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doi: 10.1111/ppe.12163
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Maternal Cigarette, Alcohol, and Coffee Consumption in 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. Mitchella a
Slone Epidemiology Center, Boston University
b
Department of Orthopaedic Surgery, Boston Children’s Hospital
d
Massachusetts Birth Defects Monitoring Program, Massachusetts Department of Public Health, Center for Birth Defects Research and Prevention, Boston, MA c
North Carolina Birth Defects Monitoring Program, State Center for Health Statistics, Raleigh, NC e
Congenital 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 this association is confined to women who smoke throughout the at-risk period. Maternal alcohol and coffee drinking have not been well studied in relation to clubfoot. Methods: The present study used data from a population-based case–control study of clubfoot conducted in Massachusetts, New York, and North Carolina from 2007 to 2011. Mothers of 646 isolated clubfoot cases and 2037 controls were interviewed about pregnancy events and exposures, including the timing and frequency of cigarette smoking, alcohol intake, and coffee drinking. Results: More mothers of cases than controls reported smoking during early pregnancy (28.9% vs. 19.1%). Of women who smoked when they became pregnant, those who quit in the month after a first missed period had a 40% increase in clubfoot risk and those who continued to smoke during the next 3 months had more than a doubling 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 pregnancy were 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 those who 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 the bones and soft tissue of the ankle and foot. When the foot cannot be manipulated by hand into normal position, the anomaly is considered a structural clubfoot, which requires serial casting and possibly surgery to correct.1,2 Even after correction in infancy, approximately 45% of cases relapse into malposition and necessitate continued orthopaedic treatment.3 On average, adults with treated clubfoot have poorer mobility, flexion, comfort, and quality of life.4 Structural clubfoot develops in early gestation, and a vascular disruption pathogenesis is one mechanism that has Correspondence: Martha M. Werler, Slone Epidemiology Center, Boston University, 1010 Commonwealth Avenue, Boston, MA 02215, USA. E-mail: [email protected]
© 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
been hypothesised.5–10 Exposures that may result in vascular disruption, therefore, should be explored as potential risk factors. Maternal cigarette smoking has been shown in several studies to increase clubfoot risk in offspring,11–15 but alcohol use and coffee drinking have not been adequately explored. Cigarette smokers, alcohol users, and coffee drinkers often change the patterns of these exposures in early pregnancy,16–18 when structural clubfoot develops. Thus, examination of these exposures as risk factors for clubfoot requires consideration of the timing of such changes. For example, despite the many studies that have identified increased risks for clubfoot in relation to maternal cigarette smoking, it is not clear if the association is present among women who quit smoking after pregnancy is recognisable.
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The present analysis used data from a populationbased case–control study of structural clubfoot. The study was specifically designed to assess changes in cigarette, alcohol, and coffee exposures, allowing examination of timing and frequency.
Methods Cases of clubfoot in this case–control study were ascertained from Massachusetts, North Carolina, and New York birth defects registries during the years 2007–11. Infants 10 per day, respectively. For alcohol and coffee exposures, the reported average number of drinks per drinking day was calculated following the same rubric described above for smoking, except low and high levels were ≤3 drinks and >3.0 drinks per drinking day, respectively. Associations between clubfoot and early pregnancy cigarette smoking, alcohol intake, and coffee drinking were estimated with logistic regression models. Unadjusted odds ratios and 95% confidence intervals (CI) were estimated. Adjusted ORs (aORs) included terms for previously reported clubfoot risk factors,19,20 including study centre, child sex, maternal race/ ethnicity, primiparity, obesity, any use of clomiphene or fertility hormones during the month before or © 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
Cigarettes, alcohol, coffee, and clubfoot 2 months after the LMP, and any uses of opioids, selective serotonin reuptake inhibitor, ondansetron, phenergan, pseudoephedrine, diphenhydramine, amoxicillin, and salicylates during the second, third, or fourth LM. Combinations of cigarette, alcohol, and coffee exposures were also evaluated. Comparisons were further stratified according to family history of clubfoot in a first-degree relative.
Table 1. Distribution of demographic and reproductive factors among 646 isolated clubfoot cases and 2037 controls
Descriptive factors Child’s sex Maternal age (years)
Results The mothers of 72% of eligible cases and 63% of eligible controls participated in the study. Among the 677 clubfoot cases, 95% had no other major malformations and were included in the present analysis. These 646 cases were compared with the 2037 control subjects. Compared with controls, a higher percentage of cases were male, from the Massachusetts study site, first-born, and had mothers who were white nonHispanic and overweight or obese (body mass index of 25.0 or higher) (Table 1). Cases were >10 times as likely as controls to have a parent or sibling affected with clubfoot. Among early pregnancy smokers, approximately 40% quit in LM 2, 9% quit in LM 3, and 50% continued to smoke during LM 2 through 4 (Table 2). With the exception of women who smoked ≤10 cigarettes per day before quitting in LM 3, aORs were increased. The largest increases in risk were observed for women who smoked during LM 2 through 4; for ≤10 cigarettes per day, the aOR was 2.21 [95% CI 1.61, 3.02], and for >10 cigarettes/day it was 2.58 [95% CI 1.38, 4.81]. Women who quit smoking in LM 2 had more modestly increased risks of clubfoot, regardless of the level of smoking. Among LM 2 quitters, the aOR 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. Higher proportions of case mothers were LM 2 quitters than control mothers, and aORs for both ≤3 and >3 drinks/ drinking day were slightly elevated. When combined, any drinking among LM 2 quitters was associated with a 1.33-fold increased risk [95% CI 0.98, 1.82]. No increase in clubfoot risk was evident for LM 3 quitters, although numbers were small. Less than 1% of women reported use LM 2 through 4, but case mothers were more than twice as likely to report an average >3 drinks/drinking day during this period (aOR, 2.38; 95% CI 0.66, 8.52). © 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
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Maternal education Mother living with child’s father Race – ethnicity
Maternal residence First-born Pre-pregnancy body mass index (kg/m2)
Clubfoot in parent or sibling
Male Female 3 coffee drinks/drinking day were examined. No case
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Table 2. Maternal cigarette, alcohol, and coffee use in early pregnancy in relation to isolated clubfoot Cases n = 646 Exposure Cigarette smoking Anytime LM 2–4 ≤10/day >10/day LM 2 quitters ≤10/day >10/day LM 3 quitters ≤10/day >10/day LM 2 through 4 ≤10/day >10/day Alcohol Anytime LM 2–4 ≤3/day >3/day LM 2 quitters ≤3/day >3/day LM 3 quitters ≤3/day >3/day LM 2 through 4 ≤3/day >3/day Coffee Anytime LM 2–4 ≤3/day >3/day LM 2 quitters ≤3/day >3/day LM 3 quitters ≤3/day >3/day LM 2 through 4 ≤3/day >3/day
Controls n = 2037
No.
%
No.
%
Unadjusted odds ratio
95% CIa
aOR
95% CIb
154 33
23.8 5.1
326 63
16.0 3.1
1.70 1.88
[1.36, 2.11] [1.22, 2.90]
1.73 2.13
[1.37, 2.21] [1.33, 3.41]
52 17
8.0 2.6
133 37
6.5 1.8
1.40 1.65
[1.00, 1.96] [0.92, 2.95]
1.35 1.62
[0.94, 1.95] [0.86, 3.05]
5 5
0.8 0.8
25 15
1.2 0.7
0.72 1.19
[0.27, 1.88] [0.43, 3.30]
0.89 1.27
[0.32, 2.45] [0.43, 3.75]
86 21
13.3 3.3
150 29
7.4 1.4
2.05 2.59
[1.55, 2.73] [1.47, 4.59]
2.21 2.58
[1.61, 3.02] [1.38, 4.81]
56 36
8.7 5.6
145 67
7.1 3.3
1.27 1.77
[0.92, 1.76] [1.17, 2.68]
1.09 1.25
[0.77, 1.54] [0.80, 1.95]
51 30
7.9 4.6
115 54
5.6 2.7
1.46 1.83
[1.04, 2.06] [1.16, 2.89]
1.35 1.30
[0.94, 1.96] [0.79, 2.14]
1 1
0.2 0.2
11 7
0.5 0.3
0.30 0.47
[0.04, 2.33] [0.06, 3.83]
0.24 0.36
[0.03, 1.96] [0.04, 3.12]
4 5
0.6 0.8
19 6
0.9 0.3
0.69 2.75
[0.24, 2.05] [0.84, 9.03]
0.54 2.38
[0.17, 1.65] [0.66, 8.52]
110 34
17.0 5.3
330 78
16.2 3.8
1.12 1.25
[0.89, 1.41] [0.80, 1.98]
0.93 0.96
[0.72, 1.19] [0.58, 1.58]
29 11
4.5 1.7
89 44
4.4 2.2
1.06 0.81
[0.69, 1.63] [0.42, 1.58]
0.85 0.66
[0.54, 1.36] [0.32, 1.36]
3 2
0.5 0.3
17 6
0.8 0.3
0.57 1.08
[0.17, 1.96] [0.22, 5.37]
0.63 0.71
[0.17, 2.29] [0.13, 3.91]
84 14
13.0 2.2
234 20
11.5 1.0
1.16 2.27
[0.89, 1.52] [1.14, 4.52]
0.98 1.77
[0.73, 1.30] [0.81, 3.87]
a
Unadjusted. Adjusted for all exposures, study centre, child sex, and maternal race/ethnicity, primiparity, obesity, fertility treatment, and LM 2–4 uses of opioids, selective serotonin reuptake inhibitor, phenergan, ondansetron, pseudoephedrine, diphenhydramine, amoxicillin, and salicylates.
b
mothers reported both high alcohol and coffee drinking. The mothers of three cases and four controls smoked and drank >3 alcohol drinks/drinking day throughout 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 additively greater than the individual effects of each exposure. The mothers of 11 cases and 10 controls smoked and drank >3 coffee drinks/drinking day; the aOR was 5.02 [95% CI 2.00, 12.55]. Synergism between cigarette © 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
Cigarettes, alcohol, coffee, and clubfoot smoking and high-level coffee intake was suggested (relative excess risk due to interaction = 2.62), but the 95% 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 of clubfoot, aORs changed 3 alcohol drinks/drinking day LM 2 through 4 increased further to 3.01 [95% CI 0.84, 10.79].
Comment Our findings confirm results of previous studies showing cigarette smoking in pregnancy increases clubfoot risk in offspring, and provide new evidence that this risk is not confined to women who choose to continue smoking after pregnancy is recognised. Women who continued to smoke during the 3 months after pregnancy is recognisable had more than a twofold increased clubfoot risk, while women who entered pregnancy as smokers and quit after a first missed menstrual period had a 1.35-fold in clubfoot risk, 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-level intake of alcohol or coffee in early pregnancy increases the risk of clubfoot, particularly in combination with cigarette smoking. While there was no evidence of increased clubfoot risk for women who quit drinking coffee the month after a first missed menstrual period, alcohol drinkers who did quit appeared to have an approximate 33% increase in risk. Of the 15 published studies that examined cigarette smoking in pregnancy in relation to clubfoot,11–15 12 reported elevated odds ratio estimates. None of these studies reported on the timing of cigarette smoking in pregnancy in relation to clubfoot risk. Far fewer studies have examined maternal alcohol21–24 and coffee drinking22 in relation to clubfoot risk. One of these studies was a series of 43 cases (without a comparison group) and noted that three mothers reported extremely high levels of alcohol intake during pregnancy.24 Two studies did not provide details on how information on alcohol was collected, and all reported no association between any alcohol consumption in pregnancy and clubfoot risk.21,23 The one longitudinal study that examined levels of alcohol and coffee exposures in the first trimester found neither was associated with clubfoot,25 nor was cigarette smoking, in contrast to other studies. © 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
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Thus, the present analysis is the first to estimate clubfoot risks by level and timing of cigarette smoke exposure. Indeed, our data showed that both aspects of exposure are relevant for identifying increased clubfoot risks. For all three exposures, elevated risks were most apparent for high-level exposures that are continued after pregnancy is recognisable. However, we also observed slightly elevated risk estimates for women who quit smoking or drinking alcohol in the second LM, which indicates women should not wait until they know they are pregnant to quit these exposures; rather, these exposures during the early days of gestation are compatible with sonogram evidence that clubfoot develops early in gestation. Cigarette smoke, alcoholic beverages, and coffee are complex exposures, each with a mixture of components and by-products that might affect foot development in early gestation. The nicotine component of cigarettes causes vasoconstriction in the mother and the fetus,26 and it has been suggested that the pathogenesis of clubfoot includes vascular disruption.27 High levels of alcohol intake adversely affect blood vessels in adults, including pregnant women.28 Caffeine exposure affects blood flow as an adenosine antagonist.29 Thus, cigarette smoking, alcohol intake, and coffee consumption might each influence foot development via vascular disruption. Animal experiments show caffeine or xanthine can affect limb development, and one study observed slightly elevated odds ratios in relation to transverse limb deficiencies and three or more cups of coffee per day.30 Interestingly, the transverse subtype of limb deficiencies is purported to also have a vascular disruption aetiology.27 High-intensity alcohol intake during pregnancy is associated with a constellation of structural and developmental defects in offspring, but isolated clubfoot is not considered a ‘fetal alcohol effect’. In animal models, alcohol exposure has been shown to amplify cell death, to contribute to the formation of free radicals, and to interfere with folate metabolism;31,32 thus, its teratogenic effects may act through any of these mechanisms. In the present analysis, the association between high-level alcohol intake and clubfoot risk was present among women who did and who did not take folic acid supplements in the first trimester; aORs were 2.46 based on three exposed cases and 1.84 based on two exposed cases, respectively. Most of the focus of alcohol teratogenesis in basic research is on the central nervous system.32 Although abnormal neurulation is present in clubfoot,
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it is not clear if the abnormalities are secondary to, part of, or a causal factor in abnormal foot development. Peripheral nervous system anomalies, such as those resulting from spina bifida, are associated with clubfoot. Animal and human data are lacking on whether either the central or peripheral nervous systems play a role in the development of clubfoot. The observed interaction for the, albeit rare, combination of cigarette smoking and high levels of coffee drinking in relation to clubfoot raises the question of a biological synergistic effect. Whereas nicotine and caffeine affect vasoactivity, they are also neuroactive, by stimulating and/or suppressing neurotransmitters.33,34 Indeed, synergistic effects of nicotine and caffeine exposures on neural functions have been observed.35,36 We previously reported a higher risk of clubfoot in association with maternal use of selective serotonin reuptake inhibitors in early pregnancy in two separate studies37,38 (one being the present study).37 This line of observations prompts us to speculate that the central nervous system may have a role in clubfoot development. Its pathogenesis is undoubtedly complex, given the high recurrence within families,37 predisposition among boys and first births,19 association with in utero exposure to cigarette smoke, and possible associations with selective serotonin reuptake inhibitors,37,38 and high-dose alcohol and coffee intakes. Thus, the present findings do not clearly point towards any one pathogenetic process for clubfoot development. A distinct advantage of the present study was its detailed data on the amount and timing of cigarette, alcohol, and coffee exposures, and many other known and suspected risk factors for clubfoot. Thus, timing and intensity of exposure were simultaneously explored, and potential confounding was rigorously assessed. We did not present results on how often women drank alcohol, although we observed no elevated ORs for clubfoot. All data were collected retrospectively, raising the possibility of random or differential misclassification. Women who report smoking or alcohol drinking throughout early pregnancy are likely exposed, but women who report little or no such use may not be unexposed. If mothers of cases are more likely to deny true exposures, the observed odds ratios would be underestimates of the truth. Another strength of this study was inclusion of population-based, orthopaedist-confirmed cases and controls from the population that gave rise to the cases. However, not all women who were eligible agreed to be interviewed. If women who did not par-
ticipate smoked, drank alcohol, or consumed coffee more or less than women who did participate, and the differences varied by case/control status, a bias could result. For example, if case mothers who did not participate were more likely to drink alcohol than control mothers who did not participate, the observed odds ratio would be underestimated. This scenario is certainly possible, since public health advisories against alcohol drinking in pregnancy have made this behaviour socially unacceptable, and women with affected infants who drank in pregnancy may therefore decline to participate. Only liveborn subjects were included in the study. If the exposures under study were positively associated with loss of isolated clubfoot-affected fetuses, odds ratio estimates would be biased downward. An additional limitation is that the numbers of women in time- and level-specific exposure categories were small for some comparisons. This was particularly true of quitters in LM 3 for all three exposures. The resulting odds ratios were unstable and do not reliably measure whether quitting in that second month after a missed menstrual period ameliorates risk. Intake of caffeine from other sources and passive smoke exposure were not considered. While coffee drinking and direct cigarette smoking correspond to higher levels of caffeine and nicotine exposures, women in the unexposed comparison groups might be exposed to these other sources of exposure, which could produce a downward bias of true effects. It is possible that the observed associations are due to uncontrolled confounding. Further, exposures in the periconceptional period were not evaluated in this analysis; if a carryover effect on clubfoot risk exists, our inclusion of such exposures in the reference group would also produce a downward bias of odds ratios. In summary, the present study found clear evidence that maternal cigarette smoking through early pregnancy increased the risk of clubfoot, even after controlling for important confounding factors. Specifically, clubfoot risk appears to be increased for offspring of women who smoke cigarettes before they become pregnant, and either quit after pregnancy is clinically recognisable or continue smoking through the next 3 months. Women who consumed throughout early pregnancy an average of more than three servings of coffee per day or more than three alcohol drinks on the days they drank may also have an increased clubfoot risk in offspring, but associations were less stable. © 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
Cigarettes, alcohol, coffee, and clubfoot
Acknowledgements Support for this work was provided by Eunice Kennedy Shriver National Institute for Child Health and Human Development Grant RO1-HD051804. We thank 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 the study.
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12 Dickinson KC, Meyer RE, Kotch J. Maternal smoking and the risk for clubfoot in infants. Birth Defects Research. Part A, Clinical and Molecular Teratology 2008; 82:86–91. 13 Kancherla V, Romitti PA, Caspers KM, Puzhankara S, Morcuende JA. Epidemiology of congenital idiopathic talipes equinovarus in Iowa, 1997–2005. American Journal of Medical Genetics. Part A 2010; 152A:1695–1700. 14 Parker SE, Mai CT, Strickland MJ, Olney RS, Rickard R, Marengo L, et al. Multistate study of the epidemiology of clubfoot. Birth Defects Research. Part A, Clinical and Molecular Teratology 2009; 85:897–904. 15 Pavone V, Bianca S, Grosso G, Pavone P, Mistretta A, Longo MR, et al. Congenital talipes equinovarus: an epidemiological study in Sicily. Acta Orthopaedica 2012; 83:294–298. 16 Chen L, Bell EM, Browne ML, Druschel CM, Romitti PA. Exploring maternal patterns of dietary caffeine consumption before conception and during pregnancy. Maternal and Child Health Journal 2014; 18:2446–2455. 17 Ethen MK, Ramadhani TA, Scheuerle AE, Canfield MA, Wyszynski DF, Druschel CM, et al. Alcohol consumption by women before and during pregnancy. Maternal and Child Health Journal 2009; 13:274–285. 18 Colman GJJT. Trends in smoking before, during, and after pregnancy in ten states. American Journal of Preventive Medicine 2003; 24:29–35. 19 Werler MM, Yazdy MM, Mitchell AA, Meyer RE, Druschel CM, Anderka M, et al. Descriptive epidemiology of idiopathic clubfoot. American Journal of Medical Genetics. Part A 2013; 161A:1569–1578. 20 Werler MM, Yazdy MM, Kasser JR, Mahan ST, Meyer RE, Anderka M, et al. Medication use in pregnancy in relation to the risk of isolated clubfoot in offspring. American Journal of Epidemiology 2014; 180:86–93. 21 Cardy AH, Barker S, Chesney D, Sharp L, Maffulli N, Miedzybrodzka Z. Pedigree analysis and epidemiological features of idiopathic congenital talipes equinovarus in the United Kingdom: a case-control study. BMC Musculoskeletal Disorders 2007; 8:62. 22 McDonald AD, Armstrong BG, Sloan M. Cigarette, alcohol, and coffee consumption and congenital defects. American Journal of Public Health 1992; 82:91–93. 23 Honein MA, Paulozzi LJ, Moore CA. Family history, maternal smoking, and clubfoot: an indication of a gene-environment interaction. American Journal of Epidemiology 2000; 152:658–665. 24 Halmesmaki E, Raivio K, Ylikorkala O. A possible association between maternal drinking and fetal clubfoot. New England Journal of Medicine 1985; 312:790. 25 Shiono PH, Klebanoff MA, Rhoads GG. Smoking and drinking during pregnancy. Their effects on preterm birth. JAMA 1986; 255:82–84. 26 Lambers D, Clark K. The maternal and fetal physiologic effects of nicotine. Seminars in Perinatology 1996; 20:115–126. 27 Van Allen MI. Fetal vascular disruptions: mechanisms and some resulting birth defects. Pediatric Annals 1981; 10:219–233. 28 Parkington HC, Kenna KR, Sozo FF, Coleman HA, Bocking A, Brien JF, et al. Maternal alcohol consumption in
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34 Fu Y, Matta SG, Brower VG, Sharp BM. Norepinephrine secretion in the hypothalamic paraventricular nucleus of rats during unlimited access to self-administered nicotine: an in vivo microdialysis study. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 2001; 21:8979–8989. 35 Jessen A, Buemann B, Toubro S, Skovgaard IM, Astrup A. The appetite-suppressant effect of nicotine is enhanced by caffeine. Diabetes, Obesity and Metabolism 2005; 7:327–333. 36 Nastase A, Ioan S, Braga RI, Zagrean L, Moldovan M. Coffee drinking enhances the analgesic effect of cigarette smoking. Neuroreport 2007; 18:921–924. 37 Yazdy MM, Mitchell AA, Werler MM. Use of selective serotonin reuptake inhibitors during pregnancy and risk of clubfoot. Epidemiology (Cambridge, Mass.) 2014; 180:86–93. 38 Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. New England Journal of Medicine 2007; 356:2675–2683.
© 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
doi: 10.1111/ppe.12163
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Maternal Cigarette, Alcohol, and Coffee Consumption in 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. Mitchella a
Slone Epidemiology Center, Boston University
b
Department of Orthopaedic Surgery, Boston Children’s Hospital
d
Massachusetts Birth Defects Monitoring Program, Massachusetts Department of Public Health, Center for Birth Defects Research and Prevention, Boston, MA c
North Carolina Birth Defects Monitoring Program, State Center for Health Statistics, Raleigh, NC e
Congenital 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 this association is confined to women who smoke throughout the at-risk period. Maternal alcohol and coffee drinking have not been well studied in relation to clubfoot. Methods: The present study used data from a population-based case–control study of clubfoot conducted in Massachusetts, New York, and North Carolina from 2007 to 2011. Mothers of 646 isolated clubfoot cases and 2037 controls were interviewed about pregnancy events and exposures, including the timing and frequency of cigarette smoking, alcohol intake, and coffee drinking. Results: More mothers of cases than controls reported smoking during early pregnancy (28.9% vs. 19.1%). Of women who smoked when they became pregnant, those who quit in the month after a first missed period had a 40% increase in clubfoot risk and those who continued to smoke during the next 3 months had more than a doubling 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 pregnancy were 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 those who 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 the bones and soft tissue of the ankle and foot. When the foot cannot be manipulated by hand into normal position, the anomaly is considered a structural clubfoot, which requires serial casting and possibly surgery to correct.1,2 Even after correction in infancy, approximately 45% of cases relapse into malposition and necessitate continued orthopaedic treatment.3 On average, adults with treated clubfoot have poorer mobility, flexion, comfort, and quality of life.4 Structural clubfoot develops in early gestation, and a vascular disruption pathogenesis is one mechanism that has Correspondence: Martha M. Werler, Slone Epidemiology Center, Boston University, 1010 Commonwealth Avenue, Boston, MA 02215, USA. E-mail: [email protected]
© 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
been hypothesised.5–10 Exposures that may result in vascular disruption, therefore, should be explored as potential risk factors. Maternal cigarette smoking has been shown in several studies to increase clubfoot risk in offspring,11–15 but alcohol use and coffee drinking have not been adequately explored. Cigarette smokers, alcohol users, and coffee drinkers often change the patterns of these exposures in early pregnancy,16–18 when structural clubfoot develops. Thus, examination of these exposures as risk factors for clubfoot requires consideration of the timing of such changes. For example, despite the many studies that have identified increased risks for clubfoot in relation to maternal cigarette smoking, it is not clear if the association is present among women who quit smoking after pregnancy is recognisable.
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The present analysis used data from a populationbased case–control study of structural clubfoot. The study was specifically designed to assess changes in cigarette, alcohol, and coffee exposures, allowing examination of timing and frequency.
Methods Cases of clubfoot in this case–control study were ascertained from Massachusetts, North Carolina, and New York birth defects registries during the years 2007–11. Infants 10 per day, respectively. For alcohol and coffee exposures, the reported average number of drinks per drinking day was calculated following the same rubric described above for smoking, except low and high levels were ≤3 drinks and >3.0 drinks per drinking day, respectively. Associations between clubfoot and early pregnancy cigarette smoking, alcohol intake, and coffee drinking were estimated with logistic regression models. Unadjusted odds ratios and 95% confidence intervals (CI) were estimated. Adjusted ORs (aORs) included terms for previously reported clubfoot risk factors,19,20 including study centre, child sex, maternal race/ ethnicity, primiparity, obesity, any use of clomiphene or fertility hormones during the month before or © 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
Cigarettes, alcohol, coffee, and clubfoot 2 months after the LMP, and any uses of opioids, selective serotonin reuptake inhibitor, ondansetron, phenergan, pseudoephedrine, diphenhydramine, amoxicillin, and salicylates during the second, third, or fourth LM. Combinations of cigarette, alcohol, and coffee exposures were also evaluated. Comparisons were further stratified according to family history of clubfoot in a first-degree relative.
Table 1. Distribution of demographic and reproductive factors among 646 isolated clubfoot cases and 2037 controls
Descriptive factors Child’s sex Maternal age (years)
Results The mothers of 72% of eligible cases and 63% of eligible controls participated in the study. Among the 677 clubfoot cases, 95% had no other major malformations and were included in the present analysis. These 646 cases were compared with the 2037 control subjects. Compared with controls, a higher percentage of cases were male, from the Massachusetts study site, first-born, and had mothers who were white nonHispanic and overweight or obese (body mass index of 25.0 or higher) (Table 1). Cases were >10 times as likely as controls to have a parent or sibling affected with clubfoot. Among early pregnancy smokers, approximately 40% quit in LM 2, 9% quit in LM 3, and 50% continued to smoke during LM 2 through 4 (Table 2). With the exception of women who smoked ≤10 cigarettes per day before quitting in LM 3, aORs were increased. The largest increases in risk were observed for women who smoked during LM 2 through 4; for ≤10 cigarettes per day, the aOR was 2.21 [95% CI 1.61, 3.02], and for >10 cigarettes/day it was 2.58 [95% CI 1.38, 4.81]. Women who quit smoking in LM 2 had more modestly increased risks of clubfoot, regardless of the level of smoking. Among LM 2 quitters, the aOR 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. Higher proportions of case mothers were LM 2 quitters than control mothers, and aORs for both ≤3 and >3 drinks/ drinking day were slightly elevated. When combined, any drinking among LM 2 quitters was associated with a 1.33-fold increased risk [95% CI 0.98, 1.82]. No increase in clubfoot risk was evident for LM 3 quitters, although numbers were small. Less than 1% of women reported use LM 2 through 4, but case mothers were more than twice as likely to report an average >3 drinks/drinking day during this period (aOR, 2.38; 95% CI 0.66, 8.52). © 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
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Maternal education Mother living with child’s father Race – ethnicity
Maternal residence First-born Pre-pregnancy body mass index (kg/m2)
Clubfoot in parent or sibling
Male Female 3 coffee drinks/drinking day were examined. No case
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Table 2. Maternal cigarette, alcohol, and coffee use in early pregnancy in relation to isolated clubfoot Cases n = 646 Exposure Cigarette smoking Anytime LM 2–4 ≤10/day >10/day LM 2 quitters ≤10/day >10/day LM 3 quitters ≤10/day >10/day LM 2 through 4 ≤10/day >10/day Alcohol Anytime LM 2–4 ≤3/day >3/day LM 2 quitters ≤3/day >3/day LM 3 quitters ≤3/day >3/day LM 2 through 4 ≤3/day >3/day Coffee Anytime LM 2–4 ≤3/day >3/day LM 2 quitters ≤3/day >3/day LM 3 quitters ≤3/day >3/day LM 2 through 4 ≤3/day >3/day
Controls n = 2037
No.
%
No.
%
Unadjusted odds ratio
95% CIa
aOR
95% CIb
154 33
23.8 5.1
326 63
16.0 3.1
1.70 1.88
[1.36, 2.11] [1.22, 2.90]
1.73 2.13
[1.37, 2.21] [1.33, 3.41]
52 17
8.0 2.6
133 37
6.5 1.8
1.40 1.65
[1.00, 1.96] [0.92, 2.95]
1.35 1.62
[0.94, 1.95] [0.86, 3.05]
5 5
0.8 0.8
25 15
1.2 0.7
0.72 1.19
[0.27, 1.88] [0.43, 3.30]
0.89 1.27
[0.32, 2.45] [0.43, 3.75]
86 21
13.3 3.3
150 29
7.4 1.4
2.05 2.59
[1.55, 2.73] [1.47, 4.59]
2.21 2.58
[1.61, 3.02] [1.38, 4.81]
56 36
8.7 5.6
145 67
7.1 3.3
1.27 1.77
[0.92, 1.76] [1.17, 2.68]
1.09 1.25
[0.77, 1.54] [0.80, 1.95]
51 30
7.9 4.6
115 54
5.6 2.7
1.46 1.83
[1.04, 2.06] [1.16, 2.89]
1.35 1.30
[0.94, 1.96] [0.79, 2.14]
1 1
0.2 0.2
11 7
0.5 0.3
0.30 0.47
[0.04, 2.33] [0.06, 3.83]
0.24 0.36
[0.03, 1.96] [0.04, 3.12]
4 5
0.6 0.8
19 6
0.9 0.3
0.69 2.75
[0.24, 2.05] [0.84, 9.03]
0.54 2.38
[0.17, 1.65] [0.66, 8.52]
110 34
17.0 5.3
330 78
16.2 3.8
1.12 1.25
[0.89, 1.41] [0.80, 1.98]
0.93 0.96
[0.72, 1.19] [0.58, 1.58]
29 11
4.5 1.7
89 44
4.4 2.2
1.06 0.81
[0.69, 1.63] [0.42, 1.58]
0.85 0.66
[0.54, 1.36] [0.32, 1.36]
3 2
0.5 0.3
17 6
0.8 0.3
0.57 1.08
[0.17, 1.96] [0.22, 5.37]
0.63 0.71
[0.17, 2.29] [0.13, 3.91]
84 14
13.0 2.2
234 20
11.5 1.0
1.16 2.27
[0.89, 1.52] [1.14, 4.52]
0.98 1.77
[0.73, 1.30] [0.81, 3.87]
a
Unadjusted. Adjusted for all exposures, study centre, child sex, and maternal race/ethnicity, primiparity, obesity, fertility treatment, and LM 2–4 uses of opioids, selective serotonin reuptake inhibitor, phenergan, ondansetron, pseudoephedrine, diphenhydramine, amoxicillin, and salicylates.
b
mothers reported both high alcohol and coffee drinking. The mothers of three cases and four controls smoked and drank >3 alcohol drinks/drinking day throughout 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 additively greater than the individual effects of each exposure. The mothers of 11 cases and 10 controls smoked and drank >3 coffee drinks/drinking day; the aOR was 5.02 [95% CI 2.00, 12.55]. Synergism between cigarette © 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
Cigarettes, alcohol, coffee, and clubfoot smoking and high-level coffee intake was suggested (relative excess risk due to interaction = 2.62), but the 95% 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 of clubfoot, aORs changed 3 alcohol drinks/drinking day LM 2 through 4 increased further to 3.01 [95% CI 0.84, 10.79].
Comment Our findings confirm results of previous studies showing cigarette smoking in pregnancy increases clubfoot risk in offspring, and provide new evidence that this risk is not confined to women who choose to continue smoking after pregnancy is recognised. Women who continued to smoke during the 3 months after pregnancy is recognisable had more than a twofold increased clubfoot risk, while women who entered pregnancy as smokers and quit after a first missed menstrual period had a 1.35-fold in clubfoot risk, 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-level intake of alcohol or coffee in early pregnancy increases the risk of clubfoot, particularly in combination with cigarette smoking. While there was no evidence of increased clubfoot risk for women who quit drinking coffee the month after a first missed menstrual period, alcohol drinkers who did quit appeared to have an approximate 33% increase in risk. Of the 15 published studies that examined cigarette smoking in pregnancy in relation to clubfoot,11–15 12 reported elevated odds ratio estimates. None of these studies reported on the timing of cigarette smoking in pregnancy in relation to clubfoot risk. Far fewer studies have examined maternal alcohol21–24 and coffee drinking22 in relation to clubfoot risk. One of these studies was a series of 43 cases (without a comparison group) and noted that three mothers reported extremely high levels of alcohol intake during pregnancy.24 Two studies did not provide details on how information on alcohol was collected, and all reported no association between any alcohol consumption in pregnancy and clubfoot risk.21,23 The one longitudinal study that examined levels of alcohol and coffee exposures in the first trimester found neither was associated with clubfoot,25 nor was cigarette smoking, in contrast to other studies. © 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
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Thus, the present analysis is the first to estimate clubfoot risks by level and timing of cigarette smoke exposure. Indeed, our data showed that both aspects of exposure are relevant for identifying increased clubfoot risks. For all three exposures, elevated risks were most apparent for high-level exposures that are continued after pregnancy is recognisable. However, we also observed slightly elevated risk estimates for women who quit smoking or drinking alcohol in the second LM, which indicates women should not wait until they know they are pregnant to quit these exposures; rather, these exposures during the early days of gestation are compatible with sonogram evidence that clubfoot develops early in gestation. Cigarette smoke, alcoholic beverages, and coffee are complex exposures, each with a mixture of components and by-products that might affect foot development in early gestation. The nicotine component of cigarettes causes vasoconstriction in the mother and the fetus,26 and it has been suggested that the pathogenesis of clubfoot includes vascular disruption.27 High levels of alcohol intake adversely affect blood vessels in adults, including pregnant women.28 Caffeine exposure affects blood flow as an adenosine antagonist.29 Thus, cigarette smoking, alcohol intake, and coffee consumption might each influence foot development via vascular disruption. Animal experiments show caffeine or xanthine can affect limb development, and one study observed slightly elevated odds ratios in relation to transverse limb deficiencies and three or more cups of coffee per day.30 Interestingly, the transverse subtype of limb deficiencies is purported to also have a vascular disruption aetiology.27 High-intensity alcohol intake during pregnancy is associated with a constellation of structural and developmental defects in offspring, but isolated clubfoot is not considered a ‘fetal alcohol effect’. In animal models, alcohol exposure has been shown to amplify cell death, to contribute to the formation of free radicals, and to interfere with folate metabolism;31,32 thus, its teratogenic effects may act through any of these mechanisms. In the present analysis, the association between high-level alcohol intake and clubfoot risk was present among women who did and who did not take folic acid supplements in the first trimester; aORs were 2.46 based on three exposed cases and 1.84 based on two exposed cases, respectively. Most of the focus of alcohol teratogenesis in basic research is on the central nervous system.32 Although abnormal neurulation is present in clubfoot,
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it is not clear if the abnormalities are secondary to, part of, or a causal factor in abnormal foot development. Peripheral nervous system anomalies, such as those resulting from spina bifida, are associated with clubfoot. Animal and human data are lacking on whether either the central or peripheral nervous systems play a role in the development of clubfoot. The observed interaction for the, albeit rare, combination of cigarette smoking and high levels of coffee drinking in relation to clubfoot raises the question of a biological synergistic effect. Whereas nicotine and caffeine affect vasoactivity, they are also neuroactive, by stimulating and/or suppressing neurotransmitters.33,34 Indeed, synergistic effects of nicotine and caffeine exposures on neural functions have been observed.35,36 We previously reported a higher risk of clubfoot in association with maternal use of selective serotonin reuptake inhibitors in early pregnancy in two separate studies37,38 (one being the present study).37 This line of observations prompts us to speculate that the central nervous system may have a role in clubfoot development. Its pathogenesis is undoubtedly complex, given the high recurrence within families,37 predisposition among boys and first births,19 association with in utero exposure to cigarette smoke, and possible associations with selective serotonin reuptake inhibitors,37,38 and high-dose alcohol and coffee intakes. Thus, the present findings do not clearly point towards any one pathogenetic process for clubfoot development. A distinct advantage of the present study was its detailed data on the amount and timing of cigarette, alcohol, and coffee exposures, and many other known and suspected risk factors for clubfoot. Thus, timing and intensity of exposure were simultaneously explored, and potential confounding was rigorously assessed. We did not present results on how often women drank alcohol, although we observed no elevated ORs for clubfoot. All data were collected retrospectively, raising the possibility of random or differential misclassification. Women who report smoking or alcohol drinking throughout early pregnancy are likely exposed, but women who report little or no such use may not be unexposed. If mothers of cases are more likely to deny true exposures, the observed odds ratios would be underestimates of the truth. Another strength of this study was inclusion of population-based, orthopaedist-confirmed cases and controls from the population that gave rise to the cases. However, not all women who were eligible agreed to be interviewed. If women who did not par-
ticipate smoked, drank alcohol, or consumed coffee more or less than women who did participate, and the differences varied by case/control status, a bias could result. For example, if case mothers who did not participate were more likely to drink alcohol than control mothers who did not participate, the observed odds ratio would be underestimated. This scenario is certainly possible, since public health advisories against alcohol drinking in pregnancy have made this behaviour socially unacceptable, and women with affected infants who drank in pregnancy may therefore decline to participate. Only liveborn subjects were included in the study. If the exposures under study were positively associated with loss of isolated clubfoot-affected fetuses, odds ratio estimates would be biased downward. An additional limitation is that the numbers of women in time- and level-specific exposure categories were small for some comparisons. This was particularly true of quitters in LM 3 for all three exposures. The resulting odds ratios were unstable and do not reliably measure whether quitting in that second month after a missed menstrual period ameliorates risk. Intake of caffeine from other sources and passive smoke exposure were not considered. While coffee drinking and direct cigarette smoking correspond to higher levels of caffeine and nicotine exposures, women in the unexposed comparison groups might be exposed to these other sources of exposure, which could produce a downward bias of true effects. It is possible that the observed associations are due to uncontrolled confounding. Further, exposures in the periconceptional period were not evaluated in this analysis; if a carryover effect on clubfoot risk exists, our inclusion of such exposures in the reference group would also produce a downward bias of odds ratios. In summary, the present study found clear evidence that maternal cigarette smoking through early pregnancy increased the risk of clubfoot, even after controlling for important confounding factors. Specifically, clubfoot risk appears to be increased for offspring of women who smoke cigarettes before they become pregnant, and either quit after pregnancy is clinically recognisable or continue smoking through the next 3 months. Women who consumed throughout early pregnancy an average of more than three servings of coffee per day or more than three alcohol drinks on the days they drank may also have an increased clubfoot risk in offspring, but associations were less stable. © 2014 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 3–10
Cigarettes, alcohol, coffee, and clubfoot
Acknowledgements Support for this work was provided by Eunice Kennedy Shriver National Institute for Child Health and Human Development Grant RO1-HD051804. We thank 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 the study.
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