American Journal of Epidemiology Vol. 183, No.

12
Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2016. This work is DOI: 10.1093/aje/kwv284
written by (a) US Government employee(s) and is in the public domain in the US. 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: Pauline.mendola@nih.gov).

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 m or less than 2.5 m in aerodynamic
diameter, nitrogen oxides, carbon monoxide, sulfur dioxide, and ozone among 223,375 singleton deliveries in the
Air Quality and Reproductive Health Study (20022008). We used log-linear models with generalized estimating
equations to estimate adjusted relative risks and 95% confidence intervals for PROM per each interquartile-
range 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 m 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 m in aerodynamic diameter; PM10, particulate matter less than 10 m in aerodynamic diameter;
PROM, premature rupture of membranes; RR, relative risk.

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 nor-
mal 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 neo-
natal sepsis (1). Rupture that occurs before 37 weeks gesta-
tion, referred to as preterm premature rupture of membranes
(PPROM), may indicate a number of underlying pathological
mechanisms associated with infection and inammation that
lead to preterm rupture (2). PPROM is responsible for 1 of every
3 preterm births and is associated with signicant morbidity
for both women and infants, including infection, sepsis, and
umbilical cord compression, as well as a higher risk of placen-
tal abruption and the short- and long-term adverse conse-
quences of neonatal prematurity (25).
The harmful consequences of exposure to air pollution
may include a higher risk of preterm birth, particularly with
exposures that are proximal to delivery (69). In a recent
meta-analysis, Stieb et al. (10) identied a 4%6% increase
in preterm delivery risk associated with third-trimester expo-
sure to the criteria air pollutants particulate matter less than
10 m in aerodynamic diameter (PM10) and carbon mon-
oxide, and others have reported acute associations in the days
and weeks preceding delivery for PM10, particulate matter

1114 Am J Epidemiol. 2016;183(12):11141121


less than 2.5 m in aerodynamic diameter (PM2.5), and sulfur
dioxide (1113).
Despite these suggested associations, the mechanisms
through which exposure to air pollution leads to preterm birth
remain unclear. Previous work has indicated that the patho-
physiology of pollutant absorption may include oxidative
stress, inammation, 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 prox-
imity 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 rst 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
inammation and oxidative stress (18, 19), but acute expo-
sure 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 nal 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 Agencys 6 criteria air pollu-
tants (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 rep-
resenting 15 hospital referral regions across 9 American Col-
lege of Obstetricians and Gynecologists US districts (20).
Data on maternal demographic characteristics; medical, repro-
ductive, and prenatal history; labor and delivery; and postpar-
tum 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 partic-
ipating institutions.
Exposure and outcome
Estimates of ambient air pollutant exposures for all preg-
nancies in the CSL were quantied as part of the Air Quality
Am J Epidemiol. 2016;183(12):11141121
Air Pollution and Premature Rupture of Membranes 1115
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 modied version of the 3-dimensional multipollutant
regional air quality model developed by the US Environmental
Protection Agency, quantied 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 pol-
lution 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). Mod-
eled data were merged with observed monitor data from the
US Environmental Protection Agencys Air Quality System
to correct for measurement error between modeled and ob-
served 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 (dened as rupture
of membranes at any time before the onset of labor regardless
of gestational age) was extracted from electronic medical rec-
ords. 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 general-
ized estimating equations were used to estimate the relative
risks (and 95% condence intervals) of PROM associated
with the mean level of each pollutant across the whole preg-
nancy, 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 17). Women who de-
livered without PROM were the comparison group. We re-
peated 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 es-
pecially 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 exam-
ined 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. Pol-
lutant 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, 20022008

All Births No PROM PROM at Any Gestational Age PPROM at <37 Weeks
Demographic (n = 223,375) (n = 207,787) (n = 15,588) (n = 5,111)
Characteristic
No. % Mean (SD) No. % Mean (SD) No. % Mean (SD) No. % Mean (SD)

Race
Asian 9,175 4.1 8,327 4.0 848 5.4 171 3.3
Black 50,255 22.5 46,448 22.4 3,807 24.4 1,614 31.6
Hispanic 38,811 17.4 36,331 17.5 2,480 15.9 832 16.3
White 110,541 49.5 103,144 49.6 7,397 47.5 2,158 42.2
Multiracial, other, or 14,592 6.5 13,536 6.5 1,056 6.8 336 6.6
unknown
Nulliparous 89,116 39.9 81,101 39.0 8,015 51.4 2,268 44.4
Smoked during pregnancy 14,930 6.7 13,705 6.6 1,225 7.9 592 11.6
Consumed alcohol during 4,090 1.8 3,848 1.9 242 1.6 123 2.4
pregnancy
Insurance type
Private 124,903 55.9 115,984 55.8 8,919 57.2 2,603 50.9
Public 72,147 32.3 67,641 32.6 4,506 28.9 1,952 38.2
Other, self-pay, or 26,325 11.8 24,162 11.6 2,163 13.9 556 10.9
unknown
Prepregnancy body mass 25.6 (6.2) 25.6 (6.2) 25.5 (6.2) 25.9 (6.4)
indexa
Age, years 27.6 (6.2) 27.5 (6.2) 28.1 (6.5) 27.9 (6.7)
Study site
Massachusetts 19,679 8.8 17,241 8.3 2,438 15.6 645 12.6
California 17,852 8.0 15,615 7.5 2,237 14.4 360 7.0
Delaware 14,350 6.4 13,419 6.5 931 6.0 317 6.2
Indiana 7,741 3.5 7,459 3.6 282 1.8 116 2.3
Utah 49,376 22.1 48,157 23.2 1,219 7.8 640 12.5
New York 20,594 9.2 18,406 8.9 2,188 14.0 355 6.9
Maryland/Washington DC 27,223 12.2 25,126 12.1 2,097 13.5 842 16.5
Ohio 13,881 6.2 12,780 6.2 1,101 7.1 456 8.9
Illinois 12,318 5.5 11,719 5.6 599 3.8 284 5.6
Florida 17,859 8.0 16,991 8.2 868 5.6 401 7.8
Texas 22,502 10.0 20,874 10.0 1,628 10.4 715 14.0
Season of conception
Spring 52,738 23.6 48,966 23.6 3,772 24.2 1,143 22.4
Summer 57,637 25.8 53,604 25.8 4,033 25.9 1,274 24.9
Fall 61,427 27.5 57,269 27.6 4,158 26.7 1,367 26.7
Winter 51,573 23.1 47,948 23.1 3,625 23.3 1,327 26.0
Birth year
2002 7,132 3.2 6,452 3.1 680 4.4 217 4.2
2003 9,373 4.2 8,556 4.1 817 5.2 270 5.3
2004 15,251 6.8 13,768 6.6 1,483 9.5 395 7.7
2005 62,293 27.9 58,048 27.9 4,245 27.2 1,412 27.6
2006 71,536 32.0 67,065 32.3 4,471 28.7 1,510 29.5
2007 57,501 25.7 53,641 25.8 3,860 24.8 1,300 25.4
2008 289 0.1 257 0.1 32 0.2 7 0.1

Abbreviations: PPROM, preterm premature rupture of membranes; PROM, premature rupture of membranes; SD, standard deviation.
b
Multiple imputation was used to impute prepregnancy body mass index (weight (kg)/height (m)2) for 74,988 (33.6%) deliveries.

Am J Epidemiol. 2016;183(12):11141121
 Air Pollution and Premature Rupture of Membranes 1117

For each time window of interest, we t a co-pollutant Table 2. Adjusted Relative Risk for Premature Rupture of
model; that is, all 6 criteria pollutants were included in the Membranes and Preterm Premature Rupture of Membranes per Each
log-linear model. The co-pollutant model was used to esti- Interquartile-RangeUnit Increase in Mean Air Pollutant Exposure
Across the Whole Pregnancy, Air Quality and Reproductive Health
mate the direct association of PROM or PPROM in relation
Study, 20022008a
to each air pollutant after accounting for correlations with
other pollutants. Models were also adjusted for maternal PROM PPROMb
Pollutant
age (continuous), race (Asian, black, Hispanic, white, or mul- RR 95% CI RR 95% CI
tiracial, other, or unknown), parity (0 or >1), prepregnancy
Carbon monoxide 1.09 1.04, 1.14 0.99 0.90, 1.07
body mass index (continuous), insurance type ( private, pub-
lic, or other or unknown), smoking during pregnancy (yes Nitrogen oxides 0.92 0.93, 1.01 0.96 0.78, 1.13
or no), alcohol consumption during pregnancy (yes or no), Ozone 1.01 0.95, 1.07 1.06 0.95, 1.17
season of conception (spring for MarchMay; summer for PM10 0.97 0.92, 1.02 0.98 0.89, 1.08
JuneAugust; fall for SeptemberNovember; winter for PM2.5 0.93 0.94, 1.02 0.88 0.73, 1.03
DecemberFebruary), and study site. We additionally included Sulfur dioxide 1.15 1.06, 1.25 1.01 0.85, 1.17
year of birth in order to adjust for potential long-term tempo-
ral trends associated with pollutant levels in the United States Abbreviations: CI, confidence interval; PM2.5, particulate matter
given the broad time frame of births analyzed (20022008). less than 2.5 m in aerodynamic diameter; PM10, particulate matter
Missing data on prepregnancy body mass index (n = 74,988; less than 10 m in aerodynamic diameter; RR, relative risk.
a
33.6%) due to a lack of height and/or weight measure rec- All pollutants were included in same model, which was adjusted
orded in the medical record was imputed using multiple im- for maternal age, race, parity, prepregnancy body mass index, smoking,
alcohol consumption, insurance type, season of conception, birth year,
putation to retain all observations for modeling. Finally, 8.6% and study site.
of the study sample contributed multiple deliveries, and we b
Exposure was censored at 37 weeks for the reference group
accounted for the within-subject correlation by using the ro- (births without preterm premature rupture of membranes).
bust 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 sam-
ple (n = 171,782; 77% of the study population). These data at 36 weeks for women without PPROM in co-pollutant mod-
were made available for a previous study of ambient air pol- els (Table 2).
lution and blood pressure at admission to delivery (24). In Figure 1 depicts acute daily estimates for all pollutants dur-
order to examine more acute windows of exposure on the day ing the nal 8 days of pregnancy. Elevated ozone exposure
of admission, the above analysis was repeated for lag 04 on the day of admission for delivery and 1 day prior was
hours preceding the hour of admission within this subgroup. associated with an increased risk of PROM (for lag day 0,

RESULTS

Seven percent (n = 15,588) of the 223,375 deliveries in 1.10

this sample were complicated by PROM. Of these, one-third
were PPROM preceding delivery that occurred at a mean ges- 1.05
tational age of 33 weeks (range, 2336). The proportion of
Relative Risk

black and Asian women, nulliparous women, smokers, and 1.00

older women was higher among PROM case patients than
among women without PROM (Table 1). A greater propor-
0.95
tion of PPROM case patients were black women, smokers,
and publicly insured women compared with the distributions Pollutant
among noncase patients. 0.90 Ozone CO NOX
The distributions of air pollutants across the whole preg- PM10 PM2.5 SO2
nancy and in the last 8 days and last 5 hours of pregnancy are 0.85
available in Web Table 1 (available at http://aje.oxfordjournals. 7 6 5 4 3 2 1 0
org/). Correlations between air pollutants across the whole Time to Delivery, days
pregnancy are available in Web Table 2. Ozone was consis-
tently negatively correlated with the remaining 5 pollutants, Figure 1. Adjusted relative risks for the associations between expo-
most strongly for PM2.5, sulfur dioxide, and nitrogen oxides. sure to air pollutants and premature rupture of membranes on the day
of admission for delivery and 7 days prior, Air Quality and Reproduc-
Exposures to elevated levels of carbon monoxide and sulfur tive Health Study, 20022008. Shown are the relative risks for prema-
dioxide across the whole pregnancy were associated with a ture rupture of membranes associated with exposure to ozone, carbon
higher risk of PROM (for carbon monoxide, relative risk monoxide (CO), nitrogen oxides (NOX), particulate matter less than
(RR) = 1.09, 95% condence interval (CI): 1.04, 1.14; for 10 m in aerodynamic diameter (PM10), particulate matter less than
sulfur dioxide, RR = 1.15, 95% CI: 1.06, 1.25; Table 2). Ex- 2.5 m in aerodynamic diameter (PM2.5), and sulfur dioxide (SO2)
that were estimated from models including all pollutants on the same
posure to pollutants across the whole pregnancy was not as- day and adjusted for maternal age, race, parity, prepregnancy body
sociated with an increased risk of PPROM when compared mass index, smoking, alcohol consumption, insurance type, season of
with exposure up to the time of delivery or exposure censored conception, birth year, and study site. Bars, 95% confidence intervals.

Am J Epidemiol. 2016;183(12):11141121
1118 Wallace et al.

Table 3. Adjusted Relative Risk for Premature Rupture of on the day of admission and 7 days prior (for lag day 0, RR =
Membranes per Each Interquartile-RangeUnit Increase in Pollutant 0.95, 95% CI: 0.92, 0.98; for lag day 7, RR = 0.93, 95% CI:
Exposure in the 5 Hours Preceding the Hour of Admission for Delivery, 0.90, 0.96). No other pollutants were associated with PROM
Air Quality and Reproductive Health Study, 20022008a
risk during the last 8 days of pregnancy.
Hour and Pollutant RR 95% CI Results for the analysis limited to women who experienced
0
PROM at term were consistent with the above results for
women who experienced PROM at any gestational age. Esti-
Ozone 1.05 1.02, 1.08 mated associations of increased risk with elevated whole-
Carbon monoxide 0.95 0.92, 0.98 pregnancy carbon monoxide and sulfur dioxide exposures, as
Nitrogen oxides 0.96 0.93, 0.99 well as elevated ozone exposure on the day of admission (lag
PM10 0.97 0.93, 1.01 day 0) were similar in magnitude, as were inverse associations
PM2.5 1.04 1.00, 1.07
with elevated nitrogen oxides exposure on lag days 0 and 7.
Examining data from the day of admission more closely, we
Sulfur dioxide 0.99 0.98, 1.01
found that the trend of a higher risk associated with acute expo-
1 sure to ozone on this day was consistent among hourly estimates
Ozone 1.07 1.04, 1.10 for the 5 hours immediately preceding admission (Table 3).
Carbon monoxide 0.94 0.92, 0.97 A 5%7% increase in risk of PROM per interquartile-range
Nitrogen oxides 0.97 0.94, 1.00 increase in ozone exposure over the 5 hours preceding the
hour of admission remained after adjustment for covariates
PM10 0.97 0.93, 1.01
and all other pollutants. Evidence of acute exposure to ele-
PM2.5 1.04 1.00, 1.07
vated levels of PM2.5 in lag hours 2, 1, and 0 suggested a
Sulfur dioxide 0.99 0.98, 1.01 3%4% increase in PROM risk. Inverse associations were
2 observed for hourly estimates of carbon monoxide, nitrogen
Ozone 1.07 1.04, 1.10 oxides, and PM10.
Carbon monoxide 0.96 0.93, 0.99
Nitrogen oxides 0.98 0.95, 1.01 DISCUSSION
PM10 0.96 0.93, 1.00 We examined the associations of both chronic (whole-
PM2.5 1.03 1.00, 1.07 pregnancy) and acute (days and hours before admission) expo-
Sulfur dioxide 1.00 0.98, 1.01 sures to 6 criteria air pollutants with the incidence of PROM in
3 a large, geographically diverse cohort of pregnant women. Al-
Ozone 1.07 1.04, 1.10
though long-term exposures to carbon monoxide and sulfur
dioxide during pregnancy were associated with PROM, acute
Carbon monoxide 0.99 0.96, 1.02
exposures of ozone and PM2.5 were associated with PROM in
Nitrogen oxides 0.98 0.95, 1.01 the days and hours leading up to delivery.
PM10 0.96 0.93, 1.00 Unlike in previous research, we found no evidence of an
PM2.5 1.03 1.00, 1.07 association between elevated chronic exposure to pollutants
Sulfur dioxide 1.00 0.99, 1.02 and risk of PPROM. In a recent study in Japan, Yorifuji et al.
(15) reported a 60% increase in risk of PPROM among wom-
4
en who lived within 200 meters of a major roadwayan
Ozone 1.06 1.03, 1.08 index for air pollution exposure. In a previous investigation
Carbon monoxide 1.02 1.00, 1.05 of criteria air pollutants, nitrogen oxides, PM2.5, PM10, and
Nitrogen oxides 0.98 0.95, 1.00 PPROM in Barcelona, Dadvand et al. (16) reported a positive
PM10 0.96 0.92, 1.00 association between PPROM and whole-pregnancy exposure
PM2.5 1.03 1.00, 1.06
to PM2.5 in a cohort analysis that was similar to our present
study. The authors further reported an increase in the odds of
Sulfur dioxide 1.01 0.99, 1.02 PPROM associated with exposure to nitrogen oxides during
Abbreviations: CI, confidence interval; PM2.5, particulate matter the entire pregnancy that was determined using a matched
less than 2.5 m in aerodynamic diameter; PM10, particulate matter case-control design, but they did not replicate this nding
less than 10 m in aerodynamic diameter; RR, relative risk. in the cohort analysis (16). Although we identied associa-
a
Hourly estimates of all pollutants were included in same model, tions during acute windows of elevated exposure to PM2.5
which was adjusted for maternal age, race, parity, prepregnancy body in the last 3 hours before delivery, there was no evidence of
mass index, smoking, alcohol consumption, insurance type, season an association of either whole-pregnancy exposure to PM2.5
of conception, birth year, and study site.
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
RR = 1.06, 95% CI: 1.02, 1.09; for lag day 1, RR = 1.04, 95% PM2.5 were 19.8 (interquartile range, 4.1) g/m3 in Barcelona
CI: 1.01, 1.07). Ozone was not associated with PROM on any compared with 11.9 (interquartile range, 4.7) g/m3 in the
of the more distally preceding days. A signicant inverse as- present study. Median levels of nitrogen oxides were 102.6
sociation with elevated nitrogen oxides exposure was evident (interquartile range, 39.5) g/m3 in the Barcelona study

Am J Epidemiol. 2016;183(12):11141121

compared with 28.9 (interquartile range, 24.2) g/m3 in the
present study. It may be that nitrogen oxides and PM2.5
are related to PPROM risk only at high levels for longer-
term exposures. An analysis of PM2.5 levels in 22 countries
by the World Health Organization found an association with
preterm birth only in Chinathe country with the highest
levels of PM2.5which suggests a threshold level for asso-
ciation that may also be true for PPROM (25).
To our knowledge, this is the rst analysis in which the
acute, potentially triggering inuence of ambient air pollutants
on PROM has been examined. Our most compelling and con-
sistent nding was that of an association between acute ozone
exposure and PROM on the day before and the day of admis-
sion for delivery, as well as in the nal 5 hours before admis-
sion. 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 photo-
chemical interactions between nitrogen oxides and volatile or-
ganic 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 evi-
dence of acute inammatory 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 in-
cluding disruption of cellular membranes and heightened in-
ammatory responses (28). In rats, acute exposure to ozone
has been shown to induce injury and oxidative stress in bron-
chiolar epithelium and programmed cell death (29, 30), pro-
cesses 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 ox-
ides, carbon monoxide, and PM10 before delivery. This is not
likely to reect the biologically implausible notion that ex-
posure to air pollution confers protection against PROM.
Rather, these ndings may be due to unmeasured confound-
ing 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 geograph-
ically 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 identied; however, whether
PROM is more likely to be inuenced 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 inter-
pretation 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 Gynecolo-
gists 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 ex-
pectant 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 hos-
pital after PPROM occurrence. For both PROM and PPROM,
Am J Epidemiol. 2016;183(12):11141121
Air Pollution and Premature Rupture of Membranes 1119
occurrence is likely to result in admission within a relatively
short time frame. Second, there is the potential for exposure
misclassication because of the assumption that women re-
sided 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 averag-
ing pollution exposures across referral region rather than by
residential address, we were able to use modeled exposure es-
timates 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 indi-
vidual exposure through which to test assumptions, if we as-
sume 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 pol-
lutants tend to be regional with less spatial variation in urban
areas, in contrast to trafc-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 deliv-
eries 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 al-
cohol consumers (1% vs. 2%), a smaller proportion of deliv-
eries covered by private insurance (46% vs. 59%), and more
cases of PROM (8% vs. 7%); however, there were no dif-
ference 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 bil-
lion for those without missing data).
We found that an interquartile-rangeunit increase in whole-
pregnancy average exposure to carbon monoxide and sulfur di-
oxide was associated with rupture of membranes before the
onset of labor, irrespective of gestational age. In the nal days
and hours before admission, ozone and PM2.5 exposure con-
tributed to PROM risk. Among the subgroup with earlier, pre-
term cases of rupture (PPROM), we did not nd evidence to
support associations with whole-pregnancy exposure to ambi-
ent air pollutants. In our multipollutant models, unexplained
inverse associations between nitrogen oxides and carbon mon-
oxide in the days and hours preceding admission suggest the
complexity of the relationship between pollutants, and their
collective and isolated inuences on the risk of membrane rup-
ture require further study. Understanding the mechanisms
through which PROM risk is exacerbated by excess exposure
to pollutants is of great public health signicance, particularly
in light of the relatively ubiquitous nature of ambient air pol-
lution and the serious maternal and neonatal health conse-
quences of premature membrane rupture.
1120 Wallace et al.
ACKNOWLEDGMENTS
Author afliations: Epidemiology Branch, Division of
Intramural Population Health Research, Eunice Kennedy
Shriver National Institute of Child Health and Human Devel-
opment, Rockville, Maryland (Maeve E. Wallace, Katherine
L. Grantz, Yeyi Zhu, Sung Soo Kim, Pauline Mendola) and
Biostatistics and Bioinformatics Branch, Division of Intra-
mural 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 Consor-
tium on Safe Labor (in alphabetical order): Baystate Medical
Center, Springeld, 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 Cen-
ter); Georgetown University Hospital, MedStar Health,
Washington, DC; Indiana University Clarian Health, India-
napolis, Indiana; Intermountain Healthcare and the Univer-
sity of Utah, Salt Lake City, Utah; Maimonides Medical
Center, Brooklyn, New York; MetroHealth Medical Center,
Cleveland, Ohio; Summa Health System, Akron City Hospi-
tal, 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.
Conict of interest: none declared.
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