Magnus Stangenberg

B-cell Function in Newborn Infants of Diabetic Mothers

SummarySerum concentrations of glucose, C-peptide, IRI (Immunoreactive insulin) and proinsulin were determined in 31 insulin-dependent diabetic mothers and their newborn infants and in 13 nondiabetic mothers and their babies at the time of delivery. Eleven mothers with long-term diabetes had insulin antibodies and low or undetectable C-peptide levels (mean ± SEM: 0.04±0.01 nmol/l). Diabetic mothers without insulin antibodies had a mean C peptide value of 1.18 nmol/1 (range 0.05–3.00) and the non-diabetics 0.95 nmol/l (0.28–2.4). Blood glucose values (2 to 4 hours after birth) of less than 1.7 mmol/l were observed in 7 of the 11 babies with antibodies and in 3 of the 20 babies without antibodies. C-peptide in the 31 babies of diabetic mothers correlated to maternal glucose (p < 0.05). In addition the mean glucose value (2–4 hours) was negatively correlated to IRI and proinsulin (p < 0.01) in the babies without antibodies, confirming that elevated maternal glucose leads to increased insulin secretion at the time of birth, which may lead to hypoglycaemia. In babies without antibodies birth weight correlated to their C-peptide (p < 0.01) and proinsulin (p < 0.01). The 31 babies of the diabetic mothers were born with higher C-peptide (1.01±0.16 nmol/ 1) than babies of non-diabetic mothers (0.39±0.04 nmol/1). The newborn infants secrete significantly more proinsulin than their mothers. Babies of mothers with insulin antibodies were born with the same concentrations of antibodies (Pearson correlation coefficient = 0.98) as in their mothers, but total IRI was higher in these babies, due in part to human proinsulin being bound to the antibodies. There were significant correlations between insulin antibodies on the one hand, and IRI, proinsulin and C-peptide on the other, in the 11 babies, p < 0.001, p < 0.001 and p < 0.01, respectively, the last indicating increasing B-cell activity with higher antibody levels.

Ontogeny of Insulin-Like Growth Factor-Binding Protein-1, −2, and −3: Quantitative Measurements by Radioimmunoassay in Human Fetal Serum

ABSTRACT: There is evidence for a role for IGF-I in the endocrine control of human fetal growth despite the low serum IGF-I concentrations. The formation in serum of binary complexes between IGF-I or -II and either of six IGF binding proteins (IGFBP-1 to −6) and, in particular, of long-lived ternary complexes between IGF-I or -II, IGFBP-3, and acid-labile subunit is thought to regulate IGF-I bioavailabil-ity by increasing its serum half-life. The present study assesses the bioavailability of circulating IGF-I in 19– to 35-wk gestation human fetuses in utero 1) by quantitative RIA measurements of IGF and IGFBP in serum and 2) by examining whether serum proteolysis of IGFBP-3 may further increase IGF-I bioavailability. Fetal serum concentrations of IGFBP-3, IGF-I, and IGF-II were low with marked or only modest increases with gestational age (p < 0.001, p < 0.005, and p < 0.05, respectively). The mean molar ratio between IGF-I plus -II and IGFBP-3 demonstrated a molar excess of IGF (50%) similar to that in adolescents but in contrast to the 1:1 molar ratio in adults. The median IGFBP-2 concentration was 3-fold elevated to a molar concentration similar to that of IGFBP-3 (adult serum displays 10-fold higher IGFBP-3 concentrations). The median serum IGFBP-1 concentration was not elevated as previously reported in newborns. IGFBP-3 protease activity was not increased in fetal serum, in contrast to pregnancy serum and amniotic fluid. Nevertheless, IGFBP-3 protease activity did interfere with IGFBP-3 determinations by Western ligand blotting, and IGFBP-1 and IGFBP-2 levels obtained by this technique did not correlate with concentrations determined by RIA, stressing the importance of quantitative IGFBP measurements. In summary, increased IGF-I bioavailability in the human fetus is suggested by the molar excess of IGF over IGFBP-3 and the increase in IGFBP-2, which do not form a long-lived ternary complex. The lack of suppression of fetal serum IGFBP-1 may suggest that the delivery of IGF-I to the tissues is normal.

Fetal beta cell function in diabetic pregnancy. Amniotic fluid concentrations of proinsulin, insulin, and C-peptide during the last trimester of pregnancy.

Proinsulin, insulin C-peptide, insulin-binding antibody, and glucose concentrations were measured in amniotic fluid samples from 43 insulin-treated diabetic patients and 17 nondiabetic control patients between the thirty-six and thirty-ninth weeks of gestation. Insulin-binding antibodies in amniotic fluid were present in only three diabetic patients, although antibodies in maternal serum were found in 22 of the diabetic subjects. In the diabetic group, maternal serum insulin-binding antibodies were statistically unrelated to levels of C-peptide in amniotic fluid. The mean amniotic fluid concentrations of proinsulin (0.07 nmole/L), insulin (0.08 nmole/L), C-peptide (1.17 nmoles/L), and glucose (2.09 mmoles/L) were markedly elevated (p less than 0.001) in diabetic patients, as compared to nondiabetic control patients, thus suggesting exaggerated fetal beta cell function. C-peptide was correlated to both insulin (r = 0.69) and proinsulin (r = 0.35) in the diabetic group only. Infant birth weight and amniotic fluid C-peptide was significantly correlated in both the control group (r = 0.54) and the diabetic group (r = 0.38). Diabetic pregnancies associated with neonatal morbidity (n = 25) had significantly higher mean amniotic fluid concentrations of both insulin and C-peptide than did pregnancies without neonatal morbidity (n = 18). The amniotic fluid values of C-peptide and insulin in these latter two subgroups were overlapping and, therefore, could not serve to predict neonatal outcome in the individual case.

Self-monitoring of blood glucose by diabetic women during the third trimester of pregnancy

The clinical value of self-monitoring blood glucose in diabetic pregnancy at home was compared with hospital care in the thirty-second to thirty-sixth week of pregnancy in a prospective randomized study including 100 pregnancies in 97 patients (Whites class B, 38; C, 25; D, 28; and F, 9) of which 54 were in the home group and 46 in the hospital group. The duration of pregnancy was not significantly different in two treatment groups, with a median duration of 266.0 days in the home group and 266.5 days in the hospital group. The mean blood glucose values during the study period were 5.9 mmol/L in the home group and 6.0 mmol/L in the hospital group, thus there were no significant group differences. There were no significant group differences in pregnancy complications; however, 10 of 54 (19%) had to interrupt home-monitoring because of pregnancy complications. The perinatal morbidity was not significantly different in the two treatment groups, with the following percentages of complications in the combined series: 4% idiopathic respiratory distress syndrome, 7% transient tachypnea, 2% symptomatic hypoglycemia, 16% hyperbilirubinemia, 22% feeding problems, and 10% erythrocytosis.

Insulin-induced hypoglycemia in pregnant diabetics. Maternal and fetal cardiovascular reactions.

Abstract. Insulin (0.1 IU/kg bw) was injected intravenously in 9 pregnant diabetics in the last trimester of pregnancy. Maternal levels of blood glucose, estriol, human placental lactogen, blood pressure and pulse rate were measured and fetal heart rate (FHR) recorded. During hypoglycemia maternal blood pressure remained unchanged but maternal pulse rate tended to increase. Plasma levels of estriol and HPL remained unchanged. In 6 of the 9 patients there was a decrease in FHR variability during the hypoglycemic period. FHR variability increased after normalization of maternal blood glucose levels. The decrease in FHR variability could be a direct effect of glucopenia on the fetal heart.

Acid-base status in fetal heart blood in erythroblastotic fetuses: A study with special reference to the effect of transfusions with adult blood

Blood gas levels, pH, and lactate concentration were studied in fetal heart blood on 70 occasions in 26 fetuses with erythroblastosis. A decreasing hemoglobin concentration correlated to a fall in pH (p = 0.006) and bicarbonate (p = 0.015) and to a rise in base deficit (p = 0.002) and lactate concentration (p = 0.05). Twenty of the fetuses underwent 63 intracardiac transfusions. A multivariance analysis for hemoglobin concentration, percentage of fetal to adult blood, and different acid-base parameters revealed a significant correlation between the presence of adult blood and a rise in PO2 (p = 0.047), but failed to demonstrate any correlation to the other studied acid-base variables. Thus the present study suggests that the fetus can compensate for the physiologic properties of adult hemoglobin that are disadvantageous to itself by increasing PO2 and thereby maintaining oxygen supply. The physiologic background and the clinical implication are discussed.

Erythropoietin concentrations in amniotic fluid and umbilical venous blood from Rh-immunized pregnancies.

We set out to investigate prospectively the levels of erythropoietin in amniotic fluid and umbilical venous blood, and to attempt to relate these to fetal haemoglobin and lactate concentrations and to pCO2 and PO2 in Rh immunised patients studied before the onset of labor. Fetal blood was obtained by cordocentesis, and amniotic fluid by amniocentesis from a consecutive series of 36 Rh immunized patients at the time of fetal blood sampling. There was a close correlation (tau = 0.357, P = 0.0001) between the concentrations of erythropoietin in umbilical venous blood and those in amniotic fluid. Erythropoietin in umbilical venous blood correlated inversely with hemoglobin (tau = 0.453, P = 0.0001), and directly with lactate concentrations (tau = 0.450, P = 0.0005). When all other variables were considered, multiple regression analysis demonstrated hemoglobin concentration to be the only variable to be related to the level of erythropoietin in umbilical venous blood taken before transfusion. When the same analysis was performed on the same variables, adding erythropoietin concentration in amniotic fluid as the dependent variable, only erythropoietin in umbilical venous blood was found to be related to the level of erythropoietin in amniotic fluid. We conclude that the erythropoietin concentration in umbilical venous blood from Rh-immunized patients before the onset of labor, is related to fetal anemia. We also conclude that erythropoietin concentration in amniotic fluid is related to that in fetal blood, thereby indicating that the fetus is an important source of amniotic fluid erythropoietin in non laboring patients.

Intrauterine intravascular transfusions in fetal erythroblastosis: The influence of net transfusion volume on fetal survival

The intravascular volume load that an anemic fetus can tolerate was studied retrospectively in 124 consecutive intravascular transfusions in 35 erythroblastotic fetuses. The tolerated volume load correlated well to the estimated fetal weight. Transfusion volume loads above 20 ml/kg of the estimated fetal weight resulted in a lower fetal survival. We recommend an upper transfusion limit at 20 ml/kg corresponding to approximately 20% of the feto‐placental blood volume.

Introduction of a programme for intravascular transfusions at severe rhesus isoimmunization.

Thirty-seven fetuses with severe rhesus isoimmunization with a gestational age of less than 30 week underwent 92 intravascular transfusions. Of these, 77 were intracardiac, 13 umbilical vein and two umbilical artery transfusions. Procedure related complications occurred at eight (10%) intracardiac and at two (14%) umbilical cord transfusions. Reversal of hydrops was observed in 10 of 16 fetuses. The perinatal mortality among transfusion treated fetuses was 8/37 (21%). It is concluded that intravascular, intrauterine transfusion leads to improved results among fetuses with early onset of hydrops. Problems concerning indications and technique are discussed.

Albumin Transfusion in Non-Immune Fetal Hydrops: Doppler Ultrasound Evaluation of the Acute Effects on Blood Circulation in the Fetal Aorta and the Umbilical Arteries

A case of non-immune fetal hydrops, diagnosed as mucopolysaccharidosis VII with hypoalbuminemia, was treated in utero with albumin transfusions via cordocentesis on five occasions. Blood samples were taken for analysis of full blood count and blood gases before and after the transfusions. Pulsed Doppler ultrasound examinations of the arterial waveform were performed in the umbilical arteries and the descending fetal aorta and analyzed for the pulsatility index (PI). The hemoglobin concentration and the hematocrit decreased from 111 +/- 5 g/l and 0.335 +/- 0.008 to 95 +/- 5 g/l and 0.282 +/- 0.023 (mean +/- SD), respectively, after the transfusions. The calculated blood volume increased more than the given volume, indicating an autotransfusion causing additional plasma volume expansion. The blood gases were not significantly changed by transfusion. The PI decreased both in the umbilical arteries (p less than 0.05) and the descending fetal aorta, indicating peripheral vasodilatation. A positive correlation was found between the umbilical artery PI and the hematocrit before and after the albumin transfusion (r = 0.59; p less than 0.05). This relation could be due to covariation with other factors, e.g. peripheral vasodilatation secondary to the increased blood volume and the puncture of the umbilical vein itself. No improvement of the hydrops was seen after the albumin transfusions. The fetus died in utero during spontaneous labor after 30 gestational weeks.