J. Perinat. Med. 2014; aop
Elad Mei-Dan*, Asnat Walfisch, Boaz Weisz, Mordechai Hallak, Richard Brown and Alon Shrim
The unborn smoker: association between smoking during pregnancy and adverse perinatal outcomes Abstract Objective: To evaluate a possible dose-response relationship between active maternal smoking during pregnancy and adverse perinatal outcome. Design: Retrospective cohort study. Setting: Population-based in Montreal, Quebec, Canada. Population: Women who gave birth to a liveborn or stillborn infant during the period of January 2001 to December 2007. Methods: Active smokers of different daily cigarette consumption (n = 1646) were identified through maternal self-reporting. The reference group comprised 19,292 nonsmoking women who delivered during the same period. Main outcome measures: Birth weight, preterm delivery rate, fetal and neonatal mortality and morbidity, and congenital malformations. Results: Preterm delivery rate was significantly higher in the smoking group compared with controls (22.2% vs. 12.4%, P < 0.05), as was intrauterine fetal demise (1.4% vs. 0.3%, P < 0.05). Newborns of active smokers were more likely to weigh less (3150 ± 759 g vs. 3377 ± 604 g, P < 0.05), suffer from respiratory distress syndrome (2.5% vs. 1.3%, P < 0.05), suffer from a cardiac malformation (1.5% vs. 0.8%, P < 0.05), and die (neonatal death 1.2% vs. 0.6%, P < 0.05). A dose-response relationship was demonstrated between levels of daily cigarette smoking and several adverse outcomes. Using multiple regression models, smoking was found to be an independent predictor of preterm delivery (odds ratios (OR) 1.9, 95% confidence intervals (95%CI) 1.6–2), and intrauterine fetal demise (OR 2.4, 95%CI 1.4–4.2).
*Corresponding author: Elad Mei-Dan, Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera 38100, PO Box 169, Israel, Tel./Fax: +972-4-6304248, E-mail: [email protected] Asnat Walfisch, Mordechai Hallak and Alon Shrim: Hillel Yaffe Medical Center, Department of Obstetrics and Gynecology, Hadera, Israel Boaz Weisz: Sheba Medical Center, Department of Obstetrics and Gynecology, Tel-Hashomer, Israel Richard Brown: McGill University Health Center, Department of Obstetrics and Gynecology, Montreal, Quebec, Canada
Conclusion: Any amount of daily smoking appears to harm the fetus and newborn. As pregnancy may be a “window of opportunity” for behavioural changes, efforts to promote smoking cessation should be encouraged. Keywords: Intrauterine fetal demise; malformation; pregnancy; preterm delivery; smoking. DOI 10.1515/jpm-2014-0299 Received September 6, 2014. Accepted October 21, 2014.
Key message box: Maternal smoking during pregnancy is a known modifiable risk factor for several adverse perinatal outcomes. Our findings suggest both a doseresponse relationship and higher risk even with low level of exposure.
Introduction Maternal smoking during pregnancy is one of the most consistently reported modifiable risk factors for a number of adverse perinatal outcomes [1–3]. Well-established complications associated with maternal smoking during pregnancy include preterm delivery (PTD), fetal growth restriction, and oral clefts [4–6]. The deleterious effects of maternal smoking are not limited to pregnancy. In the early neonatal period, maternal smoking during pregnancy increases the rates of respiratory morbidity and of infant mortality. In the long term, maternal smoking during pregnancy elevates the risk of abnormal childhood intellectual and behavioural patterns [7–9]. Cigarette smoke possesses potent teratogenic properties. It contains harmful compounds that are fetotoxic, capable of causing cellular damage and inducing alterations in placental biology and function. Although nicotine itself has been shown to increase the risk of fetal malformations [10–13], it remains undetermined whether maternal smoking during pregnancy increases the prevalence of congenital malformations other than of oral clefts. Despite the conclusive body of evidence suggesting an array of harmful effects,
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2 Mei-Dan et al., Maternal smoking and complications
maternal smoking during pregnancy remains globally prevalent with rates of 17% in Australia, 14% in the USA and 10.5% in Canada [7, 14–17]. In most studies, maternal smoking rates are inversely correlated with maternal age and level of education, and only about half of all women who smoke stop during pregnancy [7, 18]. In the present study, we assessed whether maternal smoking during pregnancy is associated with adverse perinatal outcomes in general, with perinatal mortality and with congenital malformations other than oral clefts. We also examined whether any association was dose dependent and whether there is a “smoking threshold” for any associated adverse perinatal outcomes.
and statistical analysis was performed using the Fisher’s exact test. For correlations between daily cigarette consumption and different adverse perinatal outcomes, we used the Pearson product-moment coefficient. We have conducted several multivariable regression models (logistic and linear regressions) aimed at exploring possible independent associations with maternal smoking during pregnancy. Variables included in the regression models were: smoking, alcohol intake during pregnancy, maternal age, maternal hypertensive disorders, diabetes mellitus, gestational age at delivery and abortion. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated from the regression coefficient. A P-value of 0.05 was considered statistically significant. The institutional review board of the McGill University Health Center has approved this study (reference number: 12-438-SDR).
Material and methods
Results
In this population-based cohort study, data were retrieved from the perinatal computerised database of the McGill University (Montreal, Quebec, Canada) for all deliveries occurring during the 7-year period between January 2001 and December 2007. The MOND (McGill Obstetrics and Neonatal Database) is a computerised obstetric and neonatal database that was created in 1978. Data are coded soon after discharge for all deliveries and infants born at the McGill University Health Centre in Montreal, Canada. Maternal and infant charts are coded immediately following delivery and again following discharge by a clerk for routine entries and by three professionals (nurse, obstetrician and neonatologist) for items requiring judgmental decisions. Clinical characteristics that were extracted for this study included maternal age, body mass index, history of abortions in previous pregnancies, maternal diabetes mellitus and hypertensive disorders. The following labour characteristics and perinatal outcomes were assessed: gestational age at delivery (gestational age was calculated using last menstrual period; if this was unknown or differed from first trimester ultrasound by > 10 days, then first ultrasound was used), birth weight and intrauterine growth restriction, PTD (all deliveries occurring prior to 37 completed weeks of pregnancy), mode of delivery, Apgar scores at 1 and 5 min, umbilical artery pH, neonatal haematocrit, congenital malformation, fetal and neonatal mortality, admission to neonatal intensive care unit (NICU) and neonatal respiratory distress syndrome (RDS). Maternal smoking status and daily cigarette consumption were determined through maternal self-reporting.
During the 7-year study period, 20,938 deliveries took place, 1646 (7.8%) of which were to smoking mothers. Mean maternal age in the overall study group was 31.5 ± 5.1 years, with a significantly younger mean maternal age in the smoking sub-population (29.3 ± 6.3 years). Pre-gestational maternal hypertension was significantly more common among the smokers (Table 1). Maternal smoking during pregnancy was associated with significantly higher rates of several adverse pregnancy outcomes including PTD, lower birth weight, NICU admission, lower Apgar scores, RDS and both intra-uterine and neonatal deaths. Using the univariate analysis, the odds ratio for intrauterine death reached 4.2 (95%CI: 2.6–6.8). These findings are all summarised in Table 1. Significantly higher rates of perinatal adverse outcomes were present even in the subgroup of women who reported smoking only up to five cigarettes per day. These included higher rates of PTD, NICU admission and perinatal death and lower birth weight and mean Apgar scores (Table 2). A significant negative correlation was found between maternal age and amount of daily smoking (r = –0.07, P < 0.05). Both rates of PTD and of RDS were significantly correlated with the amount of daily maternal smoking (P = 0.05, P = 0.05, respectively, Table 2). The multivariable regression models were aimed at exploring possible independent associations with maternal smoking during pregnancy. Maternal smoking was found to be an independent predictor for intrauterine fetal demise and PTD (Table 3). Of the entire study population, 1652 women (7.9%) had a neonate with a congenital anomaly. There was no significant difference in this rate between smokers and non-smokers (Table 4); however, the following types of
Statistical analyses For the statistical analysis, we have included all recorded deliveries without exclusions. Statistical analysis was performed with the SPSS package (SPSS, Armonk, NY: IBM Corp). Maternal characteristics and pregnancy outcomes were compared between active smokers having different daily cigarette consumptions and controls. Continuous parameters were summarised by mean ± standard deviation (SD) and examined using the Student’s t-test or the Mann-Whitney U test. Categorical parameters were summarised using frequency measures,
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Mei-Dan et al., Maternal smoking and complications 3
Table 1 Maternal demographic characteristics and pregnancy outcomes in the smoking vs. non-smoking group.
Non-smokers (n = 19,292)
Smokersa (n = 1646)
Odds ratiob
P-value
Maternal age (years) Pre-gestational BMI (kg/m2) Abortionsc Pre-gestational hypertension Maternal diabetes Outcome Hypertensive states of pregnancyd Gestational age at delivery (weeks) Preterm delivery < 37 weeks Cesarean section Instrumental delivery Postpartum infection Birth weight (g) Mean Apgar 1 min Mean Apgar 5 min Cord PH (arterial) Neonatal haematocrit NICU admission Respiratory distress syndrome Intrauterine fetal demise Neonatal death
31.6 ± 4.9 24.4 ± 5.2 26.6% 1.3% 7.4%
29.3 ± 6.3 24.5 ± 6.3 30.6% 2.1% 7.2%
1.2 (1.1–1.3) 1.6 (1.1–2.4) 1 (0.8–1.2)
< 0.05 0.9 < 0.05 < 0.05 0.8
4.2% 39.1 ± 2.3 12.4% 24.9% 6.3% 1.4% 3377 ± 604 8.1 ± 1.9 9.0 ± 1.1 7.27 ± 0.3 51.9 ± 7 7.1% 1.3% 0.3% 0.6%
6.6% 38.3 ± 3.3 22.2% 24.1% 4.6% 1.3% 3150 ± 759 7.9 ± 2.2 8.9 ± 1.5 7.28 ± 0.3 51.9 ± 9 12.8% 2.5% 1.4% 1.2%
1.6 (1.3–2) 2 (1.8–2.3) 1 (0.8–1.1) 0.7 (0.6–0.9) 1 (0.6–1.5) 1.9 (1.6–2.2) 2 (1.4–2.8) 4.2 (2.6–6.8) 2 (1.3–3.3)
< 0.05 < 0.05 < 0.05 0.5 < 0.05 0.9 < 0.05 < 0.05 < 0.05 0.4 0.9 < 0.05 < 0.05 < 0.05 < 0.05
Maternal characteristics
Data are percentage (%) or mean ± standard deviation. a Includes any amount of daily smoking. b Fisher exact test with odds ratio and 95% confidence interval. c Previous pregnancy ending with an abortion ( < 20 weeks of gestation). d Preeclampsia, eclampsia, HELLP syndrome. NICU = neonatal intensive care unit, BMI = body mass index, HELLP = haemolysis, elevated liver enzymes and low platelet count.
malformations were significantly more common among smokers: cardiovascular, gastrointestinal, renal and polydactyly. Interestingly, facial anomalies were not related to smokers, and hypospadias was less common in the smoker group.
Discussion Our data suggest a clear and independent relationship between maternal smoking and serious adverse perinatal outcome. Even low level of exposure (up to five cigarettes per day) does not appear to be safe as it was significantly associated with PTD, decreased birth weight, lower Apgar scores and, most concerning, perinatal death. Moreover, some of these outcomes exhibit a dose-response relationship with daily cigarette consumption. Our study’s strength lies in its size. The fact that clinical findings were entered into our database by a dedicated team and the presence of large study and control groups
both increase the reliability of our findings. The main limitation of our study relates its retrospective nature and the way maternal smoking was determined. In our study, as in most of the published literature, information on smoking during pregnancy is from self-reported data. In Canada and the United States, smoking during pregnancy is now widely viewed as unacceptable, and a number of researchers have noted that underreporting of smoking during pregnancy is common. Windsor et al. found a deception rate of 28% for self-reports provided at the end of pregnancy using salivary cotinine as a comparison [19]. This type of misclassification results in classifying heavy smokers as light smokers and minimal smokers as nonsmokers. The former underreporting is likely to negate or minimise any positive associations, while the later means that the real affect is buried amongst the controls. On the other hand, Tikkanen et al. found that self-reported smoking habits during pregnancy correlate well with serum cotinine levels [20]. PTD remains one of the principal challenges in modern obstetrics [21]. It has previously been shown that
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4 Mei-Dan et al., Maternal smoking and complications
Table 2 Maternal demographic characteristics and pregnancy outcomes according to level of smoking exposure. Maternal characteristics
Non-smokers Smokers < 5/day Smokers of 5–10/day Smokers > 10/day (n = 19,292) (n = 645) (n = 363) (n = 638)
P-valuea Non-smoking vs. < 5/day Non-smoking vs. 5–10/day Non-smoking vs. > 10/day
31.6 ± 4.9 26.6% 1.3% 7.4%
30.2 ± 6 26.7% 2.2% 5.4%
28.6 ± 6.6 34.2% 2.2% 8.3%
28.8 ± 6.5 32.4% 1.9% 8.3%
< 0.05 < 0.05 < 0.05 1 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 0.07 0.3 0.4
Cesarean section Instrumental delivery Birth weight (g) Mean Apgar 1 min Mean Apgar 5 min Cord PH (arterial) Neonatal haematocrit NICU admission Intrauterine fetal demise Neonatal death Respiratory distress syndrome
12.4% 24.9% 6.3% 3377 ± 604 8.1 ± 2 9 ± 1.1 7.27 ± 0.3 52 ± 7.6 7.1% 0.3% 0.6% 1.3%
19.8% 26.4% 5.7% 3182 ± 818 7.8 ± 2.4 8.8 ± 1.8 7.26 ± 0.5 52.3 ± 8.8 12.9% 1.9% 1.4% 1.7%
22.3% 23.1% 3.6% 3169 ± 742 8.1 ± 2.2 8.9 ± 1.4 7.3 ± 0.8 51.7 ± 8.8 15.2% 1.1% 0.8% 2.2%
24.6% 22.3% 3.9% 3105 ± 704 8.1 ± 1.9 9.0 ± 1.3 7.3 ± 0.7 52.3 ± 9.6 11.4% 1.1% 1.3% 3.4%
< 0.05 < 0.05 < 0.05 0.4 0.1 0.1 0.7 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 0.5 1 < 0.05 0.1 0.3 0.2 0.3 0.09 0.6 0.5 0.6 < 0.05 < 0.05 < 0.05 > 0.05 < 0.05 < 0.05 < 0.05 0.06 0.06 0.4 < 0.05 < 0.05
Maternal age (years)
Abortionsb
Pre-gestational hypertension
Maternal diabetes
Outcome Preterm delivery < 37 weeks
Data are percentage (%) or mean ± standard deviation. a T-test. b Previous pregnancy ending with an abortion ( < 20 weeks of gestation). NICU = neonatal intensive care unit.
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Mei-Dan et al., Maternal smoking and complications 5
Table 3 Multiple logistic regressions of adverse perinatal outcomes and maternal smoking. Maternal characteristics (covariates included in the model)
Non-smokers n = 19,292 (%)
Smokers n = 1646 (%)
P-value
Adjusted odds ratio
Preterm delivery (SMOKING, HTN, ABORTION, AGE, SOCDURGS, DIABETES, ALCOHOL) Intrauterine fetal demise (SMOKING, HTN, AGE, GA, ABORTION, SOCDURGS, DIABETES, ALCOHOL)
12.4
22.2
< 0.05
0.3
1.4
< 0.05
2.4, 95%CI: 1.4–4.2
1.8, 95%CI: 1.6–2
HTN = maternal hypertension, AGE = maternal age, GA = gestational age at delivery, SOCDURGS = hospital of origin for high-risk pregnancy referrals, DIABETES = diabetes mellitus, ALCOHOL = alcohol intake during pregnancy.
maternal smoking and PTD are connected through direct pathways that may be based upon the vasoconstrictor action of nicotine causing reduced blood flow to the placenta, the binding of carbon monoxide to haemoglobin so that less oxygen is available for placental and fetal tissues and the disruption of neoangiogenesis and of endothelial function [22, 23]. Smoking may have a direct effect of PTD rates but may also act through other mechanisms and associated pregnancy complications. For example and as opposed to previous publications [24, 25], our data demonstrate that smokers have a > 50% increase in the rate of hypertensive disorders during pregnancy, compared with non-smoking controls, and hypertension itself is associated with increased PTD rates. In a meta-analysis of 20 prospective studies, Shah and Bracken reported an overall adjusted OR for PTD of 1.2 for smokers compared with non-smokers [26]. Our numbers are slightly higher than that (OR 1.8, Table 3), possibly as a result of the retrospective design of the study. Importantly, maternal smoking is one of the few modifiable risk factors related to PTD, and thus smoking cessation is an important tool in the ongoing struggle of reducing PTD rates. Regression analysis demonstrated that the higher rates of intrauterine fetal
Table 4 Different types of congenital anomalies in the maternal smoking and non-smoking groups.
Non-smokers n = 19,292 (%)
Smokers n = 1646 (%)
P-valuea
All anomalies CNS Face and neck Cardiovascular Gastrointestinal Renal Hypospadias Polydactyly
7.8 0.3 0.7 0.8 0.7 0.1 0.4 0.2
8.7 0.5 0.7 1.5 1.4 0.3 0.1 0.5
0.2 0.09 1 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05
Congenital anomalies
a
Fisher exact test.
demise in the smoking group were independent of PTD (Table 3), emphasising the harmful effects of smoking in term deliveries as well. A dose-response relationship was demonstrated in our study, associating daily maternal cigarette consumption to PTD and RDS. In Shah’s meta-analysis, subgroup analyses stratifying maternal smoking to the number of cigarettes per day also suggested a dose-response relationship with PTD [26]. Not only is there a dose-response relationship substantiated in our study and other published literature, but the association with adverse outcome is evident even in mild smokers with a consumption of five or less cigarettes per day. Most concerning is the fact that perinatal mortality, and not merely morbidity, is significantly elevated even in this “mild smokers” subgroup. In a recent study, Varner et al. also found a dose-response in relation to stillbirth [27]. Our study demonstrated no significant difference in the overall rate of congenital anomalies between the groups (Table 4), although certain anomalies were significantly more common in the smokers group. In a comprehensive systematic review of maternal smoking during pregnancy and congenital birth defects, similar findings were published [13]. Since pregnancy presents an opportunity for encouraging smoking cessation, regardless of socio-economic circumstances, efforts should be directed at effective antismoking interventions. Such interventions, which might emphasise the harmful effects of even mild smoking during pregnancy and thereby encourage complete cessation, could reduce the associated perinatal complications and the longer-term infant effects if cessation is maintained after the pregnancy. Funding: This study was not funded. Disclosure of interests: The authors report no conflict of interest. All authors declare that no authors (nor their institutions) received payments for their efforts on this project.
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6 Mei-Dan et al., Maternal smoking and complications
References [1] England LJ, Kim SY, Shapiro-Mendoza CK, Wilson HG, Kendrick JS, Satten GA, et al. Maternal smokeless tobacco use in Alaska native women and singleton infant birth size. Acta Obstet Gynecol Scand. 2012;91:93–103. [2] Ananth CV, Cnattingius S. Influence of maternal smoking on placental abruption in successive pregnancies: a populationbased prospective cohort study in Sweden. Am J Epidemiol. 2007;166:289–95. [3] Black M, Bhattacharya S, Fairley T, Campbell DM, Shetty A. Outcomes of pregnancy in women using illegal drugs and in women who smoke cigarettes. Acta Obstet Gynecol Scand. 2013;92:47–52. [4] Roelands J, Jamison MG, Lyerly AD, James AH. Consequences of smoking during pregnancy on maternal health. J Womens Health (Larchmt). 2009;18:867–72. [5] Mehaffey K, Higginson A, Cowan J, Osborne GM, Arbour LT. Maternal smoking at first prenatal visit as a marker of risk for adverse pregnancy outcomes in the Qikiqtaaluk (Baffin) Region. Rural Remote Health. 2010;10:1484. [6] Shi M, Wehby GL, Murray JC. Review on genetic variants and maternal smoking in the etiology of oral clefts and other birth defects. Birth Defects Res C Embryo Today. 2008;84: 16–29. [7] Tong VT, Jones JR, Dietz PM, D’Angelo D, Bombard JM; Centers for Disease Control and Prevention. Trends in smoking before, during, and after pregnancy – Pregnancy Risk Assessment Monitoring System (PRAMS), United States, 31 sites, 2000–2005. MMWR Surveill Summ. 2009;58:1–29. [8] Kafouri S, Leonard G, Perron M, Richer L, Séguin JR, Veillette S, et al. Maternal cigarette smoking during pregnancy and cognitive performance in adolescence. Int J Epidemiol. 2009;38:158–72. [9] Cornelius MD, Day NL. Developmental consequences of prenatal tobacco exposure. Curr Opin Neurol. 2009;22:121–5. [10] Jauniaux E, Burton GJ. Morphological and biological effects of maternal exposure to tobacco smoke on the fetoplacental unit. Early Hum Dev. 2007;83:699–706. [11] Shea AK, Steiner M. Cigarette smoking during pregnancy. Nicotine Tob Res. 2008;10:267–78. [12] Morales-Suárez-Varela MM, Bille C, Christensen K, Olsen J. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol. 2006;107:51–7. [13] Hackshaw A, Rodeck C, Boniface S. Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls. Hum Reprod Update. 2011;17:589–604. [14] Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2003. Natl Vital Stat Rep. 2005;54:1–116.
[15] Connor SK, McIntyre L. The sociodemographic predictors of smoking cessation among pregnant women in Canada. Can J Public Health. 1999;90:352–5. [16] Mohsin M, Bauman AE. Socio-demographic factors associated with smoking and smoking cessation among 426,344 pregnant women in New South Wales, Australia. BMC Public Health. 2005;5:138. [17] Al-Sahab B, Saqib M, Hauser G, Tamim H. Prevalence of smoking during pregnancy and associated risk factors among Canadian women: a national survey. BMC Pregnancy Childbirth. 2010;10:24. [18] Centers for Disease Control (CDC). Smoking during pregnancy United States, 1990–2002. MMWR Morb Mortal Wkly Rep. 2004;53:911–5. [19] Windsor RA, Lowe JB, Perkins LL, Smith-Yoder D, Artz L, Crawford M, et al. Health education for pregnant smokers: its behavioral impact and cost benefit. Am J Public Health. 1993;83:201–6. [20] Tikkanen M, Surcel HM, Bloigu A, Nuutila M, Ylikorkala O, Hiilesmaa V, et al. Self-reported smoking habits and serum cotinine levels in women with placental abruption. Acta Obstet Gynecol Scand. 2010;89:1538–44. [21] Shapiro-Mendoza CK, Lackritz EM. Epidemiology of late and moderate preterm birth. Semin Fetal Neonatal Med. 2012;17:120–5. [22] Shiono PH, Klebanoff MA, Rhoads GG. Smoking and drinking during pregnancy. Their effects on preterm birth. J Am Med Assoc. 1986;255:82–4. [23] Rogers JM. Tobacco and pregnancy. Reprod Toxicol. 2009;28:152–60. [24] Conde-Agudelo A, Althabe F, Belizán JM, Kafury-Goeta AC. Cigarette smoking during pregnancy and risk of preeclampsia: a systematic review. Am J Obstet Gynecol. 1999;181:1026–35. [25] Cnattingius S, Mills JL, Yuen J, Eriksson O, Salonen H. The paradoxical effect of smoking in preeclamptic pregnancies: smoking reduces the incidence but increases the rates of perinatal mortality, abruptio placentae, and intrauterine growth restriction. Am J Obstet Gynecol. 1997;177:156–61. [26] Shah NR, Bracken MB. A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery. Am J Obstet Gynecol. 2000;182:465–72. [27] Varner MW, Silver RM, Rowland Hogue CJ, Willinger M, Parker CB, Thorsten VR, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Stillbirth Collaborative Research Network. Association between stillbirth and illicit drug use and smoking during pregnancy. Obstet Gynecol. 2014;123:113–25.
The authors stated that there are no conflicts of interest regarding the publication of this article.
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Elad Mei-Dan*, Asnat Walfisch, Boaz Weisz, Mordechai Hallak, Richard Brown and Alon Shrim
The unborn smoker: association between smoking during pregnancy and adverse perinatal outcomes Abstract Objective: To evaluate a possible dose-response relationship between active maternal smoking during pregnancy and adverse perinatal outcome. Design: Retrospective cohort study. Setting: Population-based in Montreal, Quebec, Canada. Population: Women who gave birth to a liveborn or stillborn infant during the period of January 2001 to December 2007. Methods: Active smokers of different daily cigarette consumption (n = 1646) were identified through maternal self-reporting. The reference group comprised 19,292 nonsmoking women who delivered during the same period. Main outcome measures: Birth weight, preterm delivery rate, fetal and neonatal mortality and morbidity, and congenital malformations. Results: Preterm delivery rate was significantly higher in the smoking group compared with controls (22.2% vs. 12.4%, P < 0.05), as was intrauterine fetal demise (1.4% vs. 0.3%, P < 0.05). Newborns of active smokers were more likely to weigh less (3150 ± 759 g vs. 3377 ± 604 g, P < 0.05), suffer from respiratory distress syndrome (2.5% vs. 1.3%, P < 0.05), suffer from a cardiac malformation (1.5% vs. 0.8%, P < 0.05), and die (neonatal death 1.2% vs. 0.6%, P < 0.05). A dose-response relationship was demonstrated between levels of daily cigarette smoking and several adverse outcomes. Using multiple regression models, smoking was found to be an independent predictor of preterm delivery (odds ratios (OR) 1.9, 95% confidence intervals (95%CI) 1.6–2), and intrauterine fetal demise (OR 2.4, 95%CI 1.4–4.2).
*Corresponding author: Elad Mei-Dan, Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera 38100, PO Box 169, Israel, Tel./Fax: +972-4-6304248, E-mail: [email protected] Asnat Walfisch, Mordechai Hallak and Alon Shrim: Hillel Yaffe Medical Center, Department of Obstetrics and Gynecology, Hadera, Israel Boaz Weisz: Sheba Medical Center, Department of Obstetrics and Gynecology, Tel-Hashomer, Israel Richard Brown: McGill University Health Center, Department of Obstetrics and Gynecology, Montreal, Quebec, Canada
Conclusion: Any amount of daily smoking appears to harm the fetus and newborn. As pregnancy may be a “window of opportunity” for behavioural changes, efforts to promote smoking cessation should be encouraged. Keywords: Intrauterine fetal demise; malformation; pregnancy; preterm delivery; smoking. DOI 10.1515/jpm-2014-0299 Received September 6, 2014. Accepted October 21, 2014.
Key message box: Maternal smoking during pregnancy is a known modifiable risk factor for several adverse perinatal outcomes. Our findings suggest both a doseresponse relationship and higher risk even with low level of exposure.
Introduction Maternal smoking during pregnancy is one of the most consistently reported modifiable risk factors for a number of adverse perinatal outcomes [1–3]. Well-established complications associated with maternal smoking during pregnancy include preterm delivery (PTD), fetal growth restriction, and oral clefts [4–6]. The deleterious effects of maternal smoking are not limited to pregnancy. In the early neonatal period, maternal smoking during pregnancy increases the rates of respiratory morbidity and of infant mortality. In the long term, maternal smoking during pregnancy elevates the risk of abnormal childhood intellectual and behavioural patterns [7–9]. Cigarette smoke possesses potent teratogenic properties. It contains harmful compounds that are fetotoxic, capable of causing cellular damage and inducing alterations in placental biology and function. Although nicotine itself has been shown to increase the risk of fetal malformations [10–13], it remains undetermined whether maternal smoking during pregnancy increases the prevalence of congenital malformations other than of oral clefts. Despite the conclusive body of evidence suggesting an array of harmful effects,
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2 Mei-Dan et al., Maternal smoking and complications
maternal smoking during pregnancy remains globally prevalent with rates of 17% in Australia, 14% in the USA and 10.5% in Canada [7, 14–17]. In most studies, maternal smoking rates are inversely correlated with maternal age and level of education, and only about half of all women who smoke stop during pregnancy [7, 18]. In the present study, we assessed whether maternal smoking during pregnancy is associated with adverse perinatal outcomes in general, with perinatal mortality and with congenital malformations other than oral clefts. We also examined whether any association was dose dependent and whether there is a “smoking threshold” for any associated adverse perinatal outcomes.
and statistical analysis was performed using the Fisher’s exact test. For correlations between daily cigarette consumption and different adverse perinatal outcomes, we used the Pearson product-moment coefficient. We have conducted several multivariable regression models (logistic and linear regressions) aimed at exploring possible independent associations with maternal smoking during pregnancy. Variables included in the regression models were: smoking, alcohol intake during pregnancy, maternal age, maternal hypertensive disorders, diabetes mellitus, gestational age at delivery and abortion. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated from the regression coefficient. A P-value of 0.05 was considered statistically significant. The institutional review board of the McGill University Health Center has approved this study (reference number: 12-438-SDR).
Material and methods
Results
In this population-based cohort study, data were retrieved from the perinatal computerised database of the McGill University (Montreal, Quebec, Canada) for all deliveries occurring during the 7-year period between January 2001 and December 2007. The MOND (McGill Obstetrics and Neonatal Database) is a computerised obstetric and neonatal database that was created in 1978. Data are coded soon after discharge for all deliveries and infants born at the McGill University Health Centre in Montreal, Canada. Maternal and infant charts are coded immediately following delivery and again following discharge by a clerk for routine entries and by three professionals (nurse, obstetrician and neonatologist) for items requiring judgmental decisions. Clinical characteristics that were extracted for this study included maternal age, body mass index, history of abortions in previous pregnancies, maternal diabetes mellitus and hypertensive disorders. The following labour characteristics and perinatal outcomes were assessed: gestational age at delivery (gestational age was calculated using last menstrual period; if this was unknown or differed from first trimester ultrasound by > 10 days, then first ultrasound was used), birth weight and intrauterine growth restriction, PTD (all deliveries occurring prior to 37 completed weeks of pregnancy), mode of delivery, Apgar scores at 1 and 5 min, umbilical artery pH, neonatal haematocrit, congenital malformation, fetal and neonatal mortality, admission to neonatal intensive care unit (NICU) and neonatal respiratory distress syndrome (RDS). Maternal smoking status and daily cigarette consumption were determined through maternal self-reporting.
During the 7-year study period, 20,938 deliveries took place, 1646 (7.8%) of which were to smoking mothers. Mean maternal age in the overall study group was 31.5 ± 5.1 years, with a significantly younger mean maternal age in the smoking sub-population (29.3 ± 6.3 years). Pre-gestational maternal hypertension was significantly more common among the smokers (Table 1). Maternal smoking during pregnancy was associated with significantly higher rates of several adverse pregnancy outcomes including PTD, lower birth weight, NICU admission, lower Apgar scores, RDS and both intra-uterine and neonatal deaths. Using the univariate analysis, the odds ratio for intrauterine death reached 4.2 (95%CI: 2.6–6.8). These findings are all summarised in Table 1. Significantly higher rates of perinatal adverse outcomes were present even in the subgroup of women who reported smoking only up to five cigarettes per day. These included higher rates of PTD, NICU admission and perinatal death and lower birth weight and mean Apgar scores (Table 2). A significant negative correlation was found between maternal age and amount of daily smoking (r = –0.07, P < 0.05). Both rates of PTD and of RDS were significantly correlated with the amount of daily maternal smoking (P = 0.05, P = 0.05, respectively, Table 2). The multivariable regression models were aimed at exploring possible independent associations with maternal smoking during pregnancy. Maternal smoking was found to be an independent predictor for intrauterine fetal demise and PTD (Table 3). Of the entire study population, 1652 women (7.9%) had a neonate with a congenital anomaly. There was no significant difference in this rate between smokers and non-smokers (Table 4); however, the following types of
Statistical analyses For the statistical analysis, we have included all recorded deliveries without exclusions. Statistical analysis was performed with the SPSS package (SPSS, Armonk, NY: IBM Corp). Maternal characteristics and pregnancy outcomes were compared between active smokers having different daily cigarette consumptions and controls. Continuous parameters were summarised by mean ± standard deviation (SD) and examined using the Student’s t-test or the Mann-Whitney U test. Categorical parameters were summarised using frequency measures,
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Mei-Dan et al., Maternal smoking and complications 3
Table 1 Maternal demographic characteristics and pregnancy outcomes in the smoking vs. non-smoking group.
Non-smokers (n = 19,292)
Smokersa (n = 1646)
Odds ratiob
P-value
Maternal age (years) Pre-gestational BMI (kg/m2) Abortionsc Pre-gestational hypertension Maternal diabetes Outcome Hypertensive states of pregnancyd Gestational age at delivery (weeks) Preterm delivery < 37 weeks Cesarean section Instrumental delivery Postpartum infection Birth weight (g) Mean Apgar 1 min Mean Apgar 5 min Cord PH (arterial) Neonatal haematocrit NICU admission Respiratory distress syndrome Intrauterine fetal demise Neonatal death
31.6 ± 4.9 24.4 ± 5.2 26.6% 1.3% 7.4%
29.3 ± 6.3 24.5 ± 6.3 30.6% 2.1% 7.2%
1.2 (1.1–1.3) 1.6 (1.1–2.4) 1 (0.8–1.2)
< 0.05 0.9 < 0.05 < 0.05 0.8
4.2% 39.1 ± 2.3 12.4% 24.9% 6.3% 1.4% 3377 ± 604 8.1 ± 1.9 9.0 ± 1.1 7.27 ± 0.3 51.9 ± 7 7.1% 1.3% 0.3% 0.6%
6.6% 38.3 ± 3.3 22.2% 24.1% 4.6% 1.3% 3150 ± 759 7.9 ± 2.2 8.9 ± 1.5 7.28 ± 0.3 51.9 ± 9 12.8% 2.5% 1.4% 1.2%
1.6 (1.3–2) 2 (1.8–2.3) 1 (0.8–1.1) 0.7 (0.6–0.9) 1 (0.6–1.5) 1.9 (1.6–2.2) 2 (1.4–2.8) 4.2 (2.6–6.8) 2 (1.3–3.3)
< 0.05 < 0.05 < 0.05 0.5 < 0.05 0.9 < 0.05 < 0.05 < 0.05 0.4 0.9 < 0.05 < 0.05 < 0.05 < 0.05
Maternal characteristics
Data are percentage (%) or mean ± standard deviation. a Includes any amount of daily smoking. b Fisher exact test with odds ratio and 95% confidence interval. c Previous pregnancy ending with an abortion ( < 20 weeks of gestation). d Preeclampsia, eclampsia, HELLP syndrome. NICU = neonatal intensive care unit, BMI = body mass index, HELLP = haemolysis, elevated liver enzymes and low platelet count.
malformations were significantly more common among smokers: cardiovascular, gastrointestinal, renal and polydactyly. Interestingly, facial anomalies were not related to smokers, and hypospadias was less common in the smoker group.
Discussion Our data suggest a clear and independent relationship between maternal smoking and serious adverse perinatal outcome. Even low level of exposure (up to five cigarettes per day) does not appear to be safe as it was significantly associated with PTD, decreased birth weight, lower Apgar scores and, most concerning, perinatal death. Moreover, some of these outcomes exhibit a dose-response relationship with daily cigarette consumption. Our study’s strength lies in its size. The fact that clinical findings were entered into our database by a dedicated team and the presence of large study and control groups
both increase the reliability of our findings. The main limitation of our study relates its retrospective nature and the way maternal smoking was determined. In our study, as in most of the published literature, information on smoking during pregnancy is from self-reported data. In Canada and the United States, smoking during pregnancy is now widely viewed as unacceptable, and a number of researchers have noted that underreporting of smoking during pregnancy is common. Windsor et al. found a deception rate of 28% for self-reports provided at the end of pregnancy using salivary cotinine as a comparison [19]. This type of misclassification results in classifying heavy smokers as light smokers and minimal smokers as nonsmokers. The former underreporting is likely to negate or minimise any positive associations, while the later means that the real affect is buried amongst the controls. On the other hand, Tikkanen et al. found that self-reported smoking habits during pregnancy correlate well with serum cotinine levels [20]. PTD remains one of the principal challenges in modern obstetrics [21]. It has previously been shown that
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4 Mei-Dan et al., Maternal smoking and complications
Table 2 Maternal demographic characteristics and pregnancy outcomes according to level of smoking exposure. Maternal characteristics
Non-smokers Smokers < 5/day Smokers of 5–10/day Smokers > 10/day (n = 19,292) (n = 645) (n = 363) (n = 638)
P-valuea Non-smoking vs. < 5/day Non-smoking vs. 5–10/day Non-smoking vs. > 10/day
31.6 ± 4.9 26.6% 1.3% 7.4%
30.2 ± 6 26.7% 2.2% 5.4%
28.6 ± 6.6 34.2% 2.2% 8.3%
28.8 ± 6.5 32.4% 1.9% 8.3%
< 0.05 < 0.05 < 0.05 1 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 0.07 0.3 0.4
Cesarean section Instrumental delivery Birth weight (g) Mean Apgar 1 min Mean Apgar 5 min Cord PH (arterial) Neonatal haematocrit NICU admission Intrauterine fetal demise Neonatal death Respiratory distress syndrome
12.4% 24.9% 6.3% 3377 ± 604 8.1 ± 2 9 ± 1.1 7.27 ± 0.3 52 ± 7.6 7.1% 0.3% 0.6% 1.3%
19.8% 26.4% 5.7% 3182 ± 818 7.8 ± 2.4 8.8 ± 1.8 7.26 ± 0.5 52.3 ± 8.8 12.9% 1.9% 1.4% 1.7%
22.3% 23.1% 3.6% 3169 ± 742 8.1 ± 2.2 8.9 ± 1.4 7.3 ± 0.8 51.7 ± 8.8 15.2% 1.1% 0.8% 2.2%
24.6% 22.3% 3.9% 3105 ± 704 8.1 ± 1.9 9.0 ± 1.3 7.3 ± 0.7 52.3 ± 9.6 11.4% 1.1% 1.3% 3.4%
< 0.05 < 0.05 < 0.05 0.4 0.1 0.1 0.7 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 0.5 1 < 0.05 0.1 0.3 0.2 0.3 0.09 0.6 0.5 0.6 < 0.05 < 0.05 < 0.05 > 0.05 < 0.05 < 0.05 < 0.05 0.06 0.06 0.4 < 0.05 < 0.05
Maternal age (years)
Abortionsb
Pre-gestational hypertension
Maternal diabetes
Outcome Preterm delivery < 37 weeks
Data are percentage (%) or mean ± standard deviation. a T-test. b Previous pregnancy ending with an abortion ( < 20 weeks of gestation). NICU = neonatal intensive care unit.
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Mei-Dan et al., Maternal smoking and complications 5
Table 3 Multiple logistic regressions of adverse perinatal outcomes and maternal smoking. Maternal characteristics (covariates included in the model)
Non-smokers n = 19,292 (%)
Smokers n = 1646 (%)
P-value
Adjusted odds ratio
Preterm delivery (SMOKING, HTN, ABORTION, AGE, SOCDURGS, DIABETES, ALCOHOL) Intrauterine fetal demise (SMOKING, HTN, AGE, GA, ABORTION, SOCDURGS, DIABETES, ALCOHOL)
12.4
22.2
< 0.05
0.3
1.4
< 0.05
2.4, 95%CI: 1.4–4.2
1.8, 95%CI: 1.6–2
HTN = maternal hypertension, AGE = maternal age, GA = gestational age at delivery, SOCDURGS = hospital of origin for high-risk pregnancy referrals, DIABETES = diabetes mellitus, ALCOHOL = alcohol intake during pregnancy.
maternal smoking and PTD are connected through direct pathways that may be based upon the vasoconstrictor action of nicotine causing reduced blood flow to the placenta, the binding of carbon monoxide to haemoglobin so that less oxygen is available for placental and fetal tissues and the disruption of neoangiogenesis and of endothelial function [22, 23]. Smoking may have a direct effect of PTD rates but may also act through other mechanisms and associated pregnancy complications. For example and as opposed to previous publications [24, 25], our data demonstrate that smokers have a > 50% increase in the rate of hypertensive disorders during pregnancy, compared with non-smoking controls, and hypertension itself is associated with increased PTD rates. In a meta-analysis of 20 prospective studies, Shah and Bracken reported an overall adjusted OR for PTD of 1.2 for smokers compared with non-smokers [26]. Our numbers are slightly higher than that (OR 1.8, Table 3), possibly as a result of the retrospective design of the study. Importantly, maternal smoking is one of the few modifiable risk factors related to PTD, and thus smoking cessation is an important tool in the ongoing struggle of reducing PTD rates. Regression analysis demonstrated that the higher rates of intrauterine fetal
Table 4 Different types of congenital anomalies in the maternal smoking and non-smoking groups.
Non-smokers n = 19,292 (%)
Smokers n = 1646 (%)
P-valuea
All anomalies CNS Face and neck Cardiovascular Gastrointestinal Renal Hypospadias Polydactyly
7.8 0.3 0.7 0.8 0.7 0.1 0.4 0.2
8.7 0.5 0.7 1.5 1.4 0.3 0.1 0.5
0.2 0.09 1 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05
Congenital anomalies
a
Fisher exact test.
demise in the smoking group were independent of PTD (Table 3), emphasising the harmful effects of smoking in term deliveries as well. A dose-response relationship was demonstrated in our study, associating daily maternal cigarette consumption to PTD and RDS. In Shah’s meta-analysis, subgroup analyses stratifying maternal smoking to the number of cigarettes per day also suggested a dose-response relationship with PTD [26]. Not only is there a dose-response relationship substantiated in our study and other published literature, but the association with adverse outcome is evident even in mild smokers with a consumption of five or less cigarettes per day. Most concerning is the fact that perinatal mortality, and not merely morbidity, is significantly elevated even in this “mild smokers” subgroup. In a recent study, Varner et al. also found a dose-response in relation to stillbirth [27]. Our study demonstrated no significant difference in the overall rate of congenital anomalies between the groups (Table 4), although certain anomalies were significantly more common in the smokers group. In a comprehensive systematic review of maternal smoking during pregnancy and congenital birth defects, similar findings were published [13]. Since pregnancy presents an opportunity for encouraging smoking cessation, regardless of socio-economic circumstances, efforts should be directed at effective antismoking interventions. Such interventions, which might emphasise the harmful effects of even mild smoking during pregnancy and thereby encourage complete cessation, could reduce the associated perinatal complications and the longer-term infant effects if cessation is maintained after the pregnancy. Funding: This study was not funded. Disclosure of interests: The authors report no conflict of interest. All authors declare that no authors (nor their institutions) received payments for their efforts on this project.
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6 Mei-Dan et al., Maternal smoking and complications
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The authors stated that there are no conflicts of interest regarding the publication of this article.
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