Placental Insufficiency and Fetal Origins of Metabolic Diseases

Poor fetal growth and development can occur in the offspring of adequately nourished women or women with normal metabolic milieu. It is believed that placental insufficiency may be largely responsible for the growth restriction observed in this subgroup of offspring. Placental transfer of nutrients and metabolites is pivotal to fetal growth and development. Interference within this transfer process can lead to placental insufficiencies and a disruption to fetal nutrition, hence disturbing the normal growth of the developing fetus.

Placental insufficiency has been artificially produced in both rats by uterine artery ligation and in sheep by placental embolization. Both models have demonstrated intrauterine growth restriction to be a direct consequence of functional disturbances within the pla-cental nutrient transfer process. To date, these studies have mainly focused on the detrimental effects present during fetal and early postnatal life. Further investigations are indeed warranted to establish whether metabolic disturbances persist into adult life.

Summary and Conclusions

Studies investigating the fetal origins of metabolic disease have confirmed a pivotal role for the in utero environment mediating the relationship between poor fetal growth and the subsequent increased risk of developing metabolic diseases in adult life. Disturbances within the critical in utero environment may be induced by maternal nutritional insults, abnormalities within the maternal metabolic milieu, or by pla-cental insufficiencies. Animal models have been developed in an attempt to elucidate the mechanistic basis of this adverse metabolic programing. However, there is still an urgent need to explore further the pathogenic mechanisms involved in order to allow suitable intervention studies to be initiated.

The escalating epidemic of obesity and type 2 diabetes may be a consequence of a vicious cycle (Figure 2). Exposure to an abnormal in utero environment may predispose the offspring to the

In utero insult Abnormal metabolic programing

In utero insult Abnormal metabolic programing

Conflict between in utero and postnatal environments

Figure 2 The vicious cycle that may be responsible for the increasing prevalences of metabolic diseases.

premature development of metabolic diseases. Consequently, the female offspring that are programed to develop the metabolic disease at a young age may, when pregnant, perpetuate this cycle. Generation after generation then has the subsequent risk of also prematurely developing metabolic diseases such as obesity and type 2 diabetes.

The ultimate aim in medical research is to prevent human disease. As maternal nutrition and their metabolic milieu status appears to have such a sizeable influence over the correct functioning of the metabolic processes in the offspring, there is an urgent need to establish ideal nutritional recommendations for pregnant and lactating women. Additionally, ways to treat the occurrence of pla-cental insufficiencies successfully need to be identified. It is of utmost importance to optimize the growth, development, and metabolic programing of the offspring during the critical phase of in utero and early life. The development of possible prevention and treatment strategies may therefore aid in combating the epidemic prevalence of metabolic diseases such as obesity, coronary heart disease, and type 2 diabetes.

See also: Alcohol: Absorption, Metabolism and Physiological Effects; Disease Risk and Beneficial Effects. Anemia: Iron-Deficiency Anemia. Cancer: Effects on Nutritional Status. Diabetes Mellitus: Etiology and Epidemiology; Classification and Chemical Pathology; Dietary Management. Early Origins of Disease: Non-Fetal. Famine. Fats and Oils. Iron. Low Birthweight and Preterm Infants: Causes, Prevalence and Prevention; Nutritional Management. Pregnancy: Nutrient Requirements; Energy Requirements and Metabolic Adaptations. Protein: Requirements and Role in Diet.

Further Reading

Barker DJP (1998) Mothers, Babies and Disease in Later Life, 2nd edn. Edinburgh, New York: Churchill Livingstone.

Bauer MK, Harding JE, Bassett NS, Breier BH, Oliver MH, Gallaher BH, Evans PC, Woodall SM, and Gluckman PD (1998) Fetal growth and placental function. Molecular and Cellular Endocrinology 140: 115-120.

Bertram CE and Hanson MA (2001) Animal models and programming of the metabolic syndrome. British Medical Bulletin 60: 103-121.

Dabelea D, Knowler WC, and Pettitt DJ (2000) Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. Journal of Maternal-Fetal Medicine 9: 83-88.

Drake AJ and Walker BR (2004) The intergenerational effects of fetal programming: non-genomic mechanisms for the inheritance of low birth weight and cardiovascular risk. Journal of Endocrinology 180: 1-16.

Godfrey KM and Barker DJP (2001) Fetal programming and adult health. Public Health Nutrition 4(2B): 611-624.

Figure 2 The vicious cycle that may be responsible for the increasing prevalences of metabolic diseases.

Hales CN and Ozanne SE (2003) The dangerous road of catch-up growth. Journal of Physiology 547(1): 5-10.

Harding JE (2001) The nutritional basis of fetal origins of adult disease. International Journal of Epidemiology 30: 15-23.

Holness MJ, Langdown ML, and Sugden MC (2000) Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of type 2 diabetes mellitus. Biochemical Journal 349: 657-665.

Khan IY, Lakasing L, Poston L, and Nicolaides KH (2003) Fetal programming for adult disease: where next? The Journal of Maternal-Fetal and Neonatal Medicine 13: 292-299.

Newnham JP, Moss TJM, Nitsos I, Sloboda DM, and Challis JRG (2002) Nutrition and the early origins of adult disease. Asia Pacific Journal of Clinical Nutrition 11(supplement): S537-S542.

Ong KKL and Dunger DB (2001) Developmental aspects in the pathogenesis of type 2 diabetes. Molecular and Cellular Endocrinology 185: 145-149.

Ozanne SE and Hales CN (2002) Early programming of glucose-insulin metabolism. Trends in Endocrinology and Metabolism 13(9): 368-373.

Roseboom TJ, van der Meulen JHP, Ravelli ACJ, Osmond O, Barker DJP, and Bleker OP (2001) Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Molecular and Cellular Endocrinology 185: 93-98.

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