P. A. M. Weiss

Insulin binding to trophoblast plasma membranes and placental glycogen content in well-controlled gestational diabetic women treated with diet or insulin, in well-controlled overt diabetic patients and in healthy control subjects

SummaryInsulin binding to trophoblast plasma membranes and the placental glycogen content were measured in twelve healthy women, in eleven well-controlled gestational diabetic women who were treated either with diet alone (n=4) or with insulin (n=7) and in 18 women with well-controlled overt diabetes mellitus (six White B; four White C; eight White D). The competitive binding assay was carried out with 22 concentrations of unlabelled insulin. Binding data were analysed by a non-linear direct model fitting procedure assuming one non-cooperative binding site. Maximum specific binding was unchanged in the total collective of gestational diabetic women, but was decreased by 30% in those treated with diet (6.2±2.2%) and increased by 90% in insulin-treated women (16.4±10.2%) as compared to the control subjects (8.7±2.5%). The diet-treated women had only 40% as many and those treated with insulin had more than twice as many receptors compared to control subjects on a per mg protein basis and if expressed per total placenta. In patients with overt diabetes mellitus maximum specific binding (18.5±10.6 %) was higher (p<0.05) due to more receptors compared to control subjects but was similar to the insulin-treated gestational diabetic patients. Maximum specific binding and receptor concentrations did not correlate linearly with maternal plasma insulin levels. Receptor affinities were virtually similar in all groups (1.8·109 l/mol). The placental glycogen content was reduced (p<0.05) to about 80% of that of control subjects in the diet-treated collective, whereas it was unchanged compared to control subjects in the insulin-treated gestational diabetic women despite a 40% increase (p<0.001) of the maternal-to-cord serum glucose ratio. In overt diabetic patients the maternal-to-cord serum glucose ratio and the placental glycogen content were higher (p<0.05) than in the control subjects. We conclude that trophoblast plasma membranes from gestational diabetic women treated with diet alone express less and those from women treated with insulin express more insulin receptors than those from a healthy control group in vitro. These differences could not have been disclosed without consideration of the mode of treatment. Trophoblast plasma membranes from overt diabetic women have more insulin receptors than those from healthy control subjects.

Insulin levels in amniotic fluid. Management of pregnancy in diabetes.

A correlation between high insulin levels in amniotic fluid and the appearance of diabetogenic fetal morbidity was found in radioimmunoassays of 487 samples of the fluid. The mean insulin level in metabolically normal pregnancies rose from 9 muU/ml (Week 27) to 15 muU/ml (Week 40). The insulin level in amniotic fluid of diabetic patients was elevated up to 27 times the mean. Insulin levels in the umbilical cord and urine of newborns of diabetic mothers were also elevated, to 29 and 21 times the mean, respectively. Elevation of insulin levels in amniotic fluid portends diabetogenic fetal morbidity. High and rising insulin levels at an early stage (26-28 weeks) may indicate a high risk of preterm onset of labor. Regular adjustment of metabolic compensation on the basis of amniotic fluid insulin made it possible to reduce the level in 12 of 17 pregnant diabetic women by increasing insulin dosage. The 12 women were thereby enabled to carry their pregnancies to term and to await the onset of spontaneous labor without diabetogenic fetal morbidity. Beta-stimulating agents affect glucose management and may cause elevated insulin levels in amniotic fluid.

Low fetal oxygen saturation at birth and acidosis.

Objective To measure umbilical cord blood oxygen saturation, to calculate preductal oxygen saturation at birth, and to assess its predictive value for acidosis. Methods Umbilical cord blood samples of 1537 live-born singleton neonates were analyzed. Oxygen saturation was measured by spectrophotometry; pH and base excess were measured by a pH and blood gas analyzer. Preductal oxygen saturation was calculated with an empirical equation. Acidosis was defined as 2 standard deviations (SDs) below the mean of umbilical artery (UA) pH or base excess (7.09 and −10.50 mmol/L, respectively). The predictive value for acidosis of UA and umbilical vein (UV) oxygen saturation and calculated preductal oxygen saturation was determined with receiver operating characteristic curves. Results The mean values (±SD) of UV, UA, and calculated preductal oxygen saturation were 52 ± 18%, 26 ± 17%, and 31 ± 16%, respectively. Forty-seven neonates had UA pH less than 7.09 and 60 had UA base excess less than −10.50 mmol/L. The UV, UA, and calculated preductal oxygen saturation showed considerably weaker relations to UA base excess (multiple r2 = .056, .003, and .017, respectively; P < .001) than to UA pH (multiple r2 = .112, .126, and .148, respectively; P < .001). Receiver operating characteristic areas under the curve were higher when predicting low pH compared with low base excess (for UV, UA, and calculated preductal oxygen saturation: 0.716 versus 0.699, 0.747 versus 0.586, and 0.765 versus 0.628, respectively). The difference was significant for UA oxygen saturation (P < .05). All tests showed high sensitivity and negative predictive values, but low specificity and positive predictive values. Conclusion Low fetal oxygen saturation measured at birth seemed to be associated with low fetal pH and base excess values, but its predictive value for acidosis in an unselected population was limited, particularly if acidosis was metabolic.

Cord blood oxygen saturation in vigorous infants at birth: what is normal?

Objective To define the normal ranges of umbilical cord blood oxygen saturation (SaO2) and acid‐base status at birth and to evaluate the effect of gestational age on cord blood values in vigorous newborn infants following spontaneous vaginal birth from a vertex position.

Can glucose tolerance test predict fetal hyperinsulinism

Objective To establish cut off levels for oral glucose tolerance test in pregnancy using fetal hyperinsulinism as a clinical endpoint.

Fetal outcome in gestational diabetes with elevated amniotic fluid insulin levels: Dietary versus insulin treatment

Of 228 women with gestational diabetes between 28 and 32 gestational weeks, 195 had a normal amniotic fluid insulin level (4.8 +/- 3.6 microU/ml) while 33 (14.5%) had an elevated level (23.1 +/- 10 microU/ml). Women with a normal amniotic fluid insulin level were treated by diet alone. Fourteen of the women with an elevated level were treated by diet alone; 19 received insulin treatment additionally. The fetal outcome of patients with a normal amniotic fluid insulin level and dietary therapy and of those with an elevated level and insulin treatment was similar to that of metabolically healthy women. The newborns of gestational diabetics with elevated amniotic fluid insulin treated by diet alone showed a significantly higher incidence of neonatal hyperinsulinism, hypoglycemia, hyperbilirubinemia, high birth weight, respiratory distress syndrome and hypocalcemia. While 2/14 (14%) of the neonates in the dietary group had fatal respiratory distress syndrome, there were no deaths in the group with elevated amniotic fluid insulin and insulin treatment. The data demonstrate that in gestational diabetics with normal amniotic fluid insulin (low-risk group), dietary therapy is sufficient while insulin therapy is required to ensure healthy offspring in patients with elevated amniotic insulin (high-risk group).

Diagnosis and Treatment of Gestational Diabetes According to Amniotic Fluid Insulin Levels

SummaryIn spite of dietary treatment, the infants of pregnant patients with abnormal glucose tolerance have hyperinsulinism and diabetogenic fetopathy in 10 to 36% of cases. Those patients, who require insulin to prevent from fetopathy cannot be reliably selected by maternal parameters such as blood glucose and glycosylated hemoglobin values. We recommend the measurement of amniotic fluid insulin between the 28 and 32 weeks of pregnancy to differentiate whether the fetus is compromised or not. Subjects with values above the 97th centile require insulin therapy. Inadequate insulin dosage or delayed fetal hyperinsulinism can be discovered by checking the amniotic fluid insulin level at 33 to 36 weeks. In a total of 88 gestational diabetic patients 19 had raised amniotic fluid insulin levels indicating the onset of diabetic fetopathy at an early stage. Diabetic patients with raised amniotic fluid insulin levels needed large doses of insulin, namely 64.6 ± 29.5 (Mean ± SD) U/24 h. This treatment reduced mean blood glucose levels from 98 ± 9 (Mean ± SD) mg/dl to 82 ± 10 mg/dl and was sufficient to prevent from diabetic fetopathy.

Levels of amniotic fluid insulin and profiles of maternal blood glucose in pregnant women with diabetes type-I

The aim of this study was to investigate the relationship between amniotic fluid insulin (AF-insulin) measurements and maternal blood glucose levels in pregnancies complicated by insulin-dependent maternal diabetes mellitus (IDDM). Twenty-five patients with IDDM underwent amniocentesis (AC) in the third trimester. Twelve patients had a second amniocentesis after 2-3 weeks. The maternal blood glucose values (MBG) 2 weeks before amniocentesis were correlated with AF-insulin. Mean (+/-S.D.) MBG in the group with AF-insulin > 97th centile (n = 7) was 6.1 +/- 1 mmol/l. MBG in the group with AF-insulin < 97th centile (n = 18) was 5.3 +/- 1.2 mmol/l (r = 0.2948; P-value 0.162). In the group with repeated AC and AF-insulin > 97th centile (n = 6) the correlation coefficient was 0.722 (P = 0.043), whereas in the group with normal AF-insulin (n = 6) no correlation was found (r = -0.213; P = 0.686). These results indicate that no significant correlation exists between MBG values and concentration of AF-insulin. MBG is not appropriate for the diagnosis of fetal hyperinsulinism in well-controlled women with IDDM. In individual cases with AF-insulin > 97th centile a decrease of MBG causes lower AF-insulin levels. These results indicate that there seems to be an individual threshold for maternal MBG which causes hyperinsulinism. Fetal hyperinsulinism not only depends on blood glucose levels. Different fetal sensitivity to maternal glucose stimuli or a different glucose transport across the placenta in the individual fetus could be responsible for these results.

Anti-insulin antibodies and birth weight in pregnancies complicated by diabetes

Free insulin cannot cross the placenta but insulin complexed to anti-insulin antibodies has been demonstrated in cord blood. We studied whether antibody-bound insulin in diabetic patients can evoke fetal macrosomia independently of maternal metabolic control. In 457 non insulin-treated controls and 173 insulin-treated diabetic patients we measured 1187 anti-insulin antibody levels and maternal blood glucose, maternal fructosamine, cord blood insulin, cord blood C-peptide, cord blood fructosamine and amniotic fluid insulin. Mean anti-insulin antibody levels in maternal blood and cord blood were significantly higher in insulin treated diabetic patients (4.6 and 5.4 U/ml) than in controls (1.8 and 1.7 U/ml) with maxima of 89.2 in maternal and 120.0 U/ml in cord blood, respectively. In insulin treated diabetic patients 16.6% (maternal blood) and 22% (cord blood) anti-insulin antibody levels were above the 97th percentile. There was a high significant correlation between maternal and cord blood anti-insulin antibodies (R = 0.987, P = < 0.0001), but no correlation of anti-insulin antibodies with maternal (glucose, fructosamine) or fetal (insulin, C-peptide, and fructosamine in cord blood, amniotic fluid insulin) metabolic parameters. While maternal and fetal metabolic parameters correlated with birth weight neither maternal nor cord blood anti-insulin antibody levels correlated with birth weight. These findings do not support the hypothesis that maternal anti-insulin antibodies independently influence fetal weight.

Cord blood insulin to assess the quality of treatment in diabetic pregnancies

According to the Pedersen hypothesis, fetal hyperinsulinism is the major cause for adverse neonatal outcome. We investigated associations between insulin levels in cord blood and fetal complications. Three groups of 21 insulin-dependent diabetic patients with different insulin levels in cord blood were matched according to White Classes. Insulin levels in cord blood of < 20 microU/ml were considered normal (controls), 20-50 microU/ml intermediate group, and > 50 microU/ml high (cases). The mean (+/-S.D.) insulin level in cord blood in the three groups was 10.7+/-5.6, 28.6+/-8.1, and 104.0+/-61.0 microU/ml, respectively. Controls and cases showed significant differences in birth weight > 90th percentile (9.5% vs. 76.2%), premature birth < 37 weeks (4.8% vs. 71.4%), caesarean delivery (28.6% vs. 66.4%), hypoglycaemia of the neonate (14.3% vs. 61.9%), cushingoid appearance (4.8% vs. 42.9%) and respiratory distress syndrome (0% vs. 33.3%). The results of the intermediate group were between the controls and the cases. Insulin levels in cord blood > 20 microU/ml represent a continuum of increasing diabetogenic fetopathy. We consider neonates with insulin levels in cord blood < 20 microU/ml as metabolically healthy, those with 20-50 microU/ml as having mild fetopathy, and those with > 50 microU/ml as having marked fetopathy, respectively.