1 INED (National Demographic Studies Institute), 75020 Paris and 2 Research Group in Human Fertility, INSERM, La Grave Hospital, 31052 Toulouse, France
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Abstract |
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Key words: ageing/fetal death/maternal age/paternal age/spontaneous abortion
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Introduction |
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One of the most frequent adverse reproductive events is spontaneous abortion, with up to 10% of recognized conceptions lost during the pregnancy (Nybo Andersen et al., 2000). Most studies concerning the risk factors for spontaneous abortion have concluded that the predominant negative effects are those of advanced maternal age (with a clear increase in risk after 35 years) and previous spontaneous abortion (Leridon, 1976
; Regan et al., 1989
; Coste et al., 1991
; Fretts et al., 1995
; Nybo Andersen et al., 2000
; Osborn et al., 2000
). Conflicting results have been obtained for other spontaneous abortion risk factors such as maternal consumption of tobacco, maternal psychological problems, interval between pregnancies, or previous use of the contraceptive pill (Risch et al., 1988
; Coste et al., 1991
; Dominguez et al., 1991
). Thus most of these studies analysed the effect of female factors on spontaneous abortion. Male factors may also affect spontaneous abortion risk, but have been little analysed. Most studies on male factors have focused on the effect of professional exposure of the man to toxic substances (such as ethylene oxide, rubber chemicals, solvents, thiocarbamates, carbaryl) on spontaneous abortion risk in his partner (Lindbohm et al., 1991
; Savitz et al., 1997
). Paternal age has only rarely been considered: only five studies (published before 1980) have investigated the risk of spontaneous abortion according to both maternal and paternal age (Yerushalmy, 1939
; Warburton and Fraser, 1964
; Woolf, 1965
; Resseguie, 1976
; Selvin and Garfinkel, 1976
). Four of these studies analysed medical certificates for fetal deaths occurring after 20 weeks gestation (Yerushalmy, 1939
; Woolf, 1965
; Resseguie, 1976
; Selvin and Garfinkel, 1976
). Three of these four studies concluded that paternal age had an effect, after adjusting for maternal age (Yerushalmy, 1939
; Woolf, 1965
; Selvin and Garfinkel, 1976
); the fourth did not (Resseguie, 1976
). However, only one of these studies used a multivariate model to take confounding effects into account but, unfortunately, in this model, the effect of age was assumed to be linear (Selvin and Garfinkel, 1976
). A fifth study analysed the risk of spontaneous abortion in mothers with a child presenting a possible genetic defect (Warburton and Fraser, 1964
). Using a multiple regression model, the authors were unable to assess the relative effects of paternal and maternal age. However, they suggested that paternal age had a greater effect than maternal age.
We addressed the question of an effect of paternal age on the risk of miscarriage by studying data recorded in the European Multicenter Study on Infertility and Subfecundity conducted between 1991 and 1993, which took the couple as the unit of analysis although only the women were interviewed. We studied maternal and paternal ages together, using a single categorical variable, `couple age', in a multivariate model of miscarriage risk.
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Materials and methods |
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We analysed last planned pregnancies ending in miscarriage or birth. We excluded other causes of death (induced abortion, ectopic pregnancy, stillbirth and death within 7 days following the birth), which may have aetiologies other than miscarriage. We also excluded pregnancies that were not completed at the time of interview. We restricted our analysis to planned pregnancies, as unplanned pregnancies ending in induced abortion may be declared by the woman as a miscarriage. Moreover, in the case of unplanned pregnancy, the notion of `time to pregnancy' is meaningless.
Constitution of age classes
Previous studies (Coste et al., 1991; Nybo Andersen et al., 2000
; Osborn et al., 2000
) have shown no significant effect of maternal age on spontaneous abortion between the ages of 20 and of 29 years. We therefore used the 2029 year age group as the reference for both women and men. As we had very few couples including a woman or man aged <20 years and as we were interested in the effects of ageing, we decided to exclude these younger couples. For couples aged
30 years, we stratified data into 5 year classes. As we found only 20 women aged
40 years and 61 men aged
45 years, we pooled these `older' individuals with the previous age group and so the oldest age group was 3544 years for women and 4064 years for men. Thus, maternal age was divided into three age classes: 2029 (reference age group), 3034 and 3544 years; and paternal age was divided into four age classes: 2029 (reference age group), 3034, 3539 and 4064 years. Maternal and paternal ages were significantly correlated (r = 0.64, P < 0.0001). As a result of this correlation, analysis of maternal age and paternal age in the same multivariate model posed problems of colinearity. To deal with this, we defined a new variable, `couple age', combining the three maternal age groups with the four paternal age groups. We defined a total of 12 classes for this variable `couple age' (presented in Figure 1a
). The `couple age' variable made it possible to study maternal and paternal ages.
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We carried out unadjusted and adjusted logistic regression analyses (using SAS®) according to the various risk factors for miscarriage. We tested goodness of fit by the HosmerLemeshow test (Hosmer and Lemeshow, 1989).
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Results |
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Discussion |
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Several studies have shown an increase in the risk of spontaneous abortion in women aged 35 years (Dominguez et al., 1991
; Nybo Andersen et al., 2000
; Osborn et al., 2000
). Multiple regression analysis in a cross-sectional unmatched casecontrol study (Dominguez et al., 1991
) has shown that maternal age begins to have an effect only after the age of 35 years. Our results are consistent with this conclusion but, taking paternal age into account, we found that (i) if the man was
40 years of age, maternal age began to have a negative effect earlier, from the age of 30 years; (ii) if the man was
40 years of age, the increase in miscarriage risk was much higher if the woman was aged
35 years. In previous studies, the effect of paternal age has rarely been analysed. The most relevant study (Selvin and Garfinkel, 1976
) assessed, in a multivariate logistic model, the risk of spontaneous abortion based on >1.5x106 birth and fetal death certificates recorded in New York State from 1959 to 1967. The authors concluded that maternal and paternal ages have effects of similar significance. However, in their logistic model, they considered that maternal and paternal age effects were linear, a controversial assumption: reproductive age patterns are usually represented as J- or U-shaped curves (Nybo Andersen et al., 2000
). We used a more appropriate methodological approach and found a clear negative effect of paternal age after 40 years.
Various hypotheses have been put forward to account for the increase in adverse reproductive outcomes with age. In women, a link between increasing age and a higher incidence of chromosomal abnormality has been established (Boue et al., 1975; Cowchock et al., 1993
). However, conflicting conclusions have been drawn concerning the possible effect of age on oocyte quality and uterus senescence (Levran et al., 1991
; Abdalla et al., 1993
; Cano et al., 1995
). In men, studies using a fluorescence in-situ hybridization approach have suggested that the probability of producing aneuploid offspring is higher for older fathers (
50 years old) than for younger fathers (<30 years old) (Griffin et al., 1995
). A recent paper comparing men aged 2339 years with men aged 5974 years also concluded that there was a higher frequency of sperm chromosome aberrations in older men (Sartorelli et al., 2001
). These results are presumably related to the higher risk of birth defects in the offspring of older fathers, especially for those linked to new dominant mutations (Penrose, 1955
; Savitz et al., 1991
; McIntosh et al., 1995
), giving a general pattern of increasing relative risk of adverse reproductive outcomes with paternal age. This paternal age effect led to fixing of the upper age limit for semen donors at 40 years (Bordson and Leonardo, 1991
). In addition, if sexual activity declines with male age, this may lead to an increase in the risk of miscarriage linked to fertilization of an `old' (time elapsed between ovulation and fertilization) oocyte (Guerrero and Rojas, 1975
). However, this hypothesis is controversial (Gray et al., 1995
).
Our study confirmed the importance of a history of miscarriage, a well-documented miscarriage risk factor (Leridon, 1976; Risch et al., 1988
; Regan et al., 1989
; Coste et al., 1991
). In this study, a history of ectopic pregnancy was also a risk factor for miscarriage, consistent with the results of other studies (Honore, 1979
; Coulam et al., 1989
; Fedele et al., 1989
). We also found that the risk of miscarriage was significantly higher for couples taking
6 months to conceive. This association between a long time being required for conception and a higher risk of miscarriage is less well documented, and has been reported in some studies (Tietze et al., 1950
; Rachootin and Olsen, 1982
; Strobino et al., 1986
; Schaumburg and Boldsen, 1992
; Baird et al., 1993
; Joffe and Li, 1994
; Hakim et al., 1995
; Gray and Wu, 2000
). In retrospective studies, reproductive outcome observations depend on the statement of the woman, and subclinical abortions are completely omitted. As estimates of the subclinical abortion rate range from 8 to 78% (Wilcox et al., 1988
; Modvig et al., 1990
; Zinaman et al., 1996
), these unnoticed spontaneous abortions may be an important factor in the time to conception declared by women. The observed higher miscarriage risk in couples taking longer to conceive may be due partly to an association with subclinical abortions. The three risk factors found in our analysis suggest that there may be a common cause for such different adverse reproductive events: delay in conception, ectopic pregnancy, miscarriage, and perhaps also infertility. This notion of the same `key reproductive disorder' giving `various adverse reproductive outcomes' requires further investigation.
Bias and limits
The data were collected from retrospective declarations by the women, so two limitations must be considered concerning pregnancy outcomes. First, it has been estimated that only three-quarters of spontaneous abortions are recalled in this type of study (Wilcox and Horney, 1984), but, as our analysis concerned the outcome of the last pregnancy, women were probably less likely to have forgotten. Second, the notion of miscarriage was not precisely defined, as it would have been in medical data. Women may have been confused to some extent concerning the type of death. However, data were collected by means of interviews by trained women who could help women to differentiate between the types of deaths if needed. Induced abortion may also have been declared as miscarriage (Simonds et al., 1998
; Houzard et al., 2000
). We restricted our analysis to planned pregnancies to limit this possible bias. Furthermore, the frequency of miscarriage observed in our study (4.9%) is consistent with that of ~56% reported in other studies of last pregnancy outcomes (Weinberg et al., 1994
). This is about half that for first pregnancies, which is 1015% (Weinberg et al., 1994
). As suggested by Weinberg et al., such a low rate for last pregnancies may reduce the statistical power of the study (Weinberg et al., 1994
). The low miscarriage rate for last pregnancy outcomes is due to the couple's attitude: couples tend to `replace' a miscarriage by another pregnancy until they achieve a live birth (a phenomenon called `reproductive compensation'). The chance of succeeding in replacing a miscarriage depends on the time required to conceive. It had been concluded that this time could increase with maternal age and paternal age (Ford et al., 2000
) but this age effect was later called into question (Sallmen and Luukkonen, 2001
). Such factors may result in overestimation of the couple-age effect in our analyses. However, our results on age effect in the `high-risk zone' (OR = 2.87) are consistent with those of other studies on maternal age. For example, an OR of 3.13 (95% CI: 1.56, 6.26) was found for women aged
35 years in a cross-sectional casecontrol study (Dominguez et al., 1991
). We thus observed no major age overestimation for these ages linked to the analysis of last pregnancies. We planned to adjust for the effect of a possible `replacement attitude' by studying first pregnancy outcomes; 10.5% of first pregnancies ended in miscarriage in the European Study of Infertility and Subfecundity. However, first pregnancy outcomes were not suitable for analysing the age effect because nearly all the couples concerned were young (for first pregnancies, 96.5% of couples were in the `standard risk' zone in Figure 1c
, 2.6% in the `high risk' zone and 0.9% in the `highest risk' zone).
Finally, the multicentre European study was carried out in urban areas. However, in our opinion, there is little or no difference between rural and urban areas because no conclusive results have been produced concerning this issue (Hemminki and Forssas, 1999).
In summary, we demonstrate here the importance of taking into account both maternal and paternal age to measure miscarriage risk: if the woman is 35 years of age and the man is
40 years of age, the risk of miscarriage is substantially higher than for couples of other age combinations. The idea of major reproductive risk for couples combining negative male and female factors has already emerged in studies of couples seeking medical advice (Emperaire et al., 1982
; Spira, 1986
; Thonneau et al., 1991
). Thus, a French multicentre survey conducted in 19881989 on couples who consulted a doctor for infertility showed that in 39% of cases, both the man and the woman presented reproductive disorders and concluded that `infertility is essentially a `couple's business" (Thonneau et al., 1991
). More generally, this work raises questions concerning the level of miscarriage risk for couples in assisted reproduction programmes: the decline in assisted reproduction success rate with the age of the woman is well known (Rosenwaks et al., 1995
). In Australia, 26% of the women who became pregnant by IVF procedures during the 19791986 period were
35 years of age. Among these women, the rate of spontaneous abortion was 34.8 versus 21.5% among women aged <35 years (Saunders and Lancaster, 1989
). In the USA, 8.4% of the women who became pregnant by IVF procedures during 1991 were
40 years of age. For these women, the rate of spontaneous abortion was 33.9 versus 18.6% among women aged <40 years (American Fertility Society, 1993
).
In conclusion, older couples (and especially those asking for assisted reproduction), i.e. couples composed of a woman aged 35 years and of a man aged
40 years, should be informed that they have a high risk of miscarriage. The importance of investigating the paternal age effect was pointed out by R.Jeffrey Chang, MD, President of ASRM at the 2000 annual meeting: "The impact of age on reproductive health is a vital issue for the 21st Century. We have known that age was an important factor for women's reproductive health. The question of declining fertility as men age is an important one that needs additional research to resolve".
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Acknowledgements |
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Notes |
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References |
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Submitted on September 27, 2001; accepted on January 1, 2002.