Long-term follow-up of infants of mothers with type 1 diabetes: evidence for hereditary and nonhereditary transmission of diabetes and precursors.

OBJECTIVE: To estimate the impact of type 1 diabetes during pregnancy on transgenerational genetically caused and/or fuel-mediated amplification of types 1 and 2 diabetes and to estimate the impact of elevated amniotic fluid insulin levels. RESEARCH DESIGN AND METHODS: A total of 75 white offspring of type 1 diabetic mothers and 49 control subjects of similar age and pubertal stage were examined at 5-15 years of age. All offspring had an oral glucose tolerance test. Glucose, insulin, and C-peptide were measured at 0, 30, 60, and 120 min after loading. Lipids and autoimmune antibodies were measured in fasting plasma. RESULTS: Of the 75 offspring, 4 (5.3%) had overt diabetes, and 16 of 71 (22.5%) had autoimmune antibodies. Offspring of diabetic mothers had significantly higher BMI; symmetry indexes; cholesterol, glucose, insulin, and C-peptide levels; and insulin resistance than control subjects. With the exception of cholesterol, these values were significantly elevated in offspring who had elevated amniotic fluid insulin levels (>8 microU/ml, >48 pmol/l) during pregnancy compared with normoinsulinemic offspring and control subjects. CONCLUSIONS: Offspring of type 1 diabetic mothers have an increased risk for diabetes later in life. The relative risk for type 1 and type 2 diabetes is 71.6 and 3.2, respectively. Type 2 diabetes-associated risk factors, such as high BMI; elevated glucose, insulin, and C-peptide levels; and insulin resistance, are related to the fetal metabolic experience in utero, as reflected by amniotic fluid insulin concentration.

The 20/20 eye in multiple sclerosis.

Using clinical and electrophysiologic measures, we evaluated the visual pathway of patients who had multiple sclerosis, 20/20 Snellen acuity, and no history of optic neuritis. Delayed latencies were found in the transient visual evoked potentials (VEPs) of 38% of the patients, and interocular latency differences were abnormal in 67%. Contrast VEPs were abnormal in 46%. Psychophysical determinations of contrast sensitivity were abnormal in 78%. Only 17% of the patients had dyschromatopsia, 36% had afferent pupillary abnormalities, and 59% had optic nerve pallor or nerve fiber layer loss. Psychophysical contrast evaluations and VEP studies were superior to other clinical evaluations in demonstrating visual dysfunction in these patients.

Intensified conventional insulin therapy for the pregnant diabetic patient.

Thirty-three normoglycemic pregnant diabetic patients (White B-R) were studied in the course of one year during 732 weeks of therapy with 176 dose adjustments of insulin to determine patterns of insulin requirements. By means of an empirical formula, the insulin requirements within a 24-hour period can be calculated. Insulin requirement in the course of pregnancy decreases significantly between the tenth and the 16th week of gestation (-12%, P = less than .001). From the 17th to the 36th week it increases slightly at first and more markedly from the 28th week onward (+ 62%), decreasing again from the 36th week onward. Insulin distribution during the day depends on whether or not a residual function of beta cells and, consequently, basal insulin secretion exists. Either four doses of regular insulin are injected or three doses of regular insulin are combined with one to two doses of variously long-acting insulin. The ideal distribution regarding the type and amount of insulin follows certain patterns and can therefore be approximated.

Insulin levels in amniotic fluid of normal and abnormal pregnancies.

The normal level of insulin in amniotic fluid between the 13th and 42nd weeks of pregnancy was determined by means of 988 single analyses in individual healthy women. Insulin passes into the amniotic fluid via the fetal urine, and its level does not depend on fetal gender. Between the 13th and 25th weeks of gestation, the insulin level increases by an average of 1.3 to 5.1 microU/ml. From the 27th to the 42nd weeks, an increase of 6 to 9.1 microU/ml is observed. In the same period, the 97th percentile rises from 11.2 to 18 microU/ml. In 543 patients with pregnancy disorders, lower levels of insulin in amniotic fluid were observed in intrauterine fetal death, placental insufficiency, fetal growth retardation, and malformations. Elevated levels of insulin were observed in rhesus disease. In the treatment of pregnant women with betamimetics and glucocorticoids, the mean amniotic fluid insulin level rose to more than double the normal values.

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.

Alpha-fetoprotein content of amniotic fluid in normal and abnormal pregnancies.

Elevation above the normal range of alpha-fetoprotein (AFP) concentration in amniotic fluid occurs in the presence of certain fetal anomalies. The value of a new method for radioimmunoassay of APF in amniotic fluid was tested by an analysis of 486 samples taken by amniocentesis at various stages of pregnancy. The normal range of concentrations during pregnancy was established by 348 samples from healthy women with normal pregnancies. This was compared with the levels found in the presence of various fetal malformations--Rh-isoimmunization, maternal diabetes, chromosomal anomalies, and fetal death in utero. The findings and their implications are discussed.

Gestational diabetes and screening during pregnancy.

The oral glucose tolerance test is an unreliable test in screening for diabetogenic fetal disease. In diabetogenic fetopathy due to gestational diabetes (White class A diabetes), the insulin content in the umbilical cord blood as well as in the fetal urine is considerably raised. As increased amounts of insulin pass into the amniotic fluid via the fetal urine, the fetal disease can be diagnosed from the amniotic fluid insulin content. In 75 pregnant women with potential diabetes, the blood sugar value was below 160 mg/dL at maximum under glucose loading in 28 patients; it was over 200 mg/dL in 25 patients. However, diabetogenic fetopathy was present in only 14 patients. The endangered and the healthy fetus could be distinguished in each case by amniotic fluid insulin content. The mean amniotic fluid insulin values in diabetogenic fetopathy were about seven times the normal.

Fetal insulin balance: gestational diabetes and postpartal screening.

It must be determined whether high neonatal birth weight (greater than or equal to 4000 g) is due to genetic factors or to a disorder of maternal carbohydrate metabolism. Oral glucose tolerance tests are known to be unreliable during the puerperium. If the mother's carbohydrate metabolism was disturbed during pregnancy, neonatal overweight may result from fetal hyperinsulinism. This can be diagnosed by determining the insulin in the umbilical cord blood. Mature neonates of metabolically healthy women show an insulin level of 9.2 +/- 4.4 microU/ml (N = 180) in the umbilical cord blood. The third, tenth, 50th, 90th, and 97th percentiles were calculated as 1.4, 4.3, 8.8, 15.4, and 17.7 microU/ml, respectively. With insulin values over 20 microU/ml in the umbilical cord blood, a disturbance of maternal carbohydrate metabolism during pregnancy is likely. Among 4560 births in one year, 335 neonates weighed 4000 g and more, corresponding to a proportion of 7.35%. In one quarter of the infants over 4000 g, high birth weight was associated with fetal hyperinsulinism. This corresponds to a frequency of 1.8% of all births.

Amniotic fluid glucose values in normal and abnormal pregnancies.

Glucose values were determined in 102 urine samples of newborn infants and in 2295 amniotic fluid (AF) samples of women between the 14th and 42nd week of pregnancy. One thousand, six hundred fifty-five of the AF samples derived from normal pregnancies, 50 from pregnancies with fetal malformations, 115 from cases of hydramnios, 246 from pregnant women with an abnormal oral glucose tolerance test, and 230 from insulin-dependent diabetics. Mean AF glucose concentration rises slightly between the 14th and 17th week of pregnancy, decreasing from 46 to about 16 mg% at the end of pregnancy. In cases of fetal malformations, 68% of the glucose levels was below the tenth percentile of normal values. Hydramnios showed no deviation from normal values. In patients with abnormal glucose tolerance, AF glucose increased by a total of 42% and by 67% in fetal hyperinsulinism. Insulin-dependent diabetics had glucose values elevated by a total of 77% and by 106% in fetal hyperinsulinism. The AF glucose profile reflects the level of maternal blood glucose that is transported to the fetus and excreted in the fetal urine as a major source of glucose in AF.

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 r(2) =.056,.003, and.017, respectively; P <.001) than to UA pH (multiple r(2) =.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.

The visual-evoked potential in tobacco-alcohol and nutritional amblyopia.

Twelve subjects, nine with tobacco-alcohol amblyopia and three with nutritional amblyopia, were studied with pattern and flash visual-evoked potentials. We found abnormal steady-state responses in all 12 patients, including those with minor visual abnormalities, when the contrast of the stimulus was decreased. The latency of the first major positive wave (P100) of the flash- or pattern-evoked potential was not delayed in 11 of the 12 patients. The normal P100 latencies differed from the prolonged latencies found in other patients with loss of central nervous system myelin caused by vitamin B12 deficiency or multiple sclerosis.

Insulin receptor binding to erythrocytes in the first half of pregnancy is increased in healthy pregnant women as compared with non-pregnant or gestational diabetic women.

Insulin binding to erythrocytes was measured longitudinally by a competitive radioreceptor assay in 21 healthy pregnant (HP) and 20 well-controlled gestational diabetic women (GD) in 4-week intervals throughout pregnancy and at day 4 post-partum. Maximum insulin binding (maxbdg) at weeks 8-14 was increased (P < 0.001) in HP (median: 6.0%) but not in GD (median: 2.7%) as compared with non-pregnant control subjects (C) (median: 3.6%; previously reported: Clin. Chim. Acta 1992;207:57-71) due to an increased number of high-affinity insulin receptors. Throughout gestation the binding decreased continuously, to reach at term the levels found in C. In GD maxbdg remained close to the level of C throughout pregnancy. Binding differences between HP and GD were independent of the body mass index. Maxbdg did not differ between diet- and insulin-treated patients. It was higher in women whose offspring had low umbilical cord insulin levels (< 10 mu units/ml). The findings suggest that (a) higher insulin binding in HP could contribute to the improved glucose tolerance in early pregnancy and (b) the lack of increase in insulin binding during early pregnancy in gestational diabetes might be one factor leading to the manifestation of the disease in late pregnancy. However, it must be kept in mind that insulin receptors on erythrocytes do not necessarily resemble those on the major target tissues of insulin.

Insulin binding to erythrocytes of nonpregnant women: a reevaluation, underlining the importance of body weights even in nonobese subjects.

Insulin binding to erythrocytes was measured in 18 healthy, non-obese women in the follicular phase and in 6 women in the mid-luteal phase of the same menstrual cycle. The presence of 55 nM and 220 nM monoclonal anti-IGF I receptor antibody (alpha-IR3) reduced only the number of low affinity binding sites for insulin by 20% and 33%, respectively. Women with relative body weights 110-119% had a lower number of high affinity receptors and an increased high affinity compared to women with relative body weights 91-109%. In women with relative body weights greater than or equal to 100%, maximum specific binding and high affinity constants increased and the receptor numbers decreased from the follicular to the luteal phase, whereas in women with relative body weights less than 100% the parameter changes were reverted. The data indicate: (1) erythrocytes contain two different classes of binding sites for insulin, (2) IGF I receptors might contribute to low-affinity binding of insulin to erythrocytes and (3) the relative body weight must be considered even for 'non-obese' control groups used in insulin binding studies of various clinical conditions.

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).

Spatiotemporal conditions which elicit or abolish the oblique effect in man: direct measurement with swept evoked potential.

Reversing sine wave gratings were electronically swept in spatial frequency and contrast. The acuity limits and contrast thresholds of 4 observers were inferred from evoked potential stimulus-response functions elicited by these stimuli and retrieved with a quadrature lock-in amplifier. The evoked potential functions, linearized in the case of contrast by increasing contrast logarithmically with time, were extrapolated to the point of zero response. This point provides an electrophysiologically defined threshold value for acuity and for contrast. An oblique effect (superior sensitivity for HV-oriented gratings) could reliably be demonstrated in both acuity and contrast threshold performance. This oblique effect could readily be abolished under low spatial/high temporal frequency conditions. The findings are discussed in terms of shifting relative strengths of X and Y contributions to the steady-state evoked potential.

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.

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.

Ultrasound growth parameters in relation to levels of amniotic fluid insulin in women with diabetes type-I.

The aim of the study was to investigate the correlation between ultrasound parameters and levels of amniotic fluid insulin (AF-insulin) in pregnancies complicated by insulin-dependent diabetes mellitus (IDDM). In 129 women with IDDM amniocentesis was performed between 28 and 35 weeks of gestation. The levels of AF-insulin were measured by radioimmunoassay (Pharmacia RIA 100) and were correlated with biparietal diameter (BPD), abdominal diameter (AD), abdominal circumference (AC), and femur length (FL). The women were maintained at good glycemic control (fructosamine level: mean +/- S.D.: 236.3 +/- 40 micromol/l) and delivered infants with a mean (+/- S.D.) birth weight of 3477 +/- 640 g. The sensitivity of BPD, AD, AC and FL to detect fetuses with pathological levels of AF-insulin was 50%, 62%, 67% and 49%, respectively. The sensitivities of AD and AC in a selected group (n = 14) with highly pathological levels of AF-insulin (> 20 microU/ml) were both 80%, whereas the specificity was 56% and 46%, respectively. In women with IDDM, fetal biparietal diameter, abdominal diameter, abdominal circumference, and femur length are not reliable markers for the identification of fetal hyperinsulinism. Only cases with highly pathological levels of AF-insulin can be detected by abdominal measurements.

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.

[The timing of amniotomy: its effect on mother and infant]. / Der Zeitpunkt der Amniotomie: sein Einfluss auf Mutter und Kind.

This study was undertaken to determine how amniotomy performed during different phases of delivery affects mother and child. 1504 out of 4770 birth recorded during one year at the University Department of Obstetrics and Gynaecology in Graz were analyzed. None of these was associated with the presence of risk factors at the onset of delivery nor when amniotomy was performed. Regardless of parity, the number of ensuing complications was clearly related to the time at which amniotomy was performed: the earlier the amnion was perforated, the higher the rate of complications, particularly with primiparae. The aim of activation of labour, thereby accelerating the process of delivery by early amniotomy, was not, however, achieved. Consequently, amniotomy should not be regarded as the method of choice for the programmed induction or the acceleration of delivery. Medication should be the first step taken towards getting delivery under way and amniotomy postponed until contractions are well established and the uterine os is at least 7 cm open in primiparae and at least 4 cm in multiparae.