The famished foetus in the land of plenty

The concept of developmental plasticity and foetal programming has been with us for almost 25 years.¹ While much of the discourse in the 1990s focused on establishing the existence of links between poor maternal nutrition, low birthweight and the risk of chronic disease, attention has turned in recent years to the specific nutrient deficits which mediate these effects, and the manner in which they do so. 

Structural constituents

For many of the nutrients in question, their importance in foetal development might be intuitively deduced from their role as structural constituents of tissue. For example, protein is the major building block of most lean tissue, be it foetal, placental or maternal. Similarly, iron is an integral component of the haemoglobin generated to facilitate maternal volaemic expansion in pregnancy, while the essential fatty acid docosahexaenoic acid (DHA) is a key element of brain and neurological tissue, and calcium and vitamin D are intimate effectors of bone mineralisation. In these circumstances, it is perhaps unsurprising that deficiency of these nutrients is associated with aberrations in the anabolic syntheses of their respective tissues.

However, what is now becoming clear is that many micronutrients play critical roles in developmental plasticity through their activity as regulators of tissue synthesis at sensitive stages of gestation.

Regulatory nutrients

Folate

Perhaps the best-established of these regulatory nutrients is folate. In 1991, the Vitamin Research Group of the Medical Research Council (MRC) in the UK published irrefutable proof that daily supplementation with 400µg of folic acid peri-conceptionally and for the first trimester of pregnancy reduced the risk of neural tube defect (NTD) births by approximately 72%.² This was a landmark study which gave further credence to the belief that not just maternal diet, but also specific nutrients within that maternal diet, could have a demonstrable and measurable impact on foetal development in utero. Because the methylation activities of folate were already well established, this work also gave important clues about the mechanism by which folic acid might confer its protective effect. 

Furthermore, it set the scene for research which highlighted potential roles for other ‘methylation nutrients’ such as vitamin B12 in this process,³ and also raised the possibility that if functional folate deficiency in early pregnancy elicited such gross abnormalities in somatic growth, less severe deficiency of folate and other ‘methylation nutrients’ might yield impairments in one-carbon metabolism, which resulted in more subtle, yet ultimately devastating, disturbances of normal cellular growth.⁴

Animal studies have now shown that the offspring of rats fed folate-deficient diets during pregnancy have a significantly increased risk of both colorectal cancer⁵ and breast cancer⁶ in adulthood. Further rat studies have demonstrated that the risk of colorectal cancer in offspring may be ameliorated by as much as 64% when the maternal diet is supplemented with moderate amounts of folic acid,⁷ presumably due to enhanced methylation and silencing of oncogenic gene loci in the colonic epithelium. 

Apart from the putative role of these methylation nutrients in oncogenesis, there is further evidence that maternal deficiency of folate and other B vitamins can elicit changes in methylation status which predispose offspring to various components of the metabolic syndrome, including hypertension and insulin resistance,⁸ dyslipidaemia and increased sensitivity to a high-fat diet,⁹ and possibly even obesity itself.¹⁰ Although methylation and the B vitamins which influence it are clearly potent epigenetic determinants of foetal outcome, it would be wrong to assume that they are the only nutrients of importance in this regard. 

Much evidence now suggests that many other micronutrients act as tissue-specific gene transcription factors at various stages of gestation. It is clear that maternal deficiency of these nutrients at sensitive periods of foetal organogenesis can also permanently affect the development, structure and function of tissues which rely on their effects. 

Vitamin A

For example, maternal deficiency of vitamin A in the form of retinoic acid has been associated with impaired myocardial development,¹¹ reduced nephron endowment in the neonatal kidney¹² and impaired foetal pancreatic islet development and β-cell mass.¹³ These predispose to arrhythmia, hypertension and insulin insufficiency, respectively, increasing the risk of later vascular disease. Additionally, low maternal vitamin A status has been strongly associated with anomalous lung development,¹⁴ a further impediment to cardio-respiratory health. 

Vitamin D

Maternal vitamin D deficiency has also been implicated in foetal left ventricular hypertrophy,¹⁵ a known risk factor for cardiac arrhythmia, as well as impaired brain development in utero.¹⁶ Perhaps more expectedly, it has also been linked to impaired skeletal development. Even in this instance there are unanticipated mechanisms at work, however, with research now demonstrating that maternal vitamin D status influences the protein architecture of the foetal osteoid¹⁷ as well as its mineralisation.¹⁸

This suggests that intra-uterine vitamin D deficiency creates deficits in skeletal development which are not retrievable by subsequent correction of this nutritional insult. Indeed, the latter study showed that total bone mineral content (a reflection of bone mass and mineralisation) in children born to women with low vitamin D status remained lower at nine years of age, implying a lifelong increase in the risk of osteoporosis. 

Zinc

Other nutrient deficiencies which impact upon tissue growth and organ development in utero include minerals such as iron and zinc. Iron deficiency is thought to inhibit the activity of insulin-like growth factor and its receptors, and may also increase foetal exposure to circulating maternal cortisol.¹⁹ Both of these contribute to intra-uterine growth restriction. Gestational iron deficiency has also been implicated in aberrant myocardial development and vascularisation,²⁰ impaired nephrogenesis and glomerular development,²¹ increased visceral adiposity²² and hypertension.^22,23

Zinc deficiency in pregnancy has also been linked to a number of metabolic and structural abnormalities in the foetus, including reduced insulin-like growth factor activity,²⁴ disrupted myocardial development,²⁵ oliogonephropathy and hypertension,^26,27 and increased body fat mass and irreversible impairment of glucose-induced insulin secretion.²⁸

Impact of gestational obesity and diabetes

Aside from the developmental abnormalities created by these micronutrient deficits, there are also emerging data which have articulated the impact of gestational obesity and diabetes on pregnancy outcomes.²⁹ The deleterious effects which arise in the adult offspring of such pregnancies are collectively referred to as ‘metabolic memory’, and include disruptions in glycaemic control and lipid metabolism, degraded antioxidant status and disturbances in immune function,³⁰ as well as the legacy effects of impaired vitamin D and folate status.^29,31

Nutritional intake in Irish women

Recent evidence suggests that nutrient intakes among young Irish women are far from optimal. The 2011 National Adult Nutrition Survey (NANS)³² found that, among 18-35-year-old women, median intakes of vitamin D, folate, calcium and iron were all below their respective recommended dietary allowances (RDA), while vitamin A intakes were only marginally adequate. 

In a study conducted at Ireland’s National Maternity Hospital among 285 pregnant women aged 20-41 years, while mean intakes of vitamin A and vitamin C exceeded the RDA for pregnancy, 35% and 34% of respondents, respectively, had insufficient intakes of these nutrients.³³ This study also showed that more than 95% of these pregnant women had insufficient intakes of folate and vitamin D, while 85-90% had inadequate intakes of iron and calcium. There are also data which indicate that these micronutrient inadequacies may be significantly more pronounced among socially disadvantaged young women in Ireland, where insufficient intakes of vitamin A, folate, vitamin C, vitamin D, iron and calcium are particularly prevalent.³⁴ 

Superimposed on these endemic micronutrient inadequacies, there has been a marked increase in the prevalence of obesity and metabolic ill health among pregnant women in Ireland. Recent research has estimated that 21% of Irish women are obese and a further 37% are overweight at presentation for their booking obstetric visit,³⁵ while the Atlantic Diabetes in Pregnancy Study revealed that 12.4% of their obstetric population in Galway had gestational diabetes.³⁶ 

Summary

Ireland continues to experience some of the highest levels of obesity, diabetes, cardiovascular disease, cancer and osteoporosis seen anywhere in the world. While the merit of addressing the nutritional antecedents of these disorders in the adult population is self-evident, the correction of these deficits among our young women before and during pregnancy must now be embraced as a critical public health priority if our long-term burden of chronic disease is to be effectively tackled.  

References

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