Anthony F. Philipps

Prognostic value of the electroencephalogram in term and preterm infants following neonatal seizures

There is controversy in the literature regarding the prognostic value of the EEG following neonatal seizures. This report reviews the results of a prospective study comparing EEG findings and outcome in 74 term and preterm infants following neonatal seizures. EEGs were evaluated for both background rhythms and epileptiform activity. Outcome was evaluated at an average age of 33 months. Background rhythms were highly correlated with outcome. Low voltage, electrocerebral inactivity and burst suppression EEGs were associated with poor outcomes while normal EEGs were associated with favorable outcomes. Slow, maturationally delayed and asymmetrical EEGs were associated with variable outcomes. The presence of epileptiform activity on the EEG was correlated with adverse outcomes but was not as highly significant as background rhythms. Electroencephalographic seizures, whether associated with clinical manifestations or not, were highly correlated with poor outcomes. The significance of these EEG findings was similar in both term and preterm infants. The study demonstrates that the EEG is predictive of outcome following neonatal seizures.

The Effects of Biosynthetic Insulin-Like Growth Factor-1 Supplementation on Somatic Growth, Maturation, and Erythropoiesis on the Neonatal Rat

ABSTRACT: Somatomedins are anabolic hormones that may stimulate growth during the perinatal period. To test this hypothesis, neonatal rats were injected with a biosynthetic somatomedin, insulin-like growth factor 1 (IGF-1) twice daily for the first 2 wk of life. Two biosynthetic IGF-1 preparations of different potency were tested as well as a preparation of human growth hormone in five litters of rats. When compared to saline-injected rats, IGF-1 injected rats had increased body weight and tail length as well as specific increases in weights of liver, brain, heart, and testes. In addition, significant increases in bone marrow erythropoietic cell precursors were apparent after IGF-1 injection. IGF-1-treated neonatal rats also exhibited precocious eye opening as a sign of epithelial cell differentiation. Five additional litters of rats received similar injections but were exposed to postnatal nutritional deprivation via artificially increasing litter size. Although IGF-1 caused stimulation of bone marrow erythropoiesis and precocious eye opening, no effects of IGF-1 on somatic or organ growth could be documented. This represents the first demonstration in vivo of the anabolic effects of IGF-1 in rapidly growing neonatal rats but suggests that nutritional sufficiency may also be necessary for the full expression of somatomedin effects.

Human Milk as a Potential Enteral Source of Erythropoietin

In addition to its content of traditional nutrients, milk is a rich source of hormones and peptides, which survive digestion in the neonatal gastrointestinal tract secondary to lower proteolytic activity and increased protein permeability. Previous studies have shown accelerated erythropoiesis or elevated serum erythropoietin (Epo) levels in neonatal (suckling) animals after maternal phlebotomy or maternal hypoxia exposure. We sought to determine whether significant quantities of Epo are present in human milk and whether Epo remains intact under physiologic digestion conditions. Immunoreactive Epo concentrations were determined in 409 human milk samples obtained from mothers of term and premature infants. Samples collected between birth and postpartum d 134 were divided into 11 postpartum day groups. Mean milk-borne Epo concentrations were within the normal range for plasma Epo concentrations and rose with postpartum day (F10,398 = 5.82, p < 0.0001). No differences were observed between milk collected from mothers of premature versus term infants. Estimated weekly human milk-borne Epo intakes approximated the lower range of published parenteral therapeutic doses. In simulated digestion at physiologic pH levels of 3.2, 5.8, and 7.4, milk-borne Epo resisted degradation at 1 and 2 h, compared with baseline. Therefore, we conclude that human milk contains considerable amounts of Epo which resist degradation after exposure to gastric juices at physiologic pH levels. These results support continued investigation into the fate and developmental roles of Epo in human milk.

Effects of chronic fetal hyperglycemia upon oxygen consumption in the ovine uterus and conceptus.

Hyperglycemia has been shown to induce arterial hypoxemia in the chronically catheterized fetal sheep. To investigate the mechanism behind this glucose-induced hypoxemia, eight pregnant ewes and their fetuses were studied. Fetal glucose infusion (11.9 +/- 0.6 mg glucose/kg per min) was associated with a doubling of the fetal plasma glucose concentration with concomitant elevation of the umbilical vein-distal arterial O2 content difference by 24 h of infusion (P less than 0.01). Calculated fetal O2 consumption increased from 8.1 +/- 0.4 ml/kg per min in the control period to a maximum value of 10.6 +/- 0.3 ml/kg per min by third infusion day (P less than 0.01), which is an increase of approximately 30%. The degree of stimulation of fetal O2 consumption was related to the degree of fetal hyperglycemia but not to the degree of fetal hyperinsulinemia. The increase in fetal O2 consumption was accompanied by a significant increase in fetal O2 extraction with no change in either fetal O2 delivery or fetal blood O2 affinity. In addition, fetal hypercapnea with a mild fetal respiratory acidosis was induced by fetal hyperglycemia. The increase in fetal arterial PCO2 was linearly related (P less than 0.001) to the magnitude of increase in fetal O2 consumption. These studies suggest that chronic fetal hyperglycemia induces a state of accelerated fetal oxidative metabolism and may be important in explaining the etiology behind certain unusual findings in human infants of diabetic mothers.

Hypophosphatemia and hypercalciuria in small premature infants fed human milk: evidence for inadequate dietary phosphorus.

Phosphorus and calcium balance was measured prospectively in stable premature infants (less than or equal to 1600 gm) fed human milk or a standard commercial formula. Throughout the study, the P and Ca intakes of the infants fed human milk were two to three times less than those of infants fed formula. Infants fed human milk showed low serum P and normal serum Ca concentrations, complete renal reabsorption of P, and elevated renal Ca excretion. The net effect in infants fed human milk was a 50% reduction in the P and Ca retention, compared with the formula-fed group. Despite the unfavorable P and Ca balance in the group fed human milk, the only evidence of rickets was elevated alkaline phosphatase activity. Nevertheless, based on the biochemical changes in these infants, low serum P values, and excess urinary calcium losses, we conclude that the stable small premature infant fed human milk exclusively is deficient in phosphorus and only slightly more sufficient in calcium.

Arterial Hypoxemia and Hyperinsulinemia in the Chronically Hyperglycemic Fetal Lamb

Summary: Sustained fetal hyperglycemia was produced in eight chronically catheterized fetal lambs (seven twins, one singleton) by means of direct fetal glucose infusion. In twin preparations, only one twin was infused, the noninfused twin serving as a simultaneous in utero control. Glucose infusions lasted 7.6 ± 118 days and resulted in significant fetal hyperglycemia (from 20.3 ± 1.1 mg/dl to 58.2 ± 4.7 mg/dl, P < 0.001). The magnitude of the hyperglycemia was linearly related to the glucose infusion rate. Elevations of fetal plasma glucose and glucose infusion rate were associated with a significant fall in fetal arterial oxygen content (P < 0.001). In twin preparations studied, these relationships remained when the simultaneously sampled, noninfused twin was used as control. The fetal glucose-induced hypoxemia was not associated with fetal acidosis (tissue hypoxia) until the arterial oxygen content fell below 30% of baseline (mean base deficit in acidotic fetuses = 11.2 ± 2.2 meq/liter). Although Pao2 fell in hypoxemic fetuses (from 13.5 ±1.2 mmHg to 9.7 ±1.2 mmHg), the difference was not significant. Fetal plasma insulin rose during hyperglycemia from 10.2 ±3.1 μU/ml to a peak concentration of 26.2 ± 3.3 μU/ml, but this response was blunted in markedly hypoxemic fetuses. Neither fetal anemia nor hemoconcentration were evident in these preparations to account for the fall in fetal oxygen content.Speculation: Glucose-induced hypoxemia may be the result of accelerated fetal and/or uteroplacental oxygen consumption. In utero hypoxemia in the fetus of the pregnant diabetic may present a unifying hypothesis linking the known clinical findings of increased fetal red blood cell production, polycythemia, and late fetal demise in fetuses of diabetic mothers.

Fate of Insulin-Like Growth Factors I and II Administered Orogastrically to Suckling Rats

ABSTRACT: Milk-borne insulin-like growth factors I and II (IGF-I and -II) may be of importance in the differentiation of the gastrointestinal tract of the suckling. To test this hypothesis, 10- to 11-d-old suckling rats were given via an orogastric tube 125I-IGF-I (n = 6) or 125I-IGF-II (n = 6) in rat milk and killed 30 min later. The results of this study demonstrated that approximately 40% of the radioactivity administered was detected in the gastrointestinal tract for both 125I-IGF-I and 125I-IGF-II experiments. Gel chromatography of acid extracts of homogenates of gastrointestinal tissues and luminal contents demonstrated that a significant fraction of recovered radioactivity eluted in a position identical to “native” IGF. These findings were confirmed by subjecting similarly treated samples to high performance liquid chromatography. In addition, radioactive material recovered from Mr 7,500 fractions bound specifically to crude membrane IGF-I and -II receptor preparations, further suggesting the preservation of biologic activity of the recovered peptides. Although skin homogenates contained large peptide fragments of 125I-IGF-I, no “intact” IGF was found in the blood or other tissues. These findings suggest that milk-borne IGFs are stable in the neonatal gastrointestinal tract and remain biologically active for as long as 30 min postingestion.

Artificial formula induces precocious maturation of the small intestine of artificially reared suckling rats.

BackgroundThe artificially reared rat model was used successfully to study the effect of nutrition during the early postnatal period on growth and development of the neonate. Overgrowth and morphologic changes of the gastrointestinal tract are known consequences of artificial rearing. The major goal of our study was to elucidate whether artificial rearing–enhanced gut development is caused by artificial diet or by gastrostomy and the artificial rearing technique itself. MethodsSuckling rats at day 8 of age underwent intragastric cannulation and were machine fed either a cows milk–based artificial rats milk substitute or pooled rats milk for 4 days. Dam-fed littermates served as a control. ResultsBody growth did not differ in the three experimental groups. In rats receiving rats milk substitute, small intestinal wet weight was approximately 60% greater than in rats fed rats milk or control rats. Additionally, the entire small intestine was approximately 20% longer in the rats milk substitute group. Morphologically, rats milk substitute–fed pups demonstrated significantly greater intestinal villus length and crypt depth compared with rats milk–fed or control rats. Jejunum and midjejunum of the rats milk and control groups did not differ in these parameters. Intestinal sucrase activity of rats milk substitute–fed rats was significantly elevated compared with rats milk–fed rats or control animals. ConclusionsThese results indicate that cows milk–based formula, not gastrostomy or artificial feeding technique, is a principal cause of the small intestine overgrowth and precocious maturation of some intestinal functions observed in artificially reared sucklings.

Maternal Zinc Deficiency in Rats Affects Growth and Glucose Metabolism in the Offspring by Inducing Insulin Resistance Postnatally

Interactions among zinc (Zn), insulin, and glucose metabolism are complex. Maternal Zn deficiency affects maternal carbohydrate metabolism, but the mechanisms underlying changes in glucose homeostasis of offspring are not well understood. Rats consumed Zn-deficient (ZnD; 7 microg/g) or control (ZnC; 25 microg/g) diets ad libitum from 3 wk preconception to 21 d postparturition. Litters were culled to 7 pups/dam postnatally and pups were allowed to nurse their original mothers; after weaning, pups were fed nonpurified diet. Insulin and glucose tolerance tests were performed on the pups at wk 5 and 10. Although there was no difference in birth weight between groups, ZnD pups weighed significantly more than controls by d 10 (+5%) and 20 (+10%). Both blood glucose and serum insulin-like growth factor (IGF-1) concentrations at wk 3 were significantly higher in ZnD pups than in controls. Both male and female ZnD rats were less sensitive to insulin and glucose stimulation than controls at wk 5 and 10. At wk 15, serum leptin concentrations were higher in male ZnD rats than in controls. Phosphorylation of muscle Akt protein, an insulin receptor (IR) signaling intermediate, was lower in female ZnD rats than in controls at wk 15, but they did not differ in phosphorylation of IR. Maternal Zn deficiency resulted in greater serum IGF-1 concentrations and the excessive postnatal weight gain in their offspring as well as impaired subsequent glucose sensitivity. It was associated with gender-specific alterations in the serum leptin concentration and the insulin signaling pathway. These findings suggest that suboptimal maternal Zn status induces long-term changes in the offspring related to abnormal glucose tolerance.

The effect of insulin on ovine fetal oxygen extraction

Infusion of exogenous insulin (54 +/- 19 mU/kg/hr) to seven fetal lambs caused hyperinsulinism and arterial hypoxemia but not hypoglycemia. We measured the relationship between fetal oxygen delivery and oxygen use for a better understanding of the cause of the observed hypoxemia. Oxygen delivered to the fetus is the product of fetal umbilical venous oxygen content and umbilical blood flow. Both of these quantities decreased as fetal insulin concentration rose. The fall in umbilical blood flow was due to a change in the distribution of cardiac output. Cardiac output rose, but placental perfusion decreased while blood flow to the fetal carcass increased. Oxygen consumption by the ovine fetus increased as insulin concentration rose. Since the delivery of oxygen to the fetus did not increase when its use was rising, fetal extraction of available oxygen increased. Fetal arterial hypoxemia is the result of this increased extraction of available oxygen.