Larry Cousins

A population-based study of maternal and perinatal outcome in patients with gestational diabetes

A prospective population-based study of gestational diabetes mellitus was done with 2272 patients to determine perinatal and maternal outcomes. A large data base was collected on all patients. Patients with gestational diabetes mellitus were older, shorter, heavier, and had more children than did the control group. The higher cesarean section rate in the patients with gestational diabetes mellitus was explained by their increased rate of repeat cesarean section compared with control patients. This was associated with increased infectious complications. Other maternal complication rates were similar in the two groups. Acceptable glucose control did not normalize birth weight percentiles in patients with gestational diabetes mellitus. Maternal weight at delivery was the only significant predictor of birth weight percentile in the group with gestational diabetes mellitus. Plasma glucose levels were a poor predictor of birth weight percentile. Factors associated with maternal obesity in well-controlled gestational diabetes mellitus may be more significant than glucose control in the development of large-for-gestational-age infants.

The 24-hour excursion and diurnal rhythm of glucose, insulin, and C-peptide in normal pregnancy☆☆☆

Abstract A longitudinal study to quantitate the progressive effects of the second and third trimesters of normal pregnancy on the levels of plasma glucose, immunoreactive insulin (IRI), and C-peptide (C-P) at hourly intervals throughout the 24-hour “metabolic clock” was made. Identical studies were conducted in each subject at 6 to 11 weeks post partum and these data were used as nonpregnant control values. Data analyses were made to determine the role of meal-activity-sleep cycles as physiologic modifiers. A diurnal rhythm of plasma glucose, IRI, and C-P was demonstrated in all study periods. During meals anabolic values of plasma glucose (increments above the 24-hour mean) in response to meal intake were remarkably small, ranging between 30 and 35 mg/100 ml in the postpartum state, and were not significantly modified by pregnancy. The corresponding IRI levels were similarly small with a mean increase on only 31% in pregnancy. However, during the third but not the second trimester of pregnancy, the peak anabolic values for both plasma glucose and IRI were significantly (p a.m. ) plasma glucose and 24-hour integrated glucose levels. This relative nocturnal hypoglycemia was associated with synchronous IRI values but without concomitant reduction of absolute IRI levels. Consequently, the fasting, premeal, and 24-hour IRI/glucose ratios were increased. Thus, basal insulin secretion is significantly augmented relative to levels of plasma glucose, but a quantitative increase in insulin secretion following food intake is relatively small during pregnancy. These observations together with the finding of a marked diurnal rhythm of plasma glucose and relative nocturnal hypoglycemia provide important insights for the formulation of guidelines for the timing, amount, and mode of delivery of exogenous insulin necessary for the management of diabetic patients during pregnancy.

Qualitative and quantitative assessment of the circadian rhythm of cortisol in pregnancy.

The effect of pregnancy on the circadian rhythm and diurnal excursion of plasma cortisol and urinary free corticoids was examined in a sequential study during the second and third trimester and 6 to 12 weeks post partum. Hourly blood samples from six subjects and 8-hour urine collections from eight subjects were obtained around the clock. While the circadian rhythm was maintained during gestation, plasma cortisol levels (24-hour mean, nadir, peak, and nadir-peak excursion) increased. The relative excursion of plasma cortisol (expressed as the percentage of deviation from the 24-hour mean) exhibited remarkable blunting compared with postpartum values. This pregnancy-associated blunting of plasma cortisol excursion was indicated by a significant reduction in the: (1) mean peak and nadir excursion, (2) integrated area between the percent deviation curve and the 24-hour mean, and (3) mean slope of the major incremental and decremental segments of the percent deviation curve. The circadian rhythm and diurnal excursion of plasma cortisol were reflected in urinary free corticoid values. Mean 24-hour urinary free corticoid concentrations increased 180% during gestation over nonpregnant levels. Nadir concentrations of urinary free corticoids in pregnancy exceeded peak nonpregnant levels. The gestational rise of metabolically active free cortisol and adrenocorticotropin (ACTH), and the pregnancy-associated blunting of the excursion of plasma cortisol may be explained by an autonomous source of ACTH during gestation.

Congenital anomalies among infants of diabetic mothers: Etiology, prevention, prenatal diagnosis

Congenital anomalies occur two to three times more frequently among infants of women diabetic before pregnancy than among infants of nondiabetic women.‘-’ In addition to being more common among infants of diabetic mothers (IDMs), anomalies are significantly more severe and more often multiple and fatal.’ Concomitant with improved medical, obstetric, and neonatal care of diabetic pregnancies over the past two decades, the frequency of many perinatal complications (respiratory distress, fetal death, birth trauma, etc.) has decreased. While the impact of these complications on perinatal morbidity has diminished, the incidence of malformations has not significantly changed. Consequently, the relative importance of congenital anomalies has increased to the extent that they are the most common cause of perinatal death among IDMs in recent reports.‘. ‘XI If anomalyassociated morbidity among IDMs is to be minimized, it is essential to understand the pathogenesis of these anomalies and formulate a preventative management plan guided by an awareness of the etiologic mechanism(s). Such a preventative program potentially could reduce the incidence of malformations to the rate seen in uncomplicated pregnancies. Should prophylaxis fail, improved diagnostic accuracy of these anomalies will facilitate prenatal management. The purpose of this report is to review the current information related to etiology and management and summarize the approach to prevention and diagnosis of congenital anomalies among IDMs utilized at our institution.*

Glycosylated hemoglobin as a screening test for carbohydrate intolerance in pregnancy

The usefulness of glycosylated hemoglobin as a prenatal screening test for carbohydrate intolerance was studied in 806 consecutive subjects by correlating glycosylated hemoglobin to 1-hour post-50 gm Glucola plasma glucose (1 degree G) levels, and 3-hour oral glucose tolerance tests (3 degrees GTT). Sixty-seven subjects whose 1 degree G greater than or equal to 150 mg/100 ml received a 3 degrees GTT; 12 were diagnostic of carbohydrate intolerance. Compared to carbohydrate-tolerant controls, carbohydrate-intolerant gravid patients had higher 1 degree G (p less than 0.001) and glycosylated hemoglobin (p less than 0.05) levels. Linear regression analysis of 1 degree G and glycosylated hemoglobin demonstrated r = 0.35 (p less than 0.0001). Compared to the glycosylated hemoglobin test, the 1 degree G screening test has greater specificity, sensitivity, and predictive value for a positive diagnosis. Consequently, the 1 degree G is a better routine screening test for carbohydrate intolerance than is glycosylated hemoglobin.

Decreased Insulin Requirement and Improved Control of Diabetes in Pregnant Women Given a High-Carbohydrate, High-Fiber, Low-Fat Diet

Five quantitative measures of diabetic control [HbA1c determinations, mean 24-h plasma glucose values, mean amplitude of glycemic excursions (MAGE), mean 24-h urinary loss of glucose, and daily exogenous insulin requirement] were compared in 20 pregnant women who were randomly assigned to either a high-carbohydrate, high-fiber diet (HCF) that was low in fat or to a control diet commonly prescribed for pregnancy. Eleven women followed the HCF diet and nine subjects, the control diet, from baseline entry into the study until delivery. Dietary compliance was excellent, with 78% of the women in each group rated good or acceptable. HbA1c values were similar in both groups at baseline (HCF: 11.0 ± 0.5% versus control: 10.2 ± 0.6%), with no different predelivery values (8.6 ± 0.4%). Mean 24-h plasma glucose levels improved in patients on both diets, with lower values noted in the HCF group at predelivery. MAGE values and standard deviations did not differ significantly in the two groups. Glycosuria decreased markedly in both dietary groups, but differences between groups were not significant. Improved control of diabetes on the HCF diet was achieved with significantly lower increments in insulin dose during gestation (HCF baseline: 32 ± 8 U/24 h to 66 ± 10 U/24 h versus control baseline: 27 ± 9 U/24 h to 108 ± 12 U/24 h, P < 0.03). Outcome of pregnancy did not differ in the two groups of patients, but women on the HCF diet gained less weight than those on the control diet (26 ± 3 lb versus 35 ± 5 lb, P < 0.05). Mean newborn gestational age was similar in the two groups (HCF: 37.2 ± 0.7 wk versus control: 36.5 ± 0.7 wk). Mean birth weight in infants of HCF mothers ± was 3809 ± 248 g versus 3313 ± 278 g in infants of control mothers (P < 0.05). We conclude that although marked improvement of diabetic control occurred on both regimens, patients on the HCF diet achieved better control of diabetes with significantly lower increments in exogenous insulin.

Oxytocin-associated rupture of an unscarred uterus in a primigravida.

BACKGROUND: Intrapartum rupture of the unscarred uterus is an uncommon event, usually associated with such risk factors as grand multiparity, malpresentation, history of gestational trophoblastic disease, or instrumented delivery. Rupture during first pregnancy is extremely rare. CASE: A 30-year-old primigravid woman was admitted for labor augmentation with oxytocin at 40.5 weeks of gestation. The oxytocin infusion rate was increased during the first and second stages of labor despite contractions occurring at a rate of 4–5 per 10 minutes. The uterus ruptured during second stage. Despite emergency cesarean delivery, the baby had evidence of severe asphyxia. CONCLUSION: This case of uterine rupture in a primigravida with no prior uterine surgery and a structurally normal uterus underscores the importance of careful contraction monitoring and judicious control of oxytocin infusion rates.

Effects of exogenous insulin on excursions and diurnal rhythm of plasma glucose in pregnant diabetic patients with and without residual β-cell function

Abstract The relative effects and consequences of split doses of exogenous insulin therapy (two thirds before breakfast and one third before the evening meal) on excursions and diurnal rhythm of circulating glucose during the 24-hour “metabolic clock” were examined. A longitudinal study in pregnant women with maturity-onset diabetes (N = 7) with substantial endogenous insulin secretion and juvenile onset diabetes (N = 6) with no measurable endogenous insulin secretion (judged by C-peptide measurement) was compared with identical studies performed in nondiabetic pregnant control subjects (N = 6). Plasma glucose levels determined at hourly intervals throughout the 24-hour meal-activity-sleep cycles revealed marked excursions of plasma glucose values with exaggerated hyperglycemia during the day hours and relative hypoglycemia at night in both types of diabetic pregnancies as compared to normal control pregnancies. The magnitude of glucose excursion was surprisingly large relative to the degree of increase in the mean 24-hour glucose levels and mean fasting blood glucose values. A striking disparity in the amount of exogenous insulin required to maintain glucose levels and diurnal rhythm toward the normal range in pregnant diabetic patients from second to the third trimester was observed. The degree of exogenous insulin increment imposed by pregnancy (from the second to third trimester) in juvenile-onset diabetes was relatively small (38%) and comparable to the increase in endogenous insulin (32%) found in nondiabetic pregnancies. In marked contrast, among patients with maturity-onset diabetes, in whom substantial endogenous insulin secretion was present, the corresponding increment in exogenous insulin was surprisingly large (98%) without a proportional reduction in 24-hour integrated glucose values. These findings indicate that the effects and consequences of exogenous insulin therapy between maturity-onset diabetes and juvenile-onset diabetes during pregnancy are clearly different. Our data further suggest that peripheral insulin resistance constitutes the major factor accounting for the persistence of hyperglycemia in maturity-onset diabetes. Although the mechanism by which the exaggeration of insulin resistance in maturity-onset diabetes with superimposed pregnancy remains unclear, there are at least three additive contributing events to consider: the inherent defect of insulin resistance in this type of diabetes, the pregnancy-induced insulin resistance, and the reduction in number or affinity of insulin receptors in target tissues occasioned by excessive exogenous insulin treatment.

Development and validation of a spontaneous preterm delivery predictor in asymptomatic women.

BACKGROUND Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries. OBJECTIVE To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women. STUDY DESIGN A total of 5501 pregnant women were enrolled between 17(0/7) and 28(6/7) weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (<37(0/7) weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed. RESULTS The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, <35(0/7) vs ≥35(0/7) weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects. CONCLUSION A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery.

Prenatally Diagnosed Vasa Previa: A Single-institution Series of 96 Cases

OBJECTIVE: To describe outcomes for a large cohort of women with prenatally diagnosed vasa previa, determine the percentage in patients without risk factors, and compare delivery timing and indications for singletons and twins. METHODS: This was a retrospective case series of women with prenatally diagnosed vasa previa delivered at a single tertiary center over 12 years. Potential participants were identified using hospital records and perinatal databases. Patients were included if vasa previa was confirmed at delivery and by pathologic examination. Maternal and newborn data were gathered from medical records. RESULTS: There were 77 singleton and 19 twin pregnancies with a prenatal diagnosis of vasa previa. There was one neonatal death from congenital heart disease. Perinatal management of recommended elective hospitalizations with corticosteroid administration and elective early delivery resulted in average gestational age for delivery in singletons at 34.7±1.6 weeks and 32.8±2.2 weeks for twins. Among the 77 singletons, delivery was elective in 48, as a result of contractions or labor in 21, bleeding in four, nonreassuring tracing in two, asymptomatic cervical shortening in one, and preeclampsia in one. Among 19 twins, delivery was elective in six and for contractions or labor in 13. Sixty-eight percent of twins compared with 37% of singletons had nonelective delivery (P<.05). Delivery occurred by 32 weeks of gestation in 6.4% of singletons and 26% of twins (P<.05) and by 34 weeks of gestation in 11% of singletons and 58% of twins (P<.001). Six neonates (5.2%) had major anomalies, all prenatally detected. Respiratory distress syndrome occurred in 57.1% of singletons and 65.7% of twins. Nineteen singletons (24.7%) had no risk factors for vasa previa. CONCLUSION: Planned preterm delivery for women with prenatally diagnosed vasa previa resulted in elective delivery for singletons in 62% and for twins 32%. Gestational age at birth on average was 34.7 weeks for singletons and 32.8 weeks of gestation for twins. Major anomalies were frequent as was respiratory distress syndrome. Elective delivery between 34 and 35 weeks of gestation for singletons is reasonable. As a result of the high rate of nonelective delivery in twins, delivery at 32–34 weeks of gestation may be risk-beneficial. The high rate of singletons without risk factors for vasa previa reinforces the recommendation to screen routinely for cord insertion site.