Stillbirth, Inflammatory Markers, and Obesity: Results from the Stillbirth Collaborative Research Network.

BACKGROUND: Obesity is associated with increased risk of stillbirth, although the mechanisms are unknown. Obesity is also associated with inflammation. Serum ferritin, C-reactive protein, white blood cell count, and histologic chorioamnionitis are all markers of inflammation. OBJECTIVE: This article determines if inflammatory markers are associated with stillbirth and body mass index (BMI). Additionally, we determined whether inflammatory markers help to explain the known relationship between obesity and stillbirth. STUDY DESIGN: White blood cell count was assessed at admission to labor and delivery, maternal serum for assessment of various biomarkers was collected after study enrollment, and histologic chorioamnionitis was based on placental histology. These markers were compared for stillbirths and live births overall and within categories of BMI using analysis of variance on logarithmic-transformed markers and logistic regression for dichotomous variables. The impact of inflammatory markers on the association of BMI categories with stillbirth status was assessed using crude and adjusted odds ratios (COR and AOR, respectively) from logistic regression models. The interaction of inflammatory markers and BMI categories on stillbirth status was also assessed through logistic regression. Additional logistic regression models were used to determine if the association of maternal serum ferritin with stillbirth is different for preterm versus term births. Analyses were weighted for the overall population from which this sample was derived. RESULTS: A total of 497 women with singleton stillbirths and 1,414 women with live births were studied with prepregnancy BMI (kg/m2) categorized as normal (18.5-24.9), overweight (25.0-29.9), or obese (30.0 + ). Overweight (COR, 1.48; 95% confidence interval [CI]: 1.14-1.94) and obese women (COR, 1.60; 95% CI: 1.23-2.08) were more likely than normal weight women to experience stillbirth. Serum ferritin levels were higher (geometric mean: 37.4 ng/mL vs. 23.3, p < 0.0001) and C-reactive protein levels lower (geometric mean: 2.9 mg/dL vs. 3.3, p = 0.0279), among women with stillbirth compared with live birth. Elevated white blood cell count (15.0 uL × 103 or greater) was associated with stillbirth (21.2% SB vs. 10.0% live birth, p < 0.0001). Histologic chorioamnionitis was more common (33.2% vs. 15.7%, p < 0.0001) among women with stillbirth compared with those with live birth. Serum ferritin, C-reactive protein, and chorioamnionitis had little impact on the ORs associating stillbirth with overweight or obesity. Adjustment for elevated white blood cell count did not meaningfully change the OR for stillbirth in overweight versus normal weight women. However, the stillbirth OR for obese versus normal BMI changed by more than 10% when adjusting for histologic chorioamnionitis (AOR, 1.38; 95% CI: 1.02-1.88), indicating confounding. BMI by inflammatory marker interaction terms were not significant. The association of serum ferritin levels with stillbirth was stronger among preterm births (p = 0.0066). CONCLUSION: Maternal serum ferritin levels, elevated white blood cell count, and histologic chorioamnionitis were positively and C-reactive protein levels negatively associated with stillbirth. Elevated BMIs, both overweight and obese, were associated with stillbirth when compared with women with normal BMI. None of the inflammatory markers fully accounted for the relationship between obesity and stillbirth. The association of maternal serum ferritin with stillbirth was stronger in preterm than term stillbirths.

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.

Racial/Ethnic Disparities in Measures of Self-reported Psychosocial States and Traits during Pregnancy.

Background The aim of this study was to determine whether racial/ethnic differences in psychosocial measures, independent of economic status, exist among a large population of pregnant nulliparas. Methods Between October 2010 and September 2013, nulliparous women at eight U.S. medical centers were followed longitudinally during pregnancy and completed validated instruments to quantify several psychosocial domains: Cohen Perceived Stress Scale, trait subscale of the Spielberger Anxiety Inventory, Connor-Davidson Resilience Scale, Multidimensional Scale of Perceived Social Support, Krieger Racism Scale, Edinburgh Postnatal Depression Scale, and the Pregnancy Experience Scale. Scores were stratified and compared by self-reported race, ethnicity, and income. Results Complete data were available for 8,128 of the 10,038 women enrolled in the study. For all measures, race and ethnicity were significantly associated (p < 0.001) with survey scores. Non-Hispanic black (NHB) women were most likely to score in the most unfavorable category for all measures, with the exception of the Pregnancy Experience Scale. The magnitude of these differences did not differ by income status (interaction, p > 0.05) except on the Krieger racism survey and the Edinburgh depression survey, which were exacerbated among NHB women with higher income (interaction, p < 0.001). Conclusion Significant racial/ethnic disparities, independent of income status, exist in psychosocial measures during pregnancy.

Karyotype versus microarray testing for genetic abnormalities after stillbirth.

BACKGROUND: Genetic abnormalities have been associated with 6 to 13% of stillbirths, but the true prevalence may be higher. Unlike karyotype analysis, microarray analysis does not require live cells, and it detects small deletions and duplications called copy-number variants. METHODS: The Stillbirth Collaborative Research Network conducted a population-based study of stillbirth in five geographic catchment areas. Standardized postmortem examinations and karyotype analyses were performed. A single-nucleotide polymorphism array was used to detect copy-number variants of at least 500 kb in placental or fetal tissue. Variants that were not identified in any of three databases of apparently unaffected persons were then classified into three groups: probably benign, clinical significance unknown, or pathogenic. We compared the results of karyotype and microarray analyses of samples obtained after delivery. RESULTS: In our analysis of samples from 532 stillbirths, microarray analysis yielded results more often than did karyotype analysis (87.4% vs. 70.5%, P<0.001) and provided better detection of genetic abnormalities (aneuploidy or pathogenic copy-number variants, 8.3% vs. 5.8%; P=0.007). Microarray analysis also identified more genetic abnormalities among 443 antepartum stillbirths (8.8% vs. 6.5%, P=0.02) and 67 stillbirths with congenital anomalies (29.9% vs. 19.4%, P=0.008). As compared with karyotype analysis, microarray analysis provided a relative increase in the diagnosis of genetic abnormalities of 41.9% in all stillbirths, 34.5% in antepartum stillbirths, and 53.8% in stillbirths with anomalies. CONCLUSIONS: Microarray analysis is more likely than karyotype analysis to provide a genetic diagnosis, primarily because of its success with nonviable tissue, and is especially valuable in analyses of stillbirths with congenital anomalies or in cases in which karyotype results cannot be obtained. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.).

Clinical sensitivity and specificity of meconium fatty acid ethyl ester, ethyl glucuronide, and ethyl sulfate for detecting maternal drinking during pregnancy.

BACKGROUND: We investigated agreement between self-reported prenatal alcohol exposure (PAE) and objective meconium alcohol markers to determine the optimal meconium marker and threshold for identifying PAE. METHODS: Meconium fatty acid ethyl esters (FAEE), ethyl glucuronide (EtG), and ethyl sulfate (EtS) were quantified by LC-MS/MS in 0.1 g meconium from infants of Safe Passage Study participants. Detailed PAE information was collected from women with a validated timeline follow-back interview. Because meconium formation begins during weeks 12-20, maternal self-reported drinking at or beyond 19 weeks was our exposure variable. RESULTS: Of 107 women, 33 reported no alcohol consumption in pregnancy, 16 stopped drinking by week 19, and 58 drank beyond 19 weeks (including 45 third-trimester drinkers). There was moderate to substantial agreement between self-reported PAE at ≥19 weeks and meconium EtG ≥30 ng/g (κ = 0.57, 95% CI 0.41-0.73). This biomarker and associated cutoff was superior to a 7 FAEE sum ≥2 nmol/g and all other individual and combination marker cutoffs. With meconium EtG ≥30 ng/g as the gold standard condition and maternal self-report at ≥19 weeks' gestation as the test condition, 82% clinical sensitivity (95% CI 71.6-92.0) and 75% specificity (95% CI 63.2-86.8) were observed. A significant dose-concentration relationship between self-reported drinks per drinking day and meconium EtG ≥30 ng/g also was observed (all P < 0.01). CONCLUSIONS: Maternal alcohol consumption at ≥19 weeks was better represented by meconium EtG ≥30 ng/g than currently used FAEE cutoffs.

A description of the methods of the Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be (nuMoM2b).

OBJECTIVE: The primary aim of the "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" is to determine maternal characteristics, which include genetic, physiologic response to pregnancy, and environmental factors that predict adverse pregnancy outcomes. STUDY DESIGN: Nulliparous women in the first trimester of pregnancy were recruited into an observational cohort study. Participants were seen at 3 study visits during pregnancy and again at delivery. We collected data from in-clinic interviews, take-home surveys, clinical measurements, ultrasound studies, and chart abstractions. Maternal biospecimens (serum, plasma, urine, cervicovaginal fluid) at antepartum study visits and delivery specimens (placenta, umbilical cord, cord blood) were collected, processed, and stored. The primary outcome of the study was defined as pregnancy ending at <37+0 weeks' gestation. Key study hypotheses involve adverse pregnancy outcomes of spontaneous preterm birth, preeclampsia, and fetal growth restriction. RESULTS: We recruited 10,037 women to the study. Basic characteristics of the cohort at screening are reported. CONCLUSION: The "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" cohort study methods and procedures can help investigators when they plan future projects.

The association of stillbirth with depressive symptoms 6-36 months post-delivery.

BACKGROUND: Stillbirths (≥ 20 weeks' gestation), which account for about 1 in 200 US pregnancies, may grieve parents deeply. Unresolved grief may lead to persistent depression. METHODS: We compared depressive symptoms in 2009 (6-36 months after index delivery) among consenting women in the Stillbirth Collaborative Research Network's population-based case-control study conducted 2006-08 (n = 275 who delivered a stillbirth and n = 522 who delivered a healthy livebirth (excluding livebirths < 37 weeks, infants who had been admitted to a neonatal intensive care unit or who died). Women scoring > 12 on the Edinburgh Depression Scale were classified as currently depressed. Crude (cOR) and adjusted (aOR) odds ratios and 95% confidence intervals [CI] were computed from univariate and multivariable logistic models, with weighting for study design and differential consent. Marginal structural models examined potential selection bias due to low follow-up. RESULTS: Current depression was more likely in women with stillbirth (14.8%) vs. healthy livebirth (8.3%, cOR 1.90 [95% CI 1.20, 3.02]). However, after control for history of depression and factors associated with both depression and stillbirth, the stillbirth association was no longer significant (aOR 1.35 [95% CI 0.79, 2.30]). Conversely, for the 76% of women with no history of depression, a significant association remained after adjustment for confounders (aOR 1.98 [95% CI 1.02, 3.82]). CONCLUSIONS: Improved screening for depression and referral may be needed for women's health care. Research should focus on defining optimal methods for support of women suffering stillbirth so as to lower the risk of subsequent depression.

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.

Bile acids in a multicenter, population-based case-control study of stillbirth.

OBJECTIVE: We sought to compare bile acids in women with and without stillbirth in a population-based study. STUDY DESIGN: The Stillbirth Collaborative Research Network conducted a multisite, population-based case-control study of stillbirth (fetal deaths ≥20 weeks). Maternal sera were obtained at the time of enrollment and frozen at -80°C until assay for bile acids. RESULTS: Assays were performed in 581 women with stillbirth and 1546 women with live births. Bile acid levels were slightly higher in women with stillbirth (geometric mean [95% confidence interval {CI}] = 3.2 [3.0-3.5]) compared to live births (2.9 [2.7-3.1], P = .0327). However, the difference was not significant after adjustment for baseline risk factors for stillbirth. The proportion of women with elevated levels (≥10 or ≥40 µmol/L) was similar in stillbirths and live births. Results were similar when the analysis was limited to subsets of stillbirths and live births. In women with stillbirths not associated with fetal anomalies or obstetric complications bile acid levels were higher than in women with term live births (geometric mean [95% CI] = 3.4 [3.0-3.8] vs 2.9 [2.7-3.0], P = .0152, unadjusted; P = .06, adjusted). However, a similar proportion of women in both groups had levels ≥10 µmol/L (10.7 vs 7.2%; odds ratio [OR], 1.54; 95% CI, 0.97-2.44; adjusted OR, 1.29; 95% CI, 0.78-2.15) and ≥40 µmol/L (1.7 vs 0.7%; OR, 2.58; 95% CI, 0.85-7.84; adjusted OR, 2.28; 95% CI, 0.79-6.56). CONCLUSION: Our data do not support testing for bile acids in cases of stillbirth in the absence of clinical evidence of intrahepatic cholestasis of pregnancy.

The safe passage study: design, methods, recruitment, and follow-up approach.

BACKGROUND: The Safe Passage Study is a large, prospective, multidisciplinary study designed to (1) investigate the association between prenatal alcohol exposure, sudden infant death syndrome (SIDS), and stillbirth, and (2) determine the biological basis of the spectrum of phenotypic outcomes from exposure, as modified by environmental and genetic factors that increase the risk of stillbirth, SIDS, and in surviving children, fetal alcohol spectrum disorders. METHODS: The results provided are based on an interim assessment of 6004 women enrolled, out of the 12,000 projected, from the Northern Plains, US, and Cape Town, South Africa, areas known to be of high risk for maternal drinking during pregnancy. Research objectives, study design, and descriptive statistics, including consent, recruitment, and retention information, are provided. RESULTS: Overall visit compliance is 87%, and includes prenatal, delivery/newborn, and postnatal contacts through 1 year post-delivery. Pregnancy outcome ascertainment is 98% prior to medical chart review; less than 2% of women withdraw. Consent for the use of DNA and placental tissue exceed 94%, and consent to participate in the autopsy portion of the study is 71%. CONCLUSIONS: The Safe Passage Study is the first multi-site study of SIDS and stillbirth to integrate prospectively collected exposure information with multidisciplinary biological information in the same maternal and fetal/infant dyad using a common protocol. Essential components of the study design and its success are close ties to the community and rigorous systems and processes to ensure compliance with the study protocol and procedures.

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.

An algorithm for the estimation of gestational age at the time of fetal death.

BACKGROUND: Accurate assignment of gestational age (GA) at time of fetal death is important for research and clinical practice. An algorithm to estimate GA at fetal death was developed and evaluated. METHODS: The algorithm developed by the Stillbirth Collaborative Research Network (SCRN) incorporated clinical and post-mortem data. The SCRN conducted a population-based case-control study of women with stillbirths and livebirths from 2006 to 2008 in five geographical catchment areas. Rules were developed to estimate a due date, identify an interval during which death likely occurred, and estimate GA at the time of fetal death. Reliability of using fetal foot length to estimate GA at death was assessed. RESULTS: The due date estimated for 620 singleton stillbirths studied was considered clinically reliable for 87%. Only 25.2% of stillbirths were documented alive within 2 days before diagnosis and 47.6% within 1 week of diagnosis. The algorithm-derived estimate of GA at time of fetal death was one or more weeks earlier than the GA at delivery for 43.5% of stillbirths. GA estimated from fetal foot length agreed with GA by algorithm within 2 weeks for 75% within a subset of well-dated stillbirths. CONCLUSIONS: Precise assignment of GA at death, defined as reliable dating criteria and a short interval (≤1 week) during which fetal death was known to have occurred, was possible in 46.6% of cases. Fetal foot length is a relatively accurate measure of GA at death and should be collected in all stillbirth cases.

Relationship between sleep position and risk of extreme cardiorespiratory events.

OBJECTIVE: To determine whether infants at sleep in the prone side positions are at higher risk for an extreme cardiorespiratory event compared with infants at sleep in the supine position. STUDY DESIGN: We used a case-control study to compare sleep position, determined with an accelerometer, in 116 infants during an extreme cardiorespiratory event with that in 231 matched control subjects (2 per case) who did not experience any extreme events during monitoring. RESULTS: From calculation of adjusted ORs and 95% CIs, infants placed in the prone or side position were no more likely to experience an extreme cardiorespiratory event compared with infants at sleep in the supine position. We used conditional logistic regression to account for the matched design of the study and to adjust for potential confounders or effect-modifiers. CONCLUSION: These findings, coupled with our earlier observation that the peak incidence of severe cardiorespiratory events occurred before the peak incidence of sudden infant death syndrome, strongly suggest that the supine sleeping position decreases the risk of sudden infant death syndrome by mechanisms other than by decreasing extreme cardiorespiratory events detected by monitoring.

Stillbirth Collaborative Research Network: design, methods and recruitment experience.

The Stillbirth Collaborative Research Network (SCRN) has conducted a multisite, population-based, case-control study, with prospective enrollment of stillbirths and livebirths at the time of delivery. This paper describes the general design, methods and recruitment experience. The SCRN attempted to enroll all stillbirths and a representative sample of livebirths occurring to residents of pre-defined geographical catchment areas delivering at 59 hospitals associated with five clinical sites. Livebirths <32 weeks gestation and women of African descent were oversampled. The recruitment hospitals were chosen to ensure access to at least 90% of all stillbirths and livebirths to residents of the catchment areas. Participants underwent a standardised protocol including maternal interview, medical record abstraction, placental pathology, biospecimen testing and, in stillbirths, post-mortem examination. Recruitment began in March 2006 and was completed in September 2008 with 663 women with a stillbirth and 1932 women with a livebirth enrolled, representing 69% and 63%, respectively, of the women identified. Additional surveillance for stillbirths continued until June 2009 and a follow-up of the case-control study participants was completed in December 2009. Among consenting women, there were high consent rates for the various study components. For the women with stillbirths, 95% agreed to a maternal interview, chart abstraction and a placental pathological examination; 91% of the women with a livebirth agreed to all of these components. Additionally, 84% of the women with stillbirths agreed to a fetal post-mortem examination. This comprehensive study is poised to systematically study a wide range of potential causes of, and risk factors for, stillbirths and to better understand the scope and incidence of the problem.

The Stillbirth Collaborative Research Network neuropathologic examination protocol.

We describe the neuropathologic procedure utilized in the Stillbirth Collaborative Research Network (SCRN), focusing on the examination of central nervous system (CNS) in stillbirth (SB). The SCRN was organized to perform a case-control study to determine the scope and causes of SB. Pathologists at all the participating centers agreed on and used the same standardized neuropathologic techniques. Standardized sections were taken and detailed data were collected. Fresh brain tissue was saved for investigative purposes. A total of 663 women with SB were enrolled into the case-control study: 620 delivered a single stillborn, 42 delivered twins, and 1 delivered triplets. Of the 560 (84.5%) who consented to postmortem examination, 465 (70.1%) also gave consent to the examination of the CNS. In the 440 stillborn infants in whom CNS examination was possible, 248 (56.4%) of the brains were intact, 72 were fragmented (16.4%), and 120 (27.3%) were liquefied. In summary, this is the largest prospective study dedicated to investigate the causes of SB and collect essential information and biological samples in the United States. A protocol for neuropathologic examination was instituted, and a brain tissue repository was created to provide samples and related data for future investigations.

Association of Prenatal Exposure to Maternal Drinking and Smoking With the Risk of Stillbirth.

Importance: Prenatal smoking is a known modifiable risk factor for stillbirth; however, the contribution of prenatal drinking or the combination of smoking and drinking is uncertain. Objective: To examine whether prenatal exposure to alcohol and tobacco cigarettes is associated with the risk of stillbirth. Design, Setting, and Participants: The Safe Passage Study was a longitudinal, prospective cohort study with data collection conducted between August 1, 2007, and January 31, 2015. Pregnant women from Cape Town, South Africa, and the Northern Plains region of the US were recruited and followed up throughout pregnancy. Data analysis was performed from November 1, 2018, to November 20, 2020. Exposure: Maternal consumption of alcohol and tobacco cigarettes in the prenatal period. Main Outcomes and Measures: The main outcomes were stillbirth, defined as fetal death at 20 or more weeks' gestation, and late stillbirth, defined as fetal death at 28 or more weeks' gestation. Self-reported alcohol and tobacco cigarette consumption was captured at the recruitment interview and up to 3 scheduled visits during pregnancy. Participants were followed up during pregnancy to obtain delivery outcome. Results: Of 11663 pregnancies (mean [SD] gestational age at enrollment, 18.6 [6.6] weeks) in 8506 women for whom the pregnancy outcome was known by 20 weeks' gestation or later and who did not terminate their pregnancies, there were 145 stillbirths (12.4 per 1000 pregnancies) and 82 late stillbirths (7.1 per 1000 pregnancies). A total of 59% of pregnancies were in women from South Africa, 59% were in multiracial women, 23% were in White women, 17% were in American Indian women, and 0.9% were in women of other races. A total of 8% were older than 35 years. In 51% of pregnancies, women reported no alcohol or tobacco cigarette exposure (risk of stillbirth, 4 per 1000 pregnancies). After the first trimester, 18% drank and smoked (risk of stillbirth, 15 per 1000 births), 9% drank only (risk of stillbirth, 10 per 1000 pregnancies), and 22% smoked only (risk of stillbirth, 8 per 1000 pregnancies). Compared with the reference group (pregnancies not prenatally exposed or without any exposure after the first trimester), the adjusted relative risk of late stillbirth was 2.78 (98.3% CI, 1.12-6.67) for pregnancies prenatally exposed to drinking and smoking, 2.22 (98.3% CI, 0.78-6.18) for pregnancies prenatally exposed to drinking only after the first trimester, and 1.60 (98.3% CI, 0.64-3.98) for pregnancies prenatally exposed to smoking only after the first trimester. The adjusted relative risk for all stillbirths was 1.75 (98.3% CI, 0.96-3.18) for dual exposure, 1.26 (98.3% CI, 0.58-2.74) for drinking only, and 1.27 (98.3% CI, 0.69-2.35) for smoking only compared with the reference group. Conclusions and Relevance: These results suggest that combined drinking and smoking after the first trimester of pregnancy, compared with no exposure or quitting before the end of the first trimester, may be associated with a significantly increased risk of late stillbirth.

Concurrent prenatal drinking and smoking increases risk for SIDS: Safe Passage Study report.

BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality. Although the rate has plateaued, any unexpected death of an infant is a family tragedy thus finding causes and contributors to risk remains a major public health concern. The primary objective of this investigation was to determine patterns of drinking and smoking during pregnancy that increase risk of SIDS. METHODS: The Safe Passage Study was a prospective, multi-center, observational study with 10,088 women, 11,892 pregnancies, and 12,029 fetuses, followed to 1-year post delivery. Subjects were from two sites in Cape Town, South Africa and five United States sites, including two American Indian Reservations. Group-based trajectory modeling was utilized to categorize patterns of drinking and smoking exposure during pregnancy. FINDINGS: One-year outcome was ascertained in 94·2% infants, with 28 SIDS (2·43/1000) and 38 known causes of death (3·30/1000). The increase in relative risk for SIDS, adjusted for key demographic and clinical characteristics, was 11·79 (98·3% CI: 2·59-53·7, p < 0·001) in infants whose mothers reported both prenatal drinking and smoking beyond the first trimester, 3.95 (98·3% CI: 0·44-35·83, p = 0·14), for drinking only beyond the first trimester and 4·86 (95% CI: 0·97-24·27, p = 0·02) for smoking only beyond the first trimester as compared to those unexposed or reported quitting early in pregnancy. INTERPRETATION: Infants prenatally exposed to both alcohol and cigarettes continuing beyond the first trimester have a substantially higher risk for SIDS compared to those unexposed, exposed to alcohol or cigarettes alone, or when mother reported quitting early in pregnancy. Given that prenatal drinking and smoking are modifiable risk factors, these results address a major global public health problem. FUNDING: National Institute on Alcohol Abuse and Alcoholism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Deafness and Other Communication Disorders.

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.

Racial disparities in stillbirth risk across gestation in the United States.

OBJECTIVE: We sought to determine factors associated with racial disparities in stillbirth risk. STUDY DESIGN: Stillbirth hazard was analyzed using 5,138,122 singleton gestations from the National Center of Health Statistics perinatal mortality and birth files, 2001-2002. RESULTS: Black women have a 2.2-fold increased risk of stillbirth compared with white women. The black/white disparity in stillbirth hazard at 20-23 weeks is 2.75, decreasing to 1.57 at 39-40 weeks. Higher education reduced the hazard for whites more than for blacks and Hispanics. Medical, pregnancy, and labor complications accounted for 30% of the hazard in blacks and 20% in whites and Hispanics. Congenital anomalies and small for gestational age contributed more to preterm stillbirth risk among whites than blacks. Pregnancy and labor conditions contributed more to preterm stillbirth risk among blacks than whites. CONCLUSION: The excess stillbirth risk for blacks was greatest at preterm gestations, and factors contributing to stillbirth risk vary by race and gestational age.

Interpregnancy interval and risk of stillbirth: a population-based case control study.

PURPOSE: We examined the association between interpregnancy intervals (IPIs) and stillbirth (defined as fetal death ≥20 weeks), as both short and long IPIs have been associated with adverse perinatal outcomes. Prior pregnancy loss is also a known risk factor for stillbirth, and women who suffer a prior loss often have shorter IPIs. For these reasons, we also sought to quantify the proportion of the association between prior pregnancy loss and subsequent stillbirth risk that may be attributed to a short IPI. METHODS: We used data from the Stillbirth Collaborative Research Network, a multisite case-control study conducted in 2006-2008, restricted to singleton pregnancies among multiparous or multigravid women (985 controls and 291 cases). We accounted for complex sample design and nonparticipation with weighted multivariable logistic regression. RESULTS: In the adjusted models, IPIs <6 months, as compared with a reference of 18-23 months, were associated with increased odds of stillbirth (aOR 1.6, 95% CI: 0.8, 3.4). Long IPIs (60-100 months) were also associated with an increased odds of stillbirth (aOR 2.4, 95% CI: 1.2, 4.5). After control for covariates, about one-fifth (21.2%) of the association of prior pregnancy loss (stillbirth, ectopic pregnancy, molar pregnancy, or spontaneous abortion) and stillbirth may be attributable to a short IPI. CONCLUSIONS: Our results suggest that women who experience a prior pregnancy loss may benefit from additional counseling on adequate birth spacing to reduce subsequent stillbirth risk.