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Editorial Indian Pediatrics 1999;36: 1262-1264 |
Glucose and Small for Gestational Age Infants |
Small for gestational age (SGA) or small for dates (SDA) infants constitute a remarkably heterogeneous group as a consequence of multiple contributing factors or etiologies which ultimately lead to intrauterine growth restriction (IUGR). In several of these the causative factor or factors are obvious, e.g., congenital infec-tions, genetic or constitutive SGA, pre-eclampsia; however, for a large proportion the real cause remains undefined. Although small for gestational age has been defined arbitrarily as an infant born with a birth weight below the 10th percentile (of the Gaussian distribution) for gestational age, recently several investigators have underscored the artificial character of such a definition and the possibility of missing a large number of cases of IUGR, e.g. a genetically destined 4000 g infant born at 3500 g. Because of these porblems with the heterogeneity of the population and definition, it has been difficult to evlauate the morbidity and mortality related to IUGR(1). Nevertheless, published data in the literature suggest that when babies with genetic defects and intrauterine infections are excluded, the overall morbidity is significantly lower than that when the entire unselected groups are evaluated, although it still remains higher than the otherwise normal appropriate for gestational age infant. Minior and Divon(2) recently documented the perinatal morbidity in 67 small for gestational age infants and compared them with 201 appropriate for gestational age babies. Pregnancies complicated by structural or chromosomal abnormalities, diabetes mellitus, pre-eclampsia, chronic hypertension and other medical problems were excluded. Their data show that a larger proportion of SGA babies admitted to the neonatal intensive care unit, were born by surgical delivery, had lower 1-minute Apgar scores, had hypoglycemia, thrombocytopenia, hyperbilirubinemia and respiratory distress(2). The frequency and magnitude of neonatal morbidity in the SGA infant remains controversial(3,4). However, it appears that in full term small for gestational age infants who are born following uncomplicated pregnancy, the overall morbidity is low and that frequency of neonatal morbidity increases with maternal and fetal complications. Among these, neonatal hypoglycemia appears to be more common than other complications(4-8). Hypoglycemia in the SGA Infant The exact frequency of hypoglycemia in the SGA infant and its occurrence in relation to postnatal age remains unknown. The changes in clinical practice for the intrapartum care of the mother and advances in the nutritional management of the neonate do not permit extrapolation of older data to the present time. Lubchenco and Bard(7) measured blood glucose concentration during 3 to 6 hours after birth in a random sample of 374 patients. They reported the highest (67%) incidence of hypoglycemia (serum glucose < 30 mg/dl) in preterm SGA group. It was 25% in the term SGA infant and 18% in post term SGA babies. A majority of the hypoglycemic infants also had a history of fetal distress and birth hypoxia. In addition, other confounding factors such as administration of intravenous glucose to the mother during labor, which can induce hypoglycemia in the neonate, were not reported. The data of Lubchenco and Bard, and those of Neligan et al.(7,8) are probably an overestimate and not applicable to the present day population. More recent studies suggest that the incidence of hypoglycemia (blood glucose less than 30 mg/dl) is much less than previously reported and ranges anywhere between 6 to 14% of SGA infants(3-6). These data also suggest that incidence of hypoglycemia is related to gestational age, being less frequent in infants near term gestation(3-6). The age at which hypoglycemia occurred was recently evaluated by Holtrop(6). In their study, 27 out of 30 SGA infants manifested either asymptomatic or symptomatic hypoglycemia during the first 12 hours after birth. The relation between so-called symmetrical and asymmetrical growth retardation and neonatal hypoglycemia has not been specifically addressed. There appears to be a consensus amongst neonatologists and other investigators that hypoglycemia may be more common in the asymmetrical growth retardation because it appears to represent true intrauterine deprivation of nutrients. Mechanism of Hypoglycemia The pathogenesis of hypoglycemia in SGA infants has been the subject of numerous investigations and speculations. Studies in animal models, e.g. the Wigglesworth model of uterine artery ligation, show a lower glucose concentration in the fetus and the newborn pup, lower fetal hepatic glycogen concentration, and delay in activity and appearance of a key gluconeogenic enzyme_phosphoenolpyruvate carboxyki-nase(9-11). In addition, a lower concentration of plasma alanine and increased ketone concentration were observed in these pups following a prolonged fast at 21 days of age. Several investigators have suggested that the mechanism of hypoglycemia in the human SGA is similar to that observed in animal models, i.e. decreased hepatic glycogen stores, impaired gluconeogenesis, hyperinsulinism, etc., al-though direct evidence for such a conclusion is either lacking or not compelling. Umbilical blood samples obtained from small for gestational age fetuses in utero have consistently shown that IUGR is associated with intrauterine hypoxemia, hyperlactic acidemia and metabolic acidosis(12-14). Of significance, similar to studies in animal models, the fetal blood glucose concentration was lower as compared with appropriate for gestational age fetuses. Marconi et al.(15) measured lactate concentration and oxygen content in 34 IUGR infants at the time of elective cesarean section and compared these with 21 normal (AGA) infants. Their data show that in IUGR infants who showed a very high pulsatility index (>4 SD), there was a marked lactic acidemia. Thus, in human IUGR, the severity of intrauterine hypoxemia and compromise in uterine blood flow (pulsatility index) are related to fetal lactic acidemia and fetal glucose concentration. The mechanism of lower blood glucose con-centration in the IUGR fetus remains unclear. It has been speculated that it may be due to decreased transport of glucose from the mother to the fetus, and/or increased non-oxidative glucose disposal by the fetus. The Neonate Several studies have examined the changes in plasma glucose, gluconeogenic substrates, fatty acids and ketones in the immediate newborn period(16-19). The rates of energy consumption and substrate oxidation in SGA infants have also been quantified. Because of clinical and ethical considerations, these studies are confounded by the need for parenterally and enterally administered glucose and other nutrients(16-18). Thus these data require caution in interpretation since it may not represent the true metabolic state, but rather the impact of clinical intervention, e.g., intravenous glucose or enteral formula, or glucose feeds. In addition, since intrapartum administration of glucose to the mother could result in neonatal hyperinsulinemia and hypoglycemia, these confounding variables also need to be considered in the interpretation of the data. Thus, the reported occurrence of hyper-inuslinemia in SGA infants could be the consequence of intrapartum or neonatal clinical interventions(17,20). The resulting increase in plasma insulin concentration could also suppress lipolysis, ketogenesis and gluco-neogenesis. Haymond and colleagues(16) reported the changes in circulating glucose, glucogenic substrates and hormonal levels in 11 small for gestational age infants and compared them with five normal vaginally delivered term infants. Their data show that the umbilical venous levels of lactate, pyruvate, alanine, other gluconeogenic-amino acids and total alpha-amino-N levels were significantly elevated in SGA infants. By two hours after birth, and prior to feeding, the SGA infant had higher lactate, alanine and total amino N levels. No significant differences in plasma glycerol or ketone levels were observed at 2 hours after birth. The authors interpreted these increases in glucogenic substrates to suggest a functional delay in the development of a rate limiting enzyme(s) involved in hepatic gluconeogenesis, similar to the observation reported in the experimental animal models(10,11). Glucose and glycerol kinetics were quantified by Patel and Kalhan(19) using stable isotopic tracer methods in 12 AGA and eight SGA infants. The infants were studied during the first 48 hours after birth following a 3-5 hour fast. The SGA infants had a slightly higher weight specific rate of oxygen consumption, and their respiratory quotient was lower than the AGA infants, suggesting a higher contribution of fat to energy consumption. The rate of glucose production in SGA infants, measured by isotopic tracer dilution method, was similar to that in the AGA infants (~22 mmole/kg.min or 4 mg/kg.min). The slightly lower estimate of rate of glucose production in this study, compared with other data of ~6 mg/kg.min, may be the consequence of the specific tracer isotope employed. The rate of lipolysis as measured by rate of turnover of glycerol was higher in SGA infants as compared with AGA infants. However, the fractional as well as quantitative contribution of glycerol to glucose was not different between the two groups. Thus these data show that healthy SGA infants appear to tolerate brief fast (8-9 hours) without any significant perturbations in circulating glucose levels, have a higher rate of lipolysis and a higher contribution of fat to oxidative metabolism as compared with AGA infants. Other studies have demonstrated the SGA infant's ability to form glucose from alanine soon after birth(21). The isotope tracer studies of gluco-neogenesis cited above are in contrast to the observed less increase in plasma glucose concentration in response to oral alanine in the SGA infant(22). Although these data could be interpreted to suggest a decreased gluco-neogenic capacity, such an interpretation is fraught with error since such studies did not quantify the actual incorporation of alanine into glucose. In summary, these data suggest that human SGA infants can maintain normal glucose concentration during a brief fast, have a normal rate of production of glucose and have a normal capacity for gluconeogenesis. Whether there is any delay in functional maturation of gluco-neogenesis, as suggested earlier (16), cannot easily be confirmed. Since the SGA infant has similar rate of glucose production as AGA infants, these data point against the prevailing concept of diminished hepatic glycogen stores in these infants. Clinical Implications Based upon the physiological and clinical data from human and animal studies, it can be inferred that small for gestational age infants appear to have a higher risk for hypoglycemia in the immediate newborn period. This risk appears to be confined to the first 24 hours after birth. They have a functional capacity to produce glucose from glycogen stores and from gluconeogenesis similar to that in normal AGA babies. Finally, the SGA infants have a higher rate of lipolysis and have a higher contribution of fat to energy consumption. The mechanism of hypoglycemia in the SGA infant remains difficult to resolve. From the clinical perspective, neonatal hypoglycemia is usually transient and is easily corrected by the administration of parenteral glucose and possibly prevented by early administration of enteral nutrients(23). The regimen for the intravenous administration of glucose in SGA infants should be no different from that for AGA infants. Glucose should be administered at rates similar to the endogenous rate of glucose production, i.e., 6-7 mg/kg. min or 80-100 ml/kg. day of 10% dextrose solution. In sympto-matic babies, i.e., in the presence of seizures, apnea, etc., the hypoglycemia should be rapidly corrected by giving a small bolus injection of glucose along with constant rate infusion. Although, hydrocortisone and glucagon have been used for the treatment of hypoglycemia in uncontrolled studies, such pharmacological interventions are usually not required in the majority of instances. Acknowledgements Studies in the author's laboratory are supported by grants HD 11089, RR00080 and HD22965 from the National Institutes of Health. The authors thanks Mrs. Joyce Nolan for her help in preparation of this manuscript. Satish Kalhan, References 1. Hay WW, Catz CS, Grave GD, Yaffe SJ. Workshop summary: Fetal Growth: Its regulation and disorders. Pediatrics 1997; 99: 585-591. 2. Minior VK, Divon MY. Fetal growth restriction at term: Myth or reality? Obstet Gynecol 1998; 92: 57-60. 3. Robertson PA, Sniderman SH, Laros RK, Cowan R, Heilbron D, Goldenberg RL, et al. Neonatal morbidity according to gestational age and birth weight from five tertiary care centers in the United States, 1983 through 1986. Am J Obstet Gynecol 1992; 166: 1629-1641. 4. Jones RAK, Roberton NRC. Small for dates babies: Are they really a problem? Arch Dis Child 1986; 61: 877-880. 5. Holtrop PC. The frequency of hypoglycemia in full-term large and small for gestational age newborns. Am J Perinatol 1993; 10: 150-154. 6. DeLeeuw R, De Vries IJ. Hypoglycemia in small-for-dates newborn infants. Pediatrics 1976; 58: 18-22. 7. Lubchenco LO, Bard H. Incidence of hypoglycemia in newborn infants classified by birth weight and gestational age. Pediatrics 1971; 47: 831-838. 8. Neligan GA, Robson E, Watson J. Hypoglycemia in the newborn: A sequel of intrauterine malnutrition. Lancet 1963; i: 1281-1284. 9. Oh W, D'Amodio MD, Yap LL, Hohenauer L, Guy JA. Carbohydrate metabolism in experi-mental intrauterine growth retardation in rats. Am J Obstet Gynecol 1970; 108: 415-421. 10. Ogata ES, Bussey ME, LaBarbera A, Finley S. Altered growth, hypoglycemia, hypoalaninemia, and ketonemia in the young rat: Postnatal consequences of intrauterine growth retardation. Pediatr Res 1985; 19: 32-37. 11. Bussey ME, Finley S, LaBarbera A, Ogata ES. Hypoglycemia in the newborn growth-retarded rat: Delayed phosphoenolpyruvate carboxykinase induction despite increased glucagon availability. Pediatr Res 1985; 19: 363-367. 12. Nicolaids KH, Economides DL, Soothill PW. Blood gases, pH, and lactate in appropriate and small for-gestational-age fetuses. Am J Obstet Gynecol 1989; 161: 996-1001. 13. Pardi G, Buscaglia M, Ferrazzi E, Bozzetti P, Marconi AM, Cetin I, et al. Cord sampling for the evaluation of oxygenation and acid-based balance in growth-retarded human fetuses. Am J Obstet Gynecol 1987; 157: 1221-1228. 14. Soothill PW, Nicolaides KH, Campbell S. Prenatal asphyxia, hyperlacticemia, hypo-glycemia, and erythroblastosis in growth retarded fetuses. Clin Res 1987; 294: 1051-1053. 15. Marconi AM, Cetin I, Ferrazzi E, Ferrari MM, Pardi G, Battaglia FC. Lactate metabolism in normal and growth-retarded humna fetuses. Pediatr Res 1990; 28: 652-656. 16. Haymond MW, Karl IE, Pagliara AS. Increased gluconeogenic substrates in the small-for-gestational-age infant. N Engl J Med 1974; 291: 322-328. 17. Hawdon JM, Ward Platt MP. Metabolic adaptation in small for gestational age infants. Arch Dis Child 1993; 68: 262-268. 18. Hawdon JM, Weddell A, Aynsley-Green A, Ward Platt MP. Hormonal and metabolic response to hypoglycemia in small for gestational age infants. Arch Dis Child 1993; 68: 269-273. 19. Patel D, Kalhan S. Glycerol metabolism and triglyceride-fatty acid cycling in the human newborn: Effect of maternal diabetes and intraueterine growth retardation. Pediatr Res 1992; 31: 52-58. 20. Collins JE, Leonard JV, Teale D, Marks D, Williams DM, Kennedy CR, et al. Hyperinsulinemic hypoglycemia in small for dates babies. Arch Dis Child 1990; 65: 1118-1120. 21. Frazer TE, Karl IE, Hillman LS, Bier DM. Direct measurement of gluconeogenesis from[2,3-13C2] alanine in the human neonate. Am J Physiol 1981; 240: E615-E621. 22. Williams PR, Fiser RH, Sperling MA, Oh W. Effects of oral alanine feeding on blood glucose, plasma glucagon and insulin concentrations in small-for-gestational-age infants. N Engl J Med 1975; 292: 612-613. 23. Kalhan SC, Saker F. Disorders of carbohydrate metabolism. In: Neonatal-Perinatal Medicine. Diseases of the Fetus and Infants. Eds. St. Louis Fanaroff AA, Martin RJ. Mosby-Year Book, 1997; pp 1439-1463. |
