Preeclampsia at delivery is associated with lower serum vitamin D and higher antiangiogenic factors: a case control study.

BACKGROUND: Preeclampsia is characterized by decreased trophoblastic angiogenesis leading to abnormal invasion of spiral arteries, shallow implantation and resulting in compromised placentation with poor uteroplacental perfusion. Vitamin D plays an important role in pregnancy influencing implantation, angiogenesis and placental development. The objective of this study was to determine whether there is an association between serum vitamin D levels, and anti-angiogenic factors at the time of delivery and the occurrence of preeclampsia. METHODS: This nested case control study analyzed frozen serum samples at the time of delivery and related clinical data from women with singleton liveborn pregnancies who had participated in studies of the NICHD Stillbirth Collaborative Research Network. Women with a recorded finding of preeclampsia and who had received magnesium sulfate treatment prior to delivery were considered index cases (N = 56). Women without a finding of preeclampsia were controls (N = 341). RESULTS: Women with preeclampsia had 14.5% lower serum vitamin D levels than women in the control group (16.5 ng/ml vs. 19 ng/ml, p = 0.014) with 64.5% higher sFlt-1 levels (11,600 pg/ml vs. 7050 pg/ml, p < 0.001) and greater than 2 times higher endoglin levels (18.6 ng/ml vs. 8.7 ng/ml, < 0.001). After controlling for gestational age at delivery and maternal BMI, vitamin D levels were 0.88 times lower (P = 0.051), while endoglin levels were 2.5 times higher and sFlt-1 levels were 2.1 times higher than in control pregnancies (P < 0.001). CONCLUSIONS: Women with preeclampsia at time of delivery have higher maternal antiangiogenetic factors and may have lower maternal serum vitamin D levels. These findings may lead to a better understanding of the underlying etiology of preeclampsia as well as possible modifiable treatment options which could include assuring adequate levels of maternal serum vitamin D prior to pregnancy.

Diagnostic Tests for Evaluation of Stillbirth: Results From the Stillbirth Collaborative Research Network.

OBJECTIVE: To estimate the usefulness of each diagnostic test in the work-up for potential causes of stillbirth. METHODS: A secondary analysis of 512 stillbirths enrolled in the Stillbirth Collaborative Research Network from 2006 to 2008 was performed. The Stillbirth Collaborative Research Network was a multisite, geographically, racially, and ethnically diverse, population-based study of stillbirth in the United States. Participants underwent standardized evaluations that included maternal interview, medical record abstraction, biospecimen collection, fetal autopsy, and placental pathology. Also, most participants had a clinical work-up that included karyotype, toxicology screen, syphilis serology, antibody screen, fetal-maternal hemorrhage testing, and testing for antiphospholipid antibodies as well as testing performed on biospecimens for research purposes. Previously, each participant had been assigned probable and possible causes of death using the Initial Causes of Fetal Death classification system. In this analysis, tests were considered useful if a positive result established (or helped to establish) this cause of death or a negative result excluded a cause of death that was suspected based on the clinical history or other results. RESULTS: The usefulness of each test was as follows: placental pathology 64.6% (95% confidence interval [CI] 57.9-72.0), fetal autopsy 42.4% (95% CI 36.9-48.4), genetic testing 11.9% (95% CI 9.1-15.3), testing for antiphospholipid antibodies 11.1% (95% CI 8.4-14.4), fetal-maternal hemorrhage 6.4% (95% CI 4.4-9.1), glucose screen 1.6% (95% CI 0.7-3.1), parvovirus 0.4% (95% CI 0.0-1.4), and syphilis 0.2% (95% CI 0.0-1.1). The utility of the tests varied by clinical presentation, suggesting a customized approach for each patient. CONCLUSION: The most useful tests were placental pathology and fetal autopsy followed by genetic testing and testing for antiphospholipid antibodies.

Factor V Leiden, prothrombin G20210A, and methylene tetrahydrofolate reductase mutations and stillbirth: the Stillbirth Collaborative Research Network.

BACKGROUND: An evaluation for heritable thrombophilias is recommended in the evaluation of stillbirth. However, the association between thrombophilias and stillbirth remains uncertain. OBJECTIVE: We sought to assess the association between maternal and fetal/placental heritable thrombophilias and stillbirth in a population-based, case-control study in a geographically, racially, and ethnically diverse population. STUDY DESIGN: We conducted secondary analysis of data from the Stillbirth Collaborative Research Network, a population-based case-control study of stillbirth. Testing for factor V Leiden, prothrombin G20210A, methylene tetrahydrofolate reductase C677T and A1298C, and plasminogen activating inhibitor (PAI)-1 4G/5G mutations was done on maternal and fetal (or placental) DNA from singleton pregnancies. Data analyses were weighted for oversampling and other aspects of the design. Odds ratios (OR) were generated from univariate models regressing stillbirth/live birth status on each thrombophilia marker. RESULTS: Results were available for ≥1 marker in 488 stillbirths and 1342 live birth mothers and 405 stillbirths and 990 live birth fetuses. There was an increased odds of stillbirth for maternal homozygous factor V Leiden mutation (2/488; 0.4% vs 1/1380; 0.0046%; OR, 87.44; 95% confidence interval, 7.88-970.92). However, there were no significant differences in the odds of stillbirth for any other maternal thrombophilia, even after stratified analyses. Fetal 4G/4G PAI-1 (OR, 0.63; 95% confidence interval, 0.43-0.91) was associated with decreased odds of stillbirth. Other fetal thrombophilias were similar among groups. CONCLUSION: Most maternal and fetal thrombophilias were not associated with stillbirth. Maternal factor V Leiden was weakly associated with stillbirth, and the fetal PAI-1 4G/4G polymorphism was associated with live birth. Our data do not support routine testing for heritable thrombophilias as part of an evaluation for possible causes of stillbirth.

Fetal growth and risk of stillbirth: a population-based case-control study.

BACKGROUND: Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth. METHODS AND FINDINGS: We conducted a population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings. CONCLUSIONS: Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies. Please see later in the article for the Editors' Summary.

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.

Racial and ethnic disparities in United States: stillbirth rates: trends, risk factors, and research needs.

As with most adverse health outcomes, there has been long standing and persistent racial and ethnic disparity for stillbirth in the United States. In 2005, the stillbirth rate (fetal deaths ≥ 20 weeks' gestation per 1000 fetal deaths and live births) for non-Hispanic blacks was 11.13 compared with 4.79 for non-Hispanic whites. Rates were intermediate for American Indian or Alaska Natives (6.17) and Hispanics (5.44). There is racial disparity for both early (< 28 weeks' gestation) and late stillbirths. We review available data regarding risk factors for stillbirth with a focus on those factors that are more prevalent in certain racial/ethnic groups and those factors that appear to have a more profound effect in certain racial/ethnic groups. Although many factors, including genetics, environment, stress, social issues, access to and quality of medical care and behavior, contribute to racial disparity in stillbirth, the reasons for the disparity remain unclear. Knowledge gaps and recommendations for further research and interventions intended to reduce racial disparity in stillbirth are highlighted.

Do vaccination strategies implemented by nursing homes narrow the racial gap in receipt of influenza vaccination in the United States?

OBJECTIVES: To determine whether the racial inequity between African Americans and Caucasians in receipt of influenza vaccine is narrower in residents of nursing homes with facility-wide vaccination strategies than in residents of facilities without vaccination strategies. DESIGN: Secondary data analysis using the National Nursing Home Survey 2004, a nationally representative survey. SETTING: One thousand one hundred seventy-four participating nursing homes sampled systematically with probability proportional to bed size. PARTICIPANTS: Thirteen thousand five hundred seven randomly sampled residents of nursing homes between August and December 2004. MEASUREMENTS: Receipt of influenza vaccine within the last year. Logistic regression was used to examine the relationship between facility-level influenza immunization strategy and racial inequity in receipt of vaccination, adjusted for characteristics at the resident, facility, state, and regional levels. RESULTS: Overall in the United States, vaccination coverage was higher for Caucasian and African-American residents; the racial vaccination gaps were smaller (<6 percentage points) and nonsignificant in residents of homes with standing orders for influenza vaccinations (P=.14), verbal consent allowed for vaccinations(P=.39), and routine review of facility-wide vaccination rates (P=.61) than for residents of homes without these strategies. The racial vaccination gap in residents of homes without these strategies were two to three times as high (P=.009, P=.002, and P=.002, respectively). CONCLUSION: The presence of several immunization strategies in nursing homes is associated with higher vaccination coverage for Caucasian and African-American residents, narrowing the national vaccination racial gap.

NIH consensus development conference draft statement on vaginal birth after cesarean: new insights.

OBJECTIVE: To provide health care providers, patients, and the general public with a responsible assessment of currently available data on vaginal birth after cesarean (VBAC). PARTICIPANTS: A non-DHHS, nonadvocate 15-member panel representing the fields of obstetrics and gynecology, urogynecology, maternal and fetal medicine, pediatrics, midwifery, clinical pharmacology, medical ethics, internal medicine, family medicine, perinatal and reproductive psychiatry, anesthesiology, nursing, biostatistics, epidemiology, health care regulation, risk management, and a public representative, and a public representative. In addition, 21 experts from pertinent fields presented data to the panel and conference audience. EVIDENCE: Presentations by experts and a systematic review of the literature prepared by the Oregon Evidence-based Practice Center, through the Agency for Healthcare Research and Quality. Scientific evidence was given precedence over anecdotal experience. CONFERENCE PROCESS: The panel drafted its statement based on scientific evidence presented in open forum and on published scientific literature. The draft statement was presented on the final day of the conference and circulated to the audience for comment. The panel released a revised statement later that day at http://consensus.nih.gov. This statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government. CONCLUSIONS: Given the available evidence, trial of labor is a reasonable option for many pregnant women with one prior low transverse uterine incision. The data reviewed in this report show that both trial of labor and elective repeat cesarean delivery for a pregnant woman with one prior transverse uterine incision have important risks and benefits and that these risks and benefits differ for the woman and her fetus. This poses a profound ethical dilemma for the woman, as well as her caregivers, because benefit for the woman may come at the price of increased risk for the fetus and vice versa. This conundrum is worsened by the general paucity of high-level evidence about both medical and nonmedical factors, which prevents the precise quantification of risks and benefits that might help to make an informed decision about trial of labor compared with elective repeat cesarean delivery. The panel was mindful of these clinical and ethical uncertainties in making the following conclusions and recommendations. One of the panel's major goals is to support pregnant women with one prior transverse uterine incision to make informed decisions about trial of labor compared with elective repeat cesarean delivery. The panel recommends that clinicians and other maternity care providers use the responses to the six questions, especially questions 3 and 4, to incorporate an evidence-based approach into the decisionmaking process. Information, including risk assessment, should be shared with the woman at a level and pace that she can understand. When trial of labor and elective repeat cesarean delivery are medically equivalent options, a shared decisionmaking process should be adopted and, whenever possible, the woman's preference should be honored. The panel is concerned about the barriers that women face in gaining access to clinicians and facilities that are able and willing to offer trial of labor. Given the low level of evidence for the requirement for "immediately available" surgical and anesthesia personnel in current guidelines, the panel recommends that the American College of Obstetricians and Gynecologists and the American Society of Anesthesiologists reassess this requirement with specific reference to other obstetric complications of comparable risk, risk stratification, and in light of limited physician and nursing resources. Healthcare organizations, physicians, and other clinicians should consider making public their trial of labor policies and VBAC rates, as well as their plans for responding to obstetric emergencies. The panel recommends that hospitals, maternity care providers, healthcare and professional liability insurers, consumers, and policymakers collaborate on the development of integrated services that could mitigate or even eliminate current barriers to trial of labor. The panel is concerned that medical-legal considerations add to, and in many instances exacerbate, these barriers to trial of labor. Policymakers, providers, and other stakeholders must collaborate in developing and implementing appropriate strategies to mitigate the chilling effect the medical-legal environment has on access to care. High-quality research is needed in many areas. The panel has identified areas that need attention in response to question 6. Research in these areas should be given appropriate priority and should be adequately funded--especially studies that would help to characterize more precisely the short-term and long-term maternal, fetal, and neonatal outcomes of trial of labor and elective repeat cesarean delivery.