)] after stratification by family education (low versus high).
Statistical analyses were performed using the programs SPSS 12 and SAS version 6.12.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Stillbirth is a complex event with multiple aetiologies, even after the exclusion of complications during pregnancy and labour, like defective placental maturation and asphyxia, and maternal pathologies, like diabetes, hypertension, thrombophilia and acquired infections (Stallmach et al., 2001; Alfirevic et al., 2002
; Kramer et al., 2002
; Kupferminc et al., 2002
; Goldenberg and Thompson, 2003
; Kunzel and Misselwitz, 2003
; Rai, 2003
). When, for the large amount of the examined data coming from the National Vital Statistics, the weight of pathological factors can be ignored and some relevant covariates (maternal age and education) are controlled for, a genetic component may be hypothesized in the defective growth and maturation of the fetus, in addition to congenital anomalies, which are continuously increasing in importance (Kramer et al., 2002
; Kunzel and Misselwitz, 2003
).
We studied the stillbirth risk as a quantitative linear function of paternal ageing. A quantitative effect, continuously cumulating with ageing, can be expected on the basis of the underlying genetic hypothesis, although slight and therefore difficult to reveal. Unlike what has been reported for specific genetic diseases (Risch et al., 1987; Crow, 1997
; 2000
), the linear model showed the best fit in comparison with exponential or power models. The effect of paternal ageing was found to be modified by maternal age and family education (Table II; Figure 1). Even when mothers live in highly educated families, where consciousness in facing pregnancy and recourse to antenatal care can be assumed, paternal ageing gradually increases the risk (OR 1.02; P<0.001). However, the effect is restricted to mothers aged
30 years, being OR 1.01 in mothers aged 3034 years and OR 1.03 in mothers aged
35 years (Figure 1). The effect of paternal ageing was not revealed among young mothers <30 years old. The finding should be supported by further investigations aimed at excluding a possible artefact due to the low frequency (5.8%) of babies born to mothers aged <30 years and to fathers
35 years. However, when the threshold ages of 35 and 40 years for mothers and fathers, respectively, are considered, even in young mothers (<35 years) the relative risk for fathers
40 years accounts for OR 1.12 (Table III).
We are conscious that one of the limits of the analysis resides, in addition to the reduced number of the considered explanatory covariates, in their coding criteria. Although maternal education is widely considered to be among the most reliable predictors of the fetal health, we considered the education of the family on the assumption that awareness of problems during pregnancy and the consequent recourse to advanced prenatal care can be enhanced by a high level of education in at least one parent. Ageing was assumed to impair fetal health, and the paternal and maternal effects were examined in 1- and 5-year intervals, respectively. The risk was also evaluated contrasting mothers >35 years old and fathers >40 years old with their younger counterparts. Such ages are generally accepted as critical thresholds, because of the strong increase in the risk of specific neonatal and maternal pathologies, miscarriage and problems during delivery (Risch et al., 1987; Cnattingius et al., 1992
; Fretts et al., 1995
; Tarin et al., 1997
; de La Rochebrochard and Thonneau, 2002
; Slama et al., 2003
).
The aim of this study was to find a possible cumulative effect of paternal ageing on stillbirth risk, and the hypothesis appears to be supported in mothers aged 30 years. When the most favourable conditions are present, i.e. in mothers aged 3034 years living in highly educated families, the 5% increase of the stillbirth risk every 5 years of paternal ageing might be indicative of a genetic paternal contribution, associated with an accumulation of harmful mutations.
![]() |
Acknowledgements |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Allen JW, Ehling UH, Moore MM and Lewis SE (1995) Germ line specific factors in chemical mutagenesis. Mutat Res 330, 219231.[ISI][Medline]
Astolfi P and Zonta LA (2002) Delayed maternity and risk at delivery. Paediatr Perinat Epidemiol 16, 6772.[CrossRef][ISI][Medline]
Astolfi P, Ulizzi L and Zonta LA (1999) Selective cost of delayed childbearing. Hum Reprod 14, 572573.
Bertram L, Busch R, Spiegl M, Lautenschlager NT, Muller U and Kurz A (1998) Paternal age is a risk factor for Alzheimer disease in the absence of a major gene. Neurogenetics 1, 277280.[CrossRef][ISI][Medline]
Bianco A, Stone J, Lynch L, Lapinski R, Berkowitz G and Berkowitz RL (1996) Pregnancy outcome at age 40 and older. Obst Gynecol 87, 917922.
Blumsohn A, McAllion SJ and Paterson CR (2001) Excess paternal age in apparently sporadic osteogenesis imperfecta. Am J Med Genet 100, 280286.[CrossRef][ISI][Medline]
Breart G (1997) Delayed childbearing. Eur J Obstet Gynecol Reprod Biol 75, 7173.[CrossRef][ISI][Medline]
Bunin GR, Needle M and Riccardi VM (1997) Paternal age and sporadic neurofibromatosis 1: a casecontrol study and consideration of the methodologic issues. Genet Epidemiol 14, 507516.[CrossRef][ISI][Medline]
Carlson KM, Bracamontes J, Jackson CE, Clark R, Lacroix A, Wells SA Jr and Goodfellow PJ (1994) Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 55, 10761082.[ISI][Medline]
Clayton D and Hills M (1995) Statistical Models in Epidemiology. Oxford Science Publications. Oxford University Press, Oxford, UK.
Cnattingius S, Forman MR, Berendes HW and Isotalo L (1992) Delayed childbearing and risk of adverse perinatal outcome. A population-based study. JAMA 268, 886890.[Abstract]
Crow JF (1997) The high spontaneous mutation rate: Is it a health risk? Proc Natl Acad Sci USA 94, 83808386.
Crow JF (2000) The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet 1, 4047.[CrossRef][ISI][Medline]
Cummings CJ and Zoghbi HY (2000) Fourteen and counting: unraveling trinucleotide repeat diseases. Hum Mol Genet 9, 909916.
de La Rochebrochard E and Thonneau P (2002) Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study. Hum Reprod 17, 16491656.
Dollberg S, Seidman DS, Armon Y, Stevenson DK and Gale R (1996) Adverse perinatal outcome in the older primiparae. J Perinatol 16, 9397.[CrossRef][Medline]
Drost JB and Lee WR (1995) Biological basis of germine mutation: Comparison of spontaneous germine mutation rates among Drosophila, mouse and human. Environ Mol Mutagen 25, 4854.[ISI][Medline]
Esplin MS, Fausett MB, Fraser A, Kerber R, Mineau G, Carrillo J and Varner MW (2001) Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 344, 867872.
Faden VB, Graubard BI and Dufour M (1997) The relationship of drinking and birth outcome in a US national sample of expectant mothers. Paediatr Perinat Epidemiol 11, 167180.[CrossRef][ISI][Medline]
Fretts RC, Schmittdiel J, McLean FH, Usher RH and Goldman MB (1995) Increased maternal age and the risk of fetal death. N Engl J Med 333, 953957.
Gilbert VM, Nesbitt TS and Danielsen B (1999) Childbearing beyond age 40: pregnancy outcome in 24,032 cases. Obstet Gynecol 93, 914.
Goldenberg RL and Thompson C (2003) The infectious origins of stillbirth. Am J Obstet Gynecol 189, 861873.[CrossRef][ISI][Medline]
Gosden R and Rutheford A (1995) Delayed childbearing. BMJ 311, 15851586.
Haldane JBS (1947) The mutation rate of the gene for hemophilia and its segregation ratios in males and females. Ann Eugen 13, 262271.[ISI]
Harlap S, Paltiel O, Deutsch L, Knaanie A, Masalha S, Tiram E, Caplan LS, Malaspina D and Friedlander Y (2002) Paternal age and preeclampsia. Epidemiology 13, 660667.[CrossRef][ISI][Medline]
Horta BL, Victora CG, Menezes AM, Halpern R and Barros FC (1997) Low birthweight, preterm births and intrauterine growth retardation in relation to maternal smoking. Paediatr Pernat Epidemiol 11, 140151.[CrossRef]
Jolly M, Sebire N, Harris J, Robinson S and Regan L (2000) The risks associated with pregnancy in women aged 35 years or older. Hum Reprod 15, 24332437.
Kramer MS, Liu S, Luo Z, Yuan H, Platt RW and Joseph KS (2002) Analysis of perinatal mortality and its components: time for a change? Am J Epidemiol 156, 493497.
Kunzel W and Misselwitz B (2003) Unexpected fetal death during pregnancya problem of unrecognized fetal disorders during antenatal care? Eur J Obstet Gynecol Reprod Biol 110, S86S92.[CrossRef][ISI][Medline]
Kupferminc MJ, Many A, Bar-Am A, Lessing JB and Ascher-Landsberg J (2002) Mid-trimester severe intrauterine growth restriction is associated with a high prevalence of thrombophilia. Br J Obstet Gynaecol 109, 13731376.
Leeflang EP, Tavare S, Marjoram P, Neal CO, Srinidhi J, MacFarlane H, MacDonald ME, Gusella JF, de Young M, Wexler NS et al. (1999) Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic mutation mechanism. Hum Mol Genet 8, 173183.
Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D and Susser ES (2001) Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 58, 361367.
Malaspina D, Corcoran C, Fahim C, Berman A, Harkavy-Friedman J, Yale S, Goetz D, Goetz R, Harlap S and Gorman J (2002) Paternal age and sporadic schizophrenia: evidence for de novo mutations. Am J Med Genet 8, 299303.
Moloney DM, Slaney SF, Oldridge M, Wall SA, Sahlin P, Stenman G and Wilkie AO (1996) Exclusive paternal origin of new mutations in Apert syndrome. Nat Genet 13, 4853.[ISI][Medline]
Pattenden S, Dolk H and Vrijheid M (1999) Inequalities in low birthweight: parental social class, area deprivation and "lone mother" status. J Epidemiol Community Health 53, 355358.[Abstract]
Rai R (2003) Is miscarriage a coagulopathy? Curr Opin Obstet Gynecol 15, 265268.[CrossRef][ISI][Medline]
Risch N, Reich EW, Wishnick MM and McCarthy JG (1987) Spontaneous mutation and parental age in humans. Am J Hum Genet 41, 218248.[ISI][Medline]
Slama R, Werwatz A, Boutou O, Ducot B, Spira A and Hardle W (2003) Does male age affect the risk of spontaneous abortion? An approach using semiparametric regression. Am J Epidemiol 157, 815824.
Stallmach T, Hebisch G, Meier K, Dudenhausen JW and Vogel M (2001) Rescue by birth: defective placental maturation and late fetal mortality. Obstet Gynecol 97, 505509.
Tarin JJ, Brines J and Cano A (1997) Long-term effects of delayed parenthood. Hum Reprod 13, 23712376.[CrossRef][ISI]
Thomas GH (1996) High male:female ratio of germ-line mutations: an alternative explanation for postulated gestational lethality in males in X-linked dominant disorders. Am J Hum Genet 58, 13641368.[ISI][Medline]
Vogel F and Rathenberg R (1975) Spontaneous mutation in man. Adv Hum Genet 5, 223318.[ISI][Medline]
Weinberg W (1912) Zur vererbung des zwargwuchses. Arch Rass Gesamte Biol 9, 710718.
Wilkin DJ, Szabo JK, Cameron R, Henderson S, Bellus GA, Mack ML, Kaitila I, Loughlin J, Munnich A, Sykes B et al. (1998) Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet 63, 711716.[CrossRef][ISI][Medline]
Submitted on February 2, 2004; resubmitted on June 3, 2004; accepted on July 13, 2004.
|