The role of the placenta in the developmental origins of health and disease—Implications for practice

Reviews in Gynaecological and Perinatal Practice 6 (2006) 70–79 www.elsevier.com/locate/rigapp

The role of the placenta in the developmental origins of health and disease—Implications for practice Rohan M. Lewis a,*, Kirsten R. Poore a,1, Keith M. Godfrey b,2 a

Centre for Developmental Origins of Health and Disease, University of Southampton, Level F (MP887), Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK. b Medical Research Council Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK Received 6 October 2005; accepted 16 December 2005 Available online 3 February 2006

Abstract The placenta is actively involved in transporting nutrients to the fetus, it has both direct and indirect effects on fetal cardiovascular function and has endocrine influences on the mother and fetus. As such, a properly functioning placenta is crucial for normal fetal development and plays a central role in mediating effects of the maternal environment on the fetus. An altered external environment or abnormal placental function can induce developmental changes in the fetus and may have important consequences for the risk of cardiovascular and metabolic disease in adult life. The developmental origins hypothesis proposes that the early environment, from the periconceptional period until early childhood, can predispose an individual to adult cardiovascular and metabolic disease. This hypothesis is supported by epidemiological studies and by work in animals. These effects do not just act in low birth weight babies but have been shown to occur within the normal range of birth weight. It is thought that fetal adaptations to an impaired intra-uterine environment may enhance survival in early life but have deleterious effects in later life. Experimental studies suggest that maternal diet and body composition can alter placental structure and function, and we have recently demonstrated associations between a woman’s nutritional state before pregnancy and placental function at term. To elucidate these relationships, further work is needed to define markers of placental function and to characterize their relation to rates of fetal growth. Understanding how the placenta mediates maternal influences will be crucial in determining the mechanisms underlying developmental programming. This will allow the design of targeted public health interventions, both before and during pregnancy, to enhance placental function and thereby improve the health of the offspring throughout life. # 2006 Elsevier B.V. All rights reserved. Keywords: Placenta; Fetus; Disease; Maternal environment

1. Introduction The developmental origins of adult disease encompasses research into how environmental influences around conception, during gestation and in early postnatal life * Corresponding author. Tel.: +44 2380 777 222x8226; fax: + 44 2380 786933. E-mail addresses: [email protected] (R.M. Lewis), [email protected] (K.R. Poore), [email protected] (K.M. Godfrey). 1 Tel.: +44 2380 777 222x8226; fax: + 44 2380 786933. 2 Tel.: +44 2380 777 624; fax +44 2380 704 021. 1871-2320/$ – see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.rigapp.2005.12.001

predispose to cardiovascular and metabolic disease in later life. The placenta plays a crucial role in this process as it is the interface between the developing fetus and the mother. As such, it is likely that many of the nutritional and endocrine influences, which predispose the fetus to disease in later life will be mediated by the placenta. The ways in which the function of the placenta and fetal development are influenced by maternal and environmental factors are only beginning to be understood. There is now evidence that maternal diet, body composition and lifestyle are important determinants of placental function and fetal

R.M. Lewis et al. / Reviews in Gynaecological and Perinatal Practice 6 (2006) 70–79

71

development. In this review we will outline the evidence for the developmental origins of adult disease and how these effects are thought to be mediated. We will then discuss how maternal diet, body composition and lifestyle may affect placental function. Finally, we will address the potential future implications for clinical practice.

postnatal environment is different from that which was predicted. This may be a particular problem in societies such as India, where there is a rapid rural to urban transition, from a high exercise, low nutrition environment to one with low exercise and high nutrition [9]. Maternal disease or problems with placental function during pregnancy could also lead the fetus to adjust its development inappropriately.

2. The developmental origins of health and disease

2.1. Mechanisms of programming

The developmental origins of adult disease hypothesis originated from observations that regions in the UK with high neonatal mortality had the highest rates of coronary heart disease [1]. This led to the discovery of associations between lower birth weight and increased rates of cardiovascular and metabolic disease in adulthood [2]. These associations have been extensively replicated in different countries, in both men and women, and are not the result of confounding variables [3,4]. The association with lower birth weight is graded, affecting individuals across the normal range of birth weights, and does not simply depend on infants born prematurely or those with intra-uterine growth restriction [5]. Studies in laboratory and farm animals provided clear evidence that the maternal environment influences the biology of the offspring and have allowed progress to be made in understanding the mechanisms underlying these phenomena [6]. This hypothesis is sometimes also referred to as ‘programming’ or ‘developmental induction’, whereby an early environmental influence, such as poor maternal nutrition, is said to ‘program’ or ‘induce’ metabolic or endocrine changes in early life, which may persist into adult life and predispose to disease. While initial work concentrated on fetal life, further studies demonstrated that the sensitive period during which the early environment can have long lasting effects on the offspring encompasses the time from conception, through gestation and into postnatal life, hence the newer terminology of the developmental origins of health and disease. It has been proposed that the link between early life environment and adult disease may have an underlying evolutionary explanation. The predictive adaptive responses (PAR) hypothesis suggests that there is an evolutionary advantage if the developing organism can predict conditions in the postnatal environment. The fetus can then adapt its development to optimize its survival in that predicted environment [7]. An example of this is the meadow vole (Microtus pennsylvanicus) in which the day length to which the pregnant dam is exposed to in early pregnancy determines the coat thickness of the offspring at birth [8]. This has no value in the womb or in the burrow but has a later survival advantage. This approach may increase the chance of survival to reproductive age, even if there are subsequent health consequences. The PAR theory suggests that the longterm consequences may be particularly severe if the

While the mechanisms underlying programming are not fully understood, epigenetic modification is a prime candidate. An epigenetic modification is one that does not alter the heritable DNA sequence but does affect gene expression. DNA methylation is the best understood epigenetic modification and maternal diet has been shown to cause specific changes in DNA methylation in the offspring. Maternal protein restriction in the rat alters DNA methylation of the glucocorticoid receptor and peroxisomal proliferator-activated receptor genes in the offspring and this methylation is associated with specific changes in the expression of these genes [10]. Maternal folate supplementation prevents the epigenetic modification associated with maternal protein restriction in these rats and has also been shown to alter expression of the agouti gene in mice [10,11]. During gametogenesis, and in the preimplantation embryo, there is considerable de-methylation and remethylation and these may be critical windows for the laying down of epigenetic modifications [12]. Epigenetic modification of trophectoderm is of particular importance to how the placenta develops and functions and, in turn, how the fetus develops. 2.2. The placenta and programming As the placenta mediates the supply of nutrients to the fetus, its structure and function will be crucial in determining how the fetus develops. Of primary importance are likely to be the surface area of the syncytiotrophoblast surrounding the placental villi, the fetal capillary network within the villi and the diffusion distance between the maternal and fetal blood. The primary barrier between the maternal and fetal circulations is the syncytiotrophoblast. The branching nature of the villi and the microvillous surface of the maternal facing syncytiotrophoblast membrane maximises the surface area of the maternal fetal exchange area. As most nutrients cannot diffuse across lipid membranes they must be transported across the apical microvillous membrane and basal membrane of the syncytiotrophoblast. In this way, both membrane surface area and transporter activity per unit surface area are important determinants of transport capacity. It is thought that transport across the basal membrane of the syncytiotrophoblast, rather than the microvillous membrane, may be the limiting step for the transport of many nutrients including glucose and amino acids. Within the villi, the

72

R.M. Lewis et al. / Reviews in Gynaecological and Perinatal Practice 6 (2006) 70–79

structure, size and branching structure of the capillary network may affect both fetal exchange capacity, vascular resistance and the diffusion distance. However, the placenta has not always received the attention it deserves, in part because the relationship between placental weight and adult disease is not as consistent as for birth weight (see Table 1). The failure to demonstrate a consistent relationship is likely to be because placental weight is a poor measure of placental function and Table 1 Associations between placental weight and the placental weight/birth weight ratio and long-term cardiovascular and metabolic outcomes

Blood pressure Small placental weight Small placental weight Small Large Large Large Large

placental placental placental placental placental

volumea weight weight weight weight

High placental ratio High placental ratio High placental ratio Placental weight/ratio Placental weight/ratio Coronary heart disease Small placental weight Placental weight Placental weight Placental weight Placental weight Low placental ratio High placental ratio High placental ratio Stroke Small placental weight Glucose tolerance Small placental weight High placental ratio Plasma fibrinogen Small placental weight High placental ratio

Association with later outcome

Reference

" Adult blood pressure " Adult hypertension with diabetes " Childhood blood pressure " Adult blood pressure " Childhood blood pressure " Childhood blood pressure " Childhood blood pressure (boys only) " Adult blood pressure " Adult blood pressure " Adult hypertension without diabetes - Childhood blood pressure - Adult blood pressure

[25] [71]

" Coronary heart disease (men) - Coronary heart disease (men) - Coronary heart disease (men & women) - Coronary heart disease (women) - Coronary heart disease (men) " Coronary heart disease (men) " Coronary heart disease (men) " Coronary heart disease (women)

[72] [2] [73] [74] [75] [76] [77] [71] [78] [79] [5] [80] [3] [81] [82] [80] [80] [81]

" Stroke death rates

[80]

" Type-2 diabetes " Prevalence of impaired glucose tolerance

[37] [83]

" Plasma fibrinogen " Plasma fibrinogen

[84] [85]

(") association found in the direction shown; (-) no significant association found. a Measured in mid-trimester. Adapted from Godfrey (2002), Placenta 23 (Suppl. A), Trophoblast Res 16.

accurate placental weights, free from membranes and blood clots, are rarely collected. More studies are now required to understand the role of the placenta in fetal programming. In particular, studies are needed which measure placental function in a population-based context rather than just placental weight.

3. Maternal and environmental influences on fetal and placental development The environment in which the feto-placental unit develops is primarily determined by the mother. This maternal environment will reflect the external environment, in the short term through maternal diet, and in the longer term through nutrient stores, as reflected by maternal body composition. Maternal environment will be modified by intrinsic factors, such as maternal genes and metabolism, and by other lifestyle factors, such as maternal exercise and smoking. Little is known about maternal influences on placental function, but there is evidence that maternal factors affect placental growth and structure. In this section we discuss maternal influences on the placenta in the periconceptional period and throughout gestation. 3.1. Periconceptional influences on fetal and placental development Animal studies provide strong evidence that periconceptional insults, resulting from maternal diet or embryo manipulation, may have long-term consequences for the developing embryo [13–15]. Recently, we have reported preliminary data suggesting that maternal pre-pregnancy nutritional status and body composition may also be a determinant of placental function in humans. We have shown that mothers who reported dieting before pregnancy had decreased term placental 11-hydroxysteroid dehydrogenase type 2 (11b-HSD2) activity [16]; this enzyme plays an important role in protecting the fetus from high levels of circulating glucocorticoids in the mother, and low placental 11b-HSD2 activity may lead to premature activation of the fetal hypothalamic pituitary adrenal axis. The trajectory of fetal growth can also be altered in response to a periconceptional nutritional restriction. Lambs whose mothers were subject to nutrient restriction around conception have a slower fetal growth trajectory but one which is less susceptible to a mid gestation nutritional insult than fast growing fetuses [17]. This suggests that, even in early pregnancy, the embryo senses the external environment and likely nutrient supply and adapts its pattern of growth to accommodate this. The wide-spread use of assisted reproductive technologies in agriculture has highlighted how embryo culture and different cell culture media can have long-term effects on the offspring. This was first noticed in cattle where embryo culture, even for short periods of time, was found to result in

R.M. Lewis et al. / Reviews in Gynaecological and Perinatal Practice 6 (2006) 70–79

‘Large Offspring Syndrome’. This syndrome, identified in both sheep and cows, is characterized by large offspring with a range of developmental abnormalities and increased rates of perinatal mortality [18,19]. In humans, assisted conception technologies have been associated with an increased risk of fetal growth restriction [20], and the possibility that more subtle longer term consequences may eventuate needs to be seriously considered. Periconceptional influences on development could be mediated through effects on the maturing ooycte or during the transit of the egg through the oviduct. Granulosa cells provide nutrients to the developing oocyte. Treating cultured granulosa cells with insulin has been shown to alter the gene expression of transcription factors involved in the regulation of cellular metabolism [20]. It is possible that in vivo changes in maternal metabolic and endocrine status relating to diet will also affect granulosa cell function and thus the maturation of the oocyte. Alternatively, programming effects could be mediated when the fertilized egg is in the oviduct, a time in which there is considerable epigenetic reprogramming [14]. In rats, a maternal low protein diet throughout gestation, which has been shown to affect blood pressure, postnatal growth and blastocyst cell number, has also been shown to alter substrate availability within the oviduct and this could affect the development of the embryo [21]. Maternal protein restriction in rats, even for short periods, can have profound effects on early development. Exposure to this diet from conception until implantation has been shown to reduce blastocyst cell number in the inner and outer cell masses, and affects growth and blood pressure in the offspring [15]. The placenta is derived from the outer cell mass, so if the number of these cells is decreased then the development of the placenta will be altered. This may be a mechanism by which early maternal influences affect placental development and function throughout gestation.

73

nourished Western community found larger placental weights in pregnant women who had reported lower dietary intakes of carbohydrate in early pregnancy, especially when combined with high intakes of dairy protein in late pregnancy [22]. Analyses of people born around the time of the Dutch famine, a period of extreme malnutrition for 5 months in 1944–1945, showed that increased placental weight was associated with the combination of famine exposure in early pregnancy and high food intakes in midlate pregnancy [23]. While famine exposure per se was not associated with raised blood pressure in the offspring, there was evidence for an association between raised blood pressure and rations with a low protein density [24]. This adds to our studies from Aberdeen, UK, which found that maternal diets with either a low or a high ratio of animal protein to carbohydrate were associated with raised blood pressure in the adult offspring [25]. Maternal diets with a high protein density were also associated with insulin deficiency and impaired glucose tolerance in the offspring [26]. While adverse effects of diets with a high protein density might appear counterintuitive, they are consistent with the results of controlled trials of dietary supplementation in pregnancy [27]. Moreover, the Aberdeen findings have been replicated in a follow-up study of men and women in Motherwell, UK, whose mothers were advised to eat a diet high in meat protein and low in carbohydrate during pregnancy [28]. The offspring’s blood pressure was higher in those whose mothers reported greater intakes of meat and fish and lower intakes of carbohydrate in late pregnancy, particularly if the mother also had a low intake of green vegetables. One possibility is that the long-term effects may be a consequence of the metabolic stress imposed on the mother by an unbalanced diet in which high intakes of essential amino acids are not accompanied by the other micronutrients required to utilize them [26].

3.2. Maternal nutrition The placenta is not a simple conduit which transports the nutrients found in maternal blood to the fetus. There is selective uptake of nutrients from maternal blood and what is taken up may be altered by placental metabolism, before being transported to the fetus. It should also be noted that the nutrients in maternal blood are a product both of diet and release from maternal stores. Maternal nutrient stores are reflected in body composition and the capacity for release of nutrients from these stores may underlie associations between maternal body composition and placental function. Maternal nutrition may affect the fetus through both underand over-nutrition and through variations in specific dietary components. 3.2.1. Macronutrients There is evidence that variation in the different macronutrient components of the diet are associated with programming in humans. Observational studies in a well-

3.2.2. Micronutrients Micronutrients are essential for fetal development with an obvious example being the importance of folate in preventing neural tube defects. In addition to folate, zinc, iron, copper, calcium and vitamins A and E are known to be important to the fetus [29]. In addition to the fetal requirement, micronutrients are also required for the development and function of the placenta [29]. Despite their importance, little is known about the role of the placenta in determining the availability of micronutrients to the fetus. The primary focus on preventing fetal micronutrient deficiency is, understandably, on maternal intake. However, placental transport and metabolism is also likely to be important, particularly if maternal nutrient intake is sub-optimal. Even a small change in fetal micronutrient supply, one which does not cause gross deformations, could have long-term effects on the offspring. For example, folate availability has been shown to mediate subtle changes in fetal DNA methylation which alter gene expression and persist into adult life [10].

74

R.M. Lewis et al. / Reviews in Gynaecological and Perinatal Practice 6 (2006) 70–79

One of the areas of particular interest is the supply of calcium to the fetus. Evidence for a long-term effect of maternal calcium intake during pregnancy has come from a follow-up study of children in Argentina whose mothers took part in a randomized controlled trial of calcium supplementation in pregnancy [30]. This study found that maternal calcium supplementation was associated with lowering of the offspring’s blood pressure in childhood, even though supplementation was not associated with any change in birth weight [30]. Fetal bone mineralization requires an adequate materno-placental supply of calcium, raising the possibility that impaired fetal development could have longterm consequences for bone health. In a study of 70-year-old men and women born in Sheffield, UK, low birth weight was associated with reduced adult bone mass, even after adjustment for adult height [31]. Follow up studies of men and women born in Helsinki, Finland, between 1924 and 1933, showed that tall maternal height was associated with an increased risk of osteoporotic hip fracture in the adult offspring, particularly if the individual had been relatively short at birth and had a below average rate of childhood growth [32]. While the mechanisms underlying these associations are unknown, some evidence suggests that both changes in fetal bone development and programming of key endocrine axes may be important [32]. Work in rats suggests that placental calcium transport increases throughout gestation in parallel with rises in the levels of calcium binding proteins [33]. In humans, we have recently shown that placental mRNA levels for the gene Plasma Membrane Calcium ATPase 3 are positively correlated with neonatal bone mineral content [34]. Understanding of the maternal factors that regulate this gene may provide a target for maternal interventions to improve placental calcium transfer. Low circulating maternal vitamin D levels in late pregnancy have recently been linked with reduced whole body bone mineral density in the offspring at 9 years of age [35]. Early life bone mineral density is related to peak bone mineral density in early adulthood and is likely to be an important determinant of osteoporosis risk. For this reason, optimizing placental calcium transfer may be important for preventing osteoporosis in later life. 3.3. Maternal body composition Maternal body composition may be one factor which signals to the fetus what life will be like outside the womb. As body composition will reflect environmental conditions over a longer period of time, it may provide a more accurate indication than current nutrient supply. Body composition will affect maternal metabolism and nutrient availability and will therefore alter the environment experienced by the fetoplacental unit throughout gestation. There is evidence that maternal body composition is associated with adult health in the offspring and we are now beginning to determine how body composition affects placental function and fetal development.

Observations linking high maternal weight and adiposity with insulin deficiency, type-2 diabetes and coronary heart disease in the offspring [5,36,37] add to those of associations between gestational diabetes and adverse long-term outcomes [38]. There is an increasing body of consistent evidence showing strong links between low weight and body mass index in the mother and insulin resistance and dyslipidaemia, but not raised blood pressure, in the adult offspring [26,39,40]. In contrast, thin maternal skinfold thicknesses and low pregnancy weight gain have been consistently associated with raised blood pressure in the offspring [41–43]. For example, in studies of Jamaican children, we found strong associations between low pregnancy weight gain and thinner maternal triceps skinfold thickness in early pregnancy and raised blood pressure in the offspring. However, no significant associations were observed with maternal body mass index in early pregnancy [43]. Recent data suggest that maternal body composition affects placental nutrient transport and endocrinology. We have found that maternal upper-arm muscle mass before pregnancy is related to activity of the amino acid transporter System A in the term placenta [44]. This study suggests that placental development and function is affected by prepregnant maternal body composition. While we do not think there is a direct relationship between factors such as upper arm muscle mass and measures of placental function, the relationship may reflect the underlying maternal metabolic capacity. For example, metabolic capacity may influence protein turnover and amino acid exchange between organs. This metabolic environment may therefore alter placental development and function through the action of nutrient sensing pathways, such as the mTOR pathway [45]. 3.4. Maternal lifestyle Apart from diet, there is evidence that maternal exercise, smoking and alcohol intake can have effects on placental function and fetal development. While it is unclear whether exercise is beneficial during pregnancy, it may affect placental growth and function [46]. In one controlled study, women who exercised in early but not late pregnancy had elevated placental volume at mid gestation and term [47]. These women also had larger babies, indicating that the increased placental weight was associated with increased function. In the same study, women who exercised at a low level in early pregnancy had smaller placentas at 20 weeks gestation than moderately exercising women. In women who exercise heavily, the placenta may be able to sense maternal activity levels and adjust its growth to allow it to better compete for nutrients. Maternal smoking is well known to reduce fetal growth and has been shown to affect placental structure [48]. Using dual-energy X-ray absorptiometry scanning to measure neonatal bone mineral content and density, women who smoked during pregnancy were shown to have infants with a lower bone mineral content and density [49]. Overall, there

R.M. Lewis et al. / Reviews in Gynaecological and Perinatal Practice 6 (2006) 70–79

was an 11% average difference between the bone mineral content of infants whose mothers did and did not smoke during pregnancy [49]. Our study found that maternal smoking was associated with reduced neonatal bone mass, but not with adipose mass [50]. Other follow-up studies suggest that the effect of maternal smoking on bone mass persists to at least 8 years of age [51]. As discussed above, the mechanism of the effect on fetal bone growth and mineralization is an area of active investigation. One possibility is an effect of the heavy metal cadmium; this is present in high concentrations as a contaminant in tobacco smoke and has toxic effects on trophoblast calcium transport [52].

4. The placenta and fetal cardiovascular adaptation Fetal cardiovascular adaptations are a recognized feature of intra-uterine growth restriction and serve to divert nutrient-rich, highly oxygenated blood to spare the growth of the brain and other critical organs. The placenta affects the fetal cardiovascular system through the transport of oxygen and other nutrients, which have metabolic effects on fetal blood flow distribution. In addition, the placenta is an important determinant of fetal cardiac load, which can have major effects on fetal cardiac and vascular development [53]. Impaired placental vasculogenesis will place an additional burden on the fetal cardiovascular system, and in some cases this may result in reversed end diastolic flow. However, this is likely to be at the severe end of a spectrum and more modest alterations in placental vascular resistance could alter fetal vascular development in ways that have persistent effects into adult life. Factors that have been shown to alter placental vascularization include anemia, high altitude hypoxia, pre-eclampsia, maternal diabetes and smoking [48]. Metabolic factors may also be important in regulating the fetal cardiovascular system and placental transport of oxygen and nutrients is the major determinant of metabolite availability in the fetus. Animal experiments have shown that fetal adaptations to hypoxemia shunt umbilical venous blood away from hepatic tissue and impair fetal liver growth [54,55]. Similarly, decreased glucose transport across the sheep placenta has been shown to cause fetal blood flow redistribution [56]. Perfusion of the liver is reduced by small decreases in pressure, by relaxation of the ductus venous, and by increases in fetal haematocrit and blood viscosity [57]. A high fetal haematocrit also impairs growth of the fetal coronary circulation, with long-term consequences for coronary reserve [53]. Analyses of 38351 births from the United States Collaborative Perinatal Study found that a lower than expected placental weight for the size of the infant was associated with higher fetal haematocrit [58]. This suggests that physiological variations in oxygen transfer could lead to adaptive changes in fetal haematocrit and raises the possibility that normal variations in placental size and oxygen transfer

75

may have important consequences for the development of the fetal liver and coronary circulation. Our recent work suggests that maternal body composition and diet are associated with altered fetal cardiovascular function [59]. Fetuses of slimmer mothers with lower body fat stores and those eating an unbalanced diet had greater liver blood flow and shunted less blood away from the liver through the ductus venosus at 36 weeks gestation. These adaptations will alter the amount of blood and nutrients that are channelled to the liver or other organs including the developing brain. This redistribution, designed to protect critical organs, may have adverse effects elsewhere in the fetus that predispose to disease in later life. These findings demonstrate the influence of maternal body composition on fetal development and may potentially underlie the increased cardiovascular risk of people whose mothers were slimmer and had lower body fat stores in pregnancy [41–43]. The mechanisms underlying the influence of maternal slimness remain to be defined, but effects on the development of the placental vasculature and on placental transport of nutrients are likely to be important.

5. The placenta and endocrinology and metabolism The placenta plays an important role as an endocrine organ secreting hormones into both the maternal and fetal circulations. Placental hormones are involved in the maintenance of pregnancy (progesterone), fetal growth (leptin), fetal maturation and parturition (glucocorticoids and prostaglandins). Animal studies have shown that changes in fetal endocrinology and metabolism can have long-term consequences for postnatal neuro-endocrine function, metabolism, and organ structure and function [60]. Fetal endocrinology and metabolism is, in turn, strongly influenced by the placenta. An example with direct relevance to the developmental origins of health and disease is the role of placental 11b-HSD2 in converting maternal cortisol to inactive cortisone, thereby protecting the fetus from the actions of maternal glucocorticoids. In rats, reduced placental 11b-HSD2 activity is associated with increased blood pressure in the offspring during adult life [61]. This is of particular interest as pregnant rats fed a low protein diet have reduced placental 11b-HSD2 activity and offspring with raised adult blood pressure [62]. We have recently found changes in human placental 11b-HSD2 that are associated with differences in maternal body composition and dieting behaviour, suggesting that such findings are also relevant to human pregnancy [16]. Maternal diabetes provides an example of altered metabolic and endocrine status in humans that is associated with programming of the offspring [38,63]. Elevated placental glucose transporter activity has been shown with insulin dependent diabetes but not with gestational diabetes [64,65]. This has led to the suggestion that placental function may be set in response to conditions in early pregnancy and

76

R.M. Lewis et al. / Reviews in Gynaecological and Perinatal Practice 6 (2006) 70–79

that the management of diabetes during early pregnancy may be important for normal placental function. Adolescent pregnancy provides an example of how maternal metabolism can affect fetal development. Adolescent pregnancy is associated with poor outcome in humans and sheep. Pregnant adolescent sheep given a high level of nutrition in an attempt to improve outcome have offspring with lower fetal and placental weights than those fed a moderate level of nutrition [66]. This outcome is not fully understood but is thought to originate from differences in nutrient partitioning, with nutrients diverted from the fetus to the still growing mother. Similar redistributions in nutrient partitioning may occur as a result of maternal illness. Endocrine and metabolic signals from the fetus may also influence placental function in order to balance nutrient supply and fetal demand. Evidence for this comes from mice with a genetic knockout of the placental-specific IGF-2 transcript [67]. This targeted gene knockout decreases placental weight by day 14 of gestation (term is day 20). Despite the decrease in placental weight, fetal weight is not affected until day 19. Studies of amino acid transport in this model show that the activity of the amino acid transporter System A is upregulated. This suggests that the placenta is upregulating nutrient transport in response to fetal demand. This allows fetal growth to continue at the normal rate until near the end of gestation, at which time fetal demand is greatest and this increase in placental transport no longer meets fetal demand. In human pregnancy, we have found that activity of the amino acid transporter System A is higher in placentas that are relatively small compared to the fetus [44]. This observation is consistent with the suggestion that fetuses with relatively small placentas signal to the placenta to increase nutrient supply and thereby match fetal demand.

6. Interventions and treatments The influence of maternal diet and body composition on placental function and fetal development does suggest that interventions that enhance placental function are likely to improve fetal development and health in postnatal life. While it is too early to make specific dietary recommendations, further studies into the role of maternal diet and body composition in determining placental function are likely to provide the basis for public health interventions in this area. However, it is important to note that maternal overfeeding or unbalanced diets may be detrimental to offspring health. Examples of this include the Motherwell cohort, where mothers were advised to eat a high protein low carbohydrate diet during pregnancy and whose children had elevated blood pressure [28]. While body composition is something that is not easily changed, measurement of body composition may allow us to identify pregnancies that are at greater risk and raises the possibility of targeted interventions. More research is required to determine how changing maternal diet or body composition affects the development of the placenta and fetus.

Where an adverse in utero environment cannot be prevented, it could be possible to treat children from highrisk pregnancies to ameliorate or prevent the long-term effects of such an environment. Rats whose mothers were undernourished during pregnancy have altered appetite regulation and became obese, an effect which disappears after a single postnatal treatment with leptin, even when the offspring are fed a high fat diet postnatally. This treatment had no apparent effect on control rats [68]. This experiment demonstrates the potential for identifying and treating infants whose in utero environment was suboptimal. Although pharmacological intervention may be possible, it is hard to imagine how the safety of such an intervention could be demonstrated in humans and attention should be focused on preventive strategies, allowing the development of public health interventions. We should also bear in mind that treatments we currently use could have unintended consequences in later life. In particular, there is evidence that the use of antenatal steroids and assisted reproductive technologies have the potential to adversely affect the offspring. Antenatal steroids have obvious and immediate benefits in premature labor where the benefits out-way concerns about possible increased risk of disease 60 years on. However, given that a single dose of antenatal steroids has been shown to affect glucose tolerance 30 years later, the potential risks of multiple doses of steroids should be kept in mind [69,70]. Similarly, although the evidence to date suggests that assisted reproduction in humans is generally safe, follow up studies of the offspring should be undertaken, given the issues raised by animal studies.

7. Conclusion Placental development and function are crucial determinants of fetal development and impaired fetal development is associated with an increased risk of cardiovascular and metabolic disease in adult life [3]. The placenta influences fetal development through the transport of nutrients, though effects on the fetal cardiovascular system and via its role as an endocrine organ. Placental function will be affected by maternal illnesses, such as diabetes and pre-eclampsia, in ways that impact on the fetus. However, we now think that the placenta is also affected by more subtle signals related to maternal diet and body composition [44,59]. The interplay of environmental signals on placental function is outlined in Fig. 1. These factors may provide the fetus, via the placenta, with information about what life will be like outside the womb and the fetus may adjust its development so that it is best adapted for the external environment. While these adaptations may improve survival in the short term, they may lead to increased rates of disease in later life [7]. Alternatively, a sub-optimal maternal environment may simply impair placental function and fetal development, such that the fetus is predisposed to disease in later life without there being any short term advantage.

R.M. Lewis et al. / Reviews in Gynaecological and Perinatal Practice 6 (2006) 70–79

77

References

Fig. 1. The placenta mediates the effects of maternal environment on the fetus. The environment sensed by the placenta will be a product of multiple maternal influences, including that of the placenta itself, which secretes hormones into the maternal and fetal circulations. Maternal factors affect the function of the placenta both in terms of nutrient transport and endocrinology. Maternal environment may also affect placental structure changing both function and fetal vascular resistance. Changes in placental function may cause redistribution of fetal blood flow and changes in the regulation of gene expression, which may affect the normal pattern of development. Alterations in gene expression and organ development may persist into adult life and have long-term effects on health.

Fetal cardiovascular adaptations, alterations in fetal body composition, and changes in fetal endocrinology and metabolism are thought to have long-term effects on health in postnatal life. There is evidence that the placenta may play an important role in determining these adaptations and developmental changes. Work in this area needs to concentrate on how the maternal environment influences placental function, and on characterization of the effects of placental function on postnatal outcomes. Optimizing placental function is likely to have lifelong health benefits for the offspring. Research directions
We need to determine the effects of maternal pre-pregnancy diet, body composition and lifestyle on placental function and fetal development.
Research is needed into the ways in which in vitro culture conditions may have long-term effects on the embryo.
Long-term monitoring of offspring following antenatal steroid treatment and assisted reproductive technologies is required to properly assess the potential consequences of these procedures.

[1] Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986;1(8489):1077–81. [2] Barker DJ, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. BMJ 1990;301(6746):259–62. [3] Leon DA, Lithell HO, Vagero D, Koupilova I, Mohsen R, Berglund L, et al. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15,000 Swedish men and women born 1915–29. BMJ 1998;317(7153):241–5. [4] Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hankinson SE, Colditz GA, et al. Birth weight and risk of cardiovascular disease in a cohort of women followed up since. BMJ 1997;315(7105):396– 400. [5] Forsen T, Eriksson JG, Tuomilehto J, Teramo K, Osmond C, Barker DJ. Mother’s weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study. BMJ 1997;315(7112):837–40. [6] McMillen IC, Robinson JS. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 2005;85(2):571–633. [7] Gluckman PD, Hanson MA. Living with the past: evolution, development, and patterns of disease. Science 2004;305(5691):1733–6. [8] Lee TM, Zucker I. Vole infant development is influenced perinatally by maternal photoperiodic history. Am J Physiol 1988;255(5 Pt 2):R831–8. [9] Bhargava SK, Sachdev HS, Fall CH, Osmond C, Lakshmy R, Barker DJ, et al. Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N Engl J Med 2004;350(9):865–75. [10] Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC. Dietary protein restriction of pregnant rats induces and folic Acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 2005;135(6):1382–6. [11] Wolff GL, Kodell RL, Moore SR, Cooney CA. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 1998;12(11):949–57. [12] Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science 2001;293(5532):1089–93. [13] Bloomfield FH, Oliver MH, Hawkins P, Campbell M, Phillips DJ, Gluckman PD, et al. A periconceptional nutritional origin for noninfectious preterm birth. Science 2003;300(5619):606. [14] Fleming TP, Kwong WY, Porter R, Ursell E, Fesenko I, Wilkins A, et al. The embryo and its future. Biol Reprod 2004;71(4):1046–54. [15] Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP. Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension. Development 2000;127(19):4195–202. [16] Johnstone JF, Zelsman M, Crozier S, Lewis RM, Inskip H, Challis JR, et al. The relationship between placental 11bHSD-2 and maternal body composition, age and dieting status. J Soc Gynecol Invest 2005;12(2):453. [17] Harding JE. Periconceptual nutrition determines the fetal growth responce to acute maternal undernutrition. Prenat Neonat Med 1997;2:310–9. [18] Leese HJ, Donnay I, Thompson JG. Human assisted conception: a cautionary tale Lessons from domestic animals. Hum Reprod 1998;13(Suppl 4):184–202. [19] Sinclair KD, Young LE, Wilmut I, McEvoy TG. In-utero overgrowth in ruminants following embryo culture: lessons from mice and a warning to men. Hum Reprod 2000;15(Suppl 5):68–86. [20] Richardson MC, Cameron IT, Simonis CD, Das MC, Hodge TE, Zhang J, et al. Insulin and human chorionic gonadotropin cause a shift in the balance of sterol regulatory element-binding protein (SREBP) isoforms toward the SREBP-1c isoform in cultures of human granulosa cells. J Clin Endocrinol Metab 2005;90(6):3738–46.

78

R.M. Lewis et al. / Reviews in Gynaecological and Perinatal Practice 6 (2006) 70–79

[21] Porter R, Humpherson P, Fussing P, Cameron IT, Osmond C, Fleming TP. Metabolic programming of the blastocyst within the uterine environment. Pediatr Res 2003;53:46A. [22] Godfrey K, Robinson S, Barker DJ, Osmond C, Cox V. Maternal nutrition in early and late pregnancy in relation to placental and fetal growth BMJ 1996;312(7028):410–4. [23] Lumey LH. Compensatory placental growth after restricted maternal nutrition in early pregnancy. Placenta 1998;19(1):105–11. [24] Roseboom TJ, van der Meulen JH, van Montfrans GA, Ravelli AC, Osmond C, Barker DJ, et al. Maternal nutrition during gestation and blood pressure in later life. J Hypertens 2001;19(1):29–34. [25] Campbell DM, Hall MH, Barker DJ, Cross J, Shiell AW, Godfrey KM. Diet in pregnancy and the offspring’s blood pressure 40 years later. Br J Obstet Gynaecol 1996;103(3):273–80. [26] Shiell AW, Campbell DM, Hall MH, Barker DJ. Diet in late pregnancy and glucose-insulin metabolism of the offspring 40 years later. BJOG 2000;107(7):890–5. [27] Rush D. Effects of change in maternal energy and protein intake during pregnancy,with special reference to fetal growth. In: Sharp f, Fraser R, Milner R, editors. Fetal growth.. London: Royal College of Obstetricians and Gynaecologists; 1989. p. 203–33. [28] Shiell AW, Campbell-Brown M, Haselden S, Robinson S, Godfrey KM, Barker DJ. High-meat, low-carbohydrate diet in pregnancy: relation to adult blood pressure in the offspring. Hypertension 2001;38(6):1282–8. [29] Ashworth CJ, Antipatis C. Micronutrient programming of development throughout gestation. Reproduction 2001;122(4):527–35. [30] Belizan JM, Villar J, Bergel E, del PA, Di FS, Galliano SV, et al. Longterm effect of calcium supplementation during pregnancy on the blood pressure of offspring: follow up of a randomised controlled trial. BMJ 1997;315(7103):281–5. [31] Gale CR, Martyn CN, Kellingray S, Eastell R, Cooper C. Intrauterine programming of adult body composition. J Clin Endocrinol Metab 2001;86(1):267–72. [32] Cooper C, Eriksson JG, Forsen T, Osmond C, Tuomilehto J, Barker DJ. Maternal height, childhood growth and risk of hip fracture in later life: a longitudinal study. Osteoporos Int 2001;12(8):623–9. [33] Glazier JD, Atkinson DE, Thornburg KL, Sharpe PT, Edwards D, Boyd RD, et al. Gestational changes in Ca2+ transport across rat placenta and mRNA for calbindin9K and Ca(2+)-ATPase. Am J Physiol 1992;263(4 Pt 2):R930–5. [34] Martin RM, Harvey NC, Crozier SR, Javaid MK, Taylor P, Dennison EM, et al. Placental calcium transporter gene (PMCA3) expression predicts intra-uterine bone mineral accrual. J Bone Miner Res 2005;20(Supp 1):F3. [35] Javaid MK, Crozier SR, Harvey NC, Dennison EM, Boucher BJ, Arden NK, et al. Maternal vitamin D status during prgnancy and childhood bone mass at age nine years: a longitudinal study. Lancet 2005;367(9504):36–43. [36] Fall CH, Stein CE, Kumaran K, Cox V, Osmond C, Barker DJ, et al. Size at birth, maternal weight, and type 2 diabetes in South India. Diabet Med 1998;15(3):220–7. [37] Forsen T, Eriksson J, Tuomilehto J, Reunanen A, Osmond C, Barker D. The fetal and childhood growth of persons who develop type 2 diabetes. Ann Intern Med 2000;133(3):176–82. [38] Silverman BL, Rizzo TA, Cho NH, Metzger BE. Long-term effects of the intrauterine environment The Northwestern University Diabetes in Pregnancy Center. Diabetes Care 1998;21(Suppl 2):B142–9. [39] Mi J, Law C, Zhang KL, Osmond C, Stein C, Barker D. Effects of infant birthweight and maternal body mass index in pregnancy on components of the insulin resistance syndrome in China. Ann Intern Med 2000;132(4):253–60. [40] Ravelli AC, van der Meulen JH, Michels RP, Osmond C, Barker DJ, Hales CN, et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet 1998;351(9097):173–7.

[41] Adair LS, Kuzawa CW, Borja J. Maternal energy stores and diet composition during pregnancy program adolescent blood pressure. Circulation 2001;104(9):1034–9. [42] Clark PM, Atton C, Law CM, Shiell A, Godfrey K, Barker DJ. Weight gain in pregnancy, triceps skinfold thickness, and blood pressure in offspring. Obstet Gynecol 1998;91(1):103–7. [43] Godfrey KM, Forrester T, Barker DJ, Jackson AA, Landman JP, Hall JS, et al. Maternal nutritional status in pregnancy and blood pressure in childhood. Br J Obstet Gynaecol 1994;101(5):398–403. [44] Lewis RM, Greenwood SL, Crozier SR, Inskip HM, Hanson MA, Cameron IT, et al. Maternal pre-pregnancy body composition influences placental system A activity. Placenta 2005;26:A46. [45] Wen HY, Abbasi S, Kellems RE, Xia Y. mTOR: a placental growth signaling sensor. Placenta 2005;26(Suppl A):S63–9. [46] Morris SN, Johnson NR. Exercise during pregnancy: a critical appraisal of the literature. J Reprod Med 2005;50(3):181–8. [47] Clapp III JF, Kim H, Burciu B, Schmidt S, Petry K, Lopez B. Continuing regular exercise during pregnancy: effect of exercise volume on fetoplacental growth. Am J Obstet Gynecol 2002;186(1):142–7. [48] Mayhew TM, Charnock-Jones DS, Kaufmann P. Aspects of human fetoplacental vasculogenesis and angiogenesis III. Changes in complicated pregnancies. Placenta 2004;25(2–3):127–39. [49] Godfrey K, Walker-Bone K, Robinson S, Taylor P, Shore S, Wheeler T, et al. Neonatal bone mass: influence of parental birthweight, maternal smoking, body composition, and activity during pregnancy. J Bone Miner Res 2001;16(9):1694–703. [50] Javaid MK, Godfrey KM, Taylor P, Shore SR, Breier B, Arden NK, et al. Umbilical venous IGF-1 concentration, neonatal bone mass, and body composition. J Bone Miner Res 2004;19(1):56–63. [51] Jones G, Riley M, Dwyer T. Maternal smoking during pregnancy, growth, and bone mass in prepubertal children. J Bone Miner Res 1999;14(1):146–51. [52] Lin FJ, Fitzpatrick JW, Iannotti CA, Martin DS, Mariani BD, Tuan RS. Effects of cadmium on trophoblast calcium transport. Placenta 1997;18(4):341–56. [53] Thornburg KL. Physiological development of the cardiovascular system in utero. In: Barker D, editor. Fetal origins of cardiovascular and lung disease. New York: Marcel Dekker; 2001. p. 97–139. [54] Behrman RE, Lees MH, Peterson EN, De Lannoy CW, Seeds AE. Distribution of the circulation in the normal and asphyxiated fetal primate. Am J Obstet Gynecol 1970;108(6):956–69. [55] Rudolph AM. The fetal circulation and its response to stress. J Dev Physiol 1984;6(1):11–9. [56] Burrage D, Braddick L, Noakes D, Hanson M, Green LR. Fetal cardiovascular responses to acute hypoglycaemia are modified by early gestation nutrient restriction in sheep. J Soc Gynecol Invest 2005;12(2):113A. [57] Kiserud T, Stratford L, Hanson MA. Umbilical flow distribution to the liver and the ductus venosus: an in vitro investigation of the fluid dynamic mechanisms in the fetal sheep. Am J Obstet Gynecol 1997;177(1):86–90. [58] Naeye RL. Do placental weights have clinical significance? Hum Pathol 1987;18(4):387–91. [59] Haugen G, Hanson M, Kiserud T, Crozier S, Inskip H, Godfrey KM. Fetal liver-sparing cardiovascular adaptations linked to mother’s slimness and diet. Circ Res 2005;96(1):12–4. [60] O’Brien P, Wheeler T, Barker d. Fetal programming-influences on development and disease in later life London: RCOG Press; 1999. [61] Edwards LJ, Coulter CL, Symonds ME, McMillen IC. Prenatal undernutrition, glucocorticoids and the programming of adult hypertension. Clin Exp Pharmacol Physiol 2001;28(11):938–41. [62] Langley Evans SC, Phillips GJ, Benediktsson R, Gardner DS, Edwards CR, Jackson AA, et al. Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat. Placenta 1996;17(2-3):169–72.

R.M. Lewis et al. / Reviews in Gynaecological and Perinatal Practice 6 (2006) 70–79 [63] Pettitt DJ, Nelson RG, Saad MF, Bennett PH, Knowler WC. Diabetes and obesity in the offspring of Pima Indian women with diabetes during pregnancy. Diabetes Care 1993;16(1):310–4. [64] Jansson T, Wennergren M, Powell TL. Placental glucose transport and GLUT 1 expression in insulin-dependent diabetes. Am J Obstet Gynecol 1999;180(1 Pt 1):163–8. [65] Jansson T, Ekstrand Y, Wennergren M, Powell TL. Placental glucose transport in gestational diabetes mellitus. Am J Obstet Gynecol 2001;184(2):111–6. [66] Wallace J, Bourke D, Da SP, Aitken R. Nutrient partitioning during adolescent pregnancy. Reproduction 2001;122(3):347–57. [67] Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, et al. Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 2002;417(6892):945–8. [68] Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A, et al. Neonatal leptin treatment reverses developmental programming. Endocrinology 2005. [69] Dalziel SR, Walker NK, Parag V, Mantell C, Rea HH, Rodgers A, et al. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet 2005;365(9474):1856–62. [70] Sloboda DM, Challis JR, Moss TJ, Newnham JP. Synthetic glucocorticoids: antenatal administration and long-term implications. Curr Pharm Des 2005;11(11):1459–72. [71] Eriksson J, Forsen T, Tuomilehto J, Osmond C, Barker D. Fetal and childhood growth and hypertension in adult life. Hypertension 2000;36(5):790–4. [72] Thame M, Osmond C, Wilks RJ, Bennett FI, Farlane-Anderson N, Forrester TE. Blood pressure is related to placental volume and birth weight. Hypertension 2000;35(2):662–7. [73] Law CM, Barker DJ, Bull AR, Osmond C. Maternal and fetal influences on blood pressure. Arch Dis Child 1991;66(11):1291–5. [74] Moore VM, Miller AG, Boulton TJ, Cockington RA, Craig IH, Magarey AM, et al. Placental weight, birth measurements, and blood pressure at age 8 years. Arch Dis Child 1996;74(6):538–41.

79

[75] Taylor SJ, Whincup PH, Cook DG, Papacosta O, Walker M. Size at birth and blood pressure: cross sectional study in 8-11 year old children. BMJ 1997;314(7079):475–80. [76] Barker DJ, Godfrey KM, Osmond C, Bull A. The relation of fetal length, ponderal index and head circumference to blood pressure and the risk of hypertension in adult life. Paediatr Perinat Epidemiol 1992;6(1):35–44. [77] Moore VM, Cockington RA, Ryan P, Robinson JS. The relationship between birth weight and blood pressure amplifies from childhood to adulthood. J Hypertens 1999;17(7):883–8. [78] Whincup P, Cook D, Papacosta O, Walker M. Birth weight and blood pressure: cross sectional and longitudinal relations in childhood. BMJ 1995;311(7008):773–6. [79] Martyn CN, Barker DJ, Jespersen S, Greenwald S, Osmond C, Berry C. Growth in utero, adult blood pressure, and arterial compliance. Br Heart J 1995;73(2):116–21. [80] Martyn CN, Barker DJ, Osmond C. Mothers’ pelvic size, fetal growth, and death from stroke and coronary heart disease in men in the UK. Lancet 1996;348(9037):1264–8. [81] Forsen T, Eriksson JG, Tuomilehto J, Osmond C, Barker DJ. Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study. BMJ 1999;319(7222): 1403–7. [82] Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ. Early growth and coronary heart disease in later life: longitudinal study. BMJ 2001;322(7292):949–53. [83] Phipps K, Barker DJ, Hales CN, Fall CH, Osmond C, Clark PM. Fetal growth and impaired glucose tolerance in men and women. Diabetologia 1993;36(3):225–8. [84] Martyn CN, Meade TW, Stirling Y, Barker DJ. Plasma concentrations of fibrinogen and factor VII in adult life and their relation to intra-uterine growth. Br J Haematol 1995;89(1): 142–6. [85] Barker DJ, Osmond C, Meade TW. Early growth and clotting factors in adult life. BMJ 1992;304(6833):1052.