Infertility and pregnancy outcome in an unselected group of women with insulin-dependent diabetes mellitus.

OBJECTIVES: The null hypothesis of this study is that infertility and pregnancy outcomes in women with insulin-dependent diabetes are identical to those of nondiabetic control subjects. STUDY DESIGN: A questionnaire survey comprising an unselected population of 18- to 49-year-old diabetic women and a comparable control group was performed. Reply rates were 94% (n = 245) and 88% (n = 253), respectively. RESULTS: Cumulative rates of pregnancies and involuntary infertility (17%) did not differ between the two groups. Diabetic women had significantly fewer pregnancies (1.4 vs 1.7) and fewer births per pregnancy than controls, and more diabetic women were nulliparous (48% vs 38%). Half of all diabetic pregnancies were planned. Diabetic women reported that their diabetes had a negative influence on their attitude toward having children. CONCLUSION: In insulin-dependent diabetic women the ability to conceive is normal, but diabetic women have fewer pregnancies and fewer births per pregnancy than controls.     

Excessive Birth Weight and Maternal Glucose Tolerance A 19-year Review

The incidence of birth-weight of 4,540 g (10 lb) or more rose from 0.87% in the years 1971 to 1977 to 1.16% in the 12 years from 1978 to 1989 with a concomitant increase in hyperglycaemia in our antenatal population. The relationship between excessive birth-weight and maternal glucose tolerance was investigated in the light of these observations. The results from glucose tolerance tests performed routinely during the pregnancies of 510 women who delivered infants with a birth-weight of 4,540 g or more were compared with those from a control series of 5,003 women with consecutively tested pregnancies. Glucose tolerance in subsequent pregnancies was also compared with the control series, and in 1991 the study group women were investigated for emergence of permanent diabetes mellitus. Excessive birth-weight was associated with maternal hyperglycaemia (p < 0.05) but not with gestational diabetes; 79% of infants with birth-weight > or = 4,540 g were born to mothers who were not hyperglycaemic. There was no increase in glucose intolerance in subsequent pregnancies in the study group and only 2 of 49 women with follow-up testing had diabetes mellitus. Birth-weight > or = 4,540 g occurred in 1.1% of the total population and 1.1% of women with gestational diabetes, and was related to maternal hyperglycaemia in about 1 in 5 cases. The increased incidence of excessive birth-weight infants was not related to the increased incidence of gestational diabetes in our pregnant population. Birth-weight > or = 4,540 g had a poor association with later development of diabetes.     

Relation of glucose control in diabetic pregnancy to fetal cholesterol homeostasis

Objective. To determine the impact of maternal diabetic glucose control on fetal cholesterol homeostasis.

Methods. Singleton pregnancies of 150 women complicated by gestational (n = 90) and pre-gestational (n = 60) diabetes were evaluated. Those with insulin-requiring diabetes had fasting blood glucose levels determined daily during the last 4 weeks of pregnancy and weekly fasting glucose values were obtained in those with A1 (diet-controlled) gestational diabetes. Umbilical cord venous serum was collected at delivery and total cholesterol levels were determined.

Results. Among the 150 women, 69 had A1 gestational diabetes and 81 were insulin-requiring. Fasting glucose levels were inversely correlated (p < 0.001) to gestational age, regardless of diabetes classification. Umbilical serum cholesterol levels were inversely related (p < 0.002) to gestational age and weight, but did not vary according to diabetic classification. Among term infants (n = 110), umbilical serum cholesterol levels were inversely related to maternal fasting glucose levels at 4 weeks (p = 0.006) and 2 weeks (p = 0.006) before delivery.

Conclusion. Maternal hyperglycemia is associated with decreased plasma fetal cholesterol levels in term infants.     

Early Fetal Growth Delay

It has been reported that the congenital anomalies frequently observed in offspring of diabetic women may be predicted by first-trimester ultrasound findings that reveal diminution in growth of the embryo/fetus. The aim of the current study was to examine the relationship between early growth delay and congenital anomalies in pregnancies complicated by diabetes.

We conducted a retrospective study of 38 patients with insulin-requiring pregestational diabetes mellitus and 81 control pregnancies who had first-trimester ultrasound examinations. A cross-sectional survey of all patients revealed a congenital anomaly rate of 18.4% among the diabetic pregnancies compared to 4.9% among controls (P < 0.02). Early fetal growth delay was defined as a difference of six or more days between the menstrual gestational age and the sonographic gestational age (menstrual age minus ultrasound age).

Early growth delay was exhibited in fifteen control pregnancies (18.5%) and eleven insulin-requiring pregestational diabetic pregnancies (28.9%) (P = 0.02). However the incidence of congenital anomalies in these two groups was significantly different, but there was no difference between groups with and without growth delay. The longitudinal growth of two anomalous fetuses of the diabetic group and three anomalous fetuses from the control group was studied. Both groups of fetuses remained within the normal growth range for their respective groups.

This study described herein fails to confirm the association of early fetal growth delay with the occurrence of congenital malformations in insulin-requiring pregestational diabetic pregnancies.     

Indications for and timing of delivery in diabetic pregnancies

The management of 430 diabetic pregnancies is presented. Our protocol emphasized "tight" metabolic control and assessment of fetal well-being by antepartum fetal heart rate testings and estriol levels. Spontaneous labor was allowed in uncomplicated Class A diabetic patients. Labor in complicated cases and insulin-dependent diabetic pregnancies was induced after establishing fetal lung maturity, except when a maternal or fetal complication dictated otherwise. A significant drop in estriol was observed in 4% of Class A diabetic patients and 10.2% of insulin-dependent diabetic patients. None developed a positive contraction stress test. Abnormal fetal well-being tests contributed minimally to the indications for induction of labor. The incidence of induced preterm delivery was 2.8% in Class A diabetic patients and 18.4% in insulin-dependent diabetic ones. The perinatal mortality was 5.6:1000 and 13:1000, respectively. The incidence of respiratory distress syndrome was very low, and none of the cases were associated with a "mature" amniotic fluid lecithin phosphorus measurement.     

Population standards of birth weight underestimate fetal growth abnormalities in diabetic pregnancies

The objective of this study was to compare the frequency of abnormal fetal growth in women with diabetes mellitus (DM) using population-based birth weight (pop BW) percentiles compared with customized birth weight (cust BW) percentiles, which include adjustments for maternal race, parity, height, weight, and fetal sex. The study design comprised a retrospective cohort of singleton DM pregnancies delivered over a 1-year period (June 2007 to May 2008) from a single tertiary care university-based medical center. Inclusion criteria were gestational age >20 weeks at delivery, live birth, and absence of major chromosomal/structural abnormalities. Small for gestational age (SGA), <10th percentile, and large for gestational age (LGA), >90th percentile pregnancies were categorized based on pop BW or cust BW standards. There were significant differences in the rates of SGA (p < 0.004) and LGA (p < 0.001) between cust BW and pop BW methods. When comparing the two methods, pop BW did not identify 13/16 (81%) of SGA and 23/39 (59%) of LGA babies defined by cust BW methods. The use of cust BW calculation in a diabetic population identified a greater percentage of neonates with pathologic fetal growth compared with pop BW standards, suggesting that the population standard may underdiagnose abnormal fetal growth in diabetic pregnancies.     

Why are cesarean delivery rates so high in diabetic pregnancies?

AIMS: The purpose of this study was to examine factors relevant to mode of delivery in term pregnancies complicated by gestational and pre-gestational diabetes. METHODS: A retrospective chart review of term (> or = 37 weeks) singleton pregnancies complicated by Class A2 through Class R pregnancies which delivered from 1991-1997 was performed. Exclusion criteria were prior cesarean delivery, non-vertex presentation, fetal structural defects, or any contraindications to vaginal delivery. Maternal and fetal factors relevant to mode of delivery were examined and compared. Stepwise logistic regression analysis was performed to examine factors predictive of delivery mode. RESULTS: A total of 148 patients met study criteria. Induction rates were 60.9% for gestational and 79.8% for pre-gestational diabetics. The overall cesarean delivery rate by Diabetes Class for A2, B, C, D-F pregnancies was 20.3%, 40%, 37%, and 57.1% respectively. In Class A2 pregnancies no factor was associated with cesarean delivery and only nulliparity (p = 0.03) was associated in Class B-F pregnancies. CONCLUSIONS: These results suggest that physician factors may play an important role in the risk for cesarean delivery in our diabetic population.     

Gestational diabetes and fetal macrosomia in a multi-ethnic population.

We set out to examine maternal and neonatal factors surrounding increased birthweight in a multi-ethnic population having an increased prevalence of diabetes mellitus. Additionally, to document the difference (if any) for such neonates in rates of obstetrical operative intervention at delivery where a specific diagnosis of maternal gestational diabetes mellitus had been made. This was an observational study of unselected mothers giving birth to a neonate of 4000 g or more. Data for this population concerning the results of antenatal screening and diagnostic testing for gestational diabetes mellitus were available as a subset of a larger independent and ongoing database. Odds ratios were used to compare group attributes subset on ethnic, diabetic screening and diabetic diagnostic status. Two ethnic groups showed an increased odds ratio for increased birthweight. A diagnosis of diabetes was associated with a twofold increase in caesarean section rate, and a significant increase in median birthweight when compared with screen positive/ diagnostic negative mothers. A total of 70.4% of mothers were overweight or obese while neonatal ponderal index showed a dependence on birthweight ( r2 = 0.17). We conclude that ethnic status is an important factor in assessing fetal size, as is maternal body mass index. A diagnosis of diabetes mellitus confers an increased risk of operative intervention at delivery. Our approach to the use of birthweight data requires re-assessment.     

Gestational diabetes: the forerunner for the development of maternal and childhood obesity and metabolic syndrome?

OBJECTIVE: To examine the risk of obesity and metabolic syndrome in women with a history of gestational diabetes mellitus and in offspring born to mothers with gestational diabetes mellitus. METHODS: A review of studies examining the development of obesity, hypertension, metabolic abnormalities, metabolic syndrome, and type II diabetes in mothers with a history of gestational diabetes mellitus and control mothers, and offspring of mothers with a history of gestational diabetes and control mothers. RESULTS: Longitudinal studies demonstrate that women with a prior history of gestational diabetes mellitus and obesity are at significantly greater risk of developing metabolic syndrome than mothers with no history of gestational diabetes or obesity. The development of metabolic syndrome in children with increasing age is related to maternal gestational diabetes mellitus, maternal glycemia in the 3rd trimester, maternal obesity, neonatal macrosomia, and childhood obesity. CONCLUSIONS: The current prevalence of obesity in both adults and children and associated disorders of blood pressure and lipid metabolism, suggest a perpetuating cycle of increasing obesity, insulin resistance, and abnormal lipid metabolism, which has ominous consequences for future generations.     

Umbilical artery resistance index in diabetic pregnancies: the associations with fetal outcome and neonatal septal hypertrophic cardiomyopathy

AIM: To determine the incidence of an abnormal umbilical artery resistance index (UARI) in diabetic pregnancies and the relation to fetal outcome and the development of neonatal septal hypertrophic cardiomyopathy. METHODS: A case-control study with subjects comprising 50 randomly selected diabetic mothers and a matched control group of 50 non-diabetic pregnancies. Doppler studies of the UARI were carried out at least once per week, beginning from 36 weeks' gestation for both groups. Within 48 h post delivery, echocardiograms were carried out on the newborn infants to identify those with hypertrophic cardiomyopathy, particularly asymmetrical septal hypertrophy. RESULTS: The numbers of patients with abnormal UARI were similar in both the diabetic and control groups. A higher proportion of operative deliveries for intrapartum fetal distress was seen in patients with an abnormal UARI in the diabetic group. However, the groups did not differ in the numbers of infants who were small for gestational age, who had low Apgar scores or umbilical artery acidosis, and who required admission to the special care nursery. Six infants of diabetic mothers (12%) had septal hypertrophy, but none of these were associated with abnormal antenatal UARI. CONCLUSION: Diabetic pregnancy is not associated with a significantly higher incidence of abnormal UARI on Doppler study than non-diabetic pregnancy. UARI is not a useful single indicator by which to predict subsequent fetal outcome or the development of neonatal septal hypertrophic cardiomyopathy in diabetic pregnancies.     

Placental Doppler velocimetry in gestational diabetes mellitus

OBJECTIVE: To evaluate if maternal glucose level and growth of the fetus were related to placental vascular impedance in pregnancy complicated by gestational diabetes mellitus. MATERIAL AND METHODS: A retrospective study of 146 gestational diabetic women of which 117 needed insulin therapy. Glycosylated hemoglobin (HbA1c) was evaluated as well as umbilical and uterine artery Doppler velocimetry. The results were related to adverse outcome of pregnancy including newborn birthweight. RESULTS: Abnormal umbilical artery blood flow velocity was seen in 5% of the cases and abnormal uterine artery flow in 16%. Uterine and umbilical artery vascular impedance was significantly lower in macrosomic newborns. There was a poor correlation between HbA1c, vascular impedance and birthweight. There were 11 cases that developed preeclampsia, all having abnormal uterine artery Doppler and two abnormal umbilical artery Doppler. CONCLUSION: Uterine and umbilical artery vascular impedance in pregnancies complicated by gestational diabetes is related to birthweight and placental weight, but not to maternal HbA1c levels. Placental Doppler ultrasound does not seem to be of clinical value for fetal surveillance in these pregnancies unless the pregnancy is complicated by preeclampsia and/or intrauterine fetal growth restriction.     

Gestational diabetes mellitus: does it recur in subsequent pregnancy?

The recurrence of glucose intolerance was examined in 36 women with an index pregnancy complicated by gestational diabetes who received antepartum care at the same institution because of a subsequent pregnancy. Standard oral or intravenous glucose tolerance tests were used to document glucose intolerance or gestational diabetes. Twenty patients had gestational diabetes in the subsequent pregnancy, whereas one third of the patients tested did not demonstrate an abnormality of carbohydrate metabolism. The patients with consecutive pregnancies complicated by gestational diabetes were heavier and were delivered of heavier neonates than the patients who did not develop gestational diabetes again. Unlike the nondiabetic group, the patients who remained gestationally diabetic weighed significantly more in the subsequent pregnancy than in the index pregnancy. These results indicate that patients with gestational diabetes should be tested in subsequent pregnancies because of the impact of gestational diabetes on birth weight. However, these results also suggest that the glucose tolerance test may not be a reliable test for the detection of abnormal carbohydrate metabolism.     

Diabetic pregnancy associated with increased epidermal growth factor in cord serum at term

OBJECTIVE: Epidermal growth factor is a ubiquitous mitogen that also possesses insulin-like properties. Fetal mal-growth is associated with altered epidermal growth factor levels. Maternal diabetes is frequently complicated by macrosomia, but the effect of maternal diabetes on fetal epidermal growth factor levels is not known. We studied cord serum epidermal growth factor concentrations in pregnancies complicated by diabetes and in normal pregnancies. METHODS: Cord serum epidermal growth factor concentrations were measured at birth by a sandwich-type time-resolved immunofluorometric assay in 63 pregnancies complicated by insulin-dependent diabetes mellitus, in 25 pregnancies complicated by insulin-treated gestational diabetes, and in 56 normal pregnancies. RESULTS: Cord serum epidermal growth factor correlated positively with the duration of pregnancy in diabetic and normal pregnancies. In a subgroup of women at similar gestational ages (38-39 weeks), cord serum epidermal growth factor concentrations were higher in pregnancies complicated by insulin-dependent diabetes mellitus (962 +/- 211 ng/L, P =.047; n = 9) and in pregnancies complicated by gestational diabetes (1133 +/- 115 ng/L, P =.001; n = 9) than in controls (564 +/- 75 ng/L; n = 22). In multiple regression analysis, only umbilical artery hemoglobin in diabetic pregnancies and vaginal delivery in normal pregnancies were associated with cord serum epidermal growth factor. CONCLUSION: Epidermal growth factor concentrations are higher than normal in fetuses of diabetic mothers at term. Pregnancy complications, such as hypertensive disorders, fetal hypoxia and fetal malgrowth, may not explain the rise in epidermal growth factor levels. We hypothesize that the rise in epidermal growth factor levels is a metabolic response of the fetoplacental unit to diabetes-related hyperglycemia. LEVEL OF EVIDENCE: III     

Oversized infant of diabetic mother: its cause and prevention

In this study the birth weights of 431 infants of diabetic mothers of the Milan series have been compared with the birth weights of infants of a control group. The averages and the centile distributions of weights of infants of gestational diabetic mothers (Class A) and of diabetic mothers without vascular complications (Classes B and C) did not differ substantially from those of control newborns (table I, figure 1). This confirms the clinical indication, based on the hyperglycemia-hyperinsulinism theory that fetal macrosomia can be prevented provided maternal metabolism is strictly controlled. In this series insulin was administered at the maximal tolerated dose (MTD), a therapeutic regimen that provides excellent metabolic control of the mother. In multiparae, the birth weights of the infants of the latest pregnancy were drastically lower than the birth weights of the infants in their previous pregnancies (without MTD insulin) (table II). Our results do not confirm the recent hypothesis that pregnant diabetics with strict metabolic control during pregnancy generally give birth to growth retarded infants. The MTD of insulin has also been administered to gestational diabetic mothers, and fetal macrosomia was prevented (table I, figure 1). This confirms the opinion of those who believe that a diet-regimen must be accompanied by insulin administration to correct the slight metabolic abnormality of these patients. As would be expected because of placental insufficiency, infants of patients with vascular complications, including those who have only calcifications of the pelvic vessels (White' Class E), were growth retarded (table I, figure 1). The risk of fetal growth retardation in Class E has not been remarked upon in the literature, since pathology of pelvic vessels is usually disregarded and the patients remain undifferentiated among Classes A-C. The possibility to prevent fetal macrosomia with a strict control of maternal diabetes has been questioned because of the lack of correlation between fetal macrosomia and the degree of maternal hyperglycemia and of fetal hyperinsulinism. We postulate that, if fetal hyperinsulinism causes hypoxia, as it does in experimental animals, the lack of correlation may be due to the fetal hyperinsulinism itself.     

Maternal plasma leptin levels and their relationship to insulin and glucose in gestational-onset diabetes

To investigate the changes in leptin levels and the relationship between this substance and insulin and glucose in pregnant women with gestational-onset diabetes, we measured plasma leptin levels in the maternal peripheral vein of 17 healthy and 17 diabetic women at 29 and 33 weeks of gestation. We also correlated maternal plasma leptin levels in diabetic women with fasting plasma insulin levels and plasma glucose levels obtained 1 h after oral administration of 50 g of glucose. Maternal serum leptin levels in women with gestational diabetes (mean +/- SD 16.52 +/- 5.07 ng/ml, range 10.84-27.4 ng/ml) were significantly higher (p < 0.001) than those found in uncomplicated pregnancies (10.61 +/- 1.47 ng/ml, range 7.28-13.4 ng/ml). A positive correlation was found between maternal serum leptin levels and glycosylated haemoglobin values in diabetic pregnant women (r = 0.94, p < 0.001). A positive correlation was also found between maternal leptin concentrations and fasting serum insulin levels, as well as between leptin concentrations and plasma glucose levels obtained 1 h after the administration of 50 g of glucose in women with gestational diabetes (r = 0.84, p < 0.001, and r = 0.92, p < 0.001, respectively). We conclude that leptin levels are elevated in pregnant women with gestational diabetes, and its metabolism depends on insulin levels and the severity of diabetes.     

Diabetes mellitus in pregnancy. Management and outcome of diabetic pregnancies in the state of Hesse, F.R.G.; a five-year-survey

From 1982 to 1986, data of 446 pregnancies in diabetic women were compared to equivalent information on 111,390 unselected non-diabetic pregnancies with the help of the Hessische Perinatalstudie (Hessian Perinatal Study, HEPS), a computerized system of collecting information on obstetrical care in the state of Hesse, F.R.G. Patient histories, pregnancy risks, birth risks, fetal outcome and maternal well-being were evaluated to survey the current situation of diabetic pregnancies in the specific constellation of widely decentralized obstetrical management and to point out possible benefits of stronger centralization of these high-risk pregnancies. Perinatal mortality in children of diabetic mothers (4.89%) remains substantially higher than in children of non-diabetic mothers (0.63%), with two thirds of the fetal loss occurring before birth. Infant morbidity, including macrosomia, shows the same impact of maternal diabetes. Maternal post-partum morbidity is increased in diabetic women. 37.9% of children of diabetic mothers were delivered in obstetrical units equipped for maximal care, 17.5% in primary care level hospitals. Perinatal mortality and morbidity as well as maternal complications indicate that diabetic women should receive obstetrical care in those centers that can provide all the necessary facilities.     

Perinatal HIV transmission: developing country considerations

Objective.?To examine the risk of obesity and metabolic syndrome in women with a history of gestational diabetes mellitus and in offspring born to mothers with gestational diabetes mellitus.

Methods.?A review of studies examining the development of obesity, hypertension, metabolic abnormalities, metabolic syndrome, and type II diabetes in mothers with a history of gestational diabetes mellitus and control mothers, and offspring of mothers with a history of gestational diabetes and control mothers.

Results.?Longitudinal studies demonstrate that women with a prior history of gestational diabetes mellitus and obesity are at significantly greater risk of developing metabolic syndrome than mothers with no history of gestational diabetes or obesity. The development of metabolic syndrome in children with increasing age is related to maternal gestational diabetes mellitus, maternal glycemia in the 3rd trimester, maternal obesity, neonatal macrosomia, and childhood obesity.

Conclusions.?The current prevalence of obesity in both adults and children and associated disorders of blood pressure and lipid metabolism, suggest a perpetuating cycle of increasing obesity, insulin resistance, and abnormal lipid metabolism, which has ominous consequences for future generations.     

Group B streptococcus infection rate unchanged by gestational diabetes

Objective: Group B streptococcal colonization in pregnancy has been associated with adverse perinatal outcomes, including intra-amniotic infection, postpartum endometritis, and neonatal sepsis. We sought to determine whether gestational diabetes increases the risk of maternal and neonatal morbidity from group B streptococcal colonization.Methods: Gestational diabetic and nondiabetic women who underwent vaginal or anogenital culture for group B streptococcus colonization in pregnancy were followed up for pregnancy outcome. Antibiotic prophylaxis was not routinely given. Major perinatal morbidity included intra-amniotic infection, endometritis, and neonatal sepsis. Potential confounding variables included induction of labor, cesarean delivery, prematurity, maternal antibiotic use, and prolonged rupture of membranes.Results: We compared 446 gestational diabetic women to 1,046 nondiabetic women for outcome. Overall, 12% were colonized with group B streptococcus, with no difference in colonization rates between gestational diabetic (12%) and nondiabetic (12%) women. There were no differences in intraamniotic infection rates between gestational diabetic and nondiabetic women, whether group B streptococcus positive (16% compared with 13%) or group B streptococcus negative (10% compared with 11%). Likewise, endometritis did not differ (6–9%) regardless of diabetes or group B streptococcus status. Neonatal sepsis was higher in group B streptococcus-positive women overall (3% compared with 1%, odds ratio 3.71, 95% confidence interval 1.23, 10.81), but did not differ between diabetic and nondiabetic pregnancies.Conclusion: Gestational diabetes does not alter the perinatal morbidity associated with group B streptococcal colonization in pregnancy.     

Major congenital anomalies in infants and glycosylated hemoglobin levels in insulin-requiring diabetic mothers

Glycosylated hemoglobin levels were obtained in 133 diabetic pregnancies. Nongestational diabetic mothers delivered of infants with major congenital anomalies had significantly higher glycosylated hemoglobin levels than the remaining nongestational diabetic mothers (P less than .001). The higher a mother's glycosylated hemoglobin level, the higher her risk of having a severely affected infant was. The positive predictive value for a nongestational diabetic mother having an infant with severe congenital anomalies was 26% if the glycosylated hemoglobin level was greater than or equal to 11%, 40% if the level was greater than or equal to 12%, and 56% if the level greater than or equal to 13%. However, high glycosylated hemoglobin levels in insulin-requiring gestational diabetic mothers were not predictive of major congenital anomalies.