Michael W. Varner

The relationship between maternal glycemia and perinatal outcome.

OBJECTIVE: To examine the relationship between varying degrees of maternal hyperglycemia and pregnancy outcomes. METHODS: This was a secondary analysis of a treatment trial for mild gestational diabetes including four cohorts: 1) 473 women with untreated mild gestational diabetes; 2) 256 women with a positive 50-g screen and one abnormal oral glucose tolerance test (OGTT) value; 3) 675 women with a positive screen and no abnormal OGTT values; and 4) 437 women with a normal 50-g screen. Groups were compared by test of trend for a composite perinatal outcome (neonatal hypoglycemia, hyperbilirubinemia, elevated cord C-peptide level, and perinatal trauma or death), frequency of large for gestational age neonates, shoulder dystocia, and pregnancy-related hypertension. Three-hour OGTT levels (fasting, 1-, 2-, and 3-hour) levels were divided into categories and analyzed for their relationship to perinatal and maternal outcomes. RESULTS: There were significant trends by glycemic status among the four cohorts for the composite and all other outcomes (P<.001). Analysis for trend according to OGTT categories showed an increasing relationship between fasting and all postload levels and the various outcomes (P<.05). Fasting glucose 90 mg/dL or greater and 1 hour 165 mg/dL or greater were associated with an increased risk for the composite outcome (odds ratios and 95% confidence intervals of 2.0 [1.03–4.15] and 1.46 [1.02–2.11] to 1.52 [1.08–2.15] for the fasting and 1 hour, respectively). A 1 hour glucose 150 mg/dL or greater was associated with an increased risk for large for gestational age (odds ratios, 1.8 [1.02–3.18] to 2.35 [1.35–4.14]); however, 2- and 3-hour glucose levels did not increase the risk for the composite or large for gestational age until well beyond current gestational diabetes diagnostic thresholds. CONCLUSION: A monotonic relationship exists between increasing maternal glycemia and perinatal morbidity. Current OGTT criteria require reevaluation in determining thresholds for the diagnosis and treatment of gestational diabetes. LEVEL OF EVIDENCE: II

Complications of anesthesia for cesarean delivery

Objective: To quantify anesthesia-related complications associated with cesarean delivery in a well-described, prospectively ascertained cohort from multiple university-based hospitals in the United States and to evaluate whether certain factors would identify women at increased risk for a failed regional anesthetic. Methods: A prospective observational study was conducted of women (n = 37,142) with singleton gestations undergoing cesarean delivery in the centers forming the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Detailed information was collected regarding choice of anesthesia and procedure-related complications, including failed regional anesthetic and maternal death. Potential risk factors for a failed regional anesthetic were analyzed. Results: Of the women studied, 34,615 (93%) received a regional anesthetic. Few (3.0%) regional procedures failed, and related maternal morbidity was rare. Increased maternal size, higher preoperative risk, rapid decision-to-incision interval, and placement later in labor were all significantly related to an increased risk of a failed regional procedure. Of the general anesthetics, 38% were administered when the decision-to-incision interval was less than 15 minutes. Women deemed at the greatest preoperative risk (American Society of Anesthesiologists score ≥ 4) were approximately 7-fold more likely to receive a general anesthetic (odds ratio 6.9, 95% confidence interval 5.83–8.07). There was one maternal death, due to a failed intubation, in which the anesthetic procedure was directly implicated. Conclusion: Regional techniques have become the preferred method of anesthesia for cesarean delivery. Procedure-related complications are rare and attest to the safety of modern obstetric anesthesia for cesarean delivery in the United States. Level of Evidence: II-2

A new system for determining the causes of stillbirth.

OBJECTIVE: To describe the methods for assigning the cause of death for stillbirths enrolled in the Stillbirth Collaborative Research Network (SCRN). METHODS: A complete evaluation, including postmortem examination, placental pathology, medical record abstraction, and maternal interview was available on 512 stillbirths among 500 women. These 512 stillbirths were evaluated for cause of death using the definitions outlined in this report. Using the best available evidence, SCRN investigators developed a new methodology to assign the cause of death of stillbirths using clinical, postmortem, and placental pathology data. This new tool, designated the Initial Causes of Fetal Death, incorporates known causes of death and assigns them as possible or probable based on strict diagnostic criteria, derived from published references and pathophysiologic sequences that lead to stillbirth. RESULTS: Six broad categories of causes of death are accounted for, including maternal medical conditions; obstetric complications; maternal or fetal hematologic conditions; fetal genetic, structural, and karyotypic abnormalities; placental infection, fetal infection, or both; and placental pathologic findings. Isolated histologic chorioamnionitis and small for gestational age were not considered causes of death. CONCLUSION: A new system, Initial Causes of Fetal Death, to assign cause of death in stillbirths was developed by the SCRN investigators for use in this study but has broader applicability. Initial Causes of Fetal Death is a standardized method to assign probable and possible causes of death of stillbirths based on information routinely collected during prenatal care and the clinical evaluation of fetal death.

Frequency of and factors associated with severe maternal morbidity

OBJECTIVE: To estimate the frequency of severe maternal morbidity, assess its underlying etiologies, and develop a scoring system to predict its occurrence. Supplemental Digital Content is Available in the Text. METHODS: This was a secondary analysis of a Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network cohort of 115,502 women and their neonates born in 25 hospitals across the United States over a 3-year period. Women were classified as having severe maternal morbidity according to a scoring system that takes into account the occurrence of red blood cell transfusion (more than three units), intubation, unanticipated surgical intervention, organ failure, and intensive care unit admission. The frequency of severe maternal morbidity was calculated and the underlying etiologies determined. Multivariable analysis identified patient factors present on admission that were independently associated with severe maternal morbidity; these were used to develop a prediction model for severe maternal morbidity. RESULTS: Among 115,502 women who delivered during the study period, 332 (2.9/1,000 births, 95% confidence interval 2.6–3.2) experienced severe maternal morbidity. Postpartum hemorrhage was responsible for approximately half of severe maternal morbidity. Multiple patient factors were found to be independently associated with severe maternal morbidity and were used to develop a predictive model with an area under the receiver operating characteristic curve of 0.80. CONCLUSION: Severe maternal morbidity occurs in approximately 2.9 per 1,000 births, is most commonly the result of postpartum hemorrhage, and occurs more commonly in association with several identifiable patient characteristics. LEVEL OF EVIDENCE: II

Timing of Delivery and Adverse Outcomes in Term Singleton Repeat Cesarean Deliveries

OBJECTIVE: To compare the maternal and neonatal risks of elective repeat cesarean delivery compared with pregnancy continuation at different gestational ages, starting from 37 weeks. METHODS: We analyzed the composite maternal and neonatal outcomes of repeat cesarean deliveries studied prospectively over 4 years at 19 U.S. centers. Maternal outcome was a composite of pulmonary edema, cesarean hysterectomy, pelvic abscess, thromboembolism, pneumonia, transfusion, or death. Composite neonatal outcome consisted of respiratory distress, transient tachypnea, necrotizing enterocolitis, sepsis, ventilation, seizure, hypoxic–ischemic encephalopathy, neonatal intensive care unit admission, 5-minute Apgar of 3 or lower, or death. Outcomes after elective repeat cesarean delivery without labor at each specific gestational age were compared with outcomes for all who were delivered later as a result of labor onset, specific obstetric indications, or both. RESULTS: Twenty-three thousand seven hundred ninety-four repeat cesarean deliveries were included. Elective delivery at 37 weeks of gestation had significantly higher risks of adverse maternal outcome (odds ratio [OR] 1.56, 95% confidence interval [CI] 1.06–2.31), whereas elective delivery at 39 weeks of gestation was associated with better maternal outcome when compared with pregnancy continuation (OR 0.51, 95% CI 0.36–0.72). Elective repeat cesarean deliveries at 37 and 38 weeks of gestation had significantly higher risks of adverse neonatal outcome (37 weeks OR 2.02, 95% CI 1.73–2.36; 38 weeks OR 1.39 95% CI 1.24–1.56), whereas delivery at 39 and 40 weeks of gestation presented better neonatal outcome as opposed to pregnancy continuation (39 weeks OR 0.79, 95% CI 0.68–0.92; 40 weeks OR 0.57, 95% CI 0.43–0.75). CONCLUSION: In women with prior cesarean delivery, 39 weeks of gestation is the optimal time for repeat cesarean delivery for both mother and neonate. LEVEL OF EVIDENCE: II

Neonatal outcomes in twin pregnancies delivered moderately preterm, late preterm, and term

We compared neonatal outcomes in twin pregnancies following moderately preterm birth (MPTB), late preterm birth (LPTB), and term birth. A secondary analysis of a multicenter, randomized controlled trial of multiple gestations was conducted. MPTB was defined as delivery between 32 (0)/(7) and 33 (6)/(7) weeks and LPTB between 34 (0)/(7) and 36 (6)/(7) weeks. Primary outcome was a neonatal outcome composite consisting of one or more of the following: neonatal death, respiratory distress syndrome, early onset culture-proven sepsis, stage 2 or 3 necrotizing enterocolitis, bronchopulmonary dysplasia, grade 3 or 4 intraventricular hemorrhage, periventricular leukomalacia, pneumonia, or severe retinopathy of prematurity. Among 552 twin pregnancies, the MPTB rate was 14.5%, LPTB 49.8%, and term birth rate 35.7%. The rate of the primary outcome was different between groups: 30.0% for MPTB, 12.8% for LPTB, 0.5% for term birth ( P < 0.001). Compared with term neonates, the primary neonatal outcome composite was increased following MPTB (relative risk [RR] 58.5; 95% confidence interval [CI] 11.3 to 1693.0) and LPTB (RR 24.9; 95% CI 4.8 to 732.2). Twin pregnancies born moderately and late preterm encounter higher rates of neonatal morbidities compared with twins born at term.

Failed Labor Induction Toward an Objective Diagnosis

OBJECTIVE: To evaluate maternal and perinatal outcomes in women undergoing labor induction with an unfavorable cervix according to duration of oxytocin administration in the latent phase of labor after ruptured membranes. METHODS: This was a secondary analysis of a randomized multicenter trial in which all cervical examinations from admission were recorded. Inclusion criteria: nulliparas at or beyond 36 weeks of gestation undergoing induction with a cervix of 2 cm or less dilated and less than completely effaced. The latent phase of labor was defined as ending at a cervical dilation of 4 cm and effacement of at least 90%, or at a cervical dilation of 5 cm regardless of effacement. RESULTS: A total of 1,347 women were analyzed. The overall vaginal delivery rate was 63.2%. Most women had exited the latent phase after 6 hours of oxytocin and membrane rupture (n=939; 69.7%); only 5% remained in the latent phase after 12 hours. The longer the latent phase, the lower the vaginal delivery rate. Even so, 39.4% of the 71 women who remained in the latent phase after 12 hours of oxytocin and membrane rupture were delivered vaginally. Chorioamnionitis, endometritis, or both, and uterine atony were the only maternal adverse outcomes related to latent-phase duration: adjusted odds ratios (95% confidence intervals) of 1.12 (1.07, 1.17) and 1.13 (1.06, 1.19), respectively, for each additional hour. Neonatal outcomes were not related to latent-phase duration. CONCLUSION: Almost 40% of the women who remained in the latent phase after 12 hours of oxytocin and membrane rupture were delivered vaginally. Therefore, it is reasonable to avoid deeming labor induction a failure in the latent phase until oxytocin has been administered for at least 12 hours after membrane rupture. LEVEL OF EVIDENCE: III

A Population-based Case-Control Study of Stillbirth: The Relationship of Significant Life Events to the Racial Disparity for African Americans

Stillbirths (fetal deaths occurring at ≥20 weeks gestation) are approximately equal in number to infant deaths in the United States and are twice as likely among non-Hispanic black births as among non-Hispanic white births. The causes of racial disparity in stillbirth remain poorly understood. A population-based case-control study conducted by the Stillbirth Collaborative Research Network in 5 US catchment areas from March 2006 to September 2008 identified characteristics associated with racial/ethnic disparity and interpersonal and environmental stressors, including a list of 13 significant life events (SLEs). The adjusted odds ratio for stillbirth among women reporting all 4 SLE factors (financial, emotional, traumatic, and partner-related) was 2.22 (95% confidence interval: 1.43, 3.46). This association was robust after additional control for the correlated variables of family income, marital status, and health insurance type. There was no interaction between race/ethnicity and other variables. Effective ameliorative interventions could have a substantial public health impact, since there is at least a 50% increased risk of stillbirth for the approximately 21% of all women and 32% of non-Hispanic black women who experience 3 or more SLE factors during the year prior to delivery.

Maternal 25-Hydroxyvitamin D and Preterm Birth in Twin Gestations

OBJECTIVE: To assess whether there was an independent association between maternal 25-hydroxyvitamin D concentrations at 24–28 weeks of gestation and preterm birth in a multicenter U.S. cohort of twin pregnancies. METHODS: Serum samples from women who participated in a clinical trial of 17 &agr;-hydroxyprogesterone caproate for the prevention of preterm birth in twin gestations (2004–2006) were assayed for 25-hydroxyvitamin D concentrations using liquid chromatography tandem mass spectrometry (n=211). Gestational age was determined early in pregnancy using a rigorous algorithm. Preterm birth was defined as delivery of the first twin or death of either twin at less than 35 weeks of gestation. RESULTS: The mean serum 25-hydroxyvitamin D concentration was 82.7 nmol/L (standard deviation 31.5); 40.3% of women had concentrations less than 75 nmol/L. Preterm birth at less than 35 weeks of gestation occurred in 49.4% of women with 25-hydroxyvitamin D concentrations less than 75 nmol/L compared with 26.2% among those with concentrations of 75 nmol/L or more (P<.001). After adjustment for maternal race and ethnicity, study site, parity, prepregnancy body mass index, season, marital status, education, gestational age at blood sampling, smoking status, and 17 &agr;-hydroxyprogesterone caproate treatment, maternal 25-hydroxyvitamin D concentration of 75 nmol/L or more was associated with a 60% reduction in the odds of preterm birth compared with concentrations less than 75 nmol/L (adjusted odds ratio [OR] 0.4, 95% confidence interval [CI] 0.2–0.8). A similar protective association was observed when studying preterm birth at less than 32 weeks of gestation (OR 0.2, 95% CI 0.1–0.6) and after confounder adjustment. CONCLUSIONS: Late second-trimester maternal 25-hydroxyvitamin D concentrations less than 75 nmol/L are associated with an increase in the risk of preterm birth in this cohort of twin pregnancies. LEVEL OF EVIDENCE: II

The effect of 17-alpha hydroxyprogesterone caproate on the risk of gestational diabetes in singleton or twin pregnancies

OBJECTIVEnTo compare the rates of gestational diabetes among women who received serial doses of 17-alpha hydroxyprogesterone caproate vs placebo.nnnSTUDY DESIGNnSecondary analysis of 2 double-blind randomized placebo-controlled trials of 17-alpha hydroxyprogesterone caproate given to women at risk for preterm delivery. The incidence of gestational diabetes was compared between women who received 17-alpha hydroxyprogesterone caproate or placebo.nnnRESULTSnWe included 1094 women; 441 had singleton and 653 had twin gestations. Combining the 2 studies, 616 received 17-alpha hydroxyprogesterone caproate and 478 received placebo. Among singleton and twin pregnancies, rates of gestational diabetes were similar in women receiving 17-alpha hydroxyprogesterone caproate vs placebo (5.8% vs 4.7%; P = .64 and 7.4% vs 7.6%; P = .94, respectively). In the multivariable model, progesterone was not associated with gestational diabetes (adjusted odds ratio, 1.04; 95% confidence interval, 0.62-1.73).nnnCONCLUSIONnWeekly administration of 17-alpha hydroxyprogesterone caproate is not associated with higher rates of gestational diabetes in either singleton or twin pregnancies.