Uma M. Reddy

Stillbirth classification-developing an international consensus for research: Executive summary of a national institute of child health and human development workshop

Stillbirth is a major obstetric complication, with 3.2 million stillbirths worldwide and 26,000 stillbirths in the United States every year. The Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop from October 22-24, 2007, to review the pathophysiology of conditions underlying stillbirth to define causes of death. The optimal classification system would identify the pathophysiologic entity initiating the chain of events that irreversibly led to death. Because the integrity of the classification is based on available pathologic, clinical, and diagnostic data, experts emphasized that a complete stillbirth workup should be performed. Experts developed evidence-based characteristics of maternal, fetal, and placental conditions to attribute a condition as a cause of stillbirth. These conditions include infection, maternal medical conditions, antiphospholipid syndrome, heritable thrombophilias, red cell alloimmunization, platelet alloimmunization, congenital malformations, chromosomal abnormalities including confined placental mosaicism, fetomaternal hemorrhage, placental and umbilical cord abnormalities including vasa previa and placental abruption, complications of multifetal gestation, and uterine complications. In all cases, owing to lack of sufficient knowledge about disease states and normal development, there will be a degree of uncertainty regarding whether a specific condition was indeed the cause of death.

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.

Association between stillbirth and illicit drug use and smoking during pregnancy

OBJECTIVE: To compare illicit drug and smoking use in pregnancies with and without stillbirth. METHODS: The Stillbirth Collaborative Research Network conducted a case–control study from March 2006 to September 2008, covering more than 90% of deliveries to residents of five a priori–defined geographically diverse regions. The study attempted to include all stillbirths and representative liveborn controls. Umbilical cord samples from cases and controls were collected and frozen for subsequent batch analysis. Maternal serum was collected at delivery and batch analyzed for cotinine. RESULTS: For 663 stillbirth deliveries, 418 (63%) had cord homogenate and 579 (87%) had maternal cotinine assays performed. For 1,932 live birth deliveries, 1,050 (54%) had cord homogenate toxicology and 1,545 (80%) had maternal cotinine assays performed. A positive cord homogenate test for any illicit drug was associated with stillbirth (odds ratio [OR] 1.94, 95% confidence interval [CI] 1.16–3.27). The most common individual drug was cannabis (OR 2.34 95% CI 1.13–4.81), although the effect was partially confounded by smoking. Both maternal self-reported smoking history and maternal serum cotinine levels were associated in a dose–response relationship with stillbirth. Positive serum cotinine less than 3 ng/mL and no reported history of smoking (proxy for passive smoke exposure) also were associated with stillbirth (OR 2.06, 95% CI 1.24–3.41). CONCLUSION: Cannabis use, smoking, illicit drug use, and apparent exposure to second-hand smoke, separately or in combination, during pregnancy were associated with an increased risk of stillbirth. Because cannabis use may be increasing with increased legalization, the relevance of these findings may increase as well. LEVEL OF EVIDENCE: II

Morbidly Adherent Placenta Treatments and Outcomes

OBJECTIVE: To describe recent maternal and neonatal delivery outcomes among women with a morbidly adherent placenta in major centers across the United States. METHODS: This study reviewed a cohort of 115,502 women and their neonates born in 25 hospitals in the United States between March 2008 and February 2011 from the Assessment of Perinatal EXcellence data set. All cases of morbidly adherent placenta were identified. Maternal demographics, procedures undertaken, and maternal and neonatal outcomes were analyzed. RESULTS: There were 158 women with a morbidly adherent placenta (1/731 births, 95% confidence interval 1/632–866). Eighteen percent of women with a morbidly adherent placenta were nulliparous and 37% had no prior cesarean delivery. Only 53% (84/158) were suspected to have a morbidly adherent placenta before delivery. Women with a prenatally suspected morbidly adherent placenta experienced large blood loss (33%), hysterectomy (92%), and intensive care unit admission (39%) compared with 19%, 45%, and 22%, respectively, in those not suspected prenatally to have a morbidly adherent placenta (P<.05 for all). CONCLUSION: Eighteen percent of women with a morbidly adherent placenta were nulliparous. Half of the morbidly adherent placenta cases were suspected before delivery and outcomes were poorer in this group, probably because the more clinically significant morbidly adherent placentas are more likely to be suspected before delivery. LEVEL OF EVIDENCE: II

Association between Sleep-Disordered Breathing and Hypertensive Disorders of Pregnancy and Gestational Diabetes Mellitus

OBJECTIVEnTo estimate whether sleep-disordered breathing during pregnancy is a risk factor for the development of hypertensive disorders of pregnancy and gestational diabetes mellitus (GDM).nnnMETHODSnIn this prospective cohort study, nulliparous women underwent in-home sleep-disordered breathing assessments in early (6-15 weeks of gestation) and midpregnancy (22-31 weeks of gestation). Participants and health care providers were blinded to the sleep test results. An apnea-hypopnea index of 5 or greater was used to define sleep-disordered breathing. Exposure-response relationships were examined, grouping participants into four apnea-hypopnea index groups: 0, greater than 0 to less than 5, 5 to less than 15, and 15 or greater. The study was powered to test the primary hypothesis that sleep-disordered breathing occurring in pregnancy is associated with an increased incidence of preeclampsia. Secondary outcomes were rates of hypertensive disorders of pregnancy, defined as preeclampsia and antepartum gestational hypertension, and GDM. Crude and adjusted odds ratios and 95% confidence intervals (CIs) were calculated from univariate and multivariate logistic regression models.nnnRESULTSnThree thousand seven hundred five women were enrolled. Apnea-hypopnea index data were available for 3,132 (84.5%) and 2,474 (66.8%) women in early and midpregnancy, respectively. The corresponding prevalence of sleep-disordered breathing was 3.6% and 8.3%. The prevalence of preeclampsia was 6.0%, hypertensive disorders of pregnancy 13.1%, and GDM 4.1%. In early and midpregnancy the adjusted odds ratios for preeclampsia when sleep-disordered breathing was present were 1.94 (95% CI 1.07-3.51) and 1.95 (95% CI 1.18-3.23), respectively; hypertensive disorders of pregnancy 1.46 (95% CI 0.91-2.32) and 1.73 (95% CI 1.19-2.52); and GDM 3.47 (95% CI 1.95-6.19) and 2.79 (95% CI 1.63-4.77). Increasing exposure-response relationships were observed between apnea-hypopnea index and both hypertensive disorders and GDM.nnnCONCLUSIONnThere is an independent association between sleep-disordered breathing and preeclampsia, hypertensive disorders of pregnancy, and GDM.

Trends in Stillbirth by Gestational Age in the United States, 2006-2012.

OBJECTIVE: To evaluate stillbirth trends by gestational age. METHODS: National Center for Health Statistics fetal death and live birth data files were used to analyze the 2006 and 2012 cohorts of deliveries and compute gestational age-specific stillbirth rates at 20 weeks of gestation or greater using two methods: traditional (eg, stillbirths at 38 weeks of gestation/live births and stillbirths at 38 weeks of gestation) and prospective (stillbirths at 38 weeks of gestation/number of women still pregnant at 38 weeks of gestation). Changes in rates and in the percent distribution of stillbirths and live births were assessed. RESULTS: In 2006 and 2012, the stillbirth rate was 6.05 stillbirths per 1,000 deliveries. There was little change in the percent distribution of stillbirths by gestational age from 2006 to 2012. However, the percent distribution of live births by gestational age changed considerably: births at 34–38 weeks of gestation decreased by 10–16%, and births at 39 weeks of gestation increased by 17%. Traditionally computed stillbirth rates were unchanged at most gestational ages, but rose at 24–27, 34–36, 37, and 38 weeks of gestation. However, rates were influenced by decreases in births at those gestational ages; the pattern of stillbirths by gestational age was unchanged. In contrast, there were no differences in prospective stillbirth rates at 21–42 weeks of gestation. CONCLUSION: The lack of change in prospective stillbirth rates from 2006 to 2012 suggests that preventing nonmedically indicated deliveries before 39 weeks of gestation did not increase the U.S. stillbirth rate. LEVEL OF EVIDENCE: II

Antiphospholipid antibodies in stillbirth.

OBJECTIVE: To compare antiphospholipid antibodies in deliveries with and without stillbirth using a multicenter, population-based case–control study of stillbirths and live births. METHODS: Maternal sera were assayed for immunoglobulin (Ig)G and IgM anticardiolipin and anti-&bgr;2-glycoprotein-I antibodies. Assays were performed in 582 stillbirth deliveries and 1,547 live birth deliveries. RESULTS: Elevated levels of IgG anticardiolipin and IgG anti-&bgr;2-glycoprotein-I antibodies were associated with an approximate threefold increased odds of stillbirth (crude odds ratio [OR] 3.43, 95% confidence interval [CI] 1.79–6.60, 3.8% compared with 1.1% and OR 3.17, 95% CI 1.30–7.72, (1.9% compared with 0.6%, respectively) when all deliveries with stillbirth were compared with all deliveries with live birth. When the subset of stillbirths not associated with fetal anomalies or obstetric complications was compared with term live births, elevated IgG anticardiolipin antibodies were associated with stillbirth (5.0% compared with 1.0%; OR 5.30, 95% CI, 2.39–11.76; IgG anti-&bgr;2-glycoprotein-I antibodies (1.9% compared with 0.6%) had an OR of 3.00 (95% CI 1.01–8.90) and IgM anticardiolipin antibodies (6.0% compared with 3.0%) had an OR of 2.03 (95% CI 1.09–3.76). Elevated levels of anticardiolipin and anti-&bgr;2-glycoprotein-I antibodies were associated with a threefold to fivefold increased odds of stillbirth. CONCLUSIONS: Our data support consideration of testing for antiphospholipid antibodies in cases of otherwise unexplained stillbirth. LEVEL OF EVIDENCE: II

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.

Association of the duration of active pushing with obstetric outcomes

OBJECTIVE: To estimate the associations between the duration of active pushing during the second stage of labor and maternal and neonatal outcomes. METHODS: We performed an observational study in which data were obtained by trained abstractors from maternal and neonatal charts of deliveries at 25 hospitals over a 3-year period. In this secondary analysis, women with no prior cesarean delivery who had a term, singleton, cephalic gestation and reached complete dilation were analyzed. The duration of pushing, defined as the time from initiation of pushing to either vaginal delivery or the decision to proceed with a cesarean delivery, was determined. The primary maternal outcome was cesarean delivery and the primary neonatal outcome was a composite that included: mechanical ventilation, proven sepsis, brachial plexus palsy, clavicular fracture, skull fracture, other fracture, seizures, hypoxic–ischemic encephalopathy, or death. Nulliparous and parous women were analyzed separately in univariable and then multivariable analyses. RESULTS: A total of 53,285 women were analyzed. In both nulliparous and parous women, longer duration of pushing was associated with increased odds of both cesarean delivery and the neonatal adverse outcome composite. Nevertheless, even after 4 hours of pushing, approximately 78% of nulliparous women who continued with active pushing had a vaginal delivery and more than 97% did not have the composite adverse neonatal outcome. Similarly, after more than 2 hours of pushing, approximately 82% of parous women who continued active pushing delivered vaginally and more than 97% did not have the adverse neonatal outcome. CONCLUSION: A longer duration of pushing is associated with an increased relative risk, but small absolute difference in risk, of neonatal complications. Approximately 78% of nulliparous women delivered vaginally even after 4 hours of pushing.

Laboratory abnormalities in pregnancy-associated hypertension: frequency and association with pregnancy outcomes

OBJECTIVE: To estimate the frequency of abnormal laboratory test results in pregnancy-associated hypertension and the relationship with pregnancy outcomes. METHODS: This was a secondary analysis of a multicenter trial of vitamin C and E for prevention of pregnancy-associated hypertension in low-risk nulliparous women. Laboratory abnormalities included: platelets less than 100,000/mm3, aspartate aminotransferase 100 units/L or greater, creatinine 1.5 mg/dL or greater, lactate dehydrogenase 600 units/L or greater, total bilirubin 1.2 mg/dL or greater, or evidence of hemolysis on peripheral smear. Mild pregnancy-associated hypertension was defined as blood pressure 140–159/90–109 mm Hg. Severe pregnancy-associated hypertension was defined as persistent blood pressure 160/110 mm Hg or greater, acute antihypertensive treatment, or any blood pressure elevation associated with clinical signs of end-organ dysfunction (one or more of headache, epigastric pain, blurred vision, pulmonary edema, eclampsia, or oliguria). Pregnancy outcomes were compared across four groups: I, mild hypertension alone; II, mild hypertension+abnormal laboratory values; III, severe pregnancy-associated hypertension alone; and IV, severe pregnancy-associated hypertension+abnormal laboratory values. RESULTS: Of 9,969 women, 2,752 (27.9%) developed pregnancy-associated hypertension and of these, laboratory abnormalities occurred in 7.3%. Laboratory abnormalities increased with severity of hypertension: mild hypertension alone (4.9%), severe hypertension alone (8.9%), and mild or severe hypertension with clinical signs of end-organ dysfunction (12.2%) (P for trend<.001). Compared with women with mild hypertension alone, the adjusted odds for the perinatal composite (2-fold to 4.8-fold in Category III–IV), preterm birth (2.1-fold to 7.8-fold in Category II–IV), and other adverse perinatal outcomes increase with disease severity, particularly with laboratory abnormalities and severe clinical signs. CONCLUSION: The frequency of abnormal laboratory values in women with pregnancy-associated hypertension increases with disease severity. Adverse perinatal outcomes increase in the presence of abnormal laboratory values, particularly in those with clinical signs, likely atttributable in part to the decision to deliver early. LEVEL OF EVIDENCE: II