Air Pollution Exposure and Markers of Placental Growth and Function: The Generation R Study

Background: Air pollution exposure during pregnancy might affect placental growth and function, perhaps leading to pregnancy complications. Objective: We prospectively evaluated the associations of maternal air pollution exposure with markers of placental growth and function among 7,801 pregnant women in the Netherlands. Methods: We estimated levels of particulate matter ≤ 10 µm in aerodynamic diameter (PM10) and nitrogen dioxide (NO2) at the home address for different periods during pregnancy using dispersion modeling techniques. Pro- and anti-angiogenic factors [placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), respectively] were measured in first- and second-trimester maternal blood and in fetal cord blood samples at delivery. Pulsatility index of the uterine and umbilical arteries was measured by Doppler ultrasound in second and third trimester, and notching was assessed in third trimester. Placenta weight and birth weight were obtained from medical records. Results: Higher PM10 and NO2 exposure levels were associated with lower second-trimester maternal sFlt-1 and PlGF levels. PM10 and NO2 exposures averaged over total pregnancy were associated with higher sFlt-1 and lower PlGF levels in fetal cord blood, consistent with an anti-angiogenic state. PM10 and NO2 exposures were not consistently associated with second- or third-trimester placental resistance indices. NO2 exposure was associated with third-trimester notching (odds ratio 1.33; 95% CI: 0.99, 1.78 per 10-µg/m3 increase in the prior 2 months). PM10 and NO2 exposures were associated with lower placenta weight (–11.8 g; 95% CI: –20.9, –2.7, and –10.7 g; 95% CI: –19.0, –2.4, respectively, per 10-µg/m3 increase in the prior 2 months), but not with placenta to birth weight ratio. Conclusions: Our results suggest that maternal air pollution exposure may influence markers of placental growth and function. Future studies are needed to confirm these findings and explore the maternal and fetal consequences.

Henk M.E. Miedema, Eric A.P. Steegers, Vincent W.V. Jaddoe  Figure S1. Population for analysis 3 Figure S2. Timing of measurements of markers of placental growth and function 4 Table S1. Details of the multiple imputation procedure 5 Table S2. Participant characteristics in the original dataset and the imputed dataset 7 Table S3. Distribution of PM 10 and NO 2 exposure levels for different periods 9 Table S4. Unadjusted associations of maternal air pollution exposure with percent changes in angiogenic factors in first and second trimester and at delivery 10 Table S5. Unadjusted associations of maternal air pollution exposure with uteroplacental and fetoplacental vascular resistance in second and third trimester 11 Table S6. Unadjusted associations of maternal air pollution exposure with uterine artery notching in third trimester 12 Table S7. Unadjusted associations of maternal air pollution exposure with placenta weight, birth weight, and placental ratio Supplemental Material, Figure S1. Population for analysis.

Enrolment of pregnant women N = 8880
Live singleton births N = 7811 Participants with a measurement of markers of placental growth and function N = 7801 Maternal angiogenic factors in first trimester: N = 5043 Maternal angiogenic factors in second trimester: N = 6368 Fetal angiogenic factors at delivery: N = 3667 Placental vascular resistance in second trimester: N = 5510 Placental vascular resistance in third trimester: N = 6080 Placenta weight, birth weight, placental ratio: N = 7688 Excluded due to twin pregnancy, abortion, or intrauterine death N = 103 No valid air pollution data N = 966 Participants with valid air pollution exposure estimates (> 75% of the days available) for at least one exposure period N = 7914 No measurement of markers of placental growth and function N = 10 a Soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) were measured in maternal blood in first trimester (median 13.2 weeks of gestation, 95% range 9.6 to 17.5) and second trimester (median 20.6 weeks of gestation, 95% range 18.5 to 23.5), and in fetal cord blood at delivery ( Air pollution exposure was estimated for two weeks (day 1-14) and two months (day 1-60) preceding the different measurements. Additionally, air pollution exposure was averaged over the period from the time of conception to outcome measurement (referred to as total pregnancy period). c Air pollution exposure averages were calculated prior to the day of the ultrasound visit in third trimester. Table S4. Unadjusted associations of maternal air pollution exposure with percent changes in angiogenic factors in first and second trimester and at delivery.

Fetal PlGF
Percent change (95% CI) Values are regression coefficients and reflect the percent change (95% range) in log-transformed soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) levels per 10 µg/m 3 increase in air pollution exposure. Models are adjusted for gestational age at measurement. a Air pollution exposure for the total pregnancy period was estimated as average exposure for the period from conception until first trimester measurement, from conception until second trimester measurement, or from conception until delivery. Table S5. Unadjusted associations of maternal air pollution exposure with uteroplacental and fetoplacental vascular resistance in second and third trimester. Values are regression coefficients and reflect the difference in SD score of uterine and umbilical artery pulsatility index per 10 µg/m 3 increase in air pollution exposure. Models are adjusted for gestational age at measurement. a Air pollution exposure for the total pregnancy period was estimated as average exposure for the period from conception until second trimester measurement or from conception until third trimester measurement. Table S6. Unadjusted associations of maternal air pollution exposure with uterine artery notching in third trimester.

Bilateral notching
Odds ratio (95% CI) Values are odds ratios and reflect the risks for unilateral and bilateral uterine artery notching in third trimester per 10 µg/m 3 increase in air pollution exposure. Models are adjusted for gestational age at measurement.
Air pollution exposure for the total pregnancy period was estimated as average exposure for the period from conception until third trimester measurement.
placenta weight, birth weight, and placental ratio.

N=5605
Birth weight ( Values are regression coefficients and reflect the difference in placenta weight, birth weight, and placental ratio ((placenta weight/birth weight)*100%) per 10 µg/m 3 increase in air pollution exposure.