Too Old to Have Children?
Too Old to Have Children?
The birth of the last child is the last noticeably major reproductive event for women living under natural fertility conditions. Nine months before she had her last effective conception leading to the birth of her last child; hence at that time she was still fertile. At some point in time during the course of gestation or the subsequent period of post-partum amenorrhoea caused by breastfeeding, she must have lost the capacity of achieving effective conceptions because thereafter, she is no longer able to have a live birth. In surveys where both the return of menses and the duration of breastfeeding were recorded, it has been shown that the period of post-partum amenorrhoea on average lasted for about 1 year (Leridon, 1977; Leridon and Ferry, 1985). The ALB is approximately between the age at last conception when she is still fertile (the ALB minus 9 months) and the time she has become definitely infertile (the ALB plus 1 year). Therefore, we may consider this age (ALB) as a proxy for the end of female fertility. There is no reason to assume that nulliparous women are different in this respect from multiparous women. While the ALB theoretically marks the imminent end of the couple's joint reproductive capacity, the female contribution is far more important (Minneau and Trussell, 1982; Menken et al., 1986). We follow the convention in demography of attributing the couple's fertility to the woman.
The first aim of our study was to review and analyse the distribution of ALB in large computerized data sets of natural fertility populations in Western countries. We selected data sets from six natural fertility populations. Although the oldest and youngest population lived 200 years apart, the distribution of ALB is remarkably similar (Fig. 1) demonstrating the universal pattern of the age-related fertility decline. From the boxes and whiskers plots it is obvious that the ALB distributions are skewed to the left in all populations. In a previous study we found a strikingly similar distribution of ALB in one of the populations selected in this study (Quebec/SLSJ) and of age at menopause in a contemporary population, suggesting that both are the consequence of the same process (Te Velde and Pearson, 2002). The left skew in both studies suggests that a considerable proportion of women exhibit premature or early ovarian failure and consequently early ALB and early age at menopause.
The three frontier populations selected in our search—Old Quebec, Quebec/SLSJ and Utah—share three important characteristics: the women married earlier and thus started to reproduce at younger ages, they had the highest parity and they continued to reproduce for longer corresponding with a later ALB. In frontier populations there are fewer intentional checks on reproduction; consequently the reproductive potential is more effectively used (Moreau et al., 2011) than in the established populations living in Germany, France and the Netherlands. The striking low level of childlessness in the Utah database is due to its genealogical nature by which selective non-inclusion of childless women occurs. Moreover, reproduction is for a significant part a heritable process (see later), thus selecting the more fertile descendants.
Was the effect of the demographic transition already noticeable in the populations selected? Not when we look at the number of children which showed no time trend, with Utah as the only exception (see Supplementary data, Table SI: Number of children). However, there was a consistent trend of earlier ALB in the later birth quartiles (see Supplementary data, Table SI: Age at last childbirth).
In a previous study we demonstrated that the first major decision Dutch women took after their newly found freedom by the introduction of the 'pill' in the 1970s, was not to have fewer children but to have no children at an advanced reproductive age (Te Velde and Pearson, 2002). This result is in line with studies in historical populations showing that the number of children ever born declined almost entirely as a result of stopping behaviour, when women were ending their reproductive period earlier (Knodel, 1987; Reher and Sanz-Gimeno, 2007; Van Poppel et al., 2012). Since we focus on the biological age-dependent fertility decline we, therefore, only used data from the oldest birth quartiles.
Lowering the age of first reproduction increases the number of subsequent children being born (Moreau et al., 2011). In Table I , where the effect of age at marriage is analysed, this expected trend is again observed.
It has been suggested (Trussell and Wilson, 1985; Menken et al., 1986) that there is a 'a childbearing-induced sterility' implying that as more children were born, the earlier the ALB and the earlier the onset of infertility, and consequently that women who married later were more fertile at that age than women who had married early. Possible explanations for such an association relate to the higher chance of secondary infertility due to the increased probability of post-partum or post-abortion infections leading to tubal disease as the number of children born increases. However, we could not confirm such an association in the much larger populations selected by us: earlier age at marriage did not lead to earlier ALB, with France as the only exception (see Table I under: Age at last childbirth). Another explanation for the differences found between the Menken curves and ours is that Menken et al. (1986) had to use an estimate of the reference age within 5-year intervals to plot a curve on. The position of these reference ages may have greatly influenced the level of the curve, given the sharp increase in level with age from 35 years onwards. In contrast, we were able to use exact ages for each individual woman. Apparently, the method needed to plot a curve based on 5-year intervals in the Menken et al. (1986) data and the necessity to correct for dependency of ALB on the age at marriage have resulted in a curve differing from ours.
The second aim is to establish the biological ALB curve: the age above which women have become biologically too old to conceive of a pregnancy leading to live birth. The frontier populations—Old Quebec and Quebec/SLSJ—contribute most to this curve until age 42 years; thereafter the data from France are the most influential in affecting the curve (see Fig. 2B).
The biological ALB curve of Fig. 2C demonstrates that the age-related loss of fertility rises slowly until somewhere between ages 35 and 40 after which it rises rapidly.
The prevailing concept of fertility decline assumes that the age-dependent loss of fertility is determined by the continuous depletion of the pool of oocytes stored in both ovaries during fetal life, leading first to a decrease of fertility and its subsequent expiration followed ~10 years later by menopause (Te Velde and Pearson, 2002). Thus, apparently ALB and age at menopause denote different stages of the same biological process of reproductive ageing. Several studies point to the strong heritable component of age at menopause with a polygenic pattern of inheritance (De Bruin et al., 2001; Van Asselt et al., 2004; Murabito et al., 2005). A Finnish study in a 19th century fertility population demonstrated a similar heritability for ALB (Pettay et al., 2005).
With regard to the strengths and weaknesses of our study, we consider a strength is that our data are not from one single place and time period, as in most previous studies, but from a variety of countries and time periods, each having their own demographic specificity which might have had an effect on fertility patterns (marriage, health and mortality characteristics). Nonetheless, the distribution of the ALB was remarkably similar suggesting that there is a universal pattern of age-related fertility decline. Moreover, our data set is much larger than in previous reports and collected from countries with complete and well-functioning registration systems, thus leading to more reliable outcomes than in earlier studies. We have applied sophisticated statistical techniques to derive our fertility estimates.
With regard to possible weaknesses we cannot exclude missing observations caused by (temporary) outmigration, during which period children may have been born outside the study area, or by under-registration of children who were born alive but died before being registered as a live birth. Furthermore, still-born children are usually not included in these data and it is possible that unfavourable factors in the past that resulted in a stillbirth could, under the present medical conditions, have led to a live birth. The consequence of these problems would be the same namely that the fertility curve derived underestimates the present reality.
More fundamentally, it is questionable whether applying conclusions drawn from natural populations living 150–200 years ago to the present time is justified. For example, as deliveries and abortions now occur in more favourable environments, the prevalence of infections after these events most probably has declined. With regard to sexually transmitted diseases we can only speculate: sexual promiscuity probably has increased but treatment is certainly more efficient. There has been widespread anxiety about the adverse effect of environmental pollutants on sperm quality during the last 50 years (Carlsen et al., 1992), which, however, has not been confirmed (Bonde et al., 2011) whereas during the last 2–5 decades population fertility did not change (Te Velde et al., 2010). The so-called 'relaxed reproductive selection hypothesis' argues that since family size decreased markedly during the 20th century, the proportion of births from the biologically most fertile couples is likely to have decreased (Czeizel and Rothman, 2002). This and the introduction of assisted reproduction technologies enabling infertile couples to reproduce may have increased the level of infertility in the population (Joffe, 2003).
In favour of extrapolation of data from natural populations to the present time is the fact that also in contemporary natural populations, the age-dependent decline of fertility appears to be comparable to the biological ALB curve of Fig. 2C, for example in the Hutterite population living in the first half of the 20th century (Tietze, 1957; Larsen and Yan, 2000) and among currently married non-contracepting women in several parts of the world (Rahman and Menken, 1993; O'Connor et al., 1998). Also, the age-dependent decline in fertility of couples treated by donor insemination is in line with the biological fertility curve (Van Noord-Zaadstra et al., 1992). Indeed, it seems unlikely that a biological phenomenon with a high degree of heritability would have noticeably changed within 1–2 centuries, i.e. a maximum of 4–8 generations.
Apart from biological factors, the frequency of coitus, showing an age-related decline across the life course (Brewis and Meyer, 2005), is also an important determinant for the occurrence of pregnancy (Stanford and Dunson, 2007). In this respect, couples from historical populations differ from modern couples who have finally taken the decision to have their first child. First, with regard to motivation: modern couples probably attempt to have more frequent intercourse than women from historical populations who became pregnant with their last child by chance rather than by intention. Second, there is more information about the frequency and timing of intercourse during the fertile window of the menstrual cycle than in the past. Using this information may well enhance the likelihood of spontaneous pregnancy (Stanford et al., 2003; Dunson et al., 2004; Rothman et al., 2013). The biological ALB curve as currently constructed may therefore provide an overly conservative estimate for the prospects for later-age conceptions for modern couples who have delayed childbearing and who seek to conceive without medical interventions.
What lessons can be learnt from the pattern of age-related decline in natural fertility populations? At present, age at childbearing has been delayed considerably since the contraceptive revolution of the 1960s. Presently, the mean maternal age at first birth is approaching age 30 in several European countries and many women deliver their first child at age 35 or older. Several studies show that most women are not aware of the fact that delaying childbearing increases the risk of infertility (Schmidt, 2010) and that the risk of abortion, chromosomal aberrations and pregnancy complications steeply increases with age (Heffner, 2004). Moreover, many women erroneously believe that IVF can always address the fertility complications associated with advancing age (Maheshwari et al., 2008). At the same time, however, others believe there is an age at which women are too old to conceive (Billari et al., 2011). Under these circumstances the question raised in the title of our manuscript 'Too old to have children?' is relevant. Regrettably, there are no reliable biological markers that accurately portend the onset of reproductive failure. Irregular menstrual cycles and hot flushes signifying imminent menopause represent symptoms that arise too late to be offered as a predictive measures because sterility is likely to have started already years earlier, when the menstrual pattern was still regular and hormone levels deviated little from the standard (van Zonneveld et al., 2003).
The biological ALB curve proposed here can be used as a tool to counsel women who are considering or are actually delaying childbearing. This information will be most beneficial provided the woman is told that the age-related chances of success are averages: for any individual woman these chances may be higher or lower, depending on the characteristics of the woman. Reports suggesting that the determination of anti-Mullerian hormone (AMH) can already be used to individualize such predictions have to be regarded as overly optimistic at this time (Loh and Maheshwari, 2011). For example, the result from a recent long-term study focussing on the age at menopause as a marker for the end of reproduction (Broer et al., 2011) demonstrates that young women with very low AMH levels have menopause about 2 years earlier than the average age of 51: it is dubious whether such knowledge will change the reproductive intentions of young women. Female age is the only realistic information available at present for estimating the magnitude of the reproductive ageing process. The biological ALB curve demonstrates that the average chance of involuntarily childlessness slowly increases to 12% at 35 and 20% at age 38. From there this chance sharply rises to 50% at about 41 and reaches almost 90% at age 45.
The biological ALB curve reveals several important lessons. For example, for women aged 32–34 who still have a very good chance of bearing children although their risk of childlessness has tripled since age 25 and will increase substantially more after age 35, the lesson is: do not wait much longer, certainly not if you want more than one child. At the same time, the curve contradicts the occasionally exaggerated pessimism about women who intend (or by circumstances are forced) to have children in their late thirties (Twenge, 2013). For them the lesson is: you still have a good chance to succeed if you don't wait any longer. For women in their early forties the lesson is: just try, your chances are still far from hopeless. Since the success rate of IVF demonstrates a similar age-related decline as the chance of a natural pregnancy (Malizia et al., 2009), women should also be told that the idea of IVF reversing the effect of age is a mistaken belief.
In conclusion, we evaluated six large natural fertility populations from a range of historical periods and locations, and found substantial resemblance in the age distribution of ALB. We constructed a biological ALB curve that can be used as a counselling tool for couples who envisage delaying their age of childbearing.
Discussion
The birth of the last child is the last noticeably major reproductive event for women living under natural fertility conditions. Nine months before she had her last effective conception leading to the birth of her last child; hence at that time she was still fertile. At some point in time during the course of gestation or the subsequent period of post-partum amenorrhoea caused by breastfeeding, she must have lost the capacity of achieving effective conceptions because thereafter, she is no longer able to have a live birth. In surveys where both the return of menses and the duration of breastfeeding were recorded, it has been shown that the period of post-partum amenorrhoea on average lasted for about 1 year (Leridon, 1977; Leridon and Ferry, 1985). The ALB is approximately between the age at last conception when she is still fertile (the ALB minus 9 months) and the time she has become definitely infertile (the ALB plus 1 year). Therefore, we may consider this age (ALB) as a proxy for the end of female fertility. There is no reason to assume that nulliparous women are different in this respect from multiparous women. While the ALB theoretically marks the imminent end of the couple's joint reproductive capacity, the female contribution is far more important (Minneau and Trussell, 1982; Menken et al., 1986). We follow the convention in demography of attributing the couple's fertility to the woman.
The first aim of our study was to review and analyse the distribution of ALB in large computerized data sets of natural fertility populations in Western countries. We selected data sets from six natural fertility populations. Although the oldest and youngest population lived 200 years apart, the distribution of ALB is remarkably similar (Fig. 1) demonstrating the universal pattern of the age-related fertility decline. From the boxes and whiskers plots it is obvious that the ALB distributions are skewed to the left in all populations. In a previous study we found a strikingly similar distribution of ALB in one of the populations selected in this study (Quebec/SLSJ) and of age at menopause in a contemporary population, suggesting that both are the consequence of the same process (Te Velde and Pearson, 2002). The left skew in both studies suggests that a considerable proportion of women exhibit premature or early ovarian failure and consequently early ALB and early age at menopause.
The three frontier populations selected in our search—Old Quebec, Quebec/SLSJ and Utah—share three important characteristics: the women married earlier and thus started to reproduce at younger ages, they had the highest parity and they continued to reproduce for longer corresponding with a later ALB. In frontier populations there are fewer intentional checks on reproduction; consequently the reproductive potential is more effectively used (Moreau et al., 2011) than in the established populations living in Germany, France and the Netherlands. The striking low level of childlessness in the Utah database is due to its genealogical nature by which selective non-inclusion of childless women occurs. Moreover, reproduction is for a significant part a heritable process (see later), thus selecting the more fertile descendants.
Was the effect of the demographic transition already noticeable in the populations selected? Not when we look at the number of children which showed no time trend, with Utah as the only exception (see Supplementary data, Table SI: Number of children). However, there was a consistent trend of earlier ALB in the later birth quartiles (see Supplementary data, Table SI: Age at last childbirth).
In a previous study we demonstrated that the first major decision Dutch women took after their newly found freedom by the introduction of the 'pill' in the 1970s, was not to have fewer children but to have no children at an advanced reproductive age (Te Velde and Pearson, 2002). This result is in line with studies in historical populations showing that the number of children ever born declined almost entirely as a result of stopping behaviour, when women were ending their reproductive period earlier (Knodel, 1987; Reher and Sanz-Gimeno, 2007; Van Poppel et al., 2012). Since we focus on the biological age-dependent fertility decline we, therefore, only used data from the oldest birth quartiles.
Lowering the age of first reproduction increases the number of subsequent children being born (Moreau et al., 2011). In Table I , where the effect of age at marriage is analysed, this expected trend is again observed.
It has been suggested (Trussell and Wilson, 1985; Menken et al., 1986) that there is a 'a childbearing-induced sterility' implying that as more children were born, the earlier the ALB and the earlier the onset of infertility, and consequently that women who married later were more fertile at that age than women who had married early. Possible explanations for such an association relate to the higher chance of secondary infertility due to the increased probability of post-partum or post-abortion infections leading to tubal disease as the number of children born increases. However, we could not confirm such an association in the much larger populations selected by us: earlier age at marriage did not lead to earlier ALB, with France as the only exception (see Table I under: Age at last childbirth). Another explanation for the differences found between the Menken curves and ours is that Menken et al. (1986) had to use an estimate of the reference age within 5-year intervals to plot a curve on. The position of these reference ages may have greatly influenced the level of the curve, given the sharp increase in level with age from 35 years onwards. In contrast, we were able to use exact ages for each individual woman. Apparently, the method needed to plot a curve based on 5-year intervals in the Menken et al. (1986) data and the necessity to correct for dependency of ALB on the age at marriage have resulted in a curve differing from ours.
The second aim is to establish the biological ALB curve: the age above which women have become biologically too old to conceive of a pregnancy leading to live birth. The frontier populations—Old Quebec and Quebec/SLSJ—contribute most to this curve until age 42 years; thereafter the data from France are the most influential in affecting the curve (see Fig. 2B).
The biological ALB curve of Fig. 2C demonstrates that the age-related loss of fertility rises slowly until somewhere between ages 35 and 40 after which it rises rapidly.
The prevailing concept of fertility decline assumes that the age-dependent loss of fertility is determined by the continuous depletion of the pool of oocytes stored in both ovaries during fetal life, leading first to a decrease of fertility and its subsequent expiration followed ~10 years later by menopause (Te Velde and Pearson, 2002). Thus, apparently ALB and age at menopause denote different stages of the same biological process of reproductive ageing. Several studies point to the strong heritable component of age at menopause with a polygenic pattern of inheritance (De Bruin et al., 2001; Van Asselt et al., 2004; Murabito et al., 2005). A Finnish study in a 19th century fertility population demonstrated a similar heritability for ALB (Pettay et al., 2005).
With regard to the strengths and weaknesses of our study, we consider a strength is that our data are not from one single place and time period, as in most previous studies, but from a variety of countries and time periods, each having their own demographic specificity which might have had an effect on fertility patterns (marriage, health and mortality characteristics). Nonetheless, the distribution of the ALB was remarkably similar suggesting that there is a universal pattern of age-related fertility decline. Moreover, our data set is much larger than in previous reports and collected from countries with complete and well-functioning registration systems, thus leading to more reliable outcomes than in earlier studies. We have applied sophisticated statistical techniques to derive our fertility estimates.
With regard to possible weaknesses we cannot exclude missing observations caused by (temporary) outmigration, during which period children may have been born outside the study area, or by under-registration of children who were born alive but died before being registered as a live birth. Furthermore, still-born children are usually not included in these data and it is possible that unfavourable factors in the past that resulted in a stillbirth could, under the present medical conditions, have led to a live birth. The consequence of these problems would be the same namely that the fertility curve derived underestimates the present reality.
More fundamentally, it is questionable whether applying conclusions drawn from natural populations living 150–200 years ago to the present time is justified. For example, as deliveries and abortions now occur in more favourable environments, the prevalence of infections after these events most probably has declined. With regard to sexually transmitted diseases we can only speculate: sexual promiscuity probably has increased but treatment is certainly more efficient. There has been widespread anxiety about the adverse effect of environmental pollutants on sperm quality during the last 50 years (Carlsen et al., 1992), which, however, has not been confirmed (Bonde et al., 2011) whereas during the last 2–5 decades population fertility did not change (Te Velde et al., 2010). The so-called 'relaxed reproductive selection hypothesis' argues that since family size decreased markedly during the 20th century, the proportion of births from the biologically most fertile couples is likely to have decreased (Czeizel and Rothman, 2002). This and the introduction of assisted reproduction technologies enabling infertile couples to reproduce may have increased the level of infertility in the population (Joffe, 2003).
In favour of extrapolation of data from natural populations to the present time is the fact that also in contemporary natural populations, the age-dependent decline of fertility appears to be comparable to the biological ALB curve of Fig. 2C, for example in the Hutterite population living in the first half of the 20th century (Tietze, 1957; Larsen and Yan, 2000) and among currently married non-contracepting women in several parts of the world (Rahman and Menken, 1993; O'Connor et al., 1998). Also, the age-dependent decline in fertility of couples treated by donor insemination is in line with the biological fertility curve (Van Noord-Zaadstra et al., 1992). Indeed, it seems unlikely that a biological phenomenon with a high degree of heritability would have noticeably changed within 1–2 centuries, i.e. a maximum of 4–8 generations.
Apart from biological factors, the frequency of coitus, showing an age-related decline across the life course (Brewis and Meyer, 2005), is also an important determinant for the occurrence of pregnancy (Stanford and Dunson, 2007). In this respect, couples from historical populations differ from modern couples who have finally taken the decision to have their first child. First, with regard to motivation: modern couples probably attempt to have more frequent intercourse than women from historical populations who became pregnant with their last child by chance rather than by intention. Second, there is more information about the frequency and timing of intercourse during the fertile window of the menstrual cycle than in the past. Using this information may well enhance the likelihood of spontaneous pregnancy (Stanford et al., 2003; Dunson et al., 2004; Rothman et al., 2013). The biological ALB curve as currently constructed may therefore provide an overly conservative estimate for the prospects for later-age conceptions for modern couples who have delayed childbearing and who seek to conceive without medical interventions.
What lessons can be learnt from the pattern of age-related decline in natural fertility populations? At present, age at childbearing has been delayed considerably since the contraceptive revolution of the 1960s. Presently, the mean maternal age at first birth is approaching age 30 in several European countries and many women deliver their first child at age 35 or older. Several studies show that most women are not aware of the fact that delaying childbearing increases the risk of infertility (Schmidt, 2010) and that the risk of abortion, chromosomal aberrations and pregnancy complications steeply increases with age (Heffner, 2004). Moreover, many women erroneously believe that IVF can always address the fertility complications associated with advancing age (Maheshwari et al., 2008). At the same time, however, others believe there is an age at which women are too old to conceive (Billari et al., 2011). Under these circumstances the question raised in the title of our manuscript 'Too old to have children?' is relevant. Regrettably, there are no reliable biological markers that accurately portend the onset of reproductive failure. Irregular menstrual cycles and hot flushes signifying imminent menopause represent symptoms that arise too late to be offered as a predictive measures because sterility is likely to have started already years earlier, when the menstrual pattern was still regular and hormone levels deviated little from the standard (van Zonneveld et al., 2003).
The biological ALB curve proposed here can be used as a tool to counsel women who are considering or are actually delaying childbearing. This information will be most beneficial provided the woman is told that the age-related chances of success are averages: for any individual woman these chances may be higher or lower, depending on the characteristics of the woman. Reports suggesting that the determination of anti-Mullerian hormone (AMH) can already be used to individualize such predictions have to be regarded as overly optimistic at this time (Loh and Maheshwari, 2011). For example, the result from a recent long-term study focussing on the age at menopause as a marker for the end of reproduction (Broer et al., 2011) demonstrates that young women with very low AMH levels have menopause about 2 years earlier than the average age of 51: it is dubious whether such knowledge will change the reproductive intentions of young women. Female age is the only realistic information available at present for estimating the magnitude of the reproductive ageing process. The biological ALB curve demonstrates that the average chance of involuntarily childlessness slowly increases to 12% at 35 and 20% at age 38. From there this chance sharply rises to 50% at about 41 and reaches almost 90% at age 45.
The biological ALB curve reveals several important lessons. For example, for women aged 32–34 who still have a very good chance of bearing children although their risk of childlessness has tripled since age 25 and will increase substantially more after age 35, the lesson is: do not wait much longer, certainly not if you want more than one child. At the same time, the curve contradicts the occasionally exaggerated pessimism about women who intend (or by circumstances are forced) to have children in their late thirties (Twenge, 2013). For them the lesson is: you still have a good chance to succeed if you don't wait any longer. For women in their early forties the lesson is: just try, your chances are still far from hopeless. Since the success rate of IVF demonstrates a similar age-related decline as the chance of a natural pregnancy (Malizia et al., 2009), women should also be told that the idea of IVF reversing the effect of age is a mistaken belief.
In conclusion, we evaluated six large natural fertility populations from a range of historical periods and locations, and found substantial resemblance in the age distribution of ALB. We constructed a biological ALB curve that can be used as a counselling tool for couples who envisage delaying their age of childbearing.
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