ABSTRACT. We studied a genetically determined diabetes in pregnancy, the heterozygous diabetes (db/+) mouse. We found that fetal mice from these pregnancies are macrosomic with increased body, lung, and placenta wt, have altered organ protein, DNA and phospholipid content, and exhibit abnormal carbohydrate metabolism with increased liver and glycogen content. We further studied the effect of increased substrate availability and utilization on lung growth and maturation in (db/+) fetal mice, by measuring lung phospholipid synthesis as represented by the incorporation of the radiolabeled precursors, [3H] The increased synthesis of lung disaturated phosphatidylcholine in diabetic fetal mice may reflect the enhancement of body and lung growth in these macrosomic fetuses. Lung maturation, as represented by phosphatidylglycerol synthesis, the phosphatidylglycerol/phosphatidylinositol ratio, and morphologic indices, was abnormal in diabetic fetuses. The diabetic mouse is a useful model for studying the mechanisms resulting in enhanced growth and concomitant alterations in lung maturation in the infant of a diabetic mother. (Pediatr Res 25:173-179, 1989) Abbreviations RDS, respiratory distress syndrome PC, phosphatidylcholine SPC, disaturated phosphatidylcholine S, sphingomyelin PI, phosphatidylinositol PE, phosphatidylethanolamine PS, phosphatidylserine PG, phosphatidylglycerol Human fetal development during maternal diabetes is abnormal, frequently resulting in obese, macrosomic newborns with delayed maturation of various organ systems. Infants of diabetic mothers whose hyperglycemia is inadequately controlled late in gestation appear to have an increased risk of lung immaturity, as manifested by RDS at birth (I). Animal models in which maternal glucose intolerance and consequent fetal hyperglycemia are artificially induced have been developed to study this phenomenon (2). However, important questions concerning maternal-fetal interactions in diabetes and the consequent effects on fetal organ growth and development might be more appropriately addressed by using a model in which the diabetes is genetically determined, therefore occuning spontaneously in the mother (2).The diabetic mouse (db/db) is a well-described model of genetic diabetes transferred as an autosomal recessive trait. Homozygous (db/db) animals exhibit visible obesity in infancy with marked hyperglycemia and insulin resistance, followed later by hypoinsulinemia and profound diabetes at 3-4 mo of age (3). As the adult (db/db) mouse is infertile, heterozygous animals must be bred to produce offspring. The heterozygous female (db/ +) exhibits normal glucose tolerance except during pregnancy, when abnormal glucose tolerance, postprandial hyperglycemia and elevated Hb A 1C levels are present (4,5).We have studied the fetus of the pregnant heterozygous (db/ +) female to learn more about growth and the development during pregnancy complicated by abnormal glucose metabolism. In this report, we describe our results in characterizing abnormal fetal growth duri...

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To examine the relationship between nutrient supply and fetal and placental growth, we examined epidermal growth factor (EGF) binding to membranes prepared from placentas of growthrestricted fetal rats. Intrauterine growth retardation was accomplished by unilateral ligation of the uterine artery; fetal rats on the contralateral uterine horn served as controls. Fetal growth restriction was accompanied by decreased placental wt at 19 and 20 days' gestation and significantly decreased placental glycogen content at 20 and 21 days, 30% and 15%, respectively. Placental DNA content and protein/DNA ratios were similar in the growthrestricted and control groups. Fetal growth and maturation is determined primarily by the fetal genome but can be influenced by a number of important genetic, environmental, and maternal factors. These include a variety of congenital malformations and chromosomal disorders, environmental toxins such as cigarette smoke and alcohol, and maternal medical conditions which can restrict nutrient supply to the fetus. Fetuses with decreased uteroplacental blood flow may exhibit to varying degrees, depending on the severity of substrate and oxygen restrictions, low birth wt with sparing of brain growth, polycythemia, hypoglycemia secondary to defective glucose homeostasis, and accelerated lung maturation. The biologic mechanisms underlying the alterations in growth seen with decreased nutrient supply are poorly understood. In previous work (1-4), we reported that placentomegaly and maturational delay in fetuses of diabetics was associated with a striking decrease in the binding of epidermal growth factor to membranes prepared from the diabetic placentas. In light of these observations and because of the role of EGF in cellular proliferation and Supported by NIH Grant HL30119-07.organ differentiation in numerous cell types and animal species (5-7), we examined EGF binding to membranes prepared from placentas of fetal rats with growth restriction secondary to uterine artery ligation. In these studies, we raise the possibility that EGF binding to placental membranes is regulated by substrate flux and is associated with maturational changes in diabetic and IUGR fetuses. MATERIALS AND METHODS Animal model. Pregnant adult female Sprague-Dawley ratswere obtained from Holtzmann Lab Animals (Madison, WI) at 7-9 days' gestation (the morning that sperm were detected was designated as day 0 of pregnancy). Females were maintained on a 121 12 h lightldark cycle at 24'2, and given food and tap water ad libitum for 7-9 days before animal surgery. On days 16, 17, or 18 of gestation, unilateral uterine artery ligation was performed by a modification of the method of Wigglesworth (8) under Metofane (Pitman-Moore, Washington Crossing, NJ) inhalation anesthesia as follows. A midline incision of the lower abdomen was made, and the uterine horns were exteriorized and inspected. A single 3.0 silk ligature was placed securely around the main branch of the uterine artery close to the cervix. Only horns containing six or more fe...

A fatality from an acquired tracheoesophageal fistula (TEF) in a very low birthweight premature infant is presented. Neonatal tracheal and esophageal injuries related to endotracheal (ET) intubation are discussed. The infant had important risk factors for the development of subglottic stenosis: birthweight less than 1000 gm, prolonged positive pressure ventilation, and repeated ET intubation. The pathologic examination was consistent with acquired fistula formation resulting from a combination of preexisting subglottic stenosis and prolonged and repeated ET intubation. The recognition of clinical signs of an acquired TEF, as observed in our patient, followed by expeditious diagnostic testing may be lifesaving.