Necrotizing Enterocolitis in Rat Offspring Exposed to Placental Insufficiency: Role of Aldosterone, Oxidative Stress and Leptin

NEC is an acute inflammatory disease of the intestine of neonates and can result in intestinal necrosis, systemic sepsis and multi-system organ failure. The incidence of NEC is inversely related to birth weight and gestational age, and when intestinal necrosis is already stablished the process is rarely reversible and mortality rates can reach up to 50-80% in severe cases. Despite, the effort of physicians and researchers the morbidity and mortality of NEC have increased in the last decade, with more severe complications and poor response to treatment. This is partially explained by the improvement in health care practices to maintain alive premature infants, but it does not explain individual differences in outcomes within the same institutional setting. One of the factors involved in infant’s susceptibility to develop NEC is perinatal morbidity, which is strongly associated with fetal-placental unit function. Currently, there are no identified factors linking placental function and the risk to develop NEC; therefore, identification of these factors could help to develop perinatal preventive strategies to decrease the morbidity and mortality associated with NEC.

Experimental and epidemiological studies suggest a multifactorial etiology for NEC including predisposing factors such as enteral feeding, hypoxia and or hypothermia, but with unclear pathogenesis. We induced NEC in premature low birth weight (LBW) rat’s offspring from a rat model of placental insufficiency. Premature birth is the major determinant of NEC. Increased oxidative stress is among the factors associated with NEC in premature infants. Oxidative stress has been observed in several maternal conditions associated with placental insufficiency. Experimental studies report a direct correlation between increased oxidative stress and Aldosterone plasma levels in newborns.

 Moreover, epidemiological studies reported increases in plasma aldosterone levels associated with LBW and preterm delivery. Aldosterone can regulate oxidative stress, hence it can be suggested that increased levels of aldosterone and oxidative stress may be associated with NEC in premature and low birth weight infants exposed to placental insufficiency. Aldosterone is involved in the developmental changes of Na+ electrogenic transport in immature intestines , resulting in alteration in the homeostasis of gastrointestinal mucus barrier, and abnormal microbial colonization of the gastro intestinal tract with exacerbated inflammatory response and necrosis. The digestive and absorptive capacity of the gastrointestinal tract is also compromised in premature infants.

Experimental studies report that postnatal leptin treatment enhances digestive function in intrauterine growth restricted offspring, by increasing cell mitosis and promoting growth of intestinal mucosa. Leptin levels were reduced in animal models of placental insufficiency induced by reduced uterine perfusion. Therefore, leptin levels at birth could be associated with growth capacity and maturation of gastrointestinal tract in newborns.