Infants Of Insulin-dependent Diabetic Mothers Research Articles

Risk of Minor and Major Fetal Malformations in Diabetics with High Haemoglobin A1c Values in Early Pregnancy

The incidence of congenital malformations is about three times higher in infants of insulin-dependent diabetic mothers than in the general population. The exact cause of this increase is not known, but experimental and clinical data show an association between congenital malformations and maternal hyperglycemia in early pregnancy, the critical period with regard to fetal malformations. The present authors report an association between the severity of maternal hyperglycemia in early pregnancy, as measured by blood hemoglobin A1c values, and the occurrence of fetal malformations in mothers with insulin-dependent diabetes. Between April 1978 and December 1982, the maternal hemoglobin A1c values had been determined at least once before the end of the 15th week of gestation in 139 insulin-dependent diabetic patients who gave birth after 24 weeks of gestation. In addition, a fetal malformation was observed in each of three cases of induced abortion in which early hemoglobin A1c determinations had been carried out. Pregnancies were classified as 1) not complicated by malformation, 2) complicated by minor malformation, and 3) complicated by major malformation. A malformation was classified as major if it was fatal or likely to cause serious handicap to the child. Other malformations were classified as minor. A total of 125 pregnancies were not complicated by fetal malformation. A malformed fetus or infant was observed in each of 17 pregnancies. In six cases, the anomalies were classified as minor, and in 11 cases they were classified as major. The mean initial hemoglobin A1c value was significantly higher in the group with minor malformations (9.3 per cent, with an SD of 1.9 per cent) and in the group with major malformations (9.6 per cent; SD, 1.8 per cent) than in the group without malformations (8.0 per cent; SD, 1.4 per cent) (P < 0.05 and P < 0.001, respectively). The difference in hemoglobin A1c values between the groups with minor and major malformations was not significant. In all of the 17 pregnancies complicated by malformation, the mean initial hemoglobin A1c value was 9.5 per cent (SD, 1.8 per cent), which was significantly higher (P < 0.001) than in the group without malformation. There was a significant positive relationship (x2 = 11.9; P = 0.001) between the maternal hemoglobin A1c value in early pregnancy and the occurrence of malformation. An initial hemoglobin A1c value of 10.0 per cent or more was associated with malformations in six of 17 pregnancies (35.3 per cent). Two of these were minor (11.8 per cent) and four were major (23.5 per cent) malformations. An intermediate hemoglobin Alc value (8.0–9.9 per cent) was associated with malformations in eight of 62 pregnancies (12.9 per cent). Relatively low initial hemoglobin A1c values, i.e., below 8.0 per cent, were associated with malformations in only three of 63 pregnancies (4.8 per cent).

Plasma Six-Keto-Prostaglandin F&lt;sub&gt;1α&lt;/sub&gt; and Endocrine Pancreatic Function in the Newborn Infant of the Diabetic Mother

Plasma concentrations of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), C-peptide and pancreatic glucagon and blood glucose levels were measured in 13 infants of insulin-dependent diabetic mothers at the age of 2 h. Plasma 6-keto-PGF1 alpha levels were lower in these infants when compared to those of healthy controls at the same age (p less than 0.05). Plasma 6-keto-PGF1 alpha correlated negatively with the C-peptide levels (r = -0.57; p less than 0.05) and positively with the pancreatic glucagon concentrations (r = 0.83; p less than 0.001) in the infants of diabetic mothers. No correlation with blood glucose concentrations was found. The data suggest that hyperinsulinemia in infants of diabetic mothers is associated with a decreased vascular prostacyclin production.

Prevention of Congenital Malformations in Infants of Insulin-dependent Diabetic Mothers

From April 1977 to April 1981, 420 deliveries of infants of insulin-dependent diabetic women were performed in our department. Of the infants delivered, 23 had congenital malformations (5.5%). The malformation rate was 1.4% for infants of 420 nondiabetic women. Strict metabolic control was begun after 8 wk gestation in 292 of the diabetic women who delivered 22 infants with congenital malformations (7.5%). Intensive treatment was begun before conception in 128 diabetic women planning pregnancy. There was only one malformation in infants of this group (0.8%), a significant reduction from the anomaly rate in the late registrants (X2 = 7.84; P less than 0.01). These observations indicate that reasonable metabolic control started before conception and continued during the first weeks of pregnancy can prevent malformations in infants of diabetic mothers.

Regulation of glucose production in newborn infants of diabetic mothers.

The glucose homeostasis in the infants of normal and diabetic mothers was elevated by examining the effects of exogenous glucose infusion at 4 mg/kg . min and quantifying the rats of glucose production and utilization. Five infants of insulin-dependent diabetic mothers (IDM), one infant of a gestationally diabetic mother and five infants of normal mothers were studied between 2-4 h of age. The rates of glucose production and utilization before and during glucose infusion were quantified by tracer dilution technique using [6,62H2] glucose tracer and gas chromatography-mass spectrometry. Fractional glucose uptake (Kt) was measured at the end of infusion by administering 0.5 g/kg glucose pulse. All diabetic women were under rigid metabolic control during pregnancy. Although basal plasma glucose levels at e 2-4 h were lower in the IDMs as compared with normal newborns (43.4 +/- 3.7 and 65.2 +/- 3.6 mg/dl, mean +/- S.E., respectively), the glucose production and utilization rates were not significantly different (3.35 +/- 0.26 and 3.39 +/- 0.08 mg/kg . min); therefore, the metabolic clearance rates were higher inthe IDMs (7.69 +/- 0.41 ml/kg . min) as compared with the normal newborn infant (5.20 +/- 0.20 ml/kg . min). Glucose infusion resulted in a greater suppression of endogenous glucose production rate in the normal newborn infants than in the IDMs. Glucose infusion resulted in an acceleration of Kt in the normals (2.38 +/- 0.25%/min). We conclude that rigid regulation of maternal diabetes normalizes glucose production rate in IDM; however, intermittent maternal hyperglycemia may result in altered regulation of hepatic glucose production.

Malformations in infants of diabetic mothers.

Maternal insulin-dependent diabetes has long been associated with congenital malformations. As other causes of mortality and morbidity have been eliminated or reduced, malformations have become increasingly prominent. Although there is not universal agreement, the great majority of investigators find a two- to threefold increase in malformations in infants of insulin-dependent diabetic mothers. This increase is not seen in infants of gestational diabetics. It probably is not present in women whose diabetes can be controlled by diet or oral hypoglycemic agents. The risk does not appear to be primarily genetic since diabetic fathers do not have an increased number of malformed offspring. Most studies show a generalized increase in malformations involving multiple organ systems. Multiple malformations seem to be more common in diabetic than nondiabetic infants. Caudal regression has the strongest association with diabetes, occurring roughly 200 times more frequently in infants of diabetic mothers than in other infants. The teratogenic mechanism in diabetes is not known. Hyperglycemia may be important but human studies focusing on the period of organogenesis are lacking. Hypoglycemia has also been suggested based mainly on animal experiments. Insulin appears unlikely. Numerous other factors including vascular disease, hypoxia, ketone and amino acid abnormalities, glycosylation of proteins, or hormone imbalances could be teratogenic. None has been studied in sufficient detail to make a judgment. A large-scale prospective study is required to determine early fetal loss rates, correlate metabolic status during organogenesis with outcome, and assess the effect of diabetic control on malformation rates.

Respiratory distress and neonatal mortality in infants of diabetic and prediabetic mothers.

The 149 live births of 19 insulin-dependent diabetic mothers and 62 prediabetic mothers between 1940 and 1970 were reviewed. The frequency of respiratory distress was 31% in infants of diabetic mothers, 2.6% in infants of prediabetic mothers, and 0.46% in all infants born at the same hospital during the same period. Neonatal mortality during the first month of life was 14% in the infants of diabetic mothers and 3.5% in the infants of prediabetic mothers. Both these rates for neonatal mortality are higher than those reported for live births in the United States and Minnesota between 1950 and 1965. Of the deaths in both groups combined, 77% occurred in the first 3 days of life in infants diagnosed as having respiratory distress. Birth weight and prematurity, gestational age, and toxemia were associated with an increased frequency of respiratory distress in the infants of prediabetic mothers, whereas gestational age, mode of delivery, and weight gain during pregnancy were so associated in infants of insulin-dependent diabetic mothers.

Monocyte insulin receptors in infants of strictly controlled diabetic mothers.

Infants of diabetic mothers have hyperinsulinism at birth, presumably resulting from maternal hyperglycemia or some other derangement of maternal metabolism, and are extremely sensitive to insulin. Such infants have significantly greater numbers of insulin receptors on cord blood monocytes compared to normal infants. To assess the role of maternal diabetic control, nine infants of insulin-dependent diabetic mothers, who were intensively treated during pregnancy, were studied. Maternal blood glucose values were measured during weekly out-patient visits throughout pregnancy, and insulin therapy was given to maintain fasting blood glucose values below 100mg/dl. When necessary, the patients were hospitalized early in pregnancy in order to achieve glucose control, and all patients were hospitalized for up to 2 weeks before delivery for strict glucose control. The mean birth weight (+/- SD) of these infants (3.23 +/- 0.23 kg) was lower than that of nine infants of mothers with gestational diabetes not receiving insulin or intensive efforts at maintenance of normoglycemia (3.99 +/- 0.12; P less than 0.01) and was not significantly different from that of normal infants (3.51 +/- 0.37 kg). Mean cord blood C-peptide levels (+/- SD), determined by RIA, were 1.6 +/- 0.78 ng/ml for infants of these strictly controlled diabetic mothers and 1.4 0.1 ng/ml for normal infants. Scatchard analysis of [125]insulin binding to cord blood monocytes yielded mean receptor numbers for infants of diabetic mothers of 22,500 vs. 105,000 sites/cell for infants of diabetic mothers (P less than 0.001) and 26,600 sites/cell for normal infants. We conclude that the strict control of maternal diabetes during the last trimester of pregnancy prevents fetal hyperinsulinemia and is associated with the development of normal numbers of insulin receptors on the infants' monocytes.

Hyperbilirubinemia in Infants of Diabetic Mothers

Large for gestational age (LGA) infants of insulin-dependent diabetic mothers (IDM), appropriate for gestational age (AGA) IDM, and infants of nondiabetic mothers were compared for the incidence of neonatal hyperbilirubinemia and related etiologic factors. At 60 hours of age, LGA IDM had significantly higher serum bilirubin concentrations (12.3 +/- 2.1 mg/100 ml) than AGA IDM (7.6 +/- 3.9 mg/100 ml) or control infants (7.8 +/- 2.8 mg/100 ml) (P < .001). Peak serum bilirubin concentrations were also significantly higher in LGA IDM (14.4 +/- 2.1 mg/100 ml) than in AGA IDM (8.4 +/- 3.7 mg/100ml) or control infants (8.6 +/- 3.3 mg/100 ml) (P < .001). Mean percent of carboxyhemoglobin was used as an indicator of hemolysis and showed a significant elevation in LGA IDM (1.51 +/- 0.19) when compared to AGA IDM (1.10 +/- 0.27) and control infants (1.19 +/- 0.33) (P < .05). No significant differences were found among the three groups with respect to mode of delivery, frequency of pitocin administration, 5-minute Apgar scores, incidence of isoimmunization, incidence of enclosed hemorrhage, hemoglobin concentration, bilirubin concentrations at 12 hours, and percent of weight loss. Our data suggest that only LGA IDM are at increased risk for hyperbilirubinemia and that increased heme turnover is a significant factor in the pathogenesis.

Long-term experiences with carbamazepine (Tegretol) in children with seizures

1. Davis WS, Allen RP, Favara BE, and Slavis TL: Neonatal small left colon syndrome, Am J Roentgenol Radium Ther Nucl Med 120:322, 1974. 2. Stewart DR, Nixon GW, Johnson DG, and Condon, VR: Neonatal small left colon, Ann Surg 86:741, 1977. 3. Sieber WK, and Girdany BR: Functional intestinal obstruction in newborn infants with morphologically normal gastrointestinal tract, Surgery 53:357, 1963. 4. Clatworthy HW, Howard WHR, and Lloyd J: The meconium plug syndrome, Surgery 39:131, I956. 5. Phillippart AL, Reed JO, and Georgeson KE: Neonatal small left colon: Intramural not intraluminal obstruction,J Pediatr Surg 10:733, 1975 6. Davis WS, and Campbell JB: Neonatal small left colon syndrome: Occurrence in asymptomatic infants of diabetic mothers, Am J Dis Child 129:1024, 1975. 7. Luyckx AS, Massi-Benedetti F, Falorni A, and Lefebvre PJ: Presence of pancreatic glucagon in the portal plasma of human neonates, Diabetologia 8:196, 1972. 8. Kalhan SC, Savin SM, and Adam PA: Attenuated glucose production rate in newborn infants of insulin-dependent diabetic mothers, N Engl J Med 296:375, 1977. 9. Williams PR, Sperling MA, and Racasa Z: Blunting of spontaneous and alanine-stimulated glucagon secretion in newborn infants of diabetic mothers, Am J Obstet Gynecol 133:51, 1979. 10. Bloom SR, and Johnson DI: Failure ofglucagon release in infants of diabetic mothers, Br Med J 4:453, 1972. 11. Sokal MM, Koenigsberger MR, Rose JS, Berdon WE, and SantuHi TV: Neonatal hypermagnesemia and the meconium plug syndrome, N Engl J Med 286:823, 1972. 12. Hallum JL, and Hatchuel WLF: Congenital paralytic ileus as a complication of hexamethonium bromide therapy for toxemia of pregnancy, Arch Dis Child 29:354, 1954. 13. Hill RM, Desmond MM, and Kay JL: Extrapyramidal dysfunction in an infant of a schizophrenic mother, J PEDIATR 69:489, 1966. 14. Tamer A, McKey R, Arias D, Worley L, and Fogel B: Phenothiazine induced extrapyramidal dysfunction in the neonate, J PEDIATR 75:479, 1969. 15. Byck R: Drugs and the treatment of psychiatric disorders, in Goodman LS, and Gilman A, editors: The pharmacological basis of therapeutics, ed 5, New York, 1975, The MacMillan Publishing Company, p 152-180.

Glucose disappearance in infants of diabetic mothers. III. Relationship of spontaneous glucose disappearance to glucose tolerance, neonatal hypoglycemia and lowest blood glucose

Spontaneous glucose disappearance in the first 90 min of life and glucose disappearance following an intravenous injection of 1 g/kg dextrose were measured in 23 infants of insulin-dependent diabetic mothers. Spontaneous disappearance was log-linear in 12/23 infants, providing for calculation of an endogenous K t which correlated significantly (P < 0.01) with the exogenous Kt determined after the dextrose injection, r = 0.74. Hypoglycemia <20 mg/dl occurred in 4/23 infants, and was identified during the spontaneous glucose disappearance (3 infants) and/or predicted by an endogenous K t > 3.0%/min (2 infants). There was also a significant inverse correlation (P < 0.01) of the lowest blood glucose obtained within the first 24 h of life with the endogenous K t, r = 0.61. There was no correlation of the endogenous or exogenous Kt, lowest blood glucose or hypoglycemia with White's classification of the maternal diabetes, diabetic control during pregnancy, the maternal blood glucose at delivery or the cord blood glucose. These data indicate that determination of spontaneous glucose disappearance within the first 90 min of life is useful in identifying infants of diabetic mothers with hypoglycemia or those who will subsequently develop hypoglycemia.

Glucose disappearance in infants of diabetic mothers II. Relationship to lowest neonatal blood glucose and amniotic fluid insulin

Neonatal glucose disappearance (K T) was measured in 26 infants of insulindependent diabetic mothers within the first 2 h of life. A significant correlation was found between the K T and the lowest blood glucose (LBG) in the first day of life (r=0.64, P <0.001). None of 21 infants developed a LBG <20 mg/dl when the K T was <3.0%/min in contrast to 4 of 5 whose K T was >3.0%/min (P <0.001). Amniotic fluid (AF) glucose and insulin were determined in 42 samples from 18 of these patients in the third trimester of pregnancy. There was a significant correlation between AF insulin values and the neonatal K T (r= 0.76, P <0.001). The correlation was higher when only amniotic fluid values obtained on the day of delivery were considered (n=17, r=0.90, P <0.001). 1 of 13 infants developed a LBG <20 mg/dl when the amniotic fluid insulin was <100 μ U/ml on the day of delivery in contrast to 3 of 4 whose AF insulin was > 100 μU/ml (P <0.001). No correlation of AF glucose was found with infants' K T or LBG. These data suggest that both neonatal K T and AF insulin are of value for predicting neonatal hypoglycemia and detecting infants who will require treatment for its prevention.

CARBON MONOXIDE EXCRETION AS AN INDEX OF BILIRUBIN PRODUCTION IN NEWBORN INFANTS

The excretion rate of endogenously produced carbon monoxide (Veco) was measured as an index of bilirubin production in human newborns. Using a simplified measurement technique, over 300 studies have been performed on infants of various gestational ages (GA) and risks for hyperbilirubinemia. Studies performed on 60 full term infants < 5 days of age resulted in a mean value for Veco of 18.0 ± 4.1 (SD) μl/kg/hr. Infants of GA < 33 weeks, 33-34 weeks, and 35-36 weeks had Veco values of 17.7 ± 5.2, 18.1 ± 5.9, and 16.2 ± 3.7 μl/kg/hr, respectively, over the first 10 days of life. No difference in Veco was noted between Caucasian newborns and those of Spanish surname. In 14 infants with ABO or Rh hemolytic disease, Veco ranged from 17.3 to 71.5 μl/kg/hr. Serial determination performed on 2 pf these infants showed Veco to be elevated for 30 days following birth. No infant with Veco less than 50 μl/kg/hr required exchange transfusion. Eight infants of insulin-dependent diabetic mothers (IDM) were studied on 13 occasions and found to have a mean Veco of 17.5 μl/kg/hr. However 2 premature newborns of this group who were also hypoglyeemic exhibited increased Veco levels of 28.7 and 29.2 μl/kg/hr. It has been shown that 1) measurement of Veco by this method is a quick, non-invasive procedure; 2) Veco seems independent of GA; 3) Ve provides valuable information concerning the rate of bilirubin production in isoimmune hemolytic disease; 4) non-hypoglycemic, full term IDM do not have elevated Veco.

Attenuated glucose production rate in newborn infants of insulin-dependent diabetic mothers.

Hypoglycemia frequently develops in infants of diabetic mothers in the immediate postnatal period.1 , 2 Even in the presence of strict metabolic control during pregnancy, a greater decrease of bloo...

Neontal hypoglycaemia in infants of insulin-dependent diabetic mothers.

Neonatal hypoglycaemia (blood glucose smaller than 20 mg/100 ml) occurred in the first 6 hours of life in 25 of 34 infants born to diabetic mothers receiving insulin. Despite severe hypoglycaemia (blood glucose smaller than 10 mg/100 ml) in 17, clinical features of hypoglycaemia were absent in all but 2. Hypoglycaemia was not related either to the level of plasma insulin in cord blood, determined as nonextracted immunoreactive insulin, or to the degree of control of maternal blood glucose during pregnancy. The frequent occurrence of severe neonatal hypoglycaemia in the infants born to diabetic mothers receiving insulin appears to be due rather to failure to maintain basal glucose homoeostasis after birth than to hyperinsulinism.

Prevention of hypoglucosemia by fructose in infants of diabetic mothers.

HYPOGLUCOSEMIA occurs consistently in infants of insulin-dependent diabetic mothers during the initial hours of life.1 2 3 4 Previous studies have not clearly related symptomatology to the level of blood glucose.5 6 7 Furthermore, the effect of hypoglucosemia on mortality, morbidity and ultimate mental development is not well defined. The following observations suggest that subtle as well as overt symptoms regularly occur in the initial hours of life in association with hypoglucosemia. Fructose administration was found to alleviate symptoms and to alter the course of blood glucose. Methods In addition to the methods and material previously described4 7 infants received fructose directly into the umbilical . . .