Infants Of Insulin-dependent Diabetic Mothers Research Articles

Outcomes of Moderately Preterm Infants of Insulin-Dependent Diabetic Mothers.

Little is known about the hospital outcomes of moderately preterm (MPT; 29 0/7-33 6/7 weeks gestational age) infants born to insulin-dependent diabetic mothers (IDDMs). We evaluated characteristics and outcomes of MPT infants born to IDDMs compared with those without IDDM (non-IDDM). Cohort study of infants from 18 centers included in the MPT infant database from 2012 to 2013. We compared characteristics and outcomes of infants born to IDDMs and non-IDDMs. Of 7,036 infants, 527 (7.5%) were born to IDDMs. Infants of IDDMs were larger at birth, more often received continuous positive pressure ventilation in the delivery room, and had higher risk of patent ductus arteriosus (adjusted relative risk or aRR: 1.49, 95% confidence interval [CI]: 1.20-1.85) and continued hospitalization at 40 weeks postmenstrual age (aRR: 1.55, 95% CI: 1.18-2.05). MPT infants of IDDM received more respiratory support and prolonged hospitalizations, providing further evidence of the important neonatal health consequences of maternal diabetes. · Little data are available on moderate preterm infants of IDDMs.. · MPT infants of IDDMs need more respiratory support.. · Longer neonatal intensive care unit stays among MPT infants of IDDMs..

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 non-diabetic 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.

Plasma Ghrelin and Resistin Concentrations Are Suppressed in Infants of Insulin-Dependent Diabetic Mothers

This study aimed to investigate 1) the effect of maternal diabetes mellitus on ghrelin, resistin, leptin, and insulin in term newborns; 2) the interrelationship of these metabolic hormones in the early postnatal period; and 3) the association of the hormones with anthropometric parameters at birth. A total of 120 term newborns were prospectively enrolled and categorized into three groups: 40 were infants of nondiabetic mothers (group N), 42 were infants born to mothers with gestational diabetes on low energy dietary treatment (group D), and 38 were infants born to mothers with preexisting or severe gestational diabetes who required exogenous insulin for stabilization of blood sugar during pregnancy (group I). Plasma ghrelin and resistin were significantly lower in group I than in either group N or group D infants (P < 0.048). Plasma ghrelin and subscapular skinfold thickness were significantly higher in female than in male infants [plasma ghrelin: median (interquartile range), 3.8 (3.0-4.8) vs. 3.0 (2.4-4.0) ng/ml in females and males, respectively; P = 0.003; subscapular skinfold thickness: 4.9 (4.2-5.6) vs. 4.6 (3.9-5.2) mm; P = 0.03]. In group N, plasma ghrelin was significantly, but negatively, associated with birth weight (r = -0.31; P = 0.05) and body length (r = -0.33; P = 0.04), whereas in group I, plasma ghrelin was negatively correlated with plasma resistin (r = -0.37; P = 0.02). Plasma ghrelin and resistin are suppressed in infants of insulin-dependent diabetic mothers, suggesting that the metabolic hormonal system is probably operational in fetal and early postnatal life. A low circulating ghrelin concentration may be advantageous to these infants, because a reduction in appetite may prevent excessive weight gain postnatally and counterbalances the in utero anabolic effect of hyperinsulinism in poorly controlled diabetic mothers. The suppressive effect of insulin on resistin may partially explain the excess accumulation of adipose tissue in infants of diabetic mothers by reducing the inhibitory effect of resistin on adipogenesis. Female infants have significantly higher plasma ghrelin levels than male infants, suggesting that sexual dimorphism exists in utero. This study has also shown an association between some of the metabolic hormones in specific groups of infants and thus suggests that these hormones could have interacted in utero to regulate growth and fat storage during this critical period.

Changes in serum lipid and lipoprotein concentrations and compositions at birth and after 1 month of life in macrosomic infants of insulin-dependent diabetic mothers.

The aim of this study was to determine whether macrosomia related to maternal diabetes alters lipoprotein metabolism and whether these abnormalities still persist or regress after 1 month of life. Serum lipoprotein compositions and concentrations as well as serum lipid fatty acid compositions were investigated in macrosomic infants (birth weight = 4840 +/- 105 g at term) of insulin-dependent diabetic mothers at birth and after 1 month of life, and were compared to those of control infants (birth weight = 3400 +/- 198 g at term) of healthy mothers. Compared to controls, at birth, macrosomic newborns had higher serum lipids, apolipoprotein A-I and B-100, and lipoprotein (very low density lipoprotein, low density lipoprotein, high density lipoprotein-2 and high density lipoprotein-3) levels. Higher percentages of C18:2n-6 in serum triacylglycerols, phospholipids and cholesteryl esters were also observed. At day 30, in macrosomics, serum triacylglycerol, apo B-100, very low density lipoprotein and low density lipoprotein levels were still significantly higher. C18:2n-6 and C18:3n-3 contents in serum phospholipids, triacylglycerols and cholesteryl esters were reduced while C20:4n-6 and C22:6n-3 contents in serum phospholipids and cholesteryl esters were enhanced, compared to control values. Macrosomia was associated with alterations in lipoprotein compositions and concentrations at birth, some of which persisted after 1 month of life, and might play a role in the pathogenesis of diabetes and atherosclerosis in adult life.

QUANTITATIVE CONCORDANCE BETWEEN GLOBIN mRNAs AND SYNTHESIS OF FETAL HEMOGLOBIN (HbF) AND ADULT HEMOGLOBIN (HbA) DURING HYPOXEMIC STRESS ERYTHROPOIESIS. † 1293

Increased production of HbF can be considered a marker for hypoxemia, since increased levels of HbF synthesis have been found in newborn infants following maternal hypoxemia, placental insufficiency, and diabetes, as well as in infants with broncho-pulmonary dysplasia and children with congenital cyanotic heart disease. To examine if a quantitative relationship exists between the mRNAs encoding globins and their translation into proteins during hypoxemic erythropoietic stress, the relative amounts of the mRNAs and the relative amounts of the α,β,γ-globin synthesis in samples obtained from cord blood from infants of insulin-dependent diabetic mothers, intrauterine growth-retarded infants of preeclamptic mothers and older infants with cyanotic heart disease were measured and compared. The synthesis of globins in reticulocytes was measured by the incorporation of [3H]-leucine followed by the separation and quantitation of the polypeptides on a C4-reverse phase HPLC. The relative proportions of the mRNAs of globins were determined by RNase protection assay. Total RNA isolated from blood (50μl) was incubated with [32P]-labelled cRNA probes ofα,β,γ-globins, followed by RNase A/T1 digestion, separation of the protected fragments and densitometry of the radioactive bands by phosphorimaging. The study population showed an increase in HbF synthesis, compared to controls. There was a strong correlation (r2=0.993; n=16) between the ratio of mRNAs encoding HbF and HbA and the ratio of de novo synthesis of HbF and HbA. Therefore, under conditions of stress erythropoiesis there is a close correlation between quantitation of globin mRNAs and HbF& HbA synthesis. As well, globin mRNA quantitation could replace the usual method of HbA & HbF synthesis determination.

A role for DNA mutations in diabetes-associated teratogenesis in transgenic embryos.

Congenital malformations are the leading cause of death in infants of insulin-dependent diabetic mothers. Although there are data to suggest that hyperglycemia itself is teratogenic, few mechanisms have been proposed to explain diabetic embryopathy. To address the possibility that DNA mutations play a role in the fetal malformations associated with diabetes, we developed a transgenic mouse model system to measure the mutation frequency of a neutral target gene, lacI, during embryonic development in a maternal hyperglycemic environment. Despite the short 21-day gestational period of the mouse, we observed a twofold increase in the mutant frequency of the lacI transgene in fetuses that developed in a mild diabetic environment (blood glucose > 8.3 mmol/l) compared with those that developed under normoglycemic conditions (blood glucose < 8.3 mmol/l). These data provide the first direct evidence of the genotoxic effect of diabetes in vivo and suggest a mechanism for the teratogenicity of the maternal diabetic environment.

Glycerol metabolism and triglyceride-fatty acid cycling in the human newborn: effect of maternal diabetes and intrauterine growth retardation.

Kinetics of glycerol metabolism and triglyceride/fatty acid cycling were quantified in 12 healthy, normal, appropriate-for-gestational-age (AGA) infants, eight small-for-gestational-age (SGA) infants, and five infants of insulin-dependent diabetic mothers (IDM) at less than 48 h of age. Stable isotope-labeled [2-13C]glycerol and [6,6-2H2]glucose in combination with indirect respiratory calorimetry were used. The tracers were used as constant rate infusion and steady state isotopic enrichment of glucose, glycerol, and bicarbonate was measured by mass spectrometric methods. After a 7- to 9-h fast, the plasma glucose, glycerol, and FFA concentrations were similar in the AGA and IDM groups. In the SGA group, the plasma glucose concentration was significantly lower than that in the AGA group throughout the study, but plasma FFA and glycerol concentrations were not different from those in the AGA infants. Plasma betahydroxybutyrate concentration was significantly elevated in the AGA group compared with IDM and SGA infants (AGA 0.59 +/- 0.39, SGA 0.35 +/- 0.09, IDM 0.33 +/- 0.21 mmol/L; mean +/- SD). The rate of appearance of glycerol was significantly elevated (p less than 0.05) in SGA infants (AGA 9.47 +/- 2.11, IDM 9.55 +/- 2.14, SGA 12.15 +/- 3.87 mumol/kg.min). Between 80 and 90% of glycerol turnover was converted to glucose, accounting for 20% of glucose turnover with no significant difference in the three groups. Approximately 35% of glycerol carbon was recovered in the bicarbonate (CO2) pool. Less than 5% of CO2 carbon was derived from glycerol. Estimation of triglyceride-fatty acid cycle revealed that the triglyceride energy mobilized was increased in SGA infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of hyperglycemia on mitochondrial morphology in the region of the anterior neuropore in the explanted rat embryo model: Evidence for a modified Reid hypothesis as a mechanism for diabetic teratogenesis

Congenital malformations are the leading cause of the increased perinatal mortality in the infants of insulin-dependent diabetic mothers. The mechanisms(s) of diabetic teratologic development has yet to be defined. Hyperglycemia is known to depress aerobic metabolism in many organisms and cell lines. Reid hypothesized that exposure to hyperglycemia could result in decreased mitochondrial biogenesis in embryonic cells. Should these cells suddenly be changed to an environment of lower glucose concentration, decreased energy capabilities would exist until sufficient numbers of mitochondria could be regenerated. Such cells may not be capable of meeting temporal-spatial requirements, thereby resulting in structural abnormalities. In our study the explanted rat embryo model demonstrated that in the head-fold region hyperglycemia produced morphologic alterations of mitochondria but no difference in the number of mitochondria per cell. Specifically, embryos cultured in euglycemia demonstrated orthodox mitochondrial configuration, whereas those cultured in hyperglycemia had mitochondria in a condensed configuration. These findings were reversible. A modification of Reid's original hypothesis may provide an explanation for the mechanism of diabetic teratologic development. (AM J OBSTET GYNECOL 1991;165:1661-6.)

Cerebral Blood Flow Velocity and Cardiac Output in Infants of Insulin-Dependent Diabetic Mothers

Cardiac output and cerebral blood flow velocity in the anterior cerebral and internal carotid arteries were investigated in eight large-for-date infants of insulin-dependent diabetic mothers and 12 healthy term infants during the first four days of life using two-dimensional/pulsed Doppler ultrasound. Temporal mean flow velocity was used as an indicator of changes in cerebral blood flow. Six of the eight infants of diabetic mothers had ventricular septal hypertrophy with reduced cardiac outputs and stroke volumes. Mean flow velocity in both cerebral vessels showed a comparable pattern in both groups throughout the study period and was independent of mean arterial pressure, suggesting unaltered cerebral hemodynamics in the infants of diabetic mothers.

Macrosomia in Infants of Insulin-Dependent Diabetic Mothers

BERK, MICHAEL A.; MIMOUNI, FRANCIS; MIODOVNIK, MENACHEM; HERTZBERG, VlCKl; VALUCK, JENNIFER Author Information

Macrosomia in Infants of Insulin-Dependent Diabetic Mothers

The purpose of the present study was to evaluate factors affecting the rate of macrosomia and related complications in a population of infants of insulin-dependent diabetic mothers. The following factors were hypothesized to be predisposing to macrosomia: increased maternal weight gain during gestation, increased number of births until infant No. 3, white race, increased maternal age, poor glycemic control from the 20th week of gestation, and increased insulin dose. Advance White classification and increased duration of diabetes were predicted to be inversely related. In addition, macrosomia was hypothesized to predispose to selected adverse perinatal outcomes including premature labor, birth asphyxia, birth injury, hypoglycemia, polycythemia, and respiratory distress syndrome. From 1978 to 1986, 127 pregnancies were prospectively studied, 86 of the total number of women were entered prior to 10 weeks' gestation, and 41 were entered after 10 weeks' gestation. Patients monitored blood glucose at least twice daily with glycemic control achieved by "split-dosage" regimens of insulin. Glycohemoglobin was measured monthly. Pregnancy dating was based on the date of the last menstrual period and the Ballard score of the infant at birth. Macrosomia was defined as a birth weight greater than the 90th percentile of the intrauterine growth curves of Lubchenco. Of the babies born to mothers with insulin-dependent diabetes, 43% were large for gestational age and 57% were appropriate for gestational age.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic Disorders and Major Extracardiac Anomalies Associated With the Hypoplastic Left Heart Syndrome

All pediatric autopsies of patients with hypoplastic left heart syndrome seen during an 11-year interval were reviewed to determine the frequency of underlying chromosomal and single-gene defects and idiopathic major extracardiac anomalies associated with this common, lethal congenital heart abnormality. Of 83 patients identified, nine had underlying chromosomal abnormalities, four had single-gene defects, ten had one or more major extracardiac anomalies without an identifiable chromosomal or mendelian disorder, and two were infants of insulin-dependent diabetic mothers. Overall, 23 patients (28%) had a genetic disorder and/or major extracardiac anomaly. The substantial prevalence of genetic causes of and major extracardiac anomalies associated with hypoplastic left heart syndrome underscores the need for a detailed genetic evaluation for all patients with hypoplastic left heart syndrome.

Perinatal asphyxia in infants of insulin-dependent diabetic mothers

Infants of diabetic mothers are thought to be at risk for perinatal asphyxia. We hypothesized that the following are significant risk factors for perinatal asphyxia: poor third-trimester glycemic control, diabetic vascular disease (nephropathy, retinopathy) appearing in pregnancy, pregnancy-associated hypertension, smoking, prematurity, fetal macrosomia, and maternal hyperglycemia and hypoglycemia within 6 hours preceding delivery. We prospectively studied 162 infants born to 149 diabetic mothers (White classes B through R-T). Perinatal asphyxia was defined clinically as fetal distress during labor (late decelerations, persistent fetal bradycardia, or both), 1-minute Apgar score less than or equal to 6, or intrauterine fetal death. Forty-four infants (26.7%) had perinatal asphyxia. The presence of perinatal asphyxia did not correlate with third-trimester glycemic control, pregnancy-associated hypertension, smoking, fetal macrosomia, or maternal hypoglycemia before delivery, but it did correlate significantly with nephropathy appearing in pregnancy, maternal hyperglycemia before delivery, and prematurity. We speculate that (1) the appearance of diabetic vasculopathy (nephropathy) during pregnancy is accompanied by placental vascular disease and subsequently by fetal compromise and (2) in pregnancy complicated by diabetes, maternal and subsequently fetal hyperglycemia before delivery leads to fetal hypoxemia.

Infants of diabetic mothers: late normalization of fetal cyclic motility persists after birth.

The prenatal development of cyclic motility (CM) in the human is disrupted by maternal diabetes, but appears normal by the end of gestation. To determine whether birth and adaptation to postnatal life reveal new or persisting abnormalities in CM, 24 newborn infants of insulin-dependent diabetic mothers (IDMs) and 24 normal newborns were studied for 2-4 hr in a controlled environment. Spectral analysis of spontaneous movement revealed that CM was common in both groups. Measures of its cyclic organization in each state did not differ between IDMs and controls. State differences were the same in the two groups, and replicated the pattern found in a previous study of normal newborns. For IDMs, there were no differences associated with neonatal evidence of increased glucose supply in utero (macrosomia, postnatal hypoglycemia), or with determinations of prenatal maternal hyperglycemia. IDMs had also been studied as fetuses, and the pattern of continuity and change in CM across birth replicated the pattern previously reported for normal fetuses. The results suggest that the development and control of CM is buffered from the prenatal metabolic insults suffered by IDMs, and support speculations that cyclic activation is a general and robust property of the developing motor system in the human.

Combing Diabetes' Teratogenic 'Suspect List'

ABSTRACT INFANTS of insulin-dependent diabetic mothers have a twofold to threefold higher rate of congenital malformations than infants of mothers without the disorder. In recent years, blood glucose has topped the list of teratogenic suspects, so much so that a recent controversial study suggested that slightly elevated levels even in nondiabetic mothers were associated with an increased incidence of congenital abnormalities in their offspring (N Engl J Med 1986;315:989-992). However, the inclusion of anomalies not typically associated with diabetic pregnancies raised questions about the study's conclusions (N Engl J Med 1987;316:1343-1346).Now, data from the Diabetes in Early Pregnancy Study, one of the largest ever to follow diabetic women throughout their pregnancies, suggest that while glucose control plays a role in malformations, investigators must redouble their search for other factors if they hope to prevent problems such as caudal regression (sacral dysgenesis and hypoplasia of the femora) and congenital heart defects

Management of the insulin-dependent diabetic during labor and delivery. Influences on neonatal outcome.

Infants of insulin-dependent diabetic mothers are at risk for neonatal polycythemia, hyperbilirubinemia, respiratory distress syndrome (RDS), and hypoglycemia. The purpose of this study was to determine whether labor and delivery management of diabetes may influence the rate of these complications. We hypothesized a priori that: infants of diabetic mothers delivered by cesarean section have a lower rate of neonatal polycythemia and hyperbilirubinemia, but a higher rate of RDS, than infants of diabetic mothers delivered by vaginal route, and poor glycemic control during labor increases the rate of neonatal hypoglycemia. We therefore prospectively studied 122 pregnancies in 100 well-controlled insulin-dependent diabetic mothers. Intravenous glucose and/or insulin was infused during labor to maintain capillary glucose concentration between 70 and 100 mg/dl. Fifty-six pregnancies were concluded by primary or elective cesarean section (group 1), 36 by cesarean section following spontaneous or induced labor (group 2), and 30 by spontaneous or induced vaginal delivery (group 3). Hemoglobin A1, birthweight, and gestational age were similar in all three groups. The rate of neonatal polycythemia was significantly lower in the cesarean section subjects, groups 1 and 2, as compared to group 3 (P less than 0.04). The rate of neonatal hyperbilirubinemia was significantly lower in group 1 (P less than 0.05) as compared to groups 2 and 3. The rate of RDS was higher in group 1 (versus groups 2 or 3), but did not reach significance on initial analysis (P = 0.06); however, group 1 was associated with a significant risk for RDS when corrected for the confounding variables of gestational age and neonatal asphyxia as defined by Apgar scores.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased platelet thromboxane B 2 production in newborn infants of diabetic mothers

Platelet thromboxane B 2(TxB 2) production, plasma concentrations of C-peptide and pancreatic glucagon as well as blood glucose levels were measured in 12 infants of insulin-dependent diabetic mothers and eight healthy controls at the age of two hours. Platelet TxB 2 production (p<0.05) and plasma C-peptide levels (p<0.02) were significantly higher and blood glucose concentrations lower (p<0.002) in the infants of the diabetic mothers than in the controls. The data suggest that platelets of infants of diabetic mothers produce increased amounts of proaggregatory thromboxane A 2, which may contribute to the hyperaggregation in these infants.

Influence of the Maternal Plasma Glucose Concentration at Delivery on the Risk of Hypoglycaemia in Infants of Insulin-Dependent Diabetic Mothers

Diabetes Centre, Department of Obstetrics and Gynaecology, and Neonatal Department, Rigshospitalet, University of Copenhagen, and Hvidore Hospital, Klampenborg, Denmark

Cardiac output in infants of insulin-dependent diabetic mothers

The purpose of our study was to quantitate left ventricular outflow obstruction in the infant of the diabetic mother (IDM) through estimation of cardiac output by pulsed Doppler ultrasound. We evaluated 42 IDMs (White class B, C, or D) and compared them with two control groups, one similar in birth weight and the other similar in gestational age. Ventricular septal hypertrophy was found in 18 (43%) of 42 of the IDMs, but in none of the control infants. Morbidity increased with advancing septal thickness. None had hyaline membrane disease. Twenty-nine IDMs were asymptomatic, 11 of whom had septal hypertrophy. Thirteen IDMs developed congestive heart failure, seven of whom had septal hypertrophy. Cardiac output per kilogram diminished linearly with increasing septal thickness (r = -0.78, P less than 0.001) secondary to reduced stroke volumes at comparable heart rates. The IDMs had higher left atrial/aortic ratios and greater right ventricular systolic time intervals than the control infants. We conclude that cardiac output is significantly reduced in IDMs with septal hypertrophy. This reduction is secondary to reduced stroke volume and is directly related to the degree of septal hypertrophy.

Relative Rates of Fetal Hemoglobin and Adult Hemoglobin Synthesis in Cord Blood of Infants of Insulin-Dependent Diabetic Mothers

Erythrocytosis, extramedullary erythropoiesis, and increased levels of plasma erythropoietin have been observed in newborn infants of diabetic mothers. Because there is evidence that there is a relationship between increased fetal hemoglobin production and acute erythropoietic expansion, it was considered important to study the proportion of fetal hemoglobin and adult hemoglobin synthesis in newborn infants of insulin-dependent diabetic mothers. Samples from nine newborn infants of diabetic mothers as well as nine control infants, ranging from 36 to 38 weeks of gestation, were incubated in an amino acid mixture containing [14C]leucine. The adult hemoglobin and fetal hemoglobin were then separated by column chromatography on DEAE [O-(diethylaminoethyl)] Sephadex. To confirm that the fetal hemoglobin obtained after Sephadex chromatography was not contaminated with other hemoglobins, several of the DEAE separations from each group were reconstituted and subjected to polypeptide chain elution using carboxyl-methyl cellulose chromatography. The data demonstrated that the newborn infants of diabetic mothers are synthesizing significantly more fetal hemoglobin than is expected for their period of development (82.2 +/- 3.6 v 72.8 +/- 4.2; P less than .005). It is suggested that the in utero environment of the fetus of the diabetic mother causes an increase in fetal hemoglobin synthesis.