Nutritional and Environmental Effects on the Fetal Circulation

Introduction

The fetus depends on its cardiovascular system for growth and development. Vascular growth is closely linked to tissue growth, and the fetal heart must develop in relation to the venous return (preload), primarily from the umbilical vein, and the similar arterial pressures in the pulmonary trunk and the aortic arch (afterload). This matching of cardiovascular function to growth is important in late gestation when the fetus may need to cope with placental insufficiency. ^, But the matching is also important for the way in which the fetus responds and adapts to many aspects of the environment, like changes in fetal nutrition (e.g., glucose, amino acid, or micronutrient provision).

The unborn baby is adaptable to many aspects of maternal modifiable environment, and this provides plausible new explanations, aside from adult lifestyle or inherited genes, for risk of noncommunicable diseases (NCDs), such as the cardiovascular diseases (CVDs) that caused death for an estimated 17.9 million people worldwide in 2016. It is now widely acknowledged by scientists and nongovernment agencies that the first 1000 days of development (conception to 2 years old) is a period of high susceptibility to the environment, and this period will influence an individual’s response to their adult environment and lifestyle, hence influencing in part their risk of disease. It might explain why not all individuals have the same risk of NCDs, even if they are in the same environment. Poverty, insecurity, and environmental toxins are some of the threats to the nutritional status of women before and during pregnancy, whether that makes the mother underweight, overweight, or obese. These pose potential health challenges for mothers and their children over their life course.

This chapter explores what is known about the effect of prenatal nutrition on cardiovascular developmental mechanisms in relation to growth and puts this into a life course perspective that could impact how pregnancies are managed clinically.

Epidemiologic Observations

Considerable evidence has now accumulated that small or disproportionate size at birth is associated with increased risk of coronary heart disease, hypertension, and stroke in later life. The studies of Barker and colleagues in adult men and women showed that the standardized mortality ratio for coronary artery disease increased in a graded manner across the normal birth weight range. Numerous studies have linked low birth weight to metabolic syndrome or to its components (defined as fasting plasma glucose concentration more than 6 mmol/L [108 mg/dL], blood pressure more than 130/85 mmHg, fasting plasma triglyceride concentration greater than 1.7 mmol/L [150 mg/dL], plasma high-density lipoprotein cholesterol concentration less than 1.1 mmol/L [40 mg/dL], and, in men, waist measurement greater than 102 cm). A meta-analysis of the blood pressure effect suggests that a 1-kg increase in birth weight is associated with a decrease of 2 mm Hg in systolic blood pressure in later life. Inevitably, the size and nature of these studies differ enormously, and the effect of study size has been questioned because larger studies (where birth weight is more likely to have been self-reported than actually measured) show weaker associations between birth weight and blood pressure than do smaller studies. Nonetheless, the direction of the effect (small size at birth predicting higher blood pressure in later life) is not under question, even if the magnitude of the effect is debated. Thus a major part of an individual’s predisposition to CVD appears to be established during early development in response to the environment, the so-called Developmental Origins of Health and Disease (DOHaD) concept.

Birth size is a measure of the fetal environment but does not give a full picture of fetal growth. Importantly, some effects of maternal diet on the offspring’s cardiovascular system (e.g., carotid intima-media thickness ) are not necessarily associated with low birth weight, suggesting that the processes operate across the normal birth weight range. For these reasons, it is vital that physiologic studies are conducted to understand the mechanisms underlying the priming of cardiovascular function by life events in utero. Moreover, it is highly unlikely that appropriate intervention measures to prevent the progression to disease (i.e., metabolic syndrome) in susceptible individuals can be developed without an understanding of the mechanisms underlying the development of the disease. Interventions may have enormous implications for public health; calculations based on epidemiologic studies conducted in Finland suggest that if all male offspring could be prevented from being thin at birth and thin and short at 1 year of age, the incidence of coronary arterial disease would be halved. The implications are not confined to high-income societies because the phenomenon exists in low-to-middle-income societies across the normal birth weight range, which averages 1 kg less than in developed societies. The problem is also more acute in low socioeconomic position groups in high-income countries.

In many populations worldwide, a substantial proportion of women of reproductive age are obese or overweight (>50% in the United Kingdom). Gestational diabetes mellitus and maternal obesity/weight gain are associated with long-term adverse consequences in the offspring and subsequent generations. These implications include increased offspring obesity, which tracks from intrauterine into adult life, and poor health in later life, including CVD risk. Human data suggest that although gestational weight gain is associated with adverse cardiovascular risk factors at 9 years, pre-pregnancy weight has a greater overall impact. Guidelines on pregnancy weight management issued in 2010 aim to break the cycle of obesity and reduce the incidence of CVD. Probably those at greatest risk throughout the world belong to transitional societies, in which, for example, children from agrarian societies in the developing world move to cities as adolescents. These considerations may explain the epidemic in coronary arterial disease and in type 2 diabetes that is developing in the Indian subcontinent, for example.

Developmental responses by the fetus to overabundant or lean maternal environments, such as the cardiovascular responses explored in this chapter, might be immediate coordinated responses that are good for survival. However, later in this chapter we will also describe the idea that under some circumstances fetal adaptive responses could give offspring a survival advantage in the postnatal environment in which they predict that they will live.

Genes Versus Environment

Many reasons exist for believing that the high prevalence of NCDs is not purely genetic in origin. The most obvious is that changes in the incidence of metabolic syndrome within a generation cannot be due purely to genetic (heritable) traits. Moreover, the maternal and paternal genetic contributions to fetal growth and to outcome measures such as systolic blood pressure in adulthood are highly dissimilar; in a study of adults in Preston, United Kingdom, systolic pressure was inversely related to maternal but not to paternal birth weight.

The processes most likely involved in mediating the maternal versus paternal genomic effects on development involve imprinting. Of the range of genes that are imprinted, the H19 / IGF2 cluster has received particular attention. The insulin-like growth factor (IGF)-2 peptide, which is paternally expressed, is a potent stimulator of fetal cell division and differentiation—showing how the paternal genome drives growth in various key tissues, such as the fetal liver and growth and nutrient transport in the placenta. The type 2 IGF receptor, which is maternally expressed, serves as a clearance receptor that modulates IGF-2 peptide action in the tissues—showing how the maternal genome can down-regulate growth in accordance with the maternal body habitus. This observation is consistent with the concept of maternal constraint of fetal growth, which was highlighted by the pioneering studies of Hammond and Walton, in which Shire horses were crossed with Shetland ponies, and confirmed by more recent studies in horses and humans. ^, It is therefore clear that the trajectory of growth in early life is determined by maternal and environmental factors acting to regulate the gene expression of the early embryo. First-trimester growth in the human sets the trajectory for later fetal growth and predicts the risk of low birth weight.

Imprinting processes are a subset of the broader epigenetic processes that are now believed to provide a mechanism whereby undernutrition during development can influence gene expression and the cardiovascular or metabolic phenotype into mature adulthood (see “Mechanisms of Fetal Cardiovascular Response to the Environment”), ^, ideas consistent with those of the Encyclopedia of DNA Elements (ENCODE) Consortium, which is looking beyond the exome to the function of all other parts of the human genome. Of importance, these processes involve not simply imprinted genes but a much wider range of the genome, which appears to be under graded epigenetic control throughout development. Numerous processes have been discovered that modify gene expression, and the production of the proteins that confer the phenotype on the organism. These go beyond genetic processes (e.g., single-nucleotide polymorphisms, deletions, or multiple repeats) to epigenetic modifications such as DNA methylation, changes in histone structure, posttranscriptional regulation by small noncoding RNAs, and also the many transcription factors that act to modify gene transcription and the processes that control the half-life of messenger RNA. So this is a way for aspects of the early developmental environment, such as nutrition, to have a persistent lifelong effect without changing the inherited DNA sequence. The effect might not be immediate; instead, it could set up later life responses by genes to transcription factors. This idea is explored further later in this chapter.

Environmental Stimuli

In investigating the interaction between gene and environment, one should take a life course perspective in considering the influence of maternal diet, body composition, social status, smoking, exposure to environmental toxicants, the effect of the tubal and uterine fluid environment on the early embryo, the development of the placenta, fetal adaptations, and postnatal effects that may exacerbate the problem. A growing area of research also highlights that environmental toxicant or nutritional effects on the father, via seminal plasma or the sperm, can effect male reproductive function and cardiovascular function across successive generations of offspring. ^,