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Original Contribution |

Association Between Stillbirth and Risk Factors Known at Pregnancy Confirmation FREE

[+] Author Affiliations

The Stillbirth Collaborative Research Network Writing Group:Radek Bukowski, MD, PhD, Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston; Marshall Carpenter, MD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Brown University School of Medicine, Providence, Rhode Island; Deborah Conway, MD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio; Donald Coustan, MD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Brown University School of Medicine; Donald J. Dudley, MD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio; Robert L. Goldenberg, MD, Department of Obstetrics and Gynecology, Drexel University School of Medicine, Philadelphia, Pennsylvania; Carol J. Rowland Hogue, PhD, MPH, Department of Epidemiology, Rollins School of Public Health, and Women's and Children's Center, Emory University; Matthew A. Koch, MD, PhD, Statistics and Epidemiology Unit, Health Sciences Division, RTI International, Research Triangle Park, North Carolina; Corette B. Parker, DrPH, Statistics and Epidemiology Unit, Health Sciences Division, RTI International; Halit Pinar, MD, Division of Perinatal and Pediatric Pathology, Department of Pathology and Laboratory Medicine, Brown University School of Medicine; Uma M. Reddy, MD, MPH, Pregnancy and Perinatology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; George R. Saade, MD, Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston; Robert M. Silver, MD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine and Maternal Fetal Medicine at Intermountain Healthcare, Salt Lake City; Barbara J. Stoll, MD, Emory University School of Medicine and Department of Pediatrics, Children's Healthcare Atlanta; Michael W. Varner, MD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine and Maternal Fetal Medicine at Intermountain Healthcare; and Marian Willinger, PhD, Pregnancy and Perinatology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development.


JAMA. 2011;306(22):2469-2479. doi:10.1001/jama.2011.1798.
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Published online

Context Stillbirths account for almost half of US deaths from 20 weeks' gestation to 1 year of life. Most large studies of risk factors for stillbirth use vital statistics with limited data.

Objective To determine the relation between stillbirths and risk factors that could be ascertained at the start of pregnancy, particularly the contribution of these factors to racial disparities.

Design, Setting, and Participants Multisite population-based case-control study conducted between March 2006 and September 2008. Fifty-nine US tertiary care and community hospitals, with access to at least 90% of deliveries within 5 catchment areas defined by state and county lines, enrolled residents with deliveries of 1 or more stillborn fetuses and a representative sample of deliveries of only live-born infants, oversampled for those at less than 32 weeks' gestation and those of African descent.

Main Outcome Measure Stillbirth.

Results Analysis included 614 case and 1816 control deliveries. In multivariate analyses, the following factors were independently associated with stillbirth: non-Hispanic black race/ethnicity (23.1% stillbirths, 11.2% live births) (vs non-Hispanic whites; adjusted odds ratio [AOR], 2.12 [95% CI, 1.41-3.20]); previous stillbirth (6.7% stillbirths, 1.4% live births); nulliparity with (10.5% stillbirths, 5.2% live births) and without (34.0% stillbirths, 29.7% live births) previous losses at fewer than 20 weeks' gestation (vs multiparity without stillbirth or previous losses; AOR, 5.91 [95% CI, 3.18-11.00]; AOR, 3.13 [95% CI, 2.06-4.75]; and AOR, 1.98 [95% CI, 1.51-2.60], respectively); diabetes (5.6% stillbirths, 1.6% live births) (vs no diabetes; AOR, 2.50 [95% CI, 1.39-4.48]); maternal age 40 years or older (4.5% stillbirths, 2.1% live births) (vs age 20-34 years; AOR, 2.41 [95% CI, 1.24-4.70]); maternal AB blood type (4.9% stillbirths, 3.0% live births) (vs type O; AOR, 1.96 [95% CI, 1.16-3.30]); history of drug addiction (4.5% stillbirths, 2.1% live births) (vs never use; AOR, 2.08 [95% CI, 1.12-3.88]); smoking during the 3 months prior to pregnancy (<10 cigarettes/d, 10.0% stillbirths, 6.5% live births) (vs none; AOR, 1.55 [95% CI, 1.02-2.35]); obesity/overweight (15.5% stillbirths, 12.4% live births) (vs normal weight; AOR, 1.72 [95% CI, 1.22-2.43]); not living with a partner (25.4% stillbirths, 15.3% live births) (vs married; AOR, 1.62 [95% CI, 1.15-2.27]); and plurality (6.4% stillbirths, 1.9% live births) (vs singleton; AOR, 4.59 [95% CI, 2.63-8.00]). The generalized R2 was 0.19, explaining little of the variance.

Conclusion Multiple risk factors that would have been known at the time of pregnancy confirmation were associated with stillbirth but accounted for only a small amount of the variance in this outcome.

Figures in this Article

The number of stillbirths (fetal deaths at ≥20 weeks' gestation) is nearly equal to the number of infant deaths in the United States (25 894 vs 28 384 in 2005).1 Although rates of stillbirth decreased in the first part of the 20th century, rates have been relatively stable over the past few decades.2 Racial/ethnic disparities have been reported, with stillbirth rates among non-Hispanic blacks being twice those among non-Hispanic whites.2

Most studies of risk factors for stillbirth use vital statistics with limited data. The Stillbirth Collaborative Research Network was created to conduct a detailed, population-based study of stillbirth in selected areas of the United States, with one of the a priori objectives to determine risk factors for stillbirth and reasons for racial disparities. Many of the factors associated with stillbirth need to be addressed early in pregnancy. Although other factors may be important later in pregnancy, clinicians providing obstetrical care frequently spend relatively more time at the initial visits counseling patients regarding their risk of adverse pregnancy outcomes. We focused this initial report on factors that could be ascertained at the start of pregnancy to provide the clinician and patient with population-based data applicable to the first prenatal visits. A subsequent report will address pregnancy predictors of stillbirth risk.

Study Design

The overall design and methods of the study have been reported.3 The study population consisted of residents in 5 geographic catchment areas defined a priori by county lines. Study participants were recruited at delivery from 59 community and academic hospitals, urban and rural, with an average of 80 000 deliveries per year. Based on prestudy vital statistics data, these hospitals were projected to provide access to at least 90% of stillbirths and 90% of live births for residents within each catchment area.

Participants were enrolled between March 2006 and September 2008. Catchment-area residents who were at least 13 years of age and nonincarcerated were potentially eligible for the study. All eligible women whose delivery resulted in 1 or more stillborn fetuses, and a representative sample of eligible women whose delivery resulted in only live-born infants, supplemented by oversampling of women delivering at less than 32 weeks' gestation and those of African descent delivering at 32 weeks' gestation or greater, were approached for enrollment.3 A stillborn fetus was defined by Apgar scores of 0 at 1 and 5 minutes and no signs of life by direct observation. Deliveries resulting from the termination of a live fetus were excluded. Gestational age was determined by the best clinical estimate using multiple sources, including information from assisted reproduction, last menstrual period, and obstetrical sonograms.4 Fetal deaths at 18 or 19 weeks without good dating were also included so that stillbirths beyond 20 weeks but with incorrect dating parameters could be enrolled.

The protocol included an in-hospital interview, medical record abstraction, placental pathology examination,5 and biospecimen collection for cases and controls. For stillbirths, a standardized postmortem examination was also performed.6,7

The study was approved by the institutional review boards of the clinical sites and associated hospitals and the data coordinating center. A limited Health Insurance Portability and Accountability Act waiver was obtained for surveillance, screening, and minimal data collection from potential participants. An advisory board reviewed the progress and safety of the study. All participants provided written informed consent.

Statistical Methods

Pregnancy, defined as a case if there were any stillbirths delivered and as a control if all live births were delivered, was the unit of analysis. For this analysis, cases and controls were excluded if the maternal interview or prenatal chart abstraction was missing. The main analysis compared all cases with all controls. To examine risk factors among potentially viable cases and controls not known to be at high risk of stillbirth, further analyses were performed in 2 subgroups: all deliveries at 24 weeks' gestation or greater and deliveries at 24 weeks' gestation or greater after exclusion of intrapartum stillbirths, multiple gestations, and major congenital anomalies. The anomalies excluded in subgroup analysis are listed in eTable 1.

A number of demographic and prepregnancy variables, including sociodemographic, medical and physiological, psychosocial, and reproductive history variables, were selected for analysis based on their potential association with stillbirth. A composite pregnancy history variable was constructed, with categories for nulliparous with and without prior spontaneous loss and for multiparous with no previous spontaneous loss, with spontaneous losses at less than 20 weeks' gestation only, and with prior stillbirth. When data were available from multiple sources, we developed decision criteria to prioritize information. In general, we prioritized data from the maternal interview regarding sociodemographic information and substance use, and data from the chart abstraction regarding medical information. Maternal race/ethnicity was self-reported in response to prespecified options provided by the investigators and evaluated because of known associations with stillbirth.

It was anticipated that approximately 1000 stillbirths would be identified across the 5 catchment areas over a 2-year period and that 700 would enroll. Sample-size considerations were directed at the number of live-birth controls needed, given the number of stillbirths to be studied. A sampling strategy was developed to produce a sample size of approximately 2:1 live births at 32 weeks' gestation or greater per stillbirth, with oversampling of live births in certain subgroups to ensure adequate numbers for stratified analyses. The planned sample size for controls was approximately 1400. Minimum detectible odds ratios (ORs) for 700 stillbirths and 1400 controls with 80% power and a 2-sided α = .05 are 1.3 at 50% exposure prevalence in the controls, 1.4 at 20%, 1.5 at 10%, 1.7 at 5%, and 2.7 at 1%.

The analyses were weighted for oversampling and other aspects of the study design as well as for differential consent based on characteristics recorded in the screened population.3 Analyses were performed using SUDAAN version 10.0.8 Crude ORs and adjusted ORs (AORs) and 95% confidence intervals were calculated from univariate and multivariable logistic models. All tests were performed at a nominal significance level of α = .05. All tests with a single degree of freedom were 2-sided.

Multivariable models included variables with P ≤ .20 for univariate association with stillbirth (overall or within the subgroups), after excluding variables missing for more than 5% of participants (paternal education, human immunodeficiency virus [HIV], hepatitis B, hepatitis C) or that were sparse in 1 or more response categories (HIV, hepatitis B, hepatitis C, hemoglobinopathy, syphilis). The multivariable models included adjustment for clinical site. A generalized R2 statistic was computed for each multivariable logistic model using the Cox and Snell9 coefficient of determination for logistic regression, scaled to a range of 0 to 1.

Positive and negative likelihood ratios (LRs) were computed for factors with an OR greater than 2.0 in any of the multivariable analyses. Each of these factors was dichotomized. Likelihood ratios for each single variable and for combinations of 2 were calculated. A positive LR between 2 and 5 (negative LR between 0.5 and 0.2) yields a small increase (decrease) in the posttest probability of disease; between 5 and 10 (0.2 and 0.1), a moderate increase (decrease); and greater than 10 (<0.1), a large increase (decrease).10,11

A woman could be enrolled in the study more than once during the 2.5 years of recruitment. For simplicity, the primary analysis treated each pregnancy as an independent observation. However, analyses were conducted to account for correlation between pregnancies in women who were enrolled twice and to confirm conclusions from the primary analysis.

Study surveillance identified 953 deliveries with stillbirth; in 70%, the mother provided consent for enrollment. Of the 3088 eligible live-birth deliveries, the mother provided consent in 63%. This resulted in a total of 663 stillbirth pregnancies (cases) and 1932 live-birth pregnancies (controls) in the study (Figure).

Place holder to copy figure label and caption
Figure. Study Enrollment and Inclusion in Case-Control Analysis
Graphic Jump Location

Details of the study design, methods, and recruitment have been reported.3 In brief, recruitment was through 59 hospitals in 5 geographic regions defined by state and county lines that included the State of Rhode Island and Bristol County, Massachusetts; DeKalb County, Georgia; Galveston and Brazoria Counties, Texas; Bexar County, Texas; and Salt Lake County, Utah. Analysis was restricted to participants with a complete or partial maternal interview and chart abstraction. Within this group, comparisons were made overall (all stillbirths compared with all live births) as well as for 2 subgroups (all stillbirths compared with all live births among deliveries at ≥24 weeks' gestation and antepartum stillbirths compared with all live births among deliveries of nonanomalous singletons at ≥24 weeks' gestation). Actual numbers of participants are shown; for weighted sample sizes, see Tables 2 through 5.

eTable 2 presents characteristics of eligible women by enrollment status. Women with stillbirths who did not enroll in the study (n = 290) did not differ from those enrolled according to maternal age, maternal race/ethnicity, insurance and method of payment, and gestational age at delivery. Women with live births who did not enroll in the study (n = 1156) did not differ from those enrolled according to maternal age and insurance/method of payment. However, nonenrolled women differed from those enrolled by maternal race/ethnicity and gestational age at delivery.

Table 1 (and eTable 2) shows unweighted and weighted distributions for the enrolled women based on whether they were included in the analysis or excluded because of missing data. The weighted total number of enrolled control pregnancies was 1439. This is smaller than the unweighted number (1932) because of the down-weighting of oversampled groups. Of pregnancies enrolled, 49 cases (7.4%) and 116 controls (6.0%) (weighted, 49 cases [7.4%] and 85 controls [6.3%]) were excluded from the analysis because of missing maternal interview or prenatal chart abstraction. Women excluded did not differ significantly from those included by maternal age, insurance status, or gestational age. Maternal race/ethnicity were similar among excluded and included pregnancies with stillbirths but differed among controls.

Table Graphic Jump LocationTable 1. Sociodemographic and Pregnancy Characteristics of Women Who Agreed to Enrolla
All Stillbirths Compared With All Live Births

Several reproductive history factors were strongly associated with stillbirth by univariate and multivariable analysis (Table 2 and Table 3). In multivariable analyses, these factors included previous stillbirth and nulliparity with and without a history of prior spontaneous losses at less than 20 weeks' gestation and plural birth in the current pregnancy.

Table Graphic Jump LocationTable 2. Sociodemographic and Maternal Substance Use Characteristics by SCRN Case Status (Overall)a
Table Graphic Jump LocationTable 3. Maternal Medical and Physiological and Pregnancy-Associated Characteristics by SCRN Case Status (Overall)a

In addition, the following maternal factors were independently associated with stillbirth: diabetes, 40 years or older, AB blood type, history of drug use with addiction, history of cigarette smoking during the 3 months prior to pregnancy, being overweight or obese, and not living with a partner. Relative to non-Hispanic whites (33.4% of cases, 45.3% of controls), the crude ORs for stillbirth were 2.78 (95% CI, 2.12-3.66) for non-Hispanic blacks (23.1% of cases, 11.2% of controls) and 1.38 (95% CI, 1.10-1.73) for Hispanics (36.3% of cases, 35.7% of controls). After adjusting for variables in the multivariable analysis, the AOR for stillbirth decreased to 2.12 (95% CI, 1.41-3.20) for non-Hispanic blacks and 1.22 (95% CI, 0.89-1.68) for Hispanics. The generalized R2 was 0.19.

To quantify the magnitude of the contribution of prepregnancy risk factors to the black-white disparity in stillbirth risk, we compared the crude OR and AOR of those participants in the multivariable model. Five percent of the live births and 7% of the stillbirths included in the univariate analysis were not included in the multivariable analysis because of missing values in 1 or more of the predictor variables. The crude OR for non-Hispanic blacks was 2.43 (95% CI, 1.82-3.24). Therefore, after adjustment for risk factors determined at the start of pregnancy, the disparity between non-Hispanic blacks and whites was reduced by 22% toward the null value of 1, from a crude OR of 2.43 to an AOR of 2.12.

Nine women were enrolled in the study twice. Each pregnancy was a singleton. Five women enrolled with a live birth for each pregnancy; 2 others had a stillbirth for each pregnancy and 2 a stillbirth followed by a live birth. Taking into account the correlations between the pregnancies for these 9 women produced results (data not shown) virtually identical to the results that treated all of the pregnancies as independent observations.

Deliveries at 24 Weeks' Gestation or Greater

Of the variables associated with stillbirth in the multivariable analysis of the overall study group, race/ethnicity, drug use, body mass index, and blood type were no longer significant in the subgroups at 24 weeks' gestation or greater, with the AORs particularly diminished for non-Hispanic blacks and AB blood type (Table 4 and Table 5). Nulliparity (overall and with prior losses or termination of pregnancy at <20 weeks' gestation), history of prior stillbirth, plurality, neither married nor cohabitating, and maternal age of 40 years or older remained independently associated with stillbirth, as did diabetes, for which the AOR was substantially larger in this subset (3.47 [95% CI, 1.86-6.49]). The generalized R2 for the multivariable model was 0.16.

Table Graphic Jump LocationTable 4. Sociodemographic and Maternal Substance Use Characteristics by SCRN Case Status and Multivariable Results for Subgroups (All Deliveries, Nonanomalous Singletons [Live Births, Antepartum Stillbirths]) at 24 Weeks' Gestational Age or Greatera
Table Graphic Jump LocationTable 5. Maternal Medical and Physiological and Pregnancy-Associated Characteristics by SCRN Case Status and Multivariable Results for Subgroups (All Deliveries, Nonanomalous Singletons [Live Births, Antepartum Stillbirths]) at 24 Weeks' Gestational Age or Greatera
Nonanomalous Singleton Deliveries at 24 Weeks' Gestation or Greater (Excluding Intrapartum Stillbirths)

To examine factors associated with stillbirths among low-risk, potentially viable fetuses, we further limited the subset of deliveries at 24 weeks' gestation or greater to the 311 antepartum stillbirths and 1593 live births with nonanomalous singleton pregnancies (Tables 4 and 5). The generalized R2 for the multivariable model was 0.14.

The results for non-Hispanic black women and for women with AB blood group were similar to those for the subgroup of deliveries at 24 weeks' gestation or greater. Advanced maternal age and cigarette smoking were no longer significant, although the AORs were not greatly diminished. Nulliparity and history of prior stillbirth remained strongly associated with increased risk of stillbirth. The independent risk associated with diabetes was again high. The adjusted association for women not living with a partner remained significant. In addition, there was an increased risk associated with being overweight or obese.

Predictive Factors in All Stillbirths Compared With All Live Births

Variables for which LRs were computed were age group, race/ethnicity, lifetime drug use, diabetes, pregnancy history, and plurality. Most of the positive LRs were in the 2 to 5 range, whereas most of the negative LRs were near 1 and none were less than 0.5. The positive LRs for combinations of factors were at least 5 for prior stillbirth/no prior live birth plus diabetes and for prior stillbirth/no prior live birth plus plural birth, but each applied to less than a half percent of the general population (Table 6).

Table Graphic Jump LocationTable 6. Diagnostic Likelihood Ratios for Selected Risk Factors and Combinations (Overall)a

This analysis focused on risk factors that would have been known at the start of pregnancy, when most women present to their obstetrical care clinicians and when a viable pregnancy is usually confirmed. Prior stillbirth, prior pregnancy loss at less than 20 weeks' gestation, non-Hispanic black race/ethnicity, nulliparity, plurality, diabetes, maternal obesity, maternal age, marital status, smoking, and illicit drug use were all associated with stillbirth by multivariable analyses. However, these risk factors explained little of the burden of stillbirth.

Pregnancy history was the strongest risk factor for stillbirth. When compared with multiparous women without previous losses at less than 20 weeks' gestation or stillbirths, there was a progressive increase in the risk for stillbirth for nulliparas, then nulliparas with previous losses at less than 20 weeks' gestation, and then multiparas with a previous stillbirth. Women with a previous stillbirth are well known to be at 5- to 10-fold increased recurrence risk for stillbirth and therefore receive more intensive prenatal care and antepartum surveillance in the subsequent pregnancy. Our findings add to the literature by showing that even a nonelective previous pregnancy loss at less than 20 weeks' gestation increased the risk for stillbirth. Because all women begin childbearing as nulliparas, findings from further investigations into the causes and mechanisms of stillbirth among nulliparas could be translated into interventions that may affect overall risk for stillbirth.

The increasing prevalence of diabetes in pregnancy12 underlines the importance of our finding that diabetes is associated with early as well as later stillbirths. A recent meta-analysis of preconception and prenatal care of diabetic women estimated that 10% of diabetes-associated stillbirth might be prevented with early detection and control.13 In this study, the association of maternal obesity with risk of stillbirth was not explained by diabetes or hypertension. Rather, the overall risk of stillbirth increased with increasing body mass index, even after taking into account the increased prevalence of preexisting maternal disease. Maternal overweight and obesity may have the greatest population-attributable risk among potentially modifiable maternal characteristics in the United States.14

Being unmarried and not cohabitating was a consistent risk factor for stillbirth and remained significant in the multivariable analyses that included other factors. The AOR of 1.62 (95% CI, 1.15-2.27) is higher than the adjusted relative risk of 1.24 (95% CI, 1.21-1.26) for being unmarried, as reported in another study for the United States from 1995-2004.15 In that study, there was no distinction between unmarried cohabitating or not cohabitating. In our study, which also controlled for additional factors not available on vital records, cohabitating unmarried women were not at increased risk of stillbirth, whereas unmarried women not cohabitating were at increased risk. Screening for partner relationship may prove useful in identifying higher-risk women who would benefit from social support during pregnancy.

Prepregnancy risk factors for stillbirth that have been found to be more frequent among African Americans include young maternal age (<20 years),16,17 low maternal education,18,19 previous stillbirth,1,18 previous cesarean delivery,16,20 obesity,21,22 chronic hypertension,19 diabetes,23 systemic lupus erythematosus,24 and multiple gestation.25 A few prepregnancy risk factors for stillbirth may be less frequent among African Americans, including smoking26 and nulliparity.16 To our knowledge, no study to date has systematically examined whether these stillbirth risk factors taken together explain the excess risk of stillbirth for African Americans.2 In our study, after adjustment for these risk factors, the relative odds of stillbirth for non-Hispanic blacks compared with whites was reduced by 22%.

The elevated risk of stillbirth for non-Hispanic blacks occurred predominantly prior to 24 weeks' gestation. This is consistent with the finding that the greatest black-white disparity in hazard for stillbirth in ongoing pregnancies is in the interval of 20 to 23 weeks' gestation.18 Also, very early preterm birth (<28 weeks' gestation) is increased more than 3-fold among African Americans,27 and the as-yet unknown reasons for excess preterm births may also be responsible for risks for early preterm stillbirth. In fact, an examination of the causes of death for the stillbirths in this study revealed a higher proportion of early intrapartum stillbirths among non-Hispanic blacks. The causes were similar to those reported for early preterm birth.28

In addition to non-Hispanic black race, AB blood group appeared to be preferentially associated with stillbirth before 24 weeks. We are unaware of a previous report of this association between AB blood type and stillbirth. Non-O blood groups are recognized risk factors for thrombosis.29 An association between blood type and adverse pregnancy outcomes, such as preeclampsia, has been reported in some studies but not confirmed in a meta-analysis.30 Mechanistic studies contrasting these risk factors may lead to better understanding of the etiology of stillbirth.

Overall, pregnancy factors known at the start of pregnancy accounted for little of the stillbirth risk, as shown by the low generalized R2 values. Apart from occurrence of previous stillbirth or pregnancy loss, the other risk factors have limited predictive value, with low positive LRs. This supports the findings of another study that noted the “relative lack of clinical utility” for prediction of term stillbirth when certain prepregnancy risk factors are present in isolation.31

Limitations of our study include the retrospective collection of some information (eg, body mass index) by maternal interview when prenatal records were missing some variables. A potential source of bias was that 30% of women experiencing stillbirth and 37% of sampled women with live births did not participate in the study. However, weighting was used to account for differential consent on a number of factors recorded in the screened population.3 In addition, the maternal interview or the chart abstraction was missing for 49 (7.3%) of enrolled stillbirth pregnancies and 116 (6.0%) of live-birth pregnancies, but differences between the enrolled and analyzed population in examined patient characteristics were small. Last, we had limited power to assess rare risk factors or those with only weak associations with stillbirth, particularly in the subgroup analyses.

To our knowledge, our study is the largest population-based study to date of stillbirth with extensive evaluation of cases as well as controls. The design of the study makes it more generalizable than prior hospital-based studies or studies with small sample sizes, less complete ascertainment, nonstandardized workup, or convenience sampling. Most other studies of risk factors for stillbirth have used large databases, including vital statistics, but these databases often contain limited information, particularly on reproductive and medical complications, and accuracy can be suboptimal.32 The detailed characterization of the study participants through maternal interview and chart abstraction enabled us to confirm prior risk factors as well as perform further in-depth analyses of risk factors.

In this study, factors known at the start of pregnancy explained little of the overall burden of stillbirth. Further research is needed to identify pregnancies at highest risk overall and for specific causes. Although some of the risk factors may not be modifiable (eg, race/ethnicity), knowledge of interactions between these factors and other modifiable ones may be useful. In addition, association studies aid in the identification of areas of investigation and preventive approaches. For example, non-Hispanic black women have a more than 2-fold increase in risk of stillbirth. However, the disparity in risk largely occurs at less than 24 weeks' gestation. Therefore, focusing on the pathophysiology of early preterm birth may reduce racial disparity in stillbirth.

Corresponding Author: George R. Saade, MD, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, 301 University Blvd, Galveston, TX 77555 (gsaade@utmb.edu).

Author Contributions: Dr Saade had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Saade, Bukowski, Carpenter, Conway, Dudley, Goldenberg, Hogue, Koch, Parker, Pinar, Reddy, Silver, Varner, Willinger.

Acquisition of data: Saade, Bukowski, Carpenter, Conway, Coustan, Dudley, Hogue, Koch, Parker, Pinar, Silver, Stoll, Varner.

Analysis and interpretation of data: Conway, Coustan, Dudley, Hogue, Koch, Parker, Pinar, Reddy, Silver, Varner, Willinger.

Drafting of the manuscript: Saade, Dudley, Hogue, Koch, Parker, Pinar, Reddy, Silver, Varner, Willinger.

Critical revision of the manuscript for important intellectual content: Saade, Bukowski, Carpenter, Conway, Coustan, Dudley, Goldenberg, Hogue, Koch, Parker, Pinar, Reddy, Silver, Stoll, Varner, Willinger.

Statistical analysis: Hogue, Koch, Parker, Parker, Reddy, Willinger.

Obtained funding: Saade, Bukowski, Carpenter, Dudley, Hogue, Koch, Parker, Pinar, Silver, Stoll, Varner.

Administrative, technical, or material support: Carpenter, Coustan, Dudley, Pinar, Reddy, Varner, Willinger.

Study supervision: Saade, Carpenter, Coustan, Dudley, Goldenberg, Koch, Parker, Pinar, Reddy, Varner, Willinger.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This study was supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health: U10-HD045953 (Brown University, Rhode Island); U10-HD045925 (Emory University, Georgia); U10-HD045952 (University of Texas Medical Branch at Galveston); U10-HDO45955 (University of Texas Health Sciences Center at San Antonio); U10-HD045944 (University of Utah Health Sciences Center); and U01-HD045954 (RTI International, North Carolina).

Role of the Sponsors: Program officers (Drs Reddy and Willinger) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development were members of the steering committee of the study and contributed to the study design; the management and interpretation of the data; and the preparation, review, and approval of the manuscript.

Stillbirth Collaborative Research Network:University of Texas Health Science Center at San Antonio: Donald J. Dudley, Deborah Conway, Karen Aufdemorte, Angela Rodriguez, Monica Pina; University of Utah School of Medicine: Robert M. Silver, Michael W. Varner, Kristi Nelson; Emory University School of Medicine and the Rollins School of Public Health: Carol J. Rowland Hogue, Barbara J.Stoll, Janice Daniels Tinsley, Bahig Shehata, Carlos Abramowsky; Brown University: Donald Coustan, Halit Pinar, Marshall Carpenter, Susan Kubaska; University of Texas Medical Branch at Galveston: George R. Saade, Radek Bukowski, Jennifer Lee Rollins, Hal Hawkins, Elena Sbrana; RTI International: Corette B. Parker, Matthew A. Koch, Vanessa R. Thorsten, Holly Franklin, Pinliang Chen; Pregnancy and Perinatalogy Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health: Marian Willinger, Uma M. Reddy; Drexel University School of Medicine: Robert L. Goldenberg.

Additional Contributions: We acknowledge the following members of the National Institute of Child Health and Human Development Scientific Advisory and Safety Monitoring Board for their review of the study protocol, materials, and progress: Reverend Phillip Cato, PhD; James W. Collins Jr, MD, MPH; Terry Dwyer, MD, MPH; William P. Fifer, PhD; John Ilekis, PhD; Marc Incerpi, MD; George Macones, MD, MSCE; Richard M. Pauli, MD, PhD; Raymond W. Redline, MD; Elizabeth Thom, PhD (chair), as well as all of the other physicians, study coordinators, research nurses, and patients who participated in the Stillbirth Collaborative Research Network. None of the individuals named received any compensation for their contributions.

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Carey JC, Klebanoff MA, Hauth JC,  et al; National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.  Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis.  N Engl J Med. 2000;342(8):534-540
PubMed   |  Link to Article
Pinar H, Koch MA, Hawkins H,  et al.  The Stillbirth Collaborative Research Network (SCRN) Placental and Umbilical Cord Examination Protocol [published online ahead of print June 29, 2011].  Am J PerinatolLink to Article
Pinar H, Koch MA, Hawkins H,  et al.  The Stillbirth Collaborative Research Network (SCRN) Postmortem Examination Protocol [published online ahead of print August 3, 2011]  Am J PerinatolLink to Article
Pinar H, Koch MA, Hawkins H,  et al.  The Stillbirth Collaborative Research Network (SCRN) Neuropathological Examination Protocol [published online ahead of print July 21, 2011]  Am J PerinatolLink to Article
Research Triangle Institute.  SUDAAN Language Manual, Release 10.0. Research Triangle Park, NC: Research Triangle Institute; 2008
Cox DR, Snell EJ. The Analysis of Binary Data.  2nd ed. London, United Kingdom: Chapman & Hall; 1989
Jaeschke R, Guyatt GH, Sackett DL.Evidence-Based Medicine Working Group.  Users' Guides to the Medical Literature, III: how to use an article about a diagnostic test: B: what are the results and will they help me in caring for my patients?  JAMA. 1994;271(9):703-707
PubMed   |  Link to Article
Grimes DA, Schulz KF. Refining clinical diagnosis with likelihood ratios.  Lancet. 2005;365(9469):1500-1505
PubMed   |  Link to Article
Hunt KJ, Schuller KL. The increasing prevalence of diabetes in pregnancy.  Obstet Gynecol Clin North Am. 2007;34(2):173-199
PubMed   |  Link to Article
Syed M, Javed H, Yakoob MY, Bhutta ZA. Effect of screening and management of diabetes during pregnancy on stillbirths.  BMC Public Health. 2011;11:(suppl 3)  S2
PubMed   |  Link to Article
Flenady V, Koopmans L, Middleton P,  et al.  Major risk factors for stillbirth in high-income countries.  Lancet. 2011;377(9774):1331-1340
PubMed   |  Link to Article
Balayla J, Azoulay L, Abenhaim HA. Maternal marital status and the risk of stillbirth and infant death [published online ahead of print June 18, 2011].  Womens Health Issues. 2011;21(5):361-365
PubMed  |  Link to Article   |  Link to Article
Martin JA, Hamilton BE, Sutton PD,  et al.  Births: final data for 2007.  Natl Vital Stat Rep. 2010;58(24):1-85
PubMed
Wilson RE, Alio AP, Kirby RS, Salihu HM. Young maternal age and risk of intrapartum stillbirth.  Arch Gynecol Obstet. 2008;278(3):231-236
PubMed   |  Link to Article
Willinger M, Ko CW, Reddy UM. Racial disparities in stillbirth risk across gestation in the United States.  Am J Obstet Gynecol. 2009;201(5):469, e1-e8
PubMed   |  Link to Article
Gold KJ, DeMonner SM, Lantz PM, Hayward RA. Prematurity and low birth weight as potential mediators of higher stillbirth risk in mixed black/white race couples.  J Womens Health (Larchmt). 2010;19(4):767-773
PubMed   |  Link to Article
Salihu HM, Sharma PP, Kristensen S,  et al.  Risk of stillbirth following a cesarean delivery: black-white disparity.  Obstet Gynecol. 2006;107(2, pt 1):383-390
PubMed   |  Link to Article
Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008.  JAMA. 2010;303(3):235-241
PubMed   |  Link to Article
Salihu HM, Dunlop AL, Hedayatzadeh M, Alio AP, Kirby RS, Alexander GR. Extreme obesity and risk of stillbirth among black and white gravidas.  Obstet Gynecol. 2007;110(3):552-557
PubMed   |  Link to Article
Centers for Disease Control and Prevention (CDC).  Prenatal care and pregnancies complicated by diabetes—U.S. reporting areas, 1989.  MMWR Morb Mortal Wkly Rep. 1993;42(6):119-122
PubMed
Pons-Estel GJ, Alarcón GS, Scofield L, Reinlib L, Cooper GS. Understanding the epidemiology and progression of systemic lupus erythematosus.  Semin Arthritis Rheum. 2010;39(4):257-268
PubMed   |  Link to Article
Salihu HM, Kinniburgh BA, Aliyu MH, Kirby RS, Alexander GR. Racial disparity in stillbirth among singleton, twin, and triplet gestations in the United States.  Obstet Gynecol. 2004;104(4):734-740
PubMed   |  Link to Article
Centers for Disease Control and Prevention, Division of Reproductive Health.  Preventing Smoking and Exposure to Secondhand Smoke Before, During and After Pregnancy. Atlanta, GA: Centers for Disease Control and Prevention; 2007
Martin JA.Centers for Disease Control and Prevention (CDC).  Preterm births—United States, 2007.  MMWR Surveill Summ. 2011;60:(suppl)  78-79
PubMed
The Stillbirth Collaborative Research Network Writing Group.  Causes of death among stillbirths.  JAMA. 2011;306(22):2459-2468
Link to Article
Wu O, Bayoumi N, Vickers MA, Clark P. ABO(H) blood groups and vascular disease.  J Thromb Haemost. 2008;6(1):62-69
PubMed   |  Link to Article
Clark P, Wu O. ABO(H) blood groups and pre-eclampsia.  Thromb Haemost. 2008;100(3):469-474
PubMed
Reddy UM, Laughon SK, Sun L,  et al.  Prepregnancy risk factors for antepartum stillbirth in the United States.  Obstet Gynecol. 2010;116(5):1119-1126
PubMed   |  Link to Article
Heuser CC, Hunn J, Varner M, Hossain S, Vered S, Silver RM. Correlation between stillbirth vital statistics and medical records.  Obstet Gynecol. 2010;116(6):1296-1301
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure. Study Enrollment and Inclusion in Case-Control Analysis
Graphic Jump Location

Details of the study design, methods, and recruitment have been reported.3 In brief, recruitment was through 59 hospitals in 5 geographic regions defined by state and county lines that included the State of Rhode Island and Bristol County, Massachusetts; DeKalb County, Georgia; Galveston and Brazoria Counties, Texas; Bexar County, Texas; and Salt Lake County, Utah. Analysis was restricted to participants with a complete or partial maternal interview and chart abstraction. Within this group, comparisons were made overall (all stillbirths compared with all live births) as well as for 2 subgroups (all stillbirths compared with all live births among deliveries at ≥24 weeks' gestation and antepartum stillbirths compared with all live births among deliveries of nonanomalous singletons at ≥24 weeks' gestation). Actual numbers of participants are shown; for weighted sample sizes, see Tables 2 through 5.

Tables

Table Graphic Jump LocationTable 1. Sociodemographic and Pregnancy Characteristics of Women Who Agreed to Enrolla
Table Graphic Jump LocationTable 2. Sociodemographic and Maternal Substance Use Characteristics by SCRN Case Status (Overall)a
Table Graphic Jump LocationTable 3. Maternal Medical and Physiological and Pregnancy-Associated Characteristics by SCRN Case Status (Overall)a
Table Graphic Jump LocationTable 4. Sociodemographic and Maternal Substance Use Characteristics by SCRN Case Status and Multivariable Results for Subgroups (All Deliveries, Nonanomalous Singletons [Live Births, Antepartum Stillbirths]) at 24 Weeks' Gestational Age or Greatera
Table Graphic Jump LocationTable 5. Maternal Medical and Physiological and Pregnancy-Associated Characteristics by SCRN Case Status and Multivariable Results for Subgroups (All Deliveries, Nonanomalous Singletons [Live Births, Antepartum Stillbirths]) at 24 Weeks' Gestational Age or Greatera
Table Graphic Jump LocationTable 6. Diagnostic Likelihood Ratios for Selected Risk Factors and Combinations (Overall)a

References

MacDorman MF, Kirmeyer S. The Challenge of Fetal MortalityHyattsville, MD: National Center for Health Statistics; 2009. NCHS Data Brief No 16
Rowland Hogue CJ, Silver RM. Racial and ethnic disparities in United States: stillbirth rates.  Semin Perinatol. 2011;35(4):221-233
PubMed   |  Link to Article
Parker CB, Hogue CJR, Koch MA,  et al; Stillbirth Collaborative Research Network.  Stillbirth Collaborative Research Network: design, methods and recruitment experience.  Paediatr Perinat Epidemiol. 2011;25(5):425-435
PubMed   |  Link to Article
Carey JC, Klebanoff MA, Hauth JC,  et al; National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.  Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis.  N Engl J Med. 2000;342(8):534-540
PubMed   |  Link to Article
Pinar H, Koch MA, Hawkins H,  et al.  The Stillbirth Collaborative Research Network (SCRN) Placental and Umbilical Cord Examination Protocol [published online ahead of print June 29, 2011].  Am J PerinatolLink to Article
Pinar H, Koch MA, Hawkins H,  et al.  The Stillbirth Collaborative Research Network (SCRN) Postmortem Examination Protocol [published online ahead of print August 3, 2011]  Am J PerinatolLink to Article
Pinar H, Koch MA, Hawkins H,  et al.  The Stillbirth Collaborative Research Network (SCRN) Neuropathological Examination Protocol [published online ahead of print July 21, 2011]  Am J PerinatolLink to Article
Research Triangle Institute.  SUDAAN Language Manual, Release 10.0. Research Triangle Park, NC: Research Triangle Institute; 2008
Cox DR, Snell EJ. The Analysis of Binary Data.  2nd ed. London, United Kingdom: Chapman & Hall; 1989
Jaeschke R, Guyatt GH, Sackett DL.Evidence-Based Medicine Working Group.  Users' Guides to the Medical Literature, III: how to use an article about a diagnostic test: B: what are the results and will they help me in caring for my patients?  JAMA. 1994;271(9):703-707
PubMed   |  Link to Article
Grimes DA, Schulz KF. Refining clinical diagnosis with likelihood ratios.  Lancet. 2005;365(9469):1500-1505
PubMed   |  Link to Article
Hunt KJ, Schuller KL. The increasing prevalence of diabetes in pregnancy.  Obstet Gynecol Clin North Am. 2007;34(2):173-199
PubMed   |  Link to Article
Syed M, Javed H, Yakoob MY, Bhutta ZA. Effect of screening and management of diabetes during pregnancy on stillbirths.  BMC Public Health. 2011;11:(suppl 3)  S2
PubMed   |  Link to Article
Flenady V, Koopmans L, Middleton P,  et al.  Major risk factors for stillbirth in high-income countries.  Lancet. 2011;377(9774):1331-1340
PubMed   |  Link to Article
Balayla J, Azoulay L, Abenhaim HA. Maternal marital status and the risk of stillbirth and infant death [published online ahead of print June 18, 2011].  Womens Health Issues. 2011;21(5):361-365
PubMed  |  Link to Article   |  Link to Article
Martin JA, Hamilton BE, Sutton PD,  et al.  Births: final data for 2007.  Natl Vital Stat Rep. 2010;58(24):1-85
PubMed
Wilson RE, Alio AP, Kirby RS, Salihu HM. Young maternal age and risk of intrapartum stillbirth.  Arch Gynecol Obstet. 2008;278(3):231-236
PubMed   |  Link to Article
Willinger M, Ko CW, Reddy UM. Racial disparities in stillbirth risk across gestation in the United States.  Am J Obstet Gynecol. 2009;201(5):469, e1-e8
PubMed   |  Link to Article
Gold KJ, DeMonner SM, Lantz PM, Hayward RA. Prematurity and low birth weight as potential mediators of higher stillbirth risk in mixed black/white race couples.  J Womens Health (Larchmt). 2010;19(4):767-773
PubMed   |  Link to Article
Salihu HM, Sharma PP, Kristensen S,  et al.  Risk of stillbirth following a cesarean delivery: black-white disparity.  Obstet Gynecol. 2006;107(2, pt 1):383-390
PubMed   |  Link to Article
Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008.  JAMA. 2010;303(3):235-241
PubMed   |  Link to Article
Salihu HM, Dunlop AL, Hedayatzadeh M, Alio AP, Kirby RS, Alexander GR. Extreme obesity and risk of stillbirth among black and white gravidas.  Obstet Gynecol. 2007;110(3):552-557
PubMed   |  Link to Article
Centers for Disease Control and Prevention (CDC).  Prenatal care and pregnancies complicated by diabetes—U.S. reporting areas, 1989.  MMWR Morb Mortal Wkly Rep. 1993;42(6):119-122
PubMed
Pons-Estel GJ, Alarcón GS, Scofield L, Reinlib L, Cooper GS. Understanding the epidemiology and progression of systemic lupus erythematosus.  Semin Arthritis Rheum. 2010;39(4):257-268
PubMed   |  Link to Article
Salihu HM, Kinniburgh BA, Aliyu MH, Kirby RS, Alexander GR. Racial disparity in stillbirth among singleton, twin, and triplet gestations in the United States.  Obstet Gynecol. 2004;104(4):734-740
PubMed   |  Link to Article
Centers for Disease Control and Prevention, Division of Reproductive Health.  Preventing Smoking and Exposure to Secondhand Smoke Before, During and After Pregnancy. Atlanta, GA: Centers for Disease Control and Prevention; 2007
Martin JA.Centers for Disease Control and Prevention (CDC).  Preterm births—United States, 2007.  MMWR Surveill Summ. 2011;60:(suppl)  78-79
PubMed
The Stillbirth Collaborative Research Network Writing Group.  Causes of death among stillbirths.  JAMA. 2011;306(22):2459-2468
Link to Article
Wu O, Bayoumi N, Vickers MA, Clark P. ABO(H) blood groups and vascular disease.  J Thromb Haemost. 2008;6(1):62-69
PubMed   |  Link to Article
Clark P, Wu O. ABO(H) blood groups and pre-eclampsia.  Thromb Haemost. 2008;100(3):469-474
PubMed
Reddy UM, Laughon SK, Sun L,  et al.  Prepregnancy risk factors for antepartum stillbirth in the United States.  Obstet Gynecol. 2010;116(5):1119-1126
PubMed   |  Link to Article
Heuser CC, Hunn J, Varner M, Hossain S, Vered S, Silver RM. Correlation between stillbirth vital statistics and medical records.  Obstet Gynecol. 2010;116(6):1296-1301
PubMed   |  Link to Article

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