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

      research-article
      , MD 1 , , PhD 2 , 3 , 4 , , , PhD 5 , 6 , , PhD 7 , , PhD 3 , , MA 2 , 4 , , MD 1 , , PhD 8 , 9 , , PhD 8 , 9 , , MPH 5 , 6 , , MD 10 , , PhD 6 , , BS 10 , , MD 10 , , MD 11 , , PhD 10 , , MA 12 , , BS 10 , , PhD 2 , 13 , , PhD 8 , , MD 14 , , MD 15 , , MPH 2 , 16 , , MD, PhD 17 , , MD 18 , , MD 19 , , MD 20 , , MD 10
      JAMA Network Open
      American Medical Association

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          Key Points

          Question

          Is prenatal exposure to maternal drinking and smoking associated with the risk of stillbirth?

          Findings

          In this cohort study of 8506 pregnant women (with 11 892 pregnancies) in Cape Town, South Africa, and the Northern Plains in the US, dual exposure to drinking and smoking after the first trimester of pregnancy had 2.78 times the risk of late stillbirth compared with those with no exposure or who had quit before the end of the first trimester of pregnancy.

          Meaning

          These findings suggest that dual exposure to drinking and smoking after the first trimester of pregnancy is associated with nearly 3 times the risk of late stillbirth.

          Abstract

          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.

          Abstract

          This cohort study assesses whether prenatal exposure to alcohol, tobacco cigarettes, or both is associated with the risk of stillbirth in pregnant women from Cape Town, South Africa, and the Northern Plains region of the US.

          Related collections

          Most cited references28

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          National, regional, and worldwide estimates of stillbirth rates in 2015, with trends from 2000: a systematic analysis

          Previous estimates have highlighted a large global burden of stillbirths, with an absence of reliable data from regions where most stillbirths occur. The Every Newborn Action Plan (ENAP) targets national stillbirth rates (SBRs) of 12 or fewer stillbirths per 1000 births by 2030. We estimate SBRs and numbers for 195 countries, including trends from 2000 to 2015.
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            Maternal smoking and the risk of still birth: systematic review and meta-analysis

            Background Smoking in pregnancy is known to be associated with a range of adverse pregnancy outcomes, yet there is a high prevalence of smoking among pregnant women in many countries, and it remains a major public health concern. We have conducted a systematic review and meta-analysis to provide contemporary estimates of the association between maternal smoking in pregnancy and the risk of stillbirth. Methods We searched four databases namely MEDLINE, EMBASE, Psych Info and Web of Science for all relevant original studies published until 31st December 2012. We included observational studies that measured the association between maternal smoking during pregnancy and the risk of stillbirth. Results 1766 studies were screened for title analysis, of which 34 papers (21 cohorts, 8 case controls and 5 cross sectional studies) met the inclusion criteria. In meta-analysis smoking during pregnancy was significantly associated with a 47% increase in the odds of stillbirth (OR 1.47, 95% CI 1.37, 1.57, p < 0.0001). In subgroup analysis, smoking 1-9 cig/day and ≥10 cig/day was associated with an 9% and 52% increase in the odds of stillbirth respectively. Subsequently, studies defining stillbirth at ≥ 20 weeks demonstrated a 43% increase in odds for smoking mothers compared to mothers who do not smoke, (OR 1.43, 95% CI 1.32, 1.54, p < 0.0001), whereas studies with stillbirth defined at ≥ 24 weeks and ≥ 28 weeks showed 58% and 33% increase in the odds of stillbirth respectively. Conclusion Our review confirms a dose-response effect of maternal smoking in pregnancy on risk of stillbirth. To minimise the risk of stillbirth, reducing current smoking prevalence in pregnancy should continue to be a key public health high priority. Electronic supplementary material The online version of this article (doi:10.1186/s12889-015-1552-5) contains supplementary material, which is available to authorized users.
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              Fetal and Perinatal Mortality: United States, 2013.

              This report presents 2013 fetal and perinatal mortality data by maternal age, marital status, race, Hispanic origin, and state of residence, as well as by fetal birthweight, gestational age, plurality, and sex. Trends in fetal and perinatal mortality are also examined.
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                Author and article information

                Journal
                JAMA Netw Open
                JAMA Netw Open
                JAMA Netw Open
                JAMA Network Open
                American Medical Association
                2574-3805
                23 August 2021
                August 2021
                23 August 2021
                : 4
                : 8
                : e2121726
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
                [2 ]DM-STAT Inc, Malden, Massachusetts
                [3 ]Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
                [4 ]Biostatistics and Epidemiology Data Analys Center, Boston University School of Public Health, Boston, Massachusetts
                [5 ]Center for Pediatric & Community Research, Avera Research Institute, Sioux Falls, South Dakota
                [6 ]Department of Pediatrics, University of South Dakota School of Medicine, Sioux Falls
                [7 ]Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland
                [8 ]Department of Psychiatry, Columbia University Medical Center, New York State Psychiatric Institute, New York
                [9 ]Department of Pediatrics, Columbia University Medical Center, New York State Psychiatric Institute, New York
                [10 ]Department of Pathology, Boston Children’s Hospital, Harvard School of Medicine, Boston, Massachusetts
                [11 ]Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston
                [12 ]Epidemiology and Statistics Program, National Institute on Deafness and Other Communication Disorders, Bethesda, Maryland
                [13 ]Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
                [14 ]Department of Pathology, University of South Dakota School of Medicine, Sioux Falls
                [15 ]Department of Pathology, Massachusetts General Hospital, Boston
                [16 ]PPD, Wilmington, North Carolina
                [17 ]Department of Pathology, University of North Dakota, School of Medicine and Health Sciences, Grand Forks
                [18 ]Department of Obstetrics and Gynecology, School of Medicine, University of North Dakota, Fargo
                [19 ]Department of Pathology, Faculty of Medicine and Health Science, Stellenbosch University, Cape Town, South Africa
                [20 ]Department of Pediatrics, Division of Genetics & Genomics, Manton Center for Orphan Diseases Research, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
                Author notes
                Article Information
                Accepted for Publication: June 21, 2021.
                Published: August 23, 2021. doi:10.1001/jamanetworkopen.2021.21726
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Odendaal H et al. JAMA Network Open.
                Corresponding Author: Kimberly A. Dukes, PhD, Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, 85 East Newton St, Room M902A, Boston, MA 02118 ( DukesKA@ 123456bu.edu ).
                Author Contributions: Drs Odendaal and Dukes are co–first authors. Dr Dukes had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Odendaal, Dukes, Elliott, Willinger, Myers, Fifer, Burd, Folkerth, Hankins, Haynes, Hoffman, Sens, Kinney.
                Acquisition, analysis, or interpretation of data: All authors.
                Drafting of the manuscript: Odendaal, Dukes, Willinger, Fifer, Cotton, Hankins, Jacobs, Pini.
                Critical revision of the manuscript for important intellectual content: Odendaal, Dukes, Elliott, Willinger, Sullivan, Tripp, Groenewald, Myers, Fifer, Angal, Boyd, Burd, Folkerth, Haynes, Hoffman, Petersen, Pini, Randall, Roberts, Robinson, Sens, Van Eerden, Wright, Holm, Kinney.
                Statistical analysis: Dukes, Sullivan, Tripp, Hoffman, Petersen, Pini, Robinson.
                Obtained funding: Odendaal, Dukes, Elliott, Myers, Fifer, Burd, Hoffman, Kinney.
                Administrative, technical, or material support: Odendaal, Dukes, Elliott, Willinger, Groenewald, Angal, Burd, Cotton, Folkerth, Hankins, Haynes, Hoffman, Petersen, Pini, Randall, Sens, Van Eerden, Wright, Kinney.
                Supervision: Odendaal, Dukes, Elliott, Fifer, Angal, Hankins, Petersen.
                Conflict of Interest Disclosures: Dr Elliott reported receiving grants from Avera Research Institute during the conduct of the study. Ms Angal reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Haynes reported receiving grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) during the conduct of the study. Dr Petersen reported receiving grants from the NICHD, National Institute on Alcohol Abuse and Alcoholism, and National Institute on Deafness and Other Communication Disorders during the conduct of the study. Dr Roberts reported receiving royalties from UpToDate as an author on placental pathology topics and from Cambridge University Press as an author and editor on a perinatology pathology textbook outside the submitted work. Dr Sens reported receiving grants from the Centers for Disease Control and Prevention outside the submitted work. No other disclosures were reported.
                Funding/Support: The research reported in this publication was supported by grants U01HD055154, U01HD045935, U01HD055155, U01HD045991, and U01AA016501 from the National Institutes of Health funded by the National Institute on Alcohol Abuse and Alcoholism, NICHD, and the National Institute on Deafness and Other Communication Disorders.
                Role of the Funder/Sponsor: These funding sources were involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
                Nonauthor Collaborators: The Prenatal Alcohol in SIDS and Stillbirth (PASS) Network members appear in Supplement 2.
                Additional Contributions: The following individuals were compensated (unless otherwise stated) under the grant awards provided above and made significant contributions to the research and warrant recognition. Data Coordinating & Analysis Center (DM-STAT Inc): Study Conduct, Collection, and Management of Data: Travis Baker, BS, DM-STAT; Rebecca A. Young, MPH, DM-STAT; Idania Ramirez, MPH, Kaiser Permanente; Laura Spurchise, MPH, Quintiles Inc; Derek Petersen, BS, Shire; Gregory Toland, MS, consultant; Michael Carmen, MS, consultant. Preliminary Statistical Analyses and Interim Statistical Reporting: Cheri Raffo, MPH, DM-STAT; Cindy Mai, BA, Atlantic Research Group; Jamie Collins, PhD, Brigham and Women’s Hospital. Editorial Assistance: Patti Folan, DM-STAT. Developmental Biology & Pathology Center (Children’s Hospital Boston): Preliminary Study Design: Ingrid A. Holm, MD, Boston Children’s Hospital; David S. Paterson, PhD, Biogen; Richard A. Belliveau, BA, Broad Institute. Data Interpretation: Richard D. Goldstein, MD, Boston Children’s Hospital. Study Conduct, Collection, and Management of Data: Kevin G. Broadbelt, PhD, Simmons College; Kyriacos Markianos, PhD, Boston Children’s Hospital; Hanno Steen, PhD, Boston Children’s Hospital; Hoa Tran, PhD, FNP, South Shore Health Care; Kristin Rivera, DO, MS, Northwell Health, Pine Manor College; Megan Minter, MS, Duke Medical School; Claire F. Maggiotto, BS, University of Buffalo, School of Medicine; Kathryn Schissler, DO, Nicklaus Children’s Hospital, Florida. Comprehensive Clinical Site Northern Plains (Sanford Research): Site Management: Whitney Adler, BA, New Horizon Farms; Elizabeth Berg, RN, University of North Dakota FAS Center and Mercy Hospital; Christa Friedrich, MS, Sanford Research; Jessica Gromer, RN, John T. Vucurevich Foundation; Margaret Jackson, BA (retired); Luke Mack, MA, Avera Health; Bethany Norton, MA, Phoenix Children’s Hospital; Liz Swenson, RN, University of North Dakota FAS Center & Mercy Hospital; Deborah Tobacco, MA, Sanford Research; Amy Willman, BS, RN, Sanford Research. Participant Recruitment & Data Collection: Deana Around Him, PhD, National Congress of American Indians; Lisa Bear Robe; Mary Berdahl, RN, BA; Donna Black, AA, University of North Dakota FAS Center; Jocelyn Bratton, BS, RDMS, Sanford Health; Chaleen Brewer, BS; Melissa Berry, RD; Cathy Christophersen, MA (retired); Sue Cote, LPN, University of North Dakota FAS Center; Kari Daron; Alexandra Draisey, BSN, RN, Regional Health; Sara Fiedler, MS; Kathy Harris, RN, BSN (retired); Lyn Haug, RN, BSN, RNC-EFM, Rapid City Regional; Lynn Heath, BS, RDMS, Sanford Health; Ann Henkin, MS (retired); Tara Herman, RDMS, Sanford Health; Jessica Holsworth, BS, Sanford Research; Kimberly Lucia, MS; Laura Medler, RN, Rapid City Regional; Libby Nail, MD, University of Minnesota; Amber Ogaard, BS; Debby Olson, JD (retired); Mary Reiner, BA, CCRP (deceased); Carol Robinson, RN, Sanford Research; Brooke Schmitt, BSN, RN, Sanford Research; Beth Shearer, MS; Monique Sioux Bob, RN, Sioux San Hospital; Lacey Stawarski, MD, Mille Lacs Band of Ojibwe; Sherri Ten Fingers, RN, Pine Ridge Indian Health Service; Rachel Thies, MD, Creighton University; Mary Thum, MS, Mayo Clinic Rochester; Elizabeth Wheeler, MPH, Sanford Health; Lisa White Bull, MS; Steve White Hat, AAN; Amy Wilson, RN; Neva Zephier, MPH, Great Plains Tribal Chairman’s Health Board; Misti Zubke, BS, RDMS, Sanford Health. Clinical Site Support: Heidi Bittner, MD, Altru Health System–Devil’s Lake and Mercy Hospital (not compensated); Jeffrey Boyle, MD, Sanford Health (not compensated); Donna Gaspar, RN, MA (deceased); Cheryl Hefta, MS, RN, Spirit Lake Early Childhood Tracking; Michael McNamara, MD, Sanford Health (not compensated). Sample Collection and Processing: Karna Colby, MD, Sanford Health; Kent Donelan, MD, Mayo Clinic Rochester; Don Habbe, MD, Clinical Laboratory of the Black Hills (not compensated); Catherine Stoos, MD, Sanford Health. Genetics and Dysmorphology Case Review: H. Eugene Hoyme, MD, Sanford Health; Amy Mroch, MS, Sanford Health. Comprehensive Clinical Site South Africa (Stellenbosch University): Project Management: Erna Carstens, RN, Stellenbosch University. Data Manager: Lucy Brink, MSc, Stellenbosch University. Ultrasonologist and Coinvestigator: Lut Geerts, MD, Stellenbosch University. Geneticist and Coinvestigator: Greetje de Jong, MBChB, MMed, MD, Stellenbosch University. Anatomical Pathologist and Coinvestigator: Pawel Schubert, MD, MMed, Stellenbosch University. Forensic Pathologists and Coinvestigators: Shabbir Wadee, MMed, Stellenbosch University; Johan Dempers, MD, Stellenbosch University; Elsie Burger, MD, MMed Forens Path, Stellenbosch University. Dietician: Janetta Harbron, PhD, Stellenbosch University. Physiology Assessment Center (Columbia University): Project Management: J. David Nugent, MA, Columbia University; Carmen Condon, BA, Columbia University. Data Analysis: Joseph Isler, PhD, Columbia University; Margaret C. Shair, BA, Columbia University; Nicolò Pini, PhD, Columbia University. Audiology Analysis: Yvonne Sininger, PhD, University of California, Los Angeles. National Institutes of Health: Chuan-Ming Li, MD, PhD (National Institute on Deafness and Other Communication Disorders); Caroline Signore, MD, MPH (NICHD); Ken Warren, PhD (National Institute on Alcohol Abuse and Alcoholism); Dale Hereld, PhD (National Institute on Alcohol Abuse and Alcoholism). We gratefully acknowledge the cooperation of the study participants, PASS investigators, and members of the National Institute on Deafness and Other Communication Disorders Advisory and Safety Monitoring Board: Elizabeth Thom, PhD (chair), George Washington University; The Reverend Phillip Cato, PhD, Duke University; James W. Collins Jr, MD, MPH, Northwestern University; Terry Dwyer, MD, MPH, University of Oxford; George Macones, MD, Washington University; Philip A. May, PhD, University of North Carolina at Chapel Hill; Richard M. Pauli, MD, PhD, University of Wisconsin, Madison; Raymond W. Redline, MD, University Hospitals Case Medical Center; and Michael Varner, MD, University of Utah Health Sciences Center.
                Article
                zoi210643
                10.1001/jamanetworkopen.2021.21726
                8383134
                34424306
                71ecfff4-0bf0-403b-8cbb-06468deb72a7
                Copyright 2021 Odendaal H et al. JAMA Network Open.

                This is an open access article distributed under the terms of the CC-BY License.

                History
                : 12 February 2021
                : 9 June 2021
                Categories
                Research
                Original Investigation
                Online Only
                Obstetrics and Gynecology

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