Environmental tobacco smoke exposure and perinatal outcomes: a systematic review and meta-analyses
Abstract
Background. While active maternal tobacco smoking has well established adverse perinatal outcomes, the effects of passive maternal smoking, also called environmental tobacco exposure (ETS), are less well studied and less consistent. Objective: To determine to the effect of ETS on perinatal outcomes. Search strategy. Medline, EMBASE and reference lists were searched. Selection criteria. Studies comparing ETS-exposed pregnant women with those unexposed which adequately addressed active maternal smoking. Data collection and analysis. Two reviewers independently assessed titles, abstracts, full studies, extracted data and assessed quality. Dichotomous data were pooled using odds ratios (OR) and continuous data with weighted mean differences (WMD) using a random effects model. Main results. Seventy-six articles were included with a total of 48,439 ETS-exposed women and 90,918 unexposed women. ETS-exposed infants weighed less [WMD –60 g, 95% confidence interval (CI) –80 to –39 g], with a trend towards increased low birthweight (LBW, < 2,500 g; RR 1.16; 95% CI 0.99–1.36), although the duration of gestation and preterm delivery were similar (WMD 0.02 weeks, 95% CI –0.09 to 0.12 weeks and RR 1.07; 95% CI 0.93–1.22). ETS-exposed infants had longer infant lengths (1.75 cm; 95% CI 1.37–2.12 cm), increased risks of congenital anomalies (OR 1.17; 95% CI 1.03–1.34) and a trend towards smaller head circumferences (–0.11 cm; 95% CI –0.22 to 0.01 cm). Conclusions. ETS-exposed women have increased risks of infants with lower birthweight, congenital anomalies, longer lengths, and trends towards smaller head circumferences and LBW.
Introduction
While active maternal tobacco smoking has well established adverse perinatal outcomes, the effects of passive maternal smoking, also known as environmental tobacco exposure (ETS), have been less well studied and are less consistent in the literature. Active maternal smoking increases the risks of perinatal mortality (1), preterm delivery (PTD) (1), miscarriage (2), ectopic pregnancy (3), antepartum hemorrhage (4), and placenta previa (4). Neonates born to active smokers weigh approximately 200 g less at birth, are at an increased risk of being small-for-gestational age (SGA) (5) and having smaller head circumferences (6). Newborns of women who smoke have increased risks of congenital anomalies such as orofacial clefts (7).
There are a number of proposed biologic mechanisms for the adverse reproductive effects of maternal smoking, including fetal hypoxia secondary to increased levels of carboxyhemoglobin, decreased unloading of blood oxygen, nicotine-induced placental vasoconstriction, and placental vascular disease (8). Tobacco smoke contains over 4,000 compounds including a number of reproductive toxins (9, 10). ETS exposure is a combination of exhaled smoke (mainstream) and smoke emitted directly from tobacco products (sidestream), the latter of which contains greater concentrations of many harmful constituents than active smoke (11).
ETS represents a potentially large public health problem given that 22–30% of non-smoking pregnant women are exposed to ETS (12). A variety of methods has been reported in the literature to determine the presence and extent of ETS exposure, including self-report and assays of nicotine or cotinine. Cotinine is a major metabolite of nicotine with a longer half-life and it is believed to be a more accurate measure of total ETS exposure than questionnaire methods (8, 13).
Although the risks of active maternal smoking are well documented, a complete summary of the effect of ETS exposure on perinatal outcomes is lacking. We undertook a systematic review of the literature to ensure a comprehensive and unbiased summary of the available evidence on the effect of ETS exposure alone without active maternal smoking on all relevant perinatal outcomes.
Methods
The Meta-analysis of Observational Studies in Epidemiology consensus statement was followed (14).
Sources
MEDLINE (1966–April 23, 2009) and EMBASE (1980–April 23, 2009) were searched using separate comprehensive search strategies for MEDLINE and EMBASE (Supplementary Material 1, S1). The reference lists of identified articles were searched for additional references.
Eligibility criteria
Case-control and cohort studies were included if they compared mothers who were exposed to ETS with mothers who were unexposed and reported on any of the outcomes of interest below. ETS exposure was defined either as a positive response on a patient questionnaire or biochemical assays within the accepted passive smoking range (serum, hair, or saliva measurements of 2–10 ng/ml of cotinine; none of the included studies assayed nicotine). To control for potential confounding by maternal smoking, studies were included only if they excluded active maternal smoking or controlled for it. Studies published in any language were eligible for inclusion.
Duplicate publications were excluded. Studies were also excluded if mothers actively smoked or if it could not be determined from the article if active maternal smoking was a confounding factor and if no response could be ascertained from the author.
Study selection
Two independent reviewers (two of G.S., R.G., J.J.) screened the titles and abstracts of all citations identified in the search. The full-text article was retrieved if either reviewer considered the citation potentially relevant. Disagreements were resolved by discussion and consensus. An independent adjudicator (S.M.) was consulted for uncertainty or disagreement.
Outcome measures
Our primary outcome was perinatal mortality. The four main secondary outcomes were birthweight, gestational age at delivery, PTD (< 37 weeks gestation), and low birthweight (LBW, < 2,500 g).
Other secondary outcomes included infant length, infant head circumference, SGA (defined in the original studies as infant birthweight below the 10th percentile for gestational age), intrauterine growth restriction (IUGR) (defined in the original studies as infant length at birth below the 10th percentile for gestational age), congenital malformations, spontaneous abortion, caesarean section, Apgar score at 1 minute and at 5 minutes, ectopic pregnancy, antepartum hemorrhage, stillbirth, and placenta previa.
Data abstraction
A data collection form was used to collect raw data. A pilot instrument was tested, and modifications were made. A perinatologist (S.M.) reviewed the data collection instrument to ensure that all relevant perinatal outcomes were included. Two independent reviewers (two of G.S., R.G., J.J.) performed the extraction of data from full articles. Disagreements were resolved by discussion and consensus and by the use of the independent adjudicator (S.M.) when necessary. Authors were contacted for further information where necessary. Study information, which included the country of origin, years of study, exposure by self-report or biochemically, characteristics of cases and control subjects, potential confounders, outcomes and quality assessment, was collected.
Data analysis and synthesis
Statistical analysis was performed with the Review Manager software (Revman 5.0; the Cochrane Collaboration, Oxford, England). When multiple categories of ETS exposure were provided in the original studies, the results of the individual categories were combined in a weighted fashion according to the number of patients in each category. Most of the studies presented unadjusted data and so unadjusted data were pooled for all studies. Dichotomous data were meta-analyzed with odds ratios (OR) using a random effect model (15) since observational studies have more variability than randomized control trials. Continuous data were analyzed with a weighted mean difference (WMD). Where required and when the incidence of the outcome was rare, in order to be able to pool data, adjusted RR were calculated from adjusted OR (16). As is typical in meta-analyses there was no adjustment for multiple analyses. The I2 value was used to examine heterogeneity in our pooled analyses. An I2 value represents the percentage of total variation across studies due to heterogeneity rather than chance and we considered an I2 value ≤ 25% as low (17). Two post-hoc sensitivity analyses were performed analyzing the effect of ETS exposure on birthweight according to (i) maternal self-report versus biochemical analysis and (ii) prospective versus retrospective data.
Quality assessment
Two independent reviewers (two of G.S., R.G., J.J.) performed the quality assessment for each study. Disagreements were resolved by the previously described consensus process. An independent adjudicator (S.M.) was available if uncertainty or disagreement existed. Quality assessments of studies were performed with the Cochrane Handbook guidelines for observational studies (18). Selection bias was defined as systematic differences in the methods of ascertainment of the cases or exposed participants and controls or unexposed participants, including factors such as whether consecutive participants were included. Performance bias was defined as systematic differences in the care or observation provided to participants in the comparison groups other than the exposure under investigation. Attrition bias was defined as systematic differences in the loss to follow-up. Detection bias was defined as systematic differences in the ascertainment of our outcomes. Publication bias was assessed using funnel plots.
Results
Description of studies
One thousand thirty-nine non-duplicate titles and abstracts were identified (Figure 1), 241 full articles reviewed and 76 articles (19–94) met inclusion criteria with a total of 48,439 women exposed to ETS and 90,918 unexposed women (Table 1). The studies originated mainly from developed countries. The most common reasons for exclusion were that ETS exposure or perinatal outcomes were not examined and active maternal active smoking was not accounted for.

Study process.
Study | Country (state, province or city where provided) | Years of study | Study design | Number of ETS exposed | Number of ETS unexposed |
---|---|---|---|---|---|
Adamek 2005 | Poland | NR | Retrospective cohort | 356 | 426 |
Ahlborg 1991 | Sweden | 1980–1983 | Prospective cohort | 678 | 2,262 |
Borlee 1978 | Belgium | 1972–1974 | Case control | 146 | 92 |
Campbell 1988 | UK | NR | Retrospective cohort | 143 | 247 |
Carbone 2007 | Italy | 1998–2002 | Case control | 182 | 202 |
Carmichael 2008 | USA | 1997–2003 | Case control | 443 | 3,527 |
Chatenoud 1998 | Italy | 1990–1998 | Case control | 1,271 | 1,044 |
Chen 1989 | China | June–December 1981 | Retrospective cohort | 304 | 446 |
Chen 1995 | USA | January–September 1991 | Case control | 70 | 165 |
Chevrier 2008 | France | 1998–2001 | Case control | 167 | 173 |
Chung 1997 | NR | NR | Retrospective cohort | 13 | 66 |
Dejin-Karlson 1998 | Sweden | September 1991–September 1992 | Prospective cohort | 323 | 240 |
Dollberg 2000 | Israel | January 1998–March 1998 | Prospective cohort | 55 | 31 |
Ekwo 1993 | USA (Iowa) | 1985–1987 | Case control | 184 | 184 |
Eliopoulos 1996 | Canada (Toronto) | September–December 1992 | Prospective cohort | 21 | 35 |
Ermis 2004 | Turkey | NR | Retrospective cohort | 14 | 15 |
Eskenazi 1995 | USA (California) | 1964–1967 | Prospective cohort | 77 | 1,610 |
Fantuzzi 2007 | Italy | 1999–2000 | Case control | 277 | 677 |
Fantuzzi 2008 | Italy | 1999–2000 | Case control | 355 | 583 |
Fayol 2005 | NR | NR | Prospective cohort | 14 | 17 |
Fortier 1994 | Canada | January–October 1989 | Retrospective cohort | 33 | 41 |
George 2006 | Sweden | 1996–1998 | Case control | 272 | 859 |
Goel 2004 | India | NR | Retrospective cohort | 141 | 435 |
Gomolka 2006 | Poland | 2002–2005 | Prospective cohort | 118 | 113 |
Hanke 1999 | Poland | 1996–1997 | Retrospective cohort | 827 | 924 |
Haug 2000 | Norway | November–December 1992 | Retrospective cohort | 4,934 | 11,496 |
Honein 2007 | USA | October 1997–December 2001 | Case control | 778 | 2,955 |
Hrubá 2000 | Czech Republic | 1999 | Retrospective cohort | 127 | 600 |
Jaddoe 2008 | The Netherlands | 2002–2006 | Prospective cohort | 2,145 | 3,681 |
Jaakola 2001 | Finland | 1996–1997 | Retrospective cohort | 261 | 258 |
Janghorbani 1998 | Iran | June–December 1994 | Prospective cohort | 278 | 424 |
Kalinka 2005 | Poland | NR | Prospective cohort | 84 | 8 |
Kharrazi 2004 | USA | 1992 | Prospective cohort | 1,744 | 1,033 |
Lackmann 2000 | Germany | NR | Prospective cohort | 167 | 187 |
Lazzaroni 1990 | Italy | 1989 | Prospective cohort | 220 | 428 |
Lie 2008 | Norway | 1996–2001 | Case control | 196 | 658 |
Little 2004 | UK | September 1997–January 2000 | Case control | 178 | 121 |
L∅drup-Carlsen1997 | Norway | January 1992–1993 | Prospective cohort | 33 | 33 |
Luciano 1998 | Italy | NR | Prospective cohort | 39 | 50 |
Macmahon 1966 | USA | May and June 1963 | Retrospective cohort | 3,540 | 2,395 |
Maconochie 2006 | UK | 1995–2001 | Case control | 2,010 | 4,560 |
Mainous 1994 | USA | 1988–1994 | Retrospective cohort | 33 | 2,410 |
Martin 1986 | USA | 1985 | Retrospective cohort | 853 | 1,620 |
Martinez 1994 | USA | NR | Retrospective cohort | 191 | 716 |
Mathai 1990 | India | January–May 1990 | Prospective cohort | 54 | 133 |
Mathai 1992 | India | NR | Retrospective cohort | 520 | 474 |
Matsubara 2000 | Japan | 1989–1991 | Prospective cohort | 1,444 | 560 |
Miller 2009 | USA | 1997–2003 | Case control | 1,181 | 3,515 |
Mitchell 2002 | New Zealand | October–December 1997 | Case control | 659 | 2,995 |
Nafstad 1998 | Norway | 1995 | Case control | 54 | 68 |
Nakamura 2004 | Brazil | NR | Prospective cohort | 267 | 329 |
Ogawa 1991 | Japan | June–August 1987 | Retrospective cohort | 4,044 | 2,454 |
Peacock 1998 | UK | 1982–1984 | Prospective cohort | 164 | 169 |
Pichini 2000 | Spain | 1997–1998 | Retrospective cohort | 139 | 146 |
Pierik 2004 | Netherlands | 1999–2001 | Case control | 41 | 41 |
Rashid 2003 | Saudi Arabia | 2001 | Retrospective cohort | 440 | 428 |
Rauh 2004 | New York | 1998–2002 | Retrospective cohort | 91 | 135 |
Roquer 1995 | Spain | 1994 | Retrospective cohort | 33 | 41 |
Sadler 1999 | USA | 1988–2002 | Prospective cohort | 606 | 1,677 |
Saito 1991 | Japan | NR | Retrospective cohort | 1,402 | 1,311 |
Savitz 1991 | USA | 1959–1966 | Retrospective cohort | 31 | 21 |
Schwartz-Bickenbach 1987 | Germany | January–December 1985 | Retrospective cohort | 28 | 26 |
Seidman 1990 | Israel | 1974–1976 | Retrospective cohort | 5,445 | 9,032 |
Shaw 1996 | USA | 1987–1989 | Case control | 198 | 579 |
Steuerer 1999 | Germany | 1992–1994 | Prospective cohort | 57 | 160 |
Steyn 2006 | South Africa | 1990 | Prospective cohort | 739 | 559 |
Suarez 2008 | USA | 1995–2000 | Case control | 153 | 196 |
Tsui 2008 | Taiwan | 2003–2004 | Prospective cohort | 184 | 175 |
Venners 2004 | China | 1996–1998 | Prospective cohort | 310 | 216 |
Ward 2007 | UK | 2000–2002 | Retrospective cohort | 2,259 | 8,100 |
Windham 1999 | USA (California) | 1990–1991 | Prospective cohort | 759 | 2,887 |
Windham 2000 | USA (California) | 1990–1991 | Prospective cohort | 112 | 2,312 |
Wong-Gibbons 2008 | USA (Iowa) | 1997–2003 | Case control | 806 | 3,471 |
Wu 2007, p. 124 | Taiwan | August 2003–October 2004 | Prospective cohort | 183 | 176 |
Wu 2007, p. 313 | China | 1996–2000 | Prospective cohort | 708 | 680 |
Zhang 1993 | China | 1986–1987 | Retrospective cohort | 1,033 | 752 |
Total | 48,439 | 90,918 |
- Note: ETS, environmental tobacco exposure; NR, information not reported by author and was not provided by authors when an attempt was made to contact.
There were no studies investigating our primary outcome, perinatal mortality. A statistically significant association was found between ETS exposure and lower mean birthweight [WMD –60 g; 95% CI –80 to –39 g, 44 studies, Table 2 and Figure 2], although the duration of gestation was similar (WMD 0.02 weeks, 95% CI –0.09 to 0.12 weeks, 17 studies, Figure 3). There was a trend towards increased PTD in the crude data (OR 1.20; 95% CI 0.99–1.46, 18 studies, Figure 4), but not in the adjusted data (RR 1.07; 95% CI 0.93–1.22, 7 studies, Table 2). There was not a significant increase in LBW in the crude data (OR 1.16; 95% CI 0.93–1.45, 19 studies, Figure 5), although there was a trend towards an increase in the adjusted data (RR 1.16; 95% CI 0.99–1.36, 9 studies, Table 2 and Figure 6).
Outcome | Number of studies | Number of ETS exposed with outcome/total number of ETS exposed | Number of ETS unexposed with outcome/total number of ETS unexposed | Pooled outcome (95% CI) |
---|---|---|---|---|
Perinatal mortality | 0 | NA | NA | NA |
Birthweight | 44 | 24,125 | 47,538 | WMD –60 g (95% CI –80 to –39) |
Birthweight (ETS assessed by self report) | 33 | 21,829 | 44,590 | WMD –58 g (95% CI –81 to –36) |
Birthweight (ETS assessed biochemically) | 12 | 3,004 | 3,628 | WMD –62 g (95% CI –101 to –24) |
Gestational age at delivery | 17 | 3,377 | 7,076 | WMD 0.02 weeks (95% CI –0.09 to 0.12) |
PTD (crude data) | 18 | 773/11,237 | 1,432/24,596 | OR 1.20 (95% CI 0.99–1.46) |
PTD (adjusted data) | 7 | NA | NA | RR 1.07 (95% CI 0.93–1.22) |
LBW (crude data) | 19 | 664/15,660 | 1,033/25,130 | OR 1.16 (95% CI 0.93–1.45) |
LBW (adjusted data) | 9 | NA | NA | RR 1.16 (95% CI 0.99–1.36) |
Infant length | 9 | 1,277 | 1,632 | WMD 1.75 cm (95% CI 1.37–2.12) |
Infant head circumference | 7 | 1,141 | 1,151 | WMD –0.11 cm (95% CI –0.22 to 0.01) |
IUGR | 1 | 91/4,044 | 62/2,454 | OR 0.89 (95% CI 0.64–1.23) |
SGA | 18 | 1,165/7,406 | 2,493/12,891 | OR 1.06 (95% CI 0.75–1.50) |
Congenital malformations | 12 | 1,428/10,474 | 3,258/26,541 | OR 1.18 (95% CI 1.04–1.34) |
Spontaneous abortion | 9 | 1,134/5,979 | 1,834/11,579 | OR 1.17 (95% CI 0.97–1.41) |
Cesarean section | 4 | 167/869 | 277/1,225 | OR 1.10 (95% CI 0.88–1.39) |
Apgar score at 1 min | 2 | 581 | 863 | WMD –0.05 (95% CI –0.35 to 0.25) |
Apgar score at 5 min | 4 | 694 | 1,033 | WMD 0.01 (95% CI –0.10 to 0.13) |
Ectopic pregnancy | 1 | 0/13 | 1/66 | Inestimable |
Antepartum hemorrhage | 0 | NA | NA | NA |
Stillbirth | 0 | NA | NA | NA |
Placenta praevia | 0 | NA | NA | NA |
- Statistically significant results are in bold. Note: ETS, environmental tobacco exposure; IUGR, intrauterine growth restriction (infant length < 10th percentile for gestational age); LBW, low birth weight < 2,500 g; OR, odds ratios; PTD, delivery < 37 weeks gestation; SGA, small-for-gestational age (birthweight < 10th percentile for gestational age); WMD, weighted mean difference.

Forest plot of environmental tobacco smoke and birthweight. Environmental tobacco exposure (ETS) was defined as passive maternal exposure to tobacco smoke assessed by self-report questionnaire or biological marker. Sizes of data markers indicate the weights of each study in the analysis. CI, confidence interval; Random, random effects model used for statistical pooling.

Forest plot of environmental tobacco smoke and gestational age at delivery. Environmental tobacco exposure (ETS) was defined as passive maternal exposure to tobacco smoke assessed by self-report questionnaire or biological marker. Gestational age is given in weeks. Sizes of data markers indicate the weights of each study in the analysis. CI, confidence interval; Random, random effects model used for statistical pooling.

Forest plot of environmental tobacco smoke and preterm delivery. Environmental tobacco exposure (ETS) was defined as passive maternal exposure to tobacco smoke assessed by self-report questionnaire or biological marker. Preterm delivery is defined as delivery at < 37 weeks gestation. Sizes of data markers indicate the weights of each study in the analysis. CI, confidence interval; Random, random effects model used for statistical pooling.

Forest plot of environmental tobacco smoke and low birthweight (LBW). Environmental tobacco exposure (ETS) was defined as passive maternal exposure to tobacco smoke assessed by self-report questionnaire or biological marker. LBW is defined as birthweight < 2,500 g at delivery. Sizes of data markers indicate the weights of each study in the analysis. CI, confidence interval; Random, random effects model used for statistical pooling.

Forest plot of environmental tobacco smoke and low birthweight (LBW, adjusted data). Environmental tobacco exposure (ETS) was defined as passive maternal exposure to tobacco smoke assessed by self-report questionnaire or biological marker. LBW is defined as birthweight < 2,500 g at delivery. Sizes of data markers indicate the weights of each study in the analysis. CI, confidence interval; Random, random effects model used for statistical pooling.
ETS exposed infants were longer at birth by 1.75 cm (95% CI 1.37–2.12 cm, 9 studies, Table 2) with a trend towards a smaller head circumference (–0.11 cm, 95% CI –0.22 to 0.01 cm, 7 studies, Table 2). No significant differences were found between SGA (defined in the original studies as birthweight < 10th percentile for gestational age, OR 1.06 (95% CI 0.75–1.50), 18 studies), spontaneous abortion (OR 1.17; 95% CI 0.97–1.41, 9 studies), cesarean section (OR 1.10; 95% CI 0.88–1.39, 4 studies), or Apgar scores at 1 minute (WMD –0.05; 95% CI –0.35 to 0.25, 2 studies) and 5 minutes (WMD 0.01; 95% CI –0.10 to 0.13, 4 studies). The risk of IUGR (defined in the original studies as birth length < 10th percentile for gestational age, OR 0.89; 95% CI 0.64–1.23) and ectopic pregnancy (0/13 in ETS exposed and 1/66 in unexposed) were each examined in a single study. Women exposed to ETS had an increased risk of having an infant with a congenital anomaly (OR 1.17; 95% CI 1.03–1.34, 12 studies). No studies examined the risk of antepartum hemorrhage, stillbirth, or placenta previa.
Heterogeneity
The heterogeneity in the pooled risk estimates of our outcomes ranged from an I2 test of 0–100%, and generally exceeded 75%, which is considered high. The heterogeneity was likely due to a variety of factors, including varying patient selection and the range of sample sizes. Importantly, both the level of the exposure and its measurement (self report versus biochemical markers such as cotinine samples from serum, hair, or saliva) varied. Hence, a post hoc sensitivity analysis was performed analyzing the effect of ETS exposure on birthweight according to (i) maternal self-report and (ii) biochemical analysis. Infants born to mothers with self-reported ETS exposure had a similar mean birthweight (WMD –58 g; 95% CI –81 to –36 g, I2 = 100%, 33 studies, Table 2) to infants born to mothers whose ETS exposure was assessed biochemically (–62 g; 95% CI –101 to –24 g, I2 = 54%, 9 studies, Table 2). The WMD in birthweight was similar in both the retrospective and prospective studies (–58 g; 95 % CI –85 to –29 g, I2 = 100%, and –61 g; 95% CI –79 to –45, I2 = 100%, respectively, data not shown).
Quality assessment
Quality assessment, performed according to the Cochrane Handbook (18), is summarized in Table 3. Selection bias was not felt to play a major role in any of the studies as often consecutive or ‘all available’ women were included. Most studies did not specifically address performance bias, however, it is unlikely given that most clinicians were not aware of the potential risks of ETS at the time patient care was provided. Attrition bias was often not well documented by authors of cohort studies and it is not applicable in case-control studies. Detection bias was felt to be unlikely given that most of the outcomes in this review are objectively assessed and have standard definitions (for instance, LBW is consistently defined as a birthweight < 2,500 g).
Study | Selection bias | Performance bias | Attrition bias | Detection bias |
---|---|---|---|---|
Adamek 2005 | Unlikely | Unlikely | Unlikely | Unlikely |
Ahlborg 1991 | Unlikely | Unlikely | Unlikely | Unlikely |
Borlee 1978 | Unlikely | Unlikely | NA | Recall bias possible as women asked to recall ETS exposure during pregnancy after delivering an infant with a congenital abnormality |
Campbell 1988 | Possible bias–information on selection limited | Unlikely | Unlikely | Unlikely |
Carbone 2007 | Unlikely | Unlikely | Unlikely | Unlikely |
Carmichael 2008 | Unlikely | Unlikely | Unlikely | Unlikely |
Chatenoud 1998 | Unlikely | Unlikely | NA | Unlikely |
Chen 1989 | Unlikely | Unlikely | NA | Unlikely |
Chen 1995 | Unlikely | Unlikely | NA | Unlikely |
Chevrier 2008 | Eligible cases were not recruited consecutively, only on days recruiter was in the hospital. Excluded non-French speaking mothers | Unlikely | NA | Unlikely |
Chung 1997 | Exposed and unexposed obtained from the same population of infertile women | Unlikely | Unlikely | Unlikely |
Dejin-Karlsson 1998 | Unlikely | Unlikely | Did not include in analysis those lost to follow-up at delivery | Unlikely |
Dollberg 2000 | Possible bias–exposed and unexposed may not be similar to the general population as study focused on nucleated red blood cell counts in the neonate | Unlikely | Unlikely | Unlikely |
Ekwo 1993 | Unlikely | Unlikely | NA | Unlikely |
Eliopoulos 1996 | Unlikely | Unlikely | Unlikely | Unlikely |
Ermis 2004 | Unlikely | Unlikely | Unlikely | Unlikely |
Eskenazi 1995 | Unlikely | Unlikely | Unlikely | Unlikely |
Fantuzzi 2007 | Population only included Caucasians | Unlikely | Unlikely | Unlikely |
Fantuzzi 2008 | Population only included Caucasians | Unlikely | Unlikely | Unlikely |
Fayol 2005 | Possible bias–did not control for potential confounders | Unlikely | Unlikely | Unlikely |
Fortier 1994 | Unlikely | Unlikely | Unlikely | Unlikely |
George 2006 | Unlikely | Unlikely | Unlikely | Unlikely |
Goel 2004 | Unlikely | Unlikely | Unlikely | Unlikely |
Gomolka 2006 | Unlikely | Unlikely | Unlikely | Unlikely |
Hanke 1999 | Unlikely | Unlikely | Unlikely | Unlikely |
Haug 2000 | Unlikely | Unlikely | Unlikely | Recall bias a possibility, study concerned SIDS and information was obtained after a long period of time |
Honein 2007 | Unlikely | Unlikely | Unlikely | Unlikely |
Hrubá 2000 | Unlikely | Unlikely | Unlikely | Unlikely |
Jaakkola 2001 | Unlikely | Unlikely | Unlikely | Unlikely |
Jaddoe 2008 | Unlikely | Unlikely | Unlikely | Unlikely |
Janghorbani 1998 | Population restricted to full term infants | Unlikely | Unlikely | Unlikely |
Kalinka 2005 | Limited information– study participants recruited from two different antenatal clinics | Unlikely | Unlikely | Unlikely |
Kharrazi 2004 | Unlikely | Unlikely | Unlikely | Unlikely |
Lackmann 2000 | Unlikely | Unlikely | Unlikely | Unlikely |
Lazzaroni 1990 | Unlikely | Unlikely | Unlikely | Unlikely |
Lie 2008 | Unlikely | Unlikely | Unlikely | Unlikely |
Little 2004 | Unlikely | Unlikely | NA | Recall bias possible as women asked to recall ETS exposure after delivering an infant with a congenital abnormality |
L∅drup-Carlsen 1997 | Unlikely | Unlikely | Unlikely | Unlikely |
Luciano 1998 | Unlikely | Unlikely | NA | Unlikely |
Macmahon 1966 | Population restricted to ‘whites’ only | Unlikely | Unlikely | Unlikely |
Maconochie 2006 | Unlikely | Unlikely | Unlikely | Unlikely |
Mainous 1994 | Information not provided | Unlikely | Unlikely | Recall bias possible as women asked to recall ETS exposure after delivering an infant with a congenital abnormality |
Martin 1986 | Unlikely | Unlikely | Unlikely | Unlikely |
Martinez 1994 | Excluded ‘unhealthy’ infants | Unlikely | Unlikely | Unlikely |
Mathai 1990 | Population restricted to ‘white’ European women | Unlikely | Unlikely | Unlikely |
Mathai 1992 | Information on selection limited | Unlikely | Unlikely | Unlikely |
Matsubara 2000 | Unlikely | Unlikely | Unlikely | Unlikely |
Miller 2009 | Unlikely | Unlikely | Unlikely | Unlikely |
Mitchell 2002 | Unlikely | Unlikely | NA | Unlikely |
Nafstad 1998 | Information not provided | Unlikely | NA | Unlikely |
Nakamura 2004 | Unlikely | Unlikely | Unlikely | Unlikely |
Ogawa 1991 | Unlikely | Unlikely | Unlikely | Unlikely |
Peacock 1998 | Population restricted to ‘white’ women | Unlikely | Unlikely | Unlikely |
Pichini 2000 | Unlikely | Unlikely | Unlikely | Unlikely |
Pierik 2004 | Unlikely | Unlikely | NA | Unlikely |
Rashid 2003 | Unlikely | Unlikely | Unlikely | Unlikely |
Rauh 2004 | Unlikely | Unlikely | Unlikely | Unlikely |
Roquer 1995 | Information not provided | Unlikely | Unlikely | Unlikely |
Sadler 1999 | Unlikely | Unlikely | Unlikely | Unlikely |
Saito 1991 | Unlikely | Unlikely | Unlikely | Unlikely |
Savitz 1991 | Unlikely | Unlikely | Unlikely | Unlikely |
Schwartz-Bickenbach 1987 | Information not provided | Unlikely | Unlikely | Unlikely |
Seidman 1990 | Unlikely | Unlikely | Unlikely | Recall bias possible as parents asked to recall ETS exposure after delivering an infant with a congenital abnormality |
Shaw 1996 | Limited information | Unlikely | NA | Recall bias possible as parents asked to recall ETS exposure after delivering an infant with a congenital abnormality |
Steuerer 1999 | Information not provided | Unlikely | Unlikely | Unlikely |
Steyn 2006 | Unlikely | Unlikely | Unlikely | Unlikely |
Suarez 2008 | Unlikely | Unlikely | Unlikely | Unlikely |
Tsui 2008 | Unlikely | Unlikely | Unlikely | Unlikely |
Venners 2004 | Population restricted to married women only | Unlikely | Unlikely | Unlikely |
Ward 2007 | Unlikely | Unlikely | Unlikely | Unlikely |
Windham 1999 | Unlikely | Unlikely | Unlikely | Unlikely |
Windham 2000 | Unlikely | Unlikely | Unlikely | Unlikely |
Wong-Gibbons 2008 | Cases included live births, fetal deaths, elective terminations while controls only included live births | Unlikely | Unlikely | Unlikely |
Wu 2007, p. 124 | Unlikely | Unlikely | Unlikely | Unlikely |
Wu 2007, p. 313 | Population restricted to employed married women who had previously obtained permission to have a child | Unlikely | Unlikely | Unlikely |
Zhang 1993 | Population restricted to full term newborns | Unlikely | Unlikely | Unlikely |
- Note: Unlikely, bias unlikely; NA, attrition not applicable to case control studies.
Assessment of publication bias
Publication bias was explored using funnel plots for our main secondary outcomes. The plot for birthweight (Figure 7) showed a relative dearth of points to the left of the effect measure, suggesting that there may be small unpublished studies with the potential for worse outcomes in ETS exposed infants. The funnel plots for PTD, gestational age at delivery, LBW, SGA, infant length, and head circumference (data not shown) showed relative symmetry suggesting publication bias is unlikely in these outcomes.

Funnel plot of environmental tobacco smoke and birthweight. Environmental tobacco exposure (ETS) was defined as passive maternal exposure to tobacco smoke assessed by self-report questionnaire or biological marker. WMD, weighted mean difference; SE, standard error.
Discussion
This meta-analysis, the first to evaluate the effect of maternal ETS exposure on a thorough set of perinatal outcomes, found significantly increased risks of having a lighter, longer neonate with an increased risk of a congenital anomaly and with trends toward a smaller head and an increased risk of LBW. Unfortunately, no comment can be made on the association between ETS and our primary outcome, perinatal mortality, as no studies examined this outcome. We hypothesize that if ETS does have an effect on perinatal mortality, it is likely small given that a meta-analysis of active maternal smoking found an OR 1.23 (95% CI 1.12–1.41) (5), although it might still potentially be important given the significance of the outcome and its preventability. Active maternal smoking is associated with shorter infants and hence we suspect that the finding of longer infants with ETS exposure was likely due to chance. However, active maternal smoking is associated with decreased infant head circumference (6), and hence the trend towards a decreased head circumference that we found is likely valid. This finding is concerning given that the redistribution of blood flow to the brain in the setting of in utero growth restriction is typically thought to result in ‘head sparing’ even when the abdomen is small.
Our study has several strengths. Our aim was to review the association of ETS and a wide breadth of plausible perinatal outcomes, guided by those which are affected by active maternal smoking. Our study adds new information by examining important outcomes including spontaneous abortion, ectopic pregnancy, cesarean section, Apgar scores, antepartum hemorrhage, placenta previa, and congenital malformations. Second, the large number of participants in the included studies yielded adequate power for many important outcomes such as birthweight, duration of gestation, and infant length. The risk of PTD, for instance, was not significantly different in more than 45,000 ETS exposed and unexposed women. Another strength of our meta-analysis was that we performed a sensitivity analysis comparing the results of birthweight according to maternal self-report of ETS exposure compared to biochemical analyses because of concerns in the literature that biochemical methods are superior to self-report. We found similar decreases in birthweight with maternal self-report of ETS exposure and biochemical analyses. These findings could potentially save significant amounts of money for research budgets and for the health care system by justifying the omission of formal biochemical verification of ETS exposure.
The results of our meta-analysis mainly corroborate those of the only other two meta-analyses examining ETS exposure during pregnancy and which focused solely on in utero growth [Windham et al. (95) and Leonardi-Bee et al. (96)] and duration of gestation [Leonardi-Bee et al. (96)]. We found a slightly larger decrease in birthweight in ETS exposed infants (–60 g; 95% CI –80 to –39 g, 44 studies) than either Windham et al. (95) (–31 g; 95% CI –42 to –20 g, 22 studies) or Leonardi-Bee et al. (96) (–34 g; 95% CI –51 to –16 g in 17 prospective studies and –40 g, –54 to –26 g in 27 retrospective studies). Neither we, Windham et al. (95), nor Leonardi-Bee et al. (96) found significant increases in SGA (OR 1.06; 95% CI 0.75–1.50, OR 1.07; 95% CI 1.0–1.15, and OR 1.21; 95% CI 1.06–1.37 in prospective studies, respectively). We found a shorter duration of gestation of ETS exposed infants (–0.4 weeks; 95% CI –0.7 to –0.1 weeks, 17 studies) and Leonardi-Bee et al. (96) did not (–0.04 weeks; 95% CI –0.22 to 0.13, 5 prospective studies, –0.03 weeks, 95% CI –0.28 to 0.22 weeks; 6 retrospective studies). Leonardi-Bee et al. (96) found a significant increase in LBW (OR 1.32; 95% CI 1.07–1.63 in 9 prospective studies and OR 1.22; 95% CI 1.08–1.37 in 17 retrospective studies), while we did not (OR 1.16; 95% CI 0.93–1.45, 19 studies). The differences between our findings and those in the other meta-analyses include variation in whether or not women with active smoking were clearly excluded [not in Windham et al. (95)] and variation in the number of studies included per outcome based on differences in inclusion criteria.
The main limitation of any meta-analysis of observational studies including ours is residual confounding. Although most studies attempted to match or control for some important confounding variables such as maternal age, parity, socioeconomic status, alcohol, and drug use, the extent of the adjustment varied between studies. Moreover, pre-eclampsia has not been well-addressed. It is well documented that active maternal smoking decreases the risk of pre-eclampsia by approximately 30%, which could be associated with fewer inductions and hence longer gestations and higher birthweights (97). ETS exposure could conceivably also decrease the risk of pre-eclampsia but only one study in our systematic review of the literature looked at the effect of ETS on pre-eclampsia (98) (The authors report 13 instances of pre-eclampsia in 606 women exposed to ETS compared to 42 episodes of pre-eclampsia out of 1,677 unexposed to ETS, p = 0.06.). Also, several authors were unable to provide requested data and thus we could not include their studies.
Further research into the potentially additive effects of passive and active maternal smoking should be explored. Additionally, it would be important for future studies to account for important confounders such as pre-eclampsia.
In conclusion, in this systematic review and meta-analyses, we found that mothers exposed to ETS have small but significantly increased risks of having lighter babies with an increased risk of congenital anomalies and trends toward smaller heads and LBW. The results of this meta-analysis suggest that clinicians can report to mothers who are exposed to ETS that the effects on their neonates are likely relatively small. However, for women at a lower threshold for poor perinatal outcomes, such as active smokers or those with other health conditions that put them at higher perinatal risk, the additional effect of ETS may be more significant and deserves further study.
Acknowledgements
We gratefully acknowledge additional data and clarification provided by Drs. Mainous, Eskenazi, Lødrup Carlsen, Borlee, Chen, Hu, Krapels, Steegers, Meeker, Jaddoe, Bakker, Maconochie, Carmichael, Perera, Ekwo and Baker. We are indebted to our translators including Marc Colangelo, Ingrid McTiernan, Sophie Kuziora, Michal Bodhanovic, Mingyu Huang, Irena Szymanska, Katherine Morrison, Issei Nakamura, and Penka Stoyanova.
Declaration of interest: None of the authors have any financial or other conflict of interest. This study was supported by funding from the Canadian Institute of Health Research (CIHR) Knowledge Synthesis/Translation grant # KRS 86242. Dr. McDonald is supported by a CIHR New Investigator Award. CIHR did not have any role in the design, data collection, management, analysis, interpretation of the data, or preparation, review, or approval of the manuscript.
*Members of Knowledge Synthesis Group on determinants of low birth weight/preterm birth: Prakesh Shah, Associate Professor, Department of Paediatrics, Mount Sinai Hospital and Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada; Arne Ohlsson, Professor Emeritus, Department of Paediatrics, Mount Sinai Hospital, New York, USA, and Departments of Paediatrics, Obstetrics and Gynaecology, and Health Policy, Management and Evaluation, University of Toronto, Canada; Vibhuti Shah, Associate Professor, Department of Paediatrics, Mount Sinai Hospital, New York, USA, and Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada; Kellie E Murphy, Assistant Professor, Department of Obstetrics and Gynecology, Mount Sinai Hospital, New York, USA, and University of Toronto, Canada; Sarah D McDonald, Assistant Professor, Division of Maternal-Fetal Medicine, Departments of Obstetrics & Gynecology and Diagnostic Imaging, and Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Canada; Eileen Hutton, Associate Professor, Department of Obstetrics and Gynecology, McMaster University, Hamilton, Canada; Christine Newburn-Cook, Associate Professor & Associate Dean Research, Faculty of Nursing, University of Alberta, Edmonton, Canada; Corine Frick, Director, Alberta Perinatal Health Program and Adjunct Professor, Faculty of Nursing, University of Calgary, Calgary, Canada; Fran Scott, Associate Professor, Dalla Lana School of Public Health, University of Toronto and Toronto Public Health, Toronto, Canada; Victoria Allen, Associate Professor, Department of Obstetrics and Gynaecology, Dalhousie University, Halifax, Canada; Joseph Beyene, Associate Professor and Senior Scientist, Research Institute of The Hospital for Sick Children and Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
References
Supplementary Material 1 (S1)
EMBASE Search Strategy
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