Beate Ritz, M.D., Ph.D.

Dept. of Epidemiology

Center for Occupational and

Environmental Health

UCLA, FSPH

Air Pollution, Fetal Development, and Children's Brains

Time to Act

Life course perspective…

Air Pollution and Pregnancy • Developing organism is uniquely sensitive to environmental

toxins • Immediate and long term health effects

• Infant morbidity and mortality • Adverse effects on adult health (fetal programming hypothesis)?

• Fetal growth measures as sensitive indicators for organ development including brain development

First study of air pollution and adverse birth outcome

published 1977

(1) Ritz B, Yu F. The effect of ambient carbon monoxide on low birth weight among children born in southern California between 1989 and 1993. Environmental Health Perspectives 1999 107(1):17-25

(2) Ritz B, Yu F, Chapa G, Fruin S. Effect of air pollution on preterm birth among children born in Southern California between 1989 and 1993. Epidemiology 2000 11:502-511.

(3) Ritz B, Yu F, Chapa G, Fruin S, Shaw G, Harris J. Ambient air pollution and birth defects. Am J Epidemiol 2002;155:17–25.

(4) Wilhelm M, Ritz B. Residential proximity to traffic and adverse birth outcomes in Los Angeles County, California, 1994-1996. Environ Health Perspect 2003 111(2):207-16.

(5) Ponce NA, Hoggatt KJ, Wilhelm M, Ritz B. Preterm Birth: The interaction of traffic-related air pollution with economic hardship In Los Angeles neighborhoods. Am J Epidemiol 2005 15:162(2):140-8.

(6) Wilhelm M, Ritz, B. Local variations in CO and particulate air pollution and adverse birth outcomes in Los Angeles County, California. Environ Health Perspect 2005 Sep;113(9):1212-21.

(7) Ritz B, Wilhelm M, Zhao Y. Ambient air pollution and infant mortality in Los Angeles County, 1989-2000. Pediatrics 2006 118:493-502

(8) Ritz B, Wilhelm M, Hoggatt KJ, Ghosh JKC. Ambient air pollution and preterm birth in the UCLA Environment and Pregnancy Outcomes Study. Am J Epidemiol 2007 166(9):1045-52

(9) Ritz B, Wilhelm M. Ambient air pollution and adverse birth outcomes: methodologic issues in an emerging field. Basic Clin Pharmacol Toxicol. 2008 Feb;102(2):182-90.

(10) Lee PC, Talbott EO; Roberts JM, Catov JM, Sharma RK, Ritz B. Particulate Air Pollution Exposure and C-Reactive Protein during Early Pregnancy. Epidemiology. 2011 Jul;22(4):524-31.

(11) Wilhelm M, Ghosh JK, Su J, Cockburn M, Jerrett M, Ritz B. Traffic-related air toxics and preterm birth: a population-based case-control study in Los Angeles County, California. Environmental Health. Environ Health. 2011 Oct 7;10:89. PMCID:PMC3204282

(12) Wilhelm M, Gosh J, Su J, Cockburn M, Jerret M, Ritz B. Traffic-Related Air Toxics and Term Low Birth Weight in Los Angeles County, California. Environ Health Perspect. 2012 Jan;120(1):132-8. PMCID:PMC3261935

.And counting….

UCLA research team publications since 1999

Ambient air pollution and pregnancy outcome studies worldwide since 2000

Studies of many different pollutants conducted in Australia, Brazil, Canada, China, Czech Republic, Great Britain, S.

Korea, Mexico, United States…

2015 Meta-analysis Results PM 2.5

Zhu et al 2015. Maternal exposure to fine particulate matter (PM2.5) and pregnancy outcomes: a meta-analysis. Environ Sci Pollut Res.

5-15% increase in risk per 10µg/m3 PM 2.5

2013

PM2.5

PM2.5

Effect of pregnancy mean exposure to air pollutants on low birthweight at term estimated in pooled analyses using

logistic regression with random effect of center adjusted for gestational age (weeks and [weeks]2), sex, parity (0,

1, 2, or more), maternal height, weight before pregnancy (broken stick model with a knot at 60 kg), maternal active

smoking during second trimester (cigarettes per day), maternal age, maternal education (low, middle, high), and

season of conception (January–March, April–June,July–September, October–December).

Neurodevelopmental Disorders: Autisms increase in California Birth Cohorts

From: Hertz-Picciotto I, Delwiche L. The rise in autism and the role of age at diagnosis. Epidemiology 2009 Jan;20(1):84-90.

1966-1991: 4 cases per

10,000 births

1994: 15 cases per

10,000 births

2001: 42.5 cases per

10,000 births

2008: 113 cases

per 10,000 births

Figure: cumulative incidence per 10,000 births by birth cohort

from 1990 to 2003, at ages 1–9 years, California, U.S.A.

Autism is a severe neurodevelopmental disorder

Air Pollution and Autisms

Autism Risk Increase by Modelled

Air-Pollutants Levels in Denmark

1989-2013 (per IQRd )

Case N=15,387; Control N=68,139

Exposure

Exposure period

OR (95% CI)

Unadjusted a Mutually adjusted c

NO2 Pregnancy 1.19 (1.16, 1.22) 1.00 (0.93, 1.08)

9 months after birth 1.20 (1.17, 1.23) 1.08 (1.01, 1.15)

SO2 Pregnancy 1.29 (1.23, 1.35) 0.96 (0.90, 1.04)

9 months after birth 1.38 (1.31, 1.45) 1.21 (1.13, 1.29)

PM10 Pregnancy 0.99 (0.95, 1.02) 0.95 (0.91, 1.00)

9 months after birth 1.03 (0.99, 1.06) 1.04 (1.00, 1.09)

PM2.5 Pregnancy 1.06 (1.02, 1.11) 0.96 (0.91, 1.02)

9 months after birth 1.11 (1.07, 1.15) 1.06 (1.01, 1.11) a note: these are pair matched on gender, birth year

c adjusted for all other covariates listed above and all exposure periods (pre-pregnancy, pregnancy and post-

pregnancy). d IQRs in controls: NO2: 11.41 ug/m3; SO2: 2.80 ug/m3; PM10: 3.80 ug/m3; PM2.5: 3.61 ug/m3

In high (Los Angeles, California, Israel) and

low pollution setting like Europe (ESCAPE)

- especially in Denmark - with excellent

exposure and health record systems

adverse impacts of air pollution are seen

on adverse pregnancy outcomes and

autism…..

Global Burden of Disease (GBD) attributable to 20 leading risk factors in

2010, expressed as a percentage of global disability-adjusted life-years

(DALYs)

Lim et al. 2012, Lancet

acute & chronic respiratory, CVD, cancer

Neonatal disorders

are absent from PM estimates

Enough Human Evidence to Add Outcomes to

GBD?e

What could be missing for adverse

birth outcomes and child brain

development to qualify for GBD

and/or policy and prevention

efforts?

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Map of SCAQMD Monitoring Stations and Zip Codes Included in Analysis

N

SoCAB County Boundaries

SoCAB Zip Code Boundaries

Zip Codes w/Areas that fall 60% w/in 2 mi Radius of a Monitor

%U Additional SCAQMD Stations Not Used in Analysis

# SCAQMD Monitoring Stations Used in Analys is

5 0 5 10 Miles

Two mile radii

More sophisticated (better?) exposure models…

aOR for Preterm Birth per IQR increase in entire pregnancy in LA

Where? Africa?

South America?

Asia?

Additional Epidemiologic Air Pollution

Studies Outside of North America and

Europe?

Associating airborne particle

types with adverse health

outcomes

M A I A

Multi-Angle Imager for Aerosols (MAIA)

21

Potential target areas

Candidate Primary Target

Area (PTA): Under serious

consideration for project

epidemiological study

Potential PTA: Further

information and tradeoffs

required

Secondary Target Area (STA):

Supports other air quality,

aerosol and cloud climate

studies

Calibration/Validation Target

Area (CVTA): Routinely

observed site for vicarious

calibration and instrument

stability monitoring

Investigate Biologic Pathways in Animals

and Humans?

Gestational Hypertension and Pre-eclampsia

Inflammation in Pregnancy

Placenta Function and Methylation

Human Placenta Project Imaging Innovations (MRI) for Placental

Assessment in Response to Environmental Pollution

Sherin U. Devaskar, M.D.

Department of Pediatrics

Carla Janzen, M.D., Ph.D.

Department of OB/GYN

Kyung Hyun Sung, Ph.D.

Department of Radiology

Beate Ritz, M.D., Ph.D.

Dept. of Epidemiology

UCLA scientists will study how pollution

affects development of the placenta

Problems with the placenta can lead to

preeclampsia, preterm birth and stillbirth

September 29, 2015

Air monitoring during pregnancy

200 Women place Purple Air particle

monitors in-and outdoors to measure

particles of multiple sizes

Biosamples during pregnancy:

• Maternal/cord blood and placenta

• Maternal urine throughout pregnancy

Generate metabolomic, oxidative stress and

inflammation markers

Improving Exposure Assessment

Indoor & Outdoor Continuous Particle Counting

Monitoring & Biomarkers

No vent in kitchen & household

smoker

xMSanalyzer Data Table

m/z, RT, Intensity Quality metrics

apLCMS, XCMS, MZmine options

Biostatistics

Bioinformatics Annotation, pathway

and network analysis:

Mummichog, MetabNet, xMSannotator, others

Metabolite forensics

Unequivocal Identification

MSn; UHRAM MS; 1-D, 2-D NMR; ion

Mobility; Chemical Reactivity, etc

MWAS

PLS-DA

Data extraction

ESI LC-MS Ultra-high resolution MS

LTQ-FT

LTQ-Velos Orbitrap

Q-Exactive HF Thermo Fusion

GC-Orbitrap

Metabolites of interest

Expanded Alphafetoprotein Screening Program (XRAF) collects and stores

mid-second trimester maternal serum samples

identified serum from ~300 Autism Cases and 300 controls

assessed air pollution exposure profiles

Biomarkers of Exposure and Effect: Untargeted High-resolution Metabolomics

Air pollution and Autism

Feature selection using

Variable Importance for

Projection (VIP) based on

PLSDA

Higher in exposed group w/ Autism

Lower in exposed group w/ Autism

1 2 3 4

Tryptophan…

Glycosphingolipid…

Lysine metabolism

Arginine and…

Pentose phosphate…

Xenobiotics…

Tyrosine metabolism

Glycolysis and…

Drug metabolism -…

Fructose and…

Fatty Acid…

Glycine, serine,…

Butanoate…

Alanine and…

TCA cycle

Urea cycle/amino…

Glycerophospholipi…

Methionine and…

Pathway enrichment analysis using Mummichog and m/z features with VIP>2

Air Pollution Studies of Birth Outcomes, and Child

Brain Health

Policy Relevant and Actionable!!!

06 February 2013

Nature | News

Air pollution delivers smaller babies

Study of 3 million infants suggests connection between inhaled particles and birth

weight.

published in Environmental Health Perspectives

An L.A. driver in 1979 Los Angeles Times

Chinese Millionaire Sells Cans of Fresh Air, 2013

Prevention! But not like this…..

Women wearing masks in Beijing, where

particulate matter levels can be tens of

times higher than World Health

Organization guidelines recommend.

Lintao Zhang/Getty Images

Special Thanks to

Funders and Collaborators

Liew, Yan, Heck, Ehrenstein, Cui, Ling, Turner, Wing UCLA Epidemiology

Michael Jerrett – UCLA --COEH

Jun Wu – UCI

Jason Su - UC Berkeley

Myles Cockburn, Denver CO

Dean Jones, Emory