Cheryl R. Stein

Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses

After the emergence of pandemic influenza viruses in 1957, 1968, and 2009, existing seasonal viruses were observed to be replaced in the human population by the novel pandemic strains. We have previously hypothesized that the replacement of seasonal strains was mediated, in part, by a population-scale boost in antibodies specific for conserved regions of the hemagglutinin stalk and the viral neuraminidase. Numerous recent studies have shown the role of stalk-specific antibodies in neutralization of influenza viruses; the finding that stalk antibodies can effectively neutralize virus alters the existing dogma that influenza virus neutralization is mediated solely by antibodies that react with the globular head of the viral hemagglutinin. The present study explores the possibility that stalk-specific antibodies were boosted by infection with the 2009 H1N1 pandemic virus and that those antibodies could have contributed to the disappearance of existing seasonal H1N1 influenza virus strains. To study stalk-specific antibodies, we have developed chimeric hemagglutinin constructs that enable the measurement of antibodies that bind the hemagglutinin protein and neutralize virus but do not have hemagglutination inhibition activity. Using these chimeric hemagglutinin reagents, we show that infection with the 2009 pandemic H1N1 virus elicited a boost in titer of virus-neutralizing antibodies directed against the hemagglutinin stalk. In addition, we describe assays that can be used to measure influenza virus-neutralizing antibodies that are not detected in the traditional hemagglutination inhibition assay.

Serum Levels of Perfluorooctanoic Acid and Perfluorooctane Sulfonate and Pregnancy Outcome

The authors examined the association of serum perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with self-reported pregnancy outcome in Mid-Ohio Valley residents (2000-2006) highly exposed to PFOA. Data on 1,845 pregnancies within the 5 years preceding exposure measurement were analyzed for PFOA, and data on 5,262 pregnancies were analyzed for PFOS. Generalized estimating equations were used to calculate adjusted odds ratios and 95% confidence intervals. Neither PFOA nor PFOS showed any association with miscarriage or preterm birth. Preeclampsia was weakly associated with PFOA (adjusted odds ratio = 1.3, 95% confidence interval: 0.9, 1.9) and PFOS (adjusted odds ratio = 1.3, 95% confidence interval: 1.1, 1.7) exposures above the median. PFOA was not associated with an increase in low birth weight, but PFOS showed an increased risk above the median (adjusted odds ratio = 1.5, 95% confidence interval: 1.1, 1.9) and a dose-response gradient. Birth defects were weakly associated with PFOA exposures above the 90th percentile (adjusted odds ratio = 1.7, 95% confidence interval: 0.8, 3.6). This study identified modest associations of PFOA with preeclampsia and birth defects and of PFOS with preeclampsia and low birth weight, but associations were small, limited in precision, and based solely on self-reported health outcomes.

Neighborhood deprivation and adverse birth outcomes among diverse ethnic groups.

PURPOSE Living in a socioeconomically deprived neighborhood has been associated with an increased risk of adverse birth outcomes. However, variation in the effect of neighborhood deprivation among diverse ethnic groups has not been studied. METHODS Using linked hospital discharge and birth data for 517,994 singleton live births in New York City from 1998 through 2002, we examined the association between neighborhood deprivation, preterm birth (PTB), and term low birthweight (TLBW) (>or=37 weeks and <2500g). Adjusted odds ratios (aORs) for PTB (<32 and 33-36 weeks) and TLBW were estimated using logistic regression. RESULTS The aOR for PTB of less than 32 weeks for the highest quartile of deprivation compared to the lowest was 1.24 (95% confidence limit [CL] = 1.13, 1.36), for PTB 33-36 weeks was 1.06 (95% CL = 1.01, 1.11), and for TLBW was 1.19 (95% CL = 1.11, 1.27). Measures of association varied by ethnicity; aORs of the greatest magnitude for PTB were found among Hispanic Caribbean women (PTB < 32 weeks: aOR = 1.63, 95% CL = 1.27, 2.10; PTB 33-36 weeks: aOR = 1.32, 95% CL = 1.02, 1.70), and for TLBW among African women (aOR = 1.47, 95% CL = 1.02, 2.13). CONCLUSIONS The mechanisms linking neighborhood deprivation to adverse birth outcomes may differ depending on individual ethnicity and/or cultural context and should be investigated in future research.

Serum Perfluorinated Compound Concentration and Attention Deficit/Hyperactivity Disorder in Children 5–18 Years of Age

Background: Perfluorinated compounds (PFCs) are persistent environmental pollutants. Toxicology studies demonstrate the potential for perfluorooctanoic acid (PFOA) and other PFCs to affect human growth and development. Attention deficit/hyperactivity disorder (ADHD) is a developmental disorder with suspected environmental and genetic etiology. Objectives: We examined the cross-sectional association between serum PFC concentration and parent or self-report of doctor-diagnosed ADHD with and without current ADHD medication. Methods: We used data from the C8 Health Project, a 2005–2006 survey in a Mid-Ohio Valley community highly exposed to PFOA through contaminated drinking water, to study non-Hispanic white children 5–18 years of age. Logistic regression models were adjusted for age and sex. Results: Of the 10,546 eligible children, 12.4% reported ADHD and 5.1% reported ADHD plus ADHD medication use. We observed an inverted J-shaped association between PFOA and ADHD, with a small increase in prevalence for the second quartile of exposure compared with the lowest, and a decrease for the highest versus lowest quartile. The prevalence of ADHD plus medication increased with perfluorohexane sulfonate (PFHxS) levels, with an adjusted odds ratio of 1.59 (95% confidence interval, 1.21–2.08) comparing the highest quartile of exposure to the lowest. We observed a modest association between perfluorooctane sulfonate and ADHD with medication. Conclusions: The most notable finding for PFOA and ADHD, a reduction in prevalence at the highest exposure level, is unlikely to be causal, perhaps reflecting a spurious finding related to the geographic determination of PFOA exposure in this population or to unmeasured behavioral or physiologic correlates of exposure and outcome. Possible positive associations between other PFCs and ADHD, particularly PFHxS, warrant continued investigation.

Localized Mucosal Response to Intranasal Live Attenuated Influenza Vaccine in Adults

BACKGROUND Influenza virus infection is a major public health burden worldwide. Available vaccines include the inactivated intramuscular trivalent vaccine and, more recently, an intranasal live attenuated influenza vaccine (LAIV). The measure of successful vaccination with the inactivated vaccine is a systemic rise in immunoglobulin G (IgG) level, but for the LAIV no such correlate has been established. METHODS Seventy-nine subjects were given the LAIV FluMist. Blood was collected prior to vaccination and 3 days and 30 days after vaccination. Nasal wash was collected 3 days and 30 days after vaccination. Responses were measured systemically and in mucosal secretions for cytokines, cell activation profiles, and antibody responses. RESULTS Only 9% of subjects who received LAIV seroconverted, while 33% of patients developed at least a 2-fold increase in influenza virus-specific immunoglobulin A (IgA) antibodies in nasal wash. LAIV induced a localized inflammation, as suggested by increased expression of interferon-response genes in mucosal RNA and increased granulocyte colony-stimulating factor (G-CSF) and IP-10 in nasal wash. Interestingly, patients who seroconverted had significantly lower serum levels of G-CSF before vaccination. CONCLUSIONS Protection by LAIV is likely provided through mucosal IgA and not by increases in systemic IgG. LAIV induces local inflammation. Seroconversion is achieved in a small fraction of subjects with a lower serum G-CSF level.

Perfluorooctanoic Acid Exposure and Pregnancy Outcome in a Highly Exposed Community

Background: We assessed the association between perfluorooctanoic acid (PFOA) and pregnancy outcome in an area with elevated exposure to PFOA from drinking water contaminated by chemical plant releases. Methods: Serum PFOA was measured, and reproductive and residential histories were obtained during 2005–2006. We estimated serum PFOA levels at the time of pregnancy for 11,737 pregnancies occurring between 1990 and 2006, based on historical information on PFOA releases, environmental distribution, pharmacokinetic modeling, and residential histories. We assessed the association between PFOA and the odds of miscarriage, stillbirth, preeclampsia, preterm birth, term low birthweight, and birth defects, controlling for calendar time, age, parity, education, and smoking. PFOA exposure was evaluated as a continuous measure (with and without log transformation) and in quintiles, combining the lowest 2 quintiles (<6.8 ng/mL) as the referent. Results: Measures of association between PFOA and miscarriage, preterm birth, term low birthweight, and birth defects were close to the null. Odds of stillbirth were elevated in the fourth quintile only. For preeclampsia, the odds ratio was 1.13 (95% confidence interval = 1.00–1.28) for an interquartile shift in log-transformed PFOA, and the odds ratios were 1.1–1.2 across the upper 3 quintiles of exposure. Conclusions: In this large, population-based study in a region with markedly elevated PFOA exposure, we found no associations between estimated serum PFOA levels and adverse pregnancy outcomes other than possibly preeclampsia. Conclusions are tempered by inherent limitations in exposure reconstruction and self-reported pregnancy outcome information.

Serum perfluorooctanoic acid and perfluorooctane sulfonate concentrations in relation to birth outcomes in the Mid-Ohio Valley, 2005-2010.

Background: Previous research suggests perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) may be associated with adverse pregnancy outcomes. Objective: We conducted a population-based study of PFOA and PFOS and birth outcomes from 2005 through 2010 in a Mid-Ohio Valley community exposed to high levels of PFOA through drinking-water contamination. Methods: Women provided serum for PFOA and PFOS measurement in 2005–2006 and reported reproductive histories in subsequent follow-up interviews. Reported singleton live births among 1,330 women after 1 January 2005 were linked to birth records (n = 1,630) to identify the outcomes of preterm birth (< 37 weeks gestation), pregnancy-induced hypertension, low birth weight (< 2,500 g), and birth weight (grams) among full-term infants. Results: We observed little or no evidence of association between maternal serum PFOA or PFOS and preterm birth (n = 158) or low birth weight (n = 88). Serum PFOA and PFOS were both positively associated with pregnancy-induced hypertension (n = 106), with adjusted odds ratios (ORs) per log unit increase in PFOA and PFOS of 1.27 (95% CI: 1.05, 1.55) and 1.47 (95% CI: 1.06, 2.04), respectively, but associations did not increase monotonically when categorized by quintiles. Results of subanalyses restricted to pregnancies conceived after blood collection were consistent with the main analyses. There was suggestion of a modest negative association between PFOS and birth weight in full-term infants (–29 g per log unit increase; 95% CI: –66, 7), which became stronger when restricted to births conceived after the blood sample collection (–49 g per log unit increase; 95% CI: –90, –8). Conclusion: Results provide some evidence of positive associations between measured serum perfluorinated compounds and pregnancy-induced hypertension and a negative association between PFOS and birth weight among full-term infants. Citation: Darrow LA, Stein CR, Steenland K. 2013. Serum perfluorooctanoic acid and perfluorooctane sulfonate concentrations in relation to birth outcomes in the Mid-Ohio Valley, 2005–2010. Environ Health Perspect 121:1207–1213; http://dx.doi.org/10.1289/ehp.1206372

Maternal Smoking, Preeclampsia, and Infant Health Outcomes in New York City, 1995–2003

A number of previous studies have reported an inverse association between maternal smoking and preeclampsia. Additionally, some have suggested that smokers who develop preeclampsia have worse maternal and fetal outcomes than nonsmokers who develop preeclampsia. The authors examined the relation of smoking to preeclampsia among 674,250 singleton pregnancies in New York City between 1995 and 2003. Although smoking was associated with a reduced risk of preeclampsia overall (adjusted odds ratio = 0.88, 95% confidence interval: 0.82, 0.94), no association was found for preeclampsia superimposed on chronic hypertension (adjusted odds ratio = 1.04, 95% confidence interval: 0.90, 1.21). Furthermore, the apparent protection conferred by maternal smoking was restricted to women aged < or =30 years. Contrary to previous reports, the authors found evidence of a negative interaction between smoking and preeclampsia with respect to preterm delivery and birth weight; smokers who developed preeclampsia had a lower risk of preterm delivery, and a lower adjusted mean difference in birth weight, than would have been expected based on the independent effects of smoking and preeclampsia. These data suggest that smoking is only protective against preeclampsia without pre gestational hypertension, and even then principally among younger women. Additionally, smokers who develop these disorders have no increased risk of adverse birth outcomes relative to nonsmokers who develop the same conditions.

Maternal ethnicity and pre-eclampsia in New York City, 1995–2003

Studies on ethnic differences in the risk of pre-eclampsia are limited. We linked birth records for 902,460 singleton births for the period 1995-2003 in New York City with hospital discharge data to evaluate the association between ethnicity and the risk of pre-eclampsia and compare risks between US-born and foreign-born women. Logistic regression models adjusted for maternal age, maternal education, parity, self-reported pre-pregnancy maternal weight, smoking during pregnancy and year of delivery were used to compare each ethnic group with non-Hispanic White women. The prevalence of pre-eclampsia in this study population was 3.2%. Among the major ethnic groups considered in our study, East Asian women had the lowest risk of pre-eclampsia (1.4%) and Mexican women had the highest risk (5.0%). Compared with non-Hispanic White women, there was a slightly decreased risk for East Asian women (adjusted OR = 0.8, [95% CI 0.7, 0.8]), similar risk for North African women (adjusted OR = 1.1, [95% CI 0.9, 1.3]), and increased risk for all other major ethnic groups (adjusted ORs: 1.3, 2.9), with the highest risk for Mexican women (adjusted OR = 2.9, [95% CI 2.7, 3.1]). No difference in risks was observed for US- vs. foreign-born women with the exception that foreign-born South-East Asian and Pacific Islanders had an increased risk of pre-eclampsia (adjusted OR = 1.8, [95% CI 1.0, 3.1]) relative to those born in the US. We concluded that there was ethnic heterogeneity in the development of pre-eclampsia among women in New York City and that Asian subgroups should be examined separately in future studies on ethnicity. Our results should contribute to screening for pre-eclampsia taking ethnic variation into account, and may help to suggest leads for the study of the aetiology of the condition.

Relationship of perfluorooctanoic acid exposure to pregnancy outcome based on birth records in the mid-Ohio Valley.

Background: Perfluorooctanoic acid (PFOA) is a potential cause of adverse pregnancy outcomes, but previous studies have been limited by low exposures and small study size. Objectives: Using birth certificate information, we examined the relation between estimated PFOA exposure and birth outcomes in an area of West Virginia and Ohio whose drinking water was contaminated by a chemical plant. Methods: Births in the study area from 1990 through 2004 were examined to generate case groups of stillbirth (n = 106), pregnancy-induced hypertension (n = 224), preterm birth (n = 3,613), term low birth weight (n = 918), term small-for-gestational-age (SGA) (n = 353), and a continuous measure of birth weight among a sample of term births (n = 4,534). A 10% sample of term births ≥ 2,500 g were selected as a source of controls (n = 3,616). Historical estimates of serum PFOA were derived from a previously developed fate and transport model. In a second study, we examined 4,547 area births linked to a survey with residential history data. Results: In the analysis based only on birth records, we found no consistent evidence of an association between estimated PFOA exposure and stillbirth, pregnancy-induced hypertension, preterm birth, or indices of fetal growth. In the analysis of birth records linked to the survey, PFOA was unrelated to pregnancy-induced hypertension or preterm birth but showed some suggestion of an association with early preterm birth. Measures of growth restriction showed weak and inconsistent associations with PFOA. Conclusions: Based on the analysis using the health survey, these results provide little support for an effect of PFOA exposure on most pregnancy outcomes, except for early preterm birth and possibly fetal growth restriction.