BackgroundRecent studies have reported developmental toxicity among rodents dosed with perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA).ObjectivesWe examined the relationship between concentrations of PFOS and PFOA in cord serum (surrogates for in utero exposures) and gestational age, birth weight, and birth size in humans.MethodsWe conducted a hospital-based cross-sectional epidemiologic study of singleton deliveries in Baltimore, Maryland. Cord serum samples (n = 293) were analyzed for PFOS and PFOA by online solid-phase extraction, coupled with reversed-phase high-performance liquid chromatography–isotope dilution tandem mass spectrometry. Maternal characteristics and anthropometric measures were obtained from medical charts.ResultsAfter adjusting for potential confounders, both PFOS and PFOA were negatively associated with birth weight [per ln-unit: β = −69 g, 95% confidence interval (CI), −149 to 10 for PFOS; β = −104 g, 95% CI, −213 to 5 for PFOA], ponderal index (per ln-unit: β = −0.074 g/cm3 × 100, 95% CI, −0.123 to −0.025 for PFOS; β = −0.070 g/cm3 × 100, 95% CI, −0.138 to −0.001 for PFOA), and head circumference (per ln-unit: β = −0.32 cm, 95% CI, −0.56 to −0.07 for PFOS; β = −0.41 cm, 95% CI, −0.76 to −0.07 for PFOA). No associations were observed between either PFOS or PFOA concentrations and newborn length or gestational age. All associations were independent of cord serum lipid concentrations.ConclusionsDespite relatively low cord serum concentrations, we observed small negative associations between both PFOS and PFOA concentrations and birth weight and size. Future studies should attempt to replicate these findings in other populations.

Objective. Hydroxychloroquine (HCQ) is often needed to manage disease activity in systemic lupus erythematosus (SLE) during pregnancy. The purpose of this study was to examine lupus activity and pregnancy outcomes in women with SLE treated or not treated with HCQ during pregnancy.Methods. This was a prospective study of pregnancies in women with SLE who were evaluated between 1987 and 2002. The pregnancies were divided into 3 groups: no HCQ exposure during pregnancy (163 pregnancies), continuous use of HCQ during pregnancy (56 pregnancies), or cessation of HCQ treatment either in the 3 months prior to or during the first trimester of pregnancy (38 pregnancies). The pregnancy outcomes, fetal outcomes, and lupus activity during pregnancy were compared among these groups.Results. The rates of miscarriage, stillbirth, pregnancy loss, and congenital abnormality were not statistically different among the 3 groups. The degree of lupus activity during pregnancy, however, was significantly higher in women who stopped taking HCQ. These women had a higher degree of lupus activity, as measured by the physician's estimate of lupus activity and the SLE Disease Activity Index, as well as an increased rate of flare, during pregnancy. More serious lupus complications, such as proteinuria and thrombocytopenia, were not significantly higher in women who stopped taking HCQ. Women who continued taking HCQ were maintained on a lower average dose of prednisone during pregnancy.Conclusion. We recommend the continuation of HCQ treatment during pregnancy. Our findings are consistent with prior reports of the absence of fetal toxicity. Similar to studies of nonpregnant women, the cessation of HCQ treatment during pregnancy increases the degree of lupus activity.Many women with systemic lupus erythematosus (SLE) take hydroxychloroquine (HCQ) to control disease activity. Studies have shown that HCQ can prevent renal and central nervous system lupus and lessen the effects of SLE (1,2). It has also been demonstrated that cessation of HCQ treatment places a woman at more than twice the risk of a lupus flare in the subsequent 6 months (3,4). Women with SLE maintain fertility, and most can have a successful pregnancy (5-7). Experts in the care of SLE during pregnancy generally recommend continuing HCQ treatment during pregnancy (8). At the Fourth International Conference on Sex Hormones, Pregnancy, and the Rheumatic Diseases in 2004, the working group on medications during pregnancy recommended continuing HCQ treatment (9). The data to support this recommendation are limited to reports of Ͻ300 pregnancies, however. A significant minority of rheumatologists, particularly those who see few lupus pregnancies per year, do not routinely continue HCQ treatment during pregnancy (8).Early reports of in utero chloroquine toxicity have led to some trepidation about the use of HCQ during pregnancy (10,11). However, more recent systematic studies of HCQ use during pregnancy have suggested its safety (12-16). There have been no reported cases of fetal malfor...

Objective. Systemic lupus erythematosus is associated with multiple adverse pregnancy outcomes. We examined the impact of disease activity on spontaneous abortions, perinatal mortality, preterm delivery, and birth weight.Methods. The study was designed to assess all pregnancies in a cohort of lupus patients who were observed prospectively from 1987 to 2002. At each visit, the physician's estimate of lupus activity was determined on a visual analog scale (high-activity lupus defined as a score of >2). Disease activity in each trimester was compared. We assessed the impact of high-activity lupus during pregnancy on gestational age, live birth rate, and small for gestational age babies. Potential confounders, including demographics of the women as well as maternal history of lupus, renal lupus, and antiphosphoplipid antibody syndrome, were analyzed through multivariate analysis.Results. Two hundred sixty-seven pregnancies were observed. Of these, 229 (85.8%) resulted in a live birth. High-activity lupus occurred in 57 pregnancies (21%). Fewer pregnancies among women with highactivity lupus ended with live births (77% versus 88% of those with low-activity lupus; P ‫؍‬ 0.063). Full-term delivery was achieved in 15 pregnancies (26%) among women with high-activity lupus, compared with 127 pregnancies (61%) achieving full-term in those with no or mild lupus activity (P < 0.001). High-activity lupus in the first and second trimesters led to a 3-fold increase in pregnancy loss (miscarriages and perinatal mortality).Conclusion. High-activity lupus during pregnancy leads to increased premature birth and a decrease in live births, with almost one-quarter of these pregnancies resulting in fetal loss. Pregnancies in lupus patients must be closely watched and treated during all trimesters to improve pregnancy outcomes.Systemic lupus erythematosus (SLE) is a disease that affects primarily women of reproductive age. The peak incidence of SLE occurs between the ages of 15 and 40 years, with an estimated female-to-male SLE incidence of 9:1. Previous studies have demonstrated that women with SLE maintain fertility, leading to the potential for a large number of pregnancies in this population (1). Pregnancies in women with lupus, however, have poorer obstetric outcomes than pregnancies in healthy women. These pregnancies have higher rates of preterm delivery and fetal loss, and the mothers and newborns have longer hospital stays than that experienced by women without lupus (2-4).The impact of increased lupus activity on pregnancy outcomes is a subject of debate in the literature. Some reports indicate that lupus activity, particularly lupus nephritis, increases the risk of fetal loss (3,(5)(6)(7). Other studies show no statistically significant difference between pregnancies in women with active lupus and those in women with inactive lupus (8-10). The first 74 pregnancies in the Hopkins Lupus Cohort were previously analyzed in a report published in 1992 (11). This analysis found that the occurrence of a lupus flare during pregnancy d...

Epigenome-wide association studies of disease widely use DNA methylation measured in blood as a surrogate tissue. Cell proportions can vary between people and confound associations of exposure or outcome. An adequate reference panel for estimating cell proportions from adult whole blood for DNA methylation studies is available, but an analogous cord blood cell reference panel is not yet available. Cord blood has unique cell types and the epigenetic signatures of standard cell types may not be consistent throughout the life course. Using magnetic bead sorting, we isolated cord blood cell types (nucleated red blood cells, granulocytes, monocytes, natural killer cells, B cells, CD4(+)T cells, and CD8(+)T cells) from 17 live births at Johns Hopkins Hospital. We confirmed enrichment of the cell types using fluorescence assisted cell sorting and ran DNA from the separated cell types on the Illumina Infinium HumanMethylation450 BeadChip array. After filtering, the final analysis was on 104 samples at 429,794 probes. We compared cell type specific signatures in cord to each other and methylation at 49.2% of CpG sites on the array differed by cell type (F-test P < 10(-8)). Differences between nucleated red blood cells and the remainder of the cell types were most pronounced (36.9% of CpG sites at P < 10(-8)) and 99.5% of these sites were hypomethylated relative to the other cell types. We also compared the mean-centered sorted cord profiles to the available adult reference panel and observed high correlation between the overlapping cell types for granulocytes and monocytes (both r=0.74), and poor correlation for CD8(+)T cells and NK cells (both r=0.08). We further provide an algorithm for estimating cell proportions in cord blood using the newly developed cord reference panel, which estimates biologically plausible cell proportions in whole cord blood samples.

Polyfluoroalkyl compounds (PFCs), such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), are ubiquitous, man-made chemicals. Human data suggest that in utero exposures to these chemicals occur and some evidence of developmental toxicity in animals exists. To assess the distribution and determinants of fetal exposure to PFCs, we analyzed cord serum samples from 299 singleton newborns delivered between 2004 and 2005 in Baltimore, MD for 10 PFCs by employing on-line solid-phase extraction coupled with reversed-phase high-performance liquid chromatography-tandem mass spectrometry. PFOS and PFOA were detected in 99 and 100% of umbilical cord sera, with geometric mean concentrations of 4.9 and 1.6 ng/mL, respectively. PFOS and PFOA concentrations were highly correlated (Pearson's r = 0.64 after natural log transformation, p < 0.01). Eight other PFCs were detected less frequently and at lower concentrations than PFOS and PFOA. Geometric mean concentrations of PFOS for Asians (6.0 ng/mL) and Blacks (5.1 ng/mL) were higher than those for Whites (4.2 ng/mL), while PFOA levels were more evenly distributed by race. Other maternal demographic and socioeconomic characteristics, including age, education, marital status, and living in the city limits were not significantly associated with cord concentrations. Our findings suggest that in utero exposure to PFOS and PFOA is ubiquitous in a population of babies born in Baltimore, MD.

Rationale: Stress-elicited disruption of immunity begins in utero. Objectives: Associations among prenatal maternal stress and cord blood mononuclear cell (CBMC) cytokine responses were prospectively examined in the Urban Environment and Childhood Asthma Study (n 5 557 families). Methods: Prenatal maternal stress included financial hardship, difficult life circumstances, community violence, and neighborhood/block and housing conditions. Factor analysis produced latent variables representing three contexts: individual stressors and ecological-level strains (housing problems and neighborhood problems), which were combined to create a composite cumulative stress indicator. CBMCs were incubated with innate (lipopolysaccharide, polyinosinic-polycytidylic acid, cytosine-phosphate-guanine dinucleotides, peptidoglycan) and adaptive (tetanus, dust mite, cockroach) stimuli, respiratory syncytial virus, phytohemagglutinin, or medium alone. Cytokines were measured using multiplex ELISAs. Using linear regression, associations among increasing cumulative stress and cytokine responses were examined, adjusting for sociodemographic factors, parity, season of birth, maternal asthma and steroid use, and potential pathway variables (prenatal smoking, birth weight for gestational age). Measurements and Main Results: Mothers were primarily minorities (Black [71%], Latino [19%]) with an income less than $15,000 (69%). Mothers with the highest cumulative stress were older and more likely to have asthma and deliver lower birth weight infants. Higher prenatal stress was related to increased IL-8 production after microbial (CpG, PIC, peptidoglycan) stimuli and increased tumor necrosis factor-a to microbial stimuli (CpG, PIC). In the adaptive panel, higher stress was associated with increased IL-13 after dust mite stimulation and reduced phytohemagglutinin-induced IFN-g. Conclusions: Prenatal stress was associated with altered innate and adaptive immune responses in CBMCs. Stress-induced perinatal immunomodulation may impact the expression of allergic disease in these children.

Environmental exposures in-utero may alter the epigenome, thus impacting chromosomal stability and gene expression. We hypothesized that in utero exposures to maternal smoking and perfluoroalkyl compounds (PFCs) are associated with global DNA hypomethylation in umbilical cord serum. Our objective was to determine if global DNA methylation could be used as a biomarker of in utero exposures to maternal smoking and PFCs. Using an ELISA-based method, global DNA methylation was quantified in umbilical cord serum from 30 newborns with high (> 10 ng/ml, mean 123.8 ng/ml), low (range 1-10 ng/ml, mean 1.6 ng/ml) and very low (< 1 ng/ml, mean 0.06 ng/ml) cord serum cotinine levels. Y chromosome analysis was performed to rule out maternal DNA cross-contamination. Cord serum global DNA methylation showed an inverse dose response to serum cotinine levels (p< 0.001). Global DNA methylation levels in cord blood were the lowest among newborns with smoking mothers (mean=15.04%; 95% CI, 8.4, 21.7) when compared to babies of mothers who were second-hand smokers (21.1%; 95% CI, 16.6, 25.5) and non-smokers (mean=29.2%; 95% CI, 20.1, 38.1). Global DNA methylation was inversely correlated with serum PFOA (r= -0.72, p < 0.01) but not PFOS levels. Serum Y chromosome analyses did not detect maternal DNA cross-contamination. This study supports the use of global DNA methylation status as a biomarker of in utero exposure to cigarette smoke and PFCs.

Low-dose aspirin decreases the incidence of preeclampsia among nulliparous women, primarily through its effect in those who have elevated systolic blood pressure initially. This treatment does not decrease perinatal morbidity but increases the risk of abruptio placentae.