Commentary
DOI: 10.1111/1471-0528.12563 www.bjog.org
Does maternal age affect pregnancy outcome? WR Cohen Department of Obstetrics and Gynecology, University of Arizona College of Medicine, Tucson, AZ, USA Correspondence: Dr WR Cohen, 4841 N. Valley View Road, Tucson, AZ 85718, USA. Email [email protected] Accepted 16 October 2013. Please cite this paper as: Cohen WR. Does maternal age affect pregnancy outcome?. BJOG 2014;121:252–254.
The question, ‘Does maternal age affect pregnancy outcome?’ is a simple one. Its answer is, however, deceptively complex, and has defied complete understanding despite several generations of research. It remains, nevertheless, a question of consequence because it addresses issues of considerable biological and clinical importance. It has long been recognised that advanced maternal age (variously defined, but generally including women over age 35 years at delivery) is associated with an elevated risk of sundry adverse pregnancy outcomes when compared with younger (post-adolescent) women.1,2 The sway of maternal age has assumed increasing importance in recent decades. In most of the industrialised world the confluence of several social and demographic trends has resulted in an increasing number of women becoming pregnant late in their reproductive lives. The rise of feminism facilitated better educational opportunities and broader career choices for women, who now tend to marry later in life than did their forebears. These societal trends, combined with the availability of effective birth control and sophisticated treatments for infertility, have resulted in an expanding population of women who first attempt pregnancy after age 35. Primigravidity after 40 is no longer uncommon and, usually with the help of assisted reproductive technology, we not infrequently see women pregnant in their sixth decade. While many pregnancies in older women are the result of personal choice, others are not voluntary. Infertility or illness can delay conception. Pregnancy at the opposite pole of the reproductive age spectrum is also of concern, and many studies suggest that being an early adolescent is a noteworthy risk factor for unfavourable pregnancy outcome. To what degree the risks of teenage pregnancy are related to insufficient maturation of the reproductive system is unclear. Concerns about the potential adverse consequences of pregnancy near the borders of a woman’s reproductive life are addressed in two articles in this issue of BJOG. These confirm our existing understanding about advanced and early reproductive age pregnancy.
252
Vaughan et al.3 examined the association between maternal age extremes and pregnancy outcome among 36 916 nulliparas in an Irish tertiary-care hospital. They found that, when compared with an optimal age group of 20– 34 years, being 40 were about 35% more likely to require intensive care, and 70% more likely to have an anomaly. The caesarean delivery rate increased in direct proportion to age, and was 54.4% in the over-40 group, nearly five-fold higher than in the adolescent group. Only about a quarter of the over-40 group escaped caesarean or operative vaginal delivery, a perplexing and disquieting finding. A Finnish population study by Klemetti et al.4 addressed the issue by comparing obstetric care and outcomes in nulliparas who delivered in 1991 and 2008, stratified by age. They found increased risks for preterm birth, low birthweight and use of critical care services for babies of parturients over age 40 in both years. Their caesarean rate was 41% in 2008, twice that of the 20–34-year-olds, and the odds of perinatal death were 2.7 times those of the younger group. The authors concluded that, although modern health care has mitigated some of the associated excess risk, advanced maternal age still confers a hefty burden of morbidity, mortality and healthcare costs. Some explanations for this observation are evident; others remain occult. The age-related risks of autosomal trisomy and some other genetic problems are well understood and can be quantified with sufficient precision to counsel women. An individual affected embryo or fetus can often be identified. Some age-related fetal and maternal adversity relates to comorbidities that may predate pregnancy and have a substantial effect on it. Any group of reproductively older women will include more individuals with chronic diseases such as obesity, diabetes, hypertension, or cardiac or renal disease than an otherwise comparable group of younger women. They will also have had more potential exposure to environmental toxins and radiation, although the consequences of such exposures are not completely
ª 2014 Royal College of Obstetricians and Gynaecologists
Does maternal age affect pregnancy outcome?
understood. In addition, certain complications develop during gestation more commonly among older women, such as pre-eclampsia, placenta praevia and gestational diabetes. There remains, however, a residuum of suboptimal outcomes, especially among women >40, even in the absence of any pre-existing or developing medical complication or recognisable genetic fault. Otherwise stated, even older gravidas who seem perfectly healthy have pregnancies at increased risk compared with younger women. Why is this so? It is mystifying, in no small part because impeccably precise coordination of dozens of events (genetic, biochemical, immunological, endocrine, mechanical) is necessary for a normal gestation. In fact, the process is so complex that it is humbling to realise that so many human pregnancies are successful. It also raises the question of whether we have been looking in all the right places in our struggle to understand the reproductive effects of age. Moreover, many of the outcomes traditionally used by epidemiologists, such as mortality, preterm birth, or need for critical care are outcomes that are final common events of a large spectrum of disease. Is aging per se (i.e. the nonspecific deterioration of most physiological functions, including those of the genital tract, that together conspire to impair fecundity) the culprit; or is age a proxy for some unrecognised conditions that can complicate pregnancy? A less sinister view of age is that it is but one factor among many that have the potential to alter the course of pregnancy. When certain combinations of these factors arise, normal gestational events may be disrupted. Age may confer an increasing proportion of risk over a reproductive lifetime. The very high rate of operative delivery among older gravidas observed by the teams of both Vaughan and Klemetti begs the question of why caesarean is so prevalent among older women. Undoubtedly, several factors, both social and biological, are at work. The high rate can be explained only in part by obstetric and medical comorbidities and the propensity of older women to have dysfunctional labour.5,6 How much of this intervention is related to physicians’ or parents’ subjective sense of urgency and anxiety about outcome is uncertain, but is probably a factor, even if it defies prudence and rationality. The ethically specious notion of a ‘premium baby’ (i.e. that the fetus of a woman with a reduced likelihood of having another pregnancy is somehow more deserving of being spared the rigours of labour than the fetus of a young woman) may play a role. We know a great deal about the biochemistry and physiology of myometrial contraction. So far, however, we lack the translational research to link that understanding to a functional clinical concept of what happens to uterine performance during normal and dysfunctional labour, and how it is affected by ageing.
ª 2014 Royal College of Obstetricians and Gynaecologists
It is important as well to remember that successful pregnancy does not depend solely on the reproductive system. Ageing results (albeit at varying rates) in changes in all organs. Certainly the normal changes associated with ageing in the heart (muscle atrophy, lipofuscin deposition, reduced reserve), vasculature (loss of compliance, atherosclerosis) and lungs (reduced capacity) may be clinically unapparent until the burden of pregnancy is placed on these organs. Further complicating the issue is that we know chronological age does not necessarily equate with an individual’s biological age or health. Ideally, some biomarker of general ageing, and of reproductive system ageing in particular, would be most helpful in determining a person’s biological age. We could thus identify the large subset of women over 35 or 40 whose pregnancy-related risks are not substantially increased by their age, and others whose probable outcomes engender less optimism. Such information would be of great value in counselling women who are pregnant or, better, contemplating pregnancy. Although we are still at a distance from this goal, some progress has been made. For example, the pattern of DNA methylation is linked to age, and epigenetic markers have been used to assess the characteristics of an individual’s methylome.6 Such an approach can be tissue-specific and holds promise for individual assessment of the biological age of a woman’s reproductive mechanisms. It is tempting to think that the causes of excess pregnancy morbidity among adolescents are also age-related; i.e. a consequence of their relative physiological and anatomic immaturity. Some markers to identify adolescent women for whom pregnancy would be hazardous might be found as well. Useful progress in understanding the consequences of reproductive aging can be made on two fronts. First, epidemiology should move beyond creating explanatory studies that link age with various kinds of reproductive adversity. That association is certain, but not necessarily helpful in counselling an individual woman, except in the most general terms. Predictive models that would allow preconception and antepartum advice to individuals based on their biological and chronological age and a host of other features would be more useful. They are not easy to create, but would help immensely in decision-making. Electronic medical record systems could incorporate such risk algorithms. Second, we need desperately to understand more about the ontogeny of the human reproductive system. The origin of many complications that present in late pregnancy may be at implantation, and our understanding of that process is gratifyingly advancing.7 Among the tantalising questions that deserve study: Is there a cervicouterine microbiome, the composition of which influences implantation and uterine contractility? If
253
Cohen
so, is it affected by ageing, and could it be manipulated to the benefit of mother and fetus? How does obesity, the public health plague of the industrialised world, affect reproductive system ageing? What are the genetic factors that control establishment, maintenance and termination of pregnancy, and how are they affected by age? Do cervical gene expression and protein profiles change with age?8 Are receptor genotypes for oxytocin and catecholamine-metabolising enzymes altered as we get older?9 What is the role of paternal age on outcome? How does the exposure to environmental toxins and radiation affect pregnancy in older women? How has the increasingly common use of assisted reproductive technology had an impact on outcome data and our ability to understand trends in natural pregnancies? To answer even a few of those questions adequately will take time, and adequate funding. Progress in these domains is essential, considering the demographic trajectory predicting more later childbearing, and the economic and emotional impact of pregnancy complications on individuals and families, as well as on the public health. That being said, it is important to remember that the great majority of pregnancies in older women are relatively uncomplicated and end quite satisfactorily. Our role is to identify those that will benefit from our help.
Disclosure of interests The author has no relevant financial, personal, political, intellectual or religious conflicts of interest to report.
254
Contribution to authorship WRC, the sole author, is responsible for the conceptualisation and writing of the article, which was done at the request of the BJOG. &
References 1 O’Reilly-Green C, Cohen WR. Pregnancy after forty. Obstet Gynecol Clin North Am 1993;20:313–31. 2 Johnson JA, Tough S. Delayed child-bearing. J Obstet Gynaecol Can 2012;34:80–93. 3 Vaughan DA, Cleary BJ, Murphy DJ. Delivery outcomes for nulliparous women at the extremes of maternal age—a cohort study. BJOG 2014;121:260–7. 4 Klemetti R, Gissler M, Sainio S, Hemminki E. Associations of maternal age with maternity care and birth outcomes in primiparous women: a comparison of results in 1991 and 2008 in Finland. BJOG 2014;121:355–61. 5 Cohen WR, Newman L, Friedman EA. Frequency of labor disorders with advancing maternal age. Obstet Gynecol 1980;55:414–6. 6 Nelson SM, Telfer EE, Anderson RA. The ageing ovary and uterus: new biological insights. Hum Reprod Update 2013;19:67–83. 7 Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 2013;49:359–67. 8 Hassan S, Romero R, Tarca AL, Sorin D, Pineles B, Bugrim A, et al. Signature pathways identified from gene expression profiles in the human cervix before and after spontaneous term parturition. Am J Obstet Gynecol 2007;197:250. e1–7 9 Terkawi AS, Jackson WM, Thiet M, Hansoti S, Tabassum R, Flood P. Oxytocin and catecholamine-O-methyltransferase receptor genotype predict the length of the first stage of labor. Am J Obstet Gynecol 2012;207:184. e1–8.
ª 2014 Royal College of Obstetricians and Gynaecologists
DOI: 10.1111/1471-0528.12563 www.bjog.org
Does maternal age affect pregnancy outcome? WR Cohen Department of Obstetrics and Gynecology, University of Arizona College of Medicine, Tucson, AZ, USA Correspondence: Dr WR Cohen, 4841 N. Valley View Road, Tucson, AZ 85718, USA. Email [email protected] Accepted 16 October 2013. Please cite this paper as: Cohen WR. Does maternal age affect pregnancy outcome?. BJOG 2014;121:252–254.
The question, ‘Does maternal age affect pregnancy outcome?’ is a simple one. Its answer is, however, deceptively complex, and has defied complete understanding despite several generations of research. It remains, nevertheless, a question of consequence because it addresses issues of considerable biological and clinical importance. It has long been recognised that advanced maternal age (variously defined, but generally including women over age 35 years at delivery) is associated with an elevated risk of sundry adverse pregnancy outcomes when compared with younger (post-adolescent) women.1,2 The sway of maternal age has assumed increasing importance in recent decades. In most of the industrialised world the confluence of several social and demographic trends has resulted in an increasing number of women becoming pregnant late in their reproductive lives. The rise of feminism facilitated better educational opportunities and broader career choices for women, who now tend to marry later in life than did their forebears. These societal trends, combined with the availability of effective birth control and sophisticated treatments for infertility, have resulted in an expanding population of women who first attempt pregnancy after age 35. Primigravidity after 40 is no longer uncommon and, usually with the help of assisted reproductive technology, we not infrequently see women pregnant in their sixth decade. While many pregnancies in older women are the result of personal choice, others are not voluntary. Infertility or illness can delay conception. Pregnancy at the opposite pole of the reproductive age spectrum is also of concern, and many studies suggest that being an early adolescent is a noteworthy risk factor for unfavourable pregnancy outcome. To what degree the risks of teenage pregnancy are related to insufficient maturation of the reproductive system is unclear. Concerns about the potential adverse consequences of pregnancy near the borders of a woman’s reproductive life are addressed in two articles in this issue of BJOG. These confirm our existing understanding about advanced and early reproductive age pregnancy.
252
Vaughan et al.3 examined the association between maternal age extremes and pregnancy outcome among 36 916 nulliparas in an Irish tertiary-care hospital. They found that, when compared with an optimal age group of 20– 34 years, being 40 were about 35% more likely to require intensive care, and 70% more likely to have an anomaly. The caesarean delivery rate increased in direct proportion to age, and was 54.4% in the over-40 group, nearly five-fold higher than in the adolescent group. Only about a quarter of the over-40 group escaped caesarean or operative vaginal delivery, a perplexing and disquieting finding. A Finnish population study by Klemetti et al.4 addressed the issue by comparing obstetric care and outcomes in nulliparas who delivered in 1991 and 2008, stratified by age. They found increased risks for preterm birth, low birthweight and use of critical care services for babies of parturients over age 40 in both years. Their caesarean rate was 41% in 2008, twice that of the 20–34-year-olds, and the odds of perinatal death were 2.7 times those of the younger group. The authors concluded that, although modern health care has mitigated some of the associated excess risk, advanced maternal age still confers a hefty burden of morbidity, mortality and healthcare costs. Some explanations for this observation are evident; others remain occult. The age-related risks of autosomal trisomy and some other genetic problems are well understood and can be quantified with sufficient precision to counsel women. An individual affected embryo or fetus can often be identified. Some age-related fetal and maternal adversity relates to comorbidities that may predate pregnancy and have a substantial effect on it. Any group of reproductively older women will include more individuals with chronic diseases such as obesity, diabetes, hypertension, or cardiac or renal disease than an otherwise comparable group of younger women. They will also have had more potential exposure to environmental toxins and radiation, although the consequences of such exposures are not completely
ª 2014 Royal College of Obstetricians and Gynaecologists
Does maternal age affect pregnancy outcome?
understood. In addition, certain complications develop during gestation more commonly among older women, such as pre-eclampsia, placenta praevia and gestational diabetes. There remains, however, a residuum of suboptimal outcomes, especially among women >40, even in the absence of any pre-existing or developing medical complication or recognisable genetic fault. Otherwise stated, even older gravidas who seem perfectly healthy have pregnancies at increased risk compared with younger women. Why is this so? It is mystifying, in no small part because impeccably precise coordination of dozens of events (genetic, biochemical, immunological, endocrine, mechanical) is necessary for a normal gestation. In fact, the process is so complex that it is humbling to realise that so many human pregnancies are successful. It also raises the question of whether we have been looking in all the right places in our struggle to understand the reproductive effects of age. Moreover, many of the outcomes traditionally used by epidemiologists, such as mortality, preterm birth, or need for critical care are outcomes that are final common events of a large spectrum of disease. Is aging per se (i.e. the nonspecific deterioration of most physiological functions, including those of the genital tract, that together conspire to impair fecundity) the culprit; or is age a proxy for some unrecognised conditions that can complicate pregnancy? A less sinister view of age is that it is but one factor among many that have the potential to alter the course of pregnancy. When certain combinations of these factors arise, normal gestational events may be disrupted. Age may confer an increasing proportion of risk over a reproductive lifetime. The very high rate of operative delivery among older gravidas observed by the teams of both Vaughan and Klemetti begs the question of why caesarean is so prevalent among older women. Undoubtedly, several factors, both social and biological, are at work. The high rate can be explained only in part by obstetric and medical comorbidities and the propensity of older women to have dysfunctional labour.5,6 How much of this intervention is related to physicians’ or parents’ subjective sense of urgency and anxiety about outcome is uncertain, but is probably a factor, even if it defies prudence and rationality. The ethically specious notion of a ‘premium baby’ (i.e. that the fetus of a woman with a reduced likelihood of having another pregnancy is somehow more deserving of being spared the rigours of labour than the fetus of a young woman) may play a role. We know a great deal about the biochemistry and physiology of myometrial contraction. So far, however, we lack the translational research to link that understanding to a functional clinical concept of what happens to uterine performance during normal and dysfunctional labour, and how it is affected by ageing.
ª 2014 Royal College of Obstetricians and Gynaecologists
It is important as well to remember that successful pregnancy does not depend solely on the reproductive system. Ageing results (albeit at varying rates) in changes in all organs. Certainly the normal changes associated with ageing in the heart (muscle atrophy, lipofuscin deposition, reduced reserve), vasculature (loss of compliance, atherosclerosis) and lungs (reduced capacity) may be clinically unapparent until the burden of pregnancy is placed on these organs. Further complicating the issue is that we know chronological age does not necessarily equate with an individual’s biological age or health. Ideally, some biomarker of general ageing, and of reproductive system ageing in particular, would be most helpful in determining a person’s biological age. We could thus identify the large subset of women over 35 or 40 whose pregnancy-related risks are not substantially increased by their age, and others whose probable outcomes engender less optimism. Such information would be of great value in counselling women who are pregnant or, better, contemplating pregnancy. Although we are still at a distance from this goal, some progress has been made. For example, the pattern of DNA methylation is linked to age, and epigenetic markers have been used to assess the characteristics of an individual’s methylome.6 Such an approach can be tissue-specific and holds promise for individual assessment of the biological age of a woman’s reproductive mechanisms. It is tempting to think that the causes of excess pregnancy morbidity among adolescents are also age-related; i.e. a consequence of their relative physiological and anatomic immaturity. Some markers to identify adolescent women for whom pregnancy would be hazardous might be found as well. Useful progress in understanding the consequences of reproductive aging can be made on two fronts. First, epidemiology should move beyond creating explanatory studies that link age with various kinds of reproductive adversity. That association is certain, but not necessarily helpful in counselling an individual woman, except in the most general terms. Predictive models that would allow preconception and antepartum advice to individuals based on their biological and chronological age and a host of other features would be more useful. They are not easy to create, but would help immensely in decision-making. Electronic medical record systems could incorporate such risk algorithms. Second, we need desperately to understand more about the ontogeny of the human reproductive system. The origin of many complications that present in late pregnancy may be at implantation, and our understanding of that process is gratifyingly advancing.7 Among the tantalising questions that deserve study: Is there a cervicouterine microbiome, the composition of which influences implantation and uterine contractility? If
253
Cohen
so, is it affected by ageing, and could it be manipulated to the benefit of mother and fetus? How does obesity, the public health plague of the industrialised world, affect reproductive system ageing? What are the genetic factors that control establishment, maintenance and termination of pregnancy, and how are they affected by age? Do cervical gene expression and protein profiles change with age?8 Are receptor genotypes for oxytocin and catecholamine-metabolising enzymes altered as we get older?9 What is the role of paternal age on outcome? How does the exposure to environmental toxins and radiation affect pregnancy in older women? How has the increasingly common use of assisted reproductive technology had an impact on outcome data and our ability to understand trends in natural pregnancies? To answer even a few of those questions adequately will take time, and adequate funding. Progress in these domains is essential, considering the demographic trajectory predicting more later childbearing, and the economic and emotional impact of pregnancy complications on individuals and families, as well as on the public health. That being said, it is important to remember that the great majority of pregnancies in older women are relatively uncomplicated and end quite satisfactorily. Our role is to identify those that will benefit from our help.
Disclosure of interests The author has no relevant financial, personal, political, intellectual or religious conflicts of interest to report.
254
Contribution to authorship WRC, the sole author, is responsible for the conceptualisation and writing of the article, which was done at the request of the BJOG. &
References 1 O’Reilly-Green C, Cohen WR. Pregnancy after forty. Obstet Gynecol Clin North Am 1993;20:313–31. 2 Johnson JA, Tough S. Delayed child-bearing. J Obstet Gynaecol Can 2012;34:80–93. 3 Vaughan DA, Cleary BJ, Murphy DJ. Delivery outcomes for nulliparous women at the extremes of maternal age—a cohort study. BJOG 2014;121:260–7. 4 Klemetti R, Gissler M, Sainio S, Hemminki E. Associations of maternal age with maternity care and birth outcomes in primiparous women: a comparison of results in 1991 and 2008 in Finland. BJOG 2014;121:355–61. 5 Cohen WR, Newman L, Friedman EA. Frequency of labor disorders with advancing maternal age. Obstet Gynecol 1980;55:414–6. 6 Nelson SM, Telfer EE, Anderson RA. The ageing ovary and uterus: new biological insights. Hum Reprod Update 2013;19:67–83. 7 Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 2013;49:359–67. 8 Hassan S, Romero R, Tarca AL, Sorin D, Pineles B, Bugrim A, et al. Signature pathways identified from gene expression profiles in the human cervix before and after spontaneous term parturition. Am J Obstet Gynecol 2007;197:250. e1–7 9 Terkawi AS, Jackson WM, Thiet M, Hansoti S, Tabassum R, Flood P. Oxytocin and catecholamine-O-methyltransferase receptor genotype predict the length of the first stage of labor. Am J Obstet Gynecol 2012;207:184. e1–8.
ª 2014 Royal College of Obstetricians and Gynaecologists
