Maternal Smoking Before and DuringPregnancy and the Risk of SuddenUnexpected Infant DeathTatiana M. Anderson, PhD,a Juan M. Lavista Ferres, MSC,b Shirley You Ren, PhD,b Rachel Y. Moon, MD,c Richard D. Goldstein, MD,d

Jan-Marino Ramirez, PhD,a,e Edwin A. Mitchell, FRACPf

abstractOBJECTIVES: Maternal smoking during pregnancy is an established risk factor for suddenunexpected infant death (SUID). Here, we aim to investigate the effects of maternalprepregnancy smoking, reduction during pregnancy, and smoking during pregnancy onSUID rates.

METHODS: We analyzed the Centers for Disease Control and Prevention Birth Cohort LinkedBirth/Infant Death Data Set (2007–2011: 20 685 463 births and 19 127 SUIDs). SUID wasdefined as deaths at ,1 year of age with International Classification of Diseases, 10th Revisioncodes R95 (sudden infant death syndrome), R99 (ill-defined or unknown cause), or W75(accidental suffocation or strangulation in bed).

RESULTS: SUID risk more than doubled (adjusted odds ratio [aOR] = 2.44; 95% confidenceinterval [CI] 2.31–2.57) with any maternal smoking during pregnancy and increased twofoldbetween no smoking and smoking 1 cigarette daily throughout pregnancy. For 1 to 20cigarettes per day, the probability of SUID increased linearly, with each additional cigarettesmoked per day increasing the odds by 0.07 from 1 to 20 cigarettes; beyond 20 cigarettes, therelationship plateaued. Mothers who quit or reduced their smoking decreased their oddscompared with those who continued smoking (reduced: aOR = 0.88, 95% CI 0.79–0.98; quit:aOR = 0.77, 95% CI 0.67–0.87). If we assume causality, 22% of SUIDs in the United States canbe directly attributed to maternal smoking during pregnancy.

CONCLUSIONS: These data support the need for smoking cessation before pregnancy. If no womensmoked in pregnancy, SUID rates in the United States could be reduced substantially.

WHAT’S KNOWN ON THIS SUBJECT: Approximately 3500infants ,1 year old die suddenly and unexpectedly eachyear in the United States. Previous research has revealedthat maternal smoking during pregnancy is a known riskfactor for sudden unexpected infant death (SUID).

WHAT THIS STUDY ADDS: In this retrospective cross-sectional analysis (20 685 463 births and 19 127 SUIDs),we use advanced modeling techniques to quantitativelydetermine the effects of maternal smoking, smokingcessation, and smoking reduction in pregnancy on SUIDrates with much higher resolution than previous studies.

To cite: Anderson TM, Lavista Ferres JM, Ren SY, et al.Maternal Smoking Before and During Pregnancy and theRisk of Sudden Unexpected Infant Death. Pediatrics. 2019;143(4):e20183325

aCenter for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington; bMicrosoft,Redmond, Washington; cDepartment of Pediatrics, School of Medicine, University of Virginia, Charlottesville,Virginia; dBoston Children’s Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts;eDepartment of Neurological Surgery and Pediatrics, School of Medicine, University of Washington, Seattle,Washington; and fDepartment of Paediatrics: Child and Youth Health, The University of Auckland, Auckland, NewZealand

Dr Anderson provided input on the data analysis, drafted the initial manuscript, and reviewed andrevised the manuscript; Mr Lavista Ferres conceptualized and designed the study, curated the data,conducted formal data analysis, and drafted the initial manuscript; Dr Ren assisted in the dataanalysis and critically reviewed and revised the manuscript; Drs Moon, Goldstein, and Ramirezassisted in the interpretation of the data and critically reviewed the manuscript for importantintellectual content; Dr Mitchell assisted in the data analysis and the drafting of the initialmanuscript and critically reviewed and revised the manuscript for important intellectual content;and all authors approved the final manuscript as submitted and agree to be accountable for allaspects of the work.

DOI: https://doi.org/10.1542/peds.2018-3325

Accepted for publication Jan 16, 2019

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In the United States, .3700 infantsdie annually from sudden unexpectedinfant death (SUID), which includessudden infant death syndrome (SIDS),accidental suffocation andstrangulation in bed, and ill-definedcauses.1 Multiple epidemiologicstudies have shown a strongrelationship between maternalsmoking and SIDS. Researchers of1 meta-analysis reported a pooledrisk associated with maternalprenatal smoking of nearly fourfold(risk ratio = 3.9; 95% confidenceinterval [CI] 3.8–4.1). Odds ratios(unadjusted) associated withpostnatal maternal smokingrange from 1.47 to 6.56.2 There aredose-dependent relationshipsbetween SIDS rates and both thenumber of cigarettes smokedprenatally3–5 and duration ofsmoke exposure postnatally.6,7

Moreover, there is compellingevidence that maternal smokingmay play a causal role in SIDSdeaths.2,8

Substantial work has beenundertaken to understand thepathophysiology underlying thisincreased risk of sudden infant death.Abnormalities in majorneurotransmitters, includingserotonin and their receptors, havebeen well documented in thebrainstems of SIDS infants,9–11 withexperimental data supportingnicotine’s effects on respiration,autonomic regulation,chemosensitivity, sleep, andarousal.12–17 Maternal smoking hasbeen linked to serotonergicabnormalities in important brainstemnuclei of SIDS infants.18,19 Inanimal models, nicotine increasesserotonin release and alters thefiring of serotonergic neurons ina dose-dependent manner.20,21

Serotonergic neuronal developmentmay be disrupted by maternalsmoking as early as the firsttrimester.18,19,22

Many conclude that maternalsmoking is the strongest prenatal

modifiable risk factor for SIDS inindustrialized nations.23–25 Althoughprevious research has focused on theassociation between pre- or postnatalsmoking and sudden infant death,these studies have given limitedattention to diagnostic preferences asthey affect measured outcomes.26,27

Additionally, only 1 published studyhas provided details aboutprepregnancy smoking.28 Here, weuse national vital statistics data29 anda logistic regression modelingapproach to analyze maternalsmoking behavior during pregnancyfor all 2007–2011 US live birthswith complete smokinginformation (∼12 million births),using higher resolution thanprevious studies and expanding theanalysis to the 3 major causes ofSUID. Additionally, beginning in2011, this data set recorded thenumber of cigarettes that motherssmoked in the 3 monthsprepregnancy. We thus analyzedmaternal smoking and the risk ofSUID by trimester by daily cigaretteconsumption, prepregnancysmoking levels, smokingreduction or cessation duringpregnancy, and individualInternational Classification ofDiseases, 10th Revision (ICD-10) causeof death to estimate population-attributable risk.

METHODS

Study Design and Population

We conducted a retrospective, cross-sectional study to assess therelationship between SUID and self-reported maternal smoking beforeand during pregnancy, using datafrom the Centers for Disease Controland Prevention (CDC) Birth CohortLinked Birth/Infant Death Data Setfor births between 2007 and 2011.29

This data set does not includedetails about the frequency ofautopsy or death scene investigation,although autopsy is an element ofdiagnostic criteria in SIDS.

We defined a SUID case as an infant(,365 days old) death with thefollowing ICD-10 codes: R95(SIDS), R99 (ill-defined andunknown cause), or W75(accidental suffocation orstrangulation in bed).

The analysis of the effects of maternalsmoking before pregnancy wasconducted by using only births in2011 (3 134 781 total births,2585 SUIDs; SUID rate 0.83 per 1000live births), the first year theCDC reported on the number of dailycigarettes smoked in the 3 monthsbefore pregnancy.

We used the complete set of20 685 463 births and 19 127 deathsand dichotomous smoking data(smoking versus no smoking)to estimate the number ofdeaths attributable to prenatalsmoking.

Covariates

In this study, we aimed to make aninference regarding the effect ofmaternal prenatal smoking on SUIDrisk. We used regression adjustmentof potential confounding variablesto decrease bias and to improvethe precision of estimates in thesmoking-SUID association. On thebasis of these calculations, we usedthe following covariates in alladjusted analyses: mother’s andfather’s race and/or ethnicity/Hispanic origin, mother’s and father’sage, mother’s marital status, mother’seducation, live birth order, numberof prenatal visits, gestationallength (weeks), delivery method(vaginal or cesarean), infant sex, andbirth weight.

Statistical Analysis

To understand the relationshipbetween the reported averagenumber of cigarettes smoked per dayand risk of SUID, we developedboth a logistic regression modeland a generalized additivemodel (GAM). CDC data includedichotomous data about maternal

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smoking (yes or no) for all births andalso include daily number ofcigarettes for 60% of births. Toensure that the data were consistentand that there was no bias effect, bothsets of data were used to calculateadjusted odds ratios (aORs). Thelogistic regression model used theaverage number of cigarettes in the 3trimesters as the predictor of primaryinterest, which was coded asa categorical variable, whereas theGAM used the same variable as thepredictor of interest but coded asa continuous numerical variable.All logistic regression andGAM models were adjusted forcovariates.

Using 2011 data and a logisticregression model, we assessed theincreased risk from prepregnancysmoking using a variable thatidentified the smoking habits beforeand during pregnancy. We then used3 logistic regression models tounderstand the effects of smoking ineach trimester. The models weresimilar to the GAM, except thatthe daily number of cigarettessmoked in the 3 trimesterswere modeled independentlyinstead of averaging across all3 trimesters.

We also examined the reduction inSUID risk when mothers quit orreduced the amount smokedcompared with smokers who did notquit or reduce smoking duringpregnancy. A new categorical variablewas created to identify the motherswho smoked in the first trimester andthen quit, reduced, or continued thenumber of daily cigarettes in latertrimesters. If the number of cigarettesby the third trimester was 0, themother was defined as having quit. Ifthe number of total daily cigarettes inthe second and third trimesters wasless than the daily number ofcigarettes in the first trimestermultiplied by 2, the mother wascategorized as a reduced smoker;those who continued to smoke thesame amount (or more) were defined

as continued smokers. In the model,we controlled for covariates and totalnumber of cigarettes smoked duringpregnancy.

To differentiate between SUIDsubcategories (R95, R99, and W75)and non-SUID causes of death, wedeveloped separate logisticregression models to estimate therisk of each cause of deathindependently.

For estimating the proportion of SUIDcases attributable to smoking, weused the same logistic regressionmodel with a database in which allmothers were artificially set asnonsmokers.30 By assumingcausation, the difference betweenthe result of this model andactual SUID rates is the proportion ofdeaths that can be attributed tosmoking.

RESULTS

We investigated 20 685463 birthsand 19 127 SUIDs during the years2007–2011 (SUID rate 0.92 in 1000live births). Of the births, 12 417 813had complete prenatal smokinginformation, and of these cases,10 737 met the SUID definition. In2011, 11.5% of mothers smoked inthe 3 months before pregnancy, and8.9% smoked during pregnancy;24.3% of smokers who smokedprepregnancy quit before the firsttrimester.

By using a dichotomous variable ofsmoking (yes or no), SUID risk morethan doubled (aOR = 2.44; 95% CI

2.31–2.57) with any maternalsmoking during pregnancy. The aORwas similar when calculated forcases in which there were data onnumber of cigarettes smoked duringpregnancy (aOR = 2.40; 95% CI2.23–2.59).

There was a positive correlationbetween average number of dailycigarettes during pregnancy and therisk of SUID (Table 1). Thiscorrelation was similar for eachtrimester when modeledindependently (Fig 1), but theaverage number of cigarettes in the 3trimesters together provided greaterpredictive power (Supplemental Fig 4). There was a twofold-increasedSUID risk between no smoking andsmoking 1 cigarette daily throughoutpregnancy (aOR = 1.98; 95% CI,1.73–2.28). For 1 to 20 cigarettes perday, the probability of SUIDincreased linearly, with eachadditional cigarette smoked per dayincreasing the odds by 0.07 (aOR =0.07 3 number of daily cigarettes +1.91) (Supplemental Fig 4). In theGAM, we observed the same twofoldincrease for smoker versusnonsmoker (aOR = 1.96; 95% CI1.72–2.23), a linear relationship inSUID risk for 1 to 20 cigarettes, anda flattening of the curve after 20+daily cigarettes with much wider CIsbecause of fewer cases (Fig 2). Forthe population mode, between 1 and20 cigarettes, the line fitted on theresults of both logistic regression andGAM were the same (aOR = 0.07 3number of cigarettes +1.91).

TABLE 1 aORs of SUID for 0–20 Cigarettes

No. Daily Cigarettes Odds Ratio 95% CI

Lower Bound UpperBound

0 1 — —

1 1.98 1.73 2.283 2 1.8 2.226 2.35 2.11 2.5610 2.69 2.5 2.9813 2.83 2.43 3.2420 3.17 2.87 3.51

aORs of SUID by average number of cigarettes (0–20) smoked daily during pregnancy. —, not applicable.

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Of mothers who smoked duringpregnancy, 55% did not reducesmoking during pregnancy, 20% quitsmoking by the beginning of the thirdtrimester, and 24% reduced theirsmoking. Those who quit or reducedsmoking by the third trimesterdecreased the amount of smokingduring pregnancy by an average of58% and 33%, respectively.Compared with continued smokers,SUID risk in the reduced group wasslightly decreased (aOR = 0.88; 95%CI 0.79–0.98), whereas thosewho quit exhibited the largestreduction in risk (aOR = 0.77; 95% CI0.67–0.87).

Compared with mothers who did notsmoke in the 3 months before orduring pregnancy, SUID riskprogressively increased for those whosmoked before pregnancy andquit before pregnancy (aOR = 1.47;95% CI 1.16–1.87), those who didnot smoke before but smoked during

pregnancy (aOR = 2.22; 95% CI1.15–4.29), and those whosmoked before and during pregnancy(aOR = 2.52; 95% CI 2.25–2.83).For mothers who smokedprepregnancy only, the number ofcigarettes smoked prepregnancydid not have a significantassociation with a change inSUID risk.

The logistic regression modelsplotting the correlation betweenmaternal smoking and specific ICD-10codes for SUID revealed a statisticallysignificant dose-effect relationshipbetween maternal smoking and oddsof R95, R99, and W75 (Fig 3).Conversely, non-SUID causes ofdeath, including P07.2 (extremeimmaturity of the newborn), P07.3(prematurity), and P01.1 (newbornaffected by premature rupture ofmembranes) did not exhibit thispositive dose-response relationship(Fig 3).

Assuming causality, an estimated∼800 infants per year, or 22% of allSUID cases in the United States, wereattributed to maternal smokingduring pregnancy.

DISCUSSION

Public health campaigns launched inthe 1990s educating parents aboutthe importance of infant sleepposition and environment led toa ∼50% decrease in US SIDS rates.31

As prevalence of prone sleeping hasdeclined, the relative contribution ofprenatal maternal smoking to the riskof sudden infant death has increased.2

We found that any smoking duringpregnancy was associated witha doubling in SUID risk. Additionally,if mothers quit or reduced smokingduring pregnancy, the relative riskof SUID decreased comparedwith those who continued smoking.Although the average number ofcigarettes across the 3 trimestersheld greater predictive power, theincrease in SUID risk due to prenatalmaternal smoking was seen evenwhen each trimester was modeledindependently, suggesting thatsmoking during any trimester isassociated with increased SUID risk.However, this phenomenon is at leastpartly explained by a high correlationbetween smoking in the firsttrimester and smoking insubsequent trimesters. In each model,there was a twofold risk forsmokers who smoked at least 1cigarette.

There was a linear correlationbetween average number of dailycigarettes smoked and increased riskfor SUID. Similar dose-dependenttrends have been describedpreviously,32,33 but not with suchresolution or sample size. In the GAM,the curve began to plateau after .20cigarettes per day, suggesting thatsmoking cessation efforts may havegreater impact on decreasing SUIDrates when directed toward thosewho smoke fewer than 1 pack per day

FIGURE 1aORs of SUID given the average number of cigarettes (between 1 and 20) smoked daily by the motherper trimester.

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versus the more traditionally targetedheavy (.20 cigarettes per day)smokers.

Compared with the pregnant smokerswho did not reduce their smokingduring pregnancy (more than half),those who reduced the number ofcigarettes smoked by the thirdtrimester demonstrated a modest(12%) decrease in the risk of SUID,and quitting by the third trimesterwas associated with a greaterreduction in risk (by 23%). However,there may be some selection biasbecause the group who reducedsmoking started at a higher averagenumber of cigarettes in thefirst trimester, whereas those whosuccessfully quit smokedfewer cigarettes in the firsttrimester.

The largest predictor of SUID riskwith maternal prenatal smoking wasthe average number of cigarettessmoked daily over the 3 trimesters.Thus, a woman who smoked 20

cigarettes per day in the firsttrimester and reduced to 10cigarettes per day in subsequenttrimesters had a similarly reducedSUID risk as a woman who averaged13 cigarettes per day in eachtrimester. Public health promotionshould specifically encourage womento quit before pregnancy.Furthermore, pregnant smokersseeking prenatal care in the firsttrimester should be strongly advisedthat the greatest benefit forreducing SUID risk unequivocallyresults from quitting but also that anyreduction in the number of cigarettessmoked is associated with a smalldecrease in risk.

Although smoking has decreasedoverall in the United States in recentyears, 11.6% of mothers reportedsmoking in the 3 months beforepregnancy in 2011. Of these, onlyone-quarter stopped smoking for theduration of the pregnancy. Theadjusted odds for SUID were slightly

but significantly increased (aOR =1.47; 95% CI 1.16–1.87) in caseswherein the mother smokedprepregnancy but quit during thepregnancy compared with those whonever smoked. Part of this increasecould be due to environmentaltobacco exposure because it is notuncommon for those who smoke tohave a partner who also smokes34;it is also likely that a proportion ofwomen who smoked prepregnancyand quit during pregnancy restartedin the postpartum period.35

This group may have also includedwomen who stopped smoking as soonas they knew they were pregnantand thus reported that they werenonsmokers in the first trimester,but the fetus had been exposedto maternal smoking during theperiod before pregnancy wasdiagnosed. Interestingly, theincreased odds ratio was similarregardless of how many cigaretteswere smoked during the 3 monthsprepregnancy. Although thestudy adjusted for manypotential confounders, residualconfounding, especially withsocioeconomic factors, might explainthis finding. There may also beother exposures (eg, women whodrink alcohol during pregnancy,another potent risk factor forSUID, are more likely to smoke atmoderate, high, and very highcontinuous levels as compared withwomen classified as nondrinkers andquitters).36

The relationship between smokingand rates for R95, R99, and W75diagnoses individually revealedsimilar linear trends. These findingssupport the idea that, despitediffering labels on the deathcertificate, there may becommonalities in intrinsic and/orextrinsic factors, and these deathsshould consistently beconsidered together as SUID.Interestingly, specific non-SUIDcauses of death, includingP07.2, P07.3, and P01.1, did not

FIGURE 2Logistic regression and GAMs. Two different computational models, logistic regression and the GAM,plot the rate of SUID given the average daily number of reported cigarettes smoked by the motheracross all 3 trimesters.

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reveal dose-effect relationships withsmoking. This was unexpectedbecause smoking increases the riskof preterm birth, which isassociated with higher mortality andmorbidity.37

Researchers in various countries,including New Zealand (33%),2 Chile(33%),38 Denmark (30%–40%),4

and the United States (23%–34%),39

have attempted to estimate the

percentage of SIDS and/or SUIDattributable to prenatal smoking.In this study, we employedsophisticated statistical analyses incombination with high populationnumbers to allow forgreater granularity in estimatingpopulation-attributable risk forprenatal smoke exposure. Therelationship between smoking andSUID meet the criteria for a causalassociation,40 including (1) strength

(effect size; the magnitude of therisk is strong), (2) a dose-effectrelationship (a linear relationshipbetween number of cigarettes andSUID risk), (3) temporal relationship(the risk factor [smoking] precedesthe event [death]), (4) consistency offindings (smoking is identified asa risk factor in many studies), (5)biological plausibility,2,3 and (6) thereduction in risk with smokingreduction and cessation. If causality isassumed in our model, we estimatethat ∼22% of all US SUID casesare directly attributable to smoking(ie, if every mother did not smokeduring pregnancy, there wouldhave been an estimated 800 fewerSUIDs in the United States in2011 alone). This suggests thata significant reduction in SIDSincidence might occur if theprevalence of maternal smoking wasreduced.

This study is limited by the likelyconservative smoking estimatesbecause our data set does not includeenvironmental smoke exposureduring pregnancy or in thepostpartum period, includingpaternal smoking, which has anindependent influence on SIDSrisk.3,41 In addition, smoking ratesare self-reported. Because it iswidely known that smoking is anunhealthy behavior, it is likelythat some women underestimatedor denied their true smokinghabits. Indeed, in studiesdocumenting serum cotinine levels,maternal self-reportedsmoking status during pregnancyunderestimated smokingprevalence by .20%.42,43

Finally, only 60% of births had dataabout the number of cigarettessmoked. However, the missingdata were not relatedto maternal characteristics butinstead to the adoption of the2003 revision of the US StandardCertificate of Live Birth, andtherefore had minimal effect on theestimates.

FIGURE 3aORs of specific causes of SUID and non-SUID infant death. Comparison is between aORs of specificcauses of infant death, including R95 (SIDS), R99 (ill-defined or unknown cause of mortality), andW75 (accidental suffocation or strangulation in bed), and other non-SUID causes of infant death,including P07.2 (extreme immaturity of the newborn), P07.3 (prematurity), and P01.1 (newbornaffected by premature rupture of membranes).

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CONCLUSIONS

Educational efforts to decrease SUIDrisk should strongly encouragenonsmoking practices beforepregnancy and smokingcessation during pregnancy. Thosewho are unable to quit entirelyshould be advised to reducethe amount smoked. We estimatethat US SUID rates could be reducedby 22% if no women smoked duringpregnancy.

ACKNOWLEDGMENTS

Dr Mitchell was supported in part bythe Gavin and Ann KellawayMedical Research Fellowship. Wethank Kelty Allen, Avleen Bijral,Urszula Chajewska, Ricky Johnston,Sushama Murthy, and JohnThompson for statisticalguidance and useful discussion,and John Kahan and DanielRubens for inspiring thiscollaboration.

ABBREVIATIONS

aOR: adjusted odds ratioCDC: Centers for Disease Control

and PreventionCI: confidence intervalGAM: generalized additive modelICD-10: International Classification

of Diseases, 10th RevisionSIDS: sudden infant death syndromeSUID: sudden unexpected

infant death

Address correspondence to Tatiana M. Anderson, PhD, Seattle Children’s Research Institute, Center for Integrative Brain Research, 1900 Ninth Ave, Seattle, WA 98101.

E-mail: tatianaa@uw.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2019 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Supported by the National Institutes of Health (grants P01HL0906654 and R01HL126523 awarded to J.M.R.), Microsoft, and the Aaron Matthew Sudden

Infant Death Syndrome Research Guild. Funded by the National Institutes of Health (NIH).

POTENTIAL CONFLICT OF INTEREST: Dr Moon has served as a paid medical expert in a case of unexpected sudden infant death; the other authors have indicated

they have no potential conflicts of interest to disclose.

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