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..
The network’s steering committee and an external advisory and safety monitoring board oversaw the research. Between August 1, 2007, and January 31, 2015, a prospective cohort of 8506 women (11 892 pregnancies) were enrolled in the Safe Passage Study. In South Africa, women were recruited from 2 residential areas within Cape Town, and in the Northern Plains of the US (South and North Dakota), from 5 clinical sites, including 2 American Indian reservations. Data analysis was performed from November 1, 2018, to November 20, 2020. Ethical approval was obtained at each clinical site; Stellenbosch University, Sanford Health, the Indian Health Service, and participating Tribal Nations. Institutional review board approval, including tribal review for reservation-based sites in the Northern Plains of the US, was obtained for all PASS entities.11,14 Written informed consent was provided at the time of recruitment. Data were not deidentified at the time of participant recruitment but were deidentified for the purpose of data analyses. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Inclusion and exclusion criteria are described elsewhere.11 In brief, consenting, pregnant women 16 years or older who were carrying 1 or 2 fetuses between 6 weeks’ gestation up to but not including the delivery admission and able to speak English or Afrikaans were eligible. Women planning to terminate their pregnancy or move out of the catchment area before the estimated date of delivery or were advised by a health care professional to not participate were excluded. The GA was determined during the recruitment visit using standard clinical practices: ultrasonography in South Africa and a combination of clinical examination, ultrasonography, and last menstrual period in the Northern Plains of the US. Women completed in-person study visits, which included a recruitment visit and up to 3 prenatal visits occurring at 20 to 24, 28 to 32, and 34 or more weeks of gestation, dependent on GA at enrollment. To reduce potential sources of bias, all participants presenting for prenatal care were approached for recruitment into the study, and subsequent study visits aligned with routine prenatal visits. At the recruitment visit in Cape Town, South Africa, and the Northern Plains of the US, pregnant women self-reported their racial background, choosing from the categories recommended by the National Institutes of Health: American Indian or Alaska Native, Asian, Black or African American, multiracial, Native Hawaiian or Pacific Islander, White, or other. Multiracial was defined in South Africa as having ancestry from more than 1 of the populations that inhabit the region, including Khoisan, Bantu, European, Austronesian, East Asian, or South Asian. In addition, participants self-reported their ethnic background as non-Hispanic or Latino or Hispanic or Latino. The primary goal of assessing race and ethnicity was to ensure that research can comprehensively describe the population and that findings can be generalizable. Clinical site coordinators monitored labor and delivery admissions daily to identify pregnancy outcome (ie, miscarriage, termination of pregnancy, stillbirth, and live birth). When a stillbirth occurred, the participant was asked to consent to fetal autopsy and to donate fetal brain tissue.15 For this analysis, the primary stillbirth outcome was defined as a fetal death delivered at 28 weeks’ gestation or later (late stillbirth ≥28 weeks), and the secondary outcome was defined as a fetal death delivered at 20 weeks or later (all stillbirth ≥20 weeks). Each stillbirth was adjudicated by a committee of multidisciplinary study investigators16 using the following clinical information: fetal autopsy and placental pathology (47% of cases), placental pathology only (32%), autopsy data only (5%), or clinical information only (16%). Diagnostic genetic testing was performed as indicated in 5% of cases. The most common cause of stillbirth was acute placental abruption (26%) followed by maternal vascular malperfusion (17%) and fetal vascular malperfusion (which includes umbilical cord pathology) (16%). Details of the methods used to collect and characterize alcohol and tobacco cigarette exposure were published elsewhere17,18 and are summarized here. Self-reported alcohol and tobacco cigarette consumption was captured at the recruitment interview and at up to 3 prenatal visits after recruitment, using a modified timeline follow-back interview for alcohol exposure and frequency and quantity of tobacco cigarettes for smoking exposure. In the event of fetal demise, exposure information was collected for the 30 days before the death. Standard drinks were calculated based on the specific alcohol content of the drinks reported. Prenatal drinking and smoking information was obtained at nearly 100% of prenatal visits. Drinking status was known for at least 6 months of the pregnancy among 94% of pregnancies and smoking status among 80% of pregnancies. Drinks per drinking-day and tobacco cigarettes per day were calculated for each month of pregnancy where exposure information was available before the stillbirth. Group-based trajectory models were used to classify pregnancies with similar prenatal drinking patterns into 1 of 5 drinking trajectory groups (based on 11 892 pregnancies): none (48%), moderate/quit early (25%), high/quit later (10%), low continuous (12%), and high continuous (6%). Similar prenatal smoking patterns were classified into 1 of 7 smoking trajectory groups: none (52%), moderate/quit early (8%), high/quit later (2%), low continuous (10%), moderate continuous (18%), high continuous (8%), and very high continuous (2%).18 Because of the small number of late stillbirths (n = 82) and stillbirths (n = 145), to improve precision in the estimates of stillbirth risk associated with exposure, we dichotomized the 5-level drinking and 7-level smoking exposure measures to create a 2-level drinking and a 2-level smoking exposure measure. The 2-level drinking and 2-level smoking measures were labeled as none/quit early, defined as no exposure during pregnancy or cessation by the end of the first trimester, and continuous/quit late, defined as continuous exposure throughout pregnancy or cessation some time after the first trimester. To address the primary hypothesis that associations exist between different combinations of drinking and smoking and stillbirth risk, we created a 4-level drinking and smoking measure: none/quit early (51%), defined as no drinking or smoking during pregnancy or cessation by the end of the first trimester; drinking only (8%), defined as continuous/quit late for drinking and none/quit early for smoking; smoking only (22%), defined as continuous/quit late for smoking and none/quit early for drinking; and dual (19%), defined as continuous/quit late for both exposures. Because stillbirth is a rare outcome, multivariable statistical approaches for adjustment were limited. Thus, propensity scores (PSs) were developed to balance the effect of nonrandom allocation of drinking and smoking exposure at baseline to increase efficiency and reduce bias caused by confounding and were included as covariates in multivariable models (K.A.D. and M.W., unpublished data, 2017). Propensity scores were developed for the 2-level and 4-level exposure measures, using baseline characteristics available on nearly the entire cohort (PS abbreviated, 2% missing) and included the following: recruitment location, maternal age, race, marital status, educational level, history of diabetes, parity, arm circumference, and statistical interactions. As a measure of nutritional status, arm circumference was used as a proxy for prepregnancy body mass index (correlation, 0.83), which was missing in 33% of pregnancies because many women did not have access to scales.19 An additional set of PSs were developed based on a more complete set of baseline characteristics (PS comprehensive, 19.5% missing). The PS comprehensive contained 40 baseline characteristics and statistical interactions between confounders (eTable 1 in Supplement 1). The primary analysis set includes all pregnancies. Maternal demographic characteristics, medical and obstetric history, and infant characteristics for each stillbirth outcome, compared with live births, were expressed as risk per 1000 pregnancies. Log binomial regression using generalized linear models and generalized estimating equations to account for correlation (exchangeable) among reenrollments were used to estimate crude and adjusted relative risks to quantify associations between exposure and outcome. Adjustment in multivariable models included the PSs described above, GA at enrollment, and multifetal pregnancy. For the death outcomes, late stillbirth (≥28 weeks) and stillbirth (≥20 weeks), the primary exposure analysis included 3 planned comparisons using the 4-level drinking and smoking measure, specifically comparing the none/quit early group with the drinking only, smoking only, or dual (drinking and smoking) exposure groups, adjusted for confounding as described. Conservatively, for statistical testing that involved multiple comparisons, 2-sided 98.3% (based on Bonferroni correction) CIs were provided; otherwise, 95% CIs were provided. A 2-sided P < .05 was considered to be statistically significant, and 95% CIs were provided for tests of interaction. The causes of stillbirth using the 4-level drinking and smoking exposure measure were presented descriptively. The study design and determination of sample size were described elsewhere.11 In brief, the study was sized for the outcome of SIDS that resulted in a sample size of 12 000 women. Assuming a sample size of 12 000, then 8 per 1000 stillbirths in the Northern Plains of the US, 15 per 1000 stillbirths in South Africa, and 49% of women prenatally exposed yields 95% power to detect a relative risk of at least 2 when comparing women with prenatal exposure with those without prenatal exposure using a χ2 test for proportions with continuity correction and a 2-sided P < .05. The study was not powered to detect effect measure modification (ie, statistical interaction between 2-level drinking and 2-level smoking main effects based on factorial design); however, the findings were provided. The study was not designed to investigate genetic and biological interactions or to perform subgroup analysis (eg, stratified by site and cause of death); however, crude assessments by site and cause of stillbirth death were provided. Analyses were performed using SAS/STAT software, version 9.4 (SAS Institute Inc).