Diabetes Pregnancy Outcomes Research Articles

Importance of genetic predisposition and maternal environment for the occurrence of congenital malformations in offspring of diabetic rats.

Previous experimental studies have implicated a genetic component in the induction of malformations in the offspring of diabetic rats. We have compared the outcome of diabetic pregnancy in two outbred (sub)strains of Sprague-Dawley rats (with low incidence [H] and high incidence [U] of skeletal malformations in the offspring) and hybrids between them. The fetuses of diabetic H mothers had no skeletal malformations and the lowest frequency of resorptions (8-9%), regardless of embryo type (H/H or H/U). When the diabetic mother was U or from the hybrid strain (H/U) and the offspring were of the mixed H/U type, we found increased resorption (16-21%) and skeletal malformation (3-5%) rates. If instead the embryos contained a major U genome [either U/U or U/(H/U)], further increased resorptions (23-30%) and skeletal malformations (17-19%) resulted. The H/H and U/U embryonic susceptibility to defined teratogens (3-6 mg/ml D-glucose, 4-8 mM B-hydroxy-butyrate) were compared in whole embryo culture and found to be similar, suggesting that the malformations occurring in vivo may have a different etiology than those found in vitro. In the rat model studied, diabetes in the mother appears to cause a disturbance of early stages of embryogenesis in genetically predisposed embryos. This early disturbance results in skeletal malformations and seems to require inducing factor(s) in addition to increased levels of D-glucose and B-hydroxybutyrate. The findings are in concert with the notion of a mixed genetic-environmental etiology of malformations in (diabetic) pregnancy.

Outcome of Pregnancy in Insulin-Dependent (Type 1) Diabetic Women between 1971 and 1984

SMALL, M.; CASSIDY, L.; LEIPER, J. M.; PATERSON, K. R.; LUNAN, C. B.; MacCUISH, A. C. Author Information

Maternal residual beta-cell function and the outcome of diabetic pregnancy.

Preservation of own insulin production (residual pancreatic beta-cell function) has been shown to have a beneficial effect on glycemic control in insulin-dependent diabetic subjects, and its total lack has been suggested to be an independent risk factor during diabetic pregnancy. We studied the influence of residual beta-cell activity on the glucose control and the outcome of pregnancy in 29 diabetic women by sequentially measuring gestational postprandial plasma C-peptide (CPR) levels, diurnal blood glucose curves and blood glycosylated hemoglobin (Hb A1c) and by analyzing the morbidity and mortality of the offsprings. The 9 diabetics with moderate own insulin secretion (CPR levels over 1.0 microgram/l, White classes B and C, later referred to as group I) had significantly better glucose control than the remaining 20 subjects with lower CPR values (White classes C, D and NF, later referred to as group II) (figure 1, table I). There were two intrauterine deaths, both in group II. These deaths (one caused by multiple congenital contracture syndrome and the other by severe intrauterine growth retardation without any evident cause) could not be straightly connected with diabetes. Respiratory distress syndrome was seen in group II only. There was no other significant difference in the neonatal morbidity between the two groups (table II). All mothers of RDS infants were in White class NF where the birthweight was also smaller than in classes B and C. These were the only differences in neonatal morbidity between the White classes (table III). In conclusion, moderate residual beta-cell function seemed to be clinically important in maintaining strict glucose control during gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

Outcome of Pregnancy in Insulin-dependent (Type 1) Diabetic Women between 1971 and 1984

We have looked at the outcome of pregnancy in women with type 1 (insulin-dependent) diabetes mellitus who were confined at Glasgow Royal Maternity Hospital between 1971 and 1984. Of 134 pregnancies, 123 proceeded beyond 28 weeks' gestation and yielded 125 live infants. The perinatal mortality rate was 16/1000, due solely to congenital foetal malformation. Malformations were not related either to the severity of maternal diabetes (as graded by the White classification) or the glycaemic control in the first trimester (as judged by maternal glycosylated haemoglobin concentration). Over the period of study, there has been a marked reduction in the frequency of ketoacidosis during pregnancy and in the delivery of small-for-dates babies; more mature lecithin:sphingomyelin ratios have been obtained by amniocentesis; and better Apgar scores have been demonstrated in the infants at delivery. The Caesarean section rate has fallen from 83 to 30 per cent, and babies now spend less time separated from their mothers in paediatric units. These improvements largely reflect better diabetic treatment (improved insulin regimens and glycaemic control) and closer obstetric assessment. Foetal malformation occurred overall in 11.4 per cent of pregnancies and did not become less frequent over the period of study. Further major improvement in the outcome of diabetic pregnancy will only come from a reduction in the congenital malformation rate, which implies better diabetic control at and around the time of conception.

Preconceptional treatment with insulin infusion pumps in insulin-dependent diabetic women with particular reference to prevention of congenital malformations.

Severe congenital malformations occur more often in infants of diabetic mothers than in infants of non-diabetic mothers. Fetuses exhibiting early fetal growth delay are in increased risk to be malformed and the early fetal growth rate seems to be related to the degree of metabolic control around the time of conception and in the early pregnancy. Nine insulin-dependent diabetic women (White classes B-F) were treated by means of continuous subcutaneous insulin infusion (CSII) initiated at least two months prior to conception and continued throughout pregnancy in order to evaluate the influence of optimized metabolic control on the course and outcome of diabetic pregnancy. Eleven conventionally treated pregnant diabetics (White classes B-D) served as controls. In the pump group the mean blood glucose values in the 4 weeks immediately before and after the conception were 7.7 +/- 0.2 mmol/l and 8.0 +/- 0.3 mmol/l, respectively, the HbA1c was 7.3 +/- 0.5% at the time of conception and 6.9 +/- 0.2% 6-10 weeks later. In the control group the HbA1c 6-10 weeks after conception was 7.2 +/- 0.5%. In the pump group two fetuses exhibited early growth delay while all of the 11 fetuses in the control group were of normal early growth. There were no malformations in either group. All pregnancies were uncomplicated except for one case of toxaemia in the control group. Thus, during CSII treatment the metabolic control was improved in all patients. A possible beneficial effect of this improved control on the early fetal growth delay was not demonstrated. Both groups are, however, still small and definite conclusions must await further results.

Treatment of diabetic pregnant women with monocomponent insulins.

Very little immunological research has been undertaken in pregnant diabetic women in relation to insulin therapy. We investigated the relations between treatment with insulins of varied immunogenic character and the presence of immune factors such as insulin antibodies, immune complexes and insulin antiinsulin complexes as well as some maternal and neonatal complications of diabetic pregnancy. 128 insulin treated diabetic pregnant women and 121 of their newborns were included in the study. The incidence of insulin antibodies, immune complexes and insulin antiinsulin complexes was lower in patients treated with highly purified insulins than in those treated with conventional insulins. The insulin antibody levels were significantly related to the occurrence of maternal and neonatal morbidity. The presence of insulin antiinsulin complexes in the cord blood of infants of diabetic mothers was related to the presence of these complexes in their mothers. Our results seem to indicate that the use of highly purified insulin could favour the outcome of diabetic pregnancy.

An epidemiological model for diabetes mellitus in the United States: Five major complications

Diabetes mellitus affects almost 5.5 million Americans each year. An estimated additional 5 million individuals may have diabetes, but remain undetected. Individuals with diabetes are at high risk for the development of micro- and macrovascular disease, diabetic coma and adverse outcome of pregnancy. The rate at which these complications develop are now partially identifiable for the United States. For 5 potentially preventable complications (retinopathy, adverse outcome of pregnancy, vascular disease, nephropathy and diabetic coma) the morbidity and mortality rates can now be calculated. There exist 50,000 cases of blindness due to diabetes with an additional 5800 new cases each year. Adverse outcome of diabetic pregnancy occurs in over 18,000 births each year, with as many as 4500 related perinatal deaths. Each year 40,000 diabetics are required to have a lower extremity amputation. Of the already 70,000 diabetics who have had an amputation, 25,000 will die this year. End stage renal disease affects 4000 diabetics each year. During the same time period, of the 7500 existing cases of end stage renal disease, 2000 will result in mortality cases. Diabetic coma (DKA and HHNK) accounts for 67,400 hospitalizations and results in 3600 deaths each year. Together these complications and those associated with cardiovascular disease account for 323,000 deaths with diabetes as the underlying or contributing cause in the United States.

An analysis of diabetic pregnancies at Mayo Clinic, 1950-79.

We reviewed the records of pregnant diabetic women attended at Mayo Clinic during the years 1950-79 and matched each nonaborted diabetic pregnancy with two control pregnancies. Abortions occurred in 49 of 277 diabetic pregnancies (17.7%). The relative risk of other adverse outcomes of pregnancy (+/- 95% confidence interval) in comparison with controls was as follows: perinatal mortality, 7.0 (3.6-13.8); major congenital birth defects, 6.3 (2.8-14.2); and respiratory distress, 9.0 (4.5-17.9). Diabetic ketoacidosis resulted in fetal death in 5 of 18 cases. Patients with mean fasting blood glucose levels of less than or equal to 140 mg/dl had a perinatal mortality of 81 per 1000 births and an incidence of respiratory distress and congenital birth defects of 18.9% and 9.9%, respectively. Patients with mean blood glucose levels greater than 140 mg/dl had corresponding rates of 306 per 1000, 20.4%, and 11.2%, respectively. Hydramnios occurred almost exclusively in diabetic women, and its presence was associated with a twofold increase in the frequency of perinatal death. Analysis of diabetic pregnancy outcome by decade showed no appreciable decrease in the occurrence of perinatal mortality, congenital birth defects, or respiratory distress over the 30-yr period.

Blood-oxygen transport in first trimester of diabetic pregnancy.

Factors involved in blood-oxygen transport were studied in 46 pregnant women during the first trimester. All had type 1 (insulin-dependent) diabetes and comparisons were made with similar measurements from 19 non-diabetic pregnant women, also in the first trimester. The concentration of hemoglobin A1c (HbA1c) was significantly increased (7.6% versus 4.4%, p less than 0.01) and arterial oxygen saturation was decreased (0.95 versus 0.98 mol/mol, p less than 0.01) in the pregnant diabetics compared with the non-diabetics. The hemoglobin concentration was significantly elevated in the diabetic women (12.9 versus 12.1 g/100 ml, p less than 0.01). Even though the red cell 2,3-diphosphoglycerate content was the same in the two groups, and pH was significantly lower in the diabetic women, hemoglobin-oxygen affinity was slightly increased in the diabetic patients (P50 at actual pH: 26.2 versus 26.7 mmHg, p less than 0.05; P50 at pH 7.40: 27.0 versus 28.0 mmHg, p less than 0.01). The study has demonstrated certain modifications in the blood oxygen transport system in the first trimester of pregnancy of diabetic women that are possibly related to the presence of excess amounts of glycosylated hemoglobin with increased oxygen affinity. This disturbance in maternal oxygen transport, particularly when associated with diabetic vascular disease, may lead to episodes of fetal hypoxia. Such fetal hypoxia may be a pathogenetic factor for the development of congenital malformations in the outcome of diabetic pregnancy.

Changing panorama of perinatal and infant mortality in diabetic pregnancy.

In a 21-year study covering 1960 to 1980, perinatal and infant mortality in 237 infants of diabetic mothers were analysed. The study was divided into three 7-year periods related to changes in management. In period I (1960-66) the perinatal mortality was 24.3%, decreasing to 5.0% in period II (1967-73) and to 1.1% in period III (1974-80). The corresponding figures for infant mortality were 31.4%, 7.5% and 4.6% respectively. Today the difference between the perinatal mortality rate in diabetic vs. non-diabetic pregnancies is almost negligible. However, perinatal mortality may give a false impression of pregnancy outcome, since owing to the high rate of lethal malformations in period III, infant mortality was still twice that of the non-diabetic population. During the 21-year period studied, complications of diabetic pregnancies such as severity and duration according to the White classification, hypertension and pyelonephritis in pregnancy and preterm delivery all decreased. Consequently the influence of these complicating factors on the overall outcome of diabetic pregnancies has declined.

Maternal blood glucose control and outcome of diabetic pregnancy

Summary The results of management of 128 consecutive pregnancies occuring in diabetic patients who received insulin from before conception and throughout pregnancy are described. Mean maternal blood glucose levels were at least 1 mmol/litre greater than levels reported in normal pregnancy. Thirty-nine percent of the neonates had significant morbidity; respiratory distress syndrome (7·7%), hypocalcaemia (4·6%) and polycythaemia (10%) could be related to higher maternal blood glucose levels. Neonatal hypoglycaemia (9·2%), hyperbilirubinaemia (13·8%) and birth weight corrected for gestational age were not directly related to maternal blood glucose. This degree of maternal blood glucose control has reduced the large for dates infants (greater than 90th centile for gestational age) to 7%. Further reduction in the morbidity of infants of diabetic mothers requires studies of physiological maternal blood glucose levels which may not be possible with conventional insulin treatment as well as further efforts to reduce prematurity.

Prenatal assessment of fetal outcome by amniotic fluid C-peptide levels in pregnant diabetic women

Amniotic fluid C-peptide (AFCP), insulin, and glucose levels were measured in 33 diabetic and 126 nondiabetic pregnant women at ≖36 weeks' gestation. Levels of AFCP distinguished diabetic from nondiabetic patients more reliably than amniotic fluid (AF) insulin or glucose. Levels of AFCP in diabetic patients correlated well with Infant birth weight adjusted for gestational ages(large for gestational age > adequate for gestational age), degree of diabetic control (fair to poor control > good control), or diabetogenic infant morbidity, but did not correlate, with classes of diabetes within the limits of the population studied. We conclude that AFCP is a usefull prognostic index tor predicting fetal outcome in diabetic pregnancies. A level of AFCP of ≖1.0 pmoles/ml is associated with an increased risk of macrosomia in infants of diabetic mothers. (Am. J. Obstet. Gynecol. 141:671, 1981.)

Impact of maternal euglycemia on fetal outcome in diabetic pregnancy

We examined the relationship between maternal euglycemia and fetal outcome in 81 cases of gestational, diet-controlled (GD) diabetes and 32 cases of insulin-dependent diabetes (IDD). The perinatal mortality rate was reduced from 2.3% to zero in an 18 month period ending in December 1977. Perinatal morbidity in GD and IDD was comparable and independent of age, parity, and severity of diabetes. Fasting maternal glucose concentrations correlated positively with the incidence of fetal macrosomia (p = < 0.025) which in this study was 8%. While neonatal hypoglycemia of less than 24 hours' duration affected 28% of the neonates, its incidence was also greater in the GD group as was macrosomia. Congenital malformations occurred in 4% of cases and were found exclusively in GD. These studies confirm our previous observations supporting the hypothesis that the control of the maternal glucose concentration is the single most important aspect in the management of the pregnant diabetic patient. With such control the perinatal mortality rate approaches zero with the outcome of pregnancy being equal for all diabetic patients. On the other hand, neonatal morbidity can be expected to be higher in women with gestational diabetes identified late in pregnancy. Likewise, congenital malformations in this group may represent the influence of uncontrolled glucose metabolism in the early months of gestation which remained undetected due to late registration for prenatal care.

Normal blood sugar variation during pregnancy.

Abstract. Blood sugar determinations were made four times daily on non‐diabetic pregnant and non‐pregnant women admitted to hospital for reasons not supposed to influence carbohydrate metabolism. All blood sugar values were found to decrease during pregnancy. The fasting blood sugar decreased from 78 to 65 mg%, and the daily mean value from 99 to 80 mg%. The increase in blood sugar after the main meal of the day was found to be smallest in late pregnancy. The results indicate a progressive change in carbohydrate tolerance during pregnancy. Some implications of the results on the management and outcome of diabetic pregnancy are discussed.

The outcome of diabetic pregnancies in relation to the mother's blood sugar level

A ten-year patient material of diabetic pregnancies was analyzed. The mean blood sugar level during the last weeks of pregnancy was calculated for each woman and used as an index of the control of the mother's disease. The perinatal mortality rate sank from 23.6 per cent in the group with a mean blood sugar level above 150 mg. per 100 ml. to 15.3 per cent in the intermediate group down to 3.8 per cent in the group with mean blood sugar levels below 100 mg. per 100 ml. The increased survival rate was parallelled by a decreased morbidity in the infants. The incidence of severe malformations in the total series is 11 per cent. Long-standing diabetes and diabetes with angiopathy carries a great increased risk of malformations, 20 to 25 per cent. Two circumstances are stressed: the active management of the pregnant diabetic subject with the goal to reduce the mean blood sugar value below 100 mg. per 100 ml., and the active management of the newborn infant with the early supply of fluid and calories.