Insulin-dependent Diabetic Mothers Research Articles

The spectrum of congenital heart defects in neonates of diabetic mothers

Introduction: Insulin-dependent diabetes mellitus (IDDM) in a mother is considered a risk factor for congenital malformation, including congenital heart diseases. Many studies signify a five to six times increased frequency of congenital heart diseases in neonates born from insulin-dependent diabetic mothers. This study aimed to identify the spectrum of congenital heart diseases (CHDs) in neonates born from insulin-dependent diabetes mellitus (IDDM) mothers. Methods: Between April 2019 and March 2021, a descriptive cross-sectional study involved 120 consecutive neonates aged 0-28 days of mothers with insulin-dependent diabetes mellitus (IDDM) at Maiwand Teaching Hospital, Kabul University of Medical Sciences. Neonates born to non-diabetic mothers were excluded. IDDM refers to mothers using Insulin upon admission to control blood glucose. CHD encompasses various heart defects affecting function. Family and maternal history were noted, focusing on health issues and delivery details. Neonatal mothers' ages ranged from 23 to 45 (mean 33), with diabetes onset spanning 2.5 to 25 years. Pediatric cardiologists conducted physical and echocardiographic exams. All CHD forms were documented using 2D echocardiography and Doppler studies (Sono Ace X-6 Machine). Result: 120 consecutive neonates born to mothers with insulin-dependent diabetes mellitus (IDDMs) were investigated during the two-year study period. Of them, 18 (15%) had congenital heart abnormalities. The prevalence of solitary and multiple CHD was 66.6 percent (12 patients) and 33.3 percent (6 patients) in the 18 infants born from IDDMs. The most prevalent isolated defects were PDA (22.2%) and Ventricular septal defect (16.6%). The most common multiple CHDs (16.6 percent) were PDA and ASD. PDA + ASD (16.6%) and VSD + PDA were the most frequent correlations with CHD (11.1 percent). Conclusion: Maternal insulin-dependent diabetes mellitus is an important risk factor for congenital heart disease. Careful assessment and early diagnosis of CHD in this high-risk group are very important in a pediatric population. Expansion of prenatal screening programs for CHDs in mothers suffering from insulin-dependent diabetes mellitus is necessary. Keywords: congenital heart diseases; diabetic mothers; insulin dependent; neonates

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..

Outcomes of Extremely Preterm Infants Born to Insulin-Dependent Diabetic Mothers.

Little is known about in-hospital morbidities and neurodevelopmental outcomes among extremely preterm infants born to women with insulin-dependent diabetes mellitus (IDDM). We examined risks of mortality, in-hospital morbidities, and neurodevelopmental outcomes at 18 to 22 months' corrected age between extremely preterm infants of women with insulin use before pregnancy (IBP), with insulin use started during pregnancy (IDP), and without IDDM. Infants 22 to 28 weeks' gestation born or cared for at a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network center (2006-2011) were studied. Regression models compared the association between maternal IDDM and timing of insulin use and the outcomes of the 3 groups. Of 10 781 infants, 536 (5%) were born to women with IDDM; 58% had IBP, and 36% had IDP. Infants of mothers with IBP had higher risks of necrotizing enterocolitis (adjusted relative risk [RR] = 1.55 [95% confidence interval (CI) 1.17-2.05]) and late-onset sepsis (adjusted RR = 1.26 [95% CI 1.07-1.48]) than infants of mothers without IDDM. There was some indication of higher in-hospital mortality risk among infants of mothers with IBP compared with those with IDP (adjusted RR = 1.33 [95% CI 1.00-1.79]). Among survivors evaluated at 18 to 22 months' corrected age, average head circumference z score was lower for infants of mothers with IBP compared with those without IDDM, but there were no differences in risk of neurodevelopmental impairment. In this cohort of extremely preterm infants, infants of mothers with IBP had higher risks of necrotizing enterocolitis, sepsis, and small head circumference.

2069007 Caudal Regression Syndrome: A Case Report and Review of Literature

To report an interesting case of Caudal Regression Syndrome diagnosed intra-utero, to compare ultrasound and magnetic resonance findings and also to perform a brief literature review on this subject. This is a Case Report and Literature Review. 21 years-old female, primigravida with uncontrolled Class C diabetes was referred to to our Maternal Fetal Medicine Service for second trimester anatomy ultrasound. The scan detected a singleton pregnancy of 21 weeks and 3 days and estimated fetal weight of 433g. The fetus had bilateral clubfoot and reduced vertebrae number of the lower spine with a total of 3 lumbar and 2 sacral vertebras. The picture was suggestive of Caudal Regression Syndrome and Agenesis of lower spine. Patient was referred to a fetal MRI at 34 weeks and the findings were compatible with ultrasound ones. Patient was submitted to an elective cesarean section at term for maternal request. Computed tomography and spine x-ray of the neonate showed absence of lumbar vertebrae L4 and L5 and fusion of sacral vertebrae confirming the diagnosis of Caudal Regression Syndrome with Sacral Agenesis type 1. Caudal regression syndrome consists of a spectrum of structural defects of the caudal region, including incomplete development of the sacrum and sometimes of the lumbar vertebrae. This syndrome seems to occur with increased incidence in children of insulin-dependent diabetic mothers, although the mechanisms for this association are not clear. It also might be associated with genetic predisposition and vascular hypopefusion. The clinical presentation is highly variable, depending on the level of the spinal lesion. Affected infants may appear to have a small pelvis, neurogenic bladder, and variable degrees of limb deformity, depending on the level of the defect. Prenatal ultrasound is the standard for the diagnosis of fetal anomalies. However, fetal MRI has emerged as a valuable diagnosis tool to complete the study of fetal malformations. The approach of those cases should be multidisciplinar since treatment options are limited and the outcomes usually irreversible.

Zinc Protoporphyrin–to–Heme Ratios in High-Risk and Preterm Infants

To refine the reference range for the zinc protoporphyrin-to-heme ratio (ZnPP/H) of preterm infants, we assessed the impact of maternal risk factors on ZnPP/H and evaluated the impact of changes in iron supplementation on iron status. The reference range for neonatal ZnPP/H was refined using prospective data from 31 reference infants ≤ 35 weeks' postmenstrual age (PMA) plus retrospective data from 51 infants <30 weeks' PMA, and 59 infants 30-40 weeks' PMA. Cord blood and first week of life values were compared when both were available. The impact of maternal risk factors was assessed by examining prospectively collected ZnPP/H from 48 high-risk infants. The effect of changing iron supplementation guidelines was evaluated by retrospective chart review of serial ZnPP/H from 194 infants. Cord ZnPP/H was lower at 30-35 weeks' gestation than at 24-26 weeks' gestation (P = .01). Cord ZnPP/H values from insulin-dependent diabetic mothers were elevated compared with reference values. Changing the iron supplementation protocol was not associated with improved ZnPP/H measurements. Cord blood and postnatal reference ranges for ZnPP/H are defined. Iron balance depends on a complex interaction of prenatal and postnatal factors.

Status of Toxic Metals in Biological Samples of Diabetic Mothers and Their Neonates

The mechanism of transport of trace elements from the mother to the newborn is still not well known. The aim of present study was to compare the status of trace toxic elements, arsenic (As), cadmium (Cd), and lead (Pb) in biological samples (whole blood, urine and scalp hair) of insulin-dependent diabetic mothers (age ranged 30-40) and their newly born infants (n = 76). An age and socioeconomics matched 68 nondiabetic mothers and their infants, residing in the same locality, who were selected as referents. The elemental concentrations in all three biological samples were determined by an electrothermal atomic absorption spectrometer, prior to microwave-assisted acid digestion. The mean values of As, Cd, and Pb in all biological samples of diabetic mothers and their infants were significantly higher as compared to the referent mother-infant pair samples (p < 0.01). The high levels of As, Cd, and Pb in biological samples of diabetic women may play a role in the pathogenesis of diabetes mellitus and impacts on their neonates.

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.

Is there a Relationship between Metabolic Control and Glucose Concentration in Breast Milk of Type 1 (Insulin-Dependent) Diabetic Mothers?

We studied glucose concentration of breast milk of nursing diabetic mothers and its possible relationship to the quality of metabolic control. Eleven Type 1 (insulin-dependent) diabetic mothers and 11 age-matched control subjects were included in the study. Although a near-normoglycemic control of diabetic mothers was accomplished by intensified insulin treatment, the HbA1 value was significantly higher in comparison to non-diabetic mothers (8.1 +/- 0.9% versus 6.2 +/- 0.5%; p less than 0.01). Regardless of this, the glucose concentration of breast milk did not differ between diabetic mothers and that of non-diabetic women (0.68 +/- 0.50 mmol/l versus 0.66 +/- 0.55 mmol/l). No correlation exists between glucose concentration of breast milk and relevant blood glucose concentration as well as glycosylated haemoglobin A1 of the mother. In conclusion, our data support the view that breast-feeding of infants of diabetic mothers is not associated with an increased offer of glucose and thus not being of importance as a possible mechanism to sustain a hyperinsulinemic state in the newborns.

Status of essential trace metals in biological samples of diabetic mother and their neonates

There is accumulating facts that the metabolism of essential trace elements is altered in diabetic patients. The aim of present study was to compare the status of essential trace elements, chromium (Cr), manganese (Mn), and zinc (Zn) in biological samples (whole blood, urine and scalp hair) of insulin dependent diabetic mothers (age ranged 30-40) and their newly born infants (n = 76). An age matched 68 non-diabetic mothers and their infants, residing in the same locality, were selected as referents. For a comparative study, the biological samples of non-diabetic and diabetic pregnant and non pregnant of same age group and socio-economics status were also analysed. The biological samples (scalp hair, blood and urine) were collected from study and referent groups. The Cr, Mn and Zn concentrations in all three biological samples were determined by a flame/electrothermal atomic absorption spectrometer, prior to microwave assisted acid digestion. The validity and accuracy of the methodology was checked by certified reference materials (CRMs) and using conventional wet acid digestion method on same CRMs. The mean values of Cr, Mn and Zn in scalp hair and blood samples of diabetic mothers and their infants were significantly lower as compared to the referent mothers-infants pairs (p < 0.01), while urinary excretion of all these elements were high in diabetic mother-infant pair samples. The deficiencies of essential trace elements, Cr, Mn and Zn in biological samples of diabetic women, may play role in the pathogenesis of diabetes mellitus and impacts on their neonates.

ENOS, COX-2, and prostacyclin production are impaired in endothelial cells from diabetics

The vascular endothelium is a well-recognized target of damage for factors leading to increased cardiovascular risk. Among the agents playing an important role in cardiovascular homeostasis, nitric oxide and prostacyclin represent key markers of endothelial integrity. In the present work, we report for the first time the reduced expression of both endothelial nitric oxide synthase and cyclooxygenase-2 (COX-2) proteins, as well as decreased prostacyclin production, in unstimulated human endothelial cells from insulin-dependent diabetic mothers when compared to cells from non-diabetic, control subjects. According to a major role of COX-2 as a source of prostacyclin production even in unstimulated endothelial cells, prostacyclin production was concentration-dependently inhibited by the selective COX-2 inhibitor SC236. Overall, our results suggest a possible link between reduced endothelial COX-2 and NO-synthase expression and the increased risk of cardiovascular diseases affecting diabetic patients, and point to the use of endothelial cells from diabetic patients as a tool for investigating early dysfunction in pathological endothelium.

Recurrence of fetal macrosomia (> 4500G) in gestational diabetes is less frequent than in non-diabetic pregnancies

LESS FREQUENT THAN IN NON-DIABETIC PREGNANCIES MICHAEL E. FOLEY, LESLIE DALY, MARY COFFEY, RICHARD FIRTH, BRENDAN KINSLEY, COLM O’HERLIHY, University College Dublin, Obstetrics and Gynaecology, Dublin, Ireland, University College Dublin, Public Health Medicine & Epidemiology, Dublin, Ireland, National Maternity Hospital, Dublin, Ireland, Ireland OBJECTIVE: To determine the incidence and rate of recurrence of fetal macrosomia (>4500 g) at term (>37 weeks) in singleton gestational diabetic (GDM) and non-diabetic pregnancies. STUDY DESIGN: GDM was diagnosed by selective screening (50 g glucose challenge), indicated by risk factors and performed at 29-32 weeks gestation; positive cases (>8.3 mmol/L) underwent a 100-g glucose tolerance test (considered positive if at least two abnormal values). GDM was audited prospectively (1998 to 2002) and the incidence of fetal macrosomia and the rate of its recurrence were compared with non-diabetic pregnancies. RESULTS: The institutional incidence of GDM was 1% (388/37,406); 3.3% of the antenatal population were screened. Among 388 GDM patients (multiparas 77%), the incidence of macrosomia at 7.9% (31/388) was significantly greater than among non-diabetic pregnancies (3.7%, 535/14,461; P ! .0001). Mean gestational age of GDM pregnancies at delivery (39.5 wk) was significantly less than among non-diabetics (40.6 wk; P ! .001). Of 535 non-diabetic women with a macrosomic infant, 34% (182/535) had undergone negative screening for GDM. The recurrence rate of macrosomia in GDM at 26%( 13/50), was half that in non-diabetics (59%, 166 /279; P ! .001). Among multiparas whose previous infant was not macrosomic, significantly more GDM mothers delivered macrosomic infants than non-diabetics (5.3% vs. 2.6%; P = .003). Best predicators of macrosomia in GDM pregnancies were previous macrosomic infant (29%), maternal age >40 years (17%), and weight >100 kg (16%). Among insulin-dependent diabetic mothers (>37 weeks), fetal macrosomia occurred in 13% (21/161) with a recurrence rate of 47% ( 8/17). CONCLUSION: Rate of recurrence of macrosomia in GDM is half that in nondiabetic pregnancies, suggesting that dietary intervention can influence birthweight outcome. Dietary modification might be considered in all women with a history of macrosomia. 159 SCREENING FOR GESTATIONAL DIABETES: DIFFERENT CUT-OFFS FOR DIFFERENT ETHNICITIES? TANIA ESAKOFF, YVONNE CHENG, AARON B. CAUGHEY, University of California, San Francisco, Department of Obstetrics, Gynecology and Reproductive Sciences, San Francisco, California OBJECTIVE: To examine whether screening guidelines for gestational diabetes should be modified based on ethnicity. STUDY DESIGN: This is a retrospective cohort study of 14,565 pregnancies screened for gestational diabetes between January 1988 and December 2001. Values of the 50-g glucose-loading test (GLT) were examined at 5-point increments from 130 mg/dL to 150 mg/dL. The sensitivity and false positive rates (FP) of various GLT cut-offs were compared among Caucasians, African Americans, Hispanics and Asians. Outcomes were compared using the c test. RESULTS: The overall prevalence of gestational diabetes in the study population was 6.3%. The prevalence of gestational diabetes when stratified by ethnicity was 4.1% in Caucasians, 4.3% in African Americans, 7.0% in Hispanics, and 9.7% in Asians. Sensitivities and false positive rates at GLT cutoffs ranging from 130 to 150 were stratified by ethnicity below (Table). CONCLUSION: To maximize the sensitivity and to minimize the false positive rate of the GLT, it may be reasonable to consider varying the cut-off based on ethnicity. For example, if the goal is to achieve maximum sensitivity but achieve approximately a 10% false-positive rate, we would recommend 135 mg/dL for African Americans, 140 mg/dL for Caucasians and Hispanics, and 145 mg/dL for Asians. Alternatively, if the goal is to achieve 95% sensitivity, the screening threshold would need to be 135 mg/dL for African Americans and 130 mg/dL for the other ethnicities.

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.

Glycosylated Hemoglobin and Protein Levels in Normal and Diabetic Pregnancies

DOI: http://dx.doi.org/10.5915/17-2_3-12756 The glycosylated fractions of hemoglobin i.e. Glycohemoglobin (GlycoHb) and of the plasma proteins i.e. Glycoprotein (GlycoPR) levels were quantitated using an affinity chromatographic technique in the cord and maternal blood of normal (Group I), White's Class A diabetic (Group II), and insulin-dependent diabetic (Group III) women. There was a significant increase of GlycoHb and GlycoPR levels in Group III compared lo Group I neonates. Maternal GlycoHb but not GlycoPR levels were significantly higher in Group Ill patients. Maternal and cord blood GlycoHb and GlycoPR levels in Class A diabetics were not different from those levels in the normal group. We conclude that the fetuses of insulin-dependent diabetic mothers are hyperglycemic in utero.

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.

Overweight and obesity in infants of mothers with long-term insulin-dependent diabetes or gestational diabetes.

To analyse the development of body weight and frequencies of overweight and obesity in infants of long-term insulin-dependent diabetic mothers as compared to those of gestational diabetic mothers. Retrospective study. Two hundred infants of mothers with pregestational insulin-dependent diabetes mellitus (IDM) and 117 infants of gestational diabetic mothers (IGDM) born between 1980 and 1990 at the Clinic of Obstetrics and Gynaecology, Berlin-Kaulsdorf, Germany. Birth weight, birth length, plasma insulin, interscapular skinfold, symmetry index (SI) and body mass index (BMI) at birth; SI and BMI in childhood (1-9y of age). Neonatally, mean relative weight (SI) was found to be increased in both groups of infants. It was positively correlated to interscapular skinfold (P < 0.001) and insulin (P < 0.005). However, IDM had higher insulin levels (P < 0.001) and a higher frequency of obesity (P < 0.05) than IGDM at birth. Throughout childhood frequencies of overweight (SI > 1.1) were elevated in both IDM as well as IGDM. In IDM the percentage of obesity (SI > 1.2) displayed a significant increase from 11.2% in children 1-4y old up to 25.8% at 5-9y (P < 0.05). Similar frequencies and a highly significant increase of overweight during childhood of IDM (P < 0.005) were observed when BMI > or = 95th percentile was used to determine overweight. Relative weight in childhood was positively correlated to relative weight at birth (P < 0.05). Large-for-gestational-age infants displayed a significantly higher percentage of overweight (SI > 1.1) in childhood than appropriate-for-gestational-age infants (P < 0.05). Infants of mothers with diabetes during pregnancy are predisposed to develop overweight and obesity during childhood. These alterations seem to be related to insulin and relative body weight at birth. Pathophysiological mechanisms which might be involved into the development of these changes are discussed. Prophylactic measures are recommended to reduce morbidity in infants of diabetic mothers.

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.

Mouse embryonic cardiac metabolism under euglycemic and hypoglycemic conditions.

Children of mothers with insulin-dependent diabetic mothers (IDDM) have a 2-4 times higher incidence of congenital birth defects as compared to the general population, including cardiac abnormalities, of unknown etiology. Using rodent embryos to explore potential teratogenic factors of the altered IDDM metabolism, it has been shown that exposure to hypoglycemia in vitro results in a variety of defects, including cardiac malformations. Since pregnant diabetics experience frequent episodes of low blood glucose, it was hypothesized that hypoglycemia may play a role in the generation of heart abnormalities seen in children born to IDDM mothers. Several studies have indicated that during embryogenesis the heart is dependent on glucose for energy production such that under hypoglycemic conditions, insufficient amounts of ATP may be produced resulting in abnormalities. To test this hypothesis, cardiac ATP content was monitored in D10-D12 (plug day = D1) hearts. In addition, the contribution of glycolysis and the Krebs cycle to ATP production was monitored. D10 hearts exposed to euglycemic control conditions were found to be primarily dependent on glycolysis for ATP production from glucose before switching to the Krebs cycle and oxidative phosphorylation for energy production from this substrate on D11. Exposure to hypoglycemia did not alter the timing of this maturation process or deplete cardiac ATP content. However, cardiac lactate levels increased approximately twofold in the presence of hypoglycemia on d10. Since increased concentrations of lactate are harmful to many tissues and have been shown to be detrimental to the adult rat heart, lactic acidosis may explain the origin of cardiac defects produced by hypoglycemia, and not a deficiency of ATP.

Cardiac Doppler Flow Velocities in Fetuses of Well- Controlled Insulin-Dependent Diabetic Mothers

The advent of Doppler echocardiography has permitted noninvasive examination of the fetal heart. In this study, computer-assisted cardiac Doppler flow velocity waveform (DFVW) analysis was used to determine whether diastolic dysfunction is manifest in the fetuses of diabetic mothers. Diastolic atrioventricular (AV) valve flow was measured in the fetuses of 40 women with well-controlled insulin-dependent diabetes mellitus (IDDM) at 18 to 22 weeks (timepoint A) and 30 to 35 weeks (timepoint B) gestation. These subjects were compared to 40 age-matched pregnant non-diabetic controls, and their maternal glycosylated hemoglobin HbA1c fractions (%) were measured to gauge the adequacy of glycemic control. HbA1c fractions showed no statistically significant difference between timepoints A and B (4.85 ± 0.2% and 5.16 ± 0.3%, respectively), and demonstrated a well-controlled diabetic state.At timepoint A, the peak velocity of rapid ventricular filling [E (cm/s)] through both AV valves, the peak velocity of atrial contraction [A (cm/s)] through the tricuspid valve, and the flow integral measurement for atrial contraction [AI (cm)] through the tricuspid valve were significantly (p &lt; 0.05) higher than those measured in the controls. Peak velocities of atrial contraction and rapid ventricular filling (A and E, respectively) for both valves, as well as the flow integral of rapid ventricular filling (EI) for the tricuspid valve, were significantly (p &lt; 0.05) higher in fetuses of diabetic mothers at timepoint B than in controls. Overall, despite the fact that both IDDM and non-diabetic mothers showed significant (p &lt; 0.05) fetal increases in rapid ventricular filling (E) between the two timepoints, the ratios E/A and EI/AI for both valves were not modified in the two study groups at either gestational age. These results therefore substantiate rare previous findings that only peak velocity of rapid ventricular filling (E) is increased, despite expected changes in E/A and EI/AI ratios, with gestational age. Furthermore, the results of the present study suggest that fetal diastolic function is not adversely affected in well-controlled maternal IDDM.

Long-term prognosis of infants of diabetic mothers. Relationship between metabolic disorders in newborns and adult offspring.

The aim of our study was to find out whether the metabolic disorders in the newborns of insulin-dependent diabetic mothers (NDM) in the neonatal adaptation period could be associated with their condition in adulthood. We examined 148 children of diabetic mothers (CDM) aged 20.75 +/- 0.31 years (mean +/- SE); 11 were diabetic patients, while in the remaining 137 CDM, the oral glucose tolerance test (OGTT) was performed. CDM were compared with 31 matched control offspring of healthy mothers. Of the characteristic abnormalities occurring in NDM, the following were present in our study: macrosomia, hypoglycaemia, hyperlactacidaemia, hyperbilirubinaemia. In adulthood, the sum of the blood glucose and plasma insulin values during OGTT, body mass index (BMI) and blood pressure were determined. The observed abnormalities and the degree of their relevance in the neonatal period were not related to the sum of blood glucose and plasma insulin levels, BMI and blood pressure in adulthood, but the values of all these parameters in adulthood were significantly higher in CDM than in controls (P < 0.05-0.001).

Pathological Flow Properties of Blood in the Fetus and Neonate

Normal Hemorheology: Plasma proteins, plasma viscosity, and red blood cell (RBC) aggregation are very low in the fetus and the preterm infant, but increase with increasing gestational and postnatal age. Moreover, both the viscosity (F~hrffius-Lindqvist effect) and the hematocrit reductions (F~hrffius effect) in narrow tubes are more pronounced in the fetus and neonate than in adults. As a result of these peculiar hemorheological properties, viscosity of blood (measured in 50 ~m diameter tubes) with given hematocrit is markedly lower in the fetus (-50% at 25 wk gestation) and neonate (-25%) than in adults. Blood viscosity in 50-~m tubes is similar in neonates with a hematocrit of 0.70 III as in adults with a hematocrit of 0.50 III. This may explain why polycythemia does not impair systemic, cerebral and intestinal RBC transport in neonates as long as the hematocrit does not exceed 0.70 III and why polycythemic neonates are less susceptible to serious complications than polycythemic children and adults. Pathological Hemorheology: Since high flow conditions in the fetus and neonate are strongly dependent on the favorable rheologic properties of their blood, hemorheolocal abnormalities may contribute to the high risk of the fetus and neonate to ischemic damage of vital organs (e.g. brain) in a variety of disorders: 1) Perinatal asphyxia may be associated with impaired RBC deformability, increased RBC aggregation and leukocyte count, thereby aggravating tissue hypoxia. 2) In growth-retarded fetuses, increased hematocrit, RBC aggregation and leukocyte count may contribute to the high risk of ischemic damage of vital organs (e.g. brain). 3) Fetal and neonatal cells are less protected from radicals than adults, thereby predisposing them to oxidative damage. 4) Neonatal septic shock may be associated with markedly decreased RBC defo rm ability , increase in the count of rigid, immature leukocytes, RBC aggregation and plasma viscosity. 5) Infants of poorly-controlled insulin-dependent diabetic mothers show markedly increased hematocrit and decreased RBC deformability. This may increase their risk of thromboses.