smoking during pregnancy research

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Cigarette Smoking Among Pregnant Women During the Perinatal Period: Prevalence and Health Care Provider Inquiries — Pregnancy Risk Assessment Monitoring System, United States, 2021

Weekly / May 2, 2024 / 73(17);393–398

Lauren Kipling, PhD 1 ; Jennifer Bombard, MSPH 1 ; Xu Wang, PhD 2 ; Shanna Cox, MSPH 1 ( View author affiliations )

What is already known about this topic?

Cigarette smoking has wide-ranging adverse health consequences, and when it occurs during pregnancy, there are increased risks of pregnancy complications and adverse outcomes for infants.

What is added by this report?

In 2021, among women with a recent live birth, 12.1% reported smoking before pregnancy, 5.4% reported smoking during pregnancy, and 7.2% reported smoking during the postpartum period. Smoking behaviors varied by demographic characteristics and jurisdiction. Overall, 73.7%, 93.7%, and 57.3% of women reported being asked about smoking by a health care provider at any health care visit before pregnancy, at any prenatal visit, and at a postpartum checkup, respectively.

What are the implications for public health practice?

Routine assessment of smoking behaviors among pregnant and postpartum women can guide the development and implementation of evidence-based tobacco control measures.

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Cigarette smoking during pregnancy increases the risk for pregnancy complications and adverse infant outcomes such as preterm delivery, restricted fetal growth, and infant death. Health care provider counseling can support smoking cessation. Data from the 2021 Pregnancy Risk Assessment Monitoring System were analyzed to estimate the prevalence of smoking before, during, and after pregnancy; quitting smoking during pregnancy; and whether health care providers asked about cigarette smoking before, during, and after pregnancy among women with a recent live birth. In 2021, the prevalence of cigarette smoking was 12.1% before pregnancy, 5.4% during pregnancy, and 7.2% during the postpartum period; 56.1% of women who smoked before pregnancy quit smoking while pregnant. Jurisdiction-specific prevalences of smoking ranged from 3.5% to 20.2% before pregnancy, 0.4% to 11.0% during pregnancy, and 1.0% to 15.1% during the postpartum period. Among women with a health care visit during the associated period, the percentage of women who reported that a health care provider asked about smoking was 73.7% at any health care visit before pregnancy, 93.7% at any prenatal care visit, and 57.3% at a postpartum checkup. Routine assessment of smoking behaviors among pregnant and postpartum women can guide the development and implementation of evidence-based tobacco control measures at the jurisdiction and health care–system level to reduce smoking among pregnant and postpartum women.

Introduction

Maternal smoking during pregnancy increases the risk for pregnancy complications, including placenta previa, placental abruption, and premature rupture of membranes, and adverse infant outcomes such as cleft lip and palate, infant death, stillbirth, preterm delivery, restricted fetal growth, and sudden infant death syndrome (SIDS) ( 1 ). Smoking before pregnancy can impair fertility, and smoking after pregnancy increases the risk for SIDS and childhood respiratory infections ( 1 ). Jurisdictions can implement evidence-based strategies to reduce smoking, including among women of reproductive age ( 2 ). The U.S. Preventive Services Task Force (USPSTF) recommends that health care providers ask all adults, including pregnant women, about tobacco use, advise them to quit, and provide support for tobacco cessation interventions ( 3 ). This report assesses jurisdiction-level prevalence of cigarette smoking before, during, and after pregnancy, and whether health care providers asked about cigarette use at health care visits before, during, and after pregnancy.

Data Source

The Pregnancy Risk Assessment Monitoring System (PRAMS) is a population-based, jurisdiction-specific surveillance system that collects information on self-reported behaviors and experiences before, during, and after pregnancy among women with a recent live birth.* Women are surveyed by U.S. mail or by telephone 2–6 months after delivery ( 4 ). Maternal age, race and ethnicity, and education were obtained from the birth certificate. Health insurance coverage and history of depression before pregnancy were derived from the PRAMS questionnaire. †

Descriptive and Statistical Analyses

The analysis includes 36,493 women (1,854,527 weighted) from 37 jurisdictions § with a ≥50% response rate during 2021. This report presents data on measures of the following smoking behaviors before, during, and after pregnancy: 1) smoking during the 3 months before pregnancy, 2) smoking during the last 3 months of pregnancy, 3) quitting smoking during the last 3 months of pregnancy among women who smoked during the 3 months before pregnancy, and 4) smoking during the postpartum period (assessed at the time of questionnaire completion). ¶ , ** Respondents with health care visits during the associated period (any health care visit during the 12 months before pregnancy, any prenatal care visit, and a postpartum checkup) reported whether a health care provider asked about cigarette smoking. †† , §§

Prevalence of smoking behaviors and whether a health care provider asked about cigarette use were estimated by jurisdiction and demographic characteristics. All analyses were conducted using SAS  software (version 9.4;  SAS  Institute). PRAMS data are weighted at the jurisdiction level; prevalence estimates and 95% CIs were calculated, and nonoverlapping CIs were considered statistically significant. ¶¶ This study was reviewed and approved by the Institutional Review Boards at CDC and each participating PRAMS site.***

Characteristics of Respondents and Smoking Behaviors

During 2021, 12.1% of surveyed women with a recent live birth reported smoking cigarettes during the 3 months before pregnancy, 5.4% smoked during the last 3 months of pregnancy, and 7.2% smoked during the postpartum period ( Table 1 ). Among women who smoked during the 3 months before pregnancy, 56.1% quit smoking during pregnancy. The prevalence of smoking before pregnancy ranged from 3.5% in Puerto Rico to 20.2% in West Virginia; during pregnancy, from 0.4% in Puerto Rico to 11.0% in Maine; and during the postpartum period, from 1.0% in Puerto Rico to 15.1% in West Virginia. The prevalence of quitting smoking during pregnancy ranged from 35.9% in Wyoming to 87.9% in Puerto Rico. The following groups of women reported higher prevalences of smoking during pregnancy: non-Hispanic American Indian or Alaska Native (AI/AN) women, those who were Medicaid-insured for prenatal care, those who had completed ≤12 years of education, and those with a history of depression before pregnancy ( Table 2 ).

Health Care Provider Asking About Smoking

Among women with a health care visit during the associated period, 73.7% reported that a health care provider asked about current cigarette smoking at a health care visit during the 12 months before pregnancy, 93.7% reported that a health care provider asked about cigarette smoking at any prenatal care visit, and 57.3% reported that a health care provider asked about cigarette smoking at a postpartum checkup ( Table 3 ). The percentage of women who were asked about cigarette smoking by a health care provider at a postpartum checkup was lower in the following groups: women aged ≥35 years, those who had completed >12 years of education, those without a history of depression, and those who did not smoke before pregnancy.

This analysis found that during 2021, one in 18 women with a recent live birth smoked during pregnancy, with wide variation by jurisdiction (range = 0.4%–11.0%). Although 56.1% of women who smoked before pregnancy quit during pregnancy, approximately one in 13 smoked during the postpartum period. USPSTF recommends that health care providers ask all adult patients about tobacco use, including pregnant and postpartum women ( 3 ). However, although 93.7% of women reported being asked about cigarette smoking during a prenatal care visit, only 57.3% reported being asked about cigarette smoking at a postpartum checkup. In addition, only 69.7% of women who reported smoking before pregnancy were asked about cigarette smoking during the postpartum period. Assessment of tobacco use by health care providers is an important first step in improving quitting success, affording an opportunity to follow up with patients about their readiness to quit and to provide access to cessation resources ( 3 ). Guidance for the comprehensive postpartum visit includes screening for tobacco use, with counseling regarding relapse during the postpartum period among women who quit smoking during pregnancy ( 5 ).

Both behavioral and pharmacological interventions are effective methods to increase smoking cessation ( 3 ). For nonpregnant adults, smoking cessation medications approved by the Food and Drug Administration can improve the likelihood of successfully quitting smoking and result in higher rates of quitting when used in combination with behavioral cessation counseling; however, these medications are not recommended during pregnancy because of insufficient evidence that nicotine replacement therapy does not affect birth outcomes ( 3 ). Insurance coverage for comprehensive and barrier-free smoking cessation counseling and treatments is cost-effective. ††† Beginning in 2010, Medicaid programs were required to cover tobacco cessation services for pregnant women without cost sharing ( 6 ). Health care providers can also refer persons who smoke to toll-free national Quitline telephone numbers §§§ to link patients to telephone-based cessation resources. In addition to health care–related strategies, effective tobacco control measures at the population level, such as tobacco taxes, public health campaigns, and smoke-free policies, support smoking cessation among adults ( 2 ). Studies have demonstrated the benefits of strategies such as public health campaigns ( 7 ) and Quitlines ( 8 ) among pregnant women.

The prevalence of smoking during the perinatal period has decreased. Analyses using PRAMS data have demonstrated a decreased prevalence of smoking before, during, and after pregnancy, as well as an increase in quitting during pregnancy, from 2000 to 2020 ( 9 ). Estimates of smoking during pregnancy from PRAMS differ from other data sources; however, methods also differ. According to the 2020 National Survey on Drug Use and Health, 8.4% of pregnant women used tobacco products. ¶¶¶ Based on 2021 birth certificate data, 4.6% of women who gave birth in the United States smoked during pregnancy.**** Similar to the current report, the National Center for Health Statistics report found the prevalence of smoking during pregnancy was higher among younger age groups and AI/AN women, with variation by jurisdiction. New York City and Puerto Rico were the only PRAMS jurisdictions that met the Healthy People 2020 goal of reducing prenatal smoking to 1.4%. ††††

Comprehensive tobacco control measures at the state and jurisdiction level have been demonstrated to reduce smoking at the population level ( 2 ). For example, in jurisdictions with low levels of prenatal smoking (New York City and Puerto Rico), cigarette excise taxes were above $4 per pack and comprehensive smoke-free indoor air legislation had been enacted jurisdiction-wide. §§§§ In contrast, among PRAMS jurisdictions with the highest levels of prenatal smoking (Maine, West Virginia, and Wyoming), cigarette excise taxes were ≤$2 per pack. West Virginia and Wyoming had no statewide comprehensive smoke-free indoor air legislation.

Limitations

The findings in this report are subject to at least six limitations. First, women might underreport socially undesirable behaviors such as smoking during pregnancy or overreport socially desirable behaviors such as quitting smoking during pregnancy. Second, because PRAMS responses are obtained 2–6 months postpartum, they might be affected by recall bias. Third, smoking prevalences in this report did not include other types of tobacco use, such as electronic vapor products, which likely results in an underestimate of the prevalence of tobacco use ( 10 ). Fourth, the reported prevalence of smoking during pregnancy was limited to the timeframe of the last 3 months of pregnancy and did not capture smoking during other periods in pregnancy. Fifth, only women who attended a health care visit could be queried by their provider regarding their smoking status. Finally, the generalizability of the findings of this report is limited to PRAMS jurisdictions included in this analysis.

Implications for Public Health Practice

Routine assessment of smoking behaviors among pregnant and postpartum women can guide the development and implementation of evidence-based tobacco control measures at the jurisdiction and health care–system level to reduce smoking. ¶¶¶¶ Health care providers can increase their efforts to assess smoking status among all adults, including pregnant and postpartum women, provide cessation counseling and medication when appropriate, refer women for more intensive cessation counseling, and promote available cessation services. Jurisdictions can support evidence-based tobacco control measures to reduce smoking among pregnant and postpartum women.

Acknowledgments

Pregnancy Risk Assessment Monitoring System (PRAMS) Working Group, PRAMS Team, Division of Reproductive Health, CDC; PRAMS Alabama, PRAMS Arkansas, PRAMS Colorado, PRAMS Connecticut, PRAMS Delaware, PRAMS District of Columbia, PRAMS Georgia, PRAMS Hawaii, PRAMS Illinois, PRAMS Kansas, PRAMS Louisiana, PRAMS Maine, PRAMS Massachusetts, PRAMS Michigan, PRAMS Minnesota, PRAMS Mississippi, PRAMS Missouri, PRAMS Montana, PRAMS Nebraska, PRAMS New Jersey, PRAMS New Mexico, PRAMS New York, PRAMS New York City, PRAMS North Dakota, PRAMS Oklahoma, PRAMS Oregon, PRAMS Pennsylvania, PRAMS Puerto Rico, PRAMS South Dakota, PRAMS Tennessee, PRAMS Utah, PRAMS Vermont, PRAMS Virginia, PRAMS Washington, PRAMS West Virginia, PRAMS Wisconsin, PRAMS Wyoming.

Corresponding author: Shanna Cox, [email protected] .

1 Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC; 2 Office on Smoking and Health, National Center for Chronic Disease Prevention and Health Promotion, CDC.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

* Not all pregnant persons identify as women. “Women” is used in this report because PRAMS data are sampled from birth certificates of women with a recent live birth.

† Health insurance coverage was defined from women’s reported coverage during prenatal care.

§ Alabama, Arkansas, Colorado, Connecticut, Delaware, District of Columbia, Georgia, Hawaii, Illinois, Kansas, Louisiana, Maine, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska, New Jersey, New Mexico, New York, New York City, North Dakota, Oklahoma, Oregon, Pennsylvania, Puerto Rico, South Dakota, Tennessee, Utah, Vermont, Virginia, Washington, West Virginia, Wisconsin, and Wyoming.

¶ PRAMS questions used to calculate cigarette smoking behavior measures included 1) “In the 3 months before you got pregnant, how many cigarettes did you smoke on an average day?”; 2) “In the last 3 months of your pregnancy, how many cigarettes did you smoke on an average day?”; and 3) “How many cigarettes do you smoke on an average day now?” Based on responses to these questions (e.g., “at least one cigarette per day on an average day”), dichotomous variables were created to define any cigarette smoking before pregnancy, during pregnancy, and during the postpartum period. Data on smoking during other time points in pregnancy are not collected.

** https://www.cdc.gov/prams/questionnaire.htm

†† PRAMS questions used to calculate health care providers asking about cigarette smoking included 1) “During any of your health care visits in the 12 months before you got pregnant, did a doctor, nurse, or other health care worker ask you if you were smoking cigarettes?”; 2) “During any of your prenatal care visits, did a doctor, nurse, or other health care worker ask you if you were smoking cigarettes?”; and 3) “During your postpartum checkup, did a doctor, nurse, or other health care worker ask you if you were smoking cigarettes?” Women could have had more than one health care visit during the postpartum period.

§§ Among women with a recent live birth, 33% did not have a health care visit during the 12 months before pregnancy, 1% did not attend prenatal care visits, and 9% did not have a postpartum care visit. Percentages are reported among those who attended a visit during the relevant period and provided a response to the question about a health care provider asking about cigarette use.

¶¶ Each participating jurisdiction selects a monthly stratified sample of women from birth certificate records. Data were weighted to adjust for noncoverage and nonresponse and to represent the total population of women with a live birth in each jurisdiction in 2021. PRAMS aggregate data are not weighted to provide national estimates. The analyses were conducted using survey analysis procedures to account for the complex sampling design of PRAMS.

*** 45 C.F.R. part 46, 21 C.F.R. part 56.

††† Barrier-free refers to health insurance coverage that removes or reduces barriers to accessing cessation treatments (e.g., copayments, coinsurance, deductibles, and prior authorization). https://archive.cdc.gov/#/details?url=https://www.cdc.gov/tobacco/quit_smoking/cessation/coverage/index.htm

§§§ https://www.cdc.gov/tobacco/campaign/tips/quit-smoking/index.html

¶¶¶ https://www.samhsa.gov/data/sites/default/files/reports/slides-2020-nsduh/2020NSDUHWomenSlides072522.pdf

**** https://www.cdc.gov/nchs/data/databriefs/db458.pdf

†††† https://wayback.archive-it.org/5774/20220415223525/https://www.healthypeople.gov/2020/topics-objectives/objective/mich-113

§§§§ https://www.cdc.gov/statesystem/statehighlights.html

¶¶¶¶ https://www.hhs.gov/sites/default/files/hhs-framework-support-accelerate-smoking-cessation-2024.pdf

• US Department of Health and Human Services. The health consequences of smoking—50 years of progress: a report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, CDC; 2014. https://www.ncbi.nlm.nih.gov/books/NBK179276/pdf/Bookshelf_NBK179276.pdf
• CDC. Best practices for comprehensive tobacco control programs. Atlanta, GA: US Department of Health and Human Services, CDC; 2014. https://www.cdc.gov/tobacco/stateandcommunity/guides/pdfs/2014/comprehensive.pdf
• Krist AH, Davidson KW, Mangione CM, et al.; US Preventive Services Task Force. Interventions for tobacco smoking cessation in adults, including pregnant persons: US Preventive Services Task Force Recommendation Statement. JAMA 2021;325:265–79. https://doi.org/10.1001/jama.2020.25019 PMID:33464343
• Shulman HB, D’Angelo DV, Harrison L, Smith RA, Warner L. The Pregnancy Risk Assessment Monitoring System (PRAMS): overview of design and methodology. Am J Public Health 2018;108:1305–13. https://doi.org/10.2105/AJPH.2018.304563 PMID:30138070
• American College of Obstetricians and Gynecologists. ACOG committee opinion no. 736: optimizing postpartum care. Obstet Gynecol 2018;131:e140–50. https://doi.org/10.1097/AOG.0000000000002633 PMID:29683911
• McMenamin SB, Halpin HA, Ganiats TG. Medicaid coverage of tobacco-dependence treatment for pregnant women: impact of the Affordable Care Act. Am J Prev Med 2012;43:e27–9. https://doi.org/10.1016/j.amepre.2012.06.012 PMID:22992368
• England L, Tong VT, Rockhill K, et al. Evaluation of a federally funded mass media campaign and smoking cessation in pregnant women: a population-based study in three states. BMJ Open 2017;7:e016826. https://doi.org/10.1136/bmjopen-2017-016826 PMID:29259054
• Cummins SE, Tedeschi GJ, Anderson CM, Zhu SH. Telephone intervention for pregnant smokers: a randomized controlled trial. Am J Prev Med 2016;51:318–26. https://doi.org/10.1016/j.amepre.2016.02.022 PMID:27056131
• Zaganjor I, Kramer RD, Kofie JN, Sawdey MD, Cullen KA. Trends in smoking before, during, and after pregnancy in the United States from 2000 to 2020: Pregnancy Risk Assessment Monitoring System. J Womens Health (Larchmt) 2024;33:283–93. https://doi.org/10.1089/jwh.2023.0641 PMID:38153374
• Kapaya M, D’Angelo DV, Tong VT, et al. Use of electronic vapor products before, during, and after pregnancy among women with a recent live birth—Oklahoma and Texas, 2015. MMWR Morb Mortal Wkly Rep 2019;68:189–94. https://doi.org/10.15585/mmwr.mm6808a1 PMID:30817748

Abbreviation: PRAMS = Pregnancy Risk Assessment Monitoring System. * All jurisdictions met the minimum overall response rate threshold of ≥50%. † Defined as any smoking during the 3 months before pregnancy. § Defined as any smoking during the last 3 months of pregnancy. ¶ Defined as no smoking during the last 3 months of pregnancy among women who smoked during the 3 months before pregnancy. ** Defined as any smoking at the time of PRAMS questionnaire administration (approximately 2–6 months after delivery). †† New York data do not include New York City.

Abbreviation: PRAMS = Pregnancy Risk Assessment Monitoring System. * Data were aggregated for the following 37 PRAMS jurisdictions with a response rate of ≥50% during 2021: Alabama, Arkansas, Colorado, Connecticut, Delaware, District of Columbia, Georgia, Hawaii, Illinois, Kansas, Louisiana, Maine, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska, New Jersey, New Mexico, New York, New York City, North Dakota, Oklahoma, Oregon, Pennsylvania, Puerto Rico, South Dakota, Tennessee, Utah, Vermont, Virginia, Washington, West Virginia, Wisconsin, and Wyoming. † Defined as any smoking during the 3 months before pregnancy. § Defined as any smoking during the last 3 months of pregnancy. ¶ Defined as no smoking during the last 3 months of pregnancy among women who smoked during the 3 months before pregnancy. ** Defined as any smoking at the time of PRAMS questionnaire administration (approximately 2–6 months after delivery). †† Persons of Hispanic or Latino (Hispanic) origin might be of any race but are categorized as Hispanic; all racial groups are single-race non-Hispanic unless otherwise specified. Another race or multiple races include those with more than one race or other race. §§ Determined from women’s reported coverage during prenatal care. ¶¶ Other health insurance coverage includes Tricare, other military health insurance, Indian Health Service, or state-specific State Children’s Health Insurance Program or Children’s Health Insurance Program. *** History of depression before pregnancy was defined as depression during the 3 months before pregnancy as reported in PRAMS.

Abbreviation: PRAMS = Pregnancy Risk Assessment Monitoring System. * Data were aggregated for the following 37 PRAMS jurisdictions with a response rate of ≥50% during 2021: Alabama, Arkansas, Colorado, Connecticut, Delaware, District of Columbia, Georgia, Hawaii, Illinois, Kansas, Louisiana, Maine, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska, New Jersey, New Mexico, New York, New York City, North Dakota, Oklahoma, Oregon, Pennsylvania, Puerto Rico, South Dakota, Tennessee, Utah, Vermont, Virginia, Washington, West Virginia, Wisconsin, and Wyoming. † Although 99% of women with a recent live birth attended prenatal care visits, 33% did not have a health care visit during the 12 months before pregnancy and 9% did not have a postpartum care visit. § Among women who reported that they had a health care visit with a doctor, nurse, or other health care worker, including a dental or mental health worker during the 12 months before pregnancy and provided a response to the PRAMS question about a health care provider asking about cigarette use. ¶ Among women who reported a prenatal care visit and provided a response to the PRAMS question about a health care provider asking about cigarette use. ** Among women who reported having had a postpartum checkup and provided a response to the PRAMS question about a health care provider asking about cigarette use. †† Persons of Hispanic or Latino (Hispanic) origin might be of any race but are categorized as Hispanic; all racial groups are single-race non-Hispanic unless otherwise specified. Another race or multiple races include those with more than one race or other race. §§ Determined from women’s reported coverage during prenatal care. ¶¶ Other health insurance coverage includes Tricare, other military health insurance, Indian Health Service, or state-specific State Children’s Health Insurance Program or Children’s Health Insurance Program. *** History of depression before pregnancy was defined as depression during the 3 months before pregnancy as reported in PRAMS. ††† Smoking before pregnancy was defined as any smoking during the 3 months before pregnancy as reported in PRAMS.

Suggested citation for this article: Kipling L, Bombard J, Wang X, Cox S. Cigarette Smoking Among Pregnant Women During the Perinatal Period: Prevalence and Health Care Provider Inquiries — Pregnancy Risk Assessment Monitoring System, United States, 2021. MMWR Morb Mortal Wkly Rep 2024;73:393–398. DOI: http://dx.doi.org/10.15585/mmwr.mm7317a2 .

MMWR and Morbidity and Mortality Weekly Report are service marks of the U.S. Department of Health and Human Services. Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services. References to non-CDC sites on the Internet are provided as a service to MMWR readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of pages found at these sites. URL addresses listed in MMWR were current as of the date of publication.

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Tobacco and Nicotine Cessation During Pregnancy

• Committee Opinion CO
• Number 807
• May 2020

Recommendations and Conclusions

Epidemiology, alternative forms of nicotine delivery, intervention, pharmacotherapy.

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Number 807 (Replaces Committee Opinion Number 721, October 2017. Reaffirmed 2023)

Committee on Obstetric Practice

This Committee Opinion was developed by the American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice in collaboration with committee member Amy M. Valent, DO, and the American Academy of Family Physicians’ liaison member Beth Choby, MD.

ABSTRACT: Pregnant women should be advised of the significant perinatal risks associated with tobacco use, including orofacial clefts, fetal growth restriction, placenta previa, abruptio placentae, preterm prelabor rupture of membranes, low birth weight, increased perinatal mortality, ectopic pregnancy, and decreased maternal thyroid function. Children born to women who smoke during pregnancy are at an increased risk of respiratory infections, asthma, infantile colic, bone fractures, and childhood obesity. Pregnancy influences many women to stop smoking, and approximately 54% of women who smoke before pregnancy quit smoking directly before or during pregnancy. Smoking cessation at any point in gestation benefits the pregnant woman and her fetus. The greatest benefit is observed with cessation before 15 weeks of gestation. Although cigarettes are the most commonly used tobacco product in pregnancy, alternative forms of tobacco use, such as e-cigarettes or vaping products, hookahs, and cigars, are increasingly common. Clinicians should advise cessation of tobacco products used in any form and provide motivational feedback. Although counseling and pregnancy-specific materials are effective cessation aids for many pregnant women, some women continue to use tobacco products. Clinicians should individualize care by offering psychosocial, behavioral, and pharmacotherapy interventions. Available cessation-aid services and resources, including digital resources, should be discussed and documented regularly at prenatal and postpartum follow-up visits.

Obstetrician–gynecologists and other obstetric care professionals should inquire about all types of tobacco or nicotine use, including cigarette smoking, use of e-cigarettes or vaping products, hookahs, snus, lozenges, patches, and gum, during the prepregnancy, pregnancy, and postpartum periods. Health care professionals should be aware that patients may not intuitively equate alternative forms of nicotine use (ie, e-cigarettes and vaping products) with tobacco use. Further, health care professionals should advise cessation of tobacco products used in any form and provide motivational feedback.

Pregnant women should be advised of the significant perinatal risks associated with tobacco use, including orofacial clefts, fetal growth restriction, placenta previa, abruptio placentae, preterm prelabor rupture of membranes, low birth weight, increased perinatal mortality, ectopic pregnancy, and decreased maternal thyroid function.

Screening and intervention for alcohol and other drug use are recommended for all pregnant women. Because smoking continuation during pregnancy is associated with the likelihood of other substance use, screening for alcohol and other substance use is an important component of care.

Clinicians should individualize care by offering psychosocial, behavioral, and pharmacotherapy interventions. Available cessation-aid services and resources, including digital resources, should be discussed and documented regularly at prenatal and postpartum follow-up visits.

Providing continual support and addressing psychosocial stressors in the postpartum period are necessary to ensure continued cessation success.

Increased community education measures and public health campaigns in the United States have led to a decrease in smoking among pregnant women and women in the postpartum period 1 . Pregnancy influences many women to stop smoking, and approximately 54% of women who smoke before pregnancy quit smoking directly before or during pregnancy 1 . Although reported rates of tobacco smoking during pregnancy in the United States decreased from 13.2% in 2006 to 7.2% overall in 2016, actual smoking prevalence varies widely by geographic locale, age, education, and race 1 2 3 . Women in certain demographic cohorts are more likely to smoke during pregnancy, including women aged 20–24 years (10.7%), women with a high school education or less (12.2% and 11.7%, respectively), and non-Hispanic American Indian or Alaska Native women (16.7%) 3 4 .

Pregnant women should be advised of the significant perinatal risks associated with tobacco use, including orofacial clefts, fetal growth restriction, placenta previa, abruptio placentae, preterm prelabor rupture of membranes 5 6 , low birth weight, increased perinatal mortality 7 , ectopic pregnancy 7 , and decreased maternal thyroid function 7 8 . An estimated 5–8% of preterm deliveries, 13–19% of term infants with low birth weight, 22–34% cases of sudden infant death syndrome, and 5–7% of preterm-related infant deaths have been attributed to prenatal maternal smoking 9 10 . In addition, secondhand prenatal exposure to tobacco smoke is associated with as much as a 20% increase in risk of a low birth weight infant 11 .

The risks of smoking during pregnancy extend beyond pregnancy-specific complications. Children born to women who smoke during pregnancy are at an increased risk of respiratory infections, asthma, infantile colic, bone fractures, and childhood obesity 12 13 14 15 16 . Researchers also have reported that infants born to women who use smokeless tobacco during pregnancy have increased levels of nicotine exposure and rates of low birth weight, shortened gestational age, stillbirth, and neonatal apnea that are as high as those in infants born to women who smoked during pregnancy 5 17 18 19 .

Although cigarettes are the most commonly used tobacco product in pregnancy, alternative forms of tobacco use, such as e-cigarettes or vaping products, hookahs, and cigars, are increasingly common 4 Table 1 . Data regarding the health effects of these agents in humans are limited in the general population and in pregnant women specifically. Whereas there is an incorrect perception that vaping represents a safer alternative to cigarette smoking because users are not inhaling tobacco combustion products, these products often contain nicotine or nicotine salts. Even if nicotine is not present in the e-liquid, exposure to flavorants and combustion products from the heating mechanism occurs. Nicotine crosses the placenta and intake in any form has considerable health risks with known adverse effects on fetal brain and lung tissue 20 21 22 . Hookah (water pipe) tobacco smoking is more commonly used by adolescents and young adults because many perceive it to be a safer alternative to conventional cigarettes 23 24 25 . However, users are exposed to nicotine and charcoal briquette combustion products, including carbon monoxide, particulates, oxidants, heavy metals, phenols, and flavorants, through inhaling tobacco smoke from heated coal 24 . Short-term effects may include increased heart rate, increased blood pressure, and impaired pulmonary function, whereas long-term use may increase risk of nicotine dependence, chronic bronchitis, emphysema, and coronary artery disease 23 25 . Although studies of hookah use during pregnancy are lacking, animal data suggest an increased risk for low birth weight, neonatal death, and growth restriction 26 .

Noncombustible products, such as snus, dissolvable tobacco, and electronic nicotine delivery systems (ENDS) (ie, e-cigarettes or vaping products, e-hookahs, mods, and pods), have nicotine-related risks and an increased risk for oral cancer similar to that of chewing tobacco 27 28 29 30 31 . Studies demonstrate an increased risk of altered fetal autonomic cardiac regulation and nicotine withdrawal in neonates born to women who used snus during pregnancy, effects that are similar to those found in women who smoke tobacco 32 33 . Although more research is needed to quantify the perinatal effects with use of these products in pregnancy, the risks of noncombustible product use should be discussed.

Electronic nicotine delivery systems are noncombustible products, which include e-cigarettes and vaping products, vaporizers, hookah pens, vape pens, mod or pod systems, and e-pipes. Health effects from heating liquid flavorants are unknown and likely vary depending on the combination of flavorants and solvents in the products inhaled 34 35 . Carbonyl compounds (formaldehyde, acetaldehyde, acetone, and acrolein); volatile organic compounds (benzene and toluene); nitrosamines; particulate matter; and heavy metals such as copper, lead, zinc, and tin have been isolated from the aerosol 36 . Although much of the data on nicotine-delivery in pregnancy are derived primarily from animal studies, e-cigarettes appear to have similar effects on lung development and offspring lung health when compared with cigarette smoking 22 . Recently, the Centers for Disease Control and Prevention (CDC) issued an advisory notice investigating a multistate outbreak of noninfectious severe pulmonary disease associated with e-cigarette and vaping product use 37 . With the recent CDC advisory and the effects of e-cigarette and vaping product use on offspring health, immediate discontinuation of e-cigarette and vaping products should be advised among all pregnant and postpartum women.

Electronic nicotine delivery systems are used by smokers who commonly believe that they are a safer and healthier alternative to cigarettes that will aid their smoking cessation efforts 38 39 . A survey of pregnant women who smoked found that 14% reported using e-cigarettes to help with smoking cessation 40 . However, nearly two thirds of adults who use e-cigarettes continue smoking cigarettes (known as “dual use”) 41 . Standardization of e-liquid and heating mechanisms is needed to better describe and understand the health effects of these products on pregnant women, fetuses, and offspring and to understand their role, if any, in smoking cessation.

Obstetrician–gynecologists and other obstetric care professionals should inquire about all types of tobacco or nicotine use, including cigarette smoking, use of e-cigarettes or vaping products, hookahs, snus, lozenges, patches, and gum, during the prepregnancy, pregnancy, and postpartum periods. Clinicians should be aware that patients may not intuitively equate alternative forms of nicotine use (ie, e-cigarettes and vaping products) with tobacco use. Further, health care professionals should advise cessation of tobacco products used in any form and provide motivational feedback. Tobacco cessation, avoidance of secondhand smoke exposure, and relapse prevention are key clinical intervention strategies. Inquiry into tobacco use and smoke exposure should be a routine part of the prenatal visit. The U.S. Preventive Services Task Force recommends that clinicians ask all pregnant women about tobacco use, advise tobacco cessation at all gestational ages, and provide behavioral interventions for those who smoke 42 . The U.S. Public Health Service recommends that clinicians offer effective tobacco cessation interventions to pregnant women who smoke at the initial prenatal visit and throughout the course of pregnancy 43 .

Addiction to and dependence on cigarettes is physiologic and psychologic, and cessation techniques should include psychosocial interventions and pharmacologic therapy. Two counseling techniques with positive effects on smoking and nicotine cessation in pregnant women include motivational interviewing and cognitive behavioral therapy. Specific aspects of cognitive behavioral therapy shown to benefit pregnant women include developing a sense of self-monitoring and control, learning to manage cravings, managing situations of stress and anxiety, promoting self-efficacy, and goal setting and action planning 44 . Counseling, financial incentives, and feedback-based interventions such as cognitive behavioral therapy are associated with a reduction in smoking during pregnancy and decreased risk for infants with low birth weight. Intervention context and strategies should be individualized 45 46 . Women who indicate that they are not ready to quit smoking can benefit from consistent motivational approaches provided by their health care professionals as outlined in the American College of Obstetricians and Gynecologists’ Committee Opinion No. 423, Motivational Interviewing 47 .

Identifying patients and individualizing interventions based on a woman’s interest in tobacco cessation begins with a brief counseling session. The 5A’s intervention Box 1 is effective when initiated by health care professionals 43 . With appropriate training, obstetrician–gynecologists, family physicians, other clinicians, or auxiliary health care professionals can perform these five steps with pregnant women who smoke 43 . Referral to a tobacco quit line may further benefit the patient. Quit lines offer information, direct support, and ongoing counseling that help women quit smoking and remain smoke free 48 . Most states offer pregnancy-specific services, focusing on the pregnant woman’s motivation to quit and providing postpartum follow-up to prevent relapse to smoking. When dialing the national quit line network (1-800-QUIT NOW) a caller is immediately routed to her state’s tobacco quit line. Many states offer facsimile referral access to their quit lines for prenatal health care professionals. Health care professionals can call the national quit line to learn about the services offered within their states. Examples of effective smoking cessation interventions delivered by a health care professional are listed in Box 2 . Although counseling and pregnancy-specific materials are effective cessation aids for many pregnant women, some women continue to use tobacco products 42 . These women often are heavily addicted to nicotine and have greater psychosocial challenges. Clinicians should individualize care by offering psychosocial, behavioral, and pharmacotherapy interventions. Available cessation-aid services and resources, including digital resources 49 , should be discussed and documented regularly at prenatal and postpartum follow-up visits 50 . There currently is insufficient evidence to determine the effect of mindfulness 51 , hypnosis 52 , or acupuncture 53 for smoking cessation 43 .

Five A’s of Tobacco and Nicotine Cessation

1. ASK the patient about all types of tobacco or nicotine use* at the first prenatal visit and follow up with her at subsequent visits. The patient should choose the statement that best describes her tobacco or nicotine use status:

A. I have never used tobacco or nicotine or have minimal amounts of tobacco or nicotine in my lifetime (for example, less than 100 cigarettes in my lifetime).

B. I stopped using tobacco or nicotine before I found out I was pregnant, and I am not using tobacco or nicotine now.

C. I stopped using tobacco or nicotine after I found out I was pregnant, and I am not using tobacco or nicotine now.

D. I use some tobacco or nicotine now, but I have cut down on the amount of tobacco or nicotine I use since I found out I was pregnant.

E. I use tobacco or nicotine regularly now, about the same as before I found out I was pregnant.

2. ADVISE the patient who uses tobacco or nicotine to stop by providing advice about quitting with information about the risks of continued tobacco and nicotine use to the woman, fetus, and newborn.

3. ASSESS the patient’s willingness to attempt to quit using tobacco or nicotine at the time. Quitting advice, assessment, and motivational assistance should be offered at subsequent prenatal care visits.

4. ASSIST the patient who is interested in quitting by providing pregnancy-specific, self-help tobacco and nicotine cessation materials. Support the importance of having tobacco and nicotine-free space at home and seeking out a quitting buddy such as a former tobacco or nicotine user. Encourage the patient to talk about the process of quitting. Offer a direct referral to the national tobacco quit line (1-800-QUIT NOW) to provide ongoing counseling and support.

5. ARRANGE follow-up visits to track the progress of the patient’s attempt to quit using tobacco and nicotine. For current and former tobacco and nicotine users, use status should be monitored and recorded throughout pregnancy, providing opportunities to congratulate and support success, reinforce steps taken towards quitting, and encourage those still considering a cessation attempt.

*Includes smoking, and use of e-cigarettes and vaping products, hookahs, snus, lozenges, patches, and gum.

Adapted from Fiore MC, Jaén CR, Baker TB, Bailey WC, Benowitz NL, Curry SJ, et al. Treating tobacco use and dependence: 2008 update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service; 2008. Available at: https://www.ahrq.gov/prevention/guidelines/tobacco/index.html . Retrieved November 7, 2019; and data from (for supplemental information in number 1) Ershoff DH, Mullen PD, Quinn VP. A randomized trial of a serialized self-help smoking cessation program for pregnant women in an HMO. Am J Public Health 1989;79:182–7.

Examples of Effective Tobacco and Nicotine Cessation Interventions for Pregnant Patients

Physician advice regarding tobacco or nicotine-related risks (2–3 minutes)

Videotape with information on risks, barriers to cessation, and tips for quitting; counseling in one 10-minute session; self-help manual; and follow-up letters

Pregnancy-specific self-help manual and one 10-minute counseling session with a health educator

Counseling in one 90-minute session plus twice monthly telephone follow-up calls during pregnancy and monthly telephone calls after delivery

Screening and intervention for alcohol and other drug use are recommended for all pregnant women. Because smoking continuation during pregnancy is associated with the likelihood of other substance use, screening for alcohol and other substance use is an important component of care 54 .

Women’s efforts to reduce the amount they smoke should be reinforced and congratulated. The benefits of reduced smoking are difficult to quantify or verify during pregnancy. Women should be reminded that quitting outright best affects the long-term health of herself, her offspring, and her family 55 . The greatest benefit is observed with cessation before 15 weeks of gestation 42 56 . Although smoking of any duration during pregnancy is associated with an increased risk of fetal growth restriction, the risk is reduced the earlier in gestation that cessation occurs 57 . Still, smoking cessation at any point in gestation benefits the pregnant woman and her fetus. Pregnant women exposed to family members or coworkers who smoke should be given advice on how to address these situations and avoid exposure.

Approximately 50–60% of women who quit smoking during pregnancy return to smoking within 1 year postpartum, resuming the risk to their health, their infant’s health, and future pregnancies 58 . Therefore, providing continual support and addressing psychosocial stressors in the postpartum period are necessary to ensure continued cessation success. During the third trimester, determining a woman’s intention to return to smoking is useful to target the potential need for smoking relapse interventions 59 . Factors associated with the highest risk for postpartum smoking recidivism include living with a partner or family member who smokes, not breastfeeding, intending to quit only during pregnancy, and exhibiting low confidence in remaining tobacco-free postpartum 60 . Encouraging close follow-up, promotion of postpartum health and overall well-being, review of tobacco use prevention strategies, recognition of psychosocial challenges, and identification of social support systems in the third trimester and postpartum are helpful in decreasing recidivism 59 61 .

The U.S. Preventive Services Task Force has concluded that current evidence is insufficient to assess the balance of benefits and harms of nicotine replacement products or other pharmaceuticals for tobacco cessation during pregnancy 42 . Recent reviews have suggested nicotine replacement therapy is associated with increased rates of smoking cessation during pregnancy 62 . However, efficacy of nicotine replacement therapy in supporting cessation during pregnancy has been inconsistent and likely explained by low adherence rates and the increased metabolism of nicotine in pregnancy 44 . Trials studying the use of nicotine replacement therapy in pregnancy have been attempted, but many of those conducted in the United States have been stopped by data and safety monitoring committees because of either adverse pregnancy effects or failure to demonstrate effectiveness 42 63 64 . Use of nicotine replacement therapy should be considered only after a detailed discussion with the patient of the known risks of continued smoking, the possible risks of nicotine replacement therapy, and need for close supervision. If nicotine replacement therapy is used, it should be with the clear resolve of the patient to quit smoking.

Pharmacotherapeutic smoking cessation agents used in the nonpregnant population include varenicline and bupropion. Varenicline is a partial agonist for nicotinic receptors in the brain. Several small studies that evaluated its safety in pregnancy have not shown teratogenicity 65 66 but, overall, data are limited. Bupropion is an antidepressant with limited data on its use in pregnancy, but there is no known risk of fetal anomalies or adverse pregnancy effects with its use 67 68 .

The U.S. Food and Drug Administration (FDA) mandated a product warning about the risk of psychiatric symptoms and suicide associated with varenicline and bupropion in 2015; however, a December 2016 update removed the boxed warning 69 70 71 . Individuals attempting smoking cessation with or without the use of pharmacotherapeutic agents may experience new or worsening adverse effects on mood, behavior, or thinking, particularly among women with a preexisting mental health disorder. Although the quality of research regarding the safety profiles for varenicline and bupropion use is not robust, a recent systematic review of 18 studies of bupropion and varenicline use in pregnancy did not demonstrate an increased risk of congenital anomalies, low birth weight, or preterm birth 67 . Obstetrician-gynecologists and other obstetric care professionals should counsel women about the risks of smoking and the benefits of cessation and discuss the resources available to help with smoking cessation, which may include the use of varenicline and bupropion. If these medications are prescribed, familiarity with the risks, benefits, and updated FDA Drug Safety Communications is prudent. Although cumulative data are limited, maternal bupropion doses of up to 300 mg are associated with low levels of detection in breastmilk that are unlikely to cause adverse effects in infants 72 . Because no published information is available regarding the use of varenicline during lactation, an alternative drug is preferable, especially with newborn or preterm infants 73 .

Office visits that specifically address smoking cessation should be coded as such, but benefits are subject to specific plan policies. The Patient Protection and Affordable Care Act expanded tobacco cessation coverage for the Medicaid pregnant population for at least all FDA-approved tobacco cessation medications as well as individual, group, and phone counseling with no cost sharing for the patient. Most private health plans are required to cover screening for tobacco use and to provide evidence-based tobacco cessation counseling and interventions to all adults and pregnant women in accordance with the recommendations by the United States Preventive Services Task Force and the U.S. departments of Health and Human Services, Labor, and Treasury. Depending on the tobacco services provided, the counseling may merit a separate code or time-based evaluation and management service code. Health care professionals are encouraged to consult coding manuals regarding billing and reimbursement variation from insurance carriers.

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Published online on April 23, 2020.

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Tobacco and nicotine cessation during pregnancy. ACOG Committee Opinion No. 807. American College of Obstetricians and Gynecologists. Obstet Gynecol 2020;135:e221–9.

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Table 1. Nicotine Delivery Products and Amount of Nicotine

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• Open access
• Published: 21 December 2022

Cigarette smoking during pregnancy and adverse perinatal outcomes: a cross-sectional study over 10 years

• Baptiste Tarasi 1 ,
• Jacques Cornuz 2 ,
• Carole Clair 3 &
• David Baud 1  

BMC Public Health volume  22 , Article number:  2403 ( 2022 ) Cite this article

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It has been shown that active exposure to tobacco is associated with adverse pregnancy outcomes including, but not limited to, intrauterine fetal death, reduced fetal weight, and higher risk of preterm birth. We want to investigate these effects in a high-income country.

This cross-sectional study examined 20,843 pregnant women who delivered over 10 years at the Maternity Hospital of the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland. The objective was to evaluate a dose–response relationship between daily cigarette use during pregnancy and possible adverse perinatal outcomes. The social and clinical characteristics as well as obstetric and neonatal outcomes were compared between the smoking and the non-smoking groups. Adjusted odds ratios (aOR) and trend analyses (p trend ) were calculated.

Nineteen thousand five hundred fifty-four pregnant women met the inclusion criteria and 2,714 (13.9%) of them were smokers. Even after adjusting for confounding factors, smoking during pregnancy was associated with preterm birth, birthweight < 2500 g, intrauterine growth restriction, neonatal respiratory and gastrointestinal diseases, transfer to the neonatal intensive care unit, and neonatal intensive care unit admissions > 7 days. Intrauterine death and neonatal infection were associated with heavy smoking (≥ 20 cigarettes/day). Smoking appeared to be a protective factor for pre-eclampsia and umbilical cord arterial pH below 7.1. A significant trend (p trend  < 0.05) was identified for preterm birth, intrauterine growth restriction, birthweight < 2500 g, umbilical cord arterial pH below 7.1, transfers to our neonatal intensive care unit, and neonatal intensive care unit admissions more than 7 days.

Cigarette smoking is associated with several adverse perinatal outcomes of pregnancy with a dose-dependent effect.

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Among adults, the consequences of cigarette use are well known and can lead to cardiovascular, pulmonary, and oncological diseases as well as other chronic illnesses [ 1 ]. These negative health consequences are remote in time and therefore do not always cause sufficient immediate concern to motivate smoking cessation, especially in younger individuals [ 2 ]. The number of smokers worldwide in 2019 was estimated to be 1.14 billion, corresponding to 7.69 million deaths and 200 million DALYs (Disability Adjusted Life Years). Globally, the proportion of smokers is much lower among women with 6.62% of female individuals identified as smokers compared to 32.7% of male individuals. However, this proportion is considerably higher among women in high-income countries with 17.6% of women compared to 26.9% of men identifying as smokers [ 3 ].

There is evidence that women are more likely to discontinue cigarette use during their pregnancy [ 4 ]. The global prevalence of smoking during pregnancy is estimated to be 1.7% [ 5 ]. This proportion, also evaluated in 2018, is significantly higher in high-income countries, reaching 7.2% in the USA [ 6 ] and 8.1% in Europe [ 5 ]. These numbers should be interpreted cautiously as up to 25% of pregnant women with cigarette use prior to pregnancy incorrectly indicated that they ceased smoking during pregnancy [ 7 ]. Pregnant women with a lower level of education and those who experience an unplanned pregnancy have a higher prevalence of smoking and a lower probability of quitting [ 8 , 9 ].

The effects of smoking during pregnancy have been the subject of numerous studies and have been associated with many adverse perinatal outcomes. Specifically active exposure to tobacco has been shown to be associated with a dose–response relationship to adverse outcomes such as preterm birth (birth before 37 weeks of pregnancy) [ 10 , 11 , 12 ], reduced birth weight [ 13 , 14 ], with the reduction in fetal measurements occurring after the first trimester [ 15 ], and transfer to a neonatal intensive care unit [ 16 ]. Smoking has also been associated in a dose-dependent manner with an increased risk of intrauterine fetal death [ 17 , 18 , 19 , 20 ]. In contrast to adverse outcomes cited, smoking has been identified to be a protective factor against pre-eclampsia [ 21 , 22 ]. Regarding the neonatal impact, smoking during pregnancy can alter fetal lung development and lead to respiratory problems [ 23 , 24 ]. Long term, fetal exposure to smoking during pregnancy can result in more frequent development of gastrointestinal pathologies [ 25 ].

In summary, many studies have already investigated adverse obstetric and neonatal outcomes [ 26 , 27 ]. However, not all of them included a large sample from a single center or adjusted their results to account for potential confounding factors. In addition, many studies have focused only on a single adverse outcome. For example, Soneji et al. focused their study on prematurity [ 12 ], and Larsen et al. focused mainly on birth weight [ 13 ]. If we take the main studies found in the literature that focused on several outcomes, Ratnasiri et al. did not focus on neonatal outcomes and did not evaluate a potential dose–response [ 28 ]. Finally, the well conducted research of Li et al. did not focus on several key outcomes including the risk of pre-eclampsia or neonatal infections, pulmonary pathologies, or gastrointestinal pathologies and did not evaluate a potential dose–response as well [ 29 ].

For all these reasons, we firstly aimed to assess multiple obstetric and neonatal outcomes associated with cigarette smoking during pregnancy within a single and large Swiss obstetric cohort with prospectively collected data. Some have already been studied, others not. Secondly, we want to evaluate a potential dose–response relationship between the quantity of cigarette use and adverse outcomes.

This cross-sectional study utilized our obstetrical database at the Maternity Hospital of the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland, where 20,843 pregnant women gave birth between 1997 and 2006. Data available in this database include demographic, labor, and delivery information, as well as maternal and neonatal outcomes.

All information regarding patient health and pregnancy was collected at the time of admission to the hospital, with the majority occurring at the time of admission for delivery or, for some, at the time of admission to the antepartum unit in the case of complicated pregnancies. A medical history was taken for each patient presenting to the hospital by the obstetrical care provider. If urgent care was required, the history was postponed to an appropriate time during the hospitalization. Our computer system did not permit closure of a patient file that did not include all the mandatory information, including smoking habits. This information was collected verbally with the following question: "Do you smoke cigarettes daily?" with a dichotomous “yes/no” answer. If the answer was “yes”, the number corresponding to the current consumption was then requested by the computer system. The number of cigarettes consumed thus represents usage in the late third trimester, and does not take into account variation of smoking during pregnancy.

Regarding neonatal data, all information was added to our database at the end of the stay by the neonatologists and/or the obstetricians. All women whose records contained all the data needed for our study were included regardless of mode of delivery. The exclusion criteria were as follows: women under 18 years of age or women with multiple pregnancies. The quality of this database of prospectively collected data has already been described elsewhere (cross-check congruent data in 98.2–99.8% of cases) [ 30 ].

The following social and clinical characteristics were extracted from the database: daily cigarette use, maternal age, country of birth, marital status, parity, previous pregnancy loss, education, professional status, health insurance, and the presence of significant psychosocial difficulties. The latter was defined as pregnant women referred for a dedicated indication for consultation associated with challenging psychosocial circumstances (psychiatric pathologies, alcohol or drug abuse, etc.…). We assessed the following obstetric and neonatal outcomes: delivery mode, pre-eclampsia, intrauterine death, neonatal death, preterm birth, intrauterine growth restriction, birthweight, umbilical cord arterial pH, APGAR score at 5 min, neonatal infection, hypoglycemia, cerebral hemorrhage or convulsion, jaundice, neonatal anemia, respiratory diseases (including pulmonary infection, pneumothorax, apnea, and hyaline membrane disease), gastrointestinal diseases (including feeding difficulties, occlusive syndrome, digestive hemorrhage, necrotizing enterocolitis, diarrhea, and vomiting), transfers to our neonatal intensive care unit, and neonatal intensive care unit admissions longer than 7 days.

The social and clinical characteristics, as well as the obstetric and neonatal outcomes, were compared between the smoking and non-smoking pregnant women. For the same comparisons, the group of smoking pregnant women was also divided into 3 subgroups according to their daily cigarette usage (< 10/day, ≥ 10/day, and ≥ 20/day). The p-value for each clinical and social characteristic, comparing smokers and non-smokers, was calculated using a Chi-squared test. Logistic regression models to assess the association between smoking and obstetric and neonatal outcomes were built and odds ratios were calculated (aOR), adjusted for maternal age, country of birth, marital status, parity, previous pregnancy loss, education, professional status, psychosocial difficulties and insurance. For some outcomes, such as birth weight, intrauterine growth restriction, umbilical cord arterial pH, APGAR score at 5 min, respiratory diseases, gastrointestinal diseases, neonatal infection, hypoglycemia, cerebral hemorrhage or convulsion, jaundice, neonatal anemia, and transfers to or stay in our neonatal intensive care unit, the odds ratios were also adjusted for the gestational age as these outcomes can occur more frequently in preterm neonates. For the calculation of adjusted estimators in multivariate logistic regression models, the baseline variables that significantly differed between both the groups (confounders) or those that are known risk factors for adverse outcomes were included in the models.

Finally, trend analyses (p trend ) were also calculated, using the Cochran-Armittage test, for all the outcomes examined to evaluate a potential dose–response relationship according to the number of daily cigarettes consumed.

Statistical analyses were performed using STATA 16 (Stata Corporation, College Station, USA).

The study was carried out in accordance with relevant guidelines and regulations (Declaration of Helsinki). This study was approved by the local IRB (Ethical Commission of the Canton of Vaud, Switzerland, protocol no. 101/08).

Over a period of 10 years, 19.554 pregnant women met the inclusion criteria. Among them, 16,840 (86.1%) identified as non-smokers and 2,714 (13.9%) identified as smokers (Fig.  1 ).

Classification of pregnant women according to the number of cigarettes consumed per day

The prevalence of pregnant women who reported cigarette use was higher among pregnant women of Swiss origin, single, divorced, or widowed, those who have had a previous spontaneous abortion, those with significant psychosocial difficulties, and nulliparous pregnant women (Table 1 ).

After adjustment for confounding factors, smoking during pregnancy was associated with preterm birth (aOR 1.16 [95%CI 1.03–1.31]), birthweight < 2500 g (aOR 1.78 [95%CI 1.53–2.08]), small for gestational age (aOR 1.83 [95%CI 1.64–2.05]), respiratory diseases (aOR 1.32 [95%CI 1.13–1.56]), gastrointestinal diseases (aOR 1.63 [95%CI 1.11–2.42]), transfers to the neonatal intensive care unit (aOR 1.44 [95%CI 1.26–1.63]), and neonatal intensive care unit admission > 7 days (aOR 1.64 [95%CI 1.42–1.90]). These associations were stronger in the groups of women with higher number of cigarettes consumed per day. Intrauterine death (aOR 1.98 [95%CI 1.01–3.89]) and neonatal infection (aOR 1.53 [95%CI 1.05–2.22]) were only associated with heavy smoking (≥ 20 cigarettes/day) but not with lower smoking exposure. In contrast, smoking appeared to be a protective factor for pre-eclampsia (aOR 0.62 [95%CI 0.44–0.88]) and umbilical cord arterial pH below 7.1 (aOR 0.65 [95%CI 0.50–0.86]). Rate of cesarean section, neonatal deaths and other neonatal outcomes such as an APGAR score below 7 at 5 min, hypoglycemia, cerebral hemorrhage or convulsion, jaundice, and neonatal anemia showed no significant differences between the smoking and the non-smoking groups (Table 2 ).

A significant dose–response relationship trend was identified between the number of daily cigarettes consumed and preterm birth (p trend  < 0.001), intrauterine growth restriction (p trend  < 0.001), birthweight < 2500 g (p trend  < 0.001), umbilical cord arterial pH below 7.1 (p trend  = 0.001), transfers to our neonatal intensive care unit (p trend  < 0.001), and neonatal intensive care unit admissions more than 7 days (p trend  < 0.001).

No trend was found for the other outcomes investigated: pre-eclampsia, increased rate of cesarean section, neonatal death, intrauterine death, APGAR score < 7 at 5 min, hypoglycemia, jaundice, neonatal anemia, neonatal infection, cerebral hemorrhage or convulsion, respiratory diseases, and gastrointestinal diseases.

As our database includes a sample of pregnant women from the 1997 to 2006, this likely explains why the rate of pregnant individuals who identify as smokers, 13.9%, is higher than the rate described in statistics from 2018, which are estimated to be 8.1% in Europe [ 5 ] and 7.2% in the USA [ 6 ].

Cigarette smoking has an impact on pregnancy with several adverse perinatal outcomes. In our study, cigarette use was strongly associated with preterm birth, lower birthweight, intrauterine growth restriction, transfers to the neonatal intensive care unit, and neonatal intensive care unit admissions > 7 days. All of the above associations have a dose–response relationship, with significant trend values. Our results align with those found in the literature [ 10 , 11 , 12 , 13 , 14 , 16 ]. Intrauterine death was associated with heavy cigarette consumption (≥ 20/day), while other studies attributed intrauterine death with lower tobacco consumption [ 17 , 18 , 19 ]. Finally, smoking during pregnancy can induce neonatal pulmonary and gastrointestinal pathologies. Heavy cigarette consumption (≥ 20/day) also increases the risk of neonatal infections.

The mechanisms by which tobacco smoking result in adverse perinatal outcomes are complex. They may occur as a result of disruption of fundamental processes such as proliferation, apoptosis, and invasion of the trophoblasts during placental development. Alteration of the vascularization and the metabolism of the placenta may also be a cause [ 31 ].

The association between neonatal gastrointestinal pathology and smoking during pregnancy, as well as the association with neonatal infections, has been little studied until now. As a comparison, it has been shown that adult smokers are themselves more susceptible to bacterial or viral infections than non-smokers which may be due to alteration of the structural, functional, and immunological functions of the host defenses [ 32 , 33 ].

Smoking during pregnancy may, however, also still be a protective factor. Cigarette use during pregnancy has been shown to reduce the risk of pre-eclampsia [ 21 , 22 ] as was also identified in our study. The protective role of smoking can be partially explained by the effects of carbon monoxide, one of the products of tobacco combustion. Carbon monoxide inhibits the placental production of anti-angiogenic proteins such as sFlt1 or sEng, which play a role in the pathogenesis of preeclampsia. However, the pathogenesis of pre-eclampsia remains complex and is still not fully understood [ 34 ]. It may be worth mentioning that Luque-Fernandez et al. have partially explained the paradoxical phenomenon of this protective effect by studying prevalent cases at birth rather than all incident cases in a pregnancy cohort, which results in selection bias [ 35 ]. In our study, tobacco smoking was also a protective factor against the risk of umbilical cord arterial pH below 7.1. This phenomenon has been little studied. However, we will qualify our results by comparing them with those of Zaigham et al. whose prospective-observational cohort study of 308 patients showed no significant differences in pH values between smokers and non-smokers [ 36 ].

Our results do not suggest a significant association for some outcomes such as an APGAR score below 7 at 5 min, hypoglycemia, cerebral hemorrhage or convulsion, jaundice, and neonatal anemia.

With the proportion of pregnant smokers estimated to be 8.1% in Europe [ 5 ] and 7.2% in the USA [ 6 ] in 2018, it is clear that there is still much to be done in terms of prevention. Although low tobacco consumption is associated with less severe outcomes than heavy consumption, it is important to inform pregnant women that even at low doses, smoking has consequences for the fetus, in addition to the consequences on their own health. Effective interventions for smoking cessation during pregnancy include regular interval counseling and the provision of nicotine replacement therapy to patients who do not respond to counseling only [ 37 ]. The use of incentives to motivate smoking cessation also showed encouraging results [ 38 ].

The strength of our study is the analysis of multiple prospectively collected outcomes within a single, large cohort. It confirms the different outcomes studied separately in the literature but also demonstrated a dose–response effect, which has not been systematically evaluated [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].

Our research also contains some weaknesses. First, we did not assess a possible change in smoking during pregnancy and we also did not include the occasional smokers. This constitutes an information bias. By using a large available database, which was not designed specifically for this research, we were also unable to utilize a standardized questionnaire to assess cigarette consumption. Second, we did not assess passive smoking or secondhand exposure, which may also affect the fetus [ 39 ]. Furthermore, we did not take into account certain factors that could be confounding, such as alcohol or cannabis use [ 40 , 41 ]. Information regarding other factors, such as comorbidities or concomitant medication use were not available and therefore were also not taken into account.

In addition, it is important to mention that some odds ratio confidence intervals are wide, especially for the subgroup of “ ≥ 20 cig/day”. This may be explained by the fact that this subgroup only includes 499 patients out of 19,554 patients. We thus acknowledge that some of the comparisons are underpowered, and therefore the lack of statistically significant relationships for some of the comparisons may not necessarily indicate that there is no relationship. Since the associations found in our study might be underestimated due to patients underreporting their consumption, this “ > 20 cig/day” group might represent the true impact of smoking during pregnancy. Indeed, about 24% of pregnant smokers stop smoking during pregnancy and up to 25% of pregnant smokers also misreport their actual tobacco consumption. This represents a possible classification bias.

We can also mention the lack of generalizability due to a localized sample. Finally, during the time period of our study (1997–2006), obstetrical management may have altered. This potential change was not taken into account as a covariate. Also, the rate of smoking in pregnancy has been declining [ 5 ]. Within the Swiss population, the latest existing data to our knowledge includes the years 2011–2016. The proportion of pregnant smokers during this time was estimated to be 6.8%, showing a decrease in consumption since the data collected for our research [ 42 ]. Although the estimate of association may hold, many characteristics of women in the study may not hold.

Cigarette smoking during pregnancy is associated with several adverse perinatal outcomes. This relationship is often dose-dependent, as with preterm birth, birthweight < 2500 g, intrauterine growth restriction, transfers to neonatal intensive care unit, and neonatal intensive care unit admissions more than 7 days. Prevention among women must be further emphasized, as some adverse outcomes could be avoided by a smoke-free pregnancy.

Availability of data and materials

The datasets analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank all midwives and doctors who computerized obstetrical data used in this study. Their involvement was essential to allow this study.

This work was supported by the research fund in obstetrics and gynecology of the University Hospital of Lausanne, Switzerland. The funding sources had no role in the study design, data collection, data analysis or the interpretation thereof, or in writing the report.

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Materno-Fetal and Obstetric Research Unit, Woman-Mother-Child Department, University Hospital of Lausanne, CHUV, 1011, Lausanne, Switzerland

Baptiste Tarasi & David Baud

Department of Ambulatory Care, Center for Primary Care and Public Health (Unisanté), University of Lausanne, 1011, Lausanne, Switzerland

Jacques Cornuz

Department of Training, Research and Innovation, Center for Primary Care and Public Health (Unisanté), University of Lausanne, 1011, Lausanne, Switzerland

Carole Clair

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BT handled the literature review as well as the writing of the manuscript. DB took care of the project development, the data collection, and the data analysis. JC also participated in the project development. Finally, CC was responsible for the manuscript's critical reviewing. The authors read and approved the final manuscript.

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Correspondence to David Baud .

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The study was carried out in accordance with relevant guidelines and regulations (Declaration of Helsinki). This study was approved by the local IRB (Ethical Commission of the Canton of Vaud, Switzerland, protocol no. 101/08). Informed consent was obtained from all subjects and/or their legal guardian.

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Tarasi, B., Cornuz, J., Clair, C. et al. Cigarette smoking during pregnancy and adverse perinatal outcomes: a cross-sectional study over 10 years. BMC Public Health 22 , 2403 (2022). https://doi.org/10.1186/s12889-022-14881-4

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DOI : https://doi.org/10.1186/s12889-022-14881-4

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Tobacco, Nicotine, and E-Cigarettes Research Report What are the risks of smoking during pregnancy?

Smoking during pregnancy is linked with a range of poor birth outcomes—including:

• Low birth weight and preterm birth 58,59
• Restricted head growth 60
• Placental problems 61
• Increased risk of still birth 62
• Increased risk of miscarriage 62,63

Health and developmental consequences among children have also been linked to prenatal smoke exposure, including:

• Poorer lung function, persistent wheezing, and asthma, possibly through DNA methylation 64
• Visual difficulties, such as strabismus, refractive errors, and retinopathy 65

Unfortunately, smoking by pregnant women is common. In 2014, 8.4 percent of women smoked at any time during pregnancy, with those aged 20 to 24 who were American Indian or Alaska Natives having higher rates, at 13 percent and 18 percent, respectively. 66 One fifth of women who smoked during the first 6 months of pregnancy quit by their third trimester. Overall cessation rates were highest for those with the highest educational attainment and private insurance. 66   Therefore, there is a clear need to expand smoking cessation treatment to younger women and to those of lower socioeconomic status (see Box: " Smoking Cessation for Pregnant Women ").

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Article Contents

Smoking in pregnancy: an ongoing challenge.

Corresponding Author: Linda Bauld, PhD, UK Centre for Tobacco and Alcohol Studies, University of Stirling, Stirling, UK. Telephone: +44-(0)7714-213-372; E-mail: [email protected]

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Linda Bauld, Cheryl Oncken, Smoking in Pregnancy: An Ongoing Challenge, Nicotine & Tobacco Research , Volume 19, Issue 5, 1 May 2017, Pages 495–496, https://doi.org/10.1093/ntr/ntx034

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Maternal smoking during pregnancy carries significant risks to mother infant and child. Smoking during pregnancy is associated with an increased risk of ectopic pregnancy, placental previa and abruption, preterm premature rupture of membranes, fetal growth restriction, preterm delivery, oral facial clefts, and sudden infant death syndrome. 1 , 2 One of the most measurable effects of smoking is approximately doubling the risk of delivering a low birth weight infant. 2 This special issue of the journal highlights the continued risks of smoking in pregnancy and the importance of policies and interventions to address this issue, despite the progress that has been made in reducing smoking in pregnancy in some countries. New data on risks, incidence, interventions and women’s own perspectives are highlighted. Together the included papers provide new data examining key issues in the field, from a wide range of countries.

On risks, two papers are included. Although most of the research examining the effects of smoking on birth weight has been conducted in high income countries, a meta-analysis in this review confirms the association between smoking during pregnancy and low birth weight in the Americas. 3 Additionally, although studies suggest a causal inference between maternal smoking and disruptive behavioral disorders and attention deficit disorder in children, 2 this edition provides new data on the potential risk of maternal smoking and a broad range of psychiatric morbidity in the offspring using sibling pairs that controls for genetic and familial factors. 4

Despite the health risks, the majority of women who smoke prior to pregnancy continue to smoke cigarettes during pregnancy. This special issue includes a number of papers that explore some of the determinants of maternal smoking during pregnancy. Although smoking during pregnancy rates are declining in many high income countries, indigenous women in these countries continue to have high smoking rates, as outlined in a narrative review this special edition. 5 Although women who quit smoking during pregnancy tend to be of a higher socioeconomic status, and have lower levels of nicotine dependence, articles in this edition indicate that psychological distress and depressive symptoms, 6 , 7 substance use disorders, 8 adverse childhood experiences 9 may also play a significant role in smoking during pregnancy. Analyses of data of Norwegian women also indicates that differences in educational status of smokers versus nonsmokers that exist during pregnancy are increasing over time and contributing to health disparities. 10 A study in Tasmania highlights that post-natal depression and whether the women are in a relationship may affect whether women continue to smoke when pregnant. 11 A further study included here also examined the factors that may influence whether spontaneous smoking cessation occurs in pregnant women, in this case from a sample in rural Poland. 12 They found the main predictors of early cessation were higher educational attainment amongst women and partners and not having children, while barriers were being single, living with a current smoker and having both parents who smoke. These and other barriers reflect those identified in earlier research and illustrate that individual and community factors continue to influence smoking status in pregnancy.

What can be offered to pregnant women who smoke to aid cessation? First, biochemical validation of smoking status can assist in reliably identifying smoking and providing an opportunity to offer support. 13 , 14 Behavioral strategies are effective, but unfortunately treatment is underutilized as indicated by an article examining Medicaid data in the United States. 15 Underutilization may be due to provider knowledge and confidence in assistance to pregnant smokers as suggested by two surveys of Australian providers 16 , 17 or lack of attention to smoking cessation in clinical curricula in the United Kingdom, for example. 18 Consequently, additional efforts may be needed to train our health care providers to deliver smoking cessation.

Additionally, because of the low success rates of many behavioral interventions, innovative strategies are needed to help women stop smoking. An article by Emery and colleagues highlights additional cognitive and behavioral indicators of quit attempts that may inform future treatment studies 19 and Joseph and colleagues describe how interventions to increase breastfeeding may decrease postpartum relapse to smoking. 20 An article by Acquvita and colleagues provides insight into facilitators and barriers for smoking cessation in women with substance use disorders. 8 Although the use of text messaging for smoking cessation during pregnancy is limited, a further article included here indicates that delivering treatment by this method is feasible and well-liked by pregnant smokers. 21 Another article included here suggests that emotion regulation interventions 22 may have promise for smoking treatment as evidenced by preliminary quit rates. In addition, electronic cigarettes 23 or complementary and alternative medicine 24 are being used by some pregnant smokers, indicating a need for further research in these areas.

In summary, smoking during pregnancy continues to be a world-wide public health problem. The risks of smoking during pregnancy are substantial, and the benefits to cessation are great. This special edition provides further insight into the epidemiology and treatment of smoking during pregnancy, which holds promise to inform better treatment for smoking during pregnancy.

RCP . Passive smoking and children, Royal College of Physicians, London . 2010 . http://shop.rcplondon.ac.uk/products/passive-smoking-and- children?variant=6634905477 . Accessed January 10, 2017.

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Ekblad M Lehtonen L Korkeila J Gissler M . Maternal smoking during pregnancy and the risk for psychiatric morbidity in singleton sibling pairs . Nicotine Tob Res . 2017 ; 19 ( 5 ): 597 – 604 .

Gould G Patten C Glover M Kira A Jayasinghe H . Smoking in pregnancy among indigenous women in high income countries: a narrative review . Nicotine Tob Res . 2017 ; 19 ( 5 ): 506 – 517 .

Goodwin R Cheslack Postava K Nelson D et al.  . Serious psychological distress and smoking during pregnancy in the United States: 2008–2014 . Nicotine Tob Res . 2017 ; 19 ( 5 ): 605 – 614 .

Kolko R Emery R Cheng Y Levine M . Do psychiatric disorders or measures of distress moderate response to postpartum relapse prevention interventions? Nicotine Tob Res . 2017 ; 19 ( 4 ): 615 – 622 .

Acquavita S Talks A Fiser K . Facilitators and barriers to smoking while pregnant for women with substance use disorders . Nicotine Tob Res . 2017 ; 19 ( 5 ): 555 – 561 .

Pear V Petito L Abrams B . The role of maternal adverse childhood experiences and race in intergenerational high-risk smoking behaviors . Nicotine Tob Res . 2017 ; 19 ( 5 ): 572 – 577 .

Grøtvedt L Kvalvik L Grøholt EK Akerkar R Egeland G . Development of social and demographic differences in maternal smoking between 1999 and 2014 in Norway . Nicotine Tob Res . 2017 ; 19 ( 5 ): 539 – 546 .

Frandsen M Thow M Ferguson S . Profile of maternal smokers who quit during pregnancy: a population-based cohort study of tasmanian women 2011–2013 . Nicotine Tob Res . 2017 ; 19 ( 5 ): 532 – 538 .

Goniewicz M Balwicki L Smith D et al.  . Factors associated with spontaneous quitting among smoking pregnant women from rural areas in Poland . Nicotine Tob Res . 2017 ; 19 ( 5 ): 647 – 651 .

Ashford K Wiggins A Rayens E Rayens MK Assef S Fallin A . Perinatal biochemical confirmation of smoking status by trimester . Nicotine Tob Res . 2017 ; 19 ( 5 ): 631 – 635 .

Shisler S Eiden R Molnar D Schuetze P Huestis M Homish G . Smoking in pregnancy and fetal growth: the case for more intensive assessment . Nicotine Tob Res . 2017 ; 19 ( 5 ): 525 – 531 .

Scheuermann T Richter K Jacobson L Shireman T . Medicaid coverage of smoking cessation counseling and medication is underutilized for pregnant and postpartum women . Nicotine Tob Res . 2017 ; 19 ( 5 ): 656 – 659 .

Tzelepis F Daly J Dowe S Bourke A Gillham K Freund M . Supporting Aboriginal women to quit smoking: antenatal and postnatal care providers’ confidence, attitudes and practices . Nicotine Tob Res . 2017 ; 19 ( 5 ): 642 – 646 .

Bar Zeev Yael Bonevski B Twyman L et al.  . Opportunities missed: a cross-sectional survey of the provision of smoking cessation care to pregnant women by Australian General Practitioners and Obstetricians . Nicotine Tob Res . 2017 ; 19 ( 5 ): 636 – 641 .

Duaso MJ Forman J Harris J Lorencatto F McEwen A . National survey of smoking and smoking cessation education within UK midwifery school curricula . Nicotine Tob Res . 2017 ; 19 ( 5 ): 591 – 596 .

Emery J Sutton S Naughton F . Cognitive and behavioural predictors of quit attempts and biochemically-validated abstinence during pregnancy . Nicotine Tob Res . 2017 ; 19 ( 5 ): 547 – 554 .

Joseph H Emery R Bogen D Levine M . The influence of smoking on breastfeeding among women who quit smoking during pregnancy . Nicotine Tob Res . 2017 ; 19 ( 5 ): 652 – 655 .

Sloan M Hopewell S Coleman T Cooper S Naughton F . Smoking cessation support by text message during pregnancy: a qualitative study of views and experiences of the MiQuit intervention . Nicotine Tob Res . 2017 ; 19 ( 5 ): 572 – 577 .

Bradizza C Stasiewicz P Zhuo Y et al.  . Smoking cessation for pregnant smokers: development and pilot test of an Emotion Regulation Treatment (ERT) for negative affect smokers . Nicotine Tob Res . 2017 ; 19 ( 5 ): 578 – 584 .

Oncken C Ricci K Kuo CL Dornelas E Kranzler H Sankey H . Correlates of electronic cigarettes use before and during pregnancy . Nicotine Tob Res . 2017 ; 19 ( 5 ): 595 – 590 .

Loree A Ondersma S Grekin E . Toward enhancing treatment for pregnant smokers: Laying the groundwork for the use of complementary and alternative medicine approaches . Nicotine Tob Res . 2017 ; 19 ( 5 ): 562 – 571 .

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• Published: 26 March 2021

Health outcomes of smoking during pregnancy and the postpartum period: an umbrella review

• Tuba Saygın Avşar   ORCID: orcid.org/0000-0002-4143-3852 1 ,
• Hugh McLeod 2 , 3 &
• Louise Jackson 1  

BMC Pregnancy and Childbirth volume  21 , Article number:  254 ( 2021 ) Cite this article

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Smoking during pregnancy (SDP) and the postpartum period has serious health outcomes for the mother and infant. Although some systematic reviews have shown the impact of maternal SDP on particular conditions, a systematic review examining the overall health outcomes has not been published. Hence, this paper aimed to conduct an umbrella review on this issue.

A systematic review of systematic reviews (umbrella review) was conducted according to a protocol submitted to PROSPERO ( CRD42018086350 ). CINAHL, EMBASE, MEDLINE, PsycINFO, Web of Science, CRD Database and HMIC databases were searched to include all studies published in English by 31 December 2017, except those focusing exclusively on low-income countries. Two researchers conducted the study selection and quality assessment independently.

The review included 64 studies analysing the relationship between maternal SDP and 46 health conditions. The highest increase in risks was found for sudden infant death syndrome, asthma, stillbirth, low birth weight and obesity amongst infants. The impact of SDP was associated with the number of cigarettes consumed. According to the causal link analysis, five mother-related and ten infant-related conditions had a causal link with SDP. In addition, some studies reported protective impacts of SDP on pre-eclampsia, hyperemesis gravidarum and skin defects on infants. The review identified important gaps in the literature regarding the dose-response association, exposure window, postnatal smoking.

Conclusions

The review shows that maternal SDP is not only associated with short-term health conditions (e.g. preterm birth, oral clefts) but also some which can have life-long detrimental impacts (e.g. obesity, intellectual impairment).

Implications

This umbrella review provides a comprehensive analysis of the overall health impacts of SDP. The study findings indicate that while estimating health and cost outcomes of SDP, long-term health impacts should be considered as well as short-term effects since studies not including the long-term outcomes would underestimate the magnitude of the issue. Also, interventions for pregnant women who smoke should consider the impact of reducing smoking due to health benefits on mothers and infants, and not solely cessation.

Peer Review reports

Smoking during pregnancy (SDP) is a significant public health concern due to adverse health outcomes on mothers and infants, such as miscarriage, low birth weight (LBW), preterm birth, and asthma [ 1 , 2 , 3 , 4 ]. The prevalence of SDP is around 10% in high-income countries (HICs) [ 5 , 6 , 7 ] and 3% in low- and middle-income countries (LMICs) [ 8 ].

Smoking during pregnancy generates a considerable cost burden and the annual cost of smoking-related pregnancy complications has been estimated to be between £8 and £64 million in the UK, depending on the estimation method chosen [ 9 ]. In addition, the costs associated with the health problems experienced by the infant during the first year following the birth were found to be between £12 and £23 million [ 9 ]. Smoking during pregnancy poses a considerable economic burden in the USA as well, since smoking-attributable neo-natal costs were estimated to be nearly $228 million in total [ 10 ]. When long-term impacts on the infant are considered, the actual figures are likely to be higher. Therefore, to have a comprehensive estimate of the health and cost impacts of SDP to inform policy decisions and ensure that scarce health resources are allocated optimally, it is necessary to review the evidence on the overall health effects for mothers and infants over the longer term.

A scoping review and a review of reviews by Godfrey and colleagues [ 9 ], and a scoping review by Jones [ 11 ] provided a picture of the health and cost outcomes associated with SDP, and several narrative reviews about the health outcomes have been published [ 12 , 13 , 14 , 15 ]. However, none of these papers were fully systematic and comprehensive. Moreover, a considerable number of systematic reviews have been published more recently on the impact of maternal SDP on separate health outcomes, which makes this overall review of the current evidence timely.

The present study aimed to investigate the overall health impacts of maternal smoking during pregnancy and the postpartum period on mothers and infants. Additionally, the evidence on the impact of the number cigarettes consumed and second-hand smoking (SHS) by partner during pregnancy was assessed [ 16 , 17 ].

The guideline provided by the Cochrane Handbook for Systematic Reviews of Interventions [ 18 ] was followed. The review was carried out according to a protocol which included a detailed description of the methodology [ 19 ]. Umbrella reviews have been increasingly used to summarise the existing evidence on an issue by analysing all systematic reviews conducted [ 18 , 20 ]. Considering the large number of original studies about health outcomes of SDP, an umbrella review was the appropriate design for this research.

Searches were undertaken of CINAHL, EMBASE, MEDLINE, PsycINFO, Web of Science, CRD Database (includes DARE, NHSEED and HTA) and HMIC databases. The search strategy for MEDLINE is presented in the Additional file 1 . All systematic reviews published in English and by December 2017. Two independent reviewers conducted the study selection and quality assessment. The data extraction toll is provided in the Additional file 1 : Table S1. The quality of included studies was assessed with a tool developed from the Centre for Reviews and Dissemination (CRD) checklist, which covers a range of issues including prior protocol use, bias in study selection, and consideration of publication bias and inclusion of a quality assessment [ 21 ]. Main outcome measures were odds ratios and relative risks for smoking women and their children compared to non-smoking women and their children.

To evaluate the causal link between SDP and the identified conditions which were found to have an association with SDP, a causal link analysis was conducted using established methods [ 11 ]. The evidence on the identified conditions was assessed and categorised using the following criteria:

Strong evidence - one systematic review with ≥8 studies (group 1) or more than one systematic review (group 2);

Weak evidence – more than one systematic review reported conflicting findings (group 3) or one systematic review reported limited number of studies (< 8) which found a relationship (group 4).

A validity assessment was conducted by reducing the threshold of eight studies to seven, and increasing it to 10 and 12. As discussed by Jones [ 11 ], this strength of evidence analysis fulfilled five of the nine items proposed by Hill [ 22 ] as conditions of a causal link (strength, consistency, specificity, temporality, and plausibility). In addition, the dose-response association was also considered. The remaining requirements (coherence, experiment, and analogy) of the Hill [ 22 ] criteria were irrelevant to this review as laboratory studies were not included and no causes other than smoking of the identified conditions were considered.

The database search yielded 744 studies and an additional five studies were found through hand searching the references of included studies. Following the removal of duplicates and abstract screening, 64 studies were selected for full-text analysis Fig.  1 .

PRISMA Diagram for Study Selection

Characteristics of the included studies

Most reviews ( n  = 46) were published since 2010. Only 13 reviews investigated a health condition related to mothers; the other 49 reviews analysed infant-related conditions, except two [ 23 , 24 ] which evaluated the impacts on both. Key characteristics of the included reviews are provided in Additional file 1 : Table S2.

In most reviews ( n  = 27 reviews), the included studies were predominantly from HICs, and 22 of the included reviews covered studies from HIC only. In two reviews [ 3 , 25 ] most of the included studies were concerned with upper-middle-income countries.

In 12 reviews, the country of focus of the included studies was not provided. However, one of them [ 26 ] conducted a meta-analysis of the studies from Europe only, and in five reviews, the language of the included studies was either only English [ 27 , 28 , 29 ] or languages [ 30 , 31 ] which are only spoken by HICs. In the remaining six reviews [ 32 , 33 , 34 , 35 , 36 ] there was no indication of whether the studies focussed on LMICs or HICs. Nevertheless, when interpreting the results of these reviews, the possibility that studies which were conducted in LMICs have been included in addition to HICs should be born in mind.

Quality of the included studies

The quality scores of the reviews are provided in Additional file 1 : Table S2. The highest achievable score was 16, and most reviews ( n  = 46) scored between nine and 14 while two reviews [ 25 , 32 ] achieved very low scores of 4 and 5. Therefore, most of the included reviews were moderate or high quality studies according to the criteria used.

Study selection was made by two reviewers independently in almost half of the reviews ( n  = 31) to minimise bias. The majority of the studies ( n  = 50) assessed publication bias. Heterogeneity was measured in all reviews although causes of heterogeneity were not analysed in some ( n  = 17). However, only seven reviews reported protocol publication [ 3 , 26 , 33 , 37 , 38 , 39 , 40 ].

Impacts of smoking during pregnancy on mothers

Overall, of the 14 reviews that reported the impact of smoking on mothers, all except two [ 41 , 42 ] conducted meta-analyses (Additional file 1 : Table S3). The reviews presented consistent findings, suggesting a significantly increased risk associated with smoking and seven health conditions. The highest risks were reported for spontaneous miscarriage in assisted reproduction (OR = 2.65, 95% CI, 1.33–5.30, 28) and ectopic pregnancy (OR = 2.30, 95% CI, 2.02–2.80, 30). Two conditions (preeclampsia and hypremesis gravidarum) were found to be negatively associated with SDP. Hence, women who smoked whilst pregnant were less likely to experience these two conditions.

Impacts of smoking during pregnancy on infants

Studies found a smoking-related increased risk for 20 conditions and the highest impact was observed for sudden infant death syndrome (SIDS) (OR = 2.98, 95% CI, 2.51–3.54) [ 24 ], asthma (OR = 1.85, 95% CI, 1.35–2.53) [ 1 ], LBW (OR = 1.75, 95% CI, 1.42–2.10), stillbirth (OR = 1.55, 95% CI, 1.36–1.78) [ 38 ] and obesity (OR = 1.60, 95% CI 1.37–1.88) [ 43 ]. Studies did not find any significant association between 15 conditions and SDP, including autism, brain tumors, breast cancer in daughters and testicular cancer in sons. On the other hand, a protective impact on skin defects was observed in one review [ 44 ].

Most studies ( n  = 42) investigating the impacts of SDP on infants conducted a meta-analysis (Additional file 1 : Table S4), and only nine did not include this (Additional file 1 : Table S5). In these studies, there was no significant relationship between maternal SDP and lung functions, or Tourette’s syndrome.

The age group of study participants varied between studies; for example, some conditions were assessed amongst infants while some were measured in adults. In some reviews, participants were both infants and adults. Table 1 lists health conditions by the life stage they were assessed.

The reviews included in this study indicated that maternal smoking increased the risk of death for the child during the prenatal period, neonatal period and infancy. The evidence showed maternal SDP did not only have short-term impact but also some long-term outcomes which could be detrimental for offspring. Moreover, some of the conditions measured in early life stages could continue later in life. For instance, some birth defects and intellectual disability would affect later stages of life.

Dose-response association

To understand the impact of reductions in smoking, the relationship between the number of cigarettes consumed and the health implications for infants or mothers were investigated. Although a dose-response impact of SDP was reported in 27 reviews (22 related to infant conditions), it was statistically tested in just 17 studies. Among them, four found no significant impact of SDP and their dose-response tests showed similar results. In addition, one review [ 62 ] reported a dose-response association for SIDS but did not provide the odds ratios. Findings of the remaining 12 studies are summarised in the Additional file 1 : Table S6.

To define light, moderate and heavy smokers, most studies [ 38 , 39 , 46 , 62 , 63 , 64 ] chose smoking 10 cigarettes daily as a cut-off point to distinguish light smokers from moderate and heavy smokers. In some studies [ 4 , 39 , 46 , 61 , 64 ], both 10 cigarettes daily and 20 cigarettes daily were utilised as the thresholds. In one review the number of cigarettes consumed daily for each category was inconsistent [ 65 ]. All studies estimated the risk ratios compared to non-smokers [ 66 ], except for one review, in which light smokers were compared to moderate smokers.

Included reviews showed that the risk of stillbirth, birth defects, preterm birth and perinatal death elevated as the number of cigarettes increased [ 4 , 38 , 39 , 46 ]. In contrast, smoking not only protected against pre-eclampsia but the risk reduced as exposure increased [ 67 ].

A dose-response relationship was found in five reviews although a pooled estimation was not calculated. They reported an increased risk for placental abruption [ 68 ], and for the offspring the risk of being overweight [ 57 ], having oral clefts [ 29 , 50 ], or a decrease in cognitive abilities [ 53 ] increased along with the number of cigarettes that the mothers consumed. Five reviews included studies reporting a dose-response relationship along with others that did not find any relationship [ 1 , 41 , 51 , 56 , 69 ]. Therefore, it was not clear whether or not the risk for some conditions (pre-eclampsia, and in the offspring asthma, attention deficit hyperactivity disorder, and vision difficulties) was affected by the number of cigarettes consumed.

Six reviews observed no significant association between the number of cigarettes consumed and the risk of health conditions for the children exposed to maternal SDP, although overall they reported a significantly increased risk. These studies covered congenital heart diseases [ 65 ], central nervous system tumors [ 64 ], childhood neuroblastoma [ 63 ], lower respiratory infections (LRI) [ 37 ] and lymphoblastic leukaemia [ 66 ], and reduced menarche age in daughters [ 61 ].

Impacts of postnatal maternal smoking on infants

The main findings of the reviews which investigated the impact of postnatal smoking on the infants are shown in Additional file 1 : Table S7. The reviews showed an increased impact on asthma, LRI, SIDS and wheezing but not on leukaemia and obesity. However, in some studies, it was not clear whether or not the mothers included in the studies smoked during the whole pregnancy as well as the postpartum period. This is a significant consideration as one study reported by Oken et al. [ 57 ] found no increase in the prevalence of obesity when the mother smoked only after birth, whereas smoking before and throughout pregnancy were found to be related with an increased risk [ 70 ].

Impact of second-hand smoking by partners

In addition to active smoking, SHS during pregnancy could have health implications. It was important to understand whether the health-related risks were higher when partners smoked during pregnancy. Therefore, partner-related findings of the included reviews were analysed. Partner smoking was considered in only 12 reviews of which six did not assess the impact of SHS specific to the pregnancy period (Additional file 1 : Table S8). None of the studies reported the combined impact of SDP and SHS by the partner during pregnancy. Two reviews reported an increased risk of SIDS [ 71 ] and delay in mental development [ 25 ] when the partners of non-smoking women smoked during pregnancy, while no association was found for brain tumors [ 72 ] or breast cancer risk in daughters [ 73 ].

Sub-group analyses in the included reviews

The reviews conducted sub-group analyses to assess the impact of study design, sample size, the duration of the infant exposure to smoking (i.e. pre-pregnancy, first trimester or the whole pregnancy) and adjustments for confounding factors. The study findings did not differ significantly in most of the analyses except for adjustments for confounding and study quality. The evidence was not sufficient to make a comparison based on country income groups because most studies were from high-income countries.

Although the included meta-analyses utilised the most adjusted estimations of observational studies when pooling their results, only 10 of the included reviews provided risk ratios for adjusted and unadjusted estimations (Additional file 1 : Table S9). Studies with unadjusted ratios estimated greater values for miscarriage, perinatal death, SDIS, overweight and obesity.

Sub-group analyses based on quality appraisal of the included studies were conducted in 14 reviews (Additional file 1 : Table S10). The results showed that high-quality studies reported higher ratios for some conditions (overweight, obesity, placenta previa) as opposed to lower or insignificant ratios for some others (e.g. LBW, miscarriage, stillbirth).

Two reviews [ 46 , 74 ] compared the type of smoking status data and found similar results for biochemical and self-reported data. The exposure period was researched in five reviews [ 40 , 41 , 46 , 64 , 75 ], and the results showed no significant difference between women who quit early in pregnancy and those who did not smoke.

Causal link analysis

The causal link analysis identified a range of health conditions found to have strong association with SDP; these are presented in Table 2 , grouped according to the strength of evidence.

Nearly all of the conditions for which a strong association was identified fulfilled the criteria for a causal link. The health conditions were largely reported by moderate- or high-quality reviews and there were consistent findings in the sub-group analyses. There was not a sufficient biological explanation to the correlation found between hyperemesis gravidarum and SDP, hence although there was a strong association, a causal link could not be confirmed.

This study analysed the health impacts of smoking during pregnancy and during the postpartum period on mothers and infants. The 64 included reviews covered 1744 studies relating to SDP or smoking during the postpartum period. The review found that maternal SDP has short-term and long-term health consequences, suggesting a positive association between 20 infant-related and seven mother-related conditions, and a negative association with two maternal conditions. The review did not find a statistically significant impact of SDP on 15 infant-related conditions while conflicting findings were reported for leukaemia and lymphoma.

The causal link analysis of the conditions that were found to have an association with SDP suggested that five mother-related and 10 infant-related conditions had a causal link with SDP. PPROM and intellectual disability in children did not fulfil the criteria for the casual link although meta-analyses reported a statistically significant relationship with SDP.

Health conditions with conflicting results

Some health conditions were assessed in multiple meta-analyses and they reported conflicting results. For instance, the increased risk of having any type of birth defect was statistically significant despite being small in the effect size (OR = 1.18, 95% CI, 1.14–1.22) in one review [ 39 ] as opposed to a borderline ratio (OR = 1.01, 95% CI, 0.96–1.07) reported in another [ 44 ]. The main difference was the reduced risk of skin defects (OR = 0.82, 95% CI, 0.75–0.89) which was included in the latter [ 44 ] while omitted in the former [ 39 ] without any justification. All five studies included in this meta-analysis reported a negative relationship and the heterogeneity was low ( P  = 0.00001, I 2  = 0%). Therefore, the evidence suggested an increased risk of birth defects except for skin defects amongst SDP exposed children. However, there was no biological explanation for the potential protective impact of SDP on skin defects.

Another health condition with mixed findings was leukaemia. One meta-analysis [ 64 ] including 19 studies indicated an insignificant decreased risk (OR = 0.99, 95% CI, 0.92–1.06) whereas another review [ 66 ] of 21 studies found an increased risk (OR = 1.10, 95% CI, 1.02–1.19). The difference could be explained by the different studies included, since there were only five studies common to both, and the association between SDP and leukaemia is unclear.

Similarly, the reviews reported different results for lymphoma. One meta-analysis [ 55 ] found an insignificant association between any lymphoma and SDP based on eight studies (OR = 1.10, 95% CI, 0.96–1.27), although positive relationship for non-Hodgkin lymphoma was reported (OR = 1.22, 95% CI, 1.03–1.45, n  = 8). Another review [ 64 ] which included six studies found an increased risk for any lymphoma (OR = 1.21, 95% CI, 1.05–1.34). Hence, SDP increases the risk of non-Hodgkin lymphoma but for other types of lymphoma the impact is unclear.

Strengths and limitations of the umbrella review

To the best of the authors’ knowledge, this is the first umbrella review on the topic and provides the most systematic and comprehensive assessment of the current evidence. The criteria to assess any causal links are an important consideration. The tool developed by Hill [ 22 ] is widely recognised for assessing causation. In addition to these criteria, this study considered the quality of reviews and the findings of sub-group analyses. Hence, the conditions identified by the causal link analysis are very likely to have a causal link with SDP.

The review has some limitations. Firstly, although systematic reviews are accepted as the highest in the evidence hierarchy [ 76 , 77 ], the focus on systematic reviews alone meant some health conditions were not covered. Some original studies have indicated the impact of SDP on other infant-related conditions, such as diabetes [ 78 ], hypomania [ 79 ], otitis [ 80 ] and pervasive development disorder [ 81 ], which were not assessed in a systematic review, and as a result were not included in this study. Furthermore, SDP has been shown to be related to the smoking uptake of the offspring [ 82 , 83 ]. There are also some maternal health conditions found to be related to smoking whilst pregnant in one study; vein thrombosis, myocardial infarction, influenza or pneumonia, bronchitis, gastrointestinal ulcers [ 84 ]. However, the current study focused on the conditions for which there was strong evidence from systematic reviews.

The methodological limitations of the original studies covered in the included reviews should be born in mind when interpreting the results of the current review. First, long-term implications of SDP were often tested retrospectively by asking mothers whether or not they had smoked during pregnancy. This clearly has limitations as these studies were not designed to compare the offspring of smoking mothers with the children of non-smoking mothers to determine differences in their health, but rather to compare the exposure in children with particular conditions and those without these conditions. The second issue is the usual reliance on mother’s memory and openness about their smoking behaviour is unsatisfactory. The third issue is the impact of confounding factors. For example, a seven-year-old child with diagnosed asthma could have a mother who smoked during pregnancy only and a father who smoked during pregnancy and the postpartum period. To minimise the impact of this the most adjusted estimations were reported in this review.

The review in the context of literature

Two previous scoping reviews were conducted to define the health outcomes of SDP although they did not focus on systematic reviews [ 9 , 11 ]. The scoping review by Jones et al. [ 11 ] was more comprehensive and included 32 health conditions. A quality assessment was not conducted but specific criteria were used to assess the strength of the evidence. According to the criteria, Jones et al. suggested that the evidence for a link between obesity and SDP was not strong [ 11 ]. However, the current analysis suggests a causal link due to the inclusion of two subsequently published systematic reviews [ 32 , 43 ].

Some of the health conditions covered in this study were also included in the review by Godfrey et al. but often higher ratios were reported [ 9 ]. This might be because they included narrative reviews which did not separate maternal SDP and postnatal passive smoke exposure while estimating the summary risk ratios [ 24 , 85 , 86 , 87 ]. Moreover, none of the previous reviews analysed the impact of the number of cigarettes consumed, partners’ smoking and postpartum smoking on infants. Therefore, the current review is more comprehensive and more systematic than previous studies.

Gaps in the literature

The study identified important gaps in the literature which warrant further research. In particular, there is a need to further our understanding of dose-response association, the impact of postnatal smoking, and SHS during pregnancy. Current evidence on the impact of number of cigarettes consumed suggests that even low amounts of cigarette consumption during pregnancy have significant health outcomes and there is a clear gradient for some conditions. This indicates the importance of smoking cessation during pregnancy and if reduction in smoking which is often not addressed in smoking cessation interventions designed for pregnant women.

Only two studies assessed the impact of SHS by partners during pregnancy when the mother was a non-smoker. There was no review reporting the combined impact of SDP and SHS by partners during pregnancy while two reviews reported increased risks for SID [ 43 ] and delay in mental development [ 25 ] when only the partner smoked during pregnancy. Hence, more research is needed to understand the impacts of having a smoking partner during pregnancy.

This study has shown that smoking during pregnancy and the postpartum period has significant health consequences for mothers and infants. It is important to encourage pregnant smokers to quit smoking or reduce the number of cigarettes consumed if they are not prepared to quit entirely since the existing evidence indicates a dose-response association. Similarly, the impact of SHS needs to be considered to promote a smoke-free environment for the mother and infant.

Availability of data and materials

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Abbreviations

• Smoking during pregnancy

Low birth weight

Lower respiratory infections

High-income countries

Low and middle-income countries

Centre for Reviews and Dissemination

Second-hand smoking

Sudden infant death syndrome

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No funding was received specifically for this review. It was conducted as part of the lead author’s PhD research at the University of Birmingham, which was funded by the Turkish Ministry of Education. Hugh McLeod’s time is supported by the National Institute for Health Research Applied Research Collaboration West (NIHR ARC West) at University Hospitals Bristol and Weston NHS Foundation Trust.

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The search strategy was developed by the research team. TSA conducted the review, analysed the data, and drafted the manuscript. Second reviewing was done by HM and LJ. HM and LJ provided inputs in analysing the data and drafting the manuscript. All authors read and approved the final manuscript.

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Avşar, T.S., McLeod, H. & Jackson, L. Health outcomes of smoking during pregnancy and the postpartum period: an umbrella review. BMC Pregnancy Childbirth 21 , 254 (2021). https://doi.org/10.1186/s12884-021-03729-1

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DOI : https://doi.org/10.1186/s12884-021-03729-1

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Study Protocol

Tobacco, nicotine, and cannabis use and exposure in an Australian Indigenous population during pregnancy: A protocol to measure parental and foetal exposure and outcomes

Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliations Wide Bay Hospital and Health Service, Hervey Bay, Australia, Rural Clinical School, The University of Queensland, Brisbane, Australia

Roles Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Writing – review & editing

Roles Conceptualization, Supervision, Writing – review & editing

Affiliation Butchulla Aboriginal Corporation, Fraser Coast, Australia

Affiliations Butchulla Aboriginal Corporation, Fraser Coast, Australia, Butchulla Mens Business Association, Fraser Coast, Australia

Roles Resources, Supervision, Writing – review & editing

Affiliation Galangoor Duwalami Primary Healthcare Service, Fraser Coast, Australia

Roles Conceptualization, Methodology, Resources, Supervision, Writing – review & editing

Roles Conceptualization, Methodology, Supervision, Writing – review & editing

Roles Methodology, Writing – review & editing

Affiliation School of Pharmacy, The University of Queensland, Brisbane, Australia

Roles Methodology, Supervision, Validation, Writing – review & editing

Roles Methodology, Resources, Supervision, Validation, Writing – review & editing

• Angela Ratsch, 
• Elizabeth A. Burmeister, 
• Aunty Veronica Bird, 
• Aunty Joyce Bonner, 
• Uncle Glen Miller, 
• Aunty Marj Speedy, 
• Graham Douglas, 
• Stevan Ober, 
• Ann Woolcock (nee Geary–Laverty), 

• Published: September 6, 2024
• https://doi.org/10.1371/journal.pone.0300406
• Reader Comments

The Australian National Perinatal Data Collection collates all live and stillbirths from States and Territories in Australia. In that database, maternal cigarette smoking is noted twice (smoking <20 weeks gestation; smoking >20 weeks gestation). Cannabis use and other forms of nicotine use, for example vaping and nicotine replacement therapy, are nor reported. The 2021 report shows the rate of smoking for Australian Indigenous mothers was 42% compared with 11% for Australian non-Indigenous mothers. Evidence shows that Indigenous babies exposed to maternal smoking have a higher rate of adverse outcomes compared to non-Indigenous babies exposed to maternal smoking ( S1 File ).

The reasons for the differences in health outcome between Indigenous and non-Indigenous pregnancies exposed to tobacco and nicotine is unknown but will be explored in this project through a number of activities. Firstly, the patterns of parental and household tobacco, nicotine and cannabis use and exposure will be mapped during pregnancy. Secondly, a range of biological samples will be collected to enable the first determination of Australian Indigenous people’s nicotine and cannabis metabolism during pregnancy; this assessment will be informed by pharmacogenomic analysis. Thirdly, the pharmacokinetic and pharmacogenomic findings will be considered against maternal, placental, foetal and neonatal outcomes. Lastly, an assessment of population health literacy and risk perception related to tobacco, nicotine and cannabis products peri-pregnancy will be undertaken.

This is a community-driven, co-designed, prospective, mixed-method observational study with regional Queensland parents expecting an Australian Indigenous baby and their close house-hold contacts during the peri-gestational period. The research utilises a multi-pronged and multi-disciplinary approach to explore interlinked objectives.

A sample of 80 mothers expecting an Australian Indigenous baby will be recruited. This sample size will allow estimation of at least 90% sensitivity and specificity for the screening tool which maps the patterns of tobacco and nicotine use and exposure versus urinary cotinine with 95% CI within ±7% of the point estimate. The sample size required for other aspects of the research is less (pharmacokinetic and genomic n = 50, and the placental aspects n = 40), however from all 80 mothers, all samples will be collected.

Conclusions

Results will be reported using the STROBE guidelines for observational studies.

We acknowledge the Traditional Custodians, the Butchulla people, of the lands and waters upon which this research is conducted. We acknowledge their continuing connections to country and pay our respects to Elders past, present and emerging.

Notation: In this document, the terms Aboriginal and Torres Strait Islander and Indigenous are used interchangeably for Australia’s First Nations People. No disrespect is intended, and we acknowledge the rich cultural diversity of the groups of peoples that are the Traditional Custodians of the land with which they identify and with whom they share a connection and ancestry.

Citation: Ratsch A, Burmeister EA, Bird AV, Bonner AJ, Miller UG, Speedy AM, et al. (2024) Tobacco, nicotine, and cannabis use and exposure in an Australian Indigenous population during pregnancy: A protocol to measure parental and foetal exposure and outcomes. PLoS ONE 19(9): e0300406. https://doi.org/10.1371/journal.pone.0300406

Editor: Souparno Mitra, NYU Grossman School of Medicine: New York University School of Medicine, UNITED STATES OF AMERICA

Received: March 17, 2024; Accepted: July 17, 2024; Published: September 6, 2024

Copyright: © 2024 Ratsch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion.

Funding: Angela Ratsch (AR) the lead author, recieved a Queensland Health Advancing Clinical Practice Research Fellowship for this project (Round 2). The funder https://www.health.qld.gov.au/research-reports/research/researchers/grants-support/clinical-research-fellowships had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript, however choose it in a Queensland-wide competitive funding round for funding ($300000 over 4 years).

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CO, carbon monoxide; DAGs, directed acyclic graphs; mRNA, messenger ribonucleic acid; nAChR, nicotinic acetylcholine receptors; NMR, nicotine metabolite ratio; NRT, nicotine replacement therapy; POC, point of care; QAIHC, Queensland Aboriginal and Torres Strait Islander Health Council; NOTICE, Ratsch Assessment of Tobacco and Nicotine; SIDS, sudden infant death syndrome; SNPs, single nucleotide polymorphisms; TNE, total nicotine equivalents

Introduction

In 1957, Simpson [ 1 ] reported a dose-response association between maternal smoking and premature birth. This observation resulted in a world-wide research agenda focusing on the impact of maternal smoking in pregnancy, the findings of which indicate that maternal tobacco smoking, and exposure to the products of tobacco combustion (i.e., secondhand smoke exposure) are the leading modifiable risk behaviours associated with adverse maternal and neonatal outcomes. Maternal exposure increases the risk for miscarriage, ectopic pregnancy, antepartum bleeding, placental abruption, placenta previa, postpartum haemorrhage and alters maternal thyroid function [ 2 , 3 ]. Counterintuitively, smoking in pregnancy is associated with decreased hypertensive disorders of pregnancy [ 4 , 5 ]. For the foetus, maternal exposure increases the risk of stillbirth, premature birth and lower birthweight [ 6 ] as well as increases the risk for a number of congenital abnormalities [ 7 , 8 ]. Longer-term, offspring exposed in-utero to maternal smoking have decreased cognitive achievement [ 9 ] and an increased risk for the development of attention-deficit/hyperactivity disorder (ADHD) [ 10 ].

In Australia, these adverse pregnancy and foetal findings have ensured a prenatal focus on maternal smoking behaviour with the mother’s cigarette smoking status obtained during antenatal assessment and recorded in the National Perinatal Data Collection [ 11 ] twice across the nine months of pregnancy (once < 20 weeks gestation, and once >20 weeks gestation). In that database, the 2021 rate of smoking by Australian non-Indigenous expectant mothers was reported as 11% compared with 42% by Australian Indigenous expectant mothers [ 12 ]. However, the maternal use of other tobacco and nicotine products including e-cigarettes, hookahs, chop-chop tobacco, nicotine tooth cleaning powder, chewing tobacco, and nicotine spray, mist, lozenges, gum and patches, and cannabis is not collected. In addition, this focus on maternal cigarette smoking fails to recognise second- and third-hand maternal nicotine vape and tobacco and cannabis smoke exposure, i.e., the impact from paternal and household tobacco, nicotine and cannabis exposure on maternal and foetal outcomes is overlooked.

This assessment gap results in maternal and foetal tobacco, nicotine and cannabis exposure misclassification and ramifications in the planning of care, and in the estimation of adverse maternal, placental, foetal and neonatal outcomes from tobacco, nicotine and cannabis exposure. Nevertheless, the literature indicates that Indigenous babies exposed to maternal smoking have a higher rate of adverse outcomes compared to non-Indigenous babies exposed to maternal smoking, for example, after adjusting for maternal age and other factors, smoking in pregnancy is attributable to 22% of pre-term Indigenous births compared with 5% for non-Indigenous births [ 13 ]. Gestational age impacts birthweight, and for Indigenous mothers who smoked in the first 20 weeks of pregnancy, the risk of a lower birthweight baby was 1.8 (or about 80% higher risk) than among Indigenous mothers who did not smoke in the first 20 weeks. For non-Indigenous mothers who smoked in pregnancy, this risk was 1.3 (or 30% higher risk) [ 14 ].

The other significant foetal outcome attributable to maternal smoking is stillbirth. In Australia, stillbirth is defined as foetal death prior to birth of the baby at 20 weeks gestation or more, and/or weighing 400 grams or more [ 15 ]. In 2020, the overall Australian stillbirth rate was 7.7/1000 births, with the rate for Indigenous mothers being 11.9/1000 compared with 7.4/1000 for non-Indigenous mothers. Smoking in pregnancy is a risk factor for stillbirth; for women who smoked in pregnancy, the stillbirth rate was 12.8 stillbirths/1000 births compared to 6.9 stillbirths/1000 births for mothers who did not smoke [ 15 ]. Sub-category analysis of smoking and stillbirth for Indigenous mothers compared to non-Indigenous mothers is not published.

The reasons for the differences in pregnancy outcome between Indigenous and non-Indigenous pregnancies exposed to tobacco and nicotine are unknown but will be explored in this project through a number of activities.

Nicotine: Pregnancy health and the developing human

Currently, tobacco assessment in pregnancy is focused on ‘smoking’. This emphasis overlooks the absorption of the pharmacologically active, dose-dependent, potentially lethal component of tobacco-which is nicotine [ 16 ]. This study is premised on some of the actions of nicotine. In brief, nicotine binds with and activates nicotinic acetylcholine receptors (nAChR) in central and peripheral neuronal and non-neuronal tissue, at neuromuscular junctions, and in the adrenal medulla [ 17 ]. Receptor type and individual variability, including genetics and pregnancy, result in receptor up-regulation or desensitization [ 16 , 18 ] and the release of neurotransmitters including acetylcholine, norepinephrine, dopamine, serotonin, vasopressin, beta-endorphin and adreno-corticotropic-hormone, thus impacting the vasculature and producing vasoconstriction, increasing heart rate and blood pressure [ 19 ].

In pregnancy, nicotine acts both directly on nAChRs in the developing placenta, reducing the number of nAChR receptors [ 20 ], and alters placental morphology and vascularity [ 21 ]. Nicotine also readily crosses the placenta and stimulates nAChRs in the developing foetus impacting foetal systems, albeit in an immature physiology [ 22 ]. During early foetal development (4–6 weeks of gestation), nAChRs emerge and begin to form connections throughout the body including the brain [ 23 ], with construction of axons and synaptic connections in the brain continuing after birth into childhood, adolescence and young adulthood [ 24 ]. In the foetal brain, nicotine exposure results in accelerated cell development relative to tissue and organ age, that is, there are fewer cells correctly developed for their stage and age [ 25 ]. Following nicotine exposure, changes in nAChRs and neural plasticity result in both a deficit in the number of neurons in the foetal brain and synaptic level damage to the respiratory center, with equivalent damage to the adrenal glands [ 26 ]. Foetal nicotine exposure ultimately results in a dampened response to hypoxic episodes [ 27 ]. These physiological changes are important in understanding links between maternal nicotine exposure and foetal outcomes, for example, stillbirth and Sudden Infant Death Syndrome (SIDS).

Nicotine metabolism and excretion

Nicotine has a half-life of about two hours and is metabolised via the CYP2A6 pathway primarily in the liver, with the brain, kidneys and lungs providing minor sites [ 28 ]. This short half-life produces large nicotine serum plasma fluctuations and poses challenges for intra- and inter-person comparisons of exposure, consumption and effect. However, cotinine (the main tobacco and nicotine metabolite) has a half-life of approximately 17 hours and serum concentrations 10-fold higher than nicotine, providing a more stable biomarker of tobacco and nicotine exposure [ 29 ]. Cotinine begins to metabolise after approximately 16 hours into trans-3’-hydroxycotinine (3-OH-cotinine), nornicotine, nicotine glucuronide and nicotine-N-oxide [ 18 ]. A more accurate assessment of tobacco and nicotine exposure is achieved by measuring serum tobacco and nicotine and metabolite concentrations (total nicotine equivalents–TNE), as opposed to measuring only nicotine concentration [ 30 ].

During pregnancy, nicotine metabolism is impacted both by individual variability [ 16 ] and the changes created by pregnancy. In the expectant mother, there is a significant induction of CYP2A6 activity which increases plasma clearances of nicotine by 60% and cotinine by 140%, in addition, there is an almost 50% reduction in cotinine half-life (down from 17 hours to 9 hours [ 31 ]). This is important in the consideration of tobacco and nicotine use in pregnancy as decreases in nicotine and cotinine measurements in late pregnancy compared with pre-pregnancy or early pregnancy may not necessarily indicate a decrease in tobacco and nicotine exposure, but rather the more rapid metabolism of nicotine [ 32 ]. In the foetus and neonate, the immature and undeveloped CYP2A6 pathway decreases their ability to metabolise nicotine and results in a much longer plasma nicotine half-life than adults (11.2 hours compared to 2 hours) whereas cotinine elimination is similar to that of adults (16.3 hour half-life compared with 17 hours) [ 33 ].

CYP2A6, the major nicotine‐oxidising enzyme, is measurable using the nicotine metabolite ratio (NMR; 3′hydroxycotinine:cotinine) and is a biomarker of nicotine clearance [ 16 ]. However, NMR is highly heritable (~80%) varying with ethnicity, in part due to CYP2A6 variants. Variation in CYP2A6 genes has not been characterised in Australian Indigenous populations and may contribute to increased/decreased pregnancy risk from tobacco and nicotine exposure.

Tobacco, nicotine and the metabolites are rapidly excreted by the kidneys with the rate dependent upon urinary pH, where increased urine alkalinity decreases excretion [ 34 ]. Urinary excretion is further impacted in pregnancy due to elevated creatinine potentially leading to fluctuations in nicotine and its metabolites [ 35 ]. Thus, serum provides a measure of exposure and the recency of that exposure, while urine analysis provides a measure of tobacco and nicotine metabolism and excretion.

Materials and methods

Aim and objectives.

The aim of this study is to develop a foundation from which approaches to tobacco and nicotine assessment, health literacy, tobacco and nicotine cessation, and maternal and neonatal health care delivery for families expecting an Australian Indigenous baby is informed by contemporary evidence. Community input on the design suggested that cannabis use (with and without tobacco) is also prevalent and continues throughout pregnancy, thus cannabis use and exposure have been included.

The objectives are to:

• Accurately describe parental and close household contact(s) peri-gestational patterns of use and exposure of tobacco, nicotine and cannabis products through the creation and use of a validated assessment tool.
• Determine the pharmacokinetic and pharmacogenomic impacts and outcomes of tobacco, nicotine and cannabis exposure. This study will be the first to establish the metabolism of tobacco, nicotine and cannabis during pregnancy by using NMR as a biomarker of individual differences in nicotine and cannabis metabolism in a parental Australian Indigenous population.
• Describe maternal, paternal, placental, foetal and neonatal outcomes according to the use and exposure to tobacco, nicotine and cannabis products and biochemical and genomic analysis.
• Describe the influences and barriers to cessation for pregnant Australian Indigenous families or close household contacts to reduce or cease tobacco, nicotine and/or cannabis use in pregnancy.

Research governance

This project is centred around the local Australian Indigenous population in the Fraser Coast area (Queensland, Australia). The research will be conducted primarily from Galangoor Duwalami Primary Healthcare Service (the local Aboriginal and Torres Strait Islander Primary Health Service in Hervey Bay and Maryborough) and at the Hervey Bay and Maryborough Hospitals within the Wide Bay Hospital and Health Service (WBHHS).

Galangoor Duwalami Primary Healthcare Service were consulted in regard to which Community members would best represent the Traditional Owners of the land where this research is to be conducted. A combined leadership group was formed which included the Butchulla Aboriginal Corporation and Butchulla Men’s Business Association and this group advised, directed and oversaw the conversations around this research from its inception and arranged for discussions with the appropriate Community members. Under the Butchulla Aboriginal Corporation’s Rule Book, the principal Objective of the corporation is to: ‘Relieve poverty and disadvantage of the Butchulla People through the advancement of education, health, social or public welfare, and culture’. Accordingly, the Elders have approved this proposal and provided a Butchulla name for the project– Ngabang (mother), Walbai (baby), Babun (father). The project logo ( Fig 1 ) reflects the aspirations of the Butchulla people for this project, which are to strive for a healthy pregnancy , which results in a healthy family , which maintains a healthy culture .

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• PNG larger image
• TIFF original image

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The logo also recognises the governance of the project by the Butchulla people, Galangoor Duwalami Primary Healthcare Service, the various Australian research guidelines, and the collaborative nature of the project with other health providers and research-intensive organisations and academic partners. The project documentation, and staff and participant shirts and onesies carry this logo (Figs 2 and 3 ).

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Research context

Galangoor Duwalami Primary Healthcare Service generally maintain the sole care of the pregnant women until approximately 20 weeks gestation (unless they have a high-risk pregnancy). The mother then moves to a shared care model with the Hervey Bay and Maryborough Hospitals. In this project, data is collected across the entire pregnancy. The preferred site of data collection from Galangoor Duwalami Primary Healthcare Service patients will be at Galangoor Duwalami Primary Healthcare Service for as long as possible during the pregnancy, however some data collection will need to occur at antenatal visits at the Hervey Bay or Maryborough Hospitals. At birth (mostly likely at the Hervey Bay Hospital), biological samples will be collected, and birthing data will be collected on the participant’s discharge from hospital.

Inclusion and exclusion criteria and consent

Potential participants who meet the following criteria will be invited to enrol in the study: pregnant mothers, aged 15 years or older at the time of enrollment, able to understand English, able to provide informed consent, and who self-identify as being pregnant with an Australian Indigenous baby. In accordance with the value of Respect outlined in the National Statement of Ethical Conduct in Human Research [ 36 ], all potential maternal participants meeting the inclusion criteria will be carefully considered by the clinic midwife or healthcare medical officer to ensure the healthcare staff believe that potential enrolment is in the best interest of the participant at this point in their pregnancy. A list of suitable potential maternal participants will then be provided to the researchers; only those participants will be provided with research information.

The project will strive to enrol the family unit i.e., the mother, and the foetus, and the biological father, or non-biological parent partner (the parents), or one close household contact. For example, if an expectant mother lives with her sister or aunty or grandmother but there is no biological father in the family at that time, or there is a partner (of either gender) and that close family contact attends the antenatal visits with the maternal participant, that person will be invited to participate with the expectant mother. Family members do not have to participate; however, ‘family’ is central to Australian Indigenous people, and enrolling participants who constitute the cultural norm of family will be especially important in the translation of findings to the participant and the community.

Consent: Participants can choose to enrol in any or all aspects of the data and sample collection, and they can withdraw from any or all aspects of the research at any time. The consent process enables participants to choose to have their individual results provided back to them at the completion of the project; for any or all samples to returned to the participant on completion of this project; or for the de-identified samples and de-identified data to be retained for ethically approved un-identified projects in the future. All enrolled participants will receive a participant shirt ( Fig 2 ), and liveborn newborns will receive a project onesie ( Fig 3 ).

A subset of information-rich tobacco, nicotine and/or cannabis use/exposed participants will be enrolled into the separate male and female qualitative aspects of the study until saturation is reached (~30 participants). Data will be collected in response to a range of trigger questions and survey questions. Participants enrolled in the qualitative data collection will receive a $50 grocery voucher in acknowledgement of their time to the project.

Tobacco, nicotine and cannabis use and exposure data and biological sample collection.

The quantitative data and sample collection for Objectives 1–3 is designed to measure maternal tobacco, nicotine and cannabis use, and maternal and foetal exposure, metabolism and excretion at varying times throughout the pregnancy and assess the findings against the maternal and foetal outcomes. At each antenatal appointment and at birth, tobacco, nicotine and cannabis use and exposure information will collected on a N ic OTI ne , tobacco , and C annabis use and E xposure ( NOTICE ) Assessment Tool ( Fig 4 (Page 1), Fig 5 (Page 2) and see Box 1 NOTICE Notes).

(Page 1). NOTICE: NicOTIne, tobacco, and Cannabis use and Exposure (NOTICE) Assessment Tool.

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(Page 2). NOTICE: NicOTIne, tobacco, and Cannabis use and Exposure (NOTICE) Assessment Tool.

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Box 1. NicOTIne tobacco, and Cannabis use and Exposure (NOTICE) Assessment Tool–Notes

The N ic OTI ne tobacco, and C annabis use and E xposure ( NOTICE ) assessment tool ( Fig 4 ) has been developed by Angela Ratsch for this study to enable a comprehensive assessment of the use of smoked and smokeless tobacco and cannabis products as well as nicotine containing products. The tool also allows for the detailing of second-hand exposure, and is used in this protocol to inform the use and exposure of all products throughout the pregnancy. The recorded information facilitates a scoring method to determine the level of self-reported use and exposure to tobacco, nicotine and cannabis products (scored for the day of assessment, previous 24 hours, and the previous week).

A self-use weekly score will be calculated for each assessment completed. Scoring for self-use will be categorized for each product as: 0—no use; 1 –low use (1 to 70 combusted or inhaled products); 2 –medium use (71–140 combusted or inhaled products); 3 –high use (141 + combusted or inhaled products). A self-use score will be calculated for each weekly product combusted or inhaled with the sum of these scores producing a total weekly self-use score with a range of 0–30. An exposure score will be calculated for each weekly product exposed to by multiplying the quantity exposed to score by the exposure. Exposure is categorized as 0—no exposure; 1- some limited exposure; 2 -moderate exposure or 3—unrestricted exposure. A total weekly exposure score is then calculated by summing all the exposure scores with a range of 0–99 for each assessment completed.

The assessment takes about 3 minutes to complete and will be conducted at each antenatal visit and immediately prior to birth.

Exhaled breathe carbon monoxide (CO) assessment

CO as a point of care (POC) assessment provides indicative information about combusted tobacco/cannabis use up to 24 hours previously. Exhaled CO monitors (Smokerlyser®) provide a CO ppm reading ranging between 0 and 30 and a percentage of oxygen replaced with CO on haemoglobin (%COHb) with higher readings indicating higher levels of combusted tobacco/cannabis use. The same device can measure foetal exposure as foetal carboxyhaemoglobin (%FCOHb). Readings for the level of CO ppm are categorized as:

• green—for no and general environmental combusted tobacco/cannabis exposure, indicated by CO <3 ppm for pregnant women, and CO <6 ppm for non-pregnant adults;
• orange—moderate combusted tobacco/cannabis exposure, indicated by CO 4–6 ppm for pregnant women, and CO 7–10 ppm in non-pregnant adults and;
• red—heavy combusted tobacco/cannabis exposure, indicated by CO >6 ppm for pregnant women, and CO >10 ppm in non-pregnant adults.

The assessment takes about 1 minute to complete and will be conducted at each antenatal visit and immediately prior to birth.

Saliva cotinine assessment

The use of non-combusted tobacco products and nicotine substances, for example, chewed tobacco, e-cigarettes, nicotine patches and gum, does not create CO. Instead, cotinine saliva assessment (Oz Drug Tests®), as a POC measurement, can detect cotinine (the major metabolite of nicotine metabolism). The test has a cotinine cut-off value of 10 ng/mL and the expected window of detection for cotinine in saliva at 10 ng/mL is expected to be up to 2–3 days after the last nicotine use. The assessment takes about 3 minutes to complete and will be conducted at each antenatal visit and immediately prior to birth.

Procedure: The CO assessment will be conducted first, and if the CO level is within the yellow or red zone (high levels), a saliva test will not be conducted as these CO levels are indicative of combusted tobacco use and negates the requirement for saliva testing.

Sample collection process

Mother . At the first antenatal appointment, maternal urine, CO and saliva samples will be collected on a NOTICE Tool.

If the CO is within the orange or red zones, a cotinine saliva test will not be conducted. Also, during this first appointment, or when maternal bloods are being collected as part of standard care, maternal vein blood will be collected for this project.

• At each follow-up antenatal visit, maternal urine, CO and saliva (if indicated) will be collected and a NOTICE assessment completed.

Biological father

• At the first antenatal appointment, if the biological father is Indigenous, paternal vein blood, urine and semen will be collected and CO, saliva (if indicated), and a NOTICE assessment completed.
• At each follow-up visit, the biologically paternal CO and saliva (if indicated) samples will be measured and a NOTICE assessment completed.

Non - biological parent, partner or close household member

• At the first antenatal visit, the non-biological parent partner or close household contact will have a CO and saliva (if indicated) measured and a NOTICE assessment completed and these same tests will be conducted at each visit.

Unaccompanied mother

• If the biological father, partner or household member is not present, the expectant mother will report her exposure to the partner’s and/or household member’s combusted tobacco or heated nicotine (e-cigarette) as second-hand exposure on the NOTICE assessment tool.
• On presentation for birth, mothers will have a venous blood sample, urine, CO and saliva samples (if indicated) collected and a NOTICE assessment will be completed.
• At spontaneous or artificial rupture of membranes or caesarean birth, amniotic fluid will be collected.
• Following birth and the separation of the placenta from the mother and neonate, arterial and venous cord bloods will be collected from the placenta.
• The placenta will be weighed in grams, and measured in centimetres at two points, the widest and narrowest to estimate the area of the placenta. Placental photographs of the maternal and foetal side and the cord will be obtained.
• Placental samples for macro, micro-morphological and genomic examination will be obtained, rinsed in a solution of phosphate buffered saline and distilled water and then placed in a solution of RNA later. The placenta sent for standard histology.
• Following birth, neonates will have a Day 0–1 urine and meconium collected. If the neonate remains in hospital after Day 1, a further urine sample will be collected. The urine will be collected with the use of a standard adhesive urine collection devise, and meconium will be collected from the nappy.
• Colostrum/breast milk will be collected when available. As active participants in the knowledge generation from this research, mothers will be encouraged to obtain their own colostrum/breast milk sample by hand/pump expression.

Clinical information.

Data contained in the Galangoor Duwalami Primary Healthcare Service and Hospital record including demographic, maternal, and neonatal data will be included in the research database. Pregnancy, labour and birthing information will be collected from the Queensland Health Perinatal Record following birth.

Biological sample analysis

After labelling, participant samples will be stored in the appropriate solution and/or temperature control manner. Placental samples in RNA later will be transferred to the University of the Sunshine Coast for storage at -80°C. Other samples (excluding the whole placenta in formalin) will be transferred to the local Sullivan and Nicolaides Pathology at standard intervals. Sullivan and Nicolaides will then transfer directly to The University of Queensland for storage at -80°C. The placenta in formalin will be transferred to Queensland Pathology. The scientists undertaking the biological examinations and analysis will be blinded to the self-reported tobacco, nicotine and cannabis status of the participant.

Pregnancy elevates creatinine levels, potentially leading to fluctuations in the levels of nicotine and its metabolites and influencing cannabinoid levels [ 35 ]. To ensure the standardisation of these levels in urine samples during pregnancy, a creatinine analysis will be conducted. The biological samples will be initially analysed for tobacco, nicotine and their metabolites and cannabinoid concentration in ng/mg creatinine or nmol/mg creatinine for urine samples and ng/mL for other biological samples using standard procedures. Following this, the samples will undergo tobacco, nicotine and cannabinoid genomic assessment in relation to tobacco, nicotine and cannabis pharmacokinetics, and other examinations including thyroid antibodies, transthyretin and sENG levels and a genomic-wide analysis of tobacco nicotine and cannabis induced alterations will be conducted. In addition, the colostrum/breast milk microbiome will be considered for the impact of tobacco, nicotine and cannabis exposure.

Qualitative data collection.

Information-rich participants will be invited to take part in a face-to-face interview and survey. The interview and survey will be in the form of a yarn [ 37 – 39 ] which will be conducted at a place of the participants choosing and audio recorded for review. Participants are welcome to have support people with them should they wish. Data will be responses to a range of trigger questions and survey questions to consider the barriers and influences to tobacco, nicotine and cannabis use and cessation, and to understand the population’s health literacy and risk perception related to tobacco, nicotine and cannabis products peri-pregnancy. Participant’s own language and slang will be used when possible. Data will be collected in a coded, but re-identifiable manner to enable researcher and participant follow-up. The code that will be used will be the same as for the participant’s biological and clinical data collection. The codebook will be kept in a separate location to the recording. During the interviews, the participant will only be identified by the unique code.

Outcome assessment

Enrollment maternal blood and urine samples provide a baseline and are correlated to exhaled carbon monoxide (CO), cotinine saliva assessment, and the self-reported tobacco, nicotine and cannabis assessment tool (see Fig 4 and Notes: Box 1 ).

At each antenatal visit, maternal urine is collected and correlated to the CO and saliva assessment and the self-reported tobacco, nicotine and cannabis assessment tool. At birth, a second maternal blood is taken to correlate to the excretion of nicotine and cannabis by the mother and neonate as measured in maternal and neonatal urine, breast milk and meconium. The transfer of nicotine and cannabis to the foetus through the placenta and return to the mother is measured by amniotic fluid, arterial and venous cord blood, and placenta samples.

Outcomes include:

• Parental and close household member’s patterns of self-reported use and exposure to tobacco, nicotine and cannabis using the NOTICE Tool score. Total self-use and total exposure scores will be calculated by summing the total weekly quantity and exposure scores. Scores will then be categorised into clinically meaningful categories, with those reporting no exposure or use categorised as the reference group.
• Tobacco, nicotine, cannabis and their metabolites concentration in ng/ml or nmol/ml. Concentrations of tobacco, nicotine, trans-3’-hydroxycotinine (3-OH-cotinine), nornicotine, nicotine glucuronide and nicotine N oxide, norcotinine, NNAL, nicotelline, anabasine and anatabine [ 40 , 41 ] will be summed with the total concentration in each sample recorded as total nicotine equivalents (TNE) and the nicotine metabolite ratio (NMR: 3′-hydroxycotinine/cotinine) will be calculated [ 42 ]. Similarly, delta-9-tetrahydrocannabinol-D3 (THC-D3) and delta-8 and/or delta-9 carboxy tetrahydrocannabinol-D3 (THC-COOH-D3) will be measured and summed.
• DNA methylation patterns influenced by tobacco, nicotine and cannabis use and exposure will be identified. Methylation levels will be assessed either by immunohistological analysis of methylation intermediates (5mC, 5-hmC) or calculated and expressed as β values (β = intensity of the methylated allele (M))/ (Intensity of the unmethylated allele (U) + intensity of the methylated allele (M) + 100).
• Specific tobacco, nicotine and cannabis induced genomic and DNA alterations related to the use and exposure tobacco, nicotine and cannabis products in the different participant groups (maternal, paternal, foetal placental and neonatal). Genotypes influenced by tobacco, nicotine and cannabis use and exposure will be identified. Genome-wide mRNA profiles will be sequenced and expressed as read counts per mRNA.
• Identified genes and alternations (including gene expression) associated with tobacco, nicotine and cannabis metabolism and pregnancy clinical outcomes. Genes, including CYP2A6 and TCF7L2, with single nucleotide polymorphisms (SNPs) with minor allele frequency greater than 10% will be chosen for inclusion in analyses. PCR results will be reported as negative or positive.
• Semen volume (mL) and quality including sperm concentrations (million per mL), count (million), progressive motility (%), vitality (%), morphology (%), pH (0–14), leucocyte counts (millions per mL).
• CO readings will be used as continuous scores and also categorised as: 1) negligible combusted tobacco/cannabis exposure—indicated by <6 CO ppm for non-pregnant adults and <3 CO ppm for pregnant women; 2) light combusted tobacco/cannabis exposure—indicated by 7–10 CO ppm in non-pregnant adults and 4–6 CO ppm for pregnant women; 3) heavy combusted tobacco/cannabis exposure—indicated by >10 CO ppm in non-pregnant adults and >6 CO ppm in pregnant women.
• Saliva readings will be used as dichotomous scores, categorised as negative or positive
• Maternal and neonatal outcomes including miscarriage, livebirth/stillbirth, gestational age (weeks), preterm birth (<37 weeks gestation), and birth weight (grams), pregnancy induced hypertension and pre-eclampsia, gestational diabetes, thyroid autoimmune disease, maternal anaemia and other factors of interest are listed S1 Table in S1 File .

Sample size.

Approximately 80 women expecting an Indigenous baby attend antenatal care at Galangoor Duwalami Primary Healthcare Service and the Hervey Bay and Maryborough Hospitals each year, and birth at the Hervey Bay Hospital.

Sample size to validate the NOTICE tool: To estimate the sensitivity and specificity of the NOTICE self-reported assessment tool for tobacco and nicotine use and exposure, assuming tobacco and nicotine exposure and use of 66% [ 43 ], a sample of 80 mothers with 5 or more assessments would allow estimation of at least 90% sensitivity and specificity for the screening tool for tobacco and nicotine use and exposure versus urinary cotinine with 95% CI within ±7% of the point estimate [ 44 ]. The collection and validation of the additional tobacco and nicotine products increases both the sensitivity and specificity of the tool. Validation will be to POC CO, saliva cotinine, and blood and urine total nicotine equivalents [ 40 , 41 ]. The collection of cannabis use and exposure measured against urinary cannabinoid concentrations provides an assessment of the tool’s broader utility in pregnancy.

Using multilevel linear regression modelling with urinary cotinine levels as an outcome and adjusted for tobacco and nicotine use and exposure, to estimate a statistically significant change in tobacco and nicotine metabolism during pregnancy in an Australian Aboriginal population, with a power of 80% and alpha level of 0.05, a total of 50 mothers would be required to have a minimum of five tobacco and nicotine urine measurements during pregnancy [ 45 ] assuming an intra-class correlation of 0.3 (or lower) between urinary cotinine levels for each mother during pregnancy. With a power of 80% and alpha level of 0.05, 34 placentas would be required to be examined to estimate a 50 cm 2 difference in area between high and low tobacco and nicotine use/exposure. Enrollment and data collection commenced on 18 th May 2022 and will continue until the sample size is achieved and all data is collected.

Data analysis

Following data cleaning, checking and validation, the participants’ results from the NOTICE scores for tobacco, nicotine and cannabis use and exposure, the biochemical analysis from all biochemical samples, and the maternal and neonatal outcomes will be examined to address the research objectives as described in Table 1 . All data analysis will be conducted using Stata 17 (Statacorp, Texas). Missing data and outliers will be examined and reported. Results will be reported with 95% confidence intervals (95% CI) and statistical significance at alpha 0.05.

https://doi.org/10.1371/journal.pone.0300406.t001

Ethical approval

This project has been approved by the Traditional Owners of the Fraser Coast area, the Butchulla people, in conjunction with Galangoor Duwalami Primary Healthcare Service. The project has the support of the Queensland Aboriginal and Torres Strait Islander Health Council (QAIHC) and has ethics approval from Qhealth (HREC/2021/QRBW/77758) and the University of Queensland (2021/HE002069).

The overarching vision of this clinically derived, clinically driven, community based, mixed method project is to Close the Gap in Aboriginal and Torres Strait health outcomes. This project takes a life-course epidemiological approach to health outcomes, focusing on the start of life, that is, maternal and neonatal health to improve whole-of-life health outcomes.

Seventy years of evidence demonstrates that maternal tobacco smoking and exposure to combusted tobacco are the leading modifiable risk behaviours associated with adverse pregnancy outcomes [ 48 ]. Currently in Australia, the assessment for tobacco and nicotine exposure during pregnancy is focused on maternal cigarette use—no information on other forms of tobacco, nicotine or cannabis use and exposure is standardly collected or considered to inform clinical care. In addition, fathers or other household members are not asked about their tobacco, nicotine and cannabis use. This limited (or absent) tobacco, nicotine and cannabis screening fails to address the broad range of contemporary products that are used in Australia and thus has ramifications for the mother, the father, the children, the clinician, Indigenous populations, and the broader profile of Australian health.

This project will be reported against the STOBE Guidelines and has purposeful and significant objectives. Firstly, the development of a validated tobacco and nicotine screening tool that can be translated to practice Australia-wide will enhance data reporting and the understanding of tobacco, nicotine and cannabis use and exposure to pregnancy outcomes. In addition, the use of a comprehensive and contemporary screening tool will provide an opportunity for women, families and health professionals to discuss tobacco, nicotine and cannabis use and reduction/cessation options.

Secondly, addressing the absence of literature related to the metabolism of nicotine and the influence of pharmacogenomic factors in Australian Indigenous populations will be transformative. As biotechnology has evolved, there has been an increasing recognition that genetics, epigenetics, and environmental interactions impact on health outcomes. The role of genomics in understanding population risks and targeting prevention or intervention programs to reduce risk or to provide treatment based on genomic knowledge (i.e., a precision medicine approach) is of enormous public health benefit. Genomic profiling allows for the understanding of different outcomes in different populations from the same exposure. Already research exists that shows that nicotine is metabolised differently in genetically different populations [ 49 – 53 ] and particular risks are higher or lower in populations based on these genetic differences, however, this same level of understanding has not been established for Australian Indigenous parental populations. A genome-wide mapping of specific biological samples from the local Australian Indigenous parental population in relation to their potential risk from tobacco and nicotine use and exposure and establishing [the start of] a pharmacogenomic profile will structure a precision medicine approach to health care [ 54 , 55 ] for this population.

Comprehension and appreciation of the barriers to tobacco, nicotine and cannabis cessation is an essential mechanism in supporting the decrease in tobacco, nicotine and cannabis use. Awareness these factors can lead to the construction of a range of education and support resources which can be selected by future pregnant women and the family to assist them to reduce or cease tobacco, nicotine and cannabis use in pregnancy.

Importantly, the findings from the tobacco, nicotine and cannabis assessment and analysis will be linked to maternal and neonatal outcomes. Using the screening tool as part of standard practice in the future will provide a predictive methodology, enabling expectant mothers, families and health services to better plan birthing and post-birthing needs in situations where tobacco, nicotine and cannabis exposure is an independent factor.

This research project is built on respect for the value of Indigenous perspectives and their contribution to the study. Indigenous knowledge systems are incorporated into the research methodology thereby mutually enriching the research. Translation to practice is an intended outcome of this project but will not be structured until findings are available. The intention is that translation will be informed by the Indigenous participants, the Aboriginal and Torres Strait Islander health service, the research-intensive organisations supporting this research and their researchers, and the chief researcher.

Limitations

The study consists of some strengths and limitations. One significant strength is the recording of tobacco, nicotine and cannabis use and exposure throughout early to late pregnancy and the collection of a range of biological samples that are used to measure:

• Recency of maternal tobacco and nicotine exposure (maternal CO, saliva, and maternal venous blood and urine),
• The transfer of nicotine to the foetus (venous cord blood, amniotic fluid and neonatal urine),
• The return of nicotine from the foetus (arterial cord blood)
• The longevity of exposure (placenta and meconium)

This approach minimises recall bias and provides a comprehensive and measurable assessment of tobacco and nicotine exposure over the duration of pregnancy. However, the study will only recruit mothers expecting an Australian Indigenous baby in the Fraser Coast area which limits the generalizability of the findings. Additionally, being an observational study, the results will not provide the strongest evidence to establish a causal relationship between nicotine exposure or metabolism and pregnancy outcomes.

Supporting information

S1 file. variables of interest for analysis..

Variables extracted from standard National Perinatal Data Collection report, together with variables of interest for this project (i.e., tobacco, nicotine and cannabis use and exposure).

https://doi.org/10.1371/journal.pone.0300406.s001

S2 File. Inclusivity statement.

https://doi.org/10.1371/journal.pone.0300406.s002

Acknowledgments

This project could not have developed without the overwhelming endorsement and governance of the Traditional Owners of the Fraser Coast area, the Butchulla people and the Butchulla Aboriginal Corporation and the Butchulla Men’s Business Association. Furthermore, this project cannot progress without the consistent and positive leadership of GD, SO, AW and SB at Galangoor Duwalami Primary Healthcare Service and the engaged involvement of the Galangoor Duwalami teams that wrap around and support the Indigenous expectant families of the Fraser Coast area. In particular, the Galangoor Duwalami midwives Skye Gardam and Emma Kendall are sentinel to this partnership. Moreover, the cooperation and involvement of Wide Bay Hospital and Health Services on the Fraser Coast including: maternity, medical, allied health, professional, administration and operational teams in maternity, operating theatre, outpatients, pathology, business support services are essential in ensuring this collaborative project can achieve its aim. Fraser Coast Sullivan and Nicolaides Pathology service are highly supportive of this project and will transport biological samples to Brisbane and the University of Queensland and are providing this service pro bono. In terms of the design, AR conceived, designed the framework of the study, and will lead the data collection. AW, GM, VB, JB and MS guided the data collection design with Indigenous mothers and families and consulted with their respective Indigenous organisations and community members to ensure cultural and community safety and expectations were established. LB designed the statistical analysis and data management plan and will undertake the data analysis. M-TW will undertake the biochemical analysis as a PhD Scholar at the University of Queensland under the supervision of JM and KS.

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• 16. Benowitz NL, Hukkanen J, Jacob P III. Nicotine Chemistry, Metabolism, Kinetics and Biomarkers. In: Henningfield JE, London ED, Pogun S, editors. Nicotine Psychopharmacology. Handbook of Experimental Pharmacology. 192: Springer Berlin Heidelberg; 2009. p. 29–60.
• 22. Beltrán-Castillo S, Bravo K, Eugenín J. Impact of Prenatal Nicotine Exposure on Placental Function and Respiratory Neural Network Development. In: Gonzalez-Ortiz M, editor. Advances in Maternal-Fetal Biomedicine: Cellular and Molecular Mechanisms of Pregnancy Pathologies. Cham: Springer International Publishing; 2023. p. 233–44.
• 24. National Research Council (US) and Institute of Medicine (US) Committee on Integrating the Science of Early Childhood Development. [Internet]. Washington (DC): From Neurons to Neighborhoods: The Science of Early Childhood Development. The Developing Brain: National Academies Press 2000 [cited 2024 29 January]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK225562/ .
• 36. The National Health and Medical Research Council, the Australian Research Council, and Universities Australia. National Statement on Ethical Conduct in Human Research 2007 (Updated 2018). Canberra: Commonwealth of Australia; 2018.
• 48. National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. Reproductive Outcomes. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention (US); 2014. p. 461–521.

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A Large Study Highlights the Dangers of Smoking During Pregnancy

Malte Mueller / Getty Images

Key Takeaways

• Researchers found that people who smoked during pregnancy were more likely to have low-weight babies, go into pre-term labor, and experience a premature rupture of membranes.
• The risks go beyond birth: the study suggests that neurological disorders in childhood might also be associated with cigarette smoking during pregnancy. 
• Quitting smoking is one of the best things you can do to ensure the health of your baby.

Research has long shown that smoking during pregnancy can greatly increase the risks of birth defects. A new study analyzing the outcomes of more than 9 million participants provides further evidence of the adverse outcomes associated with tobacco use during pregnancy.

The study, published in the Journal of Perinatal Medicine , examined the delivery outcomes in over 400,000 smokers and 8.6 million non-smokers in the United States between 2004 and 2014. 

Researchers found that pregnant people who smoked had a 130% increased risk of having a baby that was too small for its developmental stage—heightening the risk of intestinal and urinary disorders, lung problems, and adverse neurological outcomes in childhood.

They also discovered a 40% increased risk of premature birth and a 50% increased risk of rupturing the amniotic sac surrounding the fetus before labor begins.

“Smoking is also associated with congenital malformations and has a negative impact on fetal neurocognitive development,” Ido Feferkorn, MD, a researcher at the McGill University Health Care Center and a co-author of the study, tells Verywell. “Regarding complications to the mother, an increased risk of wound complications and the need for hysterectomy among the smokers was found.”

What Is Hysterectomy

A hysterectomy is the surgical removal of a  uterus . In some cases, other reproductive organs like ovaries and cervix may also be removed during this procedure.

While many studies have shown that smoking during pregnancy can lead to a damaged placenta, undernourished baby, and even stillbirth, this new research examined complications that were only studied in smaller samples.

“The study is impressive because of its size,” Caitlin Dunne, MD , a fertility specialist and co-director of the Pacific Centre for Reproductive Medicine (PCRM), tells Verywell. “In a practical sense, this data matters to doctors because we know more about what to look out for as we care for pregnant patients.”

Smoking Reduced Certain Risks Slightly, But It Doesn’t Mean You Should Start

Interestingly enough, researchers found that smokers had reduced rates of preeclampsia —a pregnancy complication characterized by high blood pressure and liver or kidney damage. If left untreated, preeclampsia could lead to premature births or the need for C-section .

But researchers warned that the lower rate of preeclampsia could simply be related to lower birth weight of the babies among smokers.

The risks associated with smoking during pregnancy still far outweigh any perceived “benefits," Dunne explains.

“I should point out that this does not mean that the authors believe smoking is beneficial,” she says. “These findings may just be a consequence of doing a very large database study without having detailed information about the context of each pregnancy.” 

Dunne also points out that large association studies like this one don't necessarily infer causation, but they can help guide future research that will hone in on the finer details of cause and effect.

Both Feferkorn and Dunne say that while quitting smoking is undeniably difficult, it’s an essential step in ensuring your baby’s well-being.

“I tell my patients: Do your best to quit or cut down on cigarette smoking or vaping. I know that quitting is hard and it often takes many attempts to kick the habit. Don’t be too hard on yourself—just keep trying,” Dunne says. “Quitting smoking is one of the best things you can do for the baby’s health. It’s worth the effort.”

What This Means For You

Smoking during pregnancy presents a host of serious risks to both the short- and long-term health of your baby as well as your own. Though quitting is difficult, it's one of the best things you can do to protect your baby’s health if you do become pregnant.

Knopik VS. Maternal smoking during pregnancy and child outcomes: real or spurious effect?   Developmental Neuropsychology . 34(1):1-36. doi:10.1080/87565640802564366

Feferkorn I, Badeghiesh A, Baghlaf H, Dahan MH. The relation between cigarette smoking with delivery outcomes. An evaluation of a database of more than nine million deliveries .  Journal of Perinatal Medicine . doi:10.1515/jpm-2021-0053

By Mira Miller Miller is a journalist specializing in mental health, women's health, and culture. Her work is published in outlets ranging from Vice to Healthnews.

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Maternal smoking during pregnancy and child outcomes: Real or spurious effect?

Valerie s. knopik.

1 Center for Alcohol and Addiction Studies, Department of Community Health, Brown University, Providence, RI

Maternal smoking during pregnancy (MSDP) is a major public health concern with clearly established consequences to both mother and newborn (e.g., low birth weight, altered cardiorespiratory responses). MSDP has also been associated with higher rates of a variety of poor cognitive and behavioral outcomes in children, including ADHD, conduct disorder, impaired learning and memory, and cognitive dysfunction. However, the evidence suggesting causal effects of MSDP for these outcomes is muddied in the existing literature due to the frequent inability to separate prenatal exposure effects from other confounding environmental and genetic factors. Carefully designed studies using genetically sensitive strategies can build upon current evidence and begin to elucidate the likely complex factors contributing to associations between MSDP and child outcomes.

Introduction

Maternal smoking during pregnancy (MSDP) is a major public health concern with nearly half of all women who smoke continuing to do so throughout their pregnancies ( Centers for Disease Control (CDC), 2002 , 2004 ; Ebrahim, Floyd, Merrit, Decoufle, & Holtzman, 2000 ). As a result, more than half a million infants per year are prenatally exposed to maternal smoking ( CDC, 2004 ; Smith, Martin, & Ventura, 1999 ). Offspring of women who smoke during pregnancy show low birth weight (e.g., Ricketts, Murray, & Schwalberg, 2005 ), increased risk of stillbirth (e.g., Salihu et al., 2008 ), altered cardiorespiratory responses (e.g., Huang et al., 2006 ; Neff, Simmens, Evans & Mendelowicz, 2004 ), and increased asthma and wheezing (e.g., Gilliland, Li, & Peters, 2001 ; Janson, 2004 ; Stocks & Dezateux, 2003 ) as well as behavioral abnormalities, including increased evidence of attentional deficits, impaired learning and memory, lowered IQ, and cognitive dysfunction ( DiFranza & Lew, 1995 ; Levin & Slotkin, 1998 ; Naeye & Peters, 1984 ; Rantakallio & Koiranen, 1987 ; Roy, Seidler & Slotkin, 2002 ; Wakschlag, Lahey, Loeber, Green, Gordon & Leventhal, 1997 ). Despite this large literature suggesting undesirable outcomes in children exposed to MSDP, the underlying biological processes in humans are not well understood. Moreover, the evidence suggesting causal effects of MSDP for these childhood outcomes is muddied in the existing literature due to the frequent inability to separate prenatal tobacco exposure effects from other confounding environmental and genetic factors. Specifically, the vast majority of existing studies provide only limited control for the fact that prenatal exposures may be correlated with parental behaviors that could act as more proximal risk factors that are in turn transmitted to their offspring. Failure to control for such (possibly heritable) confounding factors may account for a large part of the suggested associations between MSDP and offspring outcomes. For example, if mothers with ADHD more commonly smoke during pregnancy, and also confer increased child risk of ADHD via genetic transmission, the observed correlation between MSDP and childhood ADHD would be largely spurious, with limited etiological relevance. Genetically-sensitive study designs can begin to elucidate the likely complex factors contributing to the association between MSDP and child outcomes.

The outcomes associated with MSDP cover broad cognitive and behavioral domains such that a comprehensive review is beyond the scope of this report. Thus, a brief overview of the pertinent literature is provided below and will draw on two bodies of work: (i) animal models of prenatal nicotine, and (ii) human studies of maternal smoking during pregnancy (see Tables 1 and ​ and2). 2 ). The final section will focus on a review of the few genetically informative studies of MSDP. These will be presented within the context of descriptions of a number of different behavior genetic designs that can be used to study the influence of genetic and environmental factors associated with specific measures of the environment.

Selected review of animal models of prenatal nicotine exposure

Selected human models of maternal smoking during pregnancy (MSDP).

Animal models: the role and mode of action of prenatal nicotine

Animal models tend to show the most consistent support of the effects, as well as the mode of action, of prenatal nicotine, which is just one toxic component of cigarettes. Importantly, animal studies do pinpoint nicotine, which partially mimics the actions of acetylcholine, as a neuroteratogen ( Slikker, Xu, Levin & Slotkin, 2005 ). The major outcome variables examined in prenatally exposed animals include birth weight, locomotor activity, and cognitive performance.

Birth weight

Similar to results in humans (e.g., Eskenazi, Prehn, & Christianson, 1995 ; Ricketts et al., 2005 ), findings in rats consistently show lower birth weight in offspring exposed to prenatal nicotine when compared with nonexposed offspring (see Ernst, Moolchan & Robinson, 2001 for review). Although prenatally exposed mice do not exhibit significantly lower birth weight, pups born to nicotine-administered dams show a significantly slower rate in postnatal weight gain ( Ajarem & Ahmad, 1998 ). These findings are of importance since, in humans, low birth weight has been shown to be associated with long-term cognitive deficits and ADHD (e.g., Botting, Powls, Cooke & Marlow, 1997 ; Bresleau & Chilcoat, 2000).

Locomotor activity and cognitive function

In general, animal studies tend to show increased locomotor activity in offspring who have been exposed to nicotine prenatally (see Ernst et al., 2001 for review). Studies in rats and mice have reported cognitive impairment, such as attention and memory deficits in various maze tasks, associated with prenatal nicotine exposure ( Levin, Briggs, Christopher & Rose, 1993 ; Liang, Poytress, Chen, Leslie, Weinberger & Metherate, 2006 ; Martin & Becker, 1971 ; Paz, Barsness, Martenson, Tanner & Allen., 2006 ; Peters & Ngan, 1982 ; Sorenson, Raskin & Suh, 1991 ; Yanai, Pick, Rogel-Fuchs, Zahalka, 1992 ). Mild deficits in learning have also been reported in rats (e.g., Liang et al., 2006 ; Martin & Becker, 1971 ), mice (e.g., Paz et al., 2006 ) and guinea pigs (e.g., Johns, Louis, Becker & Means, 1982 ; Johns, Walters & Zimmerman, 1993 ). These impairments in attention, memory, and learning are consistent with the cognitive deficits found in children diagnosed with, for example, ADHD ( Ernst et al., 2001 ). It has also been hypothesized that the observed deficits in operant learning found in animals, might translate to, and be associated with, dysfunction in reward or motivational processes, which could also predispose to substance abuse ( Ernst et al., 2001 ).

Hypothesized mode of action (for more detail see Ernst et al., 2001 ; Slikker et al., 2005 ; Shea & Steiner, 2008 )

Prenatal exposure to nicotine evokes a spectrum of effects by discoordinating the timing of trophic events linked to a subset of cholinergic receptors, specifically nicotinic cholinergic receptors (nAChRs), present very early in the developing brain of rodents (embryonic day 10) and humans (4–5 weeks of gestation) ( Hellstrom-Lindahl, Seiger, Kjaeldgaard & Nordberg, 2001 ; Levin & Slotkin, 1998 ; Slikker et al., 2005 ; Slotkin, 1998 ; Slotkin, 1999 ; Slotkin, McCook, Lappi & Seidler, 1992 ; Slotkin, Orband-Miller & Queen, 1987 ). Once nicotine enters the fetal bloodstream it binds to nAChRs, which are found in the central and peripheral nervous system and can be found both postsynaptically (e.g., acetylcholine neurotransmission) and presynaptically influencing the release of other neurotransmitters ( Dani, 2001 ).

nAChRs are ligand-gated channels including five subunits, usually made of two alpha (a) and three beta (B) subunits. Several nAChR subtypes (or combinations of subunits) exist, each of which has a specific pharmacology, physiology, and anatomical distribution ( Pakkanen, Jokitalo & Tuominen, 2005 ). The two most abundant subtypes in vertebrate brain are: (i) α4, β2 combination, and (ii) α7. The different subtypes have important functional implications, particularly during development, as their relative distribution in the brain varies with developmental stage and age ( Ernst et al., 2001 ). nAChRs are significantly involved in brain development via promotion of cell division during gastrulation and subsequent promotion of the switch from cell replication to cell differentiation in terminal neuronal differentiation ( Shea & Steiner, 2008 ). The presence of these receptors in early embryogenesis ( Hagino & Lee, 1985 ) suggests that nicotinic signaling may be an important part of neural development. Reported changes in receptor density during normal development (e.g., high levels found at early gestation) might also imply windows of vulnerability to exogenous nicotine. In humans, periods of high density have been found in the frontal cortex, hippocampus, cerebellum, and brainstem during mid-gestation and neonatal periods ( Hellstrom-Lindahl, Gorbounova, Seiger, Mousavi & Nordberg., 1998 ; Hellstrom-Lindahl et al, 2001 ; Huizink & Mulder, 2006 ).

In the rat (e.g., Slotkin et al., 1987 ), and to a lesser extent in the mouse ( Van de Kamp & Collins, 1994 ), binding to the nAChR during development, whether during prenatal or early postnatal stages, is a necessary and key step leading to the adverse effects of nicotine. Several studies indicate that chronic prenatal nicotine exposure in rats and mice results in increased receptor density of fetal and neonatal cerebral nAChRs (for example, Slotkin, 1998 ; Van de Kamp & Collins, 1994 ). Upregulation of the nAChRs during development is conclusive evidence that the cell has experienced chronic nicotinic stimulation. The long-term effects of this up-regulation remain unclear ( Ernst et al., 2001 ); although the proposed mode of action suggests that this stimulation results in premature onset of cell differentiation, at the expense of replication, leading to (i) brain cell death, (ii) structural changes in regional brain areas, and (iii) altered neurotransmitter systems (i.e., acetylcholine, norephinephrine, epinephrine, dopamine, serotonin, as well as glutamate and gamma-aminobutyric acid; Shea & Steiner, 2008 ; Slikker et al., 2005 ). Such alterations could translate to physical deficits, such as impaired cardiac function associated with hypoxia, as well as deficits in later learning, memory, behavior, and development. Differences in developmental profiles of receptor binding between species and strains suggest that genetic factors regulate the maturation of the nicotinic receptor ( Van de Kamp & Collins, 1994 ). These genetic factors may explain interindividual differences in sensitivity to the effects of in utero exposure to nicotine ( Ernst et al., 2001 ).

There is no question that animal work is vital to the study of human problems; however the rat brain, for example, is obviously different from the human brain. Effects of MSDP in humans, for example, often show up in higher-level cognitive (executive) function, which are controlled by the prefrontal cortex. Functional and structural differences in the region of rat brain traditionally considered homologous to the dorsolateral prefrontal cortex in primates suggest that the rat may not have an equivalent region ( Preuss, 1995 ). Moreover, in humans, MSDP results in fetal exposure not only to nicotine, but to a large amount of other toxic components, such as carbon monoxide, ammonia, nitrogen oxide, lead, and other metals ( Huizink & Mulder, 2006 ). Thus, one should not limit the effects of MSDP in humans to nicotine alone. Importantly, while we can use the evidence of negative effects of prenatal nicotine exposure that we garner from animal work as a guide to narrow our focus on potential effects in humans, we cannot directly extrapolate from animal findings to the complex human condition.

Maternal smoking during pregnancy: A more complicated story

As suggested earlier, the evidence for deleterious effects of MSDP on behavior and cognition later in life in human studies is muddied in the existing literature due to the inability to separate these effects from other confounding environmental and genetic factors. In a methodological review of the literature on effects of MSDP, Ramsay and Reynolds (2000) suggest that women who smoke during pregnancy may possess a constellation of personality traits that distinguishes them from other women. They focus on traits such as (i) increased depression and thus decreased motivation to quit smoking during pregnancy (Depression-Compulsivity model), (ii) elevated antisocial traits and thus reduced awareness of their consequences of MSDP as well as reduced concern for others (Antisocial model), and (iii) reduced attention to her own and, by extension, her infant’s nutrition and general well-being (Self-Care model). Thus, the personality of pregnant smokers may reflect a familial vulnerability for later disorders. Ernst and colleagues (2001) go on to outline numerous potential confounds, which include those suggested by Ramsay and Reynolds (2000) , as well as others: (1) parental characteristics: including IQ, psychiatric history (e.g., ADHD, antisocial personality disorder, substance abuse) and parenting; (2) maternal characteristics (e.g. health, height and weight (affecting metabolism of tobacco by-products)); and (3) smoking characteristics: intensity, gestational age at consumption ( Ernst et al., 2001 ). Importantly, a number of these confounds can be controlled for via alternative genetically sensitive designs. However, there is a surprising lack of comprehensive examination of the effects of MSDP within a genetically-informative framework. Specifically, the joint roles of environmental factors (e.g., MSDP) and genetic transmission in the risk for deficits, such as behavioral, learning, and cognitive dysfunction, are downplayed and there is a lack of control for differences between women who smoke during pregnancy and those who do not.

Neurobehavioral and cognitive effects of MSDP in humans

The offspring outcomes associated with MSDP cover broad cognitive and behavioral domains and are outlined thoroughly in several well laid-out and comprehensive reviews of the effects of MSDP (see Cnattingius, 2004 ; Ernst et al., 2001 ; Huizink & Mulder, 2006 ; Linnet et al., 2003 ; Shea & Steiner, 2008 ). These reviews are presented primarily from the phenotypic association point of view and say very little about how genetic factors may influence the reported associations between MSDP and offspring outcome. The main points of these reviews are presented briefly in this section, along with results from a few recent studies. The scope of results concerning the negative impact of MSDP, both suggestive and inconclusive, are presented. What is clear from these reviews is the need for more comprehensive study design as well as the lack of genetically informed studies on MSDP. The few studies that have considered genetic effects are reviewed in the final section of this report.

Pregnancy and birth outcomes

Epidemiological evidence from prospective and case-control studies show relatively high consistency for the association of adverse pregnancy outcomes (i.e., fetal growth restriction, hypoxia and placental effects, stillbirth, sudden infant death syndrome, etc) with MSDP (see Cnattingius, 2004 for detailed review ; Ernst et al., 2001 ); however, neurobehavioral outcomes have shown less consistency, indicating the potential need for more sensitive sampling designs and strategies.

MSDP is reported to increase rates of spontaneous abortion, stillbirth, sudden infant death syndrome, cleft palate, and most relevant to long-term neurobehavioral effects, preterm birth and low birth weight ( Bada et al., 2005 ; Conter, Cortinovis, Rogari & Riva, 1995 ; DiFranza & Lew, 1985; D’Onofrio et al, 2003 ; Ernst et al., 2001 ; Knopik et al., 2005 ; Kyrklund-Blomberg, Granath & Cnattinguis, 2005 ; Levin & Slotkin, 1998 ; Meyer, Williams, Hernandez-Diaz & Cnattinguis, 2004 ; Salihu, Aliyu & Kirby, 2006 ; Salihu et al., 2008 ; Sastry, 1991 ). Recent evidence also suggests that offspring of nonsmokers who used nicotine substitutes during pregnancy are at increased risk for congenital malformations ( Morales-Suarez-Varela, Bille, Christiansen & Olson, 2006 ).

These outcomes reported to be associated with prenatal exposure may be indirect or direct toxic consequences of MSDP. Nicotine produces anorexigenic, hypoxic, vascular, and placental effects that can adversely affect fetal development ( Cnattingius, 2004 ; Ernst et al., 2001 ). Existing theories focus on (i) maternal and fetal undernutrition due to the acute anorexigen effects of tobacco smoking ( Davies & Abernethy, 1976 ; Perkins, Sexton, DiMarco & Fonte, 1994 ); (ii) intrauterine hypoxia secondary to increased carbon monoxide and dioxide, reduced blood flow, and inhibition of respiratory enzymes ( Abel, 1980 , 1984 ; Byrd & Howard, 1995 ); (iii) disruption of the function of the placenta ( Huizink & Mulder, 2006 ; Naeye, 1978 ; Sastry, 1991 ; Suzuki, Minei & Johnson, 1980 ) via nicotinic activation of placental cholinergic systems which depresses transplacental amino acid transport, which may contribute to intrauterine growth retardation ( Cnattingius, 2004 ; Ernst et al., 2001 ). Thus, prenatal exposure may have direct teratogenic effects on the fetus leading to more readily observed adverse phenotypes; however, these effects most likely depend on the specific outcome measure of interest ( D’Onofrio et al., 2003 ).

Infant and Toddler outcomes

The evidence for effects of MSDP on infant and toddler outcomes has been overall, inconsistent, perhaps due to the possibility that a certain level of brain maturation needs to be achieved before deficits become detectable ( Ernst et al., 2001 ; Huizink & Mulder, 2006 ). The inconsistency may also be due to less sensitive assessment tools for this age group. Data showing negative effects of MSDP suggest deficits in speech processing ability ( Key, Ferguson, Molfese, Peach, Lehman & Molfese, 2006 ), decreased scores in motor ability and verbal comprehension ( Gusella & Fried, 1984 ), reduced auditory acuity ( Saxton, 1978 ), increased hypotonicity, heightened tremors and startles ( Fried & Makin, 1987 ), and negative affect ( Brook, Brook & Whiteman, 2000 ) among infants who were prenatally exposed to nicotine. Since it has been shown that adverse birth outcome, such as preterm birth, is related to neurologic and developmental disabilities during the first two years of life ( Marlow, Wolke, Bracewell, Samara & EPI Cure Study Group, 2005 ), a recent study ( Law, Stroud, LaGasse, Niaura, Liu & Lester, 2003 ) adjusted their findings for factors relating to birth outcome and still found that newborns exposed to MSDP were more excitable and hypotonic and showed more stress/abstinence signs on a standard neurobehavioral assessment. Not all studies have found significantly negative relationships however. For instance, Obel, Henriksen, Hedegaard, Secher, and Ostergaard (1998) found mixed results when comparing babbling abilities in prenatally exposed 8-month olds to controls. When comparing nonbabblers to di- and polysyllable babblers, a trend toward a dose-response effect of MSDP was found, with those children exposed to more cigarettes per day showing less babbling ability. However, this trend was nonsignificant when comparing nonpolysyllable babblers to polysyllable babblers. Baghurst, Tong, Woodward, and McMichael (1992) also found no evidence for differences in verbal, perceptual, and motor scores due to prenatal exposure once adjusting for social class, home environment, and mother’s intelligence. Together, these findings suggest the possibility that MSDP is associated with motor, sensory, and cognitive deficits in infants and toddlers, which may indicate a pervasive toxic effect on early neurodevelopment.

Childhood outcomes

Findings in children also seem to support a negative influence of in utero exposure to smoking on behavior and cognitive function; however, there are again some inconsistencies. MSDP has been associated with a significant increase in externalizing (e.g., oppositional, aggressive, overactive) scores but not internalizing behavior ( Brook, Zhang, Rosenberg & Brook, 2006 ; Day, Richardson, Goldschmidt & Cornelius, 2000 ; Orlebeke, Knol, & Verhulst 1999 ). Cognitive function has also been shown to be negatively affected by MSDP, with deficits in sustained attention ( Fried, O’Connell & Watkinson., 1992a ), response inhibition, memory, and impulsivity, overall cognitive function, receptive language ( Fried, Watkinson & Gray, 1992b ), verbal learning and design memory ( Cornelius, Ryan, Day, Goldschmidt & Willford, 2001 ), problem solving ( Cornelius et al., 2001 ), speech and language ( Makin, Fried, & Watkinson, 1991 ), school performance ( Lambe, Hultman, Torrang, MacCabe & Cnattinguis, 2006 ), and auditory processing ( McCartney, Fried & Watkinson, 1994 ). Dose-response relationships, in which the smoking-related relative risk increases with amount smoked, have also been reported for general cognitive ability ( Sexton, Fox & Hebel, 1990 ), arithmetic, and spelling ( Batstra, Hadders-Algra & Neeleman, 2003 ), suggesting the presence of vulnerable periods during fetal development ( Ernst et al., 2001 ).

As with infant and toddler outcomes however, some negative findings are also reported. For example, Bauman, Flewelling and LaPrelle (1991) reported that scores on receptive language and matrices tasks of more than 3000 9–11 yr olds exposed to MSDP but whose mothers quit afterwards, were similar to those of children not exposed to MSDP; however, both of these groups performed better than children exposed to both MSDP and smoking after pregnancy, suggesting the importance of also considering postnatal environment. No clear relationship was observed for MSDP and receptive language scores at 5 yrs or at 15–17 yrs. Eskanazi and Trupin (1995) also found no dose-response relationship of MSDP during the third trimester and cognitive performance in 5 yr olds. Moreover, despite findings of adverse effects of MSDP on school performance using a between family analysis ( Lambe et al., 2006 ), a within-sibling comparison of siblings exposed to differential amounts of MSDP (an example of a case-crossover design which is detailed below) indicated that if a mother had smoked during either pregnancy, both siblings were at increased risk of poor school performance ( Lambe et al., 2006 ); results suggesting that observed associations between MSDP and poor cognitive performance might not be causal.

In one of the most comprehensive analyses to date, D’Onofrio and colleagues (2008) analyzed data from the National Longitudinal Survey of Youth (NLSY), with particular attention to controlling for differences between women who do and do not smoke during pregnancy. They focused their efforts on the association between MSDP and offspring externalizing behavior [conduct (CP), oppositional defiant (ODP), attention deficit hyperactivity (ADHP) problems]. Their comparisons of unrelated children were consistent with the results of previous studies ( Wakschlag, Pickett, Cook, Benowitz & Leventhal, 2002 ) in several respects: (a) CP, ODP, and ADHP were significantly associated with MSDP; (b) each association followed a dose-response relationship; (c) the number of CP demonstrated by children exposed to MSDP was higher for males; and (d) each association remained significant after statistically controlling for associated maternal characteristics. In addition to the use of statistical covariates used in previous studies, D’Onofrio et al. (2008) utilized the clustered nature of NLSY data to account for unmeasured confounds. The hypothesis was that if MSDP caused higher externalizing, the relation would have been evident both when comparing related (e.g. within mothers) and unrelated children (e.g., Rodgers, Cleveland, van den Oord & Rowe, 2000 ). However, similar to Lambe et al. (2006) , when siblings who differed in exposure to MSDP (i.e., none/some vs. more exposure, a broad definition of discordance for MSDP ) were compared, the offspring did not differ significantly with respect to CP or ODP. These results suggest that previous studies found a relationship between MSDP and offspring CP not because MSDP causes increased risk for CP or ODP, but because environmental influences that vary between families confound associations between MSDP and offspring externalizing ( D’Onofrio et al., 2008 ). This finding is consistent with studies that have included more precise measurement of adult characteristics that may confound the relation, such as maternal and paternal antisocial characteristics ( Maughan, Taylor, Caspi, & Moffitt, 2004 ) and maternal delinquency during adolescence ( Silberg et al., 2003 ). It is also generally supportive of a recent children-of-twins study of maternal alcohol use disorder, MSDP and ADHD ( Knopik et al., 2006 ; detailed below).

Adolescent and adult outcomes

Overall, it seems that behavioral and cognitive deficits associated with MSDP continue into late childhood and early adolescence and lead to increased risk for ADHD and Conduct Disorder (CD). MSDP has been associated with ADHD, CD, criminality and substance use (particularly smoking) in adolescence ( Ernst et al., 2001 ). Milberger and colleagues (1996 , 1997 , 1998) investigated MSDP as a risk factor for ADHD and found that 22% of children with ADHD had a history of MSDP, compared with 8% of controls. Significantly lower IQ scores were also found in children exposed to MSDP versus those who were not exposed ( Milberger, Biederman, Faraone & Jones 1998 ). Wakschlag and colleagues (1997 , 2001 , 2002) have consistently shown that MSDP is a robust, independent risk-factor for CD in males. Weissman, Warner, Wickramaratne and Kandel (1999) report similar findings reporting 4-fold increases in CD rates and 5-fold increases in adolescent drug abuse in children exposed to MSDP. Cornelius, Leech, Goldschmidt and Day (2000) and Buka, Shenassa and Niaura (2003) found increased risk for early tobacco experimentation and nicotine dependence, respectively, in children exposed to MSDP. Fergusson, Woodward and Horwood (1998) also suggested that MSDP contributes to children’s risk of later externalizing problems. Children exposed to MSDP had higher psychiatric symptom rate for CD, alcohol abuse, substance abuse, and depression compared with unexposed children. These childhood associations also appear to carry into adulthood. For example, Brennan, Grekin and Mednick (1999) and Rasanen et al. (1999) found relationships between MSDP and later criminality in male offspring up to age 28 and Mortensen, Michaelsen, Sanders and Reinisch (2005) reported a dose-response relationship between MSDP and adult intelligence.

Summary of MSDP in humans

MSDP is associated with offspring behavioral abnormalities, including increased evidence of attentional deficits, impaired learning and memory, lowered IQ, cognitive dysfunction, later childhood conduct problems, substance use, and early adult criminality; however, not all studies have reported a significantly negative relationship between MSDP and offspring outcomes.

What is clear from these reviews, however, is the need for more comprehensive study design in the study of MSDP. In short, there are a paucity of studies investigating gene-environment interplay in the proposed associations between MSDP and subsequent child outcomes. A key approach is to use a combination of strategies, such as twin, children-of-twin, and sibling-control designs, emphasizing both behavioral and molecular genetic methods, to elucidate the likely complex factors contributing to the association between MSDP and child outcomes. Preliminary findings from this work in the area of child externalizing problems ( Maughan et al., 2004 ; Knopik et al., 2006 ; D’Onofrio et al, 2008 ) indicate that, once genetic and environmental effects are accounted for, MSDP accounts for a much smaller effect than proposed by existing literature; however, while the effects were smaller, MSDP continued to be significantly linked to childhood behavior. Such results suggest that MSDP is unlikely to be a unique cause of early childhood behavior problems and illustrate the need for comprehensive study design.

Comprehensive study design – things to consider

The idea of joint roles of genetic and environmental factors can be referred to as gene-environment interplay. This is a broad term that encompasses several different concepts with different meanings and interpretations (see Rutter, Moffitt & Caspi, 2006 for detailed review). While a thorough and comprehensive review of gene-environment interplay is beyond the scope of this report, we will focus briefly on gene-environment interaction (G×E) and gene by environment correlation (rGE). G×E occurs when the effect of environmental exposure is conditional on a person’s genotype ( Moffitt, Caspi & Rutter, 2005 ). An example of G×E is phenylketonuria (PKU), a genetic disorder characterized by deficiency of the enzyme phenylalanine hydroxylase. Children who are homozygous (carry two copies) for a certain form of the phenylalanine hydrolylase gene are deficient in phenylalanine hydroxylase and cannot metabolize phenylalanine in food. Thus, phenylalanine accumulates and damages the developing brain. Phenylalanine has no harmful effects on other children who do not carry this particular genotype. However, PKU is one of the few genetic diseases that can be controlled by diet (an example of an environmental influence). A diet low in phenylalanine can be very effective treatment, yet this low phenylalanine diet has no harmful or beneficial effect on other children. Perhaps the most well-known example of G×E in the development of psychiatric disorders was reported by Caspi et al. (2002) who found that a functional polymorphism in the gene encoding the neurotransmitter-metabolizing enzyme monoamine oxidase A (MAOA) was found to moderate the effect of maltreatment, such that maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems. These findings provided the basis for a growing literature suggesting that genotypes can moderate children’s sensitivity to environmental insults.

rGE can be thought of as genetic control of exposure to the environment or, in other words, an individuals genotype influences the probability of exposure to certain environments ( Caspi & Moffit, 2006 ; D’Onofrio et al., 2003 ; Jaffee & Price, 2007; Kendler & Eaves, 1986 ). rGE has been described as passive, active or evocative (see Jaffee & Price, 2007, for a full review). (i) Passive gene-environment correlation refers to the association between the genotype a child inherits from her parents and the environment in which the child is raised. Parents create a home environment that is influenced by their own heritable characteristics. (ii) Evocative (or reactive) gene-environment correlation happens when individuals are reacted to based on their genetic propensities or, in other words, an individual's (heritable) behavior evokes an environmental response (see Burt, 2008 ). (iii) Active gene-environment correlation occurs when an individual seeks out or creates certain environments based on their genetic propensity. rGE results in “the contamination of measures of environmental exposure with genetic variation and thus clouds interpretation of results” ( Caspi & Moffitt, 2006 , p.587).

One of the main limitations of studying familial and environmental influence and child development is that the parents are providing both the environment and the genes to their offspring ( D’Onofrio et al., 2003 ). In addition to prenatal environment, separate consideration should also be given to environmental exposure to second-hand smoke (see Eskenazi & Castorina, 1999 for review) since children born to smoking mothers are more likely to be exposed to environmental tobacco smoke ( Key et al., 2006 ), which could increase risk of developmental deficits ( Yolton, Dietrich, Auinger, Lanphear & Hornung, 2005 ). Most studies that have considered prenatal nicotine exposure have considered latent genetic variables or have examined the presence of measured G×E by focusing on the dopaminergic system and genes involved in the metabolism of tobacco by-products. These few studies are included in the review below.

Adoption studies

At the time of this report, there have been no adoption studies that have specifically considered maternal smoking during pregnancy; however, two studies outlined in this section have considered prenatal drug exposure more generally ( Crea, Barth, Guo & Brooks, 2008 ; Neiderhiser et al., 2007 ). The lack of adoption studies in this arena does not preclude the potential importance of this design for MSDP. Adoption designs provide a direct way to disentangle genetic and environmental sources of variation. Adoption creates pairs of genetically related individuals who do not share a common family environment (and/or prenatal environment; i.e., biological siblings adopted apart and raised in different homes) and also creates family members who share family environment but who are not genetically related (i.e., non-biologically related children adopted into the same adoptive home). In both situations, any resemblance estimates the contributions of the family environment. A strong suit of the adoption design is the ability to study gene by environment interaction and additional processes through which gene-environment correlation creates the covariance between parents and children ( D’Onofrio et al., 2003 ). However, the adoption design does suffer from certain limitations. First, due to highly selective placement ensuring that the adoptive environment is excellent, there is an inherent difficulty in obtaining samples of children who are exposed to high-risk environments. Moreover, an assumption of this design is that there are no negative consequences of being adopted and that environmental processes operate similarly in adoptive and nonadoptive families ( D’Onofrio et al., 2003 ). Such an assumption is not needed in other genetically sensitive designs.

Crea et al (2008) did not focus on disentangling genetic and environmental influences on behavior per se, but rather examined behavioral trajectories for substance exposed adopted children, fourteen years after adoption. They found that prenatal exposure predicted elevated behavior problems but only slightly higher than those of nonexposed adopted counterparts. The overall rate of change in behavioral problems did not differ between exposed and nonexposed groups. This finding contradicts the argument that substance exposure alone is responsible for triggering a cascade of negative sequelae and encourages the investigation of protective familial environmental factors (e.g., positive rearing environment) that buffer the impact of this exposure ( Crea et al., 2008 ).

In a recent analysis of a sample from the Early Growth and Development Study ( Leve et al., 2007 ), Neiderhiser et al. (2007) examined 350 ‘yoked’ birth mothers, adopted children and adopted parents and 104 birth fathers. The focus was on toddler temperament and behavior problems at 18 months. The authors reported preliminary results suggesting that high levels of prenatal drug use significantly contributed to suppressed toddler affect and effects of genetic risk operated only via prenatal drug exposure ( Neiderhiser et al., 2007 ). Future planned work to extend these analyses in order to facilitate the disaggregation of prenatal exposure, genes (via DNA collection), as well as postnatal rearing environment will lend considerable and potentially important information to the effort to elucidate these complex relationships ( Leve et al., 2007 ).

Twin studies and their extensions

The twin method compares the similarity between identical (monozygotic or MZ) twins and fraternal (dizygotic or DZ) twins (see Plomin, DeFries, McClearn & McGuffin, 2008 for details). If a trait is genetically influenced, MZ twins will be more similar than DZ twins; however, it is also possible that this greater similarity is due to environmental rather than genetic factors. This design can offer considerable knowledge in the genetic etiology of, not only outcomes of interest (e.g., ADHD or cognitive ability), but also risk factors (e.g., MSDP; see Agrawal et al., 2008 for genetic etiology of MSDP; D’Onofrio et al, 2003 , 2008 ;). It can also determine whether genetic effects differ in two environments; however, the models may only partially control for genetic factors since they assume that the specified environments represent ‘true’ or ‘pure’ environmental risk factors which are free from genetic influences (i.e., that there is no gene-environment correlation; Caspi, Taylor, Moffitt & Plomin, 2000 ; D’Onofrio et al., 2003 ; Purcell & Koenen, 2005 ). Classical twin studies, even those that add explicit measures of the environment, are also not able to delineate the processes involved in intergenerational processes ( D’Onofrio et al., 2003 ).

Four recent studies have tested the association between MSDP and ADHD or conduct problems/antisocial behavior within a twin design ( Button, Thapar & McGuffin, 2005 ; Knopik et al., 2005 ; Maughan et al., 2004 ; Thapar et al., 2003 ). As discussed in this section, using a twin design allows the genetic effects that contribute to the outcomes in children to be estimated (see Purcell & Koenen, 2005 for details on limitations involving environmental mediation in the classical twin study). In an examination of conduct problems in 5–7 year old twins, Maughan et al. (2004) report that, once genetic and environmental risks were controlled for, the effects of MSDP were substantially reduced. Thapar et al (2003) found that, in addition to substantial genetic influences on ADHD symptoms, MSDP explains additional variance above and beyond genetic effects. Button et al. (2005) report similar results when considering the covariation between antisocial behavior and ADHD stating that MSDP contributes small but significant amounts to the variance of both phenotypes. Knopik et al. (2005) suggest that prenatal and parental risk factors (e.g., maternal and paternal psychopathology) combine additively with the important genetic risk of developing ADHD, rather than interactively (i.e., no significant findings for G×E interaction). Thus, in summary it appears that, while genetic influences on these ADHD phenotypes are important, MSDP also has an independent effect on ADHD.

An extension of the classical twin study is the bivariate twin study that investigates the relationship between an environmental risk factor (considered as a phenotype) and an outcome of interest. A limitation of this extension is that the bivariate design cannot study all of the possible environmental risk factors that are involved in developmental psychology because the model can only include environments for which twins can differ (i.e., individual-specific environment; Purcell & Koenen, 2005 ). Thus, in the case of exposure to smoking during pregnancy (i.e., an obligatory shared environment in twin offspring exposed prenatally; Purcell & Koenen, 2005 ), this is a design that cannot be used. However, if one is considering the etiology of the behavior of smoking during pregnancy (i.e., twin mothers who can differ in their smoking behaviors), this design can be used to determine the covariation of MSDP and another outcome of interest. For example, Agrawal et al (2008) considered the genetic covariation of maternal smoking during pregnancy and nicotine dependence. Results indicated that women who smoked during an entire pregnancy reported heavier dependence and more unsuccessful quit attempts, compared with a community sample of mothers and with women who smoked during only part of a pregnancy. Educational attainment, weekly church attendance, spousal current smoking, and nicotine dependence also were associated with MSDP. The authors also found that heritable influences, even after adjustment for the above-stated significant psychiatric and sociodemographic covariates, explain nearly half of the variation in MSDP, with the remainder of the variance being due to environmental factors not shared by members of a twin pair. A large proportion of the genetic influences on MSDP were shared with nicotine dependence. These results, though not focused on childhood outcomes of MSDP, do have strong implications for treatment and intervention, in that a lifetime history of difficulty with smoking cessation, in conjunction with social background and psychiatric comorbidity, especially during pregnancy, needs to be considered by treatment providers when counseling expectant mothers about the potential risks of MSDP.

Another expansion of the classical twin study incorporates assessment of the twins’ parents. This design has the ability to estimate environmental effects while controlling for genetic effects on both parents and children ( D’Onofrio et al., 2003 ; Rutter et al., 1997 ). Limitations exist, as outlined in Rutter, Pickles, Murray, and Eaves (2001) . Specifically, the twin-family design requires identical measures for parents and children and also assumes that the same genetic and environmental structure influences both generations ( D’Onofrio et al., 2003 ).

Children-of-twins

The Children-of-Twins (COT) design can begin to elucidate the role that specific environments (such as prenatal exposure) play in the etiology of psychological and behavioral phenomena ( D’Onofrio et al., 2003 ), while studying intergenerational associations with fewer assumptions than the twin-family design. In the case of prenatal exposure, it allows one to begin to disentangle genetic, prenatal exposure, and other environmental effects on offspring outcomes. It also offers the additional advantage of including offspring sibling pairs that may differ in their amounts and/or timing of prenatal exposure (an obligatory shared environment in classical twin studies).

There are several approaches within this design: (i) children of discordant twins, which essentially involves (a) a comparison between the children of affected and unaffected MZ twins, and (b) a subsequent comparison of the rates of the disorder in children of the unaffected MZ and DZ cotwins; (ii) the MZ half-sib design ( Nance, 1976 ; Nance & Corey, 1976 ; Nance, Corey, & Boughman, 1978 ) which is a nested analysis of variance approach to the study of offspring of MZ twin pairs; (iii) a structural equation model fitting approach as outlined in D’Onofrio et al. (2003) which is a variation on the twin-family study and examines (a) within-generation, (b) cross-generation, same-family, and (c) cross-generation, cross-family correlations; and (iv) inferring genetic and environmental risk on offspring outcome from the co-twin’s (parental) history of the phenotype of interest ( Jacob et al., 2003 ; Knopik et al., 2006 ).

The COT design (see Jacob et al., 2003 for general discussion of the method) has been used less often in behavioral genetic studies, and has just recently been expanded to not only assess the potentially complex relationship between parental psychopathology (such as substance dependence) and child behavior, but to also consider the role of prenatal exposure in intergenerational associations ( D’Onofrio et al., 2003 ; Knopik et al., 2006 ). For example, in an attempt to understand the underlying processes associated with MSDP, D’Onofrio et al (2003) used the structural equation model approach within a COT sample to move beyond the straight phenotypic association between MSDP and birth weight. Their results suggested that MSDP appears to have a specific environmental association with offspring birth weight with no apparent confounding by genetic factors, common environment, or other measured covariates ( D’Onofrio et al., 2003 ).

Given evidence that mothers who abuse alcohol, who are alcohol dependent, or who have an alcohol dependent partner are more likely to smoke or drink during pregnancy (e.g., Knopik et al., 2005 ), Knopik et al (2006) used the COT design to examine the relationship between maternal psychopathology (specifically alcohol use disorder, AUD), MSDP, and child ADHD. This approach provides a powerful pseudo-adoption design in which genetic and environmental risk status is inferred from the co-twin’s history of, in this case, AUD. Importantly, children raised by an AUD monozygotic (MZ) or dizygotic (DZ) twin parent are at high risk for psychiatric disorders (e.g., ADHD) and other health problems because of high genetic and high environmental risk. In contrast, children raised by a non-AUD twin of an AUD MZ co-twin are at reduced environmental risk because they have not grown up with a mother with AUD, but these children are at the same (high) genetic risk as children raised by an AUD twin because the mothers have identical genotypes. In turn, children raised by the non-AUD twin of an AUD DZ co-twin are also at reduced (low) environmental risk but at only intermediate genetic risk because DZ twin pairs share on average 50% of their genes.

Thus, in the absence of any environmental effect of maternal AUD, after controlling statistically for psychopathology in the biological parents, the child of an AUD mother should be no more likely to develop ADHD than the child of a non-AUD parent who is the MZ co-twin of an AUD individual. Excess rates of ADHD in children of AUD mothers, after controlling for comorbid psychiatric disorders and pertinent variables, would imply an environmental impact of maternal AUD. Therefore, the COT design is a powerful design to disentangle the genetic and environmental effects on the association between maternal (or paternal) psychopathology and offspring outcome, while also estimating direct effects of measured environmental variables, such as prenatal exposure.

These data ( Knopik et al., 2006 ) yielded a pattern of results consistent with a genetic contribution to the association between maternal AUD and increased offspring risk of ADHD, but also reaffirmed the potential importance of MSDP. Compared to controls, rates of offspring ADHD were significantly elevated not only in families where the mother had a history of AUD, but also in families where the mother had no history of AUD, but had a monozygotic twin sister with AUD. In addition, rates of maternal regular smoking, and maternal regular smoking during pregnancy, were significantly elevated in those mothers who had a history of AUD, and in mothers who were unaffected, but had an affected monozygotic cotwin. This is consistent with a strong genetic correlation between alcoholism and smoking that has been found in other research, and implies a potential confounding of MSDP and genetic risk of alcoholism. Thus, genetic transmission and effects of MSDP are partially confounded. Models predicting ADHD outcome from family risk (of AUD) status, as well as other maternal and paternal psychopathology, indicated that even when maternal genetic risk of AUD and maternal regular smoking were controlled for, heavy MSDP remained a significant and strong predictor of offspring ADHD risk. Thus, while MSDP is likely contributing to the association between maternal AUD and offspring ADHD, the evidence for a significant genetic correlation suggests: (i) pleiotropic genetic effects, with some genes that influence risk of AUD also influencing vulnerability to ADHD; or (ii) ADHD is a direct risk-factor for AUD ( Knopik et al., 2006 ). Thus, these results from the COT design ( D’Onofrio et al., 2003 ; Knopik et al., 2006 ) yielded a pattern of results consistent MSDP having an independent effect on offspring outcomes even after controlling for potential confounders (e.g., genetic transmission, other environmental factors, and other covariates). The ability to begin to disentangle genetic and environmental intergenerational transmission in the domain of MSDP is critical for understanding the magnitude of risk that MSDP carries as this can have real implications for future research, intervention, and prevention efforts.

Cotwin-control

The cotwin-control design is a modification of the traditional case-control design where data is considered from twin pairs that are discordant for (i) the outcome of interest (e.g., ADHD), (ii) a variable related to the outcome of interest (e.g., schizophrenia in a model examining cognitive ability, see Kremen et al., 2006 ; early cannabis use in a model examining drug use as in Lynskey et al., 2003 ), or (iii) a environmental measure. The design controls for effects of age, gestational influences, and genetic factors ( D’Onofrio et al., 2003 ). It can also control for many environmental factors; however, similar to twin studies and as pointed out in D’Onofrio et al. (2003) , it is limited by methodological problems that prohibit the examination of many environmental risk factors that are commonly examined in epidemiological studies such as divorce, parenting practices, parental psychopathology, and MSDP (see D’Onofrio et al., 2003 for detail). The difficulties also lie in finding large enough samples of twins that are discordant for salient environmental factors that are under consideration. Thus, there is typically not enough power to draw definitive and meaningful conclusions ( D’Onofrio et al., 2003 ; Kendler & Gardner, 2001 ).

Case-crossover design

A variation on the cotwin-control study is the case-crossover design (or within-mother between-pregnancy design) which examines siblings discordant for prenatal exposure to MSDP. A form of this design was used in two studies discussed earlier in this report which compared siblings exposed to a broad definition of differential amounts of prenatal smoking (more vs less; D’Onofrio et al., 2008 ; Lambe et al., 2006 ). Meyer et al (2004) also used a case-crossover approach to examine the effects of MSDP on risk of oral cleft; however, their cases were those with cleft lip with or without cleft palate rather than defined by exposure to MSDP. More recently, Salihu et al. (2008) examined MSDP and risk of stillbirth using case-control and case-crossover designs. Similar to Meyer et al (2004) , case status was not defined by MSDP but rather as a stillbirth with controls being defined as live births ( Salihu et al., 2008 ).

In general, this method provides statistical control for confounding factors (e.g., heritable and sociodemographic characteristics of the mother that predict increased probability of MSDP) that might otherwise artifactually create, or alternatively mask, an association between MSDP and child outcomes. Moreover, this design, in combination with molecular genetic information (see examples below), could offer substantial information to the delineation of genetic and environmental factors in the relationship between MSDP and child outcomes. There are potential limitations of this case-crossover design, e.g., (i) mothers who are able to quit in one pregnancy but not all, may be, on average, less nicotine dependent and therefore smoke less than mothers who are unable to quit; (ii) smoking during pregnancy may be secondary to other life stressors that were present during pregnancy and these life events may not be readily captured during assessment (particularly if retrospective reporting is used); (iii) there may be a selection bias if more women give up rather than initiate smoking during the reproductive years ( Meyer et al., 2004 ); (iv) MSDP tends to be highly correlated in sequential pregnancies introducing possible bias due to autocorrelation ( Levy, Lumley, Sheppard, Kaufman, & Checkoway, 2001 ; Mittleman, Maclure, & Robins, 1995 ); and (v) the prevalence of smoking during pregnancy has, in general, declined over time ( CDC, 2004 ) which could affect results. Some of these limitations can be overcome with the use of bi-directional case-crossover designs, where controls (nonexposed siblings) are chosen from both sides of the exposed pregnancy (e.g., Lumley & Levy, 2000 ; Meyer et al., 2004 ). To control for exposure trends, a case-time-control design can also be used in conjunction with the case-crossover design (see Meyer et al., 2004 ). The case-time-control design estimates an exposure trend by explicitly matching cases with controls. This exposure trend is then used to adjust the case-crossover estimates by the trend estimate. There is also the issue of identifying such samples and acquiring large enough samples to make meaningful conclusions. Despite these limitations, this case-crossover design in combination with molecular genetic information holds promise in the study of adverse effects of MSDP.

Molecular genetic studies

Earlier it was suggested that prenatal exposure may have direct teratogenic effects on the fetus leading to more readily observed adverse phenotypes; however, these effects most likely depend on the specific outcome measure of interest. In fact, the effect of MSDP on the fetus may also interact with other factors, such as genetic factors. In an investigation of gene-environment interaction (G×E), Wang and colleagues (2002) investigated the modifying role of two maternal xenobiotic [i.e., corresponding to a chemical compound (such as a drug, pesticide, or carcinogen) that is foreign to a living organism] metabolism genes (CYP1A1 and GSTT1) in the association between MSDP and infant birth weight. Their research was prompted by the fact that tobacco smoke contains approximately 4000 compounds ( Brunnemann & Hoffmann, 1991 ); the most important carcinogens in tobacco smoke are polycyclic aromatic hydrocarbons (PAHs), arylmines, and N-nitrosamines ( Bartsch et al, 2000 ). The ability of an individual to convert toxic metabolites of cigarette smoke to less harmful ones is important for minimizing other adverse health effects. As outlined in Wang et al. (2002) , the metabolic processing of PAH (for example) in humans occurs in two phases. The phase 1 metabolism is an activation process, in which the inhaled, hydrophobic PAHs are converted mainly through aryl hydrocarbon hydroxylase activity into hydrophilic, reactive, electrophilic intermediates that can bind covalently to macromolecules, especially DNA ( National Research Council, 1983 ). These intermediates may be more toxic than the original form. Aryl hydrocarbon hydroxylase, encoded by the CYP1A1 gene, is a phase 1 enzyme and is particularly relevant to the metabolism of cigarette smoke. The phase 2 metabolism is a detoxification process, in which these metabolic intermediates are detoxified by enzymes such as glutathione S-transferases (GSTs) or uridine diphosphate (UDP)-glucuronosyltransferase through transformation into conjugated forms that are sufficiently polar to be excreted from the body ( Timbrell, 1991 ). GSTT1, encoded by the GSTT1 gene, is a major phase 2 enzyme. Both CYP1A1 and GSTT1 are highly polymorphic ( Ishibe et al., 1997 ; Nelson et al., 1995 ; Xu, Kelsey, Wiencke, Wain & Christiani, 1996 ) and their polymorphisms have been associated with their encoded enzyme activities (Kawaijiri et al., 1990; Wiencke, Pemble, Ketterer & Kelsey, 1995 ). Wang et al. (2002) found that, when considering the CYP1A1 genotype (i.e., the combination of alleles for the CYP1A1 gene), increased reduction in infant birth weight was seen in children born to mothers with the Aa/aa genotype (OR=3.2, 95% CI=1.6–6.4). When the GSTT1 genotype was considered, there was increased reduction in birth weight (OR=3.5, 95% CI=1.5–8.3) in children born to mothers with the absent genotype group. When both CYP1A1 and GSTT1 genotypes were considered, the greatest reduction in birth weight was found among smoking mothers with the CYP1A1 Aa/aa and GSTT1 absent genotypes (−1285g). These results suggest an interaction between maternal metabolic genes and MSDP with regard to infant birth weight.

More recently, Tsai et al. (2008) observed a significant joint association of maternal smoking, CYP1A1 (Aa/aa) and GSTT1 (absent) genotypes with gestational age and with preterm delivery. Such joint association was particularly strong in certain preterm subgroups, including spontaneous preterm delivery, preterm delivery < 32 weeks, and preterm delivery accompanied by intrauterine infection/inflammation. Taken together, maternal smoking significantly increased the risk of preterm delivery among women with high-risk CYP1A1 and GSTT1 genotypes. Findings were strongest among preterm delivery accompanied by intrauterine infection/inflammation suggesting that intrauterine infection/inflammation may be a potential pathogenic pathway by which MSDP affects preterm delivery. Specifically, the gene-MSDP interactions may exert their effects synergistically on preterm delivery through maternal and fetal inflammatory responses and raise the possibility of identifying women at high risk for certain pregnancy outcomes by accounting for environmental exposures and genetic polymorphisms ( Tsai et al., 2008 ).

Infante-Rivard, Weinberg, and Guiguet (2006) studied CYP1A1, GSTT1, as well as a set of ‘repair’ genes (XRCC1, XRCC3, and XPD), due to the fact that cigarette smoke can generate reactive oxygen species, which are capable of inducing double-strand breaks in DNA. These ‘repair’ genes can maintain the integrity of the genetic code. The authors investigated these genetic polymorphisms and their interaction with MSDP in the role of small-for-gestational-age births (birth weight below the 10 th percentile according to gestational age and gender). Results indicated that certain genetic variants (maternal CYP1A1, maternal XRCC3, and newborn GSTT1) increased the risk of small-for-gestational-age birth and modified the effects of MSDP by increasing or decreasing its risk ( Infante-Rivard et al., 2006 ). Of particular interest here is the fact that not only are maternal genotypes involved, but also newborn genotypes which emphasizes the importance of obtaining DNA from mother, child, and father if available and conducting family-based studies to further examine the roles of these genes.

There are also a few studies that have focused on, and claim evidence for gene-environment interactions (dopaminergic pathway genes and prenatal smoking) on externalizing behavior in children ( Kahn, Khoury, Nichols & Lanphear, 2003 ; Neuman et al., 2007 ). However, these causal relationships need to be considered carefully. These studies, to the best of my knowledge, do not control for the fact that prenatal smoking may be correlated with parental behaviors that could act as more proximal risk factors that are in turn transmitted to their offspring. In brief, Kahn et al. (2003) found that children with the DAT1 480/480 homozygous genotype who were exposed to prenatal smoking had significantly elevated hyperactive-impulsive and oppositional scores on the Conners' Parent Rating Scale Revised-Long Version. The most striking association was with oppositional defiant behavior. Consistent with Kahn et al. (2003) , Becker, El-Faddagh, Schmidt, Esser and Laught (2008) also reported evidence of an environmentally moderated risk for ADHD behaviors, suggesting that effects of MSDP were dependent on genetic susceptibility (as reflected by individuals’ DAT1 genotypes) and thus operating via G×E interaction. Specifically, males who were exposed to MSDP and who were homozygous for the DAT1 480 allele had higher hyperactivity-impulsivity than males in other groups. This G×E effect was not evident in females. Recently, Neuman et al (2007) also reported that the risk of diagnosis for any DSM-IV ADHD was greatest for children exposed to MSDP and whose genotype contained either the DAT1 440 allele [in contrast to Kahn et al (2003) and Becker et al (2008) ] or the DRD4 exon 3 7-repeat allele. In summary, these results suggest an interaction between dopaminergic genes (in offspring) and MSDP with regard to child externalizing behavior; however, the conflicting nature of reported findings also stress the need for highly refined phenotypes, the measurement of other potential confounding factors (such as the fact that MSDP might only be a marker for maternal ADHD or other important genes transmitted to the child), and the measurement of other gene variants that might be in linkage disequilibrium (non-randomly associated) with the dopaminergic genes investigated ( Becker et al., 2008 ). Futher, the multifactorial nature of many child outcomes underscores the importance of studying both genetic and environmental factors and their interaction ( Becker et al., 2008 ).

Summary of genetically-informative studies

The few genetically-informed studies that have considered MSDP suggest that, for certain outcomes, MSDP does have a specific environmental effect that is not confounded with genetic factors, common environmental factors, and other covariates. GxE (measured gene) studies also indicate that there is suggestive evidence that certain genetic polymorphisms (both maternal and offspring) do moderate the teratogenic effects of prenatal smoking exposure on infant birth weight, preterm delivery, and externalizing behavior. Taken as a group, these results highlight the importance of including genetic and environmental variables in the study of the association between MSDP and offspring outcomes.

A note on prospective vs retrospective studies

Ideally, studies assessing effects of MSDP would recruit participants while pregnant, with continued follow-up of offspring to investigate outcomes associated with MSDP and its correlates (e.g., maternal/paternal psychopathology, home environment, exposure to second-hand smoke, etc). This, however, is not always possible. Many studies must rely on retrospective report of smoking during pregnancy. There has been some question of the reliability of retrospective reporting, in that such reporting could result in underreporting due to social desirability or greater measurement error which could cause the importance of prenatal exposure to be underestimated. Petitti, Friedman, and Kahn (1981) state that the reliability of retrospective reports is similar to the recall of other substance use. More recent reports also indicate high reliability and stability of maternal reporting about their pregnancies, including smoking ( Heath et al., 2003 ; Patrick et al., 1994 ; Reich, Todd, Joyner, Neuman & Heath, 2003 ; Tomeo et al., 1999 ;). Moreover, there is a high correlation between self-reported smoking and serum cotinine measures ( Klebanoff, Levine, Clemens, DerSimonian & Wilkins, 1998 ; McDonald, Perkins, & Walker, 2005 ).

Despite advances in interview assessment and procedures, the use of retrospective reports of the prenatal and postnatal environment should be used with caution. Retrospective recall of environmental exposures are likely to give rise to artefactual gene-environment associations arising from behavioral ‘contamination’ of the reported events (Jaffee & Price, 2007). Specifically, such reports may be influenced by individual differences in personality, mood, or mental health, or may reflect the degree to which past environments were elicited by an individuals behavior ( Kendler, 1996 ; Jaffee & Price, 2007).

It is unlikely, given methodological limitations and the risk factor under consideration (MSDP which, in twin offspring, will not differ), that a single design will provide the answers to the complicated nature of the association between MSDP and subsequent outcomes. Over the past three decades, behavioral geneticists have begun to use designs that combine many of the methods outlined in this report in order to bring more power to bear on analyses. For example, a necessary first step in mapping complex traits to genetic loci is to establish the amount of genetic variation that underlies the phenotypic variation of the trait (i.e., heritability). This is accomplished via twin studies. If phenotypic variation in a trait is found to be caused in part by genetic sources (i.e., the trait is heritable), linkage and/or association studies can be conducted in order to characterize the effects of specific genes on phenotypic variation ( Posthuma & Boomsma, 2000 ). But, if the trait of interest is not found to be heritable, the search for the measured genetic effects (i.e., direct main effects or interactive effects of, for example, dopaminergic genes) will most likely not be initiated. Researchers need to not only (i) use the knowledge that we can gain from the designs presented here as well as the information that animal models of MSDP provide (i.e., the teratogenic effect of nicotine on the fetus), but also (ii) to consider pooling resources in order to conduct studies that are powerful enough to make meaningful conclusions. Only then will we gain insight into the underlying processes involved in MSDP.

The ultimate goal of future research in prenatal tobacco exposure is to attempt to derive a relatively unbiased estimate of the magnitude of the association between exposure and outcome – to determine a real vs. statistically spurious effect. Indeed, the fully unbiased estimate is an elusive concept that is never achieved but hopefully more closely realized through increasingly rigorous and comprehensive methods. Future research in this domain should attempt to achieve as accurate as possible an assessment of the magnitude of the association between MSDP and neuropsychological as well as other more physical outcomes. There is strong reason to believe that the established estimates of MSDP-risk on outcome in the literature are upwardly biased due to lack of control for heritable and other confounding factors. A comprehensive approach incorporating genetically-informed samples is of critical importance to obtain a more refined estimate of these associations. Indeed, the more refined effect size may be smaller than what is currently accepted. This, in and of itself, is of great public health significance, not because it will identify a new putative causal agent, but because it will more accurately assess the upper limit of the potential causal association between MSDP and outcomes important for public health, such as low birth weight, cardiorespiratory illness, and ADHD. This should not diminish concern regarding MSDP, but rather could help clarify what are and are not potential causes of ADHD, other neuropsychological, and physical deficits seen in children across the developmental spectrum. Thus, not only is there the potential that findings could provide yet one more incentive for pregnant women to overcome tobacco dependence and quit, but findings can also guide treatment providers to think more comprehensively about smoking during pregnancy and the potential correlates of said behavior. In other words, treatment providers may not only treat, or be concerned with, MSDP, but also correlated behaviors (e.g., maternal psychopathology, detrimental rearing environment, secondhand exposure to smoking) that might also increase risk of certain offspring outcomes. This more informed approach to treatment or general cessation efforts could, in theory, have significant effects on the major public health concern that is smoking during pregnancy and thus result in something that is of substantial value to the field of public health.

Admittedly getting a pregnant woman to stop smoking is perhaps the most straightforward intervention; however, we have ignored other potential confounding factors for far too long. The reality is that, in humans, we do not understand how much of the association between MSDP and offspring outcomes can be attributed to either nicotine or other smoking by-products. By putting more realistic boundaries on the impact of MSDP and not continuing to ignore confounding factors, we open the door for other avenues of treatment, intervention, and prevention – opportunities that heretofore have been missed. The first step around this hurdle – and elucidating real vs. statistically spurious effects of MSDP -- are genetically informed designs.

Acknowledgement

This work was supported by grant DA17671 from the National Institute of Drug Abuse.

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Maternal smoking during pregnancy and offspring conduct problems: evidence from 3 independent genetically sensitive research designs

• PMID: 23884431
• PMCID: PMC3828999
• DOI: 10.1001/jamapsychiatry.2013.127

Importance: Several studies report an association between maternal smoking during pregnancy and offspring conduct disorder. However, past research evidences difficulty in disaggregating prenatal environmental influences from genetic and postnatal environmental influences.

Objective: To examine the relationship between maternal smoking during pregnancy and offspring conduct problems among children reared by genetically related mothers and genetically unrelated mothers.

Design, setting, and participants: The following 3 studies using distinct but complementary research designs were used: The Christchurch Health and Development Study (a longitudinal cohort study that includes biological and adopted children), the Early Growth and Development Study (a longitudinal adoption-at-birth study), and the Cardiff IVF (In Vitro Fertilization) Study (an adoption-at-conception study among genetically related families and genetically unrelated families). Maternal smoking during pregnancy was measured as the mean number of cigarettes per day (0, 1-9, or 10) smoked during pregnancy. Possible covariates were controlled for in the analyses, including child sex, birth weight, race/ethnicity, placement age, and breastfeeding, as well as maternal education and maternal age at birth and family breakdown, parenting practices, and family socioeconomic status.

Main outcomes and measure: Offspring conduct problems (age range, 4-10 years) reported by parents or teachers using the behavior rating scales by Rutter and Conners, the Child Behavior Checklist and the Children's Behavior Questionnaire Short Form, and the Strengths and Difficulties Questionnaire.

Results: A significant association between maternal smoking during pregnancy and offspring conduct problems was observed among children reared by genetically related mothers and genetically unrelated mothers. Results from a meta-analysis affirmed this pattern of findings across pooled study samples.

Conclusions and relevance: Findings across 3 studies using a complement of genetically sensitive research designs suggest that smoking during pregnancy is a prenatal risk factor for offspring conduct problems when controlling for specific perinatal and postnatal confounding factors.

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None of the authors report any conflict of interests or financial disclosures

• Maternal smoking and conduct disorder in the offspring. Slotkin TA. Slotkin TA. JAMA Psychiatry. 2013 Sep;70(9):901-2. doi: 10.1001/jamapsychiatry.2013.1951. JAMA Psychiatry. 2013. PMID: 23884399 No abstract available.

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