American Journal of Respiratory and Critical Care Medicine

Rationale: Although epidemiological studies suggest that exposure to maternal smoking during fetal and early life increases the risk of childhood wheezing and asthma, previous studies were not able to differentiate the effects of prenatal from postnatal exposure.

Objectives: To assess the effect of exposure to maternal smoking only during pregnancy on wheeze and asthma among preschool-age children.

Methods: A pooled analysis was performed based on individual participant data from eight European birth cohorts. Cohort-specific effects of maternal smoking during pregnancy, but not during the first year, on wheeze and asthma at 4 to 6 years of age were estimated using logistic regression and then combined using a random effects model. Adjustments were made for sex, parental education, parental asthma, birth weight, and siblings.

Measurements and Main Results: Among the 21,600 children included in the analysis, 735 children (3.4%) were exposed to maternal smoking exclusively during pregnancy but not in the first year after birth. In the pooled analysis, maternal smoking only during pregnancy was associated with wheeze and asthma at 4 to 6 years of age, with adjusted odds ratios of 1.39 (95% confidence interval, 1.08–1.77) and 1.65 (95% confidence interval, 1.18–2.31), respectively. The likelihood to develop wheeze and asthma increased statistically significantly in a linear dose-dependent manner in relation to maternal daily cigarette consumption during the first trimester of pregnancy.

Conclusions: Maternal smoking during pregnancy appears to increase the risk of wheeze and asthma among children who are not exposed to maternal smoking after birth.

Scientific Knowledge on the Subject

Several epidemiological studies suggest that exposure to maternal smoking during fetal and early life increases the risk of childhood wheezing and asthma. However, previous studies were not able to differentiate effects of prenatal from postnatal exposure.

What This Study Adds to the Field

This large pooled analysis of eight birth cohorts with data on more than 21,000 children showed that maternal smoking during pregnancy is associated with wheeze and asthma in preschool children, even among children who are not exposed to maternal smoking late in pregnancy or after birth.

Children are especially susceptible to environmental toxicants due to their growing and differentiating organs and tissues (13). There are critical windows of lung growth and maturation in fetal life and in the first years after birth. Thus, the impact of tobacco smoke exposure is most prominent during these periods (4). Nicotine, carcinogens, and other toxic substances pass the placental barrier and are also found in the amniotic fluid, affecting the fetus (5, 6).

An association has been reported between smoking in pregnancy and respiratory morbidity in the child, such as impaired lung function and lower airway obstruction (710). Because most women who smoke during pregnancy continue doing so after delivery (11), it has been difficult to disentangle the effects of smoking during and after pregnancy (10). However, human and animal studies indicate that different biological mechanisms influence respiratory disease development before and after birth (9, 1214). Although pregnant women may quit smoking (11, 15), the challenge for assessment of fetal smoke exposure effects on airway disease has been identifying a sufficient number of children exposed only during pregnancy.

Our principal objective was to assess the effect of exposure to maternal smoking only during pregnancy on wheeze and asthma in European children at 4 to 6 years of age followed from pregnancy or birth. Some of the results of this study have been previously reported in the form of an abstract (16).

We conducted a pooled analysis based on individual participant data from European birth cohorts from the ENRIECO (Environmental Health Risks in European Birth Cohorts) collaboration (17). Cohorts were included if they satisfied the following criteria: (1) population-based cohort focusing on allergy and asthma with ethical approval, (2) recruitment during pregnancy or shortly (i.e., in the first months) after birth, (3) at least one follow-up assessment of the outcomes wheeze or asthma during 4 to 6 years of age, and (4) information on maternal smoking from at least one time point during pregnancy and from the first year after birth. Eight cohorts met these criteria: ALSPAC (Bristol, UK); AMICS-Menorca (Island of Menorca, Spain); BAMSE (Stockholm, Sweden); DARC (Odense, Denmark); GINIplus, LISAplus, MAS (all multicenter, Germany); and PIAMA-NHS (multicenter, The Netherlands).

Definition of Exposures and Health Outcomes

All exposure information was based on parental questionnaires. The information on maternal smoking during pregnancy and the child’s first year of life available in each birth cohort is described in Tables E1 and E2 in the online supplement. “Maternal smoking during pregnancy” was defined as smoking of at least one cigarette daily during any trimester. “Maternal smoking during the first year of life” was defined as maternal smoking in the dwelling or near the child during the child’s first year of life. GINIplus lacked information on maternal smoking when the children were 1 year of age; therefore, information from 4 months were used as a proxy. “Any tobacco smoke exposure during the first year of life” was defined as mother, father, partner, or other person smoking in the dwelling or near the child during the child’s first year of life. “Current maternal smoking” was defined as smoking in the dwelling or near the child at the time of outcome assessment (4–6 yr). “Any current smoke exposure” was defined as mother, father, or other person smoking in the dwelling or near the child at the time of outcome assessment. ALSPAC lacked information on paternal and other persons smoking when the child was 4 to 6 years of age and was not included in the analyses of any current smoke exposure. To evaluate the effect of smoking during pregnancy, maternal smoking during pregnancy and during the first year of the child’s life was allocated into four categories: (1) no smoking during pregnancy or in the first year (reference category), (2) maternal smoking during pregnancy only, (3) maternal smoking in the first year only, and (4) maternal smoking during pregnancy and during the first year. The effect of maternal smoking during the first trimester was evaluated, irrespective of maternal smoking in the latter trimesters, as well as among mothers who smoked in the first but not in the third trimester. DARC lacked trimester-specific information and was excluded from these analyses.

Information on symptoms of wheeze and asthma were obtained from parental questionnaires (the information on wheeze and asthma available in each cohort is described in Table E3). “Current wheeze” was defined as parental-reported wheezing during the last 12 months according to the International Study of Asthma and Allergy in Childhood (ISAAC) core questions. This information was available from all cohorts. “Current asthma” was defined as satisfying at least two out of three of the following criteria: (1) a doctor’s diagnosis of asthma ever, (2) parental-reported wheezing during the last 12 months according to the ISAAC core questions (18), or (3) asthma medication in the last 12 months. ALSPAC lacked information on doctor’s diagnosis of asthma and was not included in the analyses of asthma. The time point for outcome assessments was 5 years of age, except for BAMSE and ALSPAC, which had available outcome data at 4 and 6 years of age, respectively.

Statistical Analysis

A pooled analysis of eight birth cohorts was performed using a two-stage approach. In stage 1, cohort-specific crude and adjusted estimates, including dose-response effects, were calculated using logistic regression analyses. Results are reported as odds ratios (OR) with 95% confidence intervals (CI). Different potential confounder models were tested. The final logistic model included adjustments for sex, parental asthma based on mother’s and/or father’s history of asthma, parental education counting the parent with the highest educational level, siblings (having older siblings at birth or not), and birth weight in grams as a continuous variable, because these covariates resulted in an OR change of more than 5% or due to prior knowledge. To further exclude the effect of smoke exposure in childhood, we performed an additional analysis among children with no current maternal smoking or any other current smoke exposure at the time of outcome assessment (i.e., at 4–6 yr of age).

In stage 2, the cohort-specific OR estimates were combined using a random effects model, which considers within-cohort and between-cohort variation (19). The results are presented as forest plots with central point estimates and 95% CI of adjusted ORs, where the size of the square represents the inverse of the variance of the individual cohort. Statistical heterogeneity among studies was evaluated using the Q-test and I2 statistics (20).

To examine dose-response relations between the numbers of cigarettes smoked per day and current wheeze or asthma, a two-stage multivariate random effects dose-response pooled analysis was performed. In the first stage, a quadratic logistic model was estimated for each study. In the second stage, we combined the two regression coefficients and the variance/covariance matrix that had been estimated within each study using a restricted maximum likelihood method in a multivariate, random effects metaanalysis. A P value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the quadratic term is equal to zero. For DARC, MAS, and PIAMA-NHS, information on number of cigarettes from any time during pregnancy was used as a proxy due to lack of trimester-specific data.

All statistical analyses were performed with STATA software, version 11 (Stata Corp., College Station, TX), and P < 0.05 was considered statistically significant.

Table 1 presents characteristics of the eight birth cohorts, including the prevalence of maternal smoking during pregnancy, in the first year after delivery, and at the time of outcome assessment as well as wheeze and asthma prevalence at 4 to 6 years of age. The proportion of internal missing on the main exposure or outcome variables (often due to loss to follow-up) ranged between 5 and 42% across the cohorts, and the final proportion of children included in the pooled analyses was 66% out of the recruited children, in total 21,600 children. These children were somewhat less exposed to maternal smoking during pregnancy (19.2%; 95% CI, 18.7–19.7) compared with all eligible children (22.7%; 95% CI, 22.3–23.2). Moreover, their parents more often had a high educational level (55.9%; 95% CI, 55.3–56.6) compared with the parents of all eligible children (52.8%; 95% CI, 52.1–53.2). No statistically significant differences were seen for other potential confounders or for wheeze and asthma prevalence (data not shown).

TABLE 1. CHARACTERISTICS OF THE EIGHT EUROPEAN BIRTH COHORTS, INCLUDING PREVALENCE OF MATERNAL SMOKING DURING PREGNANCY, IN THE FIRST YEAR AFTER DELIVERY AND AT THE TIME OF OUTCOME ASSESSMENTS AS WELL AS PREVALENCE OF WHEEZE AND ASTHMA AT 4 TO 6 YEARS OF AGE

Birth CohortCountryEnrolment PeriodNumber of Recruited ChildrenChild’s Age at RecruitmentMean Birth Weight (g)Mother Smoked during Pregnancy, n (%)*Mother Smoked First Year after Delivery, n (%)Mother Smoked when the Child Was 4–6 yr of Age, n (%)Wheeze at 4–6 yr of Age, n (%)§Asthma at 4–6 yr of Age, n (%)§
ALSPACUK1991–199214,057During pregnancy3,3843,670 (27.5)3,606 (33.9)1,918 (24.8)829 (9.9)na
AMICS-MenorcaSpain1997–1998482During pregnancy3,187182 (37.9)152 (32.8)112 (24.3)41 (8.9)34 (7.4)
BAMSESweden1994–19964,0892 mo3,530529 (12.9)584 (14.8)534 (14.3)546 (14.7)512 (13.7)
DARCDenmark1998–19995621 mo3,541183 (32.6)154 (29.8)88 (19.1)27 (5.9)18 (4.1)
GINIplusGermany1995–19985,991Shortly before or after birth3,472709 (14.8)713 (14.9)428 (12.4)341 (8.9)135 (3.5)
LISAplusGermany1997–19993,0973 d3,473536 (18.0)362 (16.4)177 (8.8)208 (9.5)70 (3.2)
MASGermany19901,3141 mo3,409308 (25.4)443 (38.9)272 (27.6)103 (10.5)34 (3.8)
PIAMA-NHSThe Netherlands1996–19973,182During pregnancy3,515676 (21.3)546 (17.6)419 (14.5)278 (9.7)122 (4.4)

*Mother smoked at least one cigarette daily during any time of pregnancy.

Mother smoked during the first year after delivery.

Mother smoked at the time of outcome assessment (i.e., when the child was 4, 5, or 6 yr of age).

§Outcome data are from follow-up visits when the children were 5 yr of age except for BAMSE (4 yr of age), and ALSPAC (6 yr of age).

Not assessed.

Information on maternal smoking collected 4 mo after delivery for GINIplus.

The prevalence of maternal smoking during pregnancy and the first year of the child’s life allocated into four disjunctive categories are presented in Table 2. On average, 23.5% of the children were exposed to maternal smoking during pregnancy or the first year of life, with a range of 16.9 to 39.2% between the cohorts. About 80% of the mothers who smoked during pregnancy continued smoking during the first postnatal year. In total, 735 children were identified who had been exposed to maternal smoke during pregnancy but not in the first year of life. The prevalence of wheeze at 4 to 6 years of age was 10.4% among the included children, and the prevalence of asthma was 6.6% (Table 2).

TABLE 2. PREVALENCE OF MATERNAL SMOKING DURING PREGNANCY AND DURING THE FIRST YEAR AFTER DELIVERY IN EIGHT EUROPEAN BIRTH COHORTS COMPRISING 21,600 CHILDREN INCLUDED IN THE POOLED ANALYSES

Birth cohortNo Smoking (Reference), n (%)*Smoking during Pregnancy Only, n (%)Smoking in the First Year Only, n (%)Smoking during Pregnancy and First Year, n (%)§Wheeze at 4–6 yr of Age, n (%)Asthma at 4–6 yr of age, n (%)
ALSPAC5,460 (71.2)157 (2.1)407 (5.3)1,584 (20.8)742 (9.7)na
AMICS-Menorca268 (60.8)28 (6.3)12 (2.7)133 (30.2)39 (8.8)33 (7.5)
BAMSE3,051 (83.1)93 (2.5)153 (4.2)376 (10.2)537 (14.7)503 (13.7)
DARC315 (63.6)35 (7.1)17 (3.4)128 (25.9)26 (6.2)18 (4.2)
GINIplus3,159 (83.3)**123 (3.2)**137 (3.6)**375 (9.9)**333 (8.9)129 (3.4)
LISAplus1,421 (80.7)106 (6.0)67 (3.8)166 (9.4)181 (10.4)61 (3.5)
MAS561 (63.6)18 (2.0)127 (13.9)188 (20.6)95 (10.7)33 (4.0)
PIAMA-NHS2,291 (78.1)175 (6.0)56 (1.9)413 (14.1)275 (9.6)121 (4.4)
Total16,526 (76.5)735 (3.4)976 (4.5)3,363 (15.6)2,228 (10.4)898 (6.6)

*No maternal smoking during pregnancy or in the first year after delivery.

Maternal smoking of at least one cigarette daily during any time of pregnancy but no smoking during the first year after delivery.

No maternal smoking during pregnancy but maternal smoking during the first year after delivery.

§Maternal smoking of at least one cigarette daily during any time of pregnancy and during the first year after delivery.

Outcome data are from follow-up visits when the children were 5 yr of age except for BAMSE (4 yr of age) and ALSPAC (6 yr of age).

Not assessed.

**Information on maternal smoking collected 4 mo after delivery.

In Figure 1, the cohort-specific and combined adjusted ORs of maternal smoking during pregnancy, but not in the first year after delivery, on current wheeze (Figure 1A) and asthma (Figure 1B) are displayed. The combined estimates were statistically significant for wheeze with an adjusted OR of 1.39 (95% CI, 1.08–1.77) and for asthma with an adjusted OR of 1.65 (95% CI, 1.18–2.31). No significant heterogeneity was observed between the studies (Q = 5.03, P = 0.656 for wheeze; Q = 4.96, P = 0.55 for asthma).

In Figure 2, the cohort-specific and combined adjusted ORs of maternal smoking in the first year of life, but not during pregnancy, on current wheeze (Figure 2A) and asthma (Figure 2B) are displayed. No increased risk for current wheeze or asthma was seen, the combined adjusted ORs being 0.91 (95% CI, 0.71–1.17) for wheeze and 1.20 (95% CI, 0.84–1.71) for asthma. There was no heterogeneity between the studies (Q = 2.23, P = 0.946; Q = 2.60, P = 0.627).

Figure 3 displays the cohort-specific and combined adjusted ORs for children exposed to maternal smoking during pregnancy as well as in the first year of life. The combined estimates were significant for wheeze (Figure 3A) (adjusted OR, 1.25; 95% CI, 1.09–1.43) and asthma (Figure 3B) (adjusted OR, 1.30; 95% CI, 1.00–1.68). Again, there was no heterogeneity (Q = 2.32, P = 0.940; Q = 7.26, P = 0.297).

Excluding children with smoke exposure not only by the mother but also by the father or other persons in the household (i.e., any smoke exposure) in the child’s first year of life resulted in similar results for all three exposure categories as those presented above (data not shown). We also restricted the analysis to children with no current maternal smoke exposure (i.e., at 4–6 yr of age) (n = 16,241; 507 children were exposed to maternal smoking during pregnancy but not thereafter). Exposure to maternal smoking during pregnancy but not during the first year of life was associated with an increased risk of wheeze (adjusted OR, 1.63; 95% CI, 1.25–2.12) and asthma (adjusted OR, 1.95; 95% CI, 1.34–2.85) among these children. Similar results were observed among children with no current smoke exposure from any persons as well as during the first year of life (n = 9,882; data not shown).

Clear effects of maternal smoking during pregnancy were seen already for the first trimester. Maternal smoking during the first trimester of pregnancy only but not during the third trimester or the first year after birth was associated with an increased risk of wheeze (adjusted OR, 1.45; 95% CI, 1.00–2.12) and asthma (adjusted OR, 2.10; 95% CI, 1.38–3.21). Of the 735 women that smoked during pregnancy but not in the first year after delivery, 496 (67%) quitted smoking during the first or second trimester. In dose-response analyses of maternal smoking during the first trimester of pregnancy and the risk of wheeze and asthma at 4 to 6 years of age, there was no evidence of nonlinearity of the association with the number of cigarettes smoked for wheeze (P = 0.505) and asthma (P = 0.268). Every five cigarette increase in daily consumption conferred an adjusted OR of 1.18 (95% CI, 1.02–1.38) for wheeze and 1.23 (95% CI, 1.03–1.47) for asthma.

This pooled analysis of individual participant data from eight European birth cohorts including 21,600 children enabled us to estimate the independent effect of maternal smoking during pregnancy on wheeze and asthma in preschool children. The results were consistent, showing an increased risk for preschool wheeze and for asthma among children exposed to cigarette smoke by their mothers during pregnancy. The effect appeared to be particularly strong for smoking during the first trimester of pregnancy with a significant dose-response effect relation.

There were several strengths with this study. Individual participant data from eight European birth cohorts were used, enabling us to assess the effect from different patterns of smoke exposure from various populations. To our knowledge, this is the largest database assessing the specific influence of maternal smoking during pregnancy on childhood respiratory disease. Information on maternal smoking during pregnancy was collected at baseline assessment in all cohorts before development of childhood respiratory disease. Moreover, data were harmonized before analyses, reducing between-study heterogeneity. Separation of pre- and postnatal smoke exposure was also possible, as well as assessment of dose-response effects for amount of cigarettes smoked in the first trimester in relation to preschool wheeze and asthma.

There were some possible limitations. In total, 66% of the eligible children in the selected cohorts were included in our analyses. Fewer children exposed to tobacco smoke during pregnancy met our inclusion criteria compared with the original cohorts. In contrast, there was no difference in the prevalence of wheeze and asthma among the included children and those not included. Thus, it is unlikely that our finding of an increased risk among children born to smoking mothers would be explained by selection.

All exposure information was based on parental questionnaire answers. The questions were not entirely standardized, but we were able to extract comparable exposure information from all cohorts. Exposure information on maternal smoking during pregnancy was collected during pregnancy or in the first months after delivery (i.e., before disease occurrence). Thus, any misclassification of prenatal smoke exposure is likely to be nondifferential. Moreover, pregnant women have been shown to report smoking accurately, although women who quit smoking may underreport smoking (21). Maternal smoking during the first year of life was assessed when the child was 1 year of age. A validation study including four of our birth cohorts demonstrated a fair agreement between parental reported tobacco smoking and indoor air nicotine or urinary cotinine measurements (22).

Questionnaire information on wheeze and asthma during the past 12 months was comparable among the cohorts. To enhance asthma outcome accuracy, we used a composite variable satisfying at least two out of three conditions to define asthma. Although some studies suggest that smoking parents may underreport symptoms of wheeze or underutilize health care for mild respiratory symptoms in their children (23, 24), such bias would primarily lead to an underestimation of the true effect of maternal smoking if nondifferential in relation to exposure.

Our results showing an increased risk of asthma and wheeze among children whose mothers smoked during pregnancy are in line with earlier findings (810, 25, 26). However, in none of the previous studies was it possible to disentangle the effect of pre- versus postnatal smoking, mainly due to small sample sizes. A positive dose-dependent effect was shown in our study estimating the odds ratio for every five-cigarette increase in daily consumption during the first trimester. The risk remained statistically significant even for the group of mothers smoking in the first but not in the third trimester. This indicates that the hazardous effects of maternal smoking on the fetal respiratory system might be present before the woman knows that she is pregnant.

An effect of maternal smoking during pregnancy on the subsequent development of childhood asthma is biologically plausible, although the underlying mechanisms remain unclear. Changes in airway sensory innervation, thickening of the airway smooth muscle layer, and altered smooth muscle relaxation causing airway hyperresponsiveness have been seen in animals exposed to tobacco smoke in utero (13, 14, 27, 28). Airway remodeling by collagen deposition rendering stiffer airways and increased lung inflammation and a TH2-biased immune response were also observed (13, 27). Several tobacco smoke constituents have been proposed as causative agents for asthma development. For example, nicotine can interfere with various aspects of lung development, disturbing alveolar architecture or changing tissue elasticity (12, 29, 30). The fetal lung begins to develop in the fourth week of pregnancy, and terminal bronchioles have been formed early in the second trimester (31). Our data indicate that the early stage of organogenesis may be affected by maternal smoking.

In our study, children exposed to maternal smoking during pregnancy and in the first year of life had an increased risk of preschool wheeze and asthma, whereas no significant associations were observed for children exposed to maternal smoking only during the first year of life. Previous studies have shown such an association (1, 3, 7), and the lack of effect in our study may be an effect of the parents avoiding direct smoke exposure of their children during early childhood (10). This might be due to increased awareness of the health hazards from second-hand smoke exposure (3). Early signs of respiratory disease in toddlers might also result in adjusted parental smoking behavior (25). Moreover, given the strong effect of maternal smoking during pregnancy, the potential adverse effects of postnatal maternal smoking might only be visible beyond preschool age.

This large pooled analysis of eight birth cohorts with data on more than 21,000 children showed that maternal smoking during pregnancy is associated with wheeze and asthma in preschool children and among children who are not exposed to maternal smoking late in pregnancy or after birth. Policy makers should be aware of the important role of motivating tobacco smoking teenage girls and young women to stop before getting pregnant to prevent asthma in their children.

The authors thank all birth cohort teams that provided data for this project, including Carel Thijs from the KOALA birth cohort, Maastricht, The Netherlands; Maria-Pia Fantini from the CO.N.ER birth cohort, Bologna, Italy; and Lorenzo Richiardi from the NINFEA birth cohort, Turin, Italy.

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Correspondence and requests for reprints should be addressed to Anna Bergström, Ph.D., Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden. E-mail:

*These authors contributed equally to this work.

Supported by the European Community’s Seventh Framework Program (FP7/2007-2013) under grant agreement no 226285. The data collection and study teams of all participating birth cohorts were funded by local and/or national research organizations.

Author Contributions: Å.N., C.H., T.K., and A.B. had full access to the data in the study. A.B. and T.K. had leadership responsibility for analyses, drafting, and final editing and contributed equally to the study. C.H., T.K., A.B., and M.W. designed the study. C.H. and T.K. collected the data from the participating birth cohorts. C.H. prepared the dataset for analyses. Å.N., N.O., and A.B. analyzed the data. Å.N., C.H., N.O., G.P., M.W., T.K., and A.B. interpreted the results. Å.N., A.B., and M.V. reviewed the literature and wrote the first draft of the manuscript. All other coauthors provided critical review of the manuscript. All authors contributed to and have full knowledge of the contents of the manuscript.

This article has online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.201203-0501OC on September 6, 2012

Author disclosures are available with the text of this article at www.atsjournals.org.

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