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.

Effects of Prenatal Exposure to Alcohol and Smoking on Fetal Heart Rate and Movement Regulation.

Negative associations of prenatal tobacco and alcohol exposure (PTE and PAE) on birth outcomes and childhood development have been well documented, but less is known about underlying mechanisms. A possible pathway for the adverse fetal outcomes associated with PTE and PAE is the alteration of fetal autonomic nervous system development. This study assessed PTE and PAE effects on measures of fetal autonomic regulation, as quantified by heart rate (HR), heart rate variability (SD-HR), movement, and HR-movement coupling in a population of fetuses at ≥ 34 weeks gestational age. Participants are a subset of the Safe Passage Study, a prospective cohort study that enrolled pregnant women from clinical sites in Cape Town, South Africa, and the Northern Plains region, United States. PAE was defined by six levels: no alcohol, low quit early, high quit early, low continuous, moderate continuous, and high continuous; while PTE by 4 levels: no smoking, quit early, low continuous, and moderate/high continuous. Linear regression analyses of autonomic measures were employed controlling for fetal sex, gestational age at assessment, site, maternal education, household crowding, and depression. Analyses were also stratified by sleep state (1F and 2F) and site (South Africa, N = 4025, Northern Plains, N = 2466). The final sample included 6491 maternal-fetal-dyad assessed in the third trimester [35.21 ± 1.26 (mean ± SD) weeks gestation]. PTE was associated with a decrease in mean HR in state 2F, in a dose dependent fashion, only for fetuses of mothers who continued smoking after the first trimester. In state 1F, there was a significant increase in mean HR in fetuses whose mother quit during the first trimester. This effect was driven by the Norther Plains cohort. PTE was also associated with a significant reduction in fetal movement in the most highly exposed group. In South Africa a significant increase in mean HR both for the high quit early and the high continuous group was observed. In conclusion, this investigation addresses a critical knowledge gap regarding the relationship between PTE and PAE and fetal autonomic regulation. We believe these results can contribute to elucidating mechanisms underlying risk for adverse outcomes.

Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002-0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla-a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

Associations of maternal smoking and drinking with fetal growth and placental abruption.

OBJECTIVE: To investigate pregnant women from the Safe Passage Study for the individual and combined effects of smoking and drinking during pregnancy on the prevalence of clinical placental abruption. STUDY DESIGN: The aim of the original Safe Passage Study was to investigate the association of alcohol use during pregnancy with stillbirths and sudden infant deaths. Recruitment for this longitudinal study occurred between August 2007 and October 2016. Information on smoking and drinking was collected prospectively at up to 4 occasions during pregnancy where a modified timeline follow-back method was used to assess the exposure to alcohol. Placentas were examined histologically in a subset of pregnant women. For this study we examined the effects of smoking and drinking on fetal growth and the prevalence rate of placental abruption. High smoking constituted of 10 or more cigarettes per day and high drinking of four or more binge drinking episodes or 32 and more standard drinks during pregnancy. Placental abruption was diagnosed in two ways, by the clinical picture or the macroscopic and microscopic examination of the placenta. RESULTS: When compared to the non-drinking/non-smoking group, the high drinking/high smoking group were significantly older, had a higher gravidity, had a lower household income and booked later for prenatal care; fewer of them were employed and had toilet and running water facilities in their houses. Clinical placental abruption was diagnosed in 49 (0.87 %) of 5806 pregnancies. Histological examination was done in 1319 placentas; macroscopic and microscopic diagnosis of placental abruption was made in 8.2 % and 11.9 % of placentas respectively. These 49 cases were then correlated with seven smoking/drinking patterns during pregnancy. When compared to rates for no smoking/no drinking (0.11 %) and low smoking/no drinking (0.55 %), the prevalence rate of placental abruption was significantly higher (p < .005) in the low smoking/low drinking group (1.25 %). There was also a significant relationship between low maternal employment and methamphetamine use with placental abruption. CONCLUSION: As many conditions and habits are associated with placental abruption, it is impossible to single out one specific cause but concomitant drinking and smoking seem to increase the risk of placental abruption.

Association Between Prenatal Exposure to Alcohol and Tobacco and Neonatal Brain Activity: Results From the Safe Passage Study.

Importance: Research to date has not determined a safe level of alcohol or tobacco use during pregnancy. Electroencephalography (EEG) is a noninvasive measure of cortical function that has previously been used to examine effects of in utero exposures and associations with neurodevelopment. Objective: To examine the association of prenatal exposure to alcohol (PAE) and tobacco smoking (PTE) with brain activity in newborns. Design, Setting, and Participants: This prospective cohort study enrolled mother-newborn dyads from December 2011 through August 2015, with data analyzed from June 2018 through June 2019. Pregnant women were recruited from clinical sites in Cape Town, South Africa, and the Northern Plains region of the US. Participants were a subset of newborns enrolled in the Safe Passage Study. Exclusions included birth at less than 37 or more than 41 weeks' gestation, multiple birth, or maternal use of psychiatric medication during pregnancy. Exposures: PAE and PTE groups were determined by cluster analysis. Main Outcomes and Measures: Analyses of covariance were run on EEG spectral power at 12 scalp locations across the frequency spectrum from 1 to 45 Hz in 3-Hz bins by sleep state. Results: The final sample consisted of 1739 newborns (median [interquartile range] gestational age at birth, 39.29 [1.57] weeks; 886 [50.9%] were female; median [interquartile range] newborn age at assessment, 48.53 [44.96] hours). Newborns whose mothers were in the low continuous (95% CI, -0.379 to -0.031; P < .05; 95% CI, -0.379 to -0.045; P < .05), quit (95% CI, -0.419 to -0.127; P < .001; 95% CI, -0.398 to -0.106; P < .005), and moderate or high continuous (95% CI, -0.430 to -0.124; P < .001; 95% CI, -0.420 to -0.119; P < .005) PAE clusters had increased 4- to 6-Hz and 7- to 9-Hz left-temporal EEG power. Newborns with moderate or high continuous PTE had decreased 19- to 21-Hz (95% CI, 0.034 to 0.327; P < .05) and 22- to 24-Hz (95% CI, 0.022 to 0.316; P < .05) right-central EEG compared with newborns with no PTE. Newborns with moderate or high continuous PTE had significantly decreased 22- to 36-Hz right-central EEG power compared with the quit smoking group (22-24 Hz, 95% CI, 0.001 to 0.579; P < .05; 25-27 Hz, 95% CI, 0.008 to 0.586; P < .05; 28-30 Hz, 95% CI, 0.028 to 0.607; P < .05; 31-33 Hz, 95% CI, 0.038 to 0.617; P < .05; 34-36 Hz, 95% CI, 0.057 to 0.636; P < .05). Conclusions and Relevance: These findings suggest that even low levels of PAE or PTE are associated with changes in offspring brain development.

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.

Association of late second trimester miscarriages with placental histology and autopsy findings.

OBJECTIVES: To describe the placental histology and autopsy findings in pregnancies where fetal demise occurred before a gestational age of 22 weeks. STUDY DESIGN: This study was a subset of a larger study where the effect of alcohol exposure during pregnancy on stillbirths was studied. In a prospective cohort, 7,010 singleton pregnancies were followed from the first antenatal visit until infant one year of age visit. Gestational age was assessed by ultrasound, preferably at the first antenatal visit. All pregnancy losses were identified and when the fetuses delivered at or after a gestation of 20 weeks, the mother or parents were approached for consent for autopsy. This study describes the placental pathology and findings at autopsy in losses before 22 weeks gestation (late second trimester miscarriages). RESULTS: Fourteen cases were identified in which 13 had an autopsy and 12 had a histological examination of the placenta. The most prevalent histological abnormality was placental abruption which was seen in 6 miscarriages, occasionally on its own, or in combination with maternal vascular malperfusion or acute chorioamnionitis. The second most frequent finding was maternal vascular malperfusion, as found in five placentas, alone or in combination with other pathology. The third most frequent pathology was acute chorioamnionitis, found in four placentas, in combination or alone. Other causes were diffuse chronic villitis due to cytomegalovirus infection and early amnion rupture with anhydramnios and cord obstruction. CONCLUSIONS: Causes of fetal demise at the end of the second trimester differ little from causes of stillbirth. There is value in using placental histology in late second trimester miscarriages to try to identify the cause of demise.

Effects of low maternal heart rate on fetal growth and birthweight.

OBJECTIVE: To evaluate the association between birthweight and maternal heart rate (MHR) or heart rate variability (HRV) under resting conditions at 20-24 gestational weeks and 34 weeks or later (34+ weeks). METHODS: Data were retrospectively reviewed from the Safe Passage Study, a prospective longitudinal cohort study of alcohol use in pregnancy and birth outcomes in Cape Town, South Africa, between August 2007 and January 2015. Using custom-designed software, MHR and indicators of HRV were obtained from the recorded maternal electrocardiograms and compared with birthweight and z-scores of birthweight adjusted for gestation and gender. RESULTS: Data from 5655 women were included. MHR increased from 84.6 bpm at 20-24 weeks to 88.3 bpm at 34+ weeks. Increasing MHR from 70-80 to 80-90 and 90-100 bpm at 20-24 weeks was associated with increasing birthweight from 2940 to 2998 and 3032 g, respectively (P<0.05). MHR and HRV contributed 29% to the variability associated with birthweight, whereas maternal body mass index at recruitment contributed 44%. Similar associations were observed for MHR at 34+ weeks. CONCLUSION: The observed association of low maternal heart rate with birthweight might help to identify pregnancies at risk of poor fetal growth.

Fetal heart rate, heart rate variability, and heart rate/movement coupling in the Safe Passage Study.

OBJECTIVE: To determine normative values for heart rate patterns in healthy fetuses. METHODS: This research is from the Safe Passage Study conducted by the Prenatal Alcohol and SIDS and Stillbirth (PASS) Network. A standardized protocol assessed fetal heart rate (FHR), heart rate variability (HRV), and movement from 1655 fetuses at three-time points during gestation (20-24 weeks, 28-32 weeks, 34-38 weeks gestation). RESULTS: FHR decreased while HRV increased over gestation. At the latter two ages, males had significantly lower FHR than females while there were no sex differences in FHR at 20-24 weeks. When accounting for the fetal state during late gestation (34-28 weeks), we found that males had significantly lower FHR than females in the active fetal state only. CONCLUSION: Results demonstrate significant state, gestational age, and sex-related changes in cardiac activity, somatic activity, and autonomic function as the fetus approaches birth.

Transabdominal recordings of fetal heart rate in extremely small fetuses.

INTRODUCTION: As part of the fetal assessment for the Safe Passage Study, we recorded raw data of the fetal ECG via five maternal abdominal wall electrodes from 20 weeks to 23 weeks 6 days' gestation. MATERIALS: For this study were extracted and analyzed the FHR patterns from the stored raw data in 16 stillbirths where the fetus weighed less than 1000 g and where autopsy was performed. RESULTS: Birth weights ranged from 190 to 970 g. The proportion FHR signal loss ranged from 0.3% to 21.1%. In the smallest fetus the heart weighed 1.3 g, yet the FHR signal loss was only 0.9%.

Maternal heart rate patterns under resting conditions in late pregnancy.

OBJECTIVES: To describe maternal heart rate patterns observed during antenatal monitoring under resting conditions between the gestational ages of 34 to 38 weeks and to demonstrate its associations with uterine activity. METHODS: Each participant had five high quality ECG electrodes attached to her anterior abdominal wall which were connected to the Monica AN24 device to collect raw electrical signals from the maternal and fetal ECG and signals of uterine activity. Proprietary software was then used to download the raw data and extract the maternal and fetal heart rate patterns and uterine activity. RESULTS: Several distinct maternal heart rate patterns were observed. These included unusually high or low levels of variability, tachycardia, bradycardia, regular and irregular periodic changes and sporadic changes where the heart rate suddenly decreased or increased. Some of the fluctuations, especially decelerations of maternal heart rate, seemed to be associated with uterine activity. CONCLUSION: The clinical implications of these different patterns, for both the mother and fetus, needs to be explored further. There is a need for computerized analyses of the different maternal patterns during different gestational ages to determine its relevance. SYNOPSIS: Various maternal heart rate patterns under resting conditions in late pregnancy are described.

A modified Timeline Followback assessment to capture alcohol exposure in pregnant women: Application in the Safe Passage Study.

Prenatal alcohol exposure (PAE) has been linked to poor pregnancy outcomes, yet there is no recognized standard for PAE assessment, and the specific effects of quantity, frequency, and timing remain largely unknown. The Safe Passage Study was designed to investigate the role of PAE in a continuum of poor peri- and postnatal outcomes. The objective of this manuscript is to describe the rationale for, and feasibility of, modifications to the traditional Timeline Followback (TLFB) for collecting PAE information in a large cohort of pregnant women. Participants from the Northern Plains region (in the United States) and Cape Town, South Africa, were followed prospectively using a modified 30-day TLFB interview, administered up to five times, to obtain detailed PAE information. Required modifications for our population included capturing information regarding sharing, type/brand, container size, and duration, in order to accurately record the amount of alcohol consumed. PAE status was defined for 99.9% of the 11,892 enrolled pregnancies at least once during pregnancy and for 92% across all trimesters. Of 53,823 drinks reported, 98% had all items necessary for standard drink computation. Sharing was reported for 74% of drinks in Cape Town, South Africa and for 10% in the Northern Plains. Compared to referent values from the traditional TLFB, 74% and 67% of drinks had different alcohol-by-volume and container size, respectively. Furthermore, a statistically significant difference was found between the number of containers reported and the number of standard drinks computed, using information from the modified TLFB. This is the first study of this size to wholly encompass all of these changes into a single measure in order to more accurately calculate daily consumption and assess patterns over time. The methods used to collect PAE information and create alcohol exposure measures likely increased the accuracy of standard drinks reported and could be generalized to other populations.

Drinking and smoking patterns during pregnancy: Development of group-based trajectories in the Safe Passage Study.

Precise identification of drinking and smoking patterns during pregnancy is crucial to better understand the risk to the fetus. The purpose of this manuscript is to describe the methodological approach used to define prenatal drinking and smoking trajectories from a large prospective pregnancy cohort, and to describe maternal characteristics associated with different exposure patterns. In the Safe Passage Study, detailed information regarding quantity, frequency, and timing of exposure was self-reported up to four times during pregnancy and at 1 month post-delivery. Exposure trajectories were developed using data from 11,692 pregnancies (9912 women) where pregnancy outcome was known. Women were from three diverse populations: white (23%) and American Indian (17%) in the Northern Plains, US, and mixed ancestry (59%) in South Africa (other/not specified [1%]). Group-based trajectory modeling was used to identify 5 unique drinking trajectories (1 none/minimal, 2 quitting groups, 2 continuous groups) and 7 smoking trajectories (1 none/minimal, 2 quitting groups, 4 continuous groups). Women with pregnancies assigned to the low- or high-continuous drinking groups were less likely to have completed high school and were more likely to have enrolled in the study in the third trimester, be of mixed ancestry, or be depressed than those assigned to the none/minimal or quit-drinking groups. Results were similar when comparing continuous smokers to none/minimal and quit-smoking groups. Further, women classified as high- or low-continuous drinkers were more likely to smoke at moderate-, high-, and very high-continuous levels, as compared to women classified as non-drinkers and quitters. This is the first study of this size to utilize group-based trajectory modeling to identify unique prenatal drinking and smoking trajectories. These trajectories will be used in future analyses to determine which specific exposure patterns subsequently manifest as poor peri- and postnatal outcomes.

Cardiorespiratory physiology in the safe passage study: protocol, methods and normative values in unexposed infants.

AIM: The Safe Passage Study, conducted by the Prenatal Alcohol in SIDS and Stillbirth Network, is investigating contributions of prenatal alcohol exposure to foetal and infant demise. This current report presents physiological data from full-term infants with no prenatal exposure to alcohol or maternal smoking. METHODS: Data are from 666 infants from the Northern Plains (North and South Dakota) and South Africa. A standardised protocol assessed cardiorespiratory function during baseline and head-up tilts shortly after birth and at one month of age. RESULTS: Analyses revealed significant increases in heart rate and decreases in BP from the newborn to one-month time period as well as diminished heart rate responses to head-up tilt in one-month-old infants. CONCLUSION: The Safe Passage Study was successful in characterising physiology in a large number of infants at sites known to have elevated risks for SIDS. Results demonstrate that even with low prenatal adverse exposures, there are significant changes in cardiorespiratory function as infants enter the window of increased risk for SIDS.