# Differential Effect of Ambient Air Pollution Exposure on Risk of Gestational Hypertension and Preeclampsia

Carrie J Nobles, Andrew Williams, Marion Ouidir, Seth Sherman, Pauline Mendola

► To cite this version:

Carrie J Nobles, Andrew Williams, Marion Ouidir, Seth Sherman, Pauline Mendola. Differential Effect of Ambient Air Pollution Exposure on Risk of Gestational Hypertension and Preeclampsia. Hypertension, 2020, 74 (2), pp.384 - 390. 10.1161/hypertensionaha.119.12731. hal-04662417

HAL Id: hal-04662417

https://hal.science/hal-04662417v1

Submitted on 25 Jul 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Published in final edited form as:

*Hypertension*. 2019 August ; 74(2): 384–390. doi:10.1161/HYPERTENSIONAHA.119.12731.

# Differential effect of ambient air pollution exposure on risk of gestational hypertension and preeclampsia

Carrie J. Nobles¹, Andrew Williams¹, Marion Ouidir¹, Seth Sherman², and Pauline Mendola¹

¹Epidemiology Branch, Division of Intramural Population Health Research, *Eunice Kennedy Shriver* National Institute of Child Health and Human Development, Bethesda, MD

²Emmes Company, Rockville, MD

## Abstract

Although ambient air pollution may increase hypertension risk through endothelial damage and oxidative stress, evidence is inconsistent regarding its effect on hypertension in pregnancy. Prior research has evaluated a limited scope of pollution species and often not differentiated preeclampsia, which may have a placental origin, from gestational hypertension. Among 49,607 women with at least two singleton deliveries in the NICHD Consecutive Pregnancies Study (2002–2010), we estimated criteria pollutant and volatile organic compound (VOC) levels during pregnancy using Community Multiscale Air Quality models and abstracted gestational hypertension and preeclampsia diagnoses from medical records. Generalized estimating equations accounted for repeat pregnancies and adjusted for ambient temperature and maternal age, race/ethnicity, BMI, smoking, alcohol, parity, insurance, marital status and asthma. Air pollution levels were low to moderate (e.g. median 41.6 (interquartile range 38.9–43.7) ppb for ozone and 35.1 (28.9–40.3) ppb for nitrogen oxides). Higher levels of most criteria pollutants during preconception and the first trimester were associated with lower preeclampsia risk, while higher second trimester levels were associated with greater gestational hypertension risk. For example, an interquartile increase in first trimester carbon monoxide was associated with a relative risk of 0.88 (95% CI 0.81–0.95) for preeclampsia and second trimester carbon monoxide a relative risk of 1.14 (95% CI 1.07–1.22) for gestational hypertension. VOCs, conversely, were not associated with gestational hypertension but consistently associated with higher preeclampsia risk. These findings further suggest air pollution may affect the development of hypertension in pregnancy, although differing etiologies of preeclampsia and gestational hypertension may alter these relationships.

## Summary

Exposure to criteria air pollution was differentially related to gestational hypertension and preeclampsia, including an increased risk of gestational hypertension and decreased risk of preeclampsia. Exposure to volatile organic compounds, conversely, was consistently associated with higher risk of preeclampsia. These findings emphasize the complex relationship of air pollution with hypertension in pregnancy.

<footnote>Corresponding author: Pauline Mendola, PhD, Epidemiology Branch, Division of Intramural Population Health Research, *Eunice Kennedy Shriver* National Institute of Child Health and Human Development, NIH, 6710B Rockledge Drive Room 3119, MSC 7004, Bethesda, MD 20892, Phone: 301-496-526, Mobile: 301-905-6118, Fax: 301-402-2084, pauline.mendola@nih.gov.</footnote>

<footnote>Conflicts of Interests/Disclosures Statement: None</footnote>
**Keywords**

Environment; air pollution; preeclampsia/pregnancy; gestational hypertension; epidemiology

**Introduction**

Ambient air pollution exposure is robustly associated with increases in blood pressure and risk of hypertension.¹ Exposure to air pollution leads to systemic increases in inflammation and oxidative stress and may subsequently lead to vasoconstriction and vascular remodeling. ² Gestational hypertension and preeclampsia are indicated by newly elevated blood pressure in the second half of pregnancy (≥140/90 mmHg) among women without clinically-diagnosed hypertension.³ Preeclampsia additionally involves development of systemic multi-organ endothelial dysfunction, often diagnosed as the presence of proteinuria, which may be a marker of kidney dysfunction. It has been theorized that preeclampsia may originate in poor placentation and subsequent placental dysfunction, with placental ischemia leading to maternal hypertension and widespread organ involvement.⁴ Given the adverse effects of air pollution on endothelial function and its association with hypertension in the general population, it has been theorized that air pollution likely increases risk of gestational hypertension and preeclampsia.⁵

Several prior studies have evaluated the relationship of ambient air pollution exposure with gestational hypertension and preeclampsia, with some studies suggesting an increased risk, but others with less conclusive or even conflicting findings.⁵⁻⁸ A meta-analysis by Pedersen et al. in 2014 it was found that exposure to fine particulate matter <2.5 microns (PM₂.₅), particulate matter <10 microns (PM₁₀) and nitrogen dioxide (NO₂) was associated with increased risk of gestational hypertension and preeclampsia jointly, as well as preeclampsia alone, although the magnitude of the associations with preeclampsia alone were smaller than for gestational hypertension and preeclampsia overall.⁵ This may be in part due to several studies finding null or even protective associations of air pollution with preeclampsia.⁶⁻¹⁰ A key challenge in summarizing prior literature is the limited number of studies that have evaluated the relationship of air pollution with gestational hypertension and preeclampsia independently, despite potential differences in their etiology. Additionally, prior research has focused largely on the association of the criteria air pollutants with gestational hypertension and preeclampsia. Other components of air pollution, including volatile organic compounds (VOCs), which are associated with oxidative stress,¹¹ may also contribute to risk of gestational hypertension and preeclampsia. We expanded on prior research by exploring the independent relationship of exposure to ambient criteria air pollutants and VOCs with both gestational hypertension and preeclampsia.

**Methods**

Consistent with National Institutes of Health policy, our data can be made available to other researchers. For details, please see http://grants.nih.gov/grants/policy/data_sharing/ for the National Institutes of Health data sharing policy.
The Consecutive Pregnancy Study was a retrospective cohort study that included all mothers with two or more singleton deliveries at ≥20 weeks gestation between 2002–2010 at one of 20 hospitals within the Intermountain Health Care system.¹² The majority of participants were from the Salt Lake City area, but study sites were additionally located in northern, central and southwest Utah (including Ogden, Provo and St. George) and southeast Idaho (Twin Falls) (Figures S1+S2, please see http://hyper.ahajournals.org). Hospitals extracted information on demographics, reproductive and prenatal history, current pregnancy and labor and delivery outcomes were abstracted from the antepartum and labor and delivery summary electronic medical records. Each delivery was linked to International Classification of Diseases-9 (ICD9) codes from maternal and newborn discharge summaries. A total of 50,005 mothers with two or more singleton deliveries were included in our analysis.

## Air pollution assessment

Air pollution was assessed for each hospital referral region using modified Community Multiscale Air Quality (CMAQ) models.¹³ Inputs included meteorologic data derived from the Weather Research and Forecasting model, emission data generated from the United States Environmental Protection Agency National Emissions Inventory and photochemical properties of pollutants. Hourly levels were estimated for seven criteria air pollutants: sulfur dioxide (SO₂), ozone (O₃), nitrogen oxides (NOₓ), NO₂, carbon monoxide (CO), PM₁₀ and PM₂.₅, as well as 14 VOCs: Benzene, 1,3-butadiene, ethylbenzene, cyclohexane, methyl-t-butyl ether, m-xylene, n-hexane, methyl ethyl ketone, o-xylene, propene, p-xylene, sesquiterpene, styrene and toluene. To correct for discrepancies with measured ambient air pollution levels at local monitoring stations, modeled estimates for the criteria pollutants were merged with inverse distance weighted monitoring data. To improve precision, merged estimates were weighted to reflect population density within the hospital referral region. Incorporation of inverse-distance weighted monitoring data and weighting for population density significantly improved model performance, with details on model performance published elsewhere.¹⁴ In brief, fused models had better coverage for several pollutants, including O₃, SO₂, and particulate matter, than monitoring data alone. In comparison to raw CMAQ output, fused models additionally had stronger agreement with monitor data for both gaseous pollutants and particulate matter. Air pollution estimates were averaged over five windows of exposure: 3-months preconception, first trimester, second trimester, first 20 weeks' gestation and whole pregnancy.

## Gestational hypertension and preeclampsia

Information on hypertensive disorders of pregnancy were abstracted from medical records and/or classified from ICD9 codes. Gestational hypertension included ICD9 code 642.4, and preeclampsia included both mild/moderate and severe preeclampsia (642.4 “Mild or unspecified preeclampsia”, 642.5 “Severe preeclampsia”). Four pregnancies affected by eclampsia (642.6 “Eclampsia”) were excluded, as were pregnancies affected by chronic hypertension (642.0), including women with chronic hypertension who developed superimposed preeclampsia (n=1,346, 2.7% of participants).
## Covariates

Individual-level covariates were abstracted from electronic medical records, and included maternal age (years), race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, Asian, other and unknown), pre-pregnancy body mass index (BMI; kg/m²), smoking during pregnancy (yes vs. no), alcohol use during pregnancy (yes vs. no), parity (nulliparous vs. parous), insurance type (public vs. private), marital status (married vs. unmarried) and history of asthma (yes vs. no). Hourly ambient temperature (degrees Kelvin) was derived from the Weather Research and Forecasting model for each hospital referral region and averaged over the same exposure windows used in the assessment of air pollution.

## Statistical methods

Participant characteristics were summarized as means and standard deviations or frequencies and percentages. Correlations between criteria air pollutants were calculated using Spearman rank correlation coefficients and between VOCs with point-biserial correlation coefficients. Exposure to criteria air pollutants was standardized by modeling an interquartile change in each pollutant, and VOCs by modeling exposure to the upper quartile versus lower three quartiles of ambient levels. Relative risk of gestational hypertension and preeclampsia were analyzed separately for each pollutant and each exposure window using Poisson binomial regression with a log link. Robust standard errors were calculated using generalized estimating equations, which accounted for dependency between pregnancies within participant. Because of the number of comparisons, we additionally accounted for the potential for a type I error by adjusting our main findings for the false discovery rate using the Benjamini-Hochberg procedure.¹⁵ Finally, we assessed the interaction of parity with ambient air pollution exposure by including an interaction term in all models in a secondary analysis. All analyses were conducted in SAS 9.4 (Cary, NC).

## Results

Of the 50,005 participants with at least two singleton pregnancies, 49,607 had at least one pregnancy without chronic hypertension or eclampsia. Mean age in the first pregnancy of follow-up was 25.5 (SD 4.5) years and the majority of participants were non-Hispanic white (86.1%). Most were married (86.2%), had private insurance (73.8%) and did not currently smoke (97.4%) or consume alcohol (98.1%). Approximately half were nulliparous (54.3%), and mean BMI was 24.3 (SD 5.2) kg/m³. Women with gestational hypertension and preeclampsia on average had a higher pre-pregnancy BMI and were more likely to be nulliparous than those without a hypertensive disorder of pregnancy. Additionally, women with preeclampsia were generally younger and less likely to be married while women with gestational hypertension were more likely to be non-Hispanic white and have private health insurance (Table 1). Ambient levels of criteria pollutants and VOCs were low to moderate (Table S1, please see http://hyper.ahajournals.org). A little more than half of first pregnancies (n=24,570, 53.5%) were conceived in the warm season (April 1st-September 30th), with most pollutants except O₃ being highest during the summer and fall for exposure during the first 20 weeks' of pregnancy (Table S2, please see http://hyper.ahajournals.org). For criteria pollutants, the median mean pregnancy level of SO₂ was 1.93 (IQR 1.57, 2.20) ppb, O₃ was 41.6 (38.9, 43.7) ppb, NOₓ was 35.1 (28.9, 40.3) ppb, NO₂ was 17.4 (15.1,
19.5) ppb, CO was 586 (489, 675) ppb, PM<sub>2.5</sub> was 8.63 (7.50, 9.75) µg/m<sup>3</sup> and PM<sub>10</sub> was 22.9 (20.7, 25.3) µg/m<sup>3</sup>. Most of the criteria pollutants were strongly correlated, except for O<sub>3</sub>, which was negatively correlated with all other criteria pollutants apart from CO (Table S3, please see http://hyper.ahajournals.org). Similarly, most VOCs were positively correlated with each other and with the criteria pollutants, with sporadic negative correlations and consistent negative correlations with O<sub>3</sub> (Tables S4+S5, please see http://hyper.ahajournals.org).

Overall, exposure to higher ambient levels of criteria air pollutants was associated with a higher risk of gestational hypertension, particularly in the second trimester (Table 2). For example, an interquartile increase in second trimester NO<sub>X</sub> and CO was associated with a relative risk of 1.17 (95% CI 1.08, 1.27) and 1.14 (95% CI 1.07, 1.22) for gestational hypertension. Risks were somewhat lower for whole pregnancy and first 20 weeks' gestation, but remained significantly elevated for NO<sub>X</sub>, NO<sub>2</sub>, CO, and PM<sub>10</sub> (e.g. RR 1.10, 95% CI 1.04, 1.16 for NO<sub>X</sub> during whole pregnancy and RR 1.10, 95% CI 1.01, 1.21 for NO<sub>X</sub> during first 20 weeks' gestation). Point estimates were elevated but not significant for preconception and first trimester exposure, except for a significantly elevated risk for NO<sub>2</sub> during the first trimester. No elevated risks were observed between ambient exposure to VOCs and gestational hypertension with two compounds, n-hexane and o-xylene, associated with lower risk. Most associations survived correction for the false discovery rate, except for the relationship of NO<sub>X</sub> during the first 20 weeks' gestation and NO<sub>2</sub> during trimester 1.

In contrast, exposure to higher levels of criteria air pollutants was generally associated with a lower risk of preeclampsia, and this association was strongest during preconception and in the first trimester (Table 3). For example, an interquartile increase in first trimester NO<sub>X</sub> and CO was associated with a relative risk of 0.90 (95% CI 0.82, 1.00) and 0.88 (95% CI 0.81, 0.95) for preeclampsia. This pattern was similar for exposure to O<sub>3</sub>, NO<sub>2</sub>, PM<sub>2.5</sub> and PM<sub>10</sub> although associations for PM<sub>2.5</sub> and PM<sub>10</sub> did not reach significance. Conversely, most VOCs were associated with a higher risk of preeclampsia across preconception and pregnancy. For example, exposure to the highest levels of MTBE was associated with a 23-30% greater risk of preeclampsia across all time windows. Only cyclohexane, o-xylene and toluene were not associated with increased risk. Most of the associations survived adjustment for the false discovery rate, with the exception of CO during whole pregnancy, NO<sub>2</sub> during the first 20 weeks' gestation, O<sub>3</sub> during 3 months preconception and NO<sub>X</sub> during trimester 1.

In a secondary analysis evaluating whether parity modified the relationship between air pollution and gestational hypertension or preeclampsia, we observed that the criteria air pollutants seemed to be more strongly associated with elevated risk of gestational hypertension among nulliparous women as compared to parous women. For example, an interquartile increase in whole pregnancy NO<sub>X</sub> exposure was associated with a relative risk of 1.18 (95% CI 1.10, 1.26) for gestational hypertension among nulliparous women and only a relative risk of 1.06 (95% CI 0.99, 1.14) among parous women (multiplicative p-interaction=0.03) (Table S6, please see http://hyper.ahajournals.org). No clear effect modification was observed for exposure to criteria pollutants and preeclampsia, or for
exposure to VOCs and either gestational hypertension or preeclampsia (Tables S7–S11, please see http://hyper.ahajournals.org).

Discussion

We found that exposure to higher levels of criteria air pollutants in the second trimester was associated with an increased risk of gestational hypertension, and that exposure to higher levels of O₃, CO and NOₓ/NO₂ during 3 months preconception and in the first trimester were associated with a lower risk of preeclampsia. Conversely, exposure to higher ambient levels of VOCs throughout pregnancy was not associated with risk of gestational hypertension but was associated with an elevated risk of preeclampsia. Differences suggest that air pollutants have differential effects on the mechanisms underlying gestational hypertension and preeclampsia. Findings are particularly notable given that most air pollution levels were below the Environmental Protection Agency's (EPA) National Ambient Air Quality Standards, even when EPA air quality standards are annual measures, longer time frames than pregnancy.¹⁶ For example, the maximum value for mean pregnancy PM₂.₅ (15.28 µg/m³) was at the EPA standard for one year (15 µg/m³), while the maximum value for mean pregnancy NO₂ (29.74 ppb) was well below the standard for one year (53 ppb) (Table S1, please see http://hyper.ahajournals.org).

Prior research has suggested that air pollution may increase risk of gestational hypertension and preeclampsia, although findings have been inconsistent across study populations. Although gestational hypertension and preeclampsia are often combined in analyses, some inverse associations have been observed particularly in relation to preeclampsia.⁵ In the Consortium on Safe Labor, we observed that criteria pollutants were associated with higher risk of gestational hypertension but not preeclampsia,⁹ and VOCs were conversely associated with higher risk of preeclampsia but not gestational hypertension.¹⁷ In a study including 268,601 births in New York City, Savitz et al. observed that a 10 µg/m³ increase in ambient PM₂.₅ and 10 ppb increase in NO₂ was associated with a relative risk of 1.7 (95% CI 1.5, 1.9) and 1.2 (95% CI 1.2, 1.3) for gestational hypertension, but a relative risk of 0.82 (95% CI 0.73, 0.92) and 0.89 (95% CI 0.85, 0.93) for mild preeclampsia in the first trimester.⁶ In a study of 17,533 women in Norway, Madsen et al. observed an association between a 10 µg/m³ increase in NO₂ and a suggested lower risk of both hypertension during pregnancy (RR 0.91, 95% CI 0.78, 1.06) and preeclampsia (RR 0.89, 95% CI 0.84, 1.08).⁷ Finally, In a study of 1.21 million singleton births in Shenzhen, China, Wang et al. observed that higher quartiles of NO₂ were associated with a lower risk of preeclampsia, and that PM₁₀ and SO₂ had a U-shaped relationship with risk of preeclampsia in the first trimester, with more consistently harmful associations for all pollutants in the second trimester.⁸

Potential differences in the etiology of gestational hypertension and preeclampsia may in part explain some of these differing findings. Gestational hypertension that does not progress to proteinuria or other organ involvement may be the result of difficulty accommodating the vascular changes of pregnancy due to pre-existing subclinical vascular dysfunction. In this case, adverse effects of air pollution later in pregnancy, as we observed in the second trimester, may be due to a similar effect on vasoconstriction as is observed in relation to elevated blood pressure with air pollution exposure in the general population.² Conversely,
although the exact etiology of preeclampsia is unknown, it is thought to be a consequence of placental insufficiency, which itself originates due to poor trophoblast invasion and spiral artery formation early in pregnancy.

CO and nitrogen dioxide (NO) are vasodilators that facilitate trophoblast invasion and spiral artery remodeling in placentation.¹⁸,¹⁹ Inhibition of these processes may play a key role in the etiology of preeclampsia, and higher levels of enzymes related to the production of NO and CO, and lower circulating levels of NO and CO have been observed in pregnancies affected by preeclampsia.²⁰ It has been suggested that protective effects of exogenous CO may explain the strong inverse association between cigarette smoking and preeclampsia,²¹ and CO has been observed to reduce pregnancy hypertension and hypertension-related growth restriction in controlled studies in animal research. For example, in a preeclampsia-like mouse model, consistent ambient exposure to 250 ppm CO during gestation was associated with reduced risk of hypertension and proteinuria.²² Low-level ambient exposure to carbon monoxide has been observed to be associated with reduced risk of preeclampsia in population-health studies. For example, a study in Ontario found that exposure to increasing higher quartiles of CO was associated with a lower risk of preeclampsia (RR 0.54, 95% CI 0.47–0.62 for CO ≤0.29 vs. <0.17 ppm).¹⁰ The potential for even low-level ambient CO and NO to reduce risk of preeclampsia is an important point for further research, as it may mask underlying associations between ambient air pollution and preeclampsia-related pregnancy complications, including fetal growth restriction and preterm birth.

Although VOCs are associated with increased oxidative stress, very few prior studies have evaluated the effect of ambient VOCs either during pregnancy or in relation to hypertension in the general population. In a study randomizing 200 homemakers in Taipei to air filtration or no intervention, researchers observed that decreases in both PM₂.₅ and VOCs were associated with lower c-reactive protein, 8-hydroxy-2'-deoxguanosine and blood pressure.¹¹ However, the difficulty of disentangling the effect of lowering PM₂.₅ and other air pollutants using filtration from lowering VOCs limits interpretation. In our study, VOCs appeared to be strongly related to risk of preeclampsia, with no association with gestational hypertension. Given the observations for criteria pollutants with gestational hypertension and preeclampsia, and that criteria pollutants and VOCs were generally highly positively correlated except for O₃, this is an important point for further investigation.

Our study had several strengths and limitations. Because our study was large (n=49,607) and had repeated measures for most participants, we were well-powered to observe differences in risk of gestational hypertension and preeclampsia. This is a low-risk population where the impact of ambient air might be easier to observe. However, participants were drawn from a relatively small geographic region with a similar climate and demographics, which limits the generalizability of our findings. A strength of our study is the wide range of air pollutant species assessed, including VOCs, which are rarely studied. However, because the air pollution estimates are averaged over the hospital referral regions and individual residential addresses was not available, we expect some non-differential misclassification of air pollution exposure which would most likely bias our findings towards the null. An additional strength of the study is the rich, detailed clinical data, but the deidentified electronic medical record does not have data on social factors so we cannot rule out unmeasured confounding
due to socioeconomic status. However, the observation of trimester-specific associations of the criteria pollutants with preeclampsia and gestational hypertension support an underlying cause that is temporally variable. Finally, due to the number of comparisons for air pollution species and windows of exposure, our findings should be interpreted with caution due to the potential for type I error. However, when adjusting for multiple comparisons, our main findings remained similar.

## Perspectives

In a large, relatively healthy cohort of women with at least two singleton pregnancies, exposure to higher levels of criteria air pollutants was associated with a higher risk of gestational hypertension but a lower risk of preeclampsia. Conversely, higher exposure to VOCs was associated with a higher risk of preeclampsia and no difference in gestational hypertension. These disparate findings suggest that many prior studies had conflicting or null findings because they combined these heterogenous case groups together. Further work on the potential for variation in the underlying pathophysiology for gestational hypertension and preeclampsia is needed, particularly related to the variation in response to these common, low-level ambient exposures.

## Supplementary Material

Refer to Web version on PubMed Central for supplementary material.

## Sources of Funding:

This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Cancer Institute (Consecutive Pregnancy Study Contract Nos. HHSN275200800002I, HH2N27500004 and the Air Quality and Reproductive Health Study Contract No. HHSN275200800002I, Task Order No. HHSN27500008).

## References

1. Cai Y, Zhang B, Ke W, Feng B, Lin H, Xiao J, Zeng W, Li X, Tao J, Yang Z, Ma W, Liu T. Associations of short-term and long-term exposure to ambient air pollutants with hypertension: A systematic review and meta-analysis. Hypertension (Dallas, Tex.: 1979). 2016;68:62–70

2. Kelly FJ, Fussell JC. Role of oxidative stress in cardiovascular disease outcomes following exposure to ambient air pollution. Free radical biology & medicine. 2017;110:345–367 [PubMed: 28669628]

3. Hypertension in pregnancy. Report of the american college of obstetricians and gynecologists’ task force on hypertension in pregnancy. Obstetrics and gynecology. 2013;122:1122–1131 [PubMed: 24150027]

4. Ahmed A, Rezai H, Broadway-Stringer S. Evidence-based revised view of the pathophysiology of preeclampsia. Advances in experimental medicine and biology. 2017;956:355–374 [PubMed: 27873232]

5. Pedersen M, Stayner L, Slama R, Sorensen M, Figueras F, Nieuwenhuijsen MJ, Raaschou-Nielsen O, Dadvand P. Ambient air pollution and pregnancy-induced hypertensive disorders: A systematic review and meta-analysis. Hypertension (Dallas, Tex.: 1979). 2014;64:494–500

6. Savitz DA, Elston B, Bobb JF, Clougherty JE, Dominici F, Ito K, Johnson S, McAlexander T, Ross Z, Shmool JL, Matte TD, Wellenius GA. Ambient fine particulate matter, nitrogen dioxide, and hypertensive disorders of pregnancy in new york city. Epidemiology (Cambridge, Mass.). 2015;26:748–757
7. Madsen C, Haberg SE, Aamodt G, Stigum H, Magnus P, London SJ, Nystad W, Nafstad P. Preeclampsia and hypertension during pregnancy in areas with relatively low levels of traffic air pollution. Maternal and child health journal. 2018;22:512–519 [PubMed: 29285630]

8. Wang Q, Zhang H, Liang Q, Knibbs LD, Ren M, Li C, Bao J, Wang S, He Y, Zhu L, Wang X, Zhao Q, Huang C. Effects of prenatal exposure to air pollution on preeclampsia in shenzhen, china. Environmental pollution (Barking, Essex: 1987). 2018;237:18–27

9. Mendola P, Wallace M, Liu D, Robledo C, Mnnist T, Grantz KL. Air pollution exposure and preeclampsia among us women with and without asthma. Environmental research. 2016;148:248–255 [PubMed: 27085496]

10. Zhai D, Guo Y, Smith G, Krewski D, Walker M, Wen SW. Maternal exposure to moderate ambient carbon monoxide is associated with decreased risk of preeclampsia. American journal of obstetrics and gynecology. 2012;207:57.e51–59 [PubMed: 22521459]

11. Chuang HC, Ho KF, Lin LY, Chang TY, Hong GB, Ma CM, Liu IJ, Chuang KJ. Long-term indoor air conditioner filtration and cardiovascular health: A randomized crossover intervention study. Environment international. 2017;106:91–96 [PubMed: 28624750]

12. Laughon SK, Albert PS, Leishear K, Mendola P. The nichd consecutive pregnancies study: Recurrent preterm delivery by subtype. American journal of obstetrics and gynecology. 2014;210:131.e131–138 [PubMed: 24036403]

13. Foley K, Roselle S, Appel K, Bhave P, Pleim J, Otte T, Mathur R, Sarwar G, Young J, Gilliam R. Incremental testing of the community multiscale air quality (cmaq) modeling system version 4.7. Geoscientific Model Development. 2010;3:205

14. Chen G, Li J, Ying Q, Sherman S, Perkins N, Sundaram R, Mendola P. Evaluation of observation-fused regional air quality model results for population air pollution exposure estimation. The Science of the total environment. 2014;485–486:563–574

15. Benjamini Y, Hochberg Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal statistical society: series B (Methodological). 1995;57:289–300

16. US Environmental Protection Agency. Naaqs table. Criteria air pollutants. 2016;2019

17. Zhu Y, Zhang C, Liu D, Ha S, Kim SS, Pollack A, Mendola P. Ambient air pollution and risk of gestational hypertension. American journal of epidemiology. 2017;186:334–343 [PubMed: 28472208]

18. Krause BJ, Hanson MA, Casanello P. Role of nitric oxide in placental vascular development and function. Placenta. 2011;32:797–805 [PubMed: 21798594]

19. Linzke N, Schumacher A, Woidacki K, Croy BA, Zenclussen AC. Carbon monoxide promotes proliferation of uterine natural killer cells and remodeling of spiral arteries in pregnant hypertensive heme oxygenase-1 mutant mice. Hypertension (Dallas, Tex.: 1979). 2014;63:580–588

20. Ehsanipoor RM, Fortson W, Fitzmaurice LE, Liao WX, Wing DA, Chen DB, Chan K. Nitric oxide and carbon monoxide production and metabolism in preeclampsia. Reproductive sciences (Thousand Oaks, Calif.). 2013;20:542–548

21. Engel SM, Scher E, Wallenstein S, Savitz DA, Alsaker ER, Trogstad L, Magnus P. Maternal active and passive smoking and hypertensive disorders of pregnancy: Risk with trimester-specific exposures. Epidemiology (Cambridge, Mass.). 2013;24:379–386

22. Venditti CC, Casselman R, Young I, Karumanchi SA, Smith GN. Carbon monoxide prevents hypertension and proteinuria in an adenovirus sflt-1 preeclampsia-like mouse model. PloS one. 2014;9:e106502 [PubMed: 25202912]
Novelty and Significance

What Is New?

* Exposure to criteria air pollutants in the second trimester appeared to increase risk of gestational hypertension but not preeclampsia

* Conversely, volatile organic compounds were associated with increased preeclampsia but not gestational hypertension risk

What Is Relevant?

* Findings highlight the importance of distinguishing preeclampsia from gestational hypertension when assessing air pollution risk
<caption>Table 1.</caption>

Participant characteristics by hypertension status in first pregnancy of follow-up (n=49,607 participants, n=110,985 pregnancies)

<table><thead><tr><th>Participant characteristics</th><th>No hypertension<br>n=45908<br>n (%)</th><th>Gestational hypertension<br>n=1987<br>n (%)</th><th>Preeclampsia<br>n=1712<br>n (%)</th></tr></thead><tbody><tr><td>Age (years; mean±SD)</td><td>25.6 (4.5)</td><td>25.1 (4.3)</td><td>24.8 (4.5)</td></tr><tr><td>Race/ethnicity</td><td></td><td></td><td></td></tr><tr><td>Non-Hispanic white</td><td>39424 (85.9)</td><td>1811 (91.2)</td><td>1469 (85.8)</td></tr><tr><td>Non-Hispanic black</td><td>194 (0.4)</td><td>11 (0.6)</td><td>8 (0.5)</td></tr><tr><td>Hispanic</td><td>5008 (10.9)</td><td>123 (6.2)</td><td>168 (9.8)</td></tr><tr><td>Asian</td><td>967 (2.1)</td><td>30 (1.5)</td><td>49 (2.9)</td></tr><tr><td>Other/unknown</td><td>315 (0.7)</td><td>11 (0.6)</td><td>18 (1.1)</td></tr><tr><td>Marital status</td><td></td><td></td><td></td></tr><tr><td>Married</td><td>39624 (86.3)</td><td>1707 (85.9)</td><td>1433 (83.7)</td></tr><tr><td>Not married</td><td>6284 (13.7)</td><td>280 (14.1)</td><td>279 (16.3)</td></tr><tr><td>Insurance</td><td></td><td></td><td></td></tr><tr><td>Public</td><td>12123 (26.4)</td><td>405 (20.4)</td><td>475 (27.8)</td></tr><tr><td>Private</td><td>33785 (73.6)</td><td>1582 (79.6)</td><td>1237 (72.3)</td></tr><tr><td>BMI (kg/m²; mean±SD)</td><td>24.1 (5.1)</td><td>27.0 (6.2)</td><td>26.5 (6.0)</td></tr><tr><td>Parity</td><td></td><td></td><td></td></tr><tr><td>0</td><td>24061 (52.4)</td><td>1531 (77.1)</td><td>1339 (78.2)</td></tr><tr><td>1</td><td>10900 (23.7)</td><td>260 (13.1)</td><td>206 (12.0)</td></tr><tr><td>2</td><td>6721 (14.6)</td><td>120 (6.0)</td><td>111 (6.5)</td></tr><tr><td>3+</td><td>4226 (9.2)</td><td>76 (3.8)</td><td>56 (3.3)</td></tr><tr><td>Smoking</td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>1140 (2.5)</td><td>32 (1.6)</td><td>45 (2.6)</td></tr><tr><td>No</td><td>44708 (97.4)</td><td>1954 (98.3)</td><td>1664 (97.2)</td></tr><tr><td>Unknown</td><td>60 (0.1)</td><td>1 (0.1)</td><td>3 (0.2)</td></tr><tr><td>Alcohol use</td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>758 (1.7)</td><td>42 (2.1)</td><td>39 (2.3)</td></tr><tr><td>No</td><td>45036 (98.1)</td><td>1943 (97.8)</td><td>1669 (97.5)</td></tr><tr><td>Unknown</td><td>114 (0.3)</td><td>2 (0.1)</td><td>4 (0.2)</td></tr><tr><td>Season of conception</td><td></td><td></td><td></td></tr><tr><td>Warm season</td><td>24570 (92.3)</td><td>1100 (4.1)</td><td>949 (3.6)</td></tr><tr><td>Cold season</td><td>21338 (92.8)</td><td>887 (3.9)</td><td>763 (3.3)</td></tr></tbody></table>

Author Manuscript

Author Manuscript

Author Manuscript

Author Manuscript
<caption>Table 2.</caption>

Ambient air pollution exposure and risk of gestational hypertension by window of exposure*,†

<table><thead><tr><th>Air pollutant species</th><th>Whole pregnancy<br>RR (95% CI)</th><th>First 20 weeks of gestation<br>RR (95% CI)</th><th>3 months preconception<br>RR (95% CI)</th><th>Trimester 1<br>RR (95% CI)</th><th>Trimester 2<br>RR (95% CI)</th></tr></thead><tbody><tr><td><strong>Criteria pollutants</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Sulfur dioxide</td><td>1.04 (0.99, 1.09)</td><td>1.04 (0.99, 1.08)</td><td>1.03 (0.98, 1.07)</td><td>1.02 (0.98, 1.07)</td><td><strong>1.05 (1.01, 1.10)</strong>‡</td></tr><tr><td>Ozone</td><td>0.95 (0.90, 1.00)</td><td>0.96 (0.91, 1.01)</td><td>1.02 (0.97, 1.06)</td><td>0.97 (0.92, 1.02)</td><td>0.96 (0.92, 1.01)</td></tr><tr><td>Nitrogen oxides</td><td><strong>1.10 (1.04, 1.16)</strong>‡</td><td><strong>1.10 (1.01, 1.21)</strong></td><td>1.01 (0.93, 1.10)</td><td>1.07 (0.98, 1.16)</td><td><strong>1.17 (1.08, 1.27)</strong>‡</td></tr><tr><td>Nitrogen dioxide</td><td><strong>1.10 (1.04, 1.15)</strong>‡</td><td><strong>1.11 (1.03, 1.20)</strong>‡</td><td>1.05 (0.98, 1.12)</td><td><strong>1.08 (1.01, 1.16)</strong></td><td><strong>1.14 (1.06, 1.22)</strong>‡</td></tr><tr><td>Carbon monoxide</td><td><strong>1.07 (1.02, 1.13)</strong>‡</td><td>1.05 (0.99, 1.12)</td><td>1.02 (0.96, 1.09)</td><td>1.03 (0.96, 1.10)</td><td><strong>1.14 (1.07, 1.22)</strong>‡</td></tr><tr><td>Particulates &lt;2.5 microns</td><td>1.04 (1.00, 1.10)</td><td>1.03 (0.97, 1.09)</td><td>1.01 (0.98, 1.05)</td><td>1.01 (0.97, 1.05)</td><td><strong>1.05 (1.02, 1.09)</strong>‡</td></tr><tr><td>Particulates &lt;10 microns</td><td><strong>1.07 (1.02, 1.11)</strong>‡</td><td>1.05 (1.00, 1.10)</td><td>1.02 (0.98, 1.07)</td><td>1.03 (0.98, 1.08)</td><td><strong>1.08 (1.03, 1.13)</strong>‡</td></tr><tr><td><strong>VOCs</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Benzene</td><td>1.00 (0.93, 1.09)</td><td>0.98 (0.89, 1.07)</td><td>0.96 (0.87, 1.06)</td><td>1.03 (0.94, 1.13)</td><td>0.98 (0.91, 1.05)</td></tr><tr><td>1,3-butadiene</td><td>1.01 (0.94, 1.09)</td><td>1.01 (0.93, 1.09)</td><td>0.97 (0.90, 1.06)</td><td>1.03 (0.96, 1.12)</td><td>1.05 (0.98, 1.14)</td></tr><tr><td>Ethylbenzene</td><td>0.99 (0.92, 1.07)</td><td>1.00 (0.92, 1.09)</td><td>1.00 (0.90, 1.10)</td><td>1.02 (0.93, 1.12)</td><td>0.99 (0.91, 1.07)</td></tr><tr><td>Cyclohexane</td><td>1.01 (0.94, 1.09)</td><td>0.98 (0.91, 1.06)</td><td>1.00 (0.93, 1.07)</td><td>0.99 (0.92, 1.06)</td><td>0.99 (0.93, 1.07)</td></tr><tr><td>methyl-t-butyl ether</td><td>0.97 (0.90, 1.05)</td><td>1.00 (0.93, 1.08)</td><td>0.97 (0.89, 1.05)</td><td>0.98 (0.91, 1.06)</td><td>0.99 (0.91, 1.07)</td></tr><tr><td>m-xylene</td><td>0.99 (0.91, 1.07)</td><td>0.96 (0.88, 1.05)</td><td>0.93 (0.84, 1.02)</td><td>1.03 (0.94, 1.13)</td><td>0.98 (0.91, 1.06)</td></tr><tr><td>n-hexane</td><td>0.99 (0.92, 1.07)</td><td>0.95 (0.88, 1.04)</td><td><strong>0.91 (0.83, 0.99)</strong></td><td>0.96 (0.89, 1.05)</td><td>0.97 (0.90, 1.04)</td></tr><tr><td>methyl ethyl ketone</td><td>1.00 (0.93, 1.09)</td><td>0.99 (0.91, 1.08)</td><td>0.96 (0.87, 1.06)</td><td>0.99 (0.91, 1.09)</td><td>1.01 (0.93, 1.10)</td></tr><tr><td>o-xylene</td><td>1.00 (0.92, 1.08)</td><td>0.97 (0.89, 1.05)</td><td><strong>0.91 (0.84, 0.99)</strong></td><td>0.93 (0.86, 1.01)</td><td>0.96 (0.89, 1.03)</td></tr><tr><td>Propene</td><td>1.01 (0.94, 1.09)</td><td>1.03 (0.95, 1.12)</td><td>1.02 (0.92, 1.12)</td><td>1.02 (0.93, 1.12)</td><td>1.04 (0.96, 1.12)</td></tr><tr><td>p-xylene</td><td>0.99 (0.91, 1.07)</td><td>1.01 (0.93, 1.10)</td><td>1.01 (0.91, 1.12)</td><td>1.02 (0.92, 1.12)</td><td>0.99 (0.91, 1.08)</td></tr><tr><td>sesquiterpene</td><td>0.98 (0.91, 1.07)</td><td>1.03 (0.94, 1.13)</td><td>0.93 (0.84, 1.02)</td><td>1.03 (0.94, 1.13)</td><td>1.01 (0.93, 1.09)</td></tr><tr><td>Styrene</td><td>1.01 (0.94, 1.09)</td><td>1.02 (0.95, 1.10)</td><td>0.96 (0.88, 1.05)</td><td>1.03 (0.95, 1.12)</td><td>1.03 (0.94, 1.12)</td></tr><tr><td>Toluene</td><td>1.00 (0.92, 1.08)</td><td>0.95 (0.88, 1.02)</td><td>0.98 (0.91, 1.06)</td><td>0.96 (0.89, 1.03)</td><td>0.97 (0.90, 1.04)</td></tr></tbody></table>

<footnote>* Models adjusted for maternal age, race/ethnicity, pre-pregnancy BMI, smoking, alcohol use, parity, insurance type, marital status, history of asthma and temperature.</footnote>
† Whole-pregnancy IQR for criteria air pollutants: sulfur dioxide 0.63 ppb, ozone 4.79 ppb, nitrogen oxides 11.40 ppb, nitrogen dioxide 4.40 ppb, carbon monoxide 186.7 ppb, particulates <2.5 microns 2.25 µg/m³, particulates <10 microns 4.55 µg/m³

‡ Associations survived correction for the false discovery rate at p<0.05.
<table><caption>Table 3.
Ambient air pollution exposure and risk of preeclampsia by window of exposure*,†</caption><thead><tr><th>Air pollutant species</th><th>Whole pregnancy<br>RR (95% CI)</th><th>First 20 weeks of gestation<br>RR (95% CI)</th><th>3 months preconception<br>RR (95% CI)</th><th>Trimester 1<br>RR (95% CI)</th><th>Trimester 2<br>RR (95% CI)</th></tr></thead><tbody><tr><td><strong>Criteria pollutants</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Sulfur dioxide</td><td>1.05 (0.99, 1.11)</td><td>1.04 (0.99, 1.10)</td><td>1.05 (1.00, 1.11)</td><td>1.04 (0.98, 1.09)</td><td>1.05 (1.00, 1.10)</td></tr><tr><td>Ozone</td><td><strong>0.81 (0.75, 0.85)</strong>†</td><td><strong>0.82 (0.77, 0.88)</strong>†</td><td><strong>0.94 (0.89, 0.99)</strong>†</td><td><strong>0.85 (0.81, 0.90)</strong>†</td><td><strong>0.85 (0.81, 0.90)</strong>†</td></tr><tr><td>Nitrogen oxides</td><td>0.96 (0.90, 1.02)</td><td>0.91 (0.82, 1.01)</td><td><strong>0.85 (0.77, 0.93)</strong>†</td><td><strong>0.90 (0.82, 1.00)</strong></td><td>0.99 (0.90, 1.09)</td></tr><tr><td>Nitrogen dioxide</td><td>0.96 (0.91, 1.02)</td><td><strong>0.92 (0.84, 1.00)</strong></td><td><strong>0.91 (0.84, 0.99)</strong>†</td><td>0.92 (0.85, 1.01)</td><td>0.96 (0.89, 1.04)</td></tr><tr><td>Carbon monoxide</td><td><strong>0.93 (0.88, 0.99)</strong></td><td><strong>0.88 (0.82, 0.96)</strong>†</td><td><strong>0.85 (0.78, 0.92)</strong>†</td><td><strong>0.88 (0.81, 0.95)</strong>†</td><td>0.93 (0.86, 1.01)</td></tr><tr><td>Particulates &lt;2.5 microns</td><td>1.01 (0.96, 1.07)</td><td>0.97 (0.91, 1.04)</td><td>0.97 (0.92, 1.02)</td><td>0.97 (0.92, 1.02)</td><td>1.03 (0.98, 1.07)</td></tr><tr><td>Particulates &lt;10 microns</td><td>1.00 (0.96, 1.06)</td><td>0.97 (0.92, 1.03)</td><td>0.97 (0.92, 1.02)</td><td>0.96 (0.91, 1.01)</td><td>1.02 (0.97, 1.07)</td></tr><tr><td><strong>VOCs</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Benzene</td><td><strong>1.18 (1.08, 1.30)</strong>†</td><td><strong>1.17 (1.05, 1.31)</strong>†</td><td>1.07 (0.95, 1.20)</td><td><strong>1.23 (1.10, 1.38)</strong>†</td><td><strong>1.12 (1.03, 1.23)</strong>†</td></tr><tr><td>1,3-butadiene</td><td><strong>1.30 (1.19, 1.42)</strong>†</td><td><strong>1.24 (1.13, 1.35)</strong>†</td><td><strong>1.18 (1.08, 1.30)</strong>†</td><td><strong>1.18 (1.08, 1.30)</strong>†</td><td><strong>1.21 (1.10, 1.32)</strong>†</td></tr><tr><td>ethylbenzene</td><td><strong>1.26 (1.15, 1.38)</strong>†</td><td><strong>1.29 (1.16, 1.43)</strong>†</td><td>1.13 (1.00, 1.27)</td><td><strong>1.25 (1.12, 1.40)</strong>†</td><td><strong>1.24 (1.13, 1.36)</strong>†</td></tr><tr><td>cyclohexane</td><td>1.00 (0.91, 1.09)</td><td>0.93 (0.84, 1.02)</td><td>0.94 (0.87, 1.03)</td><td>0.96 (0.88, 1.05)</td><td>0.98 (0.90, 1.07)</td></tr><tr><td>methyl-t-butyl ether</td><td><strong>1.24 (1.14, 1.36)</strong>†</td><td><strong>1.30 (1.19, 1.42)</strong>†</td><td><strong>1.23 (1.11, 1.35)</strong>†</td><td><strong>1.30 (1.19, 1.42)</strong>†</td><td><strong>1.27 (1.16, 1.39)</strong>†</td></tr><tr><td>m-xylene</td><td><strong>1.25 (1.14, 1.38)</strong>†</td><td><strong>1.19 (1.07, 1.33)</strong>†</td><td>1.04 (0.93, 1.17)</td><td><strong>1.18 (1.06, 1.33)</strong>†</td><td><strong>1.14 (1.04, 1.24)</strong>†</td></tr><tr><td>n-hexane</td><td>1.07 (0.98, 1.18)</td><td><strong>1.12 (1.01, 1.24)</strong>†</td><td>1.09 (0.98, 1.21)</td><td>1.08 (0.98, 1.20)</td><td>1.07 (0.98, 1.18)</td></tr><tr><td>methyl ethyl ketone</td><td><strong>1.24 (1.13, 1.36)</strong>†</td><td><strong>1.30 (1.18, 1.43)</strong>†</td><td><strong>1.25 (1.12, 1.39)</strong>†</td><td><strong>1.30 (1.17, 1.44)</strong>†</td><td><strong>1.24 (1.13, 1.36)</strong>†</td></tr><tr><td>o-xylene</td><td>1.02 (0.93, 1.11)</td><td>1.10 (1.00, 1.22)</td><td>1.01 (0.92, 1.11)</td><td>1.05 (0.95, 1.16)</td><td>1.04 (0.94, 1.14)</td></tr><tr><td>Propene</td><td><strong>1.21 (1.11, 1.32)</strong>†</td><td><strong>1.25 (1.14, 1.38)</strong>†</td><td><strong>1.29 (1.15, 1.44)</strong>†</td><td><strong>1.25 (1.12, 1.40)</strong>†</td><td><strong>1.17 (1.07, 1.29)</strong>†</td></tr><tr><td>p-xylene</td><td><strong>1.25 (1.14, 1.37)</strong>†</td><td><strong>1.33 (1.20, 1.47)</strong>†</td><td><strong>1.20 (1.07, 1.36)</strong>†</td><td><strong>1.30 (1.16, 1.46)</strong>†</td><td><strong>1.22 (1.11, 1.34)</strong>†</td></tr><tr><td>sesquiterpene</td><td><strong>1.44 (1.31, 1.58)</strong>†</td><td><strong>1.25 (1.12, 1.39)</strong>†</td><td>1.10 (0.98, 1.23)</td><td><strong>1.19 (1.07, 1.33)</strong>†</td><td><strong>1.13 (1.03, 1.24)</strong>†</td></tr><tr><td>Styrene</td><td><strong>1.22 (1.12, 1.33)</strong>†</td><td><strong>1.25 (1.15, 1.37)</strong>†</td><td><strong>1.20 (1.09, 1.34)</strong>†</td><td><strong>1.24 (1.12, 1.36)</strong>†</td><td><strong>1.21 (1.09, 1.33)</strong>†</td></tr><tr><td>Toluene</td><td>1.05 (0.96, 1.14)</td><td>0.97 (0.88, 1.06)</td><td>0.96 (0.88, 1.05)</td><td>0.98 (0.90, 1.07)</td><td>1.01 (0.93, 1.10)</td></tr></tbody></table>
<footnote>* Models adjusted for maternal age, race/ethnicity, pre-pregnancy BMI, smoking, alcohol use, parity, insurance type, marital status, history of asthma and temperature.</footnote>

<footnote>† Whole-pregnancy IQR for criteria air pollutants: sulfur dioxide 0.63 ppb, ozone 4.79 ppb, nitrogen oxides 11.40 ppb, nitrogen dioxide 4.40 ppb, carbon monoxide 186.7 ppb, particulates <2.5 microns 2.25 µg/m³, particulates <10 microns 4.55 µg/m³</footnote>

<footnote>‡ Associations survived correction for the false discovery rate at p<0.05.</footnote>