Open Access

Research Article

Population and Methods Top

Study population

This study was conducted in a subgroup of the EDEN (study of pre- and early postnatal determinants of the child’s development and health) mother–child cohort (Drouillet et al. 2009). The primary aim of the EDEN cohort is the study of prenatal and early postnatal nutritional, environmental, and social determinants of children’s development and health. Women at < 20 gestational weeks (weeks of amenorrhea) were recruited from the maternity wards of Poitiers and Nancy University hospitals (France) between September 2003 and January 2006. Exclusion criteria were personal history of diabetes, multiple pregnancies, intention to deliver outside the university hospital or to move out of the study region within the next 3 years, and inability to speak French. We estimated participation rate among eligible women to be 55%. Supplemental Material, Table 1 (doi:10.1289/ehp.0800465.S1), compares our cohort with a national sample of women who delivered in 2003 (Blondel et al. 2006). Women were given an appointment with a study midwife, planned to take place between 24 and 28 gestational weeks, during which an interview on behavioral factors was conducted and biological samples were collected. For this study, we further restricted the EDEN cohort to nonsmoking women, who were asked by the study midwives to carry a diffusive air sampler for 7 consecutive days. For logistic reasons, this part of the study was offered only to women whose study visit took place after February 2005.

The study was approved by the relevant ethical committees (Comité Consultatif pour la Protection des Personnes dans la Recherche Biomédicale, Le Kremlin-Bicêtre University hospital, and Commission Nationale de l’Informatique et des Libertés), and all participating women gave informed written consent for themselves and for their child to be part of the study.

Assessment of intrauterine growth

We assessed birth weight from maternity records. Head circumference was assessed at birth and also during a clinical examination of the newborn performed in duplicate by midwife research assistants within 3 days after birth for 95% of newborns. Our a priori choice was to use the average of these two postnatal measures; in sensitivity analyses, we also report the association between exposure and the single measure of head circumference at birth. We conducted ultrasound examinations between 29 and 36 gestational weeks (5th, 50th, and 95th percentiles, 30.7, 32.7, and 34.4 gestational weeks; third-trimester examination), between 19 and 27 gestational weeks (5th, 50th, and 95th percentiles, 20.7, 22.4, and 24.7 weeks; second-trimester examination), and before 15 gestational weeks (5th, 50th, and 95th percentiles, 11.2, 12.6, and 14.0 weeks; first-trimester examination). Because of the possible association between head circumference at birth and cognitive development in childhood (Yanney and Marlow 2004), and because of the availability of both pre- and postnatal measures of head circumference by different approaches, we a priori decided to focus on ultrasound measures of head circumference. In addition to the measurements at birth, we assessed head circumference during the second- and third-trimester (but not first-trimester) ultrasound examinations. Therefore, we also report associations of exposure with biparietal diameter (the widest diameter of the head), which we assessed at the first trimester examination; this was strongly correlated with head circumference during the second and third trimesters (coefficient of correlation, 0.92 during the second trimester and 0.80 during the third trimester, p < 10⁻³). Ultrasound measurements were performed according to Hadlock’s criteria (1994). Before the study start, the first five ultrasound measurements performed by each obstetrician were reviewed by one of us (O.T.). We assessed gestational duration at each examination and at birth from the date of the last menstrual period (LMP) (Slama et al. 2008b). When information on this date was missing or when the LMP-based gestational duration was > 44 gestational weeks, we used the obstetrician’s ultrasound-based estimate.

Exposure to benzene

We used a diffusive air sampler (Radiello, Fondazione Salvatore Maugeri–Centro di Ricerche Ambientali, Padova, Italy) (Cocheo et al. 2000), which relies on radial symmetry diffusion (Cocheo et al. 1996). The cylindrical diffusive body contains a stainless steel net cylindrical cartridge, filled with activated charcoal. The absorbing cartridge was stored in a capped glass tube before and after the 7-day exposure period and sent by post to Institut national de la santé et de la recherche médicale (Inserm) by the participating woman after use, together with a questionnaire on the conditions of use. We excluded subjects for whom the diffusive part of the sampler was broken during use (n = 4). The charcoal cartridges were then temporarily stored and then shipped to the Maugeri Foundation, where they were stored at 4°C before analysis. Cartridges were shipped together with a bar code identifier and information on the hours and days of start and end of exposure to ambient air, but no information on pregnancy outcome. We desorbed the collected vapors from the cartridge using carbon disulfide solvent with a benzene concentration < 0.1 μg/mL and analyzed the solution using high-resolution gas chromatography with flame ionization detector. Taking into account the actual number of hours of exposure of the dosimeter, we converted the benzene concentration in the solution to a mean concentration in the air during the period of exposure. The detection limit for an exposure of 5 days is 0.1 μg/m³ benzene. Women were given illustrated instructions and were asked not to touch the diffusive air sampler with their hands, avoid contact with water, carry the air sampler always with them, attaching it on their clothes as close as possible to their collar, and to keep it close to their bed when they slept.

Regression models

We studied the relationship between benzene and birth weight and the relationship between benzene and measures of head size assessed at birth and during the third trimester in distinct linear regression models (Stata SE version 10.1; StataCorp., College Station, TX, USA). We also studied the association between benzene exposure and measures of head size assessed during the first and second trimesters, assuming that benzene levels were indicative of exposure in early pregnancy. Benzene was considered either as a continuous variable, using the log-transformed values because of the skewed distribution of exposure, or as a variable whose categories corresponded to exposure tertiles defined on the whole population with an exposure estimate. We performed linear trend tests with a categorical variable whose values corresponded to the category-specific median benzene level.

Additionally, we conducted a longitudinal analysis including all three assessments of head circumference simultaneously, using multiple linear regression with a random effect variable corresponding to the mother–child pair and interaction terms with gestational age. We plotted the values of head circumference predicted by this longitudinal analysis as a function of benzene and gestational age, together with the observed values.

Sensitivity analyses

We repeated the analyses among women who declared that their schedule during the week of use of the air sampler was similar to that during the previous month (usual schedule group). We also estimated the effect of benzene levels adjusting for the ultrasound-based gestational age instead of the LMP-based gestational age (Slama et al. 2008b). To determine whether an association between benzene and head circumference could be explained by an association between benzene and birth weight, we also estimated the effect of benzene on head circumference after excluding small-for-gestational-age births (10th percentile), using sex- and gestational age–specific references (Mamelle et al. 1996). Finally, we repeated analyses for various subgroups defined according to the conditions of use of the air sampler.

Potential confounders

We selected confounders a priori, excluding all variables possibly affected by the health outcome or exposure (Rothman and Greenland 1998). We assessed exposure to passive smoking during the second trimester of pregnancy by a retrospective question filled in at birth asking whether someone smoked regularly in the presence of the woman, at home, in the workplace, or somewhere else. We also performed urinary cotinine measurements. Maternal urine was collected during the study visit at 24–28 gestational weeks and immediately frozen at −80°C. We then thawed a 1-mL aliquot and analyzed it by gas chromatography/mass spectrometry. We considered the group of women with a urinary cotinine level > 50 ng/mL (n = 5) to potentially include smokers and excluded them; additionally, we excluded two women who had declared to be nonsmokers during the interview with the midwife but who later declared to have smoked during the third trimester of pregnancy. Mean cotinine levels were 0.8 ng/mL among women who declared not to have been exposed to passive smoking and 2.3 ng/mL among women who declared to have been exposed to passive smoking (p < 0.01). In addition to passive smoking, cotinine levels, and gestational duration at the time of the measurement of fetal size (linear and quadratic terms), we also adjusted for sex of newborn, birth order, maternal height (continuous variable), prepregnancy weight [broken stick model with a knot at 60 kg (Slama and Werwatz 2005)], maternal age at end of study, and calendar month of conception. We also adjusted for maternal occupational exposure to paints, pesticides (n = 3, based on the questionnaire filled in between 24 and 28 gestational weeks), and center. We further adjusted models for head circumference at birth for cesarean sections (yes/no) and for the number of days between birth and the assessment of head circumference.

Results Top

Participants

A total of 2,002 pregnant women were recruited in the cohort. Among these women, 484 were nonsmoking women whose clinical examination took place after February 2005, and 304 women (63%) agreed to carry the dosimeter. Benzene levels and one measure of fetal growth were known for 271 women (89% of women who agreed to carry the dosimeter; overall participation rate within the cohort, 56%). Compared with approached nonsmoking women who refused to carry the air sampler or with no exposure estimate, those with an estimated benzene exposure were more often > 25 years of age and nulliparous at inclusion and more often declared to be exposed to passive smoking [Supplemental Material, Table 2 (doi:10.1289/ehp.0800465.S1)]. We found no evidence that participants and non-participants differed in terms of offspring birth weight or head circumference at any measurement (Student’s mean comparison test, all p-values > 0.29).

Benzene levels

Participants carried the air sampler in the 27th week (median) of amenorrhea for a median duration of 7.0 days (Table 1). All benzene levels exceeded the detection limit, with a mean of 2.6 μg/m³ and a median of 1.8 μg/m³ (5th, 95th percentiles, 0.5, 7.5 μg/m³; range, 0.3–19.4 μg/m³); 26 (10%) and 6 values (2%) were > 5 and 10 μg/m³, respectively. Although we found no strong evidence of an association between exposure and the main means of transportation when exposure was categorized (Table 2), mean log-transformed exposure was higher for women using a car as the main means of transportation, compared with those walking, both before (p = 0.04) and after (p = 0.02) adjustment for month of measurement, center, and passive smoking. In unadjusted analyses, benzene levels tended to increase with gestational duration (p = 0.10).

Benzene and birth weight

Median gestational week at delivery was 39.9 (5th, 95th percentiles, 35.6, 41.7 weeks). A benzene level in the highest exposure category was associated with an adjusted decrease in mean birth weight by 90 g [95% confidence interval (CI), −215 to 36 g], compared with the lowest exposure category. Each increase of one in log-transformed benzene exposure (corresponding to a multiplication of exposure by 2.72) was associated with an adjusted decrease of 68 g in birth weight (95% CI, −135 to −1 g; Table 3).

Benzene and head circumference assessed at birth by the midwife

Compared with observations in the lowest exposure category, exposures in the intermediate and highest exposure categories were associated with adjusted decreases in mean head circumference at birth of 0.9 mm (95% CI, −4.5 to 2.7 mm) and 3.7 mm (95% CI, −7.3 to 0.0 mm), respectively (linear trend test, p = 0.04; Table 3). Log-transformed exposure showed a similar trend, corresponding to a decrease by 1.9 mm for each increase by one in log-transformed exposure (95% CI, −3.8 to 0.0; Table 3).

Benzene and ultrasound measurements of head size

At the third-trimester ultrasonography, the adjusted decrease associated with benzene exposure in the highest exposure category was 4.8 mm for head circumference (95% CI, −8.8 to −0.8 mm, p-value for linear trend across exposure tertiles, 0.02) and 1.3 mm for biparietal diameter (95% CI, −2.6 to 0.1 mm; p-value for linear trend across tertiles, 0.02; Table 4). Log-transformed exposure showed consistent but statistically weaker associations with head circumference (p = 0.09) and biparietal diameter (p = 0.09).

At the second-trimester ultrasonography, the adjusted decrease in head circumference associated with exposure in the highest category was 2.5 mm (95% CI, −5.4 to 0.5 mm; p-value for linear trend across exposure categories, 0.11), and the adjusted decrease in biparietal diameter was 1.0 mm (95% CI, −2.0 to 0.0 mm; test for linear trend across categories, p = 0.06, Table 5). Each increase by one in log-transformed exposure was associated with an adjusted decrease by 1.5 mm in head circumference (95% CI, −3.1 to 0.0 mm, compared with −1.9 and −1.9 mm at birth and during the third trimester, respectively) and by 0.6 mm in biparietal diameter (95% CI, −1.1 to −0.1 mm) (Table 5).

Finally, at the first-trimester ultrasonography, compared with the lowest exposure category, the highest category was associated with an adjusted decrease in biparietal diameter by 0.9 mm (95% CI, −1.6 to −0.2 mm; p-value for linear trend, 0.03) (Table 6). Each increase by one in log-transformed exposure was associated with a decrease by 0.4 mm in biparietal diameter during the first trimester (95% CI, −0.7 to 0.0 mm, compared with −0.6 and −0.6 mm during the third and second trimesters, respectively).

Longitudinal analysis

Figure 1 shows the results of the longitudinal analysis combining second, third trimester, and birth measurements of head circumference, which are consistent with the above-described trimester-specific analyses.

Figures and Tables

Figure 1.

Head circumference as a function of gestational age at measurement and maternal benzene exposure. Head circumference was assessed between 19 gestational weeks and birth (A), between 19 and 27 gestational weeks (by ultrasonography) (B), between 27 and 35 gestational weeks (by ultrasonography) (C), and between 35 and 43 gestational weeks (after birth) (D). The predicted curves are adjusted for gestational age at examination (polynomial coding and interaction terms with all adjustment variables but education and center), sex, maternal passive smoking (questionnaire data), urinary cotinine level, prepregnancy weight, height, parity, maternal occupational exposure to paints or pesticides, month of conception, maternal education, and center.

Figure 2.

Sensitivity analysis: estimated effect of benzene levels (≥ 2.6 μg/m³, the reference being < 1.4 μg/m³) on head circumference after exclusion of specific subgroups of the population or adjustment for additional variables. Diamonds indicate point estimates; horizontal lines indicate the 95% CIs. Abbreviations: ETS, environmental tobacco smoke; SGA, small for gestational age. (A) Benzene and head circumference after birth (average of two measurements). (B) Benzene and head circumference at the third trimester (29–36 gestational weeks) ultrasound examination.

^aThe sample sizes correspond to the adjusted analyses and thus slightly differ from those given in Table 3 or Table 4. ^bExclusion of women occupationally exposed to paints or pesticides. ^cExclusion of air samplers stored for ≥ 3 months during any period including a day in the warm season (June–September). ^dThe single measure of head circumference performed right after birth was used instead of the average of the two independent measures performed shortly after birth.

Table 1.

Characteristics of use of the passive air sampler (271 nonsmoking women from the EDEN cohort).

Table 2.

Characteristics of the participants and their association with benzene levels.

Table 3.

Associations between benzene levels during pregnancy and measurements of the offspring at birth.

Table 4.

Association between benzene levels during pregnancy and head ultrasound measurements during the third trimester of pregnancy.

Table 5.

Association between benzene levels during pregnancy and head ultrasound measurements during the second trimester of pregnancy.

Table 6.

Association between benzene levels during pregnancy and ultrasound measurements of biparietal diameter during the first trimester of pregnancy.

Sensitivity analyses

When we restricted the analysis to the “usual schedule” group, the estimated birth weight change corresponded to a decrease of 87 g for each increase by one in log-transformed exposure (95% CI, −171 to −3 g; Table 3). Concerning head circumference and biparietal diameter, the results in the usual schedule group were similar to those in the whole population (Tables 3–6), although p-values were generally larger, with smaller sample sizes. The association with benzene was somewhat stronger when we assessed head circumference from the single measurement at birth (the variation in head circumference associated with the highest exposure category was −5.7 mm; 95% CI, −10.2 to −1.2 mm), compared with our original analysis using the average of two measurements within 3 days after birth (Figure 2A).

Associations remained similar after exclusion of subjects who lived in homes where wood or coal was used as a source of heating (a potential indoor source of benzene). We observed qualitatively similar results after exclusion of small-for-gestational-age births (Figure 2). Associations with head circumference were similar for subjects who had used the air samplers at least 5 days, for subjects who had not forgotten it in a room from which they were absent (or forgotten it for < 12 hr), and after exclusion of observations with an interval between the end of use of the sampler and storage in a refrigerator of > 90 days during part of the June–September period (Figure 2). As expected, associations tended to be weaker when we adjusted for ultrasound-based rather than LMP-based gestational duration (Figure 2). The estimated effect of benzene tended to be stronger among the group of 141 women who declared to have regular cycles, compared with results based on the whole population (Figure 2B).

Discussion Top

In a cohort of nonsmoking women recruited during the first half of pregnancy, we observed decreased birth weight, decreased head circumference during the second and third trimesters of pregnancy and at birth, and decreased biparietal diameter during pregnancy in association with maternal benzene exposure.

Several studies in which exposure had been estimated from the air pollution levels in the vicinity of the home address had reported decrements in birth weight (corrected for gestational age) or increases in the risk of small-for-gestational-age births in association with air pollution levels (Jedrychowski et al. 2004; Parker et al. 2005; Ritz and Wilhelm 2008; Slama et al. 2008a; Wilhelm and Ritz 2003). Our study tends to confirm the association between air pollutants and gestational age–corrected birth weight using personal exposure assessment, adjusting for many potential confounders not always considered in previous studies, and focusing on a marker of air pollution specific of traffic and combustion sources.

Several studies have tried to identify windows of sensitivity to air pollutants during pregnancy, by testing associations between trimester-specific exposure variables and birth weight, without yielding a consistent picture (reviewed by Slama et al. 2008a). Only one study assessed fetal growth during pregnancy: In a study that assessed exposure from the air quality monitoring station data, Hansen et al. (2008) reported an association between the concentration of PM with an aerodynamic diameter < 10 μm and head circumference assessed by ultrasound between 13 and 26 gestational weeks. Their results and ours suggest that air pollutants could influence fetal head circumference during the second trimester of pregnancy. The fact that in our study benzene levels exhibited associations with biparietal diameter assessed at the end of the first trimester indicates that air pollution effects might manifest even earlier in pregnancy. However, this analysis should be considered with caution because the first- trimester examination was conducted at a time point more distant from benzene monitoring than the later ultrasound examinations.

Our analyses suggested a stronger association (measured on an additive scale) between benzene and fetal growth among male than among female newborns. Ghosh et al. (2007) suggested that air pollution effects on the risk of a low-birth-weight birth (assessed by multiplicative models) may differ by sex. In a cohort of pregnant women conducted in Poland, personal PM_2.5 (PM with an aerodynamic diameter < 2.5 μm) exposure was more strongly associated with head circumference (using additive models) among male than among female newborns (Jedrychowski et al. 2009). Stronger effects of maternal smoking among male compared with female fetuses have also been reported, using either birth weight or biparietal diameter assessed by ultrasound as the outcome (Zaren et al. 2000). Our results are in line with these two studies (Jedrychowski et al. 2009; Zaren et al. 2000), relying on other measures of air pollution exposure.

Previous studies of associations between maternal benzene exposure and birth outcomes in human populations have been conducted in occupational settings, where benzene is used as a solvent and as an intermediate in the synthesis of many families of products (Chen et al. 2000; Wang et al. 2000). In a study in Taiwan, 792 women were recruited during pregnancy, among which 354 were considered occupationally exposed to benzene. After adjustment, a potential benzene exposure was associated with a nonsignificant reduction in mean birth weight of 15 g (95% CI, −52 to 82 g); in a model with an interaction term between benzene exposure and work stress, mean birth weight of offspring of the 57 women considered exposed to both factors was reduced by 183 g (95% CI, 65 to 301 g), compared with women considered exposed to neither factor (Chen et al. 2000). This study is difficult to compare with ours because it deals with occupational exposure, which generally stops during the third trimester of pregnancy (Chen et al. 2000), and because exposure assessment was performed on a binary scale by an industrial hygienist and did not consider nonoccupational exposures. Moreover, benzene exposure is probably a proxy for exposure to different mixtures of pollutants in occupational and nonoccupational settings.

The main strengths of our study are its prospective design, the use of ultrasound measurements to assess fetal growth, and the personal assessment of benzene exposure. The main limitation is that assessment was performed only once during 7 consecutive days, so we had no direct information on the variability in exposure during pregnancy. In addition, the sample size was too limited to study rare events such as occurrence of small-for-gestational-age births.

Possible implications

Head circumference is correlated with brain volume in neonates (Lindley et al. 1999). The possible long-term consequences of air pollution effects on head circumference or brain volume are difficult to establish. A review concluded that children with poor prenatal head growth may be at risk for adverse neurodevelopmental outcomes (Yanney and Marlow 2004). Few studies have directly addressed the consequences of pre-natal exposure to air pollutants on cognitive development in childhood. Within a New York City, New York, cohort, prenatal exposure to polycyclic aromatic hydrocarbons was associated with lower mental development index at 3 years of age and a greater risk of cognitive developmental delay (Perera et al. 2006). However, this association remained after adjustment for birth weight and head circumference at birth (Perera et al. 2006), so any effect of polycyclic aromatic hydrocarbons on mental development is unlikely to be entirely mediated by changes in head circumference at birth.

Benzene exposure as a proxy for exposure to traffic-related air pollutants

The mean personal benzene levels were 2.1 μg/m³ in the Poitiers area (a city of 100,000 inhabitants), compared with 2.9 μg/m³ in Nancy area, a more densely populated city of 300,000 inhabitants with higher mean environmental concentrations of NO₂ estimated by the air quality monitoring stations (F. Caïni, Atmo Poitou-Charentes, personal communication). By comparison, mean exposure levels of 5.1 μg/m³ have been reported among non-smokers in Madrid, Spain, for the year 2003, and of 2.9 μg/m³ in Dublin, Ireland, in 2004 (Ballesta et al. 2006). Among our nonsmoking population, benzene exposure exceeded the European Union limit of 5 μg/m³ planned for the ambient air in 2010 for 26 subjects (10% of the population).

The main route of exposure to benzene is through the air, and the main sources of exposure among nonsmoking subjects from the general population are fuel and environmental tobacco smoke (Wallace 1996). Benzene is a recognized carcinogen, and emissions from most consumer products are expected to be very low. Although we cannot rule out the existence of indoor sources of benzene in the general population not related to fuel or cigarette smoke, the correlation between benzene exposure and outdoor NO₂ levels does not speak in favor of important indoor sources of benzene. About 10% of women lived in a home where wood was used for heating; exclusion of these women did not modify the association between benzene and head circumference. Benzene is used as an additive in unleaded gasoline, in which a volume concentration of up to 1% is currently permitted in the United States and the European Union. Its presence in traffic exhaust is attributable to some benzene escaping the combustion process and benzene being a by-product of the partial combustion of other organic compounds. Benzene is also present in the environment because of other combustion processes such as residential heating or industrial emissions. Benzene levels much higher than common outdoor levels have been reported in car cabins (Ilgen et al. 2001b; Jo and Park 1999), so sitting in a car for about 1 hr/day can substantially increase personal exposure; a European study estimated that exposures in transit contribute to 29% of total personal benzene exposure (Bruinen de Bruin et al. 2008). Benzene environmental levels have been shown to be higher in the vicinity of roads with high traffic and in homes with a garage with a connecting door to the living rooms (Ilgen et al. 2001a). In our study, benzene exposure was higher for women who used the car as their main means of transportation. For these reasons, benzene exposure in our nonsmoking population in which effects of passive smoking have been controlled for can be seen as a proxy for exposure to traffic or combustion-related air pollutants.

Possible biological mechanisms

There is support from experiments in rodents for an effect of maternal exposure to airborne benzene (not associated to other traffic-related air pollutants) on fetal weight [reviewed by ATSDR (2007)]. More probably, if it reflects a causal mechanism, the association that we observed could be attributable to a joint effect of several traffic-related air pollutants. In mice, effects on fetal weight have been reported for traffic exhaust exposure during pregnancy (Rocha et al. 2008; Veras et al. 2008). Several mechanisms could explain an effect of traffic-related air pollutants on fetal growth (Kannan et al. 2006; Slama et al. 2008a). These pollutants might influence endothelial function and blood viscosity, which could alter maternal–placental oxygen and nutrient exchanges and thus affect fetal growth (Slama et al. 2008a). This mechanism is supported by an experiment on mice that found effects of urban PM air pollution on placental morphology assessed, among other parameters, by the diameter of vessels (Veras et al. 2008). Endocrine disruption is another possible mechanism; indeed, endocrine disruption may play a role in the occurrence of intrauterine growth restriction and might be induced by diesel exhaust (Takeda et al. 2004).

Assessment of fetal growth

The association between benzene exposure and head size at birth was stronger when we assessed head size from the single measurement right after birth than when we assessed it from the repeated measurements performed within a few days after birth, although trends were qualitatively similar. In additional analyses performed on the whole cohort, the estimated adjusted effect of maternal smoking was stronger for the single measure than for the average of the two measures (data not shown). The amplitude (but not the frequency) of measurement error is expected to be lower for the two measures than for the single measure. However, several factors that could not be adjusted for (e.g., postnatal nutrition of the newborn) might influence head size in the days after birth, so specific studies are warranted to determine which measure of head size is more relevant to characterize the influence of environmental factors on head circumference. In agreement with our expectation (Slama et al. 2008b), the estimated effect of exposure was stronger when we adjusted fetal size for gestational age based on the date of LMP, compared with based on the obstetrician estimate. The fact that the apparent effect of benzene tended to be stronger in the subgroup of women with a regular menstrual cycle than among the whole population, as highlighted by our sensitivity analyses, should be considered with caution because of the relatively small size of this subgroup. Although the direction of a bias due to measurement error on an adjustment factor is generally difficult to predict, this observation might be attributable to LMP-based gestational age being more efficiently assessed in the subgroup of women with regular cycles.

Exposure assessment

Compared with approaches relying on measures in the environment, personal air samplers have the advantage of taking into account both indoor and outdoor exposures, as well as exposure in each microenvironment such as vehicle cabins. A limitation is that, unless repeated measurements are performed, they do not allow the capture of temporal variations in exposure. In our study, women carried the sampler at the same stage of fetal development and for a whole week to try to capture most of the usual situations of exposure. A German study with repeated measurements of indoor and outdoor benzene levels 6–13 months apart showed important intraindividual variation; however, after adjustment for season of measurement and region, the between-home standard deviation of benzene levels was greater than the within-home standard deviation, and the seasonal variations in benzene levels showed similar patterns across locations of measurement (Topp et al. 2004). Although the absolute value of exposure is expected to vary with time, it is plausible that the distribution of the population into exposure tertiles exhibits limited variations across time; that is, women in the highest exposure tertile at 27 gestational weeks may also correspond to a large proportion of the women in the highest tertile of exposure averaged over a longer period. In our study, restricting analyses to women with a time schedule during the week of use of the air sampler similar to that of the previous month was meant to focus on a subpopulation with more limited temporal variations in exposure due to behavioral factors, and hence an exposure estimate likely to be representative of exposure over a longer time period. This restriction yielded effect sizes of exposure similar to those estimated among the whole population.

We adjusted for both questionnaire-based exposure to passive smoking and cotinine urinary levels; our sensitivity analyses showed that excluding subjects exposed to passive smoking, as assessed by questionnaire or cotinine urinary levels, did not alter associations between benzene and head circumference, compared with adjusted analyses. However, we cannot firmly exclude any residual confounding due to passive smoking, because questionnaires have limited validity for low levels of exposure (Proctor et al. 1991), and because cotinine urinary assays may be limited by the relatively short half-life of cotinine among pregnant women. Half-life has been reported to be around 9 hr among pregnant women (Dempsey et al. 2002), compared with 17 hr after delivery (Dempsey et al. 2002) and 19 hr among male adults (Feng et al. 2007).

Conclusion Top

We report an association between maternal pregnancy exposure of nonsmoking women to benzene and gestational age–adjusted offspring head size assessed at birth and by ultrasound imaging during pregnancy, and between exposure and birth weight. The association with head size manifested before the third trimester of pregnancy. Because benzene is a marker of exposure to traffic-related air pollutants, the association observed might be attributable to a mixture of traffic-related air pollutants, although we cannot completely rule out the existence of indoor sources of benzene not related to cigarette smoke or fuel.

References Top

1. Aguilera I, Sunyer J, Fernandez-Patier R, Hoek G, Aguirre-Alfaro A, Meliefste K, et al. 2008. Estimation of outdoor NO_x, NO₂, and BTEX exposure in a cohort of pregnant women using land use regression modeling Environ Sci Technol 42(3): 815–821. Find this article online
2. ATSDR 2007. Toxicological Profile for Benzene. Atlanta, GA: Agency for Toxic Substances and Disease Registry.
3. Ballesta PP, Field RA, Connolly R, Cao N, Baeza Caracena A, De Saeger E 2006. Population exposure to benzene: one day cross-sections in six European cities Atmos Environ 40(18): 3355–3366. Find this article online
4. Blondel B, Supernant K, Du Mazaubrun C, Breart G 2006. Trends in perinatal health in metropolitan France between 1995 and 2003: results from the National Perinatal Surveys [in French] J Gynecol Obstet Biol Reprod (Paris) 35(4): 373–387. Find this article online
5. Bruinen de Bruin Y, Koistinen K, Kephalopoulos S, Geiss O, Tirendi S, Kotzias D 2008. Characterisation of urban inhalation exposures to benzene, formaldehyde and acetaldehyde in the European Union: comparison of measured and modelled exposure data Environ Sci Pollut Res Int 15(5): 417–430. Find this article online
6. Chen D, Cho SI, Chen C, Wang X, Damokosh AI, Ryan L, et al. 2000. Exposure to benzene, occupational stress, and reduced birth weight Occup Environ Med 57(10): 661–667. Find this article online
7. Choi H, Jedrychowski W, Spengler J, Camann DE, Whyatt RM, Rauh V, et al. 2006. International studies of prenatal exposure to polycyclic aromatic hydrocarbons and fetal growth Environ Health Perspect 114: 1744–1750. Find this article online
8. Cocheo V, Boaretto C, Sacco P 1996. High uptake rate radial diffusive sampler suitable for both solvent and thermal desorption Am Ind Hyg Assoc J 57: 897–904. Find this article online
9. Cocheo V, Sacco P, Boaretto C, De Saeger E, Ballesta PP, Skov H, et al. 2000. Urban benzene and population exposure Nature 404(6774): 141–142. Find this article online
10. Cuzick J 1985. A Wilcoxon-type test for trend Stat Med 4(1): 87–90. Find this article online
11. Dempsey D, Jacob P III, Benowitz NL 2002. Accelerated metabolism of nicotine and cotinine in pregnant smokers J Pharmacol Exp Ther 301(2): 594–598. Find this article online
12. Drouillet P, Kaminski M, De Lauzon-Guillain B, Forhan A, Ducimetière P, Schweitzer M, et al. 2009. Association between maternal seafood consumption before pregnancy and fetal growth: evidence for an association in overweight women. The EDEN mother-child cohort Paediatr Perinatal Epidemiol 23(1): 76–86. Find this article online
13. Feng S, Kapur S, Sarkar M, Muhammad R, Mendes P, Newland K, et al. 2007. Respiratory retention of nicotine and urinary excretion of nicotine and its five major metabolites in adult male smokers Toxicol Lett 173(2): 101–106. Find this article online
14. Ghosh R, Rankin J, Pless-Mulloli T, Glinianaia S 2007. Does the effect of air pollution on pregnancy outcomes differ by gender? A systematic review Environ Res 105(3): 400–408. Find this article online
15. Glinianaia SV, Rankin J, Bell R, Pless-Mulloli T, Howel D 2004. Particulate air pollution and fetal health: a systematic review of the epidemiologic evidence Epidemiology 15(1): 36–45. Find this article online
16. Hadlock FP 1994. Ultrasound évaluation of fetal growth In: Callen PW, editor. Ultrasonography in Obstetrics and Gynecology. Philadelphia: W.B. Saunders. pp. 129–143.
17. Hansen CA, Barnett AG, Pritchard G 2008. The effect of ambient air pollution during early pregnancy on fetal ultrasonic measurements during mid-pregnancy Environ Health Perspect 116: 362–369. Find this article online
18. Ilgen E, Levsen K, Angerer J, Schneider P, Heinrich J, Wichmann HE 2001a. Aromatic hydrocarbons in the atmospheric environment. Part II: univariate and multivariate analysis and case studies of indoor concentrations Atmos Environ 35: 1253–1264. Find this article online
19. Ilgen E, Levsen K, Angerer J, Schneider P, Heinrich J, Wichmann HE 2001b. Aromatic hydrocarbons in the atmospheric environment. Part III: personal monitoring Atmos Environ 35: 1265–1279. Find this article online
20. Jedrychowski W, Bendkowska I, Flak E, Penar A, Jacek R, Kaim I, et al. 2004. Estimated risk for altered fetal growth resulting from exposure to fine particles during pregnancy: an epidemiologic prospective cohort study in Poland Environ Health Perspect 112: 1398–1402. Find this article online
21. Jedrychowski W, Perera F, Mrozek-Budzyn D, Mroz E, Flak E, Spengler JD, et al. 2009. Gender differences in fetal growth of newborns exposed prenatally to airborne fine particulate matter Environ Res 109(4): 447–456. Find this article online
22. Jo WK, Park KH 1999. Concentrations of volatile organic compounds in the passenger side and the back seat of automobiles J Expo Anal Environ Epidemiol 9(3): 217–227. Find this article online
23. Kannan S, Misra DP, Dvonch JT, Krishnakumar A 2006. Exposures to airborne particulate matter and adverse perinatal outcomes: a biologically plausible mechanistic framework for exploring potential effect modification by nutrition Environ Health Perspect 114: 1636–1642. Find this article online
24. Krzyzanowski M, Kuna-Dibbert B, Schneider J, editors. 2005 [[accessed 9 July 2009]]. Health Effects of Transport-Related Air Pollution. Copenhagen: World Health Organization, Regional Office for Europe.
25. Lacasana M, Esplugues A, Ballester F 2005. Exposure to ambient air pollution and prenatal and early childhood health effects Eur J Epidemiol 20(2): 183–199. Find this article online
26. Lindley AA, Benson JE, Grimes C, Cole TM III, Herman AA 1999. The relationship in neonates between clinically meas ured head circumference and brain volume estimated from head CT-scans Early Hum Dev 56(1): 17–29. Find this article online
27. Mamelle N, Munoz F, Grandjean H 1996. Fetal growth from the AUDIPOG study. I. Establishment of reference curves [in French] J Gynecol Obstet Biol Reprod (Paris) 25(1): 61–70. Find this article online
28. Parker JD, Woodruff TJ, Basu R, Schoendorf KC 2005. Air pollution and birth weight among term infants in California Pediatrics 115(1): 121–128. Find this article online
29. Perera FP, Rauh V, Whyatt RM, Tang D, Tsai WY, Bernert JT, et al. 2005. A summary of recent findings on birth outcomes and developmental effects of prenatal ETS, PAH, and pesticide exposures Neurotoxicology 26(4): 573–587. Find this article online
30. Perera FP, Rauh V, Whyatt RM, Tsai WY, Tang D, Diaz D, et al. 2006. Effect of prenatal exposure to airborne polycyclic aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner-city children Environ Health Perspect 114: 1287–1292. Find this article online
31. Proctor CJ, Warren ND, Bevan MAJ, Baker-Rogers J 1991. A comparison of methods of assessing exposure to environmental tobacco smoke in non-smoking British women Environ Int 17(4): 287–297. Find this article online
32. Ritz B, Wilhelm M 2008. Ambient air pollution and adverse birth outcomes: methodologic issues in an emerging field Basic Clin Pharmacol Toxicol 102(2): 182–190. Find this article online
33. Ritz B, Yu F 1999. The effect of ambient carbon monoxide on low birth weight among children born in southern California between 1989 and 1993 Environ Health Perspect 107: 17–25. Find this article online
34. Rocha ESIR, Lichtenfels AJ, Amador Pereira LA, Saldiva PH 2008. Effects of ambient levels of air pollution generated by traffic on birth and placental weights in mice Fertil Steril 90(5): 1921–1924. Find this article online
35. Rothman KJ, Greenland S 1998. Modern Epidemiology. 2nd edPhiladelphia: Lippincott-Raven.
36. Schauer JJ, Kleeman MJ, Cass GR, Simoneit BR 1999. Measurement of emissions from air pollution sources. 2. C1 through C30 organic compounds from medium duty diesel trucks Environ Sci Technol 33(10): 1578–1587. Find this article online
37. Schauer JJ, Kleeman MJ, Cass GR, Simoneit BR 2002. Measurement of emissions from air pollution sources. 5. C1–C32 organic compounds from gasoline-powered motor vehicles Environ Sci Technol 36(6): 1169–1180. Find this article online
38. Slama R, Darrow LA, Parker JD, Woodruff TJ, Strickland M, Nieuwenhuijsen M, et al. 2008a. Atmospheric pollution and human reproduction: report of the Munich International Workshop Environ Health Perspect 116: 791–798. Find this article online
39. Slama R, Khoshnood B, Kaminski M 2008b. How to control for gestational age in studies of effects of environmental factors on fetal growth? [Letter] Environ Health Perspect 116: A284. Find this article online
40. Slama R, Werwatz A 2005. Controlling for continuous confounding factors: non- and semi-parametric approaches Rev Epidemiol Sante Publique 53(2S): S65–S80. Find this article online
41. Takeda K, Tsukue N, Yoshida S 2004. Endocrine-disrupting activity of chemicals in diesel exhaust and diesel exhaust particles Environ Sci 11(1): 33–45. Find this article online
42. Topp R, Cyrys J, Gebefugi I, Schnelle-Kreis J, Richter K, Wichmann HE, et al. 2004. Indoor and outdoor air concentrations of BTEX and NO₂: correlation of repeated measurements J Environ Monit 6(10): 807–812. Find this article online
43. Veras MM, Damaceno-Rodrigues NR, Caldini EG, Maciel Ribeiro AA, Mayhew TM, Saldiva PH, et al. 2008. Particulate urban air pollution affects the functional morphology of mouse placenta Biol Reprod 79(3): 578–584. Find this article online
44. Wallace L 1996. Environmental exposure to benzene: an update Environ Health Perspect 104(suppl 6): 1129–1136. Find this article online
45. Wang X, Chen D, Niu T, Wang Z, Wang L, Ryan L, et al. 2000. Genetic susceptibility to benzene and shortened gestation: evidence of gene-environment interaction Am J Epidemiol 152(8): 693–700. Find this article online
46. Wilhelm M, Ritz B 2003. Residential proximity to traffic and adverse birth outcomes in Los Angeles County, California, 1994–1996 Environ Health Perspect 111: 207–216. Find this article online
47. Yanney M, Marlow N 2004. Paediatric consequences of fetal growth restriction Semin Fetal Neonatal Med 9(5): 411–418. Find this article online
48. Zaren B, Lindmark G, Bakketeig L 2000. Maternal smoking affects fetal growth more in the male fetus Paediatr Perinat Epidemiol 14(2): 118–126. Find this article online
49. Zhu Y, Eiguren-Fernandez A, Hinds WC, Miguel AH 2007. In-cabin commuter exposure to ultrafine particles on Los Angeles freeways Environ Sci Technol 41(7): 2138–2145. Find this article online