Intrauterine Growth Restriction: Need to Improve Diagnostic Accuracy and Evidence for a Key Role of Oxidative Stress in Neonatal and Long-Term Sequelae.

Intrauterine growth restriction (IUGR) and being small for gestational age (SGA) are two distinct conditions with different implications for short- and long-term child development. SGA is present if the estimated fetal or birth weight is below the tenth percentile. IUGR can be identified by additional abnormalities (pathological Doppler sonography, oligohydramnion, lack of growth in the interval, estimated weight below the third percentile) and can also be present in fetuses and neonates with weights above the tenth percentile. There is a need to differentiate between IUGR and SGA whenever possible, as IUGR in particular is associated with greater perinatal morbidity, prematurity and mortality, as well as an increased risk for diseases in later life. Recognizing fetuses and newborns being "at risk" in order to monitor them accordingly and deliver them in good time, as well as to provide adequate follow up care to ameliorate adverse sequelae is still challenging. This review article discusses approaches to differentiate IUGR from SGA and further increase diagnostic accuracy. Since adverse prenatal influences increase but individually optimized further child development decreases the risk of later diseases, we also discuss the need for interdisciplinary follow-up strategies during childhood. Moreover, we present current concepts of pathophysiology, with a focus on oxidative stress and consecutive inflammatory and metabolic changes as key molecular mechanisms of adverse sequelae, and look at future scientific opportunities and challenges. Most importantly, awareness needs to be raised that pre- and postnatal care of IUGR neonates should be regarded as a continuum.

Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice.

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.

Hippocampal mTOR Dysregulation and Morphological Changes in Male Rats after Fetal Growth Restriction.

Fetal growth restriction (FGR) has been linked to long-term neurocognitive impairment, especially in males. To determine possible underlying mechanisms, we examined hippocampal cellular composition and mTOR signaling of male rat FGR offspring during main brain growth and development (postnatal days (PND) 1 and 12). FGR was either induced by a low-protein diet throughout pregnancy, experimental placental insufficiency by bilateral uterine vessel ligation or intrauterine stress by "sham" operation. Offspring after unimpaired gestation served as common controls. Low-protein diet led to a reduced cell density in the molecular dentate gyrus subregion, while intrauterine surgical stress was associated with increased cell density in the cellular CA2 subregion. Experimental placental insufficiency caused increased mTOR activation on PND 1, whereas intrauterine stress led to mTOR activation on PND 1 and 12. To determine long-term effects, we additionally examined mTOR signaling and Tau phosphorylation, which is altered in neurodegenerative diseases, on PND 180, but did not find any changes among the experimental groups. Our findings suggest that hippocampal cellular proliferation and mTOR signaling are dysregulated in different ways depending on the cause of FGR. While a low-protein diet induced a decreased cell density, prenatal surgical stress caused hyperproliferation, possibly via increased mTOR signaling.

Treatment of congenital hypothyroidism in a newborn with malabsorption after subtotal ileum resection.

Congenital hypothyroidism requires prompt treatment to prevent adverse health outcomes. Poor intestinal levothyroxine absorption can complicate management. We present a case of a term female newborn with necrotizing enterocolitis (NEC) requiring subtotal ileum resection. Congenital hypothyroidism was diagnosed by newborn screening. Treatment was complicated by intestinal malabsorption of levothyroxine. Intravenous levothyroxine substitution restored euthyroidism and supraphysiologic PO doses subsequently maintained a euthyroid state. After several months, the required levothyroxine dose was weaned down to typical recommended dosing. In conclusion, small bowel resection secondary to NEC may lead to malabsorption of oral levothyroxine. An intravenous levothyroxine dose of approximately 50% typical PO dosing is effective in providing rapid normalization of free T4 and TSH. High PO doses may be required to maintain euthyroidism. Close thyroid function monitoring and immediate therapy adjustment are essential as the individual absorption may vary widely. Normal absorption levels may be regained due to adaption of the neonatal intestines. LEARNING POINTS: In neonates with malabsorption after ileum resection intravenous levothyroxine replacement should be used to provide normalization of free T4 and TSH.Very high doses of up to 500% usual oral levothyroxine may be required to maintain euthyroidism. The estimated degree of malabsorption can be used to determine the initial dose.Close thyroid function monitoring and immediate therapy adjustment are essential as the absorption and intestinal adaption may vary widely.