Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men

W.C.L. Ford1,4, Kate North2, Hazel Taylor2, Alexandra Farrow3, M.G.R. Hull1, Jean Golding2 and the ALSPAC StudyTeam,2

1 Division of Obstetrics and Gynaecology, 2 Division of Paediatric and Perinatal Epidemiology, University of Bristol, Bristol and 3 Brunel University, Department of Health Studies, Middlesex, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The impact of male age on fecundity remains controversial. Here, a large population study was used to investigate the effect of paternal age on time to conception. All couples in the Avon Health district expecting a baby between 1 April 1991 and 31 December 1992 were eligible. Questionnaires completed by both the man and the woman at 18 weeks gestation covered specific fertility factors, e.g. parity, paternity, cohabitation and oral contraception; and non-specific factors, e.g. educational achievement, housing, cigarette smoking, alcohol consumption, obesity. Logistic regression was used to identify factors independently related to conception in <=6 or <=12 months. Of 8515 planned pregnancies, 74% were conceived in <=6 months, 14% in the second 6 months and 12% after more than a year. Nine variables, including the age of the woman, were independently related to time to conception. After adjustment for these, the likelihood of conception within 6 or 12 months was lower in older men. Compared to men <25 years old, the adjusted odds ratios (95% confidence interval) for conception in <=12 months were 0.62 (0.40, 0.98), 0.50 (0.31, 0.81) and 0.51 (0.31, 0.86) in men aged 30–34, 35–39 and >=40 years respectively.

Key words: fecundity/fertility/male age/time to conception


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Use of the words fertility, fecundity and fecundability is inconsistent; here we use fecundity to mean the likelihood of achieving a pregnancy in a defined period of time. A decline in the fecundity of men with age has never been confirmed or quantified by studies in the general population. Ageing of the man is confounded by ageing of his partner and the decline in coital frequency associated with prolonged co-habitation (Weinstein and Stark, 1994Go). By contrast, the independent effects of female ageing have been clearly demonstrated using donor insemination as a model (Federation CECOS et al., 1982). Female fecundity declines after age 30 years, slowly at first but rapidly after 40 years and is now the main limiting factor in the treatment of infertility (Hull et al., 1996Go; Templeton et al., 1996Go; Spandorfer et al., 1998Go).

Adverse changes in semen quality with age have been reported but were slight (Nieschlag et al., 1982Go; Schwartz et al., 1983Go; Rolf et al., 1996Go). Neither sperm function in vitro (Haidl et al., 1996Go), nor the ability to fertilize donated oocytes (Gallardo et al., 1996Go) or zona-free hamster oocytes (Nieschlag et al., 1982Go) declined with age. Advancing paternal age was an adverse factor for conception in couples with secondary infertility (Ducot et al., 1988Go) but had only a minor influence in studies of fertile populations (Goldman and Montgomery, 1989Go; Joffe and Li, 1994Go), although the maximum age in the latter study was only 33 years. On the other hand, risks of miscarriage and genetic abnormalities in offspring increase with the age of the father (Lansac, 1995Go; Tarin, 1998Go). Endocrine function is also known to decline and morphological changes occur in the testis (to be discussed below).

A meta-analysis suggesting a decline in sperm counts over the past 50 years (Carlsen et al., 1992Go) and studies of semen donors in which young men have had lower sperm counts than older men (Auger et al., 1995Go; Irvine et al., 1996Go) are controversial (Giwercman, 1995Go; Irvine, 1997Go; Swan et al., 1997Go). Nevertheless, if real, these effects might result in decreased fecundity among younger as compared with older men.

Here we have examined the effect of paternal age on the likelihood of delayed conception using data derived from a geographically defined population during pregnancy. Time to conception is a useful epidemiological marker of fecundity, although it has to be used with caution because it ignores couples who fail to conceive and is subject to a number of sources of bias (Baird et al., 1986Go; Joffe and Li, 1994Go; Olsen et al., 1998Go; Spira, 1998Go; Tuntiseranee et al., 1998Go).


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Source of data
The Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC) was designed to study the effects of personal, social and environmental factors on the development of children from early pregnancy onwards (Golding and the ALSPAC Study Team, 1996). All mothers and their partners living in the area administered by the Avon Health Authority and with an expected delivery date between 1 April 1991 and 31 December 1992 were invited to enrol in the study as early as possible in pregnancy. In the event 14 893 pregnancies were included representing 85% of the total eligible.

The present study is based on pregnancies that resulted in the birth of a baby (i.e. >24 weeks gestation) and information collected by self-completion questionnaires from each woman and her partner at 18 weeks gestation. Specific fertility information included: previous obstetric and gynaecological history, sexual experience, oral contraception including duration of use, duration of co-habitation, paternity, whether the pregnancy had been planned and how long the parents had been trying to conceive divided into four bands, <=6 months, >6 but <=12 months, >12 months but <=3 years and >3 years. Other data collected included: maternal and paternal ages at the time the pregnancy was conceived, their ethnic origins, highest educational levels (5-point scale), whether the father was employed, home ownership status, housing type, crowding at home (persons/room) and all prior to pregnancy, the woman's body mass index (BMI = weight/height2), dietary habits (vegetarian or not), cigarette smoking level, and alcohol consumption, the man's smoking and alcohol consumption and the woman's exposure to environmental tobacco smoke. Cases where the mother was <16 years old or reported that her partner was not the father of the child (sometimes due to donor insemination) were excluded. Where possible, the data collected from the questionnaires were cross-checked against medical records and observations made at interview and a high degree of agreement was found. Further information is available at the ALSPAC website (www.ich.bris.ac.uk/localdir/itsus.html).

Statistical methods
The model was a population study of couples who had conceived a planned pregnancy that continued to >24 weeks gestation. Two separate stepwise logistic regression analyses were done to determine which factors influenced the likelihood that a pregnancy would be achieved in <=6 or in <=12 months or longer. For continuous variables such as parental age and BMI, quadratic and cubic terms were also offered to the regression analysis. The statistical packages used were SPSS (Statistics Package for the Social Sciences) for {chi}2 and analysis of variance to examine univariate associations with paternal age and BMDP (Biomedical Statistics Package, BMDP Statistical Software Inc., Los Angeles, CA, USA) for logistic regression. A P-value of 0.05 was used as the criterion of statistical significance.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
There were 12 106 couples eligible for study, of whom 8559 (70.7%) had planned the pregnancy, 3480 (28.7%) had conceived accidentally and 67 (0.6%) did not answer the question. Of the planned pregnancies 8515 couples (99.5%) stated the time taken to conceive; 6316 (74.2%) in the first 6 months, 1190 (13.9%) in the second 6 months, 723 (8.5%) in the second and third years and 286 (3.4%) after 3 years. Male age data were available for 7870 planned pregnancies, female age data for 8515 and complete data for 6524. The mean age of the women at conception was 28 and of the men 31 years.

Older men were significantly less likely than younger men to impregnate their partners in <=6 or in <=12 months (Table IGo). The average age of the men who took >6 months to impregnate their wives was 31.8 ± 5.75 years compared with 30.8 ± 5.27 years in men who took <=6 months (P < 0.0001). Men who took >12 months were also significantly (P < 0.0001) older (32.6 ± 5.91 years) than men who took <=12 months (30.9 ± 5.32 years). However, as expected, older women were less likely than young women to conceive in <=6 or in <=12 months. In view of the strong association between paternal and maternal age, this might explain the apparent decline in male fecundity with advancing age. Not only the woman's age but many other factors are associated with the time couples take to conceive and it is important to take these into account. Table IIGo describes the variation of paternal age with several socio-demographic and life style factors that were statistically significantly associated with conception within <=6 or <=12 months. These included maternal education, maternal and passive smoking, pill use, years of co-habitation, housing, maternal age and maternal body mass index in addition to paternal age. Conception within <=6 but not <=12 months was also significantly associated with paternal alcohol consumption. These factors will not be discussed further in the present paper except in so far as they influence the effect of paternal age.


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Table I. The observed proportion of planned pregnancies leading to birth conceived in <=6 or in <=12 months according to the father's and the mother's age
 

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Table II. Variation of paternal age (years) at conception of study pregnancy with socio-demographic and lifestyle variables
 
Men whose partners had had a previous pregnancy or a previous baby were significantly older than men whose partner had not (Table IIGo). The average age of the man increased with the female partner's age and with the duration of co-habitation and with his level of education and that of his partner. Men who owned their own home or lived in a more spacious property were older. Men who smoked were on average younger than those who did not smoke or whose partners did not smoke but men who drank >1 unit of alcohol/day were older than those who drank less or whose partner drank less (Table IIGo).

The man's age was statistically significantly associated with duration of oral contraceptive use by his partner and with the partner's BMI. Men whose partners had never used oral contraception or had used it for >=5 years were of similar age but men whose partners used it for an intermediate length of time were younger. Men whose partners were excessively thin or excessively fat were significantly younger than men whose partners had a normal BMI (Table IIGo). Neither male nor female ethnicity had any statistically significant relationship with the age of the men (data not shown).

Table IIIGo shows the odds ratios for conception within 6 or 12 months by paternal and maternal age before and after adjustment for the other factors, detailed above, that were statistically significantly associated with time to conception. After adjustment, paternal age remained highly significantly associated with conception within 6 or 12 months (P < 0.0001). Compared with men aged <=24 years the adjusted odds ratios for conceiving within 12 months were statistically significantly lower for men aged 30–34, 35–39 or >=40 years and the odds ratios decreased with advancing age. The adjusted odds ratios of conceiving within 6 months were not statistically significantly different between men <=24 years and any other 5 year age band but the overall association with age was highly statistically significant. If the man's age was treated as a continuous variable there was a significant linear relationship: the odds ratio for conception in <=6 months decreased by 2% per year of age (P < 0.01) and for conception in <=12 months by 3% (P < 0.001). After adjustment, women up to 35 years of age had the same likelihood of conceiving within 6 months as women <=24 years but at >35 years the likelihood was significantly less. A similar trend was seen for conception in <=12 months but the decline in the older age groups failed to achieve statistical significance (Table IIIGo).


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Table III. The effect of paternal or maternal age on the odds ratio (95% confidence intervals) for achieving conception within 6 or 12 months before [n = 7870 (fathers) and 8515 (mothers)] and after (n = 6524 ) adjustment for age of the other parent, BMI, smoking habit, passive smoke exposure, education, duration of cohabitation, duration of oral contraceptive use and housing and for conception within 6 months, paternal alcohol consumption
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Quantification of the effect of a man's age on his fecundity is difficult because it is confounded by many other factors. Moreover, fecundity is difficult to measure directly except in small and atypical populations such as couples attending fertility clinics. In this study, time to conception was used as an accessible index of fecundity and a logistic regression model was used to take account of the other variables that had a significant influence. After adjustment, the results demonstrated a statistically significant increase with advancing male age in the proportion of couples who took longer than 6 or 12 months to conceive. These results suggest that there is a larger decline in male fecundity with advancing age than reported in earlier population studies (see above).

We have to acknowledge that this conclusion is based on the conditional probability of conception within 6 or 12 months in couples who ultimately had a baby. This does not necessarily reflect the probability of conception in the population as a whole. Nevertheless time to conception is widely regarded as a useful index of fecundity (Baird et al., 1986Go; Joffe and Li, 1994Go) and has been used to deduce regional differences in fecundity in different parts of Europe (Juul et al., 1999Go). It is, however, subject to a number of sources of bias (Spira, 1998Go). Two of the most pertinent to the present study are differences in contraceptive practice or persistence in trying to achieve a pregnancy, between the groups compared. If the prevalence of effective contraceptive use differed between couples with men of different ages, changes in time to conceive the planned pregnancies may not reflect changes in fecundity of the whole population of that age (Baird et al., 1994Go). Bias could be in two directions: on the one hand, couples with high fecundity are more likely to have unplanned pregnancies due to contraceptive failures and so be eliminated from the study group. On the other hand, couples who have reason to believe their fertility to be low are more likely to be lax in their contraceptive precautions. The former error can be controlled by including the unplanned pregnancies in the rapidly conceiving group (Olsen et al., 1998Go). Here, substantially similar results were obtained if all the unplanned pregnancies were included in the <=6 or <=12 month groups. Therefore our conclusions would remain valid even if the most fertile of the older men had been eliminated from the study group because they achieved unplanned pregnancies. If the opposite bias predominated and the less fertile couples were lost from the older groups, we would underestimate the effect of age on male fecundity. It is unlikely that a substantial number of men aged <=24 years would believe themselves to be sub-fertile.

It has been reported that older women are less likely to persist for a long time in trying to become pregnant and that this can lead to spuriously short times to pregnancy in this group (Olsen et al., 1998Go). Were this true of older men, it would again lead to an underestimate of the effect of age on fecundity.

Despite these concerns, we believe our data are robust and widely applicable because: (i) they are based on the general population and not couples attending infertility clinics; (ii) the group is large enough to allow proper correction for confounding factors; (iii) a high participation rate (>85%) was achieved; (iv) ALSPAC was not presented to couples as a study of fertility and all were pregnant when data were collected, so any recall bias between highly and poorly fecund couples is unlikely; (v) the study included fathers of all ages; and (vi) the Avon Health area provides a good balance between urban and rural, industrial and agricultural and rich and poor communities and has a relatively stable population.

Our data confirm the already firmly established decline in female fecundity with age (Tables I and IIIGoGo). The only surprise is that the effect for conception in <=12 months failed to achieve greater statistical significance. We believe that this can be ascribed to three factors: (i) smaller numbers of older women in the study leading to loss of statistical power; (ii) only couples who ultimately conceived were included in the study; and (iii) as mentioned above, older women are less likely than young ones to persist for a long time in trying to become pregnant. The impact of all three factors is greater for conception in <=12 than in <=6 months.

It may be considered that logistic regression is not sensitive enough to untangle the different independent relationships of two variables that are so very closely related as maternal and paternal age. We investigated this in more detail by looking at the influence of the age difference between the woman and the man on the likelihood of delayed conception. After adjusting for female age together with all the other factors in the logistic regression model, women whose partners who were >=5 years older than themselves (n = 1949) had a reduced chance of conception both within 6 and 12 months when compared to women whose partners were the same age or younger (n = 2288). For conception within 6 months, the odds ratio was 0.84 (95% CI 0.71, 0.98; P = 0.007) and for conception within 12 months 0.73 (95% CI 0.59, 0.89; P = 0.001). Thus it is likely that there is an independent relationship between the man's age and delayed conception.

The data offer some reassurance that young men in the Bristol area are still more fertile than their older counterparts. However, they do not exclude the possibility that the greater fecundity of young relative to older men was more marked in the past. Moreover fecundity in the normal population is not affected by sperm count until the concentration drops below 40x106/ml (Bonde et al., 1998Go) and increased sexual activity in younger men could compensate for relatively small differences in semen quality. Therefore these observations do not preclude the existence of deleterious environmental effects on male reproductive development.

We cannot say whether the decline in male fecundity with age is due to behavioural factors, e.g. decreased coital frequency, or to effects on the fertility of semen per se, or to a combination of both. It is also possible that more fertile men complete their families sooner, and less often try to father children in their thirties or forties. Coital frequency falls with increasing male age over and above the effects of length of cohabitation and the age of the female partner (Weinstein and Stark, 1994Go). This reduces the chance that coitus occurs in the fertile period. However, there is also good evidence that the endocrine function of the testis declines in elderly men resulting in a decrease in circulating testosterone which has an augmented effect on free testosterone because of an increase in sex hormone binding globulin concentration (Kaufman and Vermeulen, 1997Go). Similar changes are seen in animal models (Wang et al., 1993Go) and appear to be modulated by a decrease in LH pulse amplitude. Although most data come from elderly men changes can be detected in middle age (Erfurth and Hagmar, 1995Go; Bonavera et al., 1997Go). There are a number of morphological changes in the ageing testis, including a decrease in the number of Leydig cells (Neaves et al., 1985Go), a decline in Sertoli cell numbers and daily sperm production (Johnson et al., 1984aGo,bGo) and an increase in the involution of seminiferous tubules (Paniagua et al., 1987Go). Spermatozoa from older men are less fertile after intrauterine insemination (Mathieu et al., 1995Go; Brzechffa and Buyalos, 1997Go) or in donor insemination (Lansac, 1995Go). These observations support the conclusion that the effects of paternal age on a couple's fecundity are real and may be greater than previously believed. After adjustment for other factors, the probability that an ultimately fertile couple will take >12 months to conceive nearly doubles from ~8% when the man is <25 years to ~15% when he is >35 years and paternal age is a further factor to take into account when deciding the prognosis for infertile couples.


    Acknowledgments
 
We are grateful to the couples who took part, the midwives for their help and the whole ALSPAC team for their continuing dedication to the study programme. ALSPAC depends on financial support from the Departments of Health and of the Environment, the Medical Research Council and various medical charities and commercial companies. The present analysis was financed by an MRC ROPA award. ALSPAC is part of the WHO initiated European Longitudinal Study of Pregnancy and Childhood.


    Notes
 
4 To whom correspondence should be addressed at: University Division of Obstetrics & Gynaecology, St Michael's Hospital, Southwell Street, Bristol BS2 8EG, UK. E-mail: chris.ford{at}bristol.ac.uk Back


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on March 17, 2000; accepted on May 11, 2000.