A C TA Obstetricia et Gynecologica
AOGS COM M ENT A R Y
Childhood consequences of maternal obesity and excessive weight gain during pregnancy ROMY GAILLARD1,2,3, JANINE F. FELIX1,2,3, LIESBETH DUIJTS2,3 & VINCENT W.V. JADDOE1,2,3 1
The Generation R Study Group, 2Department of Pediatrics, and 3Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
Key words Obesity, weight gain, childhood outcomes, prevention Correspondence Romy Gaillard, The Generation R Study Group (Na 29-15), Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands. E-mail: [email protected] Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this manuscript. Please cite this article as: Gaillard R, Felix JF, Duijts L, Jaddoe VWV. Childhood consequences of maternal obesity and excessive weight gain during pregnancy. Acta Obstet Gynecol Scand 2014; 93: 1085–1089.
Abstract Obesity is a major public health concern. In western countries, the prevalence of obesity in pregnant women has strongly increased, with reported prevalence rates reaching 30%. Also, up to 40% of women gain an excessive amount of weight during pregnancy. Recent observational studies and meta-analyses strongly suggest long-term impact of maternal obesity and excessive weight gain during pregnancy on adiposity, cardiovascular and respiratory related health outcomes in their children. These observations suggest that maternal adiposity during pregnancy may program common health problems in the offspring. Currently, it remains unclear whether the observed associations are causal, or just reflect confounding by family-based sociodemographic or lifestylerelated factors. Parent–offspring studies, sibling comparison studies, Mendelian randomization studies and randomized trials can help to explore the causality and underlying mechanisms. Also, the potential for prevention of common diseases in future generations by reducing maternal obesity and excessive weight gain during pregnancy needs to be explored.
Received: 11 September 2014 Accepted: 11 September 2014 DOI: 10.1111/aogs.12506
Introduction Obesity is common in both western and non-western countries, and is a major public health concern. Worldwide, the prevalence of obesity has nearly doubled in the last 20 years. The strong increase in obesity prevalence is also present among women of reproductive age. In western countries, the obesity prevalence rate in pregnant women goes up to 30% (1). Also, based on the US Institute of Medicine guidelines, up to 40% of women gain an excessive amount of weight during pregnancy in western countries. The Institute of Medicine guidelines define optimal ranges of maternal weight gain during pregnancy according to a mother’s prepregnancy body mass index, and have been established based on evidence from observational studies that relate gestational weight gain to
various maternal and offspring outcomes (2). An accumulating body of evidence suggests that maternal obesity and excessive weight gain during pregnancy also have long-term health effects for the offspring. In this commentary, we discuss recent observational studies and meta-analyses focused on the impact of maternal obesity and excessive weight gain during pregnancy on health outcomes in the offspring. We also discuss the potential mechanisms underlying the observed associations.
Pregnancy outcomes Maternal prepregnancy obesity and excessive gestational weight gain are important risk factors for a large number of maternal and fetal pregnancy complications (3). Maternal
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 1085–1089
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prepregnancy obesity is strongly associated with the risk of gestational hypertensive disorders and gestational diabetes. A large review among 13 cohort studies suggested that the risk of preeclampsia doubled with each 5–7 kg/m2 increase in maternal prepregnancy body mass index (4). Another meta-analysis encompassing 20 studies showed that the risk of developing gestational diabetes was four times higher for obese women compared with women of normal weight (5). Maternal prepregnancy obesity is also associated with an increased risk of cesarean delivery (3). The reported associations of maternal obesity with other delivery complications are less consistent than those for cesarean delivery. Most studies suggested that maternal obesity is associated with an increased risk of medically induced preterm birth, but not with the risk of spontaneous preterm birth (3). Meta-analyses have suggested that maternal prepregnancy obesity is associated with a two-fold increased risk of fetal death and approximate 1.5-fold increased risk of a variety of congenital anomalies (6,7). The associations of maternal prepregnancy obesity with increased fetal growth and risk of large size for gestational age at birth have frequently been reported (3,8). Furthermore, multiple studies have reported that maternal obesity is associated with an increased risk of longer maternal length of hospital stay, low Apgar scores, and referral to neonatal intensive care unit (9). Excessive gestational weight gain has further been associated with increased risks of gestational hypertensive disorders, gestational diabetes, cesarean delivery, preterm delivery and delivering a large-for-gestational age infant (9). Hence, both maternal prepregnancy obesity and excessive gestational weight gain lead to increased risks of maternal and fetal complications. Overall, the associations for maternal prepregnancy obesity with adverse pregnancy outcomes seem to be stronger than for excessive gestational weight gain (3,9).
index was also associated with a higher childhood total body fat mass, android/gynoid fat mass ratio, and abdominal subcutaneous and preperitoneal fat mass, – a measure of visceral fat mass (12). Both maternal prepregnancy obesity and excessive gestational weight gain have also been associated with a higher blood pressure, adverse lipid profile and higher inflammatory markers in childhood (12,13). Across studies, these reported associations do not seem to be explained by birthweight. However, the associations of maternal obesity and excessive gestational weight gain with childhood cardiovascular outcomes appear to be largely mediated by childhood body mass index. A recent meta-analysis among 14 studies with more than 108–000 mother–child pairs reported consistent associations of maternal prepregnancy obesity with childhood asthma, with a 31% increased risk of asthma or ever wheezing (14). Each 1-kg/m2 increase in maternal body mass index was associated with a 3% increase in childhood asthma risk. Similarly, increased gestational weight gain was associated with an increased risk of childhood asthma (15). These associations tended to be stronger among children from mothers without an asthma or atopy history or childhood respiratory infectious diseases. Also, the observed associations could not be explained by birthweight or by the child’s body mass index at the time of outcome assessment. Hence, in line with the risks of pregnancy complications, maternal prepregnancy obesity and excessive gestational weight gain also lead to increased risks of adiposity, and adverse cardiovascular and respiratory related outcomes in children. These associations seem not to be restricted to obesity or excessive gestational weight gain, but present across the full-range of body mass index and gestational weight gain.
Childhood outcomes
Causality or confounding
Previous studies on physical childhood consequences of maternal obesity and excessive gestational weight gain were mainly focused on childhood adiposity, cardiovascular risk factors and asthma. Two large meta-analyses among 45 studies and 12 studies, showed strong associations of maternal prepregnancy obesity and excessive gestational weight gain, respectively, with the risk of obesity in the offspring (10,11). Overall, maternal obesity was associated with a three-fold higher risk of offspring obesity, whereas excessive gestational weight gain was associated with a 33% increased risk of offspring obesity. Childhood body mass index may not be an accurate marker of fat mass. We have previously shown among 4871 mother–offspring pairs that a higher maternal prepregnancy body mass
Despite the large number of observational studies reporting these strong associations, it remains unclear whether these associations of maternal prepregnancy obesity or excessive gestational weight gain with childhood outcomes are explained by direct intrauterine, causal mechanisms. The observed associations may also be explained by environmental, lifestyle-related, or genetic characteristics. Despite extensive adjustment for potential confounding factors in observational studies, residual confounding may still be an issue. Several approaches can be used in epidemiological research to better control for confounding. Multiple studies have compared the strength of associations of maternal and paternal body mass index with childhood outcomes as an aid to further disentangle underlying
1086
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 1085–1089
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mechanisms (16). Stronger associations for maternal body mass index suggest direct intrauterine mechanisms, whereas similar or stronger associations for paternal body mass index suggest a role for shared family-based, lifestyle-related characteristics or genetic factors. Stronger associations for maternal prepregnancy body mass index with birthweight have been reported than for paternal prepregnancy body mass index (17). So far, studies comparing associations of maternal and paternal body mass index with childhood body mass index have shown conflicting results (16). However, studies also examining these associations with more detailed childhood fat mass measures and other cardio-metabolic risk factors, have shown that maternal prepregnancy body mass index tends to be more strongly associated with childhood total fat mass, android/gynoid fat mass ratio and clustering of cardio-metabolic risk factors than paternal body mass index (12,18). These findings suggest that maternal prepregnancy body mass index may, at least partly, influence the cardio-metabolic health of offspring through direct intrauterine mechanisms. A second approach to establish causality is by a sibling comparison study, which controls for environmental characteristics as well as maternal genotypes that are similar within siblings. In sibling studies among offspring from mothers who had high levels of prepregnancy weight loss due to gastrointestinal bypass surgery, it was observed that the prevalence of obesity and adverse cardiovascular outcomes was higher in children born to mothers before surgery than those born to mothers after surgery (19). These findings suggest that some of the effect of maternal obesity on offspring outcomes may be through direct intrauterine mechanisms. However, it remains unclear whether this is similar across the whole distribution of maternal prepregnancy body mass index. A large study among 280 866 singleton-born Swedish men observed that a higher maternal body mass index in early pregnancy was associated with higher offspring body mass index at the age of 18 years in the whole cohort and between nonsiblings, but not within siblings, which suggests that the association may be explained by confounding environmental characteristics (20). However, among the same study population it was shown that among overweight and obese mothers, higher total gestational weight gain is associated with higher offspring body mass at the age of 18 years among siblings, which suggests a possible intra-uterine effect for gestational weight gain (21). A third approach to obtain further insight into causality is a Mendelian randomization approach. This approach uses genetic variants, which are robustly associated with the exposure of interest and not affected by confounding, as an instrumental variable for a specific
Gestational weight and childhood outcomes
exposure. A study among 4091 mother–offspring pairs showed no association of the maternal fat mass and obesity (FTO) gene with childhood fat mass (18). The findings from this study do not support causality. However, these findings mark the importance for further Mendelian randomization studies with a larger sample size and multiple maternal genetic factors. Finally, multiple randomized controlled trials have been performed focused on improving diet in overweight and obese pregnant women or limiting weight gain during pregnancy (22). Results from these randomized controlled trials suggested that dietary interventions during pregnancy may lead to a small reduction in the amount of gestational weight gain. However, whether they also have a beneficial effect on maternal and childhood outcomes remains unclear. Long-term follow-up of participants in these trials will provide further insight into the causality of these observed associations as well the effectiveness of maternal lifestyle interventions during pregnancy for improving long-term health of offspring.
Potential mechanisms The underlying mechanisms for the observed associations remain unclear. Maternal prepregnancy obesity and gestational weight gain are complex traits. Maternal prepregnancy obesity reflects maternal nutritional status, fat mass and lifestyle habits. Gestational weight gain also reflects multiple components, which partly depend upon the timing of gestational weight gain. Maternal gestational weight gain in early pregnancy does, to a considerable extent, reflect maternal fat deposition, whereas weight gain in mid and late pregnancy largely reflects maternal and amniotic fluid expansion, and growth of the fetus, placenta and uterus (2). By examining critical periods of gestational weight gain, further insight in potential underlying mechanisms can be obtained. It has been shown that especially gestational weight gain in mid and late pregnancy seem to be associated with birthweight (9). A study among 5154 UK mother–offspring pairs showed that gestational weight gain in the first 14 weeks of pregnancy was positively associated with offspring body mass index, waist circumference and fat mass at 9 years, but after 14 weeks of gestation, only high levels of gestational weight gain were associated with offspring adiposity measures (13). Also, we observed among 5908 mothers and their children that maternal weight gain in early pregnancy, but not later in pregnancy, is associated with an adverse childhood cardio-metabolic profile (23). These studies suggest that especially maternal weight gain in early pregnancy, when maternal fat accumulation forms a large component of the gestational weight gain, is associated with adverse cardio-metabolic outcomes in the offspring.
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 1085–1089
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Not much is known about the potential programming effects by maternal obesity or excessive gestational weight gain. The fetal overnutrition hypothesis suggests that increased placental transfer of nutrients to the developing fetus in obese mothers and mothers with high levels of gestational weight gain, may subsequently affect fetal development, fetal fat deposition and the development of the hypothalamic–endocrine system, which controls appetite and energy metabolism (3). This may predispose individuals to a greater risk of adverse health outcomes in later life. So far, animal studies provide support for programming effects of maternal obesity and excessive gestational weight gain. Also, a small human study has suggested that gestational weight gain might be associated with epigenetic modifications in offspring cord blood (24). However, the mechanisms proposed have not been tested yet in large epidemiological studies. Further mechanistic studies are important to obtain a better understanding of the underlying mechanisms.
Conclusions
R. Gaillard et al.
3.
4.
5.
6.
7.
8.
9.
Maternal prepregnancy obesity and excessive weight gain during pregnancy are common and important risk factors for adverse childhood adiposity, cardiovascular and respiratory outcomes. Parent–offspring studies, sibling comparison studies, Mendelian randomization studies and randomized controlled trials are needed to explore the causality, underlying mechanisms and potential for prevention of common diseases in future generations by reducing maternal obesity and excessive weight gain during pregnancy.
10.
11.
12.
Funding The authors received funding from the European Union’s Seventh Framework Program (FP7/2007-2013), project EarlyNutrition under grant agreement no. 289346. Vincent Jaddoe received an additional grant from the Netherlands Organization for Health Research and Development (VIDI 016.136.361). Liesbeth Duijts received funding from the Lung Foundation Netherlands (no 3.2.12.089; 2012). References
14.
15.
1. Huda SS, Brodie LE, Sattar N. Obesity in pregnancy: prevalence and metabolic consequences. Semin Fetal Neonatal Med. 2010;15:70–6. 2. Institute of Medicine (US) and National Research Council (US) Committee to Reexamine IOM Pregnancy Weight Guidelines, Rasmussen KM, Yaktine AL, eds. Weight gain
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16.
during pregnancy: reexamining the guidelines. Washington, DC: National Academies Press, 2009. Poston L, Harthoorn LF, Van Der Beek EM, Contributors to the ILSI Europe Workshop. Obesity in pregnancy: implications for the mother and lifelong health of the child. A consensus statement. Pediatr Res. 2011;69:175–80. O’Brien TE, Ray JG, Chan WS. Maternal body mass index and the risk of preeclampsia: a systematic overview. Epidemiology. 2003;14:368–74. Chu SY, Callaghan WM, Kim SY, Schmid CH, Lau J, England LJ, et al. Maternal obesity and risk of gestational diabetes mellitus. Diabetes Care. 2007;30:2070–6. Chu SY, Kim SY, Lau J, Schmid CH, Dietz PM, Callaghan WM, et al. Maternal obesity and risk of stillbirth: a metaanalysis. Am J Obstet Gynecol. 2007;197:223–8. Stothard KJ, Tennant PW, Bell R, Rankin J. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA. 2009;301:636–50. Ay L, Kruithof CJ, Bakker R, Steegers EA, Witteman JC, Moll HA, et al. Maternal anthropometrics are associated with fetal size in different periods of pregnancy and at birth. The Generation R Study. BJOG. 2009;116:953–63. Gaillard R, Durmus B, Hofman A, Mackenbach JP, Steegers EA, Jaddoe VW. Risk factors and outcomes of maternal obesity and excessive weight gain during pregnancy. Obesity. 2013;21:1046–55. Yu Z, Han S, Zhu J, Sun X, Ji C, Guo X. Pre-pregnancy body mass index in relation to infant birth weight and offspring overweight/obesity: a systematic review and meta-analysis. PLoS ONE. 2013;8:e61627. Tie HT, Xia YY, Zeng YS, Zhang Y, Dai CL, Guo JJ, et al. Risk of childhood overweight or obesity associated with excessive weight gain during pregnancy: a meta-analysis. Arch Gynecol Obstet. 2014;289:247–57. Gaillard R, Steegers EA, Duijts L, Felix JF, Hofman A, Franco OH, et al. Childhood cardiometabolic outcomes of maternal obesity during pregnancy: the Generation R Study. Hypertension. 2014;63:683–91. Fraser A, Tilling K, Macdonald-Wallis C, Sattar N, Brion MJ, Benfield L, et al. Association of maternal weight gain in pregnancy with offspring obesity and metabolic and vascular traits in childhood. Circulation. 2010;121: 2557–64. Forno E, Young OM, Kumar R, Simhan H, Celedon JC. Maternal obesity in pregnancy, gestational weight gain, and risk of childhood asthma. Pediatrics. 2014;134: e535–46. Leermakers ET, Sonnenschein-van der Voort AM, Gaillard R, Hofman A, de Jongste JC, Jaddoe VW, et al. Maternal weight, gestational weight gain and preschool wheezing: the Generation R Study. Eur Respir J. 2013;42:1234–43. Patro B, Liber A, Zalewski B, Poston L, Szajewska H, Koletzko B. Maternal and paternal body mass index and
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17.
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offspring obesity: a systematic review. Ann Nutr Metab. 2013;63:32–41. Durmus B, Arends LR, Ay L, Hokken-Koelega AC, Raat H, Hofman A, et al. Parental anthropometrics, early growth and the risk of overweight in pre-school children: the Generation R Study. Pediatr Obes. 2013;8:339–50. Lawlor DA, Timpson NJ, Harbord RM, Leary S, Ness A, McCarthy MI, et al. Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable. PLoS Med. 2008;5:e33. Kral JG, Biron S, Simard S, Hould FS, Lebel S, Marceau S, et al. Large maternal weight loss from obesity surgery prevents transmission of obesity to children who were followed for 2 to 18 years. Pediatrics. 2006;118: e1644–9. Lawlor DA, Lichtenstein P, Langstrom N. Association of maternal diabetes mellitus in pregnancy with offspring adiposity into early adulthood: sibling study in a
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22.
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24.
prospective cohort of 280,866 men from 248,293 families. Circulation. 2011;123:258–65. Lawlor DA, Lichtenstein P, Fraser A, Langstrom N. Does maternal weight gain in pregnancy have long-term effects on offspring adiposity? A sibling study in a prospective cohort of 146,894 men from 136,050 families. Am J Clin Nutr. 2011;94:142–8. Thangaratinam S, Rogozinska E, Jolly K, Glinkowski S, Roseboom T, Tomlinson JW, et al. Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis of randomised evidence. BMJ. 2012;344: e2088. Gaillard R. Cardiovascular health in pregnant women and their children. The Generation R Study. PhD thesis, Erasmus University Rotterdam, Rotterdam, the Netherlands, 2014. ISBN: 978 90 5291 113 7. Morales E, Groom A, Lawlor DA, Relton CL. DNA methylation signatures in cord blood associated with maternal gestational weight gain: results from the ALSPAC cohort. BMC Res Notes. 2014;7:278.
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AOGS COM M ENT A R Y
Childhood consequences of maternal obesity and excessive weight gain during pregnancy ROMY GAILLARD1,2,3, JANINE F. FELIX1,2,3, LIESBETH DUIJTS2,3 & VINCENT W.V. JADDOE1,2,3 1
The Generation R Study Group, 2Department of Pediatrics, and 3Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
Key words Obesity, weight gain, childhood outcomes, prevention Correspondence Romy Gaillard, The Generation R Study Group (Na 29-15), Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands. E-mail: [email protected] Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this manuscript. Please cite this article as: Gaillard R, Felix JF, Duijts L, Jaddoe VWV. Childhood consequences of maternal obesity and excessive weight gain during pregnancy. Acta Obstet Gynecol Scand 2014; 93: 1085–1089.
Abstract Obesity is a major public health concern. In western countries, the prevalence of obesity in pregnant women has strongly increased, with reported prevalence rates reaching 30%. Also, up to 40% of women gain an excessive amount of weight during pregnancy. Recent observational studies and meta-analyses strongly suggest long-term impact of maternal obesity and excessive weight gain during pregnancy on adiposity, cardiovascular and respiratory related health outcomes in their children. These observations suggest that maternal adiposity during pregnancy may program common health problems in the offspring. Currently, it remains unclear whether the observed associations are causal, or just reflect confounding by family-based sociodemographic or lifestylerelated factors. Parent–offspring studies, sibling comparison studies, Mendelian randomization studies and randomized trials can help to explore the causality and underlying mechanisms. Also, the potential for prevention of common diseases in future generations by reducing maternal obesity and excessive weight gain during pregnancy needs to be explored.
Received: 11 September 2014 Accepted: 11 September 2014 DOI: 10.1111/aogs.12506
Introduction Obesity is common in both western and non-western countries, and is a major public health concern. Worldwide, the prevalence of obesity has nearly doubled in the last 20 years. The strong increase in obesity prevalence is also present among women of reproductive age. In western countries, the obesity prevalence rate in pregnant women goes up to 30% (1). Also, based on the US Institute of Medicine guidelines, up to 40% of women gain an excessive amount of weight during pregnancy in western countries. The Institute of Medicine guidelines define optimal ranges of maternal weight gain during pregnancy according to a mother’s prepregnancy body mass index, and have been established based on evidence from observational studies that relate gestational weight gain to
various maternal and offspring outcomes (2). An accumulating body of evidence suggests that maternal obesity and excessive weight gain during pregnancy also have long-term health effects for the offspring. In this commentary, we discuss recent observational studies and meta-analyses focused on the impact of maternal obesity and excessive weight gain during pregnancy on health outcomes in the offspring. We also discuss the potential mechanisms underlying the observed associations.
Pregnancy outcomes Maternal prepregnancy obesity and excessive gestational weight gain are important risk factors for a large number of maternal and fetal pregnancy complications (3). Maternal
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 1085–1089
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prepregnancy obesity is strongly associated with the risk of gestational hypertensive disorders and gestational diabetes. A large review among 13 cohort studies suggested that the risk of preeclampsia doubled with each 5–7 kg/m2 increase in maternal prepregnancy body mass index (4). Another meta-analysis encompassing 20 studies showed that the risk of developing gestational diabetes was four times higher for obese women compared with women of normal weight (5). Maternal prepregnancy obesity is also associated with an increased risk of cesarean delivery (3). The reported associations of maternal obesity with other delivery complications are less consistent than those for cesarean delivery. Most studies suggested that maternal obesity is associated with an increased risk of medically induced preterm birth, but not with the risk of spontaneous preterm birth (3). Meta-analyses have suggested that maternal prepregnancy obesity is associated with a two-fold increased risk of fetal death and approximate 1.5-fold increased risk of a variety of congenital anomalies (6,7). The associations of maternal prepregnancy obesity with increased fetal growth and risk of large size for gestational age at birth have frequently been reported (3,8). Furthermore, multiple studies have reported that maternal obesity is associated with an increased risk of longer maternal length of hospital stay, low Apgar scores, and referral to neonatal intensive care unit (9). Excessive gestational weight gain has further been associated with increased risks of gestational hypertensive disorders, gestational diabetes, cesarean delivery, preterm delivery and delivering a large-for-gestational age infant (9). Hence, both maternal prepregnancy obesity and excessive gestational weight gain lead to increased risks of maternal and fetal complications. Overall, the associations for maternal prepregnancy obesity with adverse pregnancy outcomes seem to be stronger than for excessive gestational weight gain (3,9).
index was also associated with a higher childhood total body fat mass, android/gynoid fat mass ratio, and abdominal subcutaneous and preperitoneal fat mass, – a measure of visceral fat mass (12). Both maternal prepregnancy obesity and excessive gestational weight gain have also been associated with a higher blood pressure, adverse lipid profile and higher inflammatory markers in childhood (12,13). Across studies, these reported associations do not seem to be explained by birthweight. However, the associations of maternal obesity and excessive gestational weight gain with childhood cardiovascular outcomes appear to be largely mediated by childhood body mass index. A recent meta-analysis among 14 studies with more than 108–000 mother–child pairs reported consistent associations of maternal prepregnancy obesity with childhood asthma, with a 31% increased risk of asthma or ever wheezing (14). Each 1-kg/m2 increase in maternal body mass index was associated with a 3% increase in childhood asthma risk. Similarly, increased gestational weight gain was associated with an increased risk of childhood asthma (15). These associations tended to be stronger among children from mothers without an asthma or atopy history or childhood respiratory infectious diseases. Also, the observed associations could not be explained by birthweight or by the child’s body mass index at the time of outcome assessment. Hence, in line with the risks of pregnancy complications, maternal prepregnancy obesity and excessive gestational weight gain also lead to increased risks of adiposity, and adverse cardiovascular and respiratory related outcomes in children. These associations seem not to be restricted to obesity or excessive gestational weight gain, but present across the full-range of body mass index and gestational weight gain.
Childhood outcomes
Causality or confounding
Previous studies on physical childhood consequences of maternal obesity and excessive gestational weight gain were mainly focused on childhood adiposity, cardiovascular risk factors and asthma. Two large meta-analyses among 45 studies and 12 studies, showed strong associations of maternal prepregnancy obesity and excessive gestational weight gain, respectively, with the risk of obesity in the offspring (10,11). Overall, maternal obesity was associated with a three-fold higher risk of offspring obesity, whereas excessive gestational weight gain was associated with a 33% increased risk of offspring obesity. Childhood body mass index may not be an accurate marker of fat mass. We have previously shown among 4871 mother–offspring pairs that a higher maternal prepregnancy body mass
Despite the large number of observational studies reporting these strong associations, it remains unclear whether these associations of maternal prepregnancy obesity or excessive gestational weight gain with childhood outcomes are explained by direct intrauterine, causal mechanisms. The observed associations may also be explained by environmental, lifestyle-related, or genetic characteristics. Despite extensive adjustment for potential confounding factors in observational studies, residual confounding may still be an issue. Several approaches can be used in epidemiological research to better control for confounding. Multiple studies have compared the strength of associations of maternal and paternal body mass index with childhood outcomes as an aid to further disentangle underlying
1086
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 1085–1089
R. Gaillard et al.
mechanisms (16). Stronger associations for maternal body mass index suggest direct intrauterine mechanisms, whereas similar or stronger associations for paternal body mass index suggest a role for shared family-based, lifestyle-related characteristics or genetic factors. Stronger associations for maternal prepregnancy body mass index with birthweight have been reported than for paternal prepregnancy body mass index (17). So far, studies comparing associations of maternal and paternal body mass index with childhood body mass index have shown conflicting results (16). However, studies also examining these associations with more detailed childhood fat mass measures and other cardio-metabolic risk factors, have shown that maternal prepregnancy body mass index tends to be more strongly associated with childhood total fat mass, android/gynoid fat mass ratio and clustering of cardio-metabolic risk factors than paternal body mass index (12,18). These findings suggest that maternal prepregnancy body mass index may, at least partly, influence the cardio-metabolic health of offspring through direct intrauterine mechanisms. A second approach to establish causality is by a sibling comparison study, which controls for environmental characteristics as well as maternal genotypes that are similar within siblings. In sibling studies among offspring from mothers who had high levels of prepregnancy weight loss due to gastrointestinal bypass surgery, it was observed that the prevalence of obesity and adverse cardiovascular outcomes was higher in children born to mothers before surgery than those born to mothers after surgery (19). These findings suggest that some of the effect of maternal obesity on offspring outcomes may be through direct intrauterine mechanisms. However, it remains unclear whether this is similar across the whole distribution of maternal prepregnancy body mass index. A large study among 280 866 singleton-born Swedish men observed that a higher maternal body mass index in early pregnancy was associated with higher offspring body mass index at the age of 18 years in the whole cohort and between nonsiblings, but not within siblings, which suggests that the association may be explained by confounding environmental characteristics (20). However, among the same study population it was shown that among overweight and obese mothers, higher total gestational weight gain is associated with higher offspring body mass at the age of 18 years among siblings, which suggests a possible intra-uterine effect for gestational weight gain (21). A third approach to obtain further insight into causality is a Mendelian randomization approach. This approach uses genetic variants, which are robustly associated with the exposure of interest and not affected by confounding, as an instrumental variable for a specific
Gestational weight and childhood outcomes
exposure. A study among 4091 mother–offspring pairs showed no association of the maternal fat mass and obesity (FTO) gene with childhood fat mass (18). The findings from this study do not support causality. However, these findings mark the importance for further Mendelian randomization studies with a larger sample size and multiple maternal genetic factors. Finally, multiple randomized controlled trials have been performed focused on improving diet in overweight and obese pregnant women or limiting weight gain during pregnancy (22). Results from these randomized controlled trials suggested that dietary interventions during pregnancy may lead to a small reduction in the amount of gestational weight gain. However, whether they also have a beneficial effect on maternal and childhood outcomes remains unclear. Long-term follow-up of participants in these trials will provide further insight into the causality of these observed associations as well the effectiveness of maternal lifestyle interventions during pregnancy for improving long-term health of offspring.
Potential mechanisms The underlying mechanisms for the observed associations remain unclear. Maternal prepregnancy obesity and gestational weight gain are complex traits. Maternal prepregnancy obesity reflects maternal nutritional status, fat mass and lifestyle habits. Gestational weight gain also reflects multiple components, which partly depend upon the timing of gestational weight gain. Maternal gestational weight gain in early pregnancy does, to a considerable extent, reflect maternal fat deposition, whereas weight gain in mid and late pregnancy largely reflects maternal and amniotic fluid expansion, and growth of the fetus, placenta and uterus (2). By examining critical periods of gestational weight gain, further insight in potential underlying mechanisms can be obtained. It has been shown that especially gestational weight gain in mid and late pregnancy seem to be associated with birthweight (9). A study among 5154 UK mother–offspring pairs showed that gestational weight gain in the first 14 weeks of pregnancy was positively associated with offspring body mass index, waist circumference and fat mass at 9 years, but after 14 weeks of gestation, only high levels of gestational weight gain were associated with offspring adiposity measures (13). Also, we observed among 5908 mothers and their children that maternal weight gain in early pregnancy, but not later in pregnancy, is associated with an adverse childhood cardio-metabolic profile (23). These studies suggest that especially maternal weight gain in early pregnancy, when maternal fat accumulation forms a large component of the gestational weight gain, is associated with adverse cardio-metabolic outcomes in the offspring.
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 1085–1089
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Gestational weight and childhood outcomes
Not much is known about the potential programming effects by maternal obesity or excessive gestational weight gain. The fetal overnutrition hypothesis suggests that increased placental transfer of nutrients to the developing fetus in obese mothers and mothers with high levels of gestational weight gain, may subsequently affect fetal development, fetal fat deposition and the development of the hypothalamic–endocrine system, which controls appetite and energy metabolism (3). This may predispose individuals to a greater risk of adverse health outcomes in later life. So far, animal studies provide support for programming effects of maternal obesity and excessive gestational weight gain. Also, a small human study has suggested that gestational weight gain might be associated with epigenetic modifications in offspring cord blood (24). However, the mechanisms proposed have not been tested yet in large epidemiological studies. Further mechanistic studies are important to obtain a better understanding of the underlying mechanisms.
Conclusions
R. Gaillard et al.
3.
4.
5.
6.
7.
8.
9.
Maternal prepregnancy obesity and excessive weight gain during pregnancy are common and important risk factors for adverse childhood adiposity, cardiovascular and respiratory outcomes. Parent–offspring studies, sibling comparison studies, Mendelian randomization studies and randomized controlled trials are needed to explore the causality, underlying mechanisms and potential for prevention of common diseases in future generations by reducing maternal obesity and excessive weight gain during pregnancy.
10.
11.
12.
Funding The authors received funding from the European Union’s Seventh Framework Program (FP7/2007-2013), project EarlyNutrition under grant agreement no. 289346. Vincent Jaddoe received an additional grant from the Netherlands Organization for Health Research and Development (VIDI 016.136.361). Liesbeth Duijts received funding from the Lung Foundation Netherlands (no 3.2.12.089; 2012). References
14.
15.
1. Huda SS, Brodie LE, Sattar N. Obesity in pregnancy: prevalence and metabolic consequences. Semin Fetal Neonatal Med. 2010;15:70–6. 2. Institute of Medicine (US) and National Research Council (US) Committee to Reexamine IOM Pregnancy Weight Guidelines, Rasmussen KM, Yaktine AL, eds. Weight gain
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