BMJ 2014;348:g175 doi: 10.1136/bmj.g175 (Published 23 January 2014)
Page 1 of 2
Editorials
EDITORIALS Early fetal growth and risk factors for cardiovascular disease Let’s start at the very beginning Catherine E M Aiken academic clinical fellow, Gordon C S Smith professor Department of Obstetrics and Gynaecology, University of Cambridge, Box 223, Rosie Hospital and NIHR Cambridge Comprehensive Biomedical Research Centre, Cambridge CB2 0SW, UK
Some readers’ principal response to the paper by Jaddoe and colleagues (doi:10.1136/bmj.g14) may be bemusement.1 Why would anyone link growth of the fetus in the first trimester to risk factors for the cardiovascular killers of middle age? However, the rationale for the study is based around two large bodies of work that have concluded that fetal growth restriction is associated with an increased risk of cardiovascular—and many other—diseases in later life,2 and also that fetal growth is profoundly influenced by conditions in the first trimester of pregnancy.3 Jaddoe and colleagues report new associations between apparently poor growth in the first trimester and a range of cardiovascular risk factors measured in school age children. Are the associations likely to be real? What mechanisms might be operating if they are? Lastly, what should we be doing about it? Many aspects of this carefully conducted prospective cohort study support the validity of the conclusions. However, as the authors acknowledge, the possibility remains that some of their significant associations may have arisen by chance. False positive findings, or type1 statistical errors, are always a risk in studies with many different outcomes and a large number of statistical tests. The many potential classifications of both outcomes and exposures are a further complication. Furthermore, the new study is one of many arising from the same cohort,4 and we know that repeated hypothesis testing increases the risk of type 1 errors still further. Although assembling such a feast of data but then denying oneself any more than a single morsel of analysis would be perverse, the conclusions of this study should be treated as hypothesis generating. The pre-existing body of work, however, suggests that Jaddoe and colleagues’ findings are not data driven and will be reproducible.
Mechanisms that may explain the link between fetal growth and later cardiovascular risk factors have been explored extensively over the past 30 years, in both human cohorts and animal models.5 The idea that subtle influences on physiological systems occur early in development and are later magnified by the effects of growth and ageing to produce pathological phenotypes is well established. Studies have identified putative mechanisms—specifically, altered DNA methylation,
mitochondrial DNA instability, and increased exposure to oxidative stress.6 7 Such mechanisms are likely to explain the trans-generational effects of certain environmental challenges in human populations.8 However, despite the plausibility and attractiveness of the developmental programming hypothesis in interpreting the results of Jaddoe and colleagues’ study, consideration must be given to other explanations for a smaller than expected fetus in early pregnancy. A fetus may measure small for dates if ovulation occurred later than usual in the menstrual cycle. Hence, a smaller than expected fetus could be a marker for reproductive disorders in the mother, such as polycystic ovary syndrome, which predisposes women to prolonged menstrual cycles. Given that polycystic ovary syndrome is associated with the metabolic syndrome, and is also likely to have an important genetic element,9 a small fetus or baby may be a marker of maternal genetic characteristics that might be inherited by the baby and lead to the associations described in the paper. Although Jaddoe and colleagues corrected estimates of fetal size for cycle length, the subtle effects of dating discrepancies are a methodological problem with many such studies. Consistent with the idea that reproductive dysfunction and cardiovascular disease could have a common genetic predisposition, we know that the birth weight of the infant is also inversely associated with the risk of cardiovascular disease in the mother and in the mother’s parents.10 11 An extensive body of work now exists that supports the view that delivery of a small baby is a marker of maternal cardiovascular dysfunction.12 Disentangling the effects on the fetus of maternal environmental stresses from the effects of maternal genetic and epigenetic predisposition to disease will be a major challenge for future studies. For doctors, the pertinent question is whether these early effects can be modified. Can we identify interventions that might improve the early life environment and promote “normal” growth trajectories? On the basis of the current analysis, these interventions might be needed in the first trimester of pregnancy, during embryogenesis. Given the potential for interventions to cause serious harm at this stage of pregnancy, compelling evidence of safety will be needed before their evaluation. Hence,
Correspondence to: G C S Smith [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g175 doi: 10.1136/bmj.g175 (Published 23 January 2014)
Page 2 of 2
EDITORIALS
the appropriate response in the short term is that we need a deeper understanding of the strength, nature, and mechanisms of the reported associations before rushing to intervene. Studies such as those of Jaddoe and colleagues and previous work suggest that researchers need to recruit cohorts of women in the very earliest stages of pregnancy or, ideally, before conception to ensure that the initiating events are captured.1 3 For future analyses of the determinants of the health of our children and the adults that they become, a key message may lie in the words written by Oscar Hammerstein II and immortalised by Julie Andrews: “Let’s start at the very beginning, a very good place to start.” Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: none. Provenance and peer review: Commissioned; not externally peer reviewed. 1
Jaddoe VW, de Jonge L, Hofman A, Franco OH, Steegers EA, Gaillard R. First trimester fetal growth restriction and cardiovascular risk factors in school age children: population based cohort study. BMJ 2014;348:g14.
For personal use only: See rights and reprints http://www.bmj.com/permissions
2 3 4
5 6 7
8 9 10 11 12
Barker DJ. Adult consequences of fetal growth restriction. Clin Obstet Gynecol 2006;49:270-83. Smith GCS. First trimester determination of complications of late pregnancy. JAMA 2010;303:561-2. Tiemeier H, Velders FP, Szekely E, Roza SJ, Dieleman G, Jaddoe VW, et al. The Generation R Study: a review of design, findings to date, and a study of the 5-HTTLPR by environmental interaction from fetal life onward. J Am Acad Child Adolesc Psychiatry 2012;51:1119-35. Tarry-Adkins JL, Ozanne SE. Mechanisms of early life programming: current knowledge and future directions. Am J Clin Nutr 2011;94(6 suppl):1765-71S. Ozanne SE, Constancia M. Mechanisms of disease: the developmental origins of disease and the role of the epigenotype. Nat Clin Pract Endocrinol Metab 2007;3:539-46. Tarry-Adkins JL, Martin-Gronert MS, Fernandez-Twinn DS, Hargreaves I, Alfaradhi MZ, Land JM, et al. Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress, and oxidative defense capacity in rat heart. FASEB J 2013;27:379-90. Aiken CE, Ozanne SE. Transgenerational developmental programming. Hum Reprod Update 2014;20:63-75. Barber TM, Franks S. Genetics of polycystic ovary syndrome. Front Horm Res 2013;40:28-39. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 2001;357:2002-6. Smith GC, Wood AM, White IR, Pell JP, Hattie J. Birth weight and the risk of cardiovascular disease in the maternal grandparents. Am J Epidemiol 2010;171:736-44. Myklestad K, Vatten LJ, Magnussen EB, Salvesen KA, Smith GD, Romundstad PR. Offspring birth weight and cardiovascular risk in parents: a population-based HUNT 2 study. Am J Epidemiol 2012;175:546-55.
Cite this as: BMJ 2014;348:g175 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
Page 1 of 2
Editorials
EDITORIALS Early fetal growth and risk factors for cardiovascular disease Let’s start at the very beginning Catherine E M Aiken academic clinical fellow, Gordon C S Smith professor Department of Obstetrics and Gynaecology, University of Cambridge, Box 223, Rosie Hospital and NIHR Cambridge Comprehensive Biomedical Research Centre, Cambridge CB2 0SW, UK
Some readers’ principal response to the paper by Jaddoe and colleagues (doi:10.1136/bmj.g14) may be bemusement.1 Why would anyone link growth of the fetus in the first trimester to risk factors for the cardiovascular killers of middle age? However, the rationale for the study is based around two large bodies of work that have concluded that fetal growth restriction is associated with an increased risk of cardiovascular—and many other—diseases in later life,2 and also that fetal growth is profoundly influenced by conditions in the first trimester of pregnancy.3 Jaddoe and colleagues report new associations between apparently poor growth in the first trimester and a range of cardiovascular risk factors measured in school age children. Are the associations likely to be real? What mechanisms might be operating if they are? Lastly, what should we be doing about it? Many aspects of this carefully conducted prospective cohort study support the validity of the conclusions. However, as the authors acknowledge, the possibility remains that some of their significant associations may have arisen by chance. False positive findings, or type1 statistical errors, are always a risk in studies with many different outcomes and a large number of statistical tests. The many potential classifications of both outcomes and exposures are a further complication. Furthermore, the new study is one of many arising from the same cohort,4 and we know that repeated hypothesis testing increases the risk of type 1 errors still further. Although assembling such a feast of data but then denying oneself any more than a single morsel of analysis would be perverse, the conclusions of this study should be treated as hypothesis generating. The pre-existing body of work, however, suggests that Jaddoe and colleagues’ findings are not data driven and will be reproducible.
Mechanisms that may explain the link between fetal growth and later cardiovascular risk factors have been explored extensively over the past 30 years, in both human cohorts and animal models.5 The idea that subtle influences on physiological systems occur early in development and are later magnified by the effects of growth and ageing to produce pathological phenotypes is well established. Studies have identified putative mechanisms—specifically, altered DNA methylation,
mitochondrial DNA instability, and increased exposure to oxidative stress.6 7 Such mechanisms are likely to explain the trans-generational effects of certain environmental challenges in human populations.8 However, despite the plausibility and attractiveness of the developmental programming hypothesis in interpreting the results of Jaddoe and colleagues’ study, consideration must be given to other explanations for a smaller than expected fetus in early pregnancy. A fetus may measure small for dates if ovulation occurred later than usual in the menstrual cycle. Hence, a smaller than expected fetus could be a marker for reproductive disorders in the mother, such as polycystic ovary syndrome, which predisposes women to prolonged menstrual cycles. Given that polycystic ovary syndrome is associated with the metabolic syndrome, and is also likely to have an important genetic element,9 a small fetus or baby may be a marker of maternal genetic characteristics that might be inherited by the baby and lead to the associations described in the paper. Although Jaddoe and colleagues corrected estimates of fetal size for cycle length, the subtle effects of dating discrepancies are a methodological problem with many such studies. Consistent with the idea that reproductive dysfunction and cardiovascular disease could have a common genetic predisposition, we know that the birth weight of the infant is also inversely associated with the risk of cardiovascular disease in the mother and in the mother’s parents.10 11 An extensive body of work now exists that supports the view that delivery of a small baby is a marker of maternal cardiovascular dysfunction.12 Disentangling the effects on the fetus of maternal environmental stresses from the effects of maternal genetic and epigenetic predisposition to disease will be a major challenge for future studies. For doctors, the pertinent question is whether these early effects can be modified. Can we identify interventions that might improve the early life environment and promote “normal” growth trajectories? On the basis of the current analysis, these interventions might be needed in the first trimester of pregnancy, during embryogenesis. Given the potential for interventions to cause serious harm at this stage of pregnancy, compelling evidence of safety will be needed before their evaluation. Hence,
Correspondence to: G C S Smith [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g175 doi: 10.1136/bmj.g175 (Published 23 January 2014)
Page 2 of 2
EDITORIALS
the appropriate response in the short term is that we need a deeper understanding of the strength, nature, and mechanisms of the reported associations before rushing to intervene. Studies such as those of Jaddoe and colleagues and previous work suggest that researchers need to recruit cohorts of women in the very earliest stages of pregnancy or, ideally, before conception to ensure that the initiating events are captured.1 3 For future analyses of the determinants of the health of our children and the adults that they become, a key message may lie in the words written by Oscar Hammerstein II and immortalised by Julie Andrews: “Let’s start at the very beginning, a very good place to start.” Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: none. Provenance and peer review: Commissioned; not externally peer reviewed. 1
Jaddoe VW, de Jonge L, Hofman A, Franco OH, Steegers EA, Gaillard R. First trimester fetal growth restriction and cardiovascular risk factors in school age children: population based cohort study. BMJ 2014;348:g14.
For personal use only: See rights and reprints http://www.bmj.com/permissions
2 3 4
5 6 7
8 9 10 11 12
Barker DJ. Adult consequences of fetal growth restriction. Clin Obstet Gynecol 2006;49:270-83. Smith GCS. First trimester determination of complications of late pregnancy. JAMA 2010;303:561-2. Tiemeier H, Velders FP, Szekely E, Roza SJ, Dieleman G, Jaddoe VW, et al. The Generation R Study: a review of design, findings to date, and a study of the 5-HTTLPR by environmental interaction from fetal life onward. J Am Acad Child Adolesc Psychiatry 2012;51:1119-35. Tarry-Adkins JL, Ozanne SE. Mechanisms of early life programming: current knowledge and future directions. Am J Clin Nutr 2011;94(6 suppl):1765-71S. Ozanne SE, Constancia M. Mechanisms of disease: the developmental origins of disease and the role of the epigenotype. Nat Clin Pract Endocrinol Metab 2007;3:539-46. Tarry-Adkins JL, Martin-Gronert MS, Fernandez-Twinn DS, Hargreaves I, Alfaradhi MZ, Land JM, et al. Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress, and oxidative defense capacity in rat heart. FASEB J 2013;27:379-90. Aiken CE, Ozanne SE. Transgenerational developmental programming. Hum Reprod Update 2014;20:63-75. Barber TM, Franks S. Genetics of polycystic ovary syndrome. Front Horm Res 2013;40:28-39. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 2001;357:2002-6. Smith GC, Wood AM, White IR, Pell JP, Hattie J. Birth weight and the risk of cardiovascular disease in the maternal grandparents. Am J Epidemiol 2010;171:736-44. Myklestad K, Vatten LJ, Magnussen EB, Salvesen KA, Smith GD, Romundstad PR. Offspring birth weight and cardiovascular risk in parents: a population-based HUNT 2 study. Am J Epidemiol 2012;175:546-55.
Cite this as: BMJ 2014;348:g175 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
