Correspondence: Rebecca Reynolds, Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 6TJ, UK. Tel.: 0131 2426762; Fax: 0131 2426779; E-mail: R.Reynolds@ed.ac.uk
The prevalence of maternal obesity has risen dramatically in recent years, with approximately one in five pregnant women in the UK now classed as obese (body mass index ≥ 30 kg/m2) at antenatal booking. Obesity during pregnancy has been hypothesized to exert long-term health effects on the developing child through ‘early life programming’. While this phenomenon has been well studied in a maternal undernutrition paradigm, the processes by which the programming effects of maternal obesity are mediated are less well understood. In humans, maternal obesity has been associated with a number of long-term adverse health outcomes in the offspring, including lifelong risk of obesity and metabolic dysregulation with increased insulin resistance, hypertension and dyslipidaemia, as well as behavioural problems and risk of asthma. The complex relationships between the maternal metabolic milieu and the developing foetus, as well as the potential influence of postnatal lifestyle and environment, have complicated efforts to study the programming effects of maternal overnutrition in humans. This review will examine the emerging evidence from human studies linking maternal obesity to adverse offspring outcomes.
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The epidemic of obesity in the Western world is escalating at an alarming rate, with over 500 million adults classified as obese in 2008, a figure expected to rise to at least 700 million by 2015. Likewise, the prevalence of maternal obesity has risen rapidly in the last two decades. In the USA, approximately 64% of women of reproductive age are overweight and 35% obese, while in the UK, one in five women are obese at the time of antenatal booking. Obesity during pregnancy increases the risk of a number of obstetric complications for both mother and child. Obesity is associated with significant maternal mortality and morbidity including increased risk of maternal death, pre-eclampsia and gestational diabetes mellitus. For the offspring of obese mothers, there is a higher incidence of foetal distress, stillbirth and neonatal death. Obese women are more likely to give birth to large for gestational age (LGA) babies, potentially increasing the risk of complications during delivery. In addition to these short-term risks, there is now evidence that maternal obesity may have longer-term influences on offspring health, either by direct effects of shared environmental or genetic factors or by ‘programming’ later risk of disease.
It is well recognized that events in utero have long-term influences on disease risk in later life. This phenomenon, known as ‘early life programming’, has been extensively studied in relation to low birthweight, whereby the developing foetus makes adaptations to an adverse intrauterine environment (e.g. due to maternal undernutrition) to maximize immediate chance for survival. These adaptations include permanent changes in structure, physiology and hormonal axes, with downregulation of growth and resultant low birthweight. In later life, these changes become mal-adaptive with consequent risk of a range of diseases including cardio-metabolic, cognitive and other outcomes. Maternal obesity and overnutrition are now recognized as ‘programming’ factors. The pregnant obese mother has increased circulating levels of inflammatory cytokines, as well as increased insulin resistance, glucose levels and lipids, with a potentially increased supply of nutrients to the developing foetus. This has led to the ‘developmental overnutrition hypothesis’ which proposes that the increased fuel supply to the foetus in maternal obesity or overnutrition leads to permanent changes in offspring metabolism, behaviour and appetite regulation with resultant obesity, metabolic and behavioural problems in adult life.[10-12] Experimental studies to test the developmental overnutrition hypothesis have been mainly carried out in animal models, and the evidence has been reviewed in detail elsewhere.[10, 11, 13] A number of potential pathways underlying the programming effects of maternal obesity have been identified from these animal models and are being investigated in human studies. These include increased maternal inflammation, changes in maternal lipid transport and storage, dysregulation of glucose metabolism, and changes to foetal appetite regulation, the microbiome and the foetal epigenome (Fig. 1). It is likely that the mechanisms underlying obesity-related programming effects are multifactorial, with complex interactions between a number of body systems contributing to a detrimental in utero environment during pregnancies complicated by maternal obesity. In addition, the complex nature of the maternal–foetal relationship during pregnancy, as well as the potential influences of postnatal maternal behaviour, is challenging to disentangle in human studies. This nonsystematic review will focus on the emerging literature from human studies, supported by data from animal models, exploring the links between maternal obesity and offspring outcomes.
Physiological changes during normal and obese pregnancy
Major physiological, anatomical, metabolic and hormonal changes occur during normal pregnancy to mobilize fuel stores for foetal growth and to prepare the mother for labour and delivery. The growing demand by the foetus for nutrients during development necessitates changes in maternal metabolism including altered glucose, lipid and amino acid metabolism. Pregnancy has a major impact on glucose homoeostatic mechanisms in the mother with significant changes in insulin secretion and sensitivity; insulin resistance progressively increases during pregnancy, particularly during the second trimester, allowing an increase in circulating glucose and therefore greater availability to the foetus. Hormones such as cortisol and progesterone, which are increased in pregnancy, also interfere with insulin signalling, exacerbating the insulin resistance. Overall, by late pregnancy, there is a 50–70% reduction in insulin sensitivity in normal-weight women compared with the nonpregnant state. During normal pregnancy, there is a change in amino acid metabolism with a switch to mainly protein synthesis in maternal tissues, the foetus and placenta with a concomitant reduction in amino acid oxidation. Indeed, this switch in amino acid metabolism accounts for 34% of the variance in birthweight. Changes in lipid metabolism accompany the changes in glucose and amino acid metabolism. In normal pregnancy, there is marked hyperlipidaemia, with threefold increases in plasma triglyceride levels and lesser increases in plasma cholesterol including rises in both high-density lipoprotein (HDL) and low-density lipoprotein (LDL). During the first two trimesters of pregnancy, maternal fat accumulation increases, fuelled by an increase in lipogenesis. In the third trimester, there is a decline or even a cessation of fat accumulation, coinciding with an increase in adipose tissue lipolysis in association with the increase in insulin resistance. This leads to an acceleration in the breakdown of maternal fat depots and results in maternal hyperlipidaemia during the period of maximal foetal growth. The increase in maternal circulating lipids allows for the accumulation of a pool of fatty acids in the placenta through hydrolysis of maternal lipoproteins by placental lipases, thus providing a source of lipids for the developing foetus; these fatty acids are transported to the foetal liver, where they are re-esterified into triglycerides. Thus, foetal fat accretion rises during pregnancy, reaching a peak in the third trimester.
In an obese mother, the ‘normal’ physiological changes of pregnancy differ from normal-weight women. As obesity in the nonpregnant state is also associated with increased insulin resistance, obese mothers are more insulin resistant than lean women in early pregnancy, with potential adverse effects for the developing foetus from very early in development during the critical window for implantation and placentation. During pregnancy, obesity-induced oxidative stress and endothelial dysfunction may interfere with trophoblast invasion and function, potentially leading to poor pregnancy outcomes. Likewise, in the obese mother, hyperlipidaemia is exaggerated and plasma free fatty acids are increased due to the relative inability of insulin to suppress whole-body lipolysis. These changes significantly increase the availability of fuel to the foetus; for example, high triglyceride levels and free fatty acid levels in late pregnancy[22, 23] and low HDL cholesterol levels are correlated with birth weight and with increased infant percentage body fat. In an obese mother, the distribution of body fat is also important. Storage in the visceral/abdominal depot has generally been associated with metabolic dysfunction including insulin resistance and inflammation. The contribution of subcutaneous fat to metabolic abnormalities remains less clear but may be related to free fatty acid concentrations and hence also influence insulin sensitivity. Further, it has been hypothesized that central fat storage in obese pregnancy with excessive release of nonesterified fatty acids (NEFAs) into the circulation and storage of excess fat in sites other than adipose tissue (ectopic fat accumulation) leads to lipotoxicity. Support of this hypothesis comes from a nonhuman primate study whereby hepatic lipotoxicity, characterized as a threefold increase in liver triglycerides, and increased evidence of hepatic oxidative stress in the third trimester was observed in the offspring of obese macaque mothers fed chronic high-fat diets. Hepatic mRNA transcript and protein levels of enzymes and transcription factors involved in gluconeogenesis were also increased, implying a persistent obesity-derived modulation of hepatic metabolic function after birth. Further, reversing the maternal high-fat diet improved both foetal hepatic triglyceride levels and gluconeogenic gene expression. Although the nonhuman primate has some flaws for modelling effects of maternal obesity, for example, nonhuman primates weigh less and have less subcutaneous fat in comparison with human neonates, this study does suggest a potential for foetal vulnerability to excess maternal lipids.
Obesity in the nonpregnant state is also associated with an increase in the storage of triglycerides, leading to adipogenesis, resulting in adipose hypertrophy and hyperplasia. The resulting cellular dysfunction is associated with dysregulation of adipokine release, increased free fatty acid release and, crucially, increased inflammation. In obese pregnancy, there is a general increase in circulating inflammatory markers, with increased plasma concentrations of a number of inflammatory markers, including plasma IL-6 and soluble intracellular cell adhesion molecule 1 (sICAM-1), CRP, TNF-α.[20, 29] In addition, adipose tissue secretes inflammatory cytokines such as tumour necrosis factor (TNF) alpha, interleukin-6 (IL-6), plasminogen activator inhibitor type 1, adiponectin and leptin and placentas from obese pregnancy have higher mRNA transcript abundance of a number of inflammatory markers, for example IL-1β, IL-8 and monocyte chemoattractant protein 1 (MCP-1). Placental infiltration by maternal macrophages and inflammation also increases in obese pregnancy, with increased expression of the inflammatory cytokines IL-1, IL-6 and TNF-α in CD14+ cells isolated from the placenta, suggesting that obesity during pregnancy may induce an exaggerated placental inflammatory response, potentially influencing foetal development.[31, 32] Thus, in an obese mother, the developing foetus will be potentially exposed to higher levels of inflammatory cytokines throughout pregnancy, with possible harmful effects.
The placenta is the key organ for the transfer of nutrients and oxygen to the developing foetus, as well as providing important endocrine and metabolic functions to support pregnancy. Transfer of nutrients can take place through a number of mechanisms, ranging from simple diffusion to receptor-mediated endocytosis. Nutrient transporters include amino acid transporters, lipid transporter and hydrolysis enzymes and glucose transporters. Changes in the density of nutrient transport proteins along with alterations in placental surface area may have effects on placental transport efficiency. There is increasing evidence that obesity during pregnancy may affect placental nutrient transport. Animal studies have shown that high-fat diets lead to increased placental nutrient transport, particularly via upregulation of the amino acid transporter SNAT2. Some have suggested that as average body mass index (BMI) has increased, average placental weight has also increased, potentially allowing for increased nutrient exchange over a larger surface area, although there is limited evidence to support this. Placental transport is also dependent on the concentration of nutrients in the maternal blood: a higher concentration gradient leads to increased diffusion and therefore increased foetal/placental growth. Therefore, in an obese pregnancy where the nutrient availability is increased, this may also affect placental growth, and therefore efficiency, directly.
Consequences of maternal obesity on offspring outcomes
In humans, studies have only recently started to dissect the influence of maternal obesity on offspring outcomes. This is largely due to lack of suitable cohorts with good recording of maternal obesity prior to or during pregnancy and offspring of suitable age to manifest the predicted outcomes. Nevertheless, there is now accumulating evidence supporting a link between maternal obesity, or excessive gestational weight gain, and offspring obesity as a neonate, child, adolescent and adulthood, as well as metabolic outcomes, including increased risk of insulin resistance hypertension and dyslipidaemia, and other outcomes such as behavioural problems and risk of asthma.
Obesity and metabolic outcomes
There are now several studies linking maternal obesity with an increased risk of childhood and adulthood obesity among offspring.[4, 10, 37] Maternal obesity, including women who are morbidly obese, is associated with increased birth weight, increased fat mass and foetal overgrowth.[5, 38-40] Higher prepregnancy maternal weight is associated with increased adiposity in childhood and adulthood as reflected by increased BMI and by increased percentage body fat.[10, 22, 40-43] The increased incidence of high birth weight among the children of obese mothers has itself been linked to increased risk of high offspring BMI later in childhood; macrosomia (birthweight > 4000 g) and excess gestational weight gain are the strongest predictors of higher BMI at 1 year of age, and BMI at 1 year of age is predictive of weight status at ages 5–8 years. Such tracking of obesity levels from birth into childhood, and potentially later life, is likely to have important implications for later disease risk. The extent to which changes in body habitus throughout life can modify intrauterine effects of maternal obesity is not known. The effect of obesity during pregnancy on offspring risk of obesity is independent of gestational diabetes, as nondiabetic obese women also have children with increased adiposity. Overall, maternal obesity during pregnancy substantially raises the risk of offspring obesity.
A handful of studies have examined associations between maternal obesity and offspring insulin resistance, a precursor of type 2 diabetes, as well as with other adverse metabolic outcomes. For example, at delivery, babies of obese mothers are more insulin resistant, as estimated by the homoeostatic model assessment of insulin resistance (HOMA-IR), suggesting that maternal obesity has an influence on foetal insulin sensitivity. This observation is supported by recent data from the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study reporting an association between increased maternal BMI and foetal hyperinsulinaemia, independent of maternal glycaemia. There is also some evidence that the effect of maternal obesity on insulin sensitivity persists into later life with offspring of overweight women (here defined as pregravid BMI > 27·3 kg/m2) having increased risk of developing insulin resistance by the age of 11 years. Another small study also reported increased insulin resistance among 51 offspring aged in their early 20s of obese mothers (BMI > 30 kg/m2) compared with 15 offspring of normal-weight mothers. Taken together, these data are supportive of a link between maternal obesity and altered offspring glucose-insulin homoeostasis. Furthermore, higher prepregnancy maternal weight is also associated with an adverse metabolic profile in the offspring including higher blood pressure,[48-51] and an adverse lipid profile when newborn and in young adulthood. Whether this translates into long-term increased risk of cardiovascular disease and death for the offspring is unknown, although animal studies suggest that the vasculature of the offspring may be significantly affected by maternal high-fat diet during pregnancy: a study in nonprimates showed that offspring of mothers fed a high-fat diet had a threefold attenuation of dilation capacity in the abdominal aorta, increased intimal wall thickness and an increase in the expression of vascular inflammation markers, suggesting a negative effect of maternal high-fat diet on offspring endothelial function. In humans, there is one published study reporting increased death from coronary heart disease in 3302 Finnish men who were thin at birth and whose mothers had a high body mass index (BMI) during pregnancy, although this finding was restricted to mothers who were of short stature.
Other potentially programmed outcomes: asthma and brain function
Other offspring outcomes that have been linked to maternal obesity in animal models have been less well studied in humans. In a study of 189 783 Swedish children, a higher maternal BMI was associated with a higher risk of asthma, with children of obese women more likely to require medication and hospitalization for asthma at ages 8–10 years. Likewise, a study of 6945 Finnish adolescents found high maternal prepregnancy BMI predicted increased wheezing and asthma in offspring at age 15–16 years. Maternal obesity has also been linked to altered brain development and behaviour in the offspring. A study involving 1004 children found that obese mothers were 67% more likely to have a child with an autism spectrum disorder, as diagnosed by standardized assessments, and twice as likely to have a child with developmental delay as measured by Mullen Scales of Early Learning scores.[57, 58] A study of 1714 5 year olds demonstrated that those born to obese women were more likely to show symptoms of attention-deficit hyperactivity disorder (ADHD), inattention and difficulty with regulating emotionality as reported by both kindergarten teachers and mothers using a DSM-IV-derived symptom list.[59, 60] Further studies are needed to determine whether these potential adverse effects of maternal obesity on offspring brain function persist into adult life.
Gestational weight gain
In addition to the association between maternal prepregnancy BMI and adverse offspring health outcomes, there is increasing evidence to suggest that excessive weight gain during pregnancy may significantly affect the future health of the unborn child. Guidelines are available recommending appropriate gestational weight gain for optimal outcomes for both mother and child. Despite this, only 30–40% of women adhere to these guidelines,[62-64] and obese women are at particular risk of gaining weight excessively.[65, 66] Thus, excessive gestational weight gain is independently associated with increased birthweight[61, 67] and gaining more than recommended levels of weight during pregnancy is independently associated with increased offspring adiposity[40, 68] and incidence of cardiovascular risk factors including increased systolic blood pressure,[40, 69, 70] as well as increased plasma levels of inflammatory markers including CRP and interleukin-6 (IL-6). As obese women generally have less gestational weight gain than women, the proportional change in weight for an obese woman, even one who has gained excessive weight, will be significantly less than for a lean woman. Indeed, some studies have suggested that excessive gestational weight gain may have less influence on offspring outcomes than obesity per se.[69, 72] Further studies are needed to disentangle influences of gestational weight gain from prevailing obesity levels.
Separating programming effects from shared environment/genetic factors
In any human study, it is almost impossible to separate the pre- and postnatal influences on offspring outcome, although lifestyle factors such as current level of obesity, behaviour, activity and diet are often considered as confounding factors in the statistical analysis. Certainly, there is much evidence for clustering of lifestyle factors, such as diet and exercise, within families,[73-75] and separating the prenatal influences of maternal obesity from postnatal influences is almost impossible in a human study. Likewise, the influence of shared maternal and offspring genes on the risk of offspring obesity needs to be considered. Genetic factors have been estimated to explain anywhere between 20% and 90% of the variance in offspring BMI, with obese parents more likely to have obese offspring. Sibling/sibling studies have been used in attempt to separate out intrauterine events from shared environmental and genetic factors, and a recent study has shown an independent influence of maternal obesity and weight gain during pregnancy on offspring obesity, particularly among obese women. However, another study including siblings concluded that shared familial traits may have a greater influence than maternal obesity on offspring BMI. Perhaps, greater evidence that maternal obesity programmes offspring obesity comes from a study utilizing a cohort of mothers who underwent surgical interventions for obesity. The authors were able to observe the effects of dramatically altered BMI in the same women during subsequent pregnancies, thus minimizing the genetic and environmental influences on offspring health. Offspring born before their mothers underwent biliopancreatic diversion (BPD) for obesity had significantly higher body weights at 12 years and at 21–25 years than offspring born after the surgery, in principal supporting the hypothesis that obesity has long-term influences of offspring body weight and BMI independent of genetic, environmental and lifestyle factors. However, it is highly likely that dietary modifications made by these mothers postsurgery would have influenced the diet and lifestyle of their offspring born postsurgery and that these changes would have contributed to obesity levels in these offspring in addition to in utero effects.
There is a growing body of evidence to suggest that obesity during pregnancy has profound effects on the future health of the offspring. The complex interactions that occur between mother, foetus and placenta shared genetic factors as well as potential for postnatal lifestyle influences make proving a causal link and elucidating exact programming mechanisms difficult. The normal physiological changes of pregnancy including alterations in inflammatory cytokines, maternal lipid profile and glucose homoeostasis certainly differ in obese pregnancy, and some of these candidate mechanisms have been explored in both animals and humans. Another potential mechanism is through changes in the epigenetic regulation of gene expression, as this is the most likely mechanism to explain how a single genotype can lead to a number of different phenotypes depending on prenatal conditions, with relatively short-term and dynamic modulation of gene activity. Most work in the field has focused on the role of methylation, whereby methyl groups are added or removed from specific cytosine bases in key genes. In general, the addition of a methyl group leads to a suppression of expression, while removal of methyl groups usually results in increased expression of the gene. The role of epigenetic changes in mediating the effects of maternal obesity on the offspring has been investigated in several recent studies (for a review, see Waterland and Jirtle). The gene insulin-like growth factor 2 (IGF2) plays an important role in the regulation of growth and development during gestation, in particular stimulating growth of the placenta. As an imprinted gene, expressed from the paternal allele, IGF2 expression is highly regulated by its methylation status.[83, 84] Plasticity of IGF2 expression has been studied as a potential mechanism mediating maternal diet-induced programming effects, with methylation a prime focus.[85, 86] Lower levels of IGF2 methylation have been associated with increased plasma IGF2 protein levels in cord blood, and the association is stronger in the children of obese women; importantly, increased levels of IGF2 protein are also associated with increased birth weight when maternal ethnicity, prepregnancy BMI, smoking, gestational diabetes and infant sex are adjusted for, suggesting that alterations in IGF2 methylation may directly affect birth weight and therefore future health. Consistent with this observation, a study of 204 infants born in North Carolina found that methylation of the maternally expressed IGF2-regulator H19 in umbilical cord blood was higher in 1-year-old infants with a high (>85th percentile) weight for age when compared to infants with a weight for age less than the 85th percentile.
Aside from IGF2, the methylation status of a number of other genes has also been investigated in the context of offspring adiposity. A study involving two independent cohorts of pregnant women in Southampton found that CpG methylation status of retinoid X receptor alpha (RXRA) and endothelial nitric oxide synthase (involved in bone development and adipogenesis) promoters in umbilical cord tissue strongly predicted sex-adjusted childhood fat mass at 9 years of age. The same study also demonstrated a negative association between maternal carbohydrate intake and RXRA methylation, raising the possibility that the gene may be involved in the mediation of the programming effects of maternal diet. Whether these genes are directly involved in programming, or whether they are simply markers of later obesity, remains unclear and requires further investigation.
Recent rodent studies have also highlighted the possibility of both intergenerational transmission of maternal high-fat diet programming effects through the paternal lineage and programming of offspring β-cell function by paternal high-fat diet, reinforcing the idea that paternal programming effects may also influence foetal development.[89, 90] Furthermore, a recent study of over 900 women showed that increasing paternal BMI is associated with IUGR in a gender-specific manner, suggesting that paternal obesity may programme later health, presumably through epigenetic modulation of imprinted genes. Despite the early stage of work in this field, the implications are profound. Maternal obesity is an increasingly common problem throughout the globe and presents a significant healthcare challenge, with the intergenerational programming effects only increasing the scale of this challenge. Further work is needed to fully characterize the effects of maternal obesity on the future health of the unborn child.
J O'R is funded from the Sir Jules Thorn Charitable Trust. We also acknowledge the support of Tommys and the British Heart Foundation.