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Associations between ambient air pollution and hypertensive disorders of pregnancy

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Associations between ambient air pollution and hypertensive disorders of pregnancy

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Content i ASSOCIATIONS BETWEEN AMBIENT AIR POLLUTION AND HYPERTENSIVE DISORDERS OF PREGNANCY by Zahra Mobasher-Liaey ______________________________________ A Master’s Thesis Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree Master of Science (MOLECULAR EPIDEMIOLOGY) August 2014 Copyright 2014 Zahra Mobasher-Liaey ii TABLE OF CONTENTS Dedication iii List of Tables iv List of Figures v Introduction 1 Materials and Methods 6 Results 16 Discussion 25 iii Dedication I dedicate this thesis to my wonderful husband, Vahid and our two amazing children, Ava and Arvin. You have brought the most joy to my life and have been a source of great learning for me. I am so proud of you and love you. I also would like to thank my wonderful parents for all of their support, inspiration and love. iv LIST OF TABLES Table 1.1: Selected Characteristics of the Study Population 18 Table 1.2: Trimester-Specific Distributions of Ambient 19 Air Pollutants and Correlations among Pollutants Table 1.3: Associations between Trimester-Specific 21 Pollutant Exposures and Hypertensive Disorder of Pregnancy Table 1.4: Associations between Trimester Specific Air 23 Pollution Exposure and Hypertensive Disorder of Pregnancy, Stratified by BMI Categories v LIST OF FIGURES Figure1: Residence locations, air quality monitoring station 11 locations, and estimated annual average concentrations in 2006 for a) CO, b) PM 2.5 , c) Ozone, and d) NO2 in the study area 1 Introduction Hypertensive disorders of pregnancy (HDP) represent major obstetric complications that affect 5% to 7% of pregnancies and are a leading cause of maternal and neonatal morbidity and mortality. In HDP cases, maternal inflammatory processes are exaggerated compared to the low level of inflammation in a normal pregnancy (Redman, 2005; Rusterholz, 2007). Therefore, factors that aggravate maternal systemic and/or placental inflammation have the potential to increase HDP risk. Normal pregnancy is a state of controlled maternal inflammation, in which specific pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 are increased in comparison to a non-pregnant state; however, this mild and controlled maternal inflammation has been suggested to be part of maternal adaptation to pregnancy (Rusterholz, 2007). It is also in general consensus that type1/type 2 cytokine balance in preeclampsia changes compared to a normal pregnancy. In HDP the levels of Th 1 (pro-inflammatory T-helper) increase, while Th 2 (suppressor T- helper) levels decrease in amount. In a normal pregnancy the opposite holds true and Th 2 levels are increased, while Th 1 levels are decreased (Rusterholz, 2007; Schiessl, 2007). In other words, a normal state of pregnancy-induced maternal inflammation is exacerbated in pregnancies affected by HDP. Both short-term and long-term exposures to air pollution may lead to various inflammatory responses. Air Pollution can trigger plaque build-up in the 2 arteries causing atherosclerosis, which leads to heart attack and stroke, and it worsens asthma (Meng, 2006; Meng, 2007). Similar to pregnancy, both atherosclerosis and asthma are considered chronic states of inflammation. There are also some reports regarding increased levels of IL-6 (a pro-inflammatory cytokine), in response to high particulate number concentration (Ruckerl, 2007). It has also been reported that exposure to PM 2.5 leads to acute airway inflammation and decrease in lung function in both asthmatic and non-asthmatic children in Mexico City (Barraza-Villarreal, 2008). In 2002 a study conducted at the University of Toronto, reported that Short-term inhalation of fine particulate air pollution and ozone results in acute arterial vasoconstriction in healthy adults (Brook, 2002). In 2005, Urch and colleagues reported that traffic related exposures to PM 2.5 and ozone caused rapid blood pressure increases, like those seen in preeclamptic pregnancies, in healthy individuals at 30-min intervals during 2-hour controlled exposures to PM 2.5 and ozone (Urch, 2005). HDP and cardiovascular disease appear to share common risk factors and a history of HDP increases the risk of subsequent hypertension, ischemic heart disease and stroke (Bellamy, 2007). Although obstetric (history of preeclampsia, family history of preeclampsia, primiparity, multiple pregnancies), clinical (chronic medical conditions such as hypertension and diabetes) and sociodemographic (race/ethnicity, obesity, maternal age) risk factors for HDP have been identified (North, 2011), the influence of environmental exposures has not been studied extensively. Because ambient and traffic-related air pollution 3 affect blood pressure (Fuks, 2011), and vascular/systemic inflammation (Bauer, 2010), several studies have examined the possible association between air pollution and HDP (Wu, 2009; Rudra, 2011; van den Hooven, 2009) with mixed results. Differences in outcome definition and/or exposure assessment may have easily accounted for the inconsistent findings. Air pollution is strongly associated with an increase in poor pregnancy outcomes (Brauer, 2008). According to several published studies (Sram, 2005; Huynh, 2006; Ritz, 2007; Ritz, 2008), air pollution has been linked to pre-term birth, low birth weight, intrauterine growth retardation (IUGR), and childhood and infant mortality (Ritz, 2000; Ritz, 2006). It has been proposed that there are shared etiologic pathways between IUGR and PE (Roberts, 2008). Associations between traffic-related air pollution and birth outcomes were observed in a population-based cohort in Vancouver, Canada, even with relatively low ambient air pollution exposure (Brauer, 2008). Some propose that exposure to particulate matter can increase maternal blood pressure and pulmonary and placental inflammation, which would impact transplacental oxygen transport. Moreover, these very same pathogenic processes have been described in pregnancies affected by HDP. The first trimester likely represents a critical window of susceptibility for developing HDP, as it is during this period that trophoblast invasion into the maternal decidua occurs, establishing the fetal blood supply. The initial stages of 4 HDP development start early on in pregnancy in most cases. Therefore it is especially essential to study the exposure effects on HDP risk during the first pregnancy trimester in order to better understand the processes involved in disease etiology and formation. Preeclampsia is widely considered to be a disease of endothelial cells, which become injured in many organs such as liver, brain and placenta (Lain, 2002). It has also been suggested that the placenta is the trigger for endothelial cell injury (Redman, 2005) and that different factors that are capable of injuring endothelial cells are produced by ischemic placentae. Early placentation occurs in a low oxygen (hypoxic) environment. Later in pregnancy, there is a switch in oxygen level from low to higher (normoxic) levels. Failure to undergo this essential switch, allows for shallow placentation, which is a hallmark of preeclampsia. The potential effects of air pollution in subsequent trimesters are unknown, but could be involved via pro-inflammatory processes. In addition to air pollution, obesity is associated with systemic inflammation (Ndumele, 2011), and air pollution may exaggerate systemic inflammation in obese individuals (Dubowsky, 2006). Whether pre-pregnancy body mass index (BMI) influences the relationship between air pollution and HDP risk is unknown, but given that body mass index is an established risk factor for preeclampsia, but not for Hemolysis Elevated Liver Enzyme Low Platelet count (HELLP) syndrome (Leeners, 2006), it could be an important modifier of 5 disease risk. In this study, we explored the potential influence of BMI on the relationship between ambient pollutants and HDP beyond its role as an independent risk factor for HDP. The aim of the current study was to investigate the role of trimester- specific ambient air pollution (particulate matter less than 2.5µm and 10 µm in diameter [PM 2.5 , PM 10 , respectively], nitrogen dioxide [NO 2 ], carbon monoxide [CO], and ozone [O 3 ]) on HDP risk. Specifically, we hypothesized that (1) the first trimester-specific ambient air pollution exposures are associated with HDP, and (2) maternal pre-pregnancy BMI modifies the associations between ambient air pollution and HDP occurrence. We tested these hypotheses in a study that was conducted in 298 predominantly Hispanic women. 6 Materials and Methods Study Population As described previously (Wilson, 2009; Wilson, 2011), cases of clinically- defined preeclampsia (n = 136) and controls (n = 162) were recruited retrospectively from delivery logs at the Los Angeles County + University of Southern California Women’s and Children’s Hospital from 1999-2006 (103 subjects) and during their postpartum stay at the hospital from 2007-2008 (202 subjects). Medical charts were abstracted to verify case diagnosis, confirm the absence of significant hypertension among controls and to obtain information on comorbidities and other clinically relevant data for both cases and controls. The term “clinically-defined preeclampsia” refers to the diagnosis made by the doctor in charge of patient care (prior to chart review) and refers to patients with hypertension, plus one or more symptoms, including but not limited to proteinuria. For research purposes, mild preeclampsia was defined as blood pressure ≥ 140 mmHg (systolic) or ≥ 90 mmHg (diastolic) on two or more occasions at least six hours apart plus proteinuria ≥300 mg/dL in a 24-hour urine collection or +1 on a dipstick in women who were normotensive in early pregnancy (less than 20 weeks gestation). Severe preeclampsia was defined as blood pressure ≥160 mmHg (systolic) or ≥110 mmHg (diastolic) on two or more occasions at least six hours apart plus proteinuria ≥500 mg/dL in a 24-hour urine collection or +3 on a 7 dipstick. Gestational hypertension was defined as elevated blood pressure (mild or severe, as described above) without evidence of proteinuria. Eclampsia was defined as hypertension, with or without proteinuria, plus at least one observed seizure in a woman with no prior history of a seizure disorder, and HELLP syndrome was defined as hemolysis (abnormal peripheral smear, bilirubin >1.2 mg/dl, or lactose dehydrogenase >600 IU/L), elevated liver enzymes (Aspartate Aminotransferase or Alanine Aminotransferase >70 IU/L) and low platelets (<100,000 mm 3 ). Partial HELLP syndrome was defined as two out of the previous three criteria (Egerman, 1999). Having any of these conditions resulted in a woman being categorized as having HDP. Women with lupus, chronic renal disease, multiple gestations, or sickle cell disease/trait were excluded. Starting in 2004, recruitment letters were sent to all cases of HDP who were diagnosed at Los Angeles County + University of Southern California Women’s and Children’s Hospital and delivered between 1999 and 2006. Letters were also sent to 10 randomly selected controls for each case already in the study, matched on birth year and age ± 5 years. Due to an anticipated lower response rate among controls, 10 controls per case were initially contacted. Follow-up phone calls were made within 2-4 weeks if no response was received after the initial letter was sent. However, due to the high motility in this population, this method proved extremely inefficient. 8 From 2007-2008, cases and controls were identified while they were still on service in the Women’s and Children’s Hospital. We approached every case of clinically diagnosed preeclampsia and randomly approached five controls for each case recruited (every woman not diagnosed with preeclampsia and without one of the exclusion criteria) for participation in the study. Participation rates during the in-house recruitment phase were 80% for cases and 77% for controls. Seven controls were excluded from the analysis due to missing data for the exposure assessment, and one case was excluded from the 3 rd trimester analyses because she had delivered during the second trimester, leaving X cases and X controls available for analysis. This study was approved by the University of Southern California Health Sciences Campus Institutional Review Board. All participants signed an informed consent for herself and her infant and, for women under the age of 18 at the time of recruitment (n=14), parental permission for participation was also obtained. Air Pollution Exposure Assessment The subject’s residential addresses during three pregnancy trimesters were entered into the dataset by the author. These residential addresses were then used for subsequent assessment of air pollution exposure among these subjects. Air pollution exposure assignments were based on spatially mapped ambient air quality data obtained from the US Environmental Protection Agency’s Air Quality System (EPA, 2010) and additional exposure data available from the 9 Southern California Children’s Health Study (Peters, 2004; Gauderman, 2007). Data for NO 2 , O 3 , CO, PM 2.5 and PM 10 ambient concentrations were acquired for California and Nevada for 1998-2008, the states and time-frame covering gestational locations and period for all our study subjects. These databases include gaseous NO 2 , O 3 , and CO concentrations that were monitored hourly at a network of 22 to 30 stations in southern California where all but 3 subjects lived. PM 2.5 was measured by a variety of methods, including continuous Beta Attenuation Monitors, daily and once every third day integrated 24-hr filters (the Federal Reference Method – FRM-PM 2.5 ), and two-week integrated filters (from the Children’s Health Study). PM 10 was measured continuously by Tapered Element Oscillating Microbalance, Beta Attenuations Monitors, and by once every third or sixth day High Volume 24-hr integrated filters (Federal Reference Method – FRM-PM 10 ). All PM measurements were standardized to represent Federal Reference Method measurements. PM measurements were available at 20 to 23 locations in southern California during this period. Only data that met a 75% completeness criterion were used to make exposure assignments, except at locations where only 1-in-3 day or 1-in-6 day daily data were collected (where 75% of expected data completeness was used). At four stations where Air Quality System and Children’s Health Study data overlapped, Children’s Health Study data were used when available because they received a higher level of quality assurance than the Air Quality System data. 10 Air quality data were first time averaged for the time periods relevant for each subject and then spatially mapped to the residence location. The relevant exposure time periods for the subjects were the trimesters of pregnancy. Trimester start dates were calculated as follows: 1 st trimester start date: date of birth - gestational age at delivery, 2 nd trimester start date: 1st trimester start date + 92 days, and 3 rd trimester start date: 1st trimester start date + 185 days. Gestational age was dated using the date of Last Menstrual Period and were confirmed by ultra-sound. The relevant locations were the geocoded residence locations in each time period. For subjects who moved, the trimester average exposures were calculated for the location with the longest duration in each trimester. The time- averaged air pollution data were spatially mapped inverse distance-squared weighting of data from up to four closest stations located within 50 km (25 km for CO) of each participant residence (Kinney, 1998). However, if one or more stations were located within 5 km of a residence then only data from the stations within 5 km were used for the interpolation. An additional requirement to assure consistency in this application is that the interpolations for all 3 periods were based on data from the same stations. The typical spatial patterns of O 3 , NO 2 , CO, and PM 2.5 concentrations are illustrated in Figure 1 (annual average estimates for 2006). As indicated in the maps, many of the residences were in areas with good spatial monitoring coverage. As a result, 31%, 31%, 31%, 27%, and 22% of the trimester exposure assignments for O 3 , NO 2 , CO, PM 2.5 , and PM 10 , respectively, were based on data from stations located with 5 km of the residence. For 96% to 11 100% of the trimester average exposure assignments, the closest air quality station with valid data was located within 25 km of the residence. Figure 1(a): Patterns of annual average CO concentration (ppb) in selected areas of Southern California in 2006 12 Figure 1(b): Patterns of annual average PM 2.5 concentration (µg/m 3 ) in selected areas of Southern California in 2006 13 Figure 1(c): Patterns of annual average ozone concentration (ppb) in selected areas of Southern California in 2006 14 Figure 1(d): Patterns of annual average NO 2 concentration (ppb) in selected areas of Southern California in 2006 Statistical Analyses The Pearson chi-square test (categorical variables) or the Student t test (continuous variables) was used to compare basic characteristics between cases and controls. Correlation analyses were performed using Pearson’s correlation coefficients to assess the linear relationship between all air pollutants in this study. These analyses were performed separately for each pregnancy trimester. Unconditional Logistic Regression was used to examine the association between 15 ambient air pollution and odds of HDP, adjusting for maternal age (continuous), parity (nulliparous vs. parous), maternal smoking status (recorded as yes/no) and exposure to secondhand tobacco smoke during pregnancy (yes/no). Covariates for the regression analysis were chosen on the basis of a priori knowledge. Both age and parity are known HDP risk factors; while maternal smoking is a known protective factor. We have also included an indicator variable for calendar year of pregnancy, as the air quality trends in the Los Angeles basin have been downward for CO, PM 10 , PM 2.5 and NO 2 , and flat or slightly upward for O 3 . Specifically, children born after 2002 were exposed to less of the above mentioned pollutants compared to children born before 2002. Pre-pregnancy body mass index did not change the effect estimates by more than 10%, so we did not adjust for it in our models. To test for the modifying effect of BMI on the relationships between air pollution and HDP, we evaluated BMI as a dichotomous variable (Obese versus non-obese: BMI<30 and ≥30). Odds ratios and 95% confidence intervals were computed for 2 standard- deviation increase in the pollutant level to obtain unit changes that are more comparable for interpretation purposes. The likelihood ratio test was used to test for interaction. 16 Results Among 136 cases, 67 (49%) met the criteria for mild preeclampsia, 27 (20%) had severe preeclampsia, and 42 (31%) had gestational hypertension. Among those classified as having gestational hypertension, 30 (72%) had signs or symptoms of more severe disease, including elevated liver enzymes, uric acid, or lactose dehydrogenase or decreased platelets (n=16); symptoms of preeclampsia such as headache, right upper quadrant pain, epigastric pain or visual disturbances (n=16); and/or a history of preeclampsia in a previous pregnancy (n=8). Among women with preeclampsia, five (4%) had superimposed preeclampsia, four (3%) had eclampsia, and six (5%) had HELLP syndrome or partial HELLP syndrome. The patient population was 97% Hispanic, and cases and controls did not differ by race or maternal age (Table 1.1). Controls in the study population, on average delivered two weeks later than the cases (P<0.001), indicating that controls, as a group, had ample opportunity to develop preeclampsia and be classified as cases. As expected, cases were more likely to be nulliparous than controls (P=0.06), have a higher BMI than controls (P=0.004), and have infants with lower birth weight than controls (P< 0.001), Cases and controls did not differ on preexisting or comorbid conditions (Table 1.1). However, women with preeclampsia were more likely to have chronic hypertension (4% vs. 1%, P=0.09), have a history of previous HDP (11% vs. 4%, P=0.014), and have small for gestational age (SGA) babies (12% vs. 5%, P=0.03), defined as less than the 17 10th percentile of weight at each gestational age. This referent standard was obtained using this current dataset. Moreover, as expected, the maximum systolic and diastolic blood pressures were significantly higher among cases than controls (P<0.001). Cases and controls did not differ in their smoking status (P=0.21); however, higher proportion of cases were exposed to secondhand smoking than controls (P = 0.03). 18 Table 1.1 Selected Characteristics of the Study Population Variable Controls (n= 162) Cases (n =136) P value Maternal age (mean ± SE; years) 27.0 ± 7.0 27.7 ± 7.4 0.42 * Gestational week * Range (28-42) Range (25-41) < 0.01 ** < 37 14 (9) 44 (32) 37 -38 48 (29) 43 (30) >38 100 (62) 49 (38) Gestational week at first prenatal visit Range (1-38) Range (1-36) 0.70 ** < 12 121 (77) 102 (78) 12 -20 22 (14) 19 (14.5) >20 14 (9) 10 (7.5) Parity (%) 0.06 ** Nulliparous 51 (32) 60 (44) Multiparous 111 (68) 74 (56) Race/Ethnicity Hispanic White 157 (97) 132 (97) 0.99 *** Non-Hispanic Black 3 (2) 3(2) Arab 1 (0.5) 1 (1) Filipino 1 (0.5) 0 Birth-weight (mean ± SE; gm) 3290 ± 536 2903 ± 884 < 0.01 * Maternal body mass index (kg/m 2 ) 25.8 ± 5.0 27.9 ± 6.3 <0.01 * Had prenatal care (%) 151 (93) 119 (90) 0.27 ** Gestational week for cases represents the week when they were diagnosed with HDP and for controls represents the week they delivered (duration of pregnancy). 19 Four cases and 9 controls were missing birth weight. BMI was measured pre-pregnancy using mother’s height and weight. Body Mass Index was missing for 17 subjects (13 controls and 4 cases). * P value obtained by t test; ** P value obtained by Pearson x 2 test; *** P value obtained by Fisher’s exact test. Similar patterns of correlations among the pollutants were seen across three trimesters (Table 1.2). Carbon monoxide, PM 10 , PM 2.5 , and NO 2 were positively correlated with each other. Ozone was negatively correlated with CO, PM 2.5 , and NO 2 , and it was uncorrelated with PM 10 . Table 1.2 Trimester-Specific Distributions of Ambient Air Pollutants and Correlations among Pollutants Exposure mean ±SD Correlations * NO 2 O 3 PM 10 PM 2.5 1 st Trimester CO (ppm) 0.58± 0.47 0.86 - 0.64 0.36 0.77 NO 2 (ppb) 28.63± 7.1 - 0.72 0.43 0.74 O 3 (ppb) 21.5± 7.4 - 0.03 - 0.45 PM 10 (µg/m 3 ) 34.5 ± 6.0 0.53 PM 2.5 (µg/m 3 ) 17 ± 3.5 2 nd Trimester CO (ppm) 0.67± 0.50 0.84 - 0.57 0.37 0.76 NO 2 (ppb) 30 ±6.9 - 0.74 0.44 0.80 O 3 (ppb) 18.2± 6.8 0.01 - 0.53 PM 10 (µg/m 3 ) 34.9 ± 6.3 0.52 PM 2.5 (µg/m 3 ) 17.5 ± 3.5 3 rd Trimester CO (ppm) 0.62 ±0.55 0.87 - 0.66 0.54 0.79 NO 2 (ppb) 30± 7.9 - 0.78 0.61 0.81 O 3 (ppb) 18.2± 8.1 - 0.18 - 0.55 PM 10 (µg/m 3 ) 35.1 ± 7.2 0.68 PM 2.5 (µg/m 3 ) 18.1 ± 5.0 * Values obtained by Pearson’s correlation test. Air pollution was associated with HDP in the 1 st trimester (Table 1.3). Specifically, each 2-standard deviation increase in carbon monoxide (1ppm) increased the odds of developing HDP in the 1 st trimester (OR = 2.83, 95% CI: 20 1.29, 6.20); however, CO exposure in the remaining two trimesters was not associated with HDP. Exposure to PM 2.5 in the 1 st trimester was also associated with HDP. Each 2-standard deviation increase in PM 2.5 (7µg/m 3 ) was associated with nearly a 4-fold increase in the odds of developing HDP (OR = 3.94, 95% CI: 1.82, 8.55). Similar to CO, exposure to PM 2.5 in the remaining two trimesters were not associated with HDP. When 1 st trimester PM 2.5 and CO were jointly included in the model, the association between HDP and PM 2.5 was attenuated but remained statistically significant (OR= 3.3; 95%CI: 1.30, 8.4), while CO exposure was no longer statistically significantly associated with HDP (OR = 1.4; 95% CI: 0.53, 3.6). Second trimester ozone was associated with a 2-fold increase in odds of HDP (OR per 2-standard deviation increase = 2.05, 95% CI: 1.22, 3.46). Exposures to PM 10 and NO 2 in any trimester were not significantly associated with HDP. We repeated the analyses excluding subjects with gestational hypertension (n=42) and found no change in the results. Similarly, excluding women with chronic hypertension (2 controls and 6 cases) did not change our results. 21 Table1. 3 Associations between trimester-specific pollutant exposures and Hypertensive Disorder of Pregnancy Pollutant Trimester Case/Control Adjusted OR (95% CI) CO (ppm) 1 st 136/162 2.83 (1.29, 6.20) 2 nd 136/162 0.90 (0.45, 1.79) 3 rd 135/162 1.16 (0.61, 2.20) NO 2 (ppb) 1 st 136/162 1.42 (0.75, 2.67) 2 nd 136/162 0.60 (0.33, 1.11) 3 rd 135/162 1.00 (0.56, 1.79) O 3 (ppb) 1 st 136/162 0.91 (0.54, 1.52) 2 nd 136/162 2.05 (1.22, 3.46) 3 rd 135/162 1.19 (0.71, 1.98) PM 2.5 (µg/m 3 ) 1 st 136/162 3.94 (1.82, 8.55) 2 nd 136/162 1.86 (0.95, 3.63) 3 rd 135/162 1.44 (0.76, 2.70) PM 10 (µg/m 3 ) 1 st 136/162 0.76 (0.43, 1.36) 2 nd 136/162 0.76 (0.44, 1.32) 3 rd 135/162 1.41 (0.77, 2.57) The odds ratios (ORs) and 95% confidence intervals (CIs) are reported per 2 standard deviations (2SD) increase in the pollutant concentration. The 2SDs for CO, NO 2 , O 3 , PM 2.5 , and PM 10 were 1ppm, 14 ppb, 15 ppb, 7µg/m 3 and 13µg/m 3 , respectively. ORs adjusted for maternal age (continuous), parity, maternal smoking history, exposure to secondhand smoke during pregnancy, and year of conception (before or after 2002). One case was excluded from the 3 rd trimester analyses due to missing exposure. 22 Maternal BMI influenced the association between some of the pollutants and HDP occurrence (Table 1.4). Exposure to CO in the first trimester was significantly associated with increased odds of HDP among non-obese individuals (OR per 2-standard deviation = 4.68, 95%CI: 1.69, 12.99), while such exposure was not associated with HDP among obese individuals (P for interaction = 0.02). The first trimester PM 2.5 exposure was significantly associated with HDP among non-obese women (OR = 8.63, 95%CI: 3.10, 24.14), but was not associated with HDP among obese women (OR = 0.72, 95%CI: 0.14, 3.56). 23 Table 1.4. Associations between Trimester Specific Air Pollution Exposure and Hypertensive Disorder of Pregnancy, Stratified by BMI Categories Pollutant Trimester Non-Obese (BMI <30kg/m 2 ) Obese (BMI 30kg/m 2 ) P interaction Case/control OR (95% CI) * Case/control OR (95% CI) * CO (ppm) 1 st 94/119 4.68 (1.69, 12.99) 38/30 0.81 (0.21, 3.10) 0.02 2 nd 94/119 0.71 (0.27, 1.83) 38/30 1.28 (0.34, 4.78) 0.79 3 rd 94/119 0.84 (0.37, 1.87) 38/30 1.85 (0.45, 7.60) 0.06 NO 2 (ppb) 1 st 94/119 2.05 (0.94, 4.48) 38/30 0.51 (0.11, 2.40) 0.04 2 nd 94/119 0.52 (0.24, 1.16) 38/30 0.94 (0.27, 3.31) 0.32 3 rd 94/119 0.92 (0.46, 1.88) 38/30 0.84 (0.24, 3.00) 0.25 O 3 (ppb) 1 st 94/119 0.68 (0.36, 1.29) 38/30 1.42 (0.44, 4.57) 0.17 2 nd 94/119 2.16 (1.12, 4.17) 38/30 1.36 (0.43, 4.26) 0.34 3 rd 94/119 1.44 (0.77, 2.70) 38/30 1.03 (0.37, 2.91) 0.04 PM 2.5 (µg/m 3 ) 1 st 94/119 8.63 (3.10, 24.14) 38/30 0.72 (0.14, 3.56) 0.06 2 nd 94/119 1.74 (0.75, 4.01) 38/30 2.41 (0.66, 8.76) 0.51 3 rd 94/119 1.28 (0.59, 2.78) 38/30 1.39 (0.34, 5.60) 0.23 PM 10 (µg/m 3 ) 1 st 94/119 0.75 (0.36, 1.55) 38/30 0.89 (0.26, 3.09) 0.97 2 nd 94/119 0.63 (0.31, 1.28) 38/30 0.75 (0.28, 2.00) 0.64 3 rd 94/119 1.99 (0.90, 4.41) 38/30 0.68 (0.22, 2.04) 0.09 * The odds ratios (ORs) and 95% confidence intervals (CIs) are reported per 2 standard deviations (2SD) increase in the pollutant concentration. The 2SDs for CO, NO 2, O 3, PM 2.5, and PM 10 were 1ppm, 14 ppb, 15 ppb, 7µg/m 3 and 13µg/m 3 , respectively. P values for interaction are obtained using the likelihood ratio test. All models are adjusted for maternal age (continuous), parity, maternal smoking history, exposure to secondhand smoke during pregnancy, and year of conception (before or after 2002). 24 Approximately 90% of this population had their first prenatal visit before 12 weeks gestation. Restricting the analyses to these women provided similar results. All but one subject developed HDP during the last trimester. As such, while the air pollution exposures in the 1 st and 2 nd pregnancy trimesters represent pre-diagnosis exposures for the cases, the estimation of average exposures in the third trimester included exposures that occurred after diagnosis for a small minority of cases. Therefore, the third trimester- specific results should be interpreted with caution. 25 Discussion In this study, we report that first-trimester exposures to PM 2.5 and CO are associated with increased odds of developing HDP, particularly among non-obese women. While the etiology of HDP is largely unknown, it is widely believed to begin in the first trimester with impaired placental development (Zhong, 2010; Redman, 2010). It has also been suggested that placenta is the trigger for endothelial cell injury (Redman, 2005), and that different factors that are capable of injuring endothelial cells are produced by ischemic placentae. In healthy women with no preexisting conditions such as hypertension or connective tissue disorders, abnormally shallow placentation is to blame for the ischemic placenta. In a healthy normal pregnancy, subset of cytotrophoblasts called invasive cytotrophoblasts migrate through the implantation site and invade decidua tunica media of maternal spiral arteries and replace its endothelium in a process called pseudovascularization (Zhou, 1997). Consequently, these vessels undergo some transformations from muscular resistant vessels into low resistance vessels which lead to increased blood flow to the placenta. This transformation begins sometime in the first pregnancy trimester and ends somewhere around 18-20 weeks gestation. Early placentation occurs in a low oxygen (hypoxic) environment. During the second trimester, there is a switch from hypoxia to normoxia (Caniggia, 2000), which results in a dramatic shift in gene expression (Goldman-Wohl, 2002). Failure to undergo this essential switch results in inadequate trophoblast invasion into the spiral arteries, 26 leading to shallow placentation, and in some cases, HDP (Goldman-Wohl, 2002; McMaster, 2004). Carbone Monoxide has a much higher affinity to bind hemoglobin compared to Oxygen in maternal blood flow. It can also cross the placental barrier (Sangalli, 2003). Moreover, fetal hemoglobin has even a lower affinity for biding oxygen than maternal hemoglobin. Consequently, the ischemic placenta would persist followed by a poor placentation, which may allow for increased HDP risk. Consistent with this hypothesis, only first trimester CO increased the odds of developing HDP in our population. A link between CO and HDP has been previously suggested. Rudra and Williams reported a strong and positive association between CO and HDP risk (Rudra, 2011), although this association was no longer significant after adjustment for the year of conception. Vigeh et al, reported twice the rate of pregnancy hypertension in mothers exposed to higher CO concentrations than mothers exposed to lower CO concentrations (OR= 2.02, 95% CI= 1.35, 3.03) (Vigeh, 2011). Exposure to CO has been linked to other adverse pregnancy outcomes including Intrauterine Growth Restriction. Like HDP, Intrauterine Growth Restriction is believed to be a disorder of early placental dysfunction in most, but not all cases (Furuya, 2008). Intrauterine Growth Restriction and HDP share common pathological pathways, which often result in their comorbid occurrence (Ness, 2006). Salam et al found that first trimester exposure to CO was associated with a 20% increased risk of Intrauterine Growth Restriction (Salam, 2005). Similarly Liu et al showed that each 1ppm increase in CO exposure during the 1 st trimester was associated with a statistically significant increase in the risk of Intrauterine Growth Restriction (Liu, 2003). In the light of 27 important shared etiologic factors between HDP and Intrauterine Growth Restriction, the finding of an association between HDP and CO exposure during the 1 st trimester in women with HDP lends support to the putative importance of hypoxemia in the development of these conditions. First trimester PM 2.5 was strongly associated with HDP in non-obese subjects. Our results are consistent with an earlier study in which women exposed in the highest PM 2.5 quartile during their pregnancy were at 42% increased risk of developing preeclampsia compared to those whose exposure was in the lowest quartile (Wu, 2009). Rudra et al reported a positive but non-significant association between PM 2.5 exposure during the periconceptional (7-months surrounding the pregnancy) and the last 3-months of pregnancy and preeclampsia (Rudra, 2011). The reason for the difference in the windows of exposure (e.g., trimester-specific vs. periconceptional) between these studies is not clear. The relationship between PM 10 and HDP has been recently explored in a prospective cohort study in the Netherlands (van den Hooven, 2011). They reported a positive association between PM 10 concentrations and the risk of Pregnancy Induced Hypertension (odds ratio 1.72 [95% CI 1.12 to 2.63] per 10 g/m3 increase), but not with preeclampsia (odds ratio 1.34 [95% CI 0.78 to 2.31] per 10 g/m3 increase) (van den Hooven, 2011). However, consistent with our own findings, the same authors reported no association between NO 2 exposures and Pregnancy Induced Hypertension or preeclampsia (van den Hooven, 2011). 28 Interestingly, the observed associations between first trimester CO and PM 2.5 on HDP occurrence were stronger and statistically significant only among non-obese women (BMI<30). One possible explanation is that the preexisting state of inflammation in obese women may have masked any additional influence of air pollution on HDP. In contrast, exposure to air pollution in non-obese subjects may have initiated inflammatory processes, which would trigger the subsequent pathophysiologic events leading to the development of HDP. Other alternatives include the possibility that biochemical pathways by which CO and PM 2.5 are processed may vary between obese and non-obese women and the prospect that HDP heterogeneity – that the condition itself is different between obese and non-obese women – could explain observed differences. We found that O 3 was significantly associated with HDP in the second trimester. While there are currently no studies investigating the role of O 3 in predisposing to HDP, Liu et al showed a significant association between O 3 and Intrauterine Growth Restriction during the 2 nd trimester of pregnancy (OR = 1.08, 95%CI= 1.01, 1-15) (Liu, 2003). This finding was subsequently confirmed by Salam et al (Salam, 2005). The exact mechanism by which ozone acts to increase risk is unknown; however, it is likely that increased levels of O 3 leads to increased lipid peroxidation, resulting in the release of pro- inflammatory cytokines into the circulation. Lipid peroxides are involved in oxidative stress, which is believed to be one of the main etiologic factors in formation of HDP (reviewed in Wilson, 2003). Circulating cytokines in maternal circulation could impair placental circulation (Larini, 2005) due to endothelial cell dysfunction, which in turn could lead to increased risk for HDP. 29 We acknowledge the following study limitations. Exposure misclassification, especially with regard to CO, is a frequent concern of any study investigating this pollutant. CO levels exhibit monthly variation with higher amounts in spring and summer compared to fall and winter. However; the impact of this limitation on our findings is minimal since we have roughly equal distribution of births during winter and fall compared to summer and spring months. Moreover, in the presence of any possible exposure misclassification, it would be non-differential with respect to case/control status, which tends to result in a bias toward the null. Pollutant exposure is also subject to misclassification by work environment. While we collected information on occupation, we did not have detailed data on occupational history, location and time-activity at workplace. However, because over 90% of women in the study population reported “housewife” as their occupation during their pregnancy (the exposure period of interest), we do not expect that information on occupational exposure would significantly alter the classification status of women in the study. Exposure misclassification during the third trimester remains a concern, since average exposure assignment to women diagnosed with HDP during the 3 rd trimester covered both pre- and post-diagnosis levels. In this study the majority of cases were diagnosed with HDP after 35 weeks. Therefore, the third trimester analyses may be somewhat biased due to exposure misclassification as a result of mixing of pre- and post- diagnosis exposure levels among cases. Additionally, we could not examine the 3 rd trimester exposure based on diagnostic (birth) dates due to complications in exposure assignment to controls. For instance, one month before birth would usually represent 30 exposure levels during gestational ages 37-40 weeks in controls, while one month before birth among cases (due to the earlier delivery date) would usually represent exposure levels during gestational ages 31-34 weeks. The resultant comparison would be between different at-risk periods for cases and controls. Thus, we recommend that the third trimester results be interpreted with caution. We used two different recruitment methods to ascertain our subjects. However, we can find no evidence that method of recruitment resulted in any differences in the study populations selected. To evaluate the possibility that subjects recruited retrospectively (1999-2006) differed from those recruited while on service (2007-2008), we evaluated the distribution of all covariate data with respect to these two methods of recruitment and found no significant differences between the groups. Furthermore, restricting the analyses to subjects who were recruited in 2007-2008 produced results in the similar direction but not significant. We were unable to calculate an exact response rate due to the high proportion of disconnected phone numbers, undeliverable mail and homeless women for the retrospective enrollment phase of the study (1999-2006). However, based on the number of women diagnosed with HDP at the Los Angeles County + University of Southern California Women’s and Children’s Hospital during the time period in question and the number of women recruited during that period, our recruitment rates during retrospective recruitment were approximately 39% and 8% among cases and controls, respectively. These rates represent an underestimate of our true recruitment rate. 31 Last, as this study was conducted among a population that was 97% Hispanic, generalizability to other ethnic groups may be limited. We acknowledge that the relatively small sample size available for this study may have limited our power to comprehensively examine the association between ambient air pollution and Hypertensive Disorders of Pregnancy across different pregnancy trimesters, especially given the heterogeneity of the outcome. These results will need to be confirmed in a larger, ideally prospective study. This study has several advantages compared to similar studies. We were able to test the associations of five criteria pollutants in a trimester-specific manner. Los Angeles County has varying levels of air pollution, and the study subjects came from different parts of the County. This provided the opportunity to examine associations between a wide range of air pollution on HDP occurrence. Moreover, we were able to examine the impact of O 3 in this study, which has not been reported previously. The study subjects were primarily Hispanics, who represent the fastest growing population in America and represent an under-studied segment of the population. Finally, the extensive chart review for all of the subjects provided detailed information on case diagnosis as well as on co-morbid conditions on both cases and controls. In conclusion, PM 2.5 and CO exhibited significant associations with HDP during the 1 st pregnancy trimester, and the associations were stronger in non-obese women. In addition, ozone exhibited a statistically significant positive association with HDP risk in the second pregnancy trimester. Our results may have important public health implications in promoting maternal and child health and advocating for public policy changes regarding pollutant levels. Since HDP is itself a risk factor for future maternal 32 cardiovascular disease (Freibert, 2011) as well as a number of diseases among children born to mothers with preeclampsia (Wu, 2011), further reductions in ambient air pollution is likely to provide a wide array of health benefits. 33 BIBLIOGRAPHY 1. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. 2000. Am J Obstet Gynecol. 183,S1-22. 2. Rusterholz, C., Hahn, S., & Holzgreve, W. (2007). Role of placentally produced inflammatory and regulatory cytokines in pregnancy and the etiology of preeclampsia. Semin Immunopathol, 29(2), 151-162. 3. Redman, C. W., & Sargent, I. L. (2005). 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Abstract (if available)

Abstract Background: Exposure to ambient air pollution is linked to adverse pregnancy outcomes. Previous reports examining the relationship between ambient air pollution and Hypertensive Disorders of Pregnancy have been inconsistent. ❧ Objectives: We evaluated the effects of ambient air pollution on the odds of Hypertensive Disorder of Pregnancy and whether these associations varied by body mass index (BMI). ❧ Methods: We conducted a retrospective, case‐control study among 298 predominantly Hispanic women (136 clinically‐confirmed cases) who attended the Los Angeles County + University of Southern California Women’s and Children’s Hospital during 1996-2008. Trimester‐specific carbon monoxide (CO), nitrogen dioxide (NO₂), ozone (O₃), and particulate matter with aerodynamic diameter <10μm and <2.5μm (PM₁₀, PM2.5) exposure were estimated based on 24‐hr exposure level at residential address. Logistic regression models were fitted to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for 2 standard deviation increase in exposure levels. ❧ Results: Exposures to CO and PM2.5 in the first trimester were significantly associated with Hypertensive Disorders of Pregnancy, and these associations were modified by BMI. In non‐obese women (BMI <30), first trimester exposures to PM2.5 and CO were significantly associated with increased odds of Hypertensive Disorder of Pregnancy (ORs per 2‐standard deviation increase in PM2.5 (7μg/m3) and CO (1ppm) exposures were 9.10 [95% CI: 3.33-24.6] and 4.96 [95% CI: 1.85-13.31], respectively). Additionally, there was a significantly positive association between exposure to O₃ in the second trimester and Hypertensive Disorder of Pregnancy (OR per 15ppb=2.05

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Creator Mobasher-Liaey, Zahra (author)

Core Title Associations between ambient air pollution and hypertensive disorders of pregnancy

School Keck School of Medicine

Degree Master of Science

Degree Program Molecular Epidemiology

Publication Date 08/28/2014

Defense Date 08/12/2014

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag Air pollution,body mass index,carbon monoxide,OAI-PMH Harvest,particulate matter,preeclampsia

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Language English

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Advisor Azen, Stanley P. (committee chair), Cockburn, Myles (committee member), Ingles, Sue Ann (committee member)

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