maternal cigarette, alcohol, and coffee consumption in relation to risk of clubfoot

Maternal Cigarette, Alcohol, and Coffee Consumptionin Relation to Risk of Clubfoot

Martha M. Werler,a Mahsa M. Yazdy,a James R. Kasser,b Susan T. Mahan,b Robert E. Meyer,c

Marlene Anderka,d Charlotte M. Druschel,e Allen A. MitchellaaSlone Epidemiology Center, Boston University

bDepartment of Orthopaedic Surgery, Boston Childrens HospitaldMassachusetts Birth Defects Monitoring Program, Massachusetts Department of Public Health, Center for Birth Defects Research and

Prevention, Boston, MAcNorth Carolina Birth Defects Monitoring Program, State Center for Health Statistics, Raleigh, NC

eCongenital Malformations Registry, New York State Department of Health, Albany, NY

Abstract

Background: Clubfoot is associated with maternal cigarette smoking in several studies, but it is not clear if thisassociation is confined to women who smoke throughout the at-risk period. Maternal alcohol and coffee drinkinghave not been well studied in relation to clubfoot.Methods: The present study used data from a population-based casecontrol study of clubfoot conducted in Mas-sachusetts, New York, and North Carolina from 2007 to 2011. Mothers of 646 isolated clubfoot cases and 2037controls were interviewed about pregnancy events and exposures, including the timing and frequency of cigarettesmoking, alcohol intake, and coffee drinking.Results: More mothers of cases than controls reported smoking during early pregnancy (28.9% vs. 19.1%). Ofwomen who smoked when they became pregnant, those who quit in the month after a first missed period had a40% increase in clubfoot risk and those who continued to smoke during the next 3 months had more than adoubling in risk, after controlling for demographic factors, parity, obesity, and specific medication exposures.Adjusted odds ratios for women who drank >3 servings of alcohol or coffee per day throughout early pregnancywere 2.38 and 1.77, respectively, but the numbers of exposed women were small and odds ratios were unstable.Conclusions: Clubfoot risk appears to be increased for offspring of women who smoke cigarettes, particularly thosewho continue smoking after pregnancy is recognisable, regardless of amount. For alcohol and coffee drinkers,suggested increased risks were only observed in higher levels of intake.

Keywords: Pregnancy, malformation, clubfoot, alcohol, smoking, coffee.

Clubfoot involves congenital malpositions of thebones and soft tissue of the ankle and foot. When thefoot cannot be manipulated by hand into normal posi-tion, the anomaly is considered a structural clubfoot,which requires serial casting and possibly surgery tocorrect.1,2 Even after correction in infancy, approxi-mately 45% of cases relapse into malposition andnecessitate continued orthopaedic treatment.3 Onaverage, adults with treated clubfoot have poorermobility, flexion, comfort, and quality of life.4 Struc-tural clubfoot develops in early gestation, and a vascu-lar disruption pathogenesis is one mechanism that has

been hypothesised.510 Exposures that may result invascular disruption, therefore, should be explored aspotential risk factors.Maternal cigarette smoking has been shown

in several studies to increase clubfoot risk inoffspring,1115 but alcohol use and coffee drinking havenot been adequately explored. Cigarette smokers,alcohol users, and coffee drinkers often change thepatterns of these exposures in early pregnancy,1618

when structural clubfoot develops. Thus, examinationof these exposures as risk factors for clubfoot requiresconsideration of the timing of such changes. Forexample, despite the many studies that have identifiedincreased risks for clubfoot in relation to maternalcigarette smoking, it is not clear if the association ispresent among women who quit smoking after preg-nancy is recognisable.

Correspondence:Martha M. Werler, Slone Epidemiology Center, BostonUniversity, 1010 Commonwealth Avenue, Boston, MA 02215,USA.E-mail: [email protected]

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3doi: 10.1111/ppe.12163

2014 John Wiley & Sons Ltd

Paediatric and Perinatal Epidemiology, 2015, 29, 310

The present analysis used data from a population-based casecontrol study of structural clubfoot. Thestudy was specifically designed to assess changes incigarette, alcohol, and coffee exposures, allowingexamination of timing and frequency.

Methods

Cases of clubfoot in this casecontrol study wereascertained from Massachusetts, North Carolina, andNew York birth defects registries during the years200711. Infants 10 per day, respectively. For alcohol andcoffee exposures, the reported average number ofdrinks per drinking day was calculated following thesame rubric described above for smoking, except lowand high levels were 3 drinks and >3.0 drinks perdrinking day, respectively.Associations between clubfoot and early pregnancy

cigarette smoking, alcohol intake, and coffee drinkingwere estimated with logistic regression models.Unadjusted odds ratios and 95% confidence intervals(CI) were estimated. Adjusted ORs (aORs) includedterms for previously reported clubfoot risk factors,19,20

including study centre, child sex, maternal race/ethnicity, primiparity, obesity, any use of clomipheneor fertility hormones during the month before or

4 M. M. Werler et al.



2 months after the LMP, and any uses of opioids,selective serotonin reuptake inhibitor, ondansetron,phenergan, pseudoephedrine, diphenhydramine, amo-xicillin, and salicylates during the second, third, orfourth LM. Combinations of cigarette, alcohol, andcoffee exposures were also evaluated. Comparisonswere further stratified according to family history ofclubfoot in a first-degree relative.

Results

The mothers of 72% of eligible cases and 63% of eli-gible controls participated in the study. Among the677 clubfoot cases, 95% had no other major malforma-tions and were included in the present analysis. These646 cases were compared with the 2037 control sub-jects. Compared with controls, a higher percentage ofcases were male, from the Massachusetts study site,first-born, and had mothers who were white non-Hispanic and overweight or obese (body mass indexof 25.0 or higher) (Table 1). Cases were >10 times aslikely as controls to have a parent or sibling affectedwith clubfoot.Among early pregnancy smokers, approximately

40% quit in LM 2, 9% quit in LM 3, and 50% con-tinued to smoke during LM 2 through 4 (Table 2).With the exception of women who smoked 10 ciga-rettes per day before quitting in LM 3, aORs wereincreased. The largest increases in risk were observedfor women who smoked during LM 2 through 4; for10 cigarettes per day, the aOR was 2.21 [95% CI 1.61,3.02], and for >10 cigarettes/day it was 2.58 [95% CI1.38, 4.81]. Women who quit smoking in LM 2 hadmore modestly increased risks of clubfoot, regardlessof the level of smoking. Among LM 2 quitters, theaOR for both levels combined was 1.41 [95% CI 1.02,1.95].Most women who drank alcohol in early pregnancy

quit in LM 2 and relatively few quit in LM 3. Higherproportions of case mothers were LM 2 quitters thancontrol mothers, and aORs for both 3 and >3 drinks/drinking day were slightly elevated. When combined,any drinking among LM 2 quitters was associatedwith a 1.33-fold increased risk [95% CI 0.98, 1.82]. Noincrease in clubfoot risk was evident for LM 3 quit-ters, although numbers were small. Less than 1% ofwomen reported use LM 2 through 4, but casemothers were more than twice as likely to report anaverage >3 drinks/drinking day during this period(aOR, 2.38; 95% CI 0.66, 8.52).

Like cigarette smoking, coffee drinkers in earlypregnancy were most likely to continue through LM4. The timing and amount of coffee intake were simi-larly distributed among case and control mothers,with one exception. The aOR for women whoreported >3 drinks/drinking day for LM 2 through 4was 1.77 [95% CI 0.81, 3.87].In considering combinations of exposures, we

focused on the period LM 2 through 4, when elevatedaORs were most apparent. During this period, onlythe higher level of alcohol or coffee drinking con-ferred increased risks, whereas any smoking wasassociated with at least a doubling in clubfootrisk. Thus, the combinations of any smoking and >3alcohol drinks/drinking day and any smoking and >3coffee drinks/drinking day were examined. No case

Table 1. Distribution of demographic and reproductive factorsamong 646 isolated clubfoot cases and 2037 controls

Descriptive factorsCases Controlsn (%) n (%)

Childs sex Male 466 (72.1) 1006 (49.4)Female 180 (27.9) 1031 (50.6)

Maternal age(years)

mothers reported both high alcohol and coffee drink-ing. The mothers of three cases and four controlssmoked and drank >3 alcohol drinks/drinking daythroughout LM 2 to 4, producing an aOR = 3.97 [95%CI 0.82, 19.21]. However, there was no evidence of

synergism; the combined effect was not additivelygreater than the individual effects of each exposure.The mothers of 11 cases and 10 controls smoked anddrank >3 coffee drinks/drinking day; the aOR was5.02 [95% CI 2.00, 12.55]. Synergism between cigarette

Table 2. Maternal cigarette, alcohol, and coffee use in early pregnancy in relation to isolated clubfoot

Exposure

Cases n = 646 Controls n = 2037Unadjustedodds ratio 95% CIa aOR 95% CIbNo. % No. %

Cigarette smokingAnytime LM 24

10/day 154 23.8 326 16.0 1.70 [1.36, 2.11] 1.73 [1.37, 2.21]>10/day 33 5.1 63 3.1 1.88 [1.22, 2.90] 2.13 [1.33, 3.41]

LM 2 quitters10/day 52 8.0 133 6.5 1.40 [1.00, 1.96] 1.35 [0.94, 1.95]>10/day 17 2.6 37 1.8 1.65 [0.92, 2.95] 1.62 [0.86, 3.05]


LM 2 through 410/day 86 13.3 150 7.4 2.05 [1.55, 2.73] 2.21 [1.61, 3.02]>10/day 21 3.3 29 1.4 2.59 [1.47, 4.59] 2.58 [1.38, 4.81]

AlcoholAnytime LM 24

3/day 56 8.7 145 7.1 1.27 [0.92, 1.76] 1.09 [0.77, 1.54]>3/day 36 5.6 67 3.3 1.77 [1.17, 2.68] 1.25 [0.80, 1.95]




CoffeeAnytime LM 24

3/day 110 17.0 330 16.2 1.12 [0.89, 1.41] 0.93 [0.72, 1.19]>3/day 34 5.3 78 3.8 1.25 [0.80, 1.98] 0.96 [0.58, 1.58]




aUnadjusted.bAdjusted for all exposures, study centre, child sex, and maternal race/ethnicity, primiparity, obesity, fertility treatment, and LM 24uses of opioids, selective serotonin reuptake inhibitor, phenergan, ondansetron, pseudoephedrine, diphenhydramine, amoxicillin, andsalicylates.




smoking and high-level coffee intake was suggested(relative excess risk due to interaction = 2.62), but the95% CI included the null [2.26, 7.50].When analyses were restricted to the 570 cases and

2022 controls without a first degree family history ofclubfoot, aORs changed 3 alcohol drinks/drinking day LM 2through 4 increased further to 3.01 [95% CI 0.84,10.79].

Comment

Our findings confirm results of previous studiesshowing cigarette smoking in pregnancy increasesclubfoot risk in offspring, and provide new evidencethat this risk is not confined to women who choose tocontinue smoking after pregnancy is recognised.Women who continued to smoke during the 3 monthsafter pregnancy is recognisable had more than atwofold increased clubfoot risk, while women whoentered pregnancy as smokers and quit after a firstmissed menstrual period had a 1.35-fold in clubfootrisk, with a lower 95% confidence bound of 0.94.Although risk estimates included the null value of 1.0,our findings also suggest that consistent high-levelintake of alcohol or coffee in early pregnancyincreases the risk of clubfoot, particularly in combina-tion with cigarette smoking. While there was no evi-dence of increased clubfoot risk for women who quitdrinking coffee the month after a first missed men-strual period, alcohol drinkers who did quit appearedto have an approximate 33% increase in risk.Of the 15 published studies that examined cigarette

smoking in pregnancy in relation to clubfoot,1115 12reported elevated odds ratio estimates. None of thesestudies reported on the timing of cigarette smoking inpregnancy in relation to clubfoot risk.Far fewer studies have examined maternal

alcohol2124 and coffee drinking22 in relation to clubfootrisk. One of these studies was a series of 43 cases(without a comparison group) and noted that threemothers reported extremely high levels of alcoholintake during pregnancy.24 Two studies did notprovide details on how information on alcohol wascollected, and all reported no association between anyalcohol consumption in pregnancy and clubfootrisk.21,23 The one longitudinal study that examinedlevels of alcohol and coffee exposures in the first tri-mester found neither was associated with clubfoot,25

nor was cigarette smoking, in contrast to other studies.

Thus, the present analysis is the first to estimateclubfoot risks by level and timing of cigarette smokeexposure. Indeed, our data showed that both aspectsof exposure are relevant for identifying increasedclubfoot risks. For all three exposures, elevated riskswere most apparent for high-level exposures that arecontinued after pregnancy is recognisable. However,we also observed slightly elevated risk estimates forwomen who quit smoking or drinking alcohol in thesecond LM, which indicates women should not waituntil they know they are pregnant to quit these expo-sures; rather, these exposures during the early days ofgestation are compatible with sonogram evidence thatclubfoot develops early in gestation.Cigarette smoke, alcoholic beverages, and coffee are

complex exposures, each with a mixture of compo-nents and by-products that might affect foot develop-ment in early gestation. The nicotine component ofcigarettes causes vasoconstriction in the mother andthe fetus,26 and it has been suggested that the patho-genesis of clubfoot includes vascular disruption.27

High levels of alcohol intake adversely affect bloodvessels in adults, including pregnant women.28 Caf-feine exposure affects blood flow as an adenosineantagonist.29 Thus, cigarette smoking, alcohol intake,and coffee consumption might each influence footdevelopment via vascular disruption. Animal experi-ments show caffeine or xanthine can affect limbdevelopment, and one study observed slightlyelevated odds ratios in relation to transverse limb defi-ciencies and three or more cups of coffee per day.30

Interestingly, the transverse subtype of limb deficien-cies is purported to also have a vascular disruptionaetiology.27 High-intensity alcohol intake during preg-nancy is associated with a constellation of structuraland developmental defects in offspring, but isolatedclubfoot is not considered a fetal alcohol effect. Inanimal models, alcohol exposure has been shown toamplify cell death, to contribute to the formation offree radicals, and to interfere with folate metabo-lism;31,32 thus, its teratogenic effects may act throughany of these mechanisms. In the present analysis, theassociation between high-level alcohol intake andclubfoot risk was present among women who did andwho did not take folic acid supplements in the firsttrimester; aORs were 2.46 based on three exposedcases and 1.84 based on two exposed cases, respec-tively. Most of the focus of alcohol teratogenesis inbasic research is on the central nervous system.32

Although abnormal neurulation is present in clubfoot,

Cigarettes, alcohol, coffee, and clubfoot 7



it is not clear if the abnormalities are secondary to,part of, or a causal factor in abnormal foot develop-ment. Peripheral nervous system anomalies, such asthose resulting from spina bifida, are associated withclubfoot. Animal and human data are lacking onwhether either the central or peripheral nervoussystems play a role in the development of clubfoot.The observed interaction for the, albeit rare, combi-

nation of cigarette smoking and high levels of coffeedrinking in relation to clubfoot raises the question of abiological synergistic effect. Whereas nicotine and caf-feine affect vasoactivity, they are also neuroactive, bystimulating and/or suppressing neurotransmitters.33,34

Indeed, synergistic effects of nicotine and caffeineexposures on neural functions have been observed.35,36

We previously reported a higher risk of clubfoot inassociation with maternal use of selective serotoninreuptake inhibitors in early pregnancy in two separatestudies37,38 (one being the present study).37 This line ofobservations prompts us to speculate that the centralnervous system may have a role in clubfoot develop-ment. Its pathogenesis is undoubtedly complex, giventhe high recurrence within families,37 predispositionamong boys and first births,19 association with in uteroexposure to cigarette smoke, and possible associationswith selective serotonin reuptake inhibitors,37,38 andhigh-dose alcohol and coffee intakes. Thus, thepresent findings do not clearly point towards any onepathogenetic process for clubfoot development. A dis-tinct advantage of the present study was its detaileddata on the amount and timing of cigarette, alcohol,and coffee exposures, and many other known andsuspected risk factors for clubfoot. Thus, timing andintensity of exposure were simultaneously explored,and potential confounding was rigorously assessed.We did not present results on how often womendrank alcohol, although we observed no elevated ORsfor clubfoot. All data were collected retrospectively,raising the possibility of random or differentialmisclassification. Women who report smoking oralcohol drinking throughout early pregnancy arelikely exposed, but women who report little or nosuch use may not be unexposed. If mothers of casesare more likely to deny true exposures, the observedodds ratios would be underestimates of the truth.Another strength of this study was inclusion of

population-based, orthopaedist-confirmed cases andcontrols from the population that gave rise to thecases. However, not all women who were eligibleagreed to be interviewed. If women who did not par-

ticipate smoked, drank alcohol, or consumed coffeemore or less than women who did participate, andthe differences varied by case/control status, a biascould result. For example, if case mothers who didnot participate were more likely to drink alcohol thancontrol mothers who did not participate, the observedodds ratio would be underestimated. This scenario iscertainly possible, since public health advisoriesagainst alcohol drinking in pregnancy have made thisbehaviour socially unacceptable, and women withaffected infants who drank in pregnancy may there-fore decline to participate. Only liveborn subjectswere included in the study. If the exposures understudy were positively associated with loss of isolatedclubfoot-affected fetuses, odds ratio estimates wouldbe biased downward. An additional limitation is thatthe numbers of women in time- and level-specificexposure categories were small for some compari-sons. This was particularly true of quitters in LM 3 forall three exposures. The resulting odds ratios wereunstable and do not reliably measure whether quit-ting in that second month after a missed menstrualperiod ameliorates risk. Intake of caffeine from othersources and passive smoke exposure were not consid-ered. While coffee drinking and direct cigarettesmoking correspond to higher levels of caffeine andnicotine exposures, women in the unexposed com-parison groups might be exposed to these othersources of exposure, which could produce a down-ward bias of true effects. It is possible that theobserved associations are due to uncontrolled con-founding. Further, exposures in the periconceptionalperiod were not evaluated in this analysis; if a carry-over effect on clubfoot risk exists, our inclusion ofsuch exposures in the reference group would alsoproduce a downward bias of odds ratios.In summary, the present study found clear evidence

that maternal cigarette smoking through earlypregnancy increased the risk of clubfoot, even aftercontrolling for important confounding factors. Specifi-cally, clubfoot risk appears to be increased for off-spring of women who smoke cigarettes before theybecome pregnant, and either quit after pregnancy isclinically recognisable or continue smoking throughthe next 3 months. Women who consumed through-out early pregnancy an average of more than threeservings of coffee per day or more than three alcoholdrinks on the days they drank may also have anincreased clubfoot risk in offspring, but associationswere less stable.




Acknowledgements

Support for this work was provided by EuniceKennedy Shriver National Institute for Child Healthand Human Development Grant RO1-HD051804. Wethank Lisa Crowell RN and Mary Beth Pender RN,interviewers; Michelle Heinz and Eileen Mack,research assistants; Michael Bairos, Oleg Starobinets,and Elie Sirotta, database analysts; Katherine E Kelley,MPH, RPh; and the mothers who participated in thestudy.

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maternal cigarette, alcohol, and coffee consumption in relation to risk of clubfoot

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