Frank R. Witter

Cord Serum Concentrations of Perfluorooctane Sulfonate (PFOS) and Perfluorooctanoate (PFOA) in Relation to Weight and Size at Birth

Background Recent studies have reported developmental toxicity among rodents dosed with perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). Objectives We 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. Methods We 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. Results After 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. Conclusions Despite 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.

Birth delivery mode modifies the associations between prenatal polychlorinated biphenyl (PCB) and polybrominated diphenyl ether (PBDE) and neonatal thyroid hormone levels

Background Developing infants may be especially sensitive to hormone disruption from chemicals including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). Objective We investigated relationships between cord serum levels of PCBs and PBDEs and thyroid hormones measured in cord blood serum and neonatal blood spots. Methods We measured PCBs and PBDEs, thyrotropin (TSH), thyroxine (T4) and free T4 (FT4) in cord blood serum from 297 infants who were delivered at the Johns Hopkins Hospital in 2004–2005. We abstracted results of total T4 (TT4) measured in blood spots collected in the hospital and at neonatal visits. We used delivery mode (augmented vaginal deliveries and nonelective cesarean deliveries) as a surrogate for intrapartum stress, which is known to alter cord blood thyroid hormones. Results In the full study population, no compounds were associated with a change in average TSH, FT4, or TT4. BDE-100 was associated with increased odds of low cord TT4, BDE-153 with increased odds of low cord TT4 and FT4, and no compounds were associated with increased odds of high TSH. For infants born by spontaneous, vaginal, unassisted deliveries, PCBs were associated with lower cord TT4 and FT4 and lower TT4 measured in neonatal blood spots. PBDEs showed consistent but mainly nonsignificant negative associations with TT4 and FT4 measurements. Conclusions Prenatal PCB and PBDE exposures were associated with reduced TT4 and FT4 levels among infants born by spontaneous, unassisted vaginal delivery. Intrapartum stress associated with delivery mode may mask hormonal effects of PCBs and PBDEs.

Prenatal Maternal Stress and Cord Blood Innate and Adaptive Cytokine Responses in an Inner-City Cohort

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 = 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

Early risk factors for pregnancy loss in lupus

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-alpha 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-gamma. 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.

Global DNA hypomethylation is associated with in utero exposure to cotinine and perfluorinated alkyl compounds.

OBJECTIVE: To identify early risk factors for pregnancy loss in lupus pregnancies. METHODS: We conducted a cohort study of all pregnancies seen in the first trimester in lupus patients followed from 1987 to 2002 at the Hopkins Lupus Center. At each visit, vital signs, a complete blood count, a urinalysis, and a 24-hour urine collection for total protein, if the dipstick revealed proteinuria, were obtained. Proteinuria was defined as protein greater than 500 mg in a 24-hour urine collection. Secondary antiphospholipid syndrome was diagnosed by using the Sapporo criteria. Thrombocytopenia was defined as platelets under 150,000. Hypertension was defined as blood pressure over 140/90 mm Hg during the first trimester. Pregnancies electively terminated were excluded from this study. RESULTS: One hundred sixty-six pregnancies in 125 women were followed in the Hopkins Lupus Cohort from the first trimester onward. Twenty-seven pregnancies (16%) ended with a loss. Pregnancy loss was increased 2.6 times in women with first-trimester proteinuria (P = .04). A diagnosis of secondary antiphospholipid syndrome led to a 3.1-fold increase in pregnancy loss, predominantly after 20 weeks of gestation (P = .004). Thrombocytopenia in the first trimester led to an increase in pregnancy loss by 3.3 fold (P ≤ .001). First-trimester hypertension led to a 2.4-fold increase in pregnancy loss (P = .027). Each risk factor was independent in raising pregnancy loss risk. CONCLUSION: The acronym PATH can help remind clinicians to monitor for Proteinuria, Antiphospholipid syndrome, Thrombocytopenia, and Hypertension early in pregnancy. Close observation, with frequent laboratory analysis and appropriate therapy, is important to pregnancy success in women with lupus. LEVEL OF EVIDENCE: II-2

Determinants of gestational weight gain outside the recommended ranges among black and white women

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.

Influence of maternal anthropometric status and birth weight on the risk of cesarean delivery

Objectives To identify factors influencing risk of gaining outside the Institute of Medicine recommendations for pregnancy weight gain, and to determine whether these factors differ by race. Methods Multivariate methods were used to identify risk factors for under- and over-gain among 2617 black and 1253 white women delivering at the Johns Hopkins Hospital during 1987–1989. Results Only 28.2% of black women and 32.5% of white women gained the recommended amounts of weight during pregnancy, Maternal pre-pregnancy body mass index (BMI), height, parity, education, smoking, hypertension, duration of pregnancy, and fetal sex influenced risk for under-gain or over-gain. Black women were 1.51 (95% confidence interval [CI] 1.23–1.85) times more likely to under-gain, but 0.89% (95% CI 0.74–1.08) times less likely to over-gain than white women. No interactions were found between any factor examined and BMI or race. Conclusion Only about one-third of women are gaining the recommended amounts of weight during pregnancy. Black women are at increased risk for gaining less weight than recommended, and selected maternal characteristics associated with race do not explain this difference. Further, risk factors for under- or over-gain do not differ between black and white women.

Determinants of Prenatal Exposure to Polychlorinated Biphenyls (PCBs) and Polybrominated Diphenyl Ethers (PBDEs) in an Urban Population

Objective To determine whether greater weight gain during pregnancy is associated with an increased risk of cesarean delivery, and, if so, whether this effect is explained by the positive influence of weight gain on birth weight and if there is a threshold of pregnancy weight gain above which the risk of cesarean delivery is increased differentially. Methods We analyzed live births at Johns Hopkins Hospital for the period 1987–1989. A multiple logistic regression model was used to evaluate the risk of cesarean delivery recorded in the hospitals perinatal data base. Results The study sample contained 4346 patients, 1086 of whom delivered by cesarean. Associated independently with an increased risk of cesarean delivery were the following: 1) greater weight gain during pregnancy, 2) older maternal age, 3) greater maternal prepregnant body mass index, 4) maternal height of 1.57 m or less, 5) the diagnosis of preeclampsia during current pregnancy, and 6) carrying a fetus weighing more than 3591 g at birth. An additional risk factor for cesarean delivery was a fetus less than 2847 g at birth, with the risk more marked the lower the gestational age. Maternal height of 1.73 m or more and a history of at least one previous viable pregnancy were associated independently with a decreased risk of cesarean delivery. Conclusion The risk of cesarean delivery increases linearly with pregnancy weight gain, independent of birth weight. No specific threshold of weight gain can be determined above which the cesarean risk climbs more rapidly.

Neonatal outcome after indomethacin treatment for preterm labor

Background Recent studies have reported blood levels of polybrominated diphenyl ethers (PBDEs) in the U.S. population. Information about neonatal levels and about the relationship to polychlorinated biphenyls (PCBs) exposures is limited. Objectives The objective was to characterize levels and determinants of fetal exposure to PBDEs and PCBs among newborns from Baltimore, Maryland. Methods We analyzed umbilical cord blood for eight PBDEs and 35 PCBs from infants delivered at the Johns Hopkins Hospital. Maternal and infant characteristics were abstracted from medical records. Results Ninety-four percent of cord serum samples had quantifiable levels of at least one PBDE congener, and > 99% had at least one detectable PCB congener. PBDE concentrations in cord blood were similar to those reported in other studies from North America. Strong correlations were observed within but not across PCB and PBDE classes. Multivariate models showed that many factors independently predicted exposure to BDE-47, BDE-100, and BDE-153 and CB-118, CB-138/158, CB-153, and CB-180. Generally, infants of Asian mothers had lower PBDE and PCB levels, and infants of smokers had higher levels. Increased maternal body mass index was associated with lower levels of PCBs but not PBDEs. Levels of PCBs but not PBDEs were lower in births from married and multiparous mothers. Increased maternal age was associated with higher PCB levels but lower PBDE levels. Conclusions Although many of the factors we investigated were independent predictors of both PBDE and PCB levels, in some cases the direction of associations was different. More research is needed to better understand the sources and pathways of PBDE exposure.

Characteristics and risk factors for adverse birth outcomes in pregnant black adolescents

Forty-six infants exposed to indomethacin in utero for treatment for preterm labor were compared with infants from two control groups. In one control group the next consecutive patient treated with a tocolytic agent was used, and the other control group was formed by picking the next consecutive patient matched by gestational age who did not receive any tocolytic agent. There was no significant difference in Apgar scores, birth weight, or gestational age in the three groups. The incidence of neonatal complications including hypocalcemia, hypoglycemia, respiratory distress syndrome, patient ductus arteriosus, sepsis, and neonatal mortality were not significantly different in the three groups. No cases of premature closure of the ductus arteriosus or persistent fetal circulation were seen.