Long-Term Exposure to Low-Level PM2.5 and Mortality: Investigation of Heterogeneity by Harmonizing Analyses in Large Cohort Studies in Canada, United States, and Europe.

BACKGROUND: Studies across the globe generally reported increased mortality risks associated with particulate matter with aerodynamic diameter ≤2.5µm (PM2.5) exposure with large heterogeneity in the magnitude of reported associations and the shape of concentration-response functions (CRFs). We aimed to evaluate the impact of key study design factors (including confounders, applied exposure model, population age, and outcome definition) on PM2.5 effect estimates by harmonizing analyses on three previously published large studies in Canada [Mortality-Air Pollution Associations in Low Exposure Environments (MAPLE), 1991-2016], the United States (Medicare, 2000-2016), and Europe [Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), 2000-2016] as much as possible. METHODS: We harmonized the study populations to individuals 65+ years of age, applied the same satellite-derived PM2.5 exposure estimates, and selected the same sets of potential confounders and the same outcome. We evaluated whether differences in previously published effect estimates across cohorts were reduced after harmonization among these factors. Additional analyses were conducted to assess the influence of key design features on estimated risks, including adjusted covariates and exposure assessment method. A combined CRF was assessed with meta-analysis based on the extended shape-constrained health impact function (eSCHIF). RESULTS: More than 81 million participants were included, contributing 692 million person-years of follow-up. Hazard ratios and 95% confidence intervals (CIs) for all-cause mortality associated with a 5-µg/m3 increase in PM2.5 were 1.039 (1.032, 1.046) in MAPLE, 1.025 (1.021, 1.029) in Medicare, and 1.041 (1.014, 1.069) in ELAPSE. Applying a harmonized analytical approach marginally reduced difference in the observed associations across the three studies. Magnitude of the association was affected by the adjusted covariates, exposure assessment methodology, age of the population, and marginally by outcome definition. Shape of the CRFs differed across cohorts but generally showed associations down to the lowest observed PM2.5 levels. A common CRF suggested a monotonically increased risk down to the lowest exposure level. https://doi.org/10.1289/EHP12141.

Association of air particulate pollution with bone loss over time and bone fracture risk: analysis of data from two independent studies.

BACKGROUND: Air particulate matter (PM) is a ubiquitous environmental exposure associated with oxidation, inflammation, and age-related chronic disease. Whether PM is associated with loss of bone mineral density (BMD) and risk of bone fractures is undetermined. METHODS: We conducted two complementary studies of: (i) long-term PM <2.5 µm (PM2.5) levels and osteoporosis-related fracture hospital admissions among 9.2 million Medicare enrollees of the Northeast/Mid-Atlantic United States between 2003-2010; (ii) long-term black carbon [BC] and PM2.5 levels, serum calcium homeostasis biomarkers (parathyroid hormone, calcium, and 25-hydroxyvitamin D), and annualized BMD reduction over a 8-year follow-up of 692 middle-aged (46.7±12.3 yrs), low-income BACH/Bone cohort participants. FINDINGS: In the Medicare analysis, risk of bone fracture admissions at osteoporosis-related sites was greater in areas with higher PM2.5 levels (Risk ratio [RR] 1.041, 95% Confidence Interval [CI], 1.030, 1.051). This risk was particularly high among low-income communities (RR 1.076; 95% CI, 1.052, 1.100). In the longitudinal BACH/Bone study, baseline BC and PM2.5 levels were associated with lower serum PTH (Estimate for baseline one interquartile increase in 1-year average BC= -1.16, 95% CI -1.93, -0.38; Estimate for baseline one interquartile increase in 1-year average PM2.5= -7.39; 95%CI -14.17, -0.61). BC level was associated with higher BMD loss over time at multiple anatomical sites, including femoral neck (-0.08%/year per one interquartile increase; 95% CI -0.14, -0.02%/year) and ultradistal radius (-0.06%/year per one interquartile increase; 95% CI -0.12, -0.01%/year). INTERPRETATION: Our results suggest that poor air quality is a modifiable risk factor for bone fractures and osteoporosis, especially in low-income communities.

Treatment effects of maternal micronutrient supplementation vary by percentiles of the birth weight distribution in rural Nepal.

Certain antenatal micronutrient supplements increased birth weight by 40-70 g in rural Nepal. The effect was estimated by calculating the mean difference in birth weight between control and treatment groups, which assumes a constant treatment effect across the birth weight distribution. By estimating differences (and CI) in birth weight between treatment and control groups as a nonlinear, smooth function of the percentiles of the birth weight distribution, we can examine whether the shape of the birth weight distribution for a treatment group is different from that of the control group. Supplementation groups were folic acid, folic acid and iron, folic acid and iron and zinc, and a multiple micronutrient supplement all with vitamin A, compared with the control group of vitamin A alone. The shape of the birth weight distribution in the multiple micronutrient group was the same as that of the control group; however, the location of the distribution had shifted. The folic acid and iron group had fewer infants in the lower tail of its distribution but a similar proportion in the upper tail compared with the control group. The biologic pathways affecting intrauterine growth may vary by micronutrients such that some may confer a benefit among the most vulnerable infants, whereas others may have a more constant effect across the birth weight distribution. Future analytic approaches to estimating benefits of maternal supplementation on birth weight should examine whether there is a constant or variable treatment effect across the distribution of birth weight.

Randomized controlled trial of prenatal zinc supplementation and the development of fetal heart rate.

OBJECTIVES: This study was undertaken to evaluate whether prenatal zinc supplementation affects maturation of fetal cardiac patterns. STUDY DESIGN: A randomized double-blind controlled trial among 242 low-income Peruvian women was performed. Beginning at 10 to 16 weeks' gestation, women received supplements containing 60 mg iron, 250 microg folic acid with or without 25 mg zinc. Fetal heart rate (mean FHR, variability [HRV], number of accelerations) and movements (number and amplitude of movement bouts, time spent moving) were electronically monitored monthly from 20 weeks' gestation. Developmental trends were evaluated by supplement type among 195 women who completed the trial and had no serious complications of pregnancy. RESULTS: Zinc supplementation was associated with lower FHR, greater number of accelerations, and greater HRV. Supplementation effects on HRV and accelerations were more pronounced after 28 weeks' gestation. No differences in motor activity were observed. CONCLUSION: Prenatal supplementation of zinc-deficient mothers may be beneficial to fetal neurobehavioral development.

Randomized controlled trial of prenatal zinc supplementation and fetal bone growth.

BACKGROUND: Maternal zinc deficiency is relatively common in developing countries, but its consequences for fetal growth are not established. OBJECTIVE: The goal was to examine whether improvement in maternal gestational zinc status is positively associated with fetal growth as assessed by ultrasonography. DESIGN: We conducted a double-masked, randomized trial among 242 pregnant Peruvian women in an impoverished shantytown in Lima, Peru. At 10-16 wk of gestation, the women were randomly assigned to receive daily supplements containing 60 mg Fe and 250 microg folic acid, with or without 25 mg Zn. We measured fetal head circumference, biparietal diameter, abdominal circumference, and femur diaphysis length at 20, 24, 28, 32, 36, and 38 wk of gestation. Fetal measures were analyzed longitudinally to evaluate differences in trends of fetal growth by supplement type, and within-subject correlations were taken into account. RESULTS: Femur diaphysis length was greater in fetuses whose mothers received zinc supplements (P < 0.05), and the difference tended to increase with gestational age. No significant differences by supplement type were observed for the other anatomical sites measured. CONCLUSIONS: The observed positive effect of prenatal zinc on fetal femur diaphysis length is consistent with the results of experimental studies in animals and in vitro. The supplementation effect represents an upward shift in mean femur diaphysis length at term of about one-quarter of the reference SD. These findings suggest the potential importance of maternal zinc status for fetal bone growth in humans and illustrate the value of ultrasonography for evaluating the effect of prenatal nutritional interventions on components of fetal growth.