American Journal of Epidemiology Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Vol. 183, No. 12 DOI: 10.1093/aje/kwv284 Advance Access publication: May 17, 2016
Original Contribution Exposure to Ambient Air Pollution and Premature Rupture of Membranes
Maeve E. Wallace, Katherine L. Grantz, Danping Liu, Yeyi Zhu, Sung Soo Kim, and Pauline Mendola* * Correspondence to Dr. Pauline Mendola, Epidemiology Branch, Division of Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6100 Executive Boulevard, Rockville, MD 20852 (e-mail: [email protected]).
Initially submitted May 22, 2015; accepted for publication October 13, 2015.
Premature rupture of membranes (PROM) is a major factor that predisposes women to preterm delivery. Results from previous studies have suggested that there are associations between exposure to air pollution and preterm birth, but evidence of a relationship with PROM is sparse. Modified Community Multiscale Air Quality models were used to estimate mean exposures to particulate matter less than 10 µm or less than 2.5 µm in aerodynamic diameter, nitrogen oxides, carbon monoxide, sulfur dioxide, and ozone among 223,375 singleton deliveries in the Air Quality and Reproductive Health Study (2002–2008). We used log-linear models with generalized estimating equations to estimate adjusted relative risks and 95% confidence intervals for PROM per each interquartilerange increase in pollutants across the whole pregnancy, on the day of delivery, and 5 hours before delivery. Whole-pregnancy exposures to carbon monoxide and sulfur dioxide were associated with an increased risk of PROM (for carbon monoxide, relative risk (RR) = 1.09, 95% confidence interval (CI): 1.04, 1.14; for sulfur dioxide, RR = 1.15, 95% CI: 1.06, 1.25) but not preterm PROM. Ozone exposure increased the risk of PROM on the day of delivery (RR = 1.06, 95% CI: 1.02, 1.09) and 1 day prior (RR = 1.04, 95% CI: 1.01, 1.07). In the 5 hours preceding delivery, there were 3%–7% increases in risk associated with exposure to ozone and particulate matter less than 2.5 µm in aerodynamic diameter and inverse associations with exposure to carbon monoxide and nitrogen oxides. Acute and long-term air pollutant exposures merit further study in relation to PROM. ambient air pollution; premature rupture of membranes; preterm birth
Abbreviations: CI, confidence interval; CSL, Consortium on Safe Labor; PPROM, preterm premature rupture of membranes; PM2.5, particulate matter less than 2.5 µm in aerodynamic diameter; PM10, particulate matter less than 10 µm in aerodynamic diameter; PROM, premature rupture of membranes; RR, relative risk.
for both women and infants, including infection, sepsis, and umbilical cord compression, as well as a higher risk of placental abruption and the short- and long-term adverse consequences of neonatal prematurity (2–5). The harmful consequences of exposure to air pollution may include a higher risk of preterm birth, particularly with exposures that are proximal to delivery (6–9). In a recent meta-analysis, Stieb et al. (10) identified a 4%–6% increase in preterm delivery risk associated with third-trimester exposure to the criteria air pollutants particulate matter less than 10 µm in aerodynamic diameter (PM10) and carbon monoxide, and others have reported acute associations in the days and weeks preceding delivery for PM10, particulate matter
Premature rupture of membranes (PROM) is rupture of membranes that occurs before the onset of labor. PROM at 37 weeks of gestation or later is thought to result from a normal physiological process of membrane weakening near the end of pregnancy and occurs in approximately 8% of term pregnancies. PROM has been shown to increase the risk of maternal chorioamnionitis, infectious endometritis, and neonatal sepsis (1). Rupture that occurs before 37 weeks gestation, referred to as preterm premature rupture of membranes (PPROM), may indicate a number of underlying pathological mechanisms associated with infection and inflammation that lead to preterm rupture (2). PPROM is responsible for 1 of every 3 preterm births and is associated with significant morbidity 1114
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Air Pollution and Premature Rupture of Membranes 1115
less than 2.5 µm in aerodynamic diameter (PM2.5), and sulfur dioxide (11–13). Despite these suggested associations, the mechanisms through which exposure to air pollution leads to preterm birth remain unclear. Previous work has indicated that the pathophysiology of pollutant absorption may include oxidative stress, inflammation, endothelial dysfunction, cell apoptosis, and hemodynamic responses, which lead to preterm birth (14). Likewise, these factors may predispose women to PROM, which in turn may lead to preterm delivery if PROM occurs before 37 weeks of gestation. It has been suggested in 2 recent studies that residential proximity to major roadways (15) and chronic (whole-pregnancy) exposure to PM2.5 and nitrogen oxides (16) increase the risk of PPROM. In a third Australian-based study, Pereira et al. (17) reported a 3% increase in PROM risk (at any gestational age) associated with elevated exposure to PM2.5 in the second trimester but not with exposure in the first or third trimester or with whole-pregnancy exposure. Some evidence has suggested that acute exposure to air pollution may also be related to elevated levels of systemic inflammation and oxidative stress (18, 19), but acute exposure windows have not been examined in relation to rupture of membranes. It may be that exposure to high levels of air pollution in the days leading up to rupture is the final insult to already weakening (whether by normal or pathological processes) membranes that results in premature rupture. In the present study, our purpose was to estimate the risk of PROM associated with chronic and acute exposure to the US Environmental Protection Agency’s 6 criteria air pollutants (PM10, PM2.5, nitrogen oxides, carbon monoxide, sulfur dioxide, and ozone) across the whole pregnancy and in the days and hours preceding rupture in a large contemporary US obstetrical cohort. METHODS Study population
The Consortium on Safe Labor (CSL) is a retrospective cohort study of 228,438 deliveries assembled from electronic medical records at 12 centers located in 16 counties and representing 15 hospital referral regions across 9 American College of Obstetricians and Gynecologists US districts (20). Data on maternal demographic characteristics; medical, reproductive, and prenatal history; labor and delivery; and postpartum and newborn information were extracted from electronic medical records for births at 23 weeks of gestation or later. Electronic discharge summaries for mothers and infants were linked to the medical records. Data were limited to 223,375 singleton pregnancies among 204,165 women for the purposes of the present analysis because multifetal gestations are known to be at higher risk of both PROM and preterm birth (21). The CSL was approved by institutional review boards at all participating institutions. Exposure and outcome
Estimates of ambient air pollutant exposures for all pregnancies in the CSL were quantified as part of the Air Quality Am J Epidemiol. 2016;183(12):1114–1121
and Reproductive Health Study. Hospital referral region was used as a proxy for residence and local mobility. The size of hospital referral regions ranged from 415 to 312,644 square kilometers. The Community Multiscale Air Quality model (22), a modified version of the 3-dimensional multipollutant regional air quality model developed by the US Environmental Protection Agency, quantified hourly air pollution exposure in each region based on reported air pollution emissions and accounted for weather-related factors, complex mixtures, and chemical reactions between pollutants on the exposure (22). Meteorology inputs and pollutant emissions used in the model simulations were obtained from the Weather Research and Forecasting model and the National Emission Inventories, respectively (23). Maternal exposure to air pollution was estimated based on the hourly predictions of air pollutant concentration weighted by population density within the hospital referral region; the places where women were unlikely to live and work were discounted (23). Modeled data were merged with observed monitor data from the US Environmental Protection Agency’s Air Quality System to correct for measurement error between modeled and observed values of air pollutants (23). For each subject, hourly estimates of air pollution were averaged to obtain daily means for each of the 8 days before hospital admission, as well as whole-pregnancy means. The primary outcome of interest, PROM (defined as rupture of membranes at any time before the onset of labor regardless of gestational age) was extracted from electronic medical records. Cases of PPROM, that is, PROM that occurred before 37 weeks of gestation, were examined as a secondary outcome. Statistical analysis
Descriptive statistics were used to compare women with and without PROM or PPROM. Log-linear models with generalized estimating equations were used to estimate the relative risks (and 95% confidence intervals) of PROM associated with the mean level of each pollutant across the whole pregnancy, on the day of admission for delivery (lag day 0; 24 hours preceding the date and time of admission), and in the 7 days preceding admission (lags day 1–7). Women who delivered without PROM were the comparison group. We repeated this analysis after restricting the sample to women who delivered at term (>37 weeks gestation: n = 197,246; 88.3% of the total study population, 5.3% of whom had PROM) to examine whether later gestational cases were especially vulnerable to risks associated with exposure to air pollution. To assess the risk of PPROM, whole-pregnancy exposure was censored at delivery for cases and up to 37 weeks for women without PPROM to account for the time they were at risk of PPROM. Acute pollutant estimates were not examined in relation to PPROM because women whose last 8 days of pregnancy were later than 37 weeks of gestation were no longer at risk for PPROM, and daily estimates before week 37 were unavailable for women who delivered at term. Pollutant exposures were analyzed in continuous scale, and the relative risks were calculated per interquartile-range (the difference between the 25th and 75th percentile) increase in each pollutant.
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Table 1. Demographic Characteristics of Women With and Without Premature Rupture of Membranes During Pregnancy, Air Quality and Reproductive Health Study, 2002–2008 All Births (n = 223,375)
Demographic Characteristic No.
%
9,175
4.1
Mean (SD)
No PROM (n = 207,787) Mean (SD)
PROM at Any Gestational Age (n = 15,588)
No.
%
No.
%
8,327
4.0
848
5.4
Mean (SD)
PPROM at 1), prepregnancy body mass index (continuous), insurance type ( private, public, or other or unknown), smoking during pregnancy (yes or no), alcohol consumption during pregnancy (yes or no), season of conception (spring for March–May; summer for June–August; fall for September–November; winter for December–February), and study site. We additionally included year of birth in order to adjust for potential long-term temporal trends associated with pollutant levels in the United States given the broad time frame of births analyzed (2002–2008). Missing data on prepregnancy body mass index (n = 74,988; 33.6%) due to a lack of height and/or weight measure recorded in the medical record was imputed using multiple imputation to retain all observations for modeling. Finally, 8.6% of the study sample contributed multiple deliveries, and we accounted for the within-subject correlation by using the robust variance estimation in generalized estimating equations. Data on mean pollutant levels for the 5 hours preceding the hour of admission were available in a subset of the study sample (n = 171,782; 77% of the study population). These data were made available for a previous study of ambient air pollution and blood pressure at admission to delivery (24). In order to examine more acute windows of exposure on the day of admission, the above analysis was repeated for lag 0–4 hours preceding the hour of admission within this subgroup.
Table 2. Adjusted Relative Risk for Premature Rupture of Membranes and Preterm Premature Rupture of Membranes per Each Interquartile-Range–Unit Increase in Mean Air Pollutant Exposure Across the Whole Pregnancy, Air Quality and Reproductive Health Study, 2002–2008a PPROMb
PROM
Pollutant RR
95% CI
RR
95% CI
Carbon monoxide
1.09
1.04, 1.14
0.99
0.90, 1.07
Nitrogen oxides
0.92
0.93, 1.01
0.96
0.78, 1.13
Ozone
1.01
0.95, 1.07
1.06
0.95, 1.17
PM10
0.97
0.92, 1.02
0.98
0.89, 1.08
PM2.5
0.93
0.94, 1.02
0.88
0.73, 1.03
Sulfur dioxide
1.15
1.06, 1.25
1.01
0.85, 1.17
Abbreviations: CI, confidence interval; PM2.5, particulate matter less than 2.5 µm in aerodynamic diameter; PM10, particulate matter less than 10 µm in aerodynamic diameter; RR, relative risk. a All pollutants were included in same model, which was adjusted for maternal age, race, parity, prepregnancy body mass index, smoking, alcohol consumption, insurance type, season of conception, birth year, and study site. b Exposure was censored at 37 weeks for the reference group (births without preterm premature rupture of membranes).
at 36 weeks for women without PPROM in co-pollutant models (Table 2). Figure 1 depicts acute daily estimates for all pollutants during the final 8 days of pregnancy. Elevated ozone exposure on the day of admission for delivery and 1 day prior was associated with an increased risk of PROM (for lag day 0,
RESULTS
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1.10 1.05 Relative Risk
Seven percent (n = 15,588) of the 223,375 deliveries in this sample were complicated by PROM. Of these, one-third were PPROM preceding delivery that occurred at a mean gestational age of 33 weeks (range, 23–36). The proportion of black and Asian women, nulliparous women, smokers, and older women was higher among PROM case patients than among women without PROM (Table 1). A greater proportion of PPROM case patients were black women, smokers, and publicly insured women compared with the distributions among noncase patients. The distributions of air pollutants across the whole pregnancy and in the last 8 days and last 5 hours of pregnancy are available in Web Table 1 (available at http://aje.oxfordjournals. org/). Correlations between air pollutants across the whole pregnancy are available in Web Table 2. Ozone was consistently negatively correlated with the remaining 5 pollutants, most strongly for PM2.5, sulfur dioxide, and nitrogen oxides. Exposures to elevated levels of carbon monoxide and sulfur dioxide across the whole pregnancy were associated with a higher risk of PROM (for carbon monoxide, relative risk (RR) = 1.09, 95% confidence interval (CI): 1.04, 1.14; for sulfur dioxide, RR = 1.15, 95% CI: 1.06, 1.25; Table 2). Exposure to pollutants across the whole pregnancy was not associated with an increased risk of PPROM when compared with exposure up to the time of delivery or exposure censored
1.00 0.95 0.90
Ozone PM10
Pollutant CO
NOX
PM2.5
SO2
0.85 7
6
5
2 4 3 Time to Delivery, days
1
0
Figure 1. Adjusted relative risks for the associations between exposure to air pollutants and premature rupture of membranes on the day of admission for delivery and 7 days prior, Air Quality and Reproductive Health Study, 2002–2008. Shown are the relative risks for premature rupture of membranes associated with exposure to ozone, carbon monoxide (CO), nitrogen oxides (NOX), particulate matter less than 10 µm in aerodynamic diameter (PM10), particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5), and sulfur dioxide (SO2) that were estimated from models including all pollutants on the same day and adjusted for maternal age, race, parity, prepregnancy body mass index, smoking, alcohol consumption, insurance type, season of conception, birth year, and study site. Bars, 95% confidence intervals.
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Table 3. Adjusted Relative Risk for Premature Rupture of Membranes per Each Interquartile-Range–Unit Increase in Pollutant Exposure in the 5 Hours Preceding the Hour of Admission for Delivery, Air Quality and Reproductive Health Study, 2002–2008a Hour and Pollutant
on the day of admission and 7 days prior (for lag day 0, RR = 0.95, 95% CI: 0.92, 0.98; for lag day 7, RR = 0.93, 95% CI: 0.90, 0.96). No other pollutants were associated with PROM risk during the last 8 days of pregnancy. Results for the analysis limited to women who experienced PROM at term were consistent with the above results for women who experienced PROM at any gestational age. Estimated associations of increased risk with elevated wholepregnancy carbon monoxide and sulfur dioxide exposures, as well as elevated ozone exposure on the day of admission (lag day 0) were similar in magnitude, as were inverse associations with elevated nitrogen oxides exposure on lag days 0 and 7. Examining data from the day of admission more closely, we found that the trend of a higher risk associated with acute exposure to ozone on this day was consistent among hourly estimates for the 5 hours immediately preceding admission (Table 3). A 5%–7% increase in risk of PROM per interquartile-range increase in ozone exposure over the 5 hours preceding the hour of admission remained after adjustment for covariates and all other pollutants. Evidence of acute exposure to elevated levels of PM2.5 in lag hours 2, 1, and 0 suggested a 3%–4% increase in PROM risk. Inverse associations were observed for hourly estimates of carbon monoxide, nitrogen oxides, and PM10.
RR
95% CI
Ozone
1.05
1.02, 1.08
Carbon monoxide
0.95
0.92, 0.98
Nitrogen oxides
0.96
0.93, 0.99
PM10
0.97
0.93, 1.01
PM2.5
1.04
1.00, 1.07
Sulfur dioxide
0.99
0.98, 1.01
Ozone
1.07
1.04, 1.10
Carbon monoxide
0.94
0.92, 0.97
Nitrogen oxides
0.97
0.94, 1.00
PM10
0.97
0.93, 1.01
PM2.5
1.04
1.00, 1.07
Sulfur dioxide
0.99
0.98, 1.01
Ozone
1.07
1.04, 1.10
Carbon monoxide
0.96
0.93, 0.99
Nitrogen oxides
0.98
0.95, 1.01
DISCUSSION
PM10
0.96
0.93, 1.00
PM2.5
1.03
1.00, 1.07
Sulfur dioxide
1.00
0.98, 1.01
Ozone
1.07
1.04, 1.10
Carbon monoxide
0.99
0.96, 1.02
Nitrogen oxides
0.98
0.95, 1.01
PM10
0.96
0.93, 1.00
PM2.5
1.03
1.00, 1.07
Sulfur dioxide
1.00
0.99, 1.02
Ozone
1.06
1.03, 1.08
We examined the associations of both chronic (wholepregnancy) and acute (days and hours before admission) exposures to 6 criteria air pollutants with the incidence of PROM in a large, geographically diverse cohort of pregnant women. Although long-term exposures to carbon monoxide and sulfur dioxide during pregnancy were associated with PROM, acute exposures of ozone and PM2.5 were associated with PROM in the days and hours leading up to delivery. Unlike in previous research, we found no evidence of an association between elevated chronic exposure to pollutants and risk of PPROM. In a recent study in Japan, Yorifuji et al. (15) reported a 60% increase in risk of PPROM among women who lived within 200 meters of a major roadway—an index for air pollution exposure. In a previous investigation of criteria air pollutants, nitrogen oxides, PM2.5, PM10, and PPROM in Barcelona, Dadvand et al. (16) reported a positive association between PPROM and whole-pregnancy exposure to PM2.5 in a cohort analysis that was similar to our present study. The authors further reported an increase in the odds of PPROM associated with exposure to nitrogen oxides during the entire pregnancy that was determined using a matched case-control design, but they did not replicate this finding in the cohort analysis (16). Although we identified associations during acute windows of elevated exposure to PM2.5 in the last 3 hours before delivery, there was no evidence of an association of either whole-pregnancy exposure to PM2.5 or nitrogen oxides with PROM or PPROM in our data. It is important to note the considerable difference in air pollution distributions between the 2 studies: Median reported levels of PM2.5 were 19.8 (interquartile range, 4.1) μg/m3 in Barcelona compared with 11.9 (interquartile range, 4.7) μg/m3 in the present study. Median levels of nitrogen oxides were 102.6 (interquartile range, 39.5) μg/m3 in the Barcelona study
0
1
2
3
4 Carbon monoxide
1.02
1.00, 1.05
Nitrogen oxides
0.98
0.95, 1.00
PM10
0.96
0.92, 1.00
PM2.5
1.03
1.00, 1.06
Sulfur dioxide
1.01
0.99, 1.02
Abbreviations: CI, confidence interval; PM2.5, particulate matter less than 2.5 µm in aerodynamic diameter; PM10, particulate matter less than 10 µm in aerodynamic diameter; RR, relative risk. a Hourly estimates of all pollutants were included in same model, which was adjusted for maternal age, race, parity, prepregnancy body mass index, smoking, alcohol consumption, insurance type, season of conception, birth year, and study site.
RR = 1.06, 95% CI: 1.02, 1.09; for lag day 1, RR = 1.04, 95% CI: 1.01, 1.07). Ozone was not associated with PROM on any of the more distally preceding days. A significant inverse association with elevated nitrogen oxides exposure was evident
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Air Pollution and Premature Rupture of Membranes 1119
compared with 28.9 (interquartile range, 24.2) μg/m3 in the present study. It may be that nitrogen oxides and PM2.5 are related to PPROM risk only at high levels for longerterm exposures. An analysis of PM2.5 levels in 22 countries by the World Health Organization found an association with preterm birth only in China—the country with the highest levels of PM2.5—which suggests a threshold level for association that may also be true for PPROM (25). To our knowledge, this is the first analysis in which the acute, potentially triggering influence of ambient air pollutants on PROM has been examined. Our most compelling and consistent finding was that of an association between acute ozone exposure and PROM on the day before and the day of admission for delivery, as well as in the final 5 hours before admission. However, chronic exposure to ozone, as measured using average exposure during pregnancy, was not associated with PROM or PPROM. Ground-level ozone is the result of photochemical interactions between nitrogen oxides and volatile organic compounds emitted from industrial facilities, electric utilities, motor vehicle exhaust, gasoline vapors, and chemical solvents (26). In histological examinations of placentas from women with PPROM, Arias et al. (27) found many with evidence of acute inflammatory and vascular lesions. Animal studies and epidemiologic observations have demonstrated health risks associated with acute ozone response primarily focusing on pulmonary function and lung cell processes including disruption of cellular membranes and heightened inflammatory responses (28). In rats, acute exposure to ozone has been shown to induce injury and oxidative stress in bronchiolar epithelium and programmed cell death (29, 30), processes common to the etiology of PROM (31, 32). Our results also indicate negative associations of PROM risk with elevated exposure to nitrogen oxides on the day of delivery, as well as with hourly estimates of nitrogen oxides, carbon monoxide, and PM10 before delivery. This is not likely to reflect the biologically implausible notion that exposure to air pollution confers protection against PROM. Rather, these findings may be due to unmeasured confounding by socioeconomic status, behavioral factors, or contextual factors that were unavailable for this analysis. Although our data include a large number of PROM cases from a geographically diverse cohort, details on further potential social and environmental confounders were lacking, as is typical of medical record data. Such factors may likewise explain the positive associations that we identified; however, whether PROM is more likely to be influenced by a chronic or acute exposure is not known, and our data suggest that both time windows merit further investigation. There are additional limitations to consider in the interpretation of these results. In the absence of rupture event time, we used the time of admission for delivery as a proxy (33). The American College of Obstetricians and Gynecologists’ Practice Bulletin recommends induction of labor at the time of presentation with PROM at term to reduce the risk of chorioamnionitis (1). Because induction is preferred over expectant management, it is a reasonable assumption that women would go to the hospital without a long delay after the PROM occurred. Although delivery after PPROM might be delayed in some cases, women will routinely be admitted to the hospital after PPROM occurrence. For both PROM and PPROM, Am J Epidemiol. 2016;183(12):1114–1121
occurrence is likely to result in admission within a relatively short time frame. Second, there is the potential for exposure misclassification because of the assumption that women resided within the referral region of their delivery hospital for the duration of their pregnancy and the broad range in region size (415 to 312,644 square kilometers). However, by averaging pollution exposures across referral region rather than by residential address, we were able to use modeled exposure estimates to account for some local mobility within regions. We also adjusted our models for site, which removes some of the variability associated with the characteristics of the hospital and regions. We acknowledge that exposure measurement error is likely to be greater in smaller time windows (hours) and smaller in larger time windows because errors in hourly estimates are averaged up into days and days are averaged up into the whole-pregnancy window. Although ambient air pollution studies lack a gold-standard measurement of individual exposure through which to test assumptions, if we assume the measurement error is additive with a mean of 0, our estimated associations are attenuated towards the null. It is interesting that both ozone and PM2.5 were associated with increased odds of PROM in our hourly data because both pollutants tend to be regional with less spatial variation in urban areas, in contrast to traffic-related pollutants (34). Third, we used multiple imputation to overcome the large proportion of deliveries with missing data on prepregnancy body mass index to retain this covariate as an important risk factor for PROM. Complete case analysis results were similar. Finally, the hourly analysis was conducted on a subset of the study population for whom data were available. The 51,593 deliveries missing hourly data differed from those with hourly data available in that they included a greater proportion of black women (25% vs. 22%), more smokers (9% vs. 6%), fewer alcohol consumers (1% vs. 2%), a smaller proportion of deliveries covered by private insurance (46% vs. 59%), and more cases of PROM (8% vs. 7%); however, there were no difference in rates of PPROM. Exposure levels were similar (median ozone exposure on the day of admission was 1.5 (standard deviation, 0.6) parts per billion for those with missing data vs. 1.7 (standard deviation, 0.7) parts per billion for those without missing data). We found that an interquartile-range–unit increase in wholepregnancy average exposure to carbon monoxide and sulfur dioxide was associated with rupture of membranes before the onset of labor, irrespective of gestational age. In the final days and hours before admission, ozone and PM2.5 exposure contributed to PROM risk. Among the subgroup with earlier, preterm cases of rupture (PPROM), we did not find evidence to support associations with whole-pregnancy exposure to ambient air pollutants. In our multipollutant models, unexplained inverse associations between nitrogen oxides and carbon monoxide in the days and hours preceding admission suggest the complexity of the relationship between pollutants, and their collective and isolated influences on the risk of membrane rupture require further study. Understanding the mechanisms through which PROM risk is exacerbated by excess exposure to pollutants is of great public health significance, particularly in light of the relatively ubiquitous nature of ambient air pollution and the serious maternal and neonatal health consequences of premature membrane rupture.
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ACKNOWLEDGMENTS
Author affiliations: Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Maryland (Maeve E. Wallace, Katherine L. Grantz, Yeyi Zhu, Sung Soo Kim, Pauline Mendola) and Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Maryland (Danping Liu). All authors contributed equally to the work. This research was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, including funding for the Consortium on Safe Labor (contract HHSN267200603425C) and the Air Quality and Reproductive Health Study (contract HHSN275200800002I, task order HHSN27500008). The following institutions were involved in the Consortium on Safe Labor (in alphabetical order): Baystate Medical Center, Springfield, Massachusetts; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, California; Christiana Care Health System, Newark, Delaware; The Emmes Corporation, Rockville Maryland (Data Coordinating Center); Georgetown University Hospital, MedStar Health, Washington, DC; Indiana University Clarian Health, Indianapolis, Indiana; Intermountain Healthcare and the University of Utah, Salt Lake City, Utah; Maimonides Medical Center, Brooklyn, New York; MetroHealth Medical Center, Cleveland, Ohio; Summa Health System, Akron City Hospital, Akron, Ohio; University of Illinois at Chicago, Chicago, Illinois; University of Miami, Miami, Florida; and University of Texas Health Science Center at Houston, Houston, Texas. Conflict of interest: none declared.
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27. Arias F, Victoria A, Cho K, et al. Placental histology and clinical characteristics of patients with preterm premature rupture of membranes. Obstet Gynecol. 1997;89(2): 265–271. 28. Kriebel D, Smith TJ. A nonlinear pharmacologic model of the acute effects of ozone on the human lungs. Environ Res. 1990; 51(2):120–146. 29. Kirichenko A, Li L, Morandi MT, et al. 4-hydroxy-2-nonenalprotein adducts and apoptosis in murine lung cells after acute ozone exposure. Toxicol Appl Pharmacol. 1996;141(2): 416–424. 30. Kadono T, Tran D, Errakhi R, et al. Increased anion channel activity is an unavoidable event in ozone-induced programmed cell death. PLoS One. 2010;5(10):e13373.
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Vol. 183, No. 12 DOI: 10.1093/aje/kwv284 Advance Access publication: May 17, 2016
Original Contribution Exposure to Ambient Air Pollution and Premature Rupture of Membranes
Maeve E. Wallace, Katherine L. Grantz, Danping Liu, Yeyi Zhu, Sung Soo Kim, and Pauline Mendola* * Correspondence to Dr. Pauline Mendola, Epidemiology Branch, Division of Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6100 Executive Boulevard, Rockville, MD 20852 (e-mail: [email protected]).
Initially submitted May 22, 2015; accepted for publication October 13, 2015.
Premature rupture of membranes (PROM) is a major factor that predisposes women to preterm delivery. Results from previous studies have suggested that there are associations between exposure to air pollution and preterm birth, but evidence of a relationship with PROM is sparse. Modified Community Multiscale Air Quality models were used to estimate mean exposures to particulate matter less than 10 µm or less than 2.5 µm in aerodynamic diameter, nitrogen oxides, carbon monoxide, sulfur dioxide, and ozone among 223,375 singleton deliveries in the Air Quality and Reproductive Health Study (2002–2008). We used log-linear models with generalized estimating equations to estimate adjusted relative risks and 95% confidence intervals for PROM per each interquartilerange increase in pollutants across the whole pregnancy, on the day of delivery, and 5 hours before delivery. Whole-pregnancy exposures to carbon monoxide and sulfur dioxide were associated with an increased risk of PROM (for carbon monoxide, relative risk (RR) = 1.09, 95% confidence interval (CI): 1.04, 1.14; for sulfur dioxide, RR = 1.15, 95% CI: 1.06, 1.25) but not preterm PROM. Ozone exposure increased the risk of PROM on the day of delivery (RR = 1.06, 95% CI: 1.02, 1.09) and 1 day prior (RR = 1.04, 95% CI: 1.01, 1.07). In the 5 hours preceding delivery, there were 3%–7% increases in risk associated with exposure to ozone and particulate matter less than 2.5 µm in aerodynamic diameter and inverse associations with exposure to carbon monoxide and nitrogen oxides. Acute and long-term air pollutant exposures merit further study in relation to PROM. ambient air pollution; premature rupture of membranes; preterm birth
Abbreviations: CI, confidence interval; CSL, Consortium on Safe Labor; PPROM, preterm premature rupture of membranes; PM2.5, particulate matter less than 2.5 µm in aerodynamic diameter; PM10, particulate matter less than 10 µm in aerodynamic diameter; PROM, premature rupture of membranes; RR, relative risk.
for both women and infants, including infection, sepsis, and umbilical cord compression, as well as a higher risk of placental abruption and the short- and long-term adverse consequences of neonatal prematurity (2–5). The harmful consequences of exposure to air pollution may include a higher risk of preterm birth, particularly with exposures that are proximal to delivery (6–9). In a recent meta-analysis, Stieb et al. (10) identified a 4%–6% increase in preterm delivery risk associated with third-trimester exposure to the criteria air pollutants particulate matter less than 10 µm in aerodynamic diameter (PM10) and carbon monoxide, and others have reported acute associations in the days and weeks preceding delivery for PM10, particulate matter
Premature rupture of membranes (PROM) is rupture of membranes that occurs before the onset of labor. PROM at 37 weeks of gestation or later is thought to result from a normal physiological process of membrane weakening near the end of pregnancy and occurs in approximately 8% of term pregnancies. PROM has been shown to increase the risk of maternal chorioamnionitis, infectious endometritis, and neonatal sepsis (1). Rupture that occurs before 37 weeks gestation, referred to as preterm premature rupture of membranes (PPROM), may indicate a number of underlying pathological mechanisms associated with infection and inflammation that lead to preterm rupture (2). PPROM is responsible for 1 of every 3 preterm births and is associated with significant morbidity 1114
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less than 2.5 µm in aerodynamic diameter (PM2.5), and sulfur dioxide (11–13). Despite these suggested associations, the mechanisms through which exposure to air pollution leads to preterm birth remain unclear. Previous work has indicated that the pathophysiology of pollutant absorption may include oxidative stress, inflammation, endothelial dysfunction, cell apoptosis, and hemodynamic responses, which lead to preterm birth (14). Likewise, these factors may predispose women to PROM, which in turn may lead to preterm delivery if PROM occurs before 37 weeks of gestation. It has been suggested in 2 recent studies that residential proximity to major roadways (15) and chronic (whole-pregnancy) exposure to PM2.5 and nitrogen oxides (16) increase the risk of PPROM. In a third Australian-based study, Pereira et al. (17) reported a 3% increase in PROM risk (at any gestational age) associated with elevated exposure to PM2.5 in the second trimester but not with exposure in the first or third trimester or with whole-pregnancy exposure. Some evidence has suggested that acute exposure to air pollution may also be related to elevated levels of systemic inflammation and oxidative stress (18, 19), but acute exposure windows have not been examined in relation to rupture of membranes. It may be that exposure to high levels of air pollution in the days leading up to rupture is the final insult to already weakening (whether by normal or pathological processes) membranes that results in premature rupture. In the present study, our purpose was to estimate the risk of PROM associated with chronic and acute exposure to the US Environmental Protection Agency’s 6 criteria air pollutants (PM10, PM2.5, nitrogen oxides, carbon monoxide, sulfur dioxide, and ozone) across the whole pregnancy and in the days and hours preceding rupture in a large contemporary US obstetrical cohort. METHODS Study population
The Consortium on Safe Labor (CSL) is a retrospective cohort study of 228,438 deliveries assembled from electronic medical records at 12 centers located in 16 counties and representing 15 hospital referral regions across 9 American College of Obstetricians and Gynecologists US districts (20). Data on maternal demographic characteristics; medical, reproductive, and prenatal history; labor and delivery; and postpartum and newborn information were extracted from electronic medical records for births at 23 weeks of gestation or later. Electronic discharge summaries for mothers and infants were linked to the medical records. Data were limited to 223,375 singleton pregnancies among 204,165 women for the purposes of the present analysis because multifetal gestations are known to be at higher risk of both PROM and preterm birth (21). The CSL was approved by institutional review boards at all participating institutions. Exposure and outcome
Estimates of ambient air pollutant exposures for all pregnancies in the CSL were quantified as part of the Air Quality Am J Epidemiol. 2016;183(12):1114–1121
and Reproductive Health Study. Hospital referral region was used as a proxy for residence and local mobility. The size of hospital referral regions ranged from 415 to 312,644 square kilometers. The Community Multiscale Air Quality model (22), a modified version of the 3-dimensional multipollutant regional air quality model developed by the US Environmental Protection Agency, quantified hourly air pollution exposure in each region based on reported air pollution emissions and accounted for weather-related factors, complex mixtures, and chemical reactions between pollutants on the exposure (22). Meteorology inputs and pollutant emissions used in the model simulations were obtained from the Weather Research and Forecasting model and the National Emission Inventories, respectively (23). Maternal exposure to air pollution was estimated based on the hourly predictions of air pollutant concentration weighted by population density within the hospital referral region; the places where women were unlikely to live and work were discounted (23). Modeled data were merged with observed monitor data from the US Environmental Protection Agency’s Air Quality System to correct for measurement error between modeled and observed values of air pollutants (23). For each subject, hourly estimates of air pollution were averaged to obtain daily means for each of the 8 days before hospital admission, as well as whole-pregnancy means. The primary outcome of interest, PROM (defined as rupture of membranes at any time before the onset of labor regardless of gestational age) was extracted from electronic medical records. Cases of PPROM, that is, PROM that occurred before 37 weeks of gestation, were examined as a secondary outcome. Statistical analysis
Descriptive statistics were used to compare women with and without PROM or PPROM. Log-linear models with generalized estimating equations were used to estimate the relative risks (and 95% confidence intervals) of PROM associated with the mean level of each pollutant across the whole pregnancy, on the day of admission for delivery (lag day 0; 24 hours preceding the date and time of admission), and in the 7 days preceding admission (lags day 1–7). Women who delivered without PROM were the comparison group. We repeated this analysis after restricting the sample to women who delivered at term (>37 weeks gestation: n = 197,246; 88.3% of the total study population, 5.3% of whom had PROM) to examine whether later gestational cases were especially vulnerable to risks associated with exposure to air pollution. To assess the risk of PPROM, whole-pregnancy exposure was censored at delivery for cases and up to 37 weeks for women without PPROM to account for the time they were at risk of PPROM. Acute pollutant estimates were not examined in relation to PPROM because women whose last 8 days of pregnancy were later than 37 weeks of gestation were no longer at risk for PPROM, and daily estimates before week 37 were unavailable for women who delivered at term. Pollutant exposures were analyzed in continuous scale, and the relative risks were calculated per interquartile-range (the difference between the 25th and 75th percentile) increase in each pollutant.
1116 Wallace et al.
Table 1. Demographic Characteristics of Women With and Without Premature Rupture of Membranes During Pregnancy, Air Quality and Reproductive Health Study, 2002–2008 All Births (n = 223,375)
Demographic Characteristic No.
%
9,175
4.1
Mean (SD)
No PROM (n = 207,787) Mean (SD)
PROM at Any Gestational Age (n = 15,588)
No.
%
No.
%
8,327
4.0
848
5.4
Mean (SD)
PPROM at 1), prepregnancy body mass index (continuous), insurance type ( private, public, or other or unknown), smoking during pregnancy (yes or no), alcohol consumption during pregnancy (yes or no), season of conception (spring for March–May; summer for June–August; fall for September–November; winter for December–February), and study site. We additionally included year of birth in order to adjust for potential long-term temporal trends associated with pollutant levels in the United States given the broad time frame of births analyzed (2002–2008). Missing data on prepregnancy body mass index (n = 74,988; 33.6%) due to a lack of height and/or weight measure recorded in the medical record was imputed using multiple imputation to retain all observations for modeling. Finally, 8.6% of the study sample contributed multiple deliveries, and we accounted for the within-subject correlation by using the robust variance estimation in generalized estimating equations. Data on mean pollutant levels for the 5 hours preceding the hour of admission were available in a subset of the study sample (n = 171,782; 77% of the study population). These data were made available for a previous study of ambient air pollution and blood pressure at admission to delivery (24). In order to examine more acute windows of exposure on the day of admission, the above analysis was repeated for lag 0–4 hours preceding the hour of admission within this subgroup.
Table 2. Adjusted Relative Risk for Premature Rupture of Membranes and Preterm Premature Rupture of Membranes per Each Interquartile-Range–Unit Increase in Mean Air Pollutant Exposure Across the Whole Pregnancy, Air Quality and Reproductive Health Study, 2002–2008a PPROMb
PROM
Pollutant RR
95% CI
RR
95% CI
Carbon monoxide
1.09
1.04, 1.14
0.99
0.90, 1.07
Nitrogen oxides
0.92
0.93, 1.01
0.96
0.78, 1.13
Ozone
1.01
0.95, 1.07
1.06
0.95, 1.17
PM10
0.97
0.92, 1.02
0.98
0.89, 1.08
PM2.5
0.93
0.94, 1.02
0.88
0.73, 1.03
Sulfur dioxide
1.15
1.06, 1.25
1.01
0.85, 1.17
Abbreviations: CI, confidence interval; PM2.5, particulate matter less than 2.5 µm in aerodynamic diameter; PM10, particulate matter less than 10 µm in aerodynamic diameter; RR, relative risk. a All pollutants were included in same model, which was adjusted for maternal age, race, parity, prepregnancy body mass index, smoking, alcohol consumption, insurance type, season of conception, birth year, and study site. b Exposure was censored at 37 weeks for the reference group (births without preterm premature rupture of membranes).
at 36 weeks for women without PPROM in co-pollutant models (Table 2). Figure 1 depicts acute daily estimates for all pollutants during the final 8 days of pregnancy. Elevated ozone exposure on the day of admission for delivery and 1 day prior was associated with an increased risk of PROM (for lag day 0,
RESULTS
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1.10 1.05 Relative Risk
Seven percent (n = 15,588) of the 223,375 deliveries in this sample were complicated by PROM. Of these, one-third were PPROM preceding delivery that occurred at a mean gestational age of 33 weeks (range, 23–36). The proportion of black and Asian women, nulliparous women, smokers, and older women was higher among PROM case patients than among women without PROM (Table 1). A greater proportion of PPROM case patients were black women, smokers, and publicly insured women compared with the distributions among noncase patients. The distributions of air pollutants across the whole pregnancy and in the last 8 days and last 5 hours of pregnancy are available in Web Table 1 (available at http://aje.oxfordjournals. org/). Correlations between air pollutants across the whole pregnancy are available in Web Table 2. Ozone was consistently negatively correlated with the remaining 5 pollutants, most strongly for PM2.5, sulfur dioxide, and nitrogen oxides. Exposures to elevated levels of carbon monoxide and sulfur dioxide across the whole pregnancy were associated with a higher risk of PROM (for carbon monoxide, relative risk (RR) = 1.09, 95% confidence interval (CI): 1.04, 1.14; for sulfur dioxide, RR = 1.15, 95% CI: 1.06, 1.25; Table 2). Exposure to pollutants across the whole pregnancy was not associated with an increased risk of PPROM when compared with exposure up to the time of delivery or exposure censored
1.00 0.95 0.90
Ozone PM10
Pollutant CO
NOX
PM2.5
SO2
0.85 7
6
5
2 4 3 Time to Delivery, days
1
0
Figure 1. Adjusted relative risks for the associations between exposure to air pollutants and premature rupture of membranes on the day of admission for delivery and 7 days prior, Air Quality and Reproductive Health Study, 2002–2008. Shown are the relative risks for premature rupture of membranes associated with exposure to ozone, carbon monoxide (CO), nitrogen oxides (NOX), particulate matter less than 10 µm in aerodynamic diameter (PM10), particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5), and sulfur dioxide (SO2) that were estimated from models including all pollutants on the same day and adjusted for maternal age, race, parity, prepregnancy body mass index, smoking, alcohol consumption, insurance type, season of conception, birth year, and study site. Bars, 95% confidence intervals.
1118 Wallace et al.
Table 3. Adjusted Relative Risk for Premature Rupture of Membranes per Each Interquartile-Range–Unit Increase in Pollutant Exposure in the 5 Hours Preceding the Hour of Admission for Delivery, Air Quality and Reproductive Health Study, 2002–2008a Hour and Pollutant
on the day of admission and 7 days prior (for lag day 0, RR = 0.95, 95% CI: 0.92, 0.98; for lag day 7, RR = 0.93, 95% CI: 0.90, 0.96). No other pollutants were associated with PROM risk during the last 8 days of pregnancy. Results for the analysis limited to women who experienced PROM at term were consistent with the above results for women who experienced PROM at any gestational age. Estimated associations of increased risk with elevated wholepregnancy carbon monoxide and sulfur dioxide exposures, as well as elevated ozone exposure on the day of admission (lag day 0) were similar in magnitude, as were inverse associations with elevated nitrogen oxides exposure on lag days 0 and 7. Examining data from the day of admission more closely, we found that the trend of a higher risk associated with acute exposure to ozone on this day was consistent among hourly estimates for the 5 hours immediately preceding admission (Table 3). A 5%–7% increase in risk of PROM per interquartile-range increase in ozone exposure over the 5 hours preceding the hour of admission remained after adjustment for covariates and all other pollutants. Evidence of acute exposure to elevated levels of PM2.5 in lag hours 2, 1, and 0 suggested a 3%–4% increase in PROM risk. Inverse associations were observed for hourly estimates of carbon monoxide, nitrogen oxides, and PM10.
RR
95% CI
Ozone
1.05
1.02, 1.08
Carbon monoxide
0.95
0.92, 0.98
Nitrogen oxides
0.96
0.93, 0.99
PM10
0.97
0.93, 1.01
PM2.5
1.04
1.00, 1.07
Sulfur dioxide
0.99
0.98, 1.01
Ozone
1.07
1.04, 1.10
Carbon monoxide
0.94
0.92, 0.97
Nitrogen oxides
0.97
0.94, 1.00
PM10
0.97
0.93, 1.01
PM2.5
1.04
1.00, 1.07
Sulfur dioxide
0.99
0.98, 1.01
Ozone
1.07
1.04, 1.10
Carbon monoxide
0.96
0.93, 0.99
Nitrogen oxides
0.98
0.95, 1.01
DISCUSSION
PM10
0.96
0.93, 1.00
PM2.5
1.03
1.00, 1.07
Sulfur dioxide
1.00
0.98, 1.01
Ozone
1.07
1.04, 1.10
Carbon monoxide
0.99
0.96, 1.02
Nitrogen oxides
0.98
0.95, 1.01
PM10
0.96
0.93, 1.00
PM2.5
1.03
1.00, 1.07
Sulfur dioxide
1.00
0.99, 1.02
Ozone
1.06
1.03, 1.08
We examined the associations of both chronic (wholepregnancy) and acute (days and hours before admission) exposures to 6 criteria air pollutants with the incidence of PROM in a large, geographically diverse cohort of pregnant women. Although long-term exposures to carbon monoxide and sulfur dioxide during pregnancy were associated with PROM, acute exposures of ozone and PM2.5 were associated with PROM in the days and hours leading up to delivery. Unlike in previous research, we found no evidence of an association between elevated chronic exposure to pollutants and risk of PPROM. In a recent study in Japan, Yorifuji et al. (15) reported a 60% increase in risk of PPROM among women who lived within 200 meters of a major roadway—an index for air pollution exposure. In a previous investigation of criteria air pollutants, nitrogen oxides, PM2.5, PM10, and PPROM in Barcelona, Dadvand et al. (16) reported a positive association between PPROM and whole-pregnancy exposure to PM2.5 in a cohort analysis that was similar to our present study. The authors further reported an increase in the odds of PPROM associated with exposure to nitrogen oxides during the entire pregnancy that was determined using a matched case-control design, but they did not replicate this finding in the cohort analysis (16). Although we identified associations during acute windows of elevated exposure to PM2.5 in the last 3 hours before delivery, there was no evidence of an association of either whole-pregnancy exposure to PM2.5 or nitrogen oxides with PROM or PPROM in our data. It is important to note the considerable difference in air pollution distributions between the 2 studies: Median reported levels of PM2.5 were 19.8 (interquartile range, 4.1) μg/m3 in Barcelona compared with 11.9 (interquartile range, 4.7) μg/m3 in the present study. Median levels of nitrogen oxides were 102.6 (interquartile range, 39.5) μg/m3 in the Barcelona study
0
1
2
3
4 Carbon monoxide
1.02
1.00, 1.05
Nitrogen oxides
0.98
0.95, 1.00
PM10
0.96
0.92, 1.00
PM2.5
1.03
1.00, 1.06
Sulfur dioxide
1.01
0.99, 1.02
Abbreviations: CI, confidence interval; PM2.5, particulate matter less than 2.5 µm in aerodynamic diameter; PM10, particulate matter less than 10 µm in aerodynamic diameter; RR, relative risk. a Hourly estimates of all pollutants were included in same model, which was adjusted for maternal age, race, parity, prepregnancy body mass index, smoking, alcohol consumption, insurance type, season of conception, birth year, and study site.
RR = 1.06, 95% CI: 1.02, 1.09; for lag day 1, RR = 1.04, 95% CI: 1.01, 1.07). Ozone was not associated with PROM on any of the more distally preceding days. A significant inverse association with elevated nitrogen oxides exposure was evident
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compared with 28.9 (interquartile range, 24.2) μg/m3 in the present study. It may be that nitrogen oxides and PM2.5 are related to PPROM risk only at high levels for longerterm exposures. An analysis of PM2.5 levels in 22 countries by the World Health Organization found an association with preterm birth only in China—the country with the highest levels of PM2.5—which suggests a threshold level for association that may also be true for PPROM (25). To our knowledge, this is the first analysis in which the acute, potentially triggering influence of ambient air pollutants on PROM has been examined. Our most compelling and consistent finding was that of an association between acute ozone exposure and PROM on the day before and the day of admission for delivery, as well as in the final 5 hours before admission. However, chronic exposure to ozone, as measured using average exposure during pregnancy, was not associated with PROM or PPROM. Ground-level ozone is the result of photochemical interactions between nitrogen oxides and volatile organic compounds emitted from industrial facilities, electric utilities, motor vehicle exhaust, gasoline vapors, and chemical solvents (26). In histological examinations of placentas from women with PPROM, Arias et al. (27) found many with evidence of acute inflammatory and vascular lesions. Animal studies and epidemiologic observations have demonstrated health risks associated with acute ozone response primarily focusing on pulmonary function and lung cell processes including disruption of cellular membranes and heightened inflammatory responses (28). In rats, acute exposure to ozone has been shown to induce injury and oxidative stress in bronchiolar epithelium and programmed cell death (29, 30), processes common to the etiology of PROM (31, 32). Our results also indicate negative associations of PROM risk with elevated exposure to nitrogen oxides on the day of delivery, as well as with hourly estimates of nitrogen oxides, carbon monoxide, and PM10 before delivery. This is not likely to reflect the biologically implausible notion that exposure to air pollution confers protection against PROM. Rather, these findings may be due to unmeasured confounding by socioeconomic status, behavioral factors, or contextual factors that were unavailable for this analysis. Although our data include a large number of PROM cases from a geographically diverse cohort, details on further potential social and environmental confounders were lacking, as is typical of medical record data. Such factors may likewise explain the positive associations that we identified; however, whether PROM is more likely to be influenced by a chronic or acute exposure is not known, and our data suggest that both time windows merit further investigation. There are additional limitations to consider in the interpretation of these results. In the absence of rupture event time, we used the time of admission for delivery as a proxy (33). The American College of Obstetricians and Gynecologists’ Practice Bulletin recommends induction of labor at the time of presentation with PROM at term to reduce the risk of chorioamnionitis (1). Because induction is preferred over expectant management, it is a reasonable assumption that women would go to the hospital without a long delay after the PROM occurred. Although delivery after PPROM might be delayed in some cases, women will routinely be admitted to the hospital after PPROM occurrence. For both PROM and PPROM, Am J Epidemiol. 2016;183(12):1114–1121
occurrence is likely to result in admission within a relatively short time frame. Second, there is the potential for exposure misclassification because of the assumption that women resided within the referral region of their delivery hospital for the duration of their pregnancy and the broad range in region size (415 to 312,644 square kilometers). However, by averaging pollution exposures across referral region rather than by residential address, we were able to use modeled exposure estimates to account for some local mobility within regions. We also adjusted our models for site, which removes some of the variability associated with the characteristics of the hospital and regions. We acknowledge that exposure measurement error is likely to be greater in smaller time windows (hours) and smaller in larger time windows because errors in hourly estimates are averaged up into days and days are averaged up into the whole-pregnancy window. Although ambient air pollution studies lack a gold-standard measurement of individual exposure through which to test assumptions, if we assume the measurement error is additive with a mean of 0, our estimated associations are attenuated towards the null. It is interesting that both ozone and PM2.5 were associated with increased odds of PROM in our hourly data because both pollutants tend to be regional with less spatial variation in urban areas, in contrast to traffic-related pollutants (34). Third, we used multiple imputation to overcome the large proportion of deliveries with missing data on prepregnancy body mass index to retain this covariate as an important risk factor for PROM. Complete case analysis results were similar. Finally, the hourly analysis was conducted on a subset of the study population for whom data were available. The 51,593 deliveries missing hourly data differed from those with hourly data available in that they included a greater proportion of black women (25% vs. 22%), more smokers (9% vs. 6%), fewer alcohol consumers (1% vs. 2%), a smaller proportion of deliveries covered by private insurance (46% vs. 59%), and more cases of PROM (8% vs. 7%); however, there were no difference in rates of PPROM. Exposure levels were similar (median ozone exposure on the day of admission was 1.5 (standard deviation, 0.6) parts per billion for those with missing data vs. 1.7 (standard deviation, 0.7) parts per billion for those without missing data). We found that an interquartile-range–unit increase in wholepregnancy average exposure to carbon monoxide and sulfur dioxide was associated with rupture of membranes before the onset of labor, irrespective of gestational age. In the final days and hours before admission, ozone and PM2.5 exposure contributed to PROM risk. Among the subgroup with earlier, preterm cases of rupture (PPROM), we did not find evidence to support associations with whole-pregnancy exposure to ambient air pollutants. In our multipollutant models, unexplained inverse associations between nitrogen oxides and carbon monoxide in the days and hours preceding admission suggest the complexity of the relationship between pollutants, and their collective and isolated influences on the risk of membrane rupture require further study. Understanding the mechanisms through which PROM risk is exacerbated by excess exposure to pollutants is of great public health significance, particularly in light of the relatively ubiquitous nature of ambient air pollution and the serious maternal and neonatal health consequences of premature membrane rupture.
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ACKNOWLEDGMENTS
Author affiliations: Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Maryland (Maeve E. Wallace, Katherine L. Grantz, Yeyi Zhu, Sung Soo Kim, Pauline Mendola) and Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Maryland (Danping Liu). All authors contributed equally to the work. This research was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, including funding for the Consortium on Safe Labor (contract HHSN267200603425C) and the Air Quality and Reproductive Health Study (contract HHSN275200800002I, task order HHSN27500008). The following institutions were involved in the Consortium on Safe Labor (in alphabetical order): Baystate Medical Center, Springfield, Massachusetts; Cedars-Sinai Medical Center Burnes Allen Research Center, Los Angeles, California; Christiana Care Health System, Newark, Delaware; The Emmes Corporation, Rockville Maryland (Data Coordinating Center); Georgetown University Hospital, MedStar Health, Washington, DC; Indiana University Clarian Health, Indianapolis, Indiana; Intermountain Healthcare and the University of Utah, Salt Lake City, Utah; Maimonides Medical Center, Brooklyn, New York; MetroHealth Medical Center, Cleveland, Ohio; Summa Health System, Akron City Hospital, Akron, Ohio; University of Illinois at Chicago, Chicago, Illinois; University of Miami, Miami, Florida; and University of Texas Health Science Center at Houston, Houston, Texas. Conflict of interest: none declared.
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