Jerome H. Aarons

Maternal postprandial glucose levels and infant birth weight: The Diabetes in Early Pregnancy Study

The cause of macrosomia in the infant of the diabetic woman is still not completely defined. The National Institute of Child Health and Human Development--Diabetes in Early Pregnancy Study, which recruited insulin-dependent diabetic and control women before conception, provided an opportunity to address the relationship between maternal glycemia and percentile birth weight. Data were analyzed from 323 diabetic and 361 control women. Fasting and nonfasting venous plasma glucose were measured on alternate weeks in the first trimester and monthly thereafter. Glycosylated hemoglobin was measured weekly in the first trimester and monthly thereafter. More infants of the diabetic women were at or above the 90th percentile for birth weight than infants of control women (28.5% versus 13.1%, p less than 0.001). Although first-trimester nonfasting glucose and glycosylated hemoglobin levels were positively correlated with infant birth weight (p less than 0.001 and p = 0.008), when the analyses were adjusted for the variables of the subsequent trimesters the values became insignificant, whereas the third-trimester nonfasting glucose levels adjusted for values in prior trimesters emerged as the stronger predictor of percentile birth weight (p = 0.001). After adjusting for maternal hypertension, smoking, and ponderal index, the above relationships remained. In conclusion, monitoring of nonfasting glucose levels rather than the fasting levels, which are more commonly monitored in clinical practice, are necessary to prevent macrosomia.

Metabolic Control and Progression of Retinopathy: The Diabetes in Early Pregnancy Study

OBJECTIVE To evaluate the role of metabolic control in the progression of diabetic retinopathy during pregnancy. RESEARCH DESIGN AND METHODS We conducted a prospective cohort study of 155 diabetic women in the Diabetes in Early Pregnancy Study followed from the periconceptional period to 1 month postpartum. Fundus photographs were obtained shortly after conception (95% within 5 weeks of conception) and within 1 month postpartum. Glycosylated hemoglobin was measured weekly during the 1st trimester and monthly thereafter. RESULTS In the 140 patients who did not have proliferative retinopathy at baseline, progression of retinopathy was seen in 10.3, 21.1, 18.8, and 54.8% of patients with no retinopathy, microaneurysms only, mild nonproliferative retinopathy, and moderate-to-severe nonproliferative retinopathy at baseline, respectively. Proliferative retinopathy developed in 6.3% with mild and 29% with moderate-to-severe baseline retinopathy. Elevated glycosylated hemoglobin at baseline and the magnitude of improvement of glucose control through week 14 were associated with a higher risk of progression of retinopathy (adjusted odds ratio for progression in those with glycohe-moglobin ≥ 6 SD above the control mean versus those within 2 SD was 2.7; 95% confidence interval was 1.1-7.2; P = 0.039). CONCLUSIONS The risk for progression of diabetic retinopathy was increased by initial glycosylated hemoglobin elevations as low as 6 SD above the control mean. This increased risk maybe due to suboptimal control itself or to the rapid improvement in metabolic control that occurred in early pregnancy. Excellent metabolic control before conception may be required to avoid this increase in risk. Those with moderate-to-severe retinopathy at conception need more careful ophthalmic monitoring, particularly if their diabetes was suboptimally controlled at conception.

Physiological Reduction in Fasting Plasma Glucose Concentration in the First Trimester of Normal Pregnancy: The Diabetes in Early Pregnancy Study

Previous studies indicate that fasting plasma glucose decreases during gestation, but the timing and extent are not consistent from study to study. We had an opportunity to examine this question in the normal pregnancy cohort of women studied in the Diabetes in Early Pregnancy Study. Subjects were monitored to identify pregnancy by human chorionic gonadotropin testing, enrolled within 21 days of conception, and screened to rule out gestational diabetes at the juncture of the second and third trimesters. All subjects were instructed to fast overnight for 10 to 12 hours. Three hundred sixty-one women were studied between 6 and 12 weeks of gestation. A median decrease in plasma glucose of 2 mg/dL was observed between weeks 6 and 10 (P=.007). In a smaller group of subjects evaluated through the third trimester, little further glucose reduction was observed. A reduction in glycosylated hemoglobin levels between 10 and 20 weeks (P=.002) followed the earlier reduction in first trimester glucose levels. Analysis by body mass index (BMI) showed a smaller first trimester reduction with increasing BMI, and none among severely obese women (BMI > 29.9 kg/m2). The decline in fasting plasma glucose in pregnancy begins early in the first trimester, well before fetal glucose requirements can contribute to the decline in the glucose level. Thereafter, plasma glucose levels decrease little. These results suggest that in the setting in which this study was performed (an overnight fast) maternal physiologic adjustments account for a reduction in plasma glucose early in the first trimester of pregnancy, and possibly even later in gestation as well.

The Diabetes in Early Pregnancy Study: Changes incholesterol, triglycerides, body weight, and blood pressure

Summary This study examined changes in cholesterol, triglycerides, body weight, and blood pressure duringpregnancy in 312 diabetic and 356 control women recruited within 21 days after conception. Cholesterol values rose in both groups but were significantly lower in diabetic women at each time point (166 vs 178 mg/dl at week 12, p=0.0004). Triglyceride values also rose in both groups. Triglyceride levels did not differ between groups up to week 8 of gestation, but by weeks 10 to 12 they were significantly lower in diabetic women than in controls (75 vs 89 mg/dl at week 12, p = 0.0004). Although they were no heavier at entry, diabetic women gained significantly more weight between weeks 6 and 8 ( p p = 0.0006 at term). Diastolic blood pressure was higher in diabetic women on entry (70.7 vs 67.3 mm Hg, p = 0.0006) and throughout gestation. Significant correlations were found in the diabetic group between maternal blood pressure and lipids and infant birth weight. These newly found differences in cholesterol and triglyceride levels, weight gain, and blood pressure between type I diabetic and control women during gestation may have long-term cardiovascular implicationsThis study examined changes in cholesterol, triglycerides, body weight, and blood pressure during pregnancy in 312 diabetic and 356 control women recruited within 21 days after conception. Cholesterol values rose in both groups but were significantly lower in diabetic women at each time point (166 vs 178 mg/dl at week 12, p = 0.0004). Triglyceride values also rose in both groups. Triglyceride levels did not differ between groups up to week 8 of gestation, but by weeks 10 to 12 they were significantly lower in diabetic women than in controls (75 vs 89 mg/dl at week 12, p = 0.0004). Although they were no heavier at entry, diabetic women gained significantly more weight between weeks 6 and 8 (p less than 0.001), resulting in a mean difference between groups of 1 kg. Systolic blood pressure increased steadily and significantly in the diabetic but not the control women (115.8 +/- 16.2 SD vs 109.3 +/- 11.8 mm Hg, p = 0.0006 at term). Diastolic blood pressure was higher in diabetic women on entry (70.7 vs 67.3 mm Hg, p = 0.0006) and throughout gestation. Significant correlations were found in the diabetic group between maternal blood pressure and lipids and infant birth weight. These newly found differences in cholesterol and triglyceride levels, weight gain, and blood pressure between type I diabetic and control women during gestation may have long-term cardiovascular implications.

Early sonographic evaluation for fetal growth delay and congenital malformations in pregnancies complicated by insulin-requiring diabetes

Objective It has been reported that early fetal growth retardation may be a useful marker for congenital malformations in diabetic pregnancies. To test this hypothesis, diabetic and nondiabetic women were sonographically evaluated during the first trimester. Research Desihn and Methods Fetal crown-rump lengths were measured sonographically at least once during the first 15 wk of pregnancy in 329 nondiabetic and 312 diabetic women. Of these, 289 nondiabetic and 269 diabetic women had sonograms before 10 wk of gestation and 283 nondiabetic and 269 diabetic women had sonograms between 10 and 15 wk of gestation. Early fetal growth delay was defined as a sonographic gestational age of ≥6 days less than menstrual gestational age. Results The mean crown-rump lengths at 8 wk were 17.9 ± 4.6 mm in the diabetic and 18.7 ± 4.9 mm in the nondiabetic groups (P = 0.13). At 12 wk, the mean fetal crown-rump length was 58.5 ± 8.8 mm for diabetic subjects and 60.6 ± 8.7 mm for nondiabetic subjects (P = 0.04). Between 5 and 9 wk, 28 of 289 (9.7%) fetuses of nondiabetic subjects, 34 of 259 (13.1%) normal fetuses of diabetic subjects, and 2 of 10 (20%) malformed fetuses of diabetic subjects demonstrated growth delay (P = 0.31, normal vs. malformed diabetic). Between 10 and 15 wk of gestation, 28 of 283 (9.9%) fetuses of nondiabetic subjects, 32 of 256 (12.5%) normal fetuses of diabetic subjects, and 4 of 13 (30.8%) malformed fetuses of diabetic subjects demonstrated growth delay (P = 0.06, normal vs. malformed diabetic). Early fetal growth delay did not predict a reduced birth weight at term. Conclusions Among insulin-dependent diabetic subjects who were moderately well controlled at conception, statistically significant but mild early fetal growth delay was present but did not appear to be useful clinically in predicting congenital malformations. Recommendations that growth delay demonstrated on early ultrasound be used as a predictor of congenital malformation require careful reexamination.

Infectious processes: an infrequent cause of first trimester spontaneous abortions

A systematic assessment of infections beginning early in pregnancy is necessary to determine the true role of infections in pregnancy loss, given that infections could readily arise only after fetal demise. To this end, we have prospectively determined the frequency of infections in pregnant women who were subjects in a multi-centre US study. Insulin-dependent diabetic subjects and controlled subjects were recruited either before conception (86%) or at the latest within 21 days of conception (14%). We collected data prospectively on all important risk factors and potential confounding variables, seeing 386 diabetic subjects weekly and 432 control subjects every other week during the first trimester. At each visit we inquired about untoward events and explicitly about fever or infections. We found no clinical evidence that infection occurred more often in the 116 subjects experiencing pregnancy loss as compared to the 702 having successful pregnancies. This held both for the 2 week interval in which a given loss was recognized clinically as well as in the prior 2 week interval. Similar findings were not only observed for both the control as well as diabetic subjects but also when data were stratified by genital infection only or by systemic infection only. Our prospective data suggest that the attributable risk of infection in first trimester spontaneous abortion is small.

Temporal trends in spontaneous abortion associated with Type 1 diabetes

The objective of this study was to investigate temporal changes in the reported rates of spontaneous abortion associated with Type 1 diabetes. Individuals from the Childrens Hospital of Pittsburgh Type 1 Diabetes Registry for 1950-1964 (n=495) completed a self-report reproductive history questionnaire in 1981 that was updated in 1990. Data from both surveys, which proved to be valid and reliable, were utilized for this report. More spontaneous abortions (26.8 vs. 7.7%, P<0.001), stillbirths (4.7 vs. 1.2%, P<0.001) and induced abortions (7.0 vs. 0.9%, P<0.001) were reported for Type 1 diabetic women than for the non-diabetic partners of Type 1 diabetic men. A significant temporal decline in the rates of spontaneous abortion for Type 1 diabetic women was observed (< or = 1969: 26.4%; 1970-1979: 31.0%; 1980-1989: 15.7%; P<0.05). No differences were apparent for the non-diabetic partners of Type 1 diabetic men (< or = 1969: 4.2%; 1970-1979: 9.5%; 1980-1989: 5.7%; P>0.05). Temporal changes in medical care for women with diabetes (i.e. self-monitoring of glycemic control) may have contributed to a recent reduction in spontaneous abortions associated with maternal Type 1 diabetes.

Verification of Early Pregnancy Tests in a Multicenter Trial

Abstract Tests for the diagnosis of early pregnancy have been available since 1974. However, no studies have systematically verified the accuracy of routine clinical laboratories in measuring human chorionic gonadotropin (hCG) prior to the time that pregnancy is clinically evident. We have conducted such a study in association with the NICHD-funded Diabetes in Early Pregnancy Study (DIEP). The purpose of this study was to elucidate the etiology of malformations in pregnancies complicated by diabetes mellitus, which probably occurs within the first few weeks of pregnancy, and therefore uniformity of pregnancy testing was necessary among the five centers to find an association of a teratogen at the time of organogenesis. We confirmed that routine clinical laboratories, in fact, could measure accurately hCG at the time of the missed menses; however, detection was not necessarily possible prior to that time. We conclude that in order to assure accurate diagnosis of early pregnancy, tests should ordinarily be delayed until time of the missed menses. When the test is used at this time, it is a reliable tool for early pregnancy testing and thus can be used to resolve questions relating to early pregnancy pathophysiology.

Insulinoma in a 94-year-old Woman: Long-term Therapy with Verapamil

Several drugs can be used to control hypoglycemia caused by insulin-secreting pancreatic tumors but none are reliably efficacious or free of side effects. We report the case of a woman with an insulinoma who refused surgical intervention and was successfully treated with the Ca2+-channel blocker verapamil.

Evaluation of recruitment strategies for prospective studies of spontaneous abortion.

The examination of spontaneous abortions may offer a sensitive index to potential adverse health effects due to environmental exposures. However, difficulties in ascertaining spontaneous abortions on a population basis, as well as problems in recruiting unselected women into studies of this nature, have severely limited the use of this end point in environmental epidemiology studies. The current research assesses the feasibility of recruiting a representative sample of women into a prospective pregnancy study. Four protocols varying in intensity of data collection were offered to the participants. Fifty-two percent of the eligible women agreed to participate. Seventy-four percent chose the most intensive protocol level. Overall compliance for urine collection and questionnaire completion were 80% and 81%, respectively. Four pregnancies were observed, which was the expected number for the study area during this time frame, suggesting that the majority of pregnancies occurring within a population could be ascertained with this approach.