Human and animal studies have consistently shown that maternal diet during pregnancy has a profound impact on fetal growth and future risk of chronic disease. Children born to poorly nourished (high protein and fat intake) mothers have a significantly higher incidence of coronary heart disease and hypertension in adulthood [27
]. As mentioned above, recent studies from the Helsinki Birth Cohort demonstrate that placental size and shape, conditioned by maternal height, are also important risk factors for offspring hypertension [8
]. Analyses of maternal diets in relation to fetal outcomes in the Southampton Women’s Survey cohort have demonstrated that placental weight is inversely related to energy intake in early pregnancy, a condition also related to an infant’s thinness at birth [29
]. Farmers have long recognized that different nutrition regimens can be used to manipulate placental growth and lamb size. Farmers will often graze well-fed ewes on poor pastures at mid-pregnancy in order to increase placental weight and birth size of the lamb [31
]. This reduction in nutritional supply leads to a potentially adaptive increase in placental growth and nutrient transport capacity. Despite the importance of diet during pregnancy, a mother’s nutritional history has a profound influence on pregnancy outcomes. Undernutrition in ewes stimulates placental growth only in those ewes that were well nourished before
]. Interestingly, women with low pre-pregnancy body weight give birth to smaller babies compared to women of average weight, even if their weight gains during pregnancy are similar [32
]. This suggests that pre-pregnancy nutritional status is as important to placental function and fetal growth as is maternal diet during pregnancy.
A woman’s periconceptional height and body mass index (BMI) are markers of her nutritional history [32
]; maternal BMI predicts birth weight [32
] and childhood fat mass of her offspring [34
]. Maternal BMI also has a significant impact on a child’s risk of developing type 2 diabetes and is a major risk factor for coronary artery disease (see ) [6
]. Obese women (BMI >30 kg/m2
) who are pregnant have an increased risk of gestational diabetes, venous thromboembolism, preeclampsia and fetal loss among other poor outcomes [38
]. Markers of poor placental function, such as the plasminogen activator inhibitor (PAI)-1/PAI-2 ratio, are elevated in obese women [39
]. Furthermore, reports of inflammation [40
] and nitrative stress [41
] in obese placentas (similar to preeclamptic placentas) may explain the increased risk for fetal morbidity. Conversely, low maternal pre-pregnancy weight (BMI<20) is associated with fetal growth restriction and preterm delivery [42
]. The degree to which the placenta is responsible for the slowed fetal growth in these pregnancies has not been determined, but is likely to play a key role.
Figure 2 Standardized mortality ratios (SMR) for coronary heart disease for adult offspring of short women (<158 cm) according to maternal BMI at term. Data from Forsen et al. .
Given that the placenta regulates nutrient flow from the mother to the fetus, one would presume that the placenta plays a central role in the programming of cardiovascular disease. If true, taking into account the above studies, the placenta must be sensitive to maternal nutritional markers (i.e. diet and body composition). Consistent with this notion, intrauterine growth restriction reported in offspring of rats fed a low protein diet during pregnancy was preceded by a decrease in placental amino acid transporter activity and gene expression [43
] indicating that placental function is sensitive to maternal nutrition, leading to changes in fetal growth. Intrauterine growth restriction in humans (below 10th
percentile) is associated with increases in placental inflammatory cytokines, alterations in angiogenesis, nutrient metabolism-related genes and decreases in placental growth factor gene expression [44
]. In addition to nutritional deficits as associated with growth restriction, the placenta is sensitive to the ‘over-nourished’ state. Obese women have elevated placental inflammatory cytokine expression [40
] and nitrative stress [41
] which can impact placental nutrient transport. Pro-inflammatory molecules such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α stimulate system A amino acid transport by cytotrophoblast cells in vitro
]; conversely, a previous study found that the pro-inflammatory IL-1β inhibited this system in cytotrophoblasts [48
]. Thus, although evidence suggests that inflammatory cytokines alter placental nutrient transport, further studies are required to determine the effect of a general pro-inflammatory state on placental function.
Little is known about how the placenta “senses” maternal nutritional status. Jansson et al.
have proposed the concept of a “nutrient sensor” within the placenta which is linked to nutrient transport and cell growth pathways and may be “dialed” up or down in response to placental nutrient supply [49
]. This idea is very attractive. These authors suggested that the mammalian target of rapamycin (mTOR) plays this role. Indeed, placental mTOR stimulates amino acid transporters, cell growth and differentiation, is responsive to amino acid levels and is associated with fetal growth. Maternal nutrition is also likely to have an important effect on epigenetic mechanisms within the placenta [50
]; epigenetic control of placental gene expression and function is an additional potential ‘nutrient sensor’ mechanism. Furthermore, nutrient transporters have been shown to be responsive to inflammatory cytokines in several tissues, including the placenta [47
] and thus a pro-inflammatory state, as associated with maternal obesity is a potential contributing factor to modified nutrient transport in the placenta.
Recent evidence suggests that maternal body composition during the periconceptional period affects placental development from the blastocyst stage onward. Early nutritional conditions may affect placental nutrient transport, metabolism, inflammation, oxidative stress and blood flow. A number of animal models using either “undernutrition” or “excessive nutrition” support this view [43
]. In humans, placental oxidative stress is associated with poor placental vascular function and preeclampsia. IUGR fetuses also have elevated oxidative stress but at present, the contribution made by maternal body composition and diet to feto-placental oxidative stress is not known. Another understudied area is placental function in low risk obese pregnancies. Much attention has been paid to the effects of diabetes on placental function and fetal growth. While it is well known that gestational diabetes often accompanies obesity, the separate effects of obesity and diabetes on placental function require further investigation. Wijendran et al.
suggest that maternal BMI explains the association between gestational diabetes and fetal omega-3 fatty acid deficiency [52
]. This could be due to the effects on placental lipid transport, given that circulating maternal omega-3 levels were increased. Both maternal obesity and neonatal omega-3 fatty acid deficiencies are known risk factors for development of future cardiovascular disease; the placenta potentially plays a critical role in this pathway.