Marshall Carpenter

A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes

BACKGROUND It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes. METHODS Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus (i.e., an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [5.3 mmol per liter]) were randomly assigned to usual prenatal care (control group) or dietary intervention, self-monitoring of blood glucose, and insulin therapy, if necessary (treatment group). The primary outcome was a composite of stillbirth or perinatal death and neonatal complications, including hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma. RESULTS A total of 958 women were randomly assigned to a study group--485 to the treatment group and 473 to the control group. We observed no significant difference between groups in the frequency of the composite outcome (32.4% and 37.0% in the treatment and control groups, respectively; P=0.14). There were no perinatal deaths. However, there were significant reductions with treatment as compared with usual care in several prespecified secondary outcomes, including mean birth weight (3302 vs. 3408 g), neonatal fat mass (427 vs. 464 g), the frequency of large-for-gestational-age infants (7.1% vs. 14.5%), birth weight greater than 4000 g (5.9% vs. 14.3%), shoulder dystocia (1.5% vs. 4.0%), and cesarean delivery (26.9% vs. 33.8%). Treatment of gestational diabetes mellitus, as compared with usual care, was also associated with reduced rates of preeclampsia and gestational hypertension (combined rates for the two conditions, 8.6% vs. 13.6%; P=0.01). CONCLUSIONS Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications, it did reduce the risks of fetal overgrowth, shoulder dystocia, cesarean delivery, and hypertensive disorders. (ClinicalTrials.gov number, NCT00069576.)

Maternal Morbidity Associated With Multiple Repeat Cesarean Deliveries

OBJECTIVE: Although repeat cesarean deliveries often are associated with serious morbidity, they account for only a portion of abdominal deliveries and are overlooked when evaluating morbidity. Our objective was to estimate the magnitude of increased maternal morbidity associated with increasing number of cesarean deliveries. METHODS: Prospective observational cohort of 30,132 women who had cesarean delivery without labor in 19 academic centers over 4 years (1999–2002). RESULTS: There were 6,201 first (primary), 15,808 second, 6,324 third, 1,452 fourth, 258 fifth, and 89 sixth or more cesarean deliveries. The risks of placenta accreta, cystotomy, bowel injury, ureteral injury, and ileus, the need for postoperative ventilation, intensive care unit admission, hysterectomy, and blood transfusion requiring 4 or more units, and the duration of operative time and hospital stay significantly increased with increasing number of cesarean deliveries. Placenta accreta was present in 15 (0.24%), 49 (0.31%), 36 (0.57%), 31 (2.13%), 6 (2.33%), and 6 (6.74%) women undergoing their first, second, third, fourth, fifth, and sixth or more cesarean deliveries, respectively. Hysterectomy was required in 40 (0.65%) first, 67 (0.42%) second, 57 (0.90%) third, 35 (2.41%) fourth, 9 (3.49%) fifth, and 8 (8.99%) sixth or more cesarean deliveries. In the 723 women with previa, the risk for placenta accreta was 3%, 11%, 40%, 61%, and 67% for first, second, third, fourth, and fifth or more repeat cesarean deliveries, respectively. CONCLUSION: Because serious maternal morbidity increases progressively with increasing number of cesarean deliveries, the number of intended pregnancies should be considered during counseling regarding elective repeat cesarean operation versus a trial of labor and when debating the merits of elective primary cesarean delivery. LEVEL OF EVIDENCE: II-2

Timing of elective repeat cesarean delivery at term and neonatal outcomes

BACKGROUND Because of increased rates of respiratory complications, elective cesarean delivery is discouraged before 39 weeks of gestation unless there is evidence of fetal lung maturity. We assessed associations between elective cesarean delivery at term (37 weeks of gestation or longer) but before 39 weeks of gestation and neonatal outcomes. METHODS We studied a cohort of consecutive patients undergoing repeat cesarean sections performed at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network from 1999 through 2002. Women with viable singleton pregnancies delivered electively (i.e., before the onset of labor and without any recognized indications for delivery before 39 weeks of gestation) were included. The primary outcome was the composite of neonatal death and any of several adverse events, including respiratory complications, treated hypoglycemia, newborn sepsis, and admission to the neonatal intensive care unit (ICU). RESULTS Of 24,077 repeat cesarean deliveries at term, 13,258 were performed electively; of these, 35.8% were performed before 39 completed weeks of gestation (6.3% at 37 weeks and 29.5% at 38 weeks) and 49.1% at 39 weeks of gestation. One neonatal death occurred. As compared with births at 39 weeks, births at 37 weeks and at 38 weeks were associated with an increased risk of the primary outcome (adjusted odds ratio for births at 37 weeks, 2.1; 95% confidence interval [CI], 1.7 to 2.5; adjusted odds ratio for births at 38 weeks, 1.5; 95% CI, 1.3 to 1.7; P for trend <0.001). The rates of adverse respiratory outcomes, mechanical ventilation, newborn sepsis, hypoglycemia, admission to the neonatal ICU, and hospitalization for 5 days or more were increased by a factor of 1.8 to 4.2 for births at 37 weeks and 1.3 to 2.1 for births at 38 weeks. CONCLUSIONS Elective repeat cesarean delivery before 39 weeks of gestation is common and is associated with respiratory and other adverse neonatal outcomes.

A Randomized, Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy

BACKGROUND Research suggests that fetal exposure to magnesium sulfate before preterm birth might reduce the risk of cerebral palsy. METHODS In this multicenter, placebo-controlled, double-blind trial, we randomly assigned women at imminent risk for delivery between 24 and 31 weeks of gestation to receive magnesium sulfate, administered intravenously as a 6-g bolus followed by a constant infusion of 2 g per hour, or matching placebo. The primary outcome was the composite of stillbirth or infant death by 1 year of corrected age or moderate or severe cerebral palsy at or beyond 2 years of corrected age. RESULTS A total of 2241 women underwent randomization. The baseline characteristics were similar in the two groups. Follow-up was achieved for 95.6% of the children. The rate of the primary outcome was not significantly different in the magnesium sulfate group and the placebo group (11.3% and 11.7%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.77 to 1.23). However, in a prespecified secondary analysis, moderate or severe cerebral palsy occurred significantly less frequently in the magnesium sulfate group (1.9% vs. 3.5%; relative risk, 0.55; 95% CI, 0.32 to 0.95). The risk of death did not differ significantly between the groups (9.5% vs. 8.5%; relative risk, 1.12; 95% CI, 0.85 to 1.47). No woman had a life-threatening event. CONCLUSIONS Fetal exposure to magnesium sulfate before anticipated early preterm delivery did not reduce the combined risk of moderate or severe cerebral palsy or death, although the rate of cerebral palsy was reduced among survivors. (ClinicalTrials.gov number, NCT00014989.)

Vitamins C and E to prevent complications of pregnancy-associated hypertension

BACKGROUND Oxidative stress has been proposed as a mechanism linking the poor placental perfusion characteristic of preeclampsia with the clinical manifestations of the disorder. We assessed the effects of antioxidant supplementation with vitamins C and E, initiated early in pregnancy, on the risk of serious adverse maternal, fetal, and neonatal outcomes related to pregnancy-associated hypertension. METHODS We conducted a multicenter, randomized, double-blind trial involving nulliparous women who were at low risk for preeclampsia. Women were randomly assigned to begin daily supplementation with 1000 mg of vitamin C and 400 IU of vitamin E or matching placebo between the 9th and 16th weeks of pregnancy. The primary outcome was severe pregnancy-associated hypertension alone or severe or mild hypertension with elevated liver-enzyme levels, thrombocytopenia, elevated serum creatinine levels, eclamptic seizure, medically indicated preterm birth, fetal-growth restriction, or perinatal death. RESULTS A total of 10,154 women underwent randomization. The two groups were similar with respect to baseline characteristics and adherence to the study drug. Outcome data were available for 9969 women. There was no significant difference between the vitamin and placebo groups in the rates of the primary outcome (6.1% and 5.7%, respectively; relative risk in the vitamin group, 1.07; 95% confidence interval [CI], 0.91 to 1.25) or in the rates of preeclampsia (7.2% and 6.7%, respectively; relative risk, 1.07; 95% CI, 0.93 to 1.24). Rates of adverse perinatal outcomes did not differ significantly between the groups. CONCLUSIONS Vitamin C and E supplementation initiated in the 9th to 16th week of pregnancy in an unselected cohort of low-risk, nulliparous women did not reduce the rate of adverse maternal or perinatal outcomes related to pregnancy-associated hypertension (ClinicalTrials.gov number, NCT00135707).

Causes of death among stillbirths

CONTEXT Stillbirth affects 1 in 160 pregnancies in the United States, equal to the number of infant deaths each year. Rates are higher than those of other developed countries and have stagnated over the past decade. There is significant racial disparity in the rate of stillbirth that is unexplained. OBJECTIVE To ascertain the causes of stillbirth in a population that is diverse by race/ethnicity and geography. DESIGN, SETTING, AND PARTICIPANTS A population-based study from March 2006 to September 2008 with surveillance for all stillbirths at 20 weeks or later in 59 tertiary care and community hospitals in 5 catchment areas defined by state and county boundaries to ensure access to at least 90% of all deliveries. Termination of a live fetus was excluded. Standardized evaluations were performed at delivery. MAIN OUTCOME MEASURES Medical history, fetal postmortem and placental pathology, karyotype, other laboratory tests, systematic assignment of causes of death. RESULTS Of 663 women with stillbirth enrolled, 500 women consented to complete postmortem examinations of 512 neonates. A probable cause of death was found in 312 stillbirths (60.9%; 95% CI, 56.5%-65.2%) and possible or probable cause in 390 (76.2%; 95% CI, 72.2%-79.8%). The most common causes were obstetric conditions (150 [29.3%; 95% CI, 25.4%-33.5%]), placental abnormalities (121 [23.6%; 95% CI, 20.1%-27.6%]), fetal genetic/structural abnormalities (70 [13.7%; 95% CI, 10.9%-17.0%]), infection (66 [12.9%; 95% CI, 10.2%-16.2%]), umbilical cord abnormalities (53 [10.4%; 95% CI, 7.9%-13.4%]), hypertensive disorders (47 [9.2%; 95% CI, 6.9%-12.1%]), and other maternal medical conditions (40 [7.8%; 95% CI, 5.7%-10.6%]). A higher proportion of stillbirths in non-Hispanic black women compared with non-Hispanic white and Hispanic ones was associated with obstetric complications (43.5% [50] vs 23.7% [85]; difference, 19.8%; 95% CI, 9.7%-29.9%; P < .001) and infections (25.2% [29] vs 7.8% [28]; difference, 17.4%; 95% CI, 9.0%-25.8%; P < .001). Stillbirths occurring intrapartum and early in gestation were more common in non-Hispanic black women. Sources most likely to provide positive information regarding cause of death were placental histology (268 [52.3%; 95% CI, 47.9%-56.7%]), perinatal postmortem examination (161 [31.4%; 95% CI, 27.5%-35.7%]), and karyotype (32 of 357 with definitive results [9%; 95% CI, 6.3%-12.5%]). CONCLUSIONS A systematic evaluation led to a probable or possible cause in the majority of stillbirths. Obstetric conditions and placental abnormalities were the most common causes of stillbirth, although the distribution differed by race/ethnicity.

Development of a nomogram for prediction of vaginal birth after cesarean delivery.

OBJECTIVE: To develop a model based on factors available at the first prenatal visit that predicts chance of successful vaginal birth after cesarean delivery (VBAC) for individual patients who undergo a trial of labor. METHODS: All women with one prior low transverse cesarean who underwent a trial of labor at term with a vertex singleton gestation were identified from a concurrently collected database of deliveries at 19 academic centers during a 4-year period. Using factors identifiable at the first prenatal visit, we analyzed different classification techniques in an effort to develop a meaningful prediction model for VBAC success. After development and cross-validation, this model was represented by a graphic nomogram. RESULTS: Seven-thousand six hundred sixty women were available for analysis. The prediction model is based on a multivariable logistic regression, including the variables of maternal age, body mass index, ethnicity, prior vaginal delivery, the occurrence of a VBAC, and a potentially recurrent indication for the cesarean delivery. After analyzing the model with cross-validation techniques, it was found to be both accurate and discriminating. CONCLUSION: A predictive nomogram, which incorporates six variables easily ascertainable at the first prenatal visit, has been developed that allows the determination of a patient-specific chance for successful VBAC for those women who undertake trial of labor. LEVEL OF EVIDENCE: II

Risk of uterine rupture with a trial of labor in women with multiple and single prior cesarean delivery

OBJECTIVE: To determine whether the risk for uterine rupture is increased in women attempting vaginal birth after multiple cesarean deliveries. METHODS: We conducted a prospective multicenter observational study of women with prior cesarean delivery undergoing trial of labor and elective repeat operation. Maternal and perinatal outcomes were compared among women attempting vaginal birth after multiple cesarean deliveries and those with a single prior cesarean delivery. We also compared outcomes for women with multiple prior cesarean deliveries undergoing trial of labor with those electing repeat cesarean delivery. RESULTS: Uterine rupture occurred in 9 of 975 (0.9%) women with multiple prior cesarean compared with 115 of 16,915 (0.7%) women with a single prior operation (P = .37). Multivariable analysis confirmed that multiple prior cesarean delivery was not associated with an increased risk for uterine rupture. The rates of hysterectomy (0.6% versus 0.2%, P = .023) and transfusion (3.2% versus 1.6%, P < .001) were increased in women with multiple prior cesarean deliveries compared with women with a single prior cesarean delivery attempting trial of labor. Similarly, a composite of maternal morbidity was increased in women with multiple prior cesarean deliveries undergoing trial of labor compared with those having elective repeat cesarean delivery (odds ratio 1.41, 95% confidence interval 1.02–1.93). CONCLUSION: A history of multiple cesarean deliveries is not associated with an increased rate of uterine rupture in women attempting vaginal birth compared with those with a single prior operation. Maternal morbidity is increased with trial of labor after multiple cesarean deliveries, compared with elective repeat cesarean delivery, but the absolute risk for complications is small. Vaginal birth after multiple cesarean deliveries should remain an option for eligible women. LEVEL OF EVIDENCE: II-2

The Apgar score revisited: Influence of gestational age

We tested the hypothesis that Apgar scores are in part related to the newborn infants level of maturity. Seventy-three pregnant women with normal fetuses of gestational age 22 to 42 weeks were studied. Fetal well-being was documented by a prospectively designed recording of pregnancy history, labor complications, and birth outcome, including cord blood pH and base deficit measurements. The 1- and 5-minute Apgar scores were directly related to gestational age. Respiratory efforts, muscle tone, and reflex were the major determinants for a decreasing Apgar score with declining gestational age. We conclude that the 1- and 5-minute Apgar scores are influenced by the infants level of maturity and that our data may be useful in evaluating the true value of Apgar scores in assessing the fetal and neonatal condition of low birth weight infants.

First-trimester prediction of preeclampsia in nulliparous women at low risk

OBJECTIVE: To identify clinical characteristics and biochemical markers in first-trimester samples that would possibly predict the subsequent development of preeclampsia. METHODS: We conducted a multicenter observational study in 2,434 nulliparous women at low risk to identify biomarkers that possibly predict preeclampsia. Clinical history, complete blood count, and biochemical markers were assessed in the first trimester. The trophoblast and angiogenesis markers ADAM-12, pregnancy-associated plasma protein-A, placental protein 13, placental growth factor, soluble fms-like tyrosine kinase-1, and endoglin were measured in a case-control subset of 174 women with preeclampsia and 509 women in the control group. RESULTS: Univariable analysis revealed maternal age, race, marital status, years of education, source of medical payment, prenatal caregiver, body mass index (BMI, calculated as weight (kg)/[height (m)]2), and systolic blood pressure at enrollment were significantly associated with preeclampsia. Mean platelet volume was greater at enrollment in women who later had development of preeclampsia (median 9.4 compared with 9.0 femtoliter (fl); P=.02). First-trimester concentrations (multiples of the median) of ADAM-12 (1.14 compared with 1.04; P=.003), pregnancy-associated plasma protein-A (0.94 compared with 0.98; P=.04), and placental growth factor (0.83 compared with 1.04; P<.001) were significantly different in women who had development of preeclampsia compared with women in the control group. The optimal multivariable model included African American race, systolic blood pressure, BMI, education level, ADAM-12, pregnancy-associated plasma protein-A, and placental growth factor, and yielded an area under the curve of 0.73 (95% confidence interval 0.69–0.77) and a sensitivity of 46.1% (95% confidence interval 38.3–54.0) for 80% specificity. CONCLUSION: A multivariable analysis of clinical data and biochemical markers in the first trimester did not identify a model that had clinical utility for predicting preeclampsia in a nulliparous population at low risk. LEVEL OF EVIDENCE: II