Evaluating congenital syphilis in a reverse sequence testing environment.

OBJECTIVES: To examine the effect of maternal reverse-sequence (RS) syphilis screening on management of infants at risk for congenital syphilis (CS) using a standardized approach. STUDY DESIGN: A retrospective study from 2011 to 2014 at an academic medical center using RS testing, involving chemiluminescent immunoassay (CIA), rapid plasma  reagin (RPR), and fluorescent treponemal antibody-absorption (FTA-ABS) assays for syphilis. Clinical management and outcomes of infants born to mothers with discordant (CIA+/RPR-/FTA+) serology were compared with national or internal guidelines. RESULTS: Sixty-three infants were classified as discordant (n = 21), presumed false positive (CIA+/RPR-/FTA-; n = 16), or true positive (CIA+/RPR+; n = 26) based on maternal serology. Only 24% of cases in the discordant group underwent recommended full evaluation. None of the evaluated infants in the discordant group (n = 8) were diagnosed with CS. CONCLUSIONS: Management of infants with discordant maternal RS serology remained reliant on clinical judgment. In our high-risk population, RS testing did not identify additional cases of CS.

Methyl mercury, but not inorganic mercury, associated with higher blood pressure during pregnancy.

Prior studies addressing associations between mercury and blood pressure have produced inconsistent findings; some of this may result from measuring total instead of speciated mercury. This cross-sectional study of 263 pregnant women assessed total mercury, speciated mercury, selenium, and n-3 polyunsaturated fatty acids in umbilical cord blood and blood pressure during labor and delivery. Models with a) total mercury or b) methyl and inorganic mercury were evaluated. Regression models adjusted for maternal age, race/ethnicity, prepregnancy body mass index, neighborhood income, parity, smoking, n-3 fatty acids and selenium. Geometric mean total, methyl, and inorganic mercury concentrations were 1.40µg/L (95% confidence interval: 1.29, 1.52); 0.95µg/L (0.84, 1.07); and 0.13µg/L (0.10, 0.17), respectively. Elevated systolic BP, diastolic BP, and pulse pressure were found, respectively, in 11.4%, 6.8%, and 19.8% of mothers. In adjusted multivariable models, a one-tertile increase of methyl mercury was associated with 2.83mmHg (0.17, 5.50) higher systolic blood pressure and 2.99mmHg (0.91, 5.08) higher pulse pressure. In the same models, an increase of one tertile of inorganic mercury was associated with -1.18mmHg (-3.72, 1.35) lower systolic blood pressure and -2.51mmHg (-4.49, -0.53) lower pulse pressure. No associations were observed with diastolic pressure. There was a non-significant trend of higher total mercury with higher systolic blood pressure. We observed a significant association of higher methyl mercury with higher systolic and pulse pressure, yet higher inorganic mercury was significantly associated with lower pulse pressure. These results should be confirmed with larger, longitudinal studies.

A Model for the Departmental Quality Management Infrastructure Within an Academic Health System.

As quality improvement and patient safety come to play a larger role in health care, academic medical centers and health systems are poised to take a leadership role in addressing these issues. Academic medical centers can leverage their large integrated footprint and have the ability to innovate in this field. However, a robust quality management infrastructure is needed to support these efforts. In this context, quality and safety are often described at the executive level and at the unit level. Yet, the role of individual departments, which are often the dominant functional unit within a hospital, in realizing health system quality and safety goals has not been addressed. Developing a departmental quality management infrastructure is challenging because departments are diverse in composition, size, resources, and needs.In this article, the authors describe the model of departmental quality management infrastructure that has been implemented at the Johns Hopkins Hospital. This model leverages the fractal approach, linking departments horizontally to support peer and organizational learning and connecting departments vertically to support accountability to the hospital, health system, and board of trustees. This model also provides both structure and flexibility to meet individual departmental needs, recognizing that independence and interdependence are needed for large academic medical centers. The authors describe the structure, function, and support system for this model as well as the practical and essential steps for its implementation. They also provide examples of its early success.

A home calendar and recall method of last menstrual period for estimating gestational age in rural Bangladesh: a validation study.

BACKGROUND: The best method of gestational age assessment is by ultrasound in the first trimester; however, this method is impractical in large field trials in rural areas. Our objective was to assess the validity of gestational age estimated from prospectively collected date of last menstrual period (LMP) using crown-rump length (CRL) measured in early pregnancy by ultrasound. METHODS: As part of a large, cluster-randomized, controlled trial in rural Bangladesh, we collected dates of LMP by recall and as marked on a calendar every 5 weeks in women likely to become pregnant. Among those with a urine-test confirmed pregnancy, a subset with gestational age of <15 weeks (n = 353) were enrolled for ultrasound follow-up to measure CRL. We compared interview-assessed LMP with CRL gestational age estimates and classification of preterm, term, and post-term births. RESULTS: LMP-based gestational age was higher than CRL by a mean (SD) of 2.8 (10.7) days; differences varied by maternal education and preterm birth (P < 0.05). Lin's concordance correlation coefficient was good at ultrasound [0.63 (95 % CI 0.56, 0.69)] and at birth [0.77 (95 % CI 0.73, 0.81)]. Validity of classifying preterm birth was high but post-term was lower, with specificity of 96 and 89 % and sensitivity of 86 and 67 %, respectively. Results were similar by parity. CONCLUSIONS: Prospectively collected LMP provided a valid estimate of gestational age and preterm birth in a rural, low-income setting and may be a suitable alternative to ultrasound in programmatic settings and large field trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00860470.

The influence of atopy and asthma on immune responses in inner-city adults.

Asthma in the inner-city population is usually atopic in nature, and is associated with significant morbidity and mortality. However, the underlying immune abnormalities that underlie asthma in urban adults have not been well defined. We investigated the influence of atopy and asthma on cytokine responses of inner-city adult women to define immune abnormalities associated with asthma and atopy. Blood samples were collected from 509 of 606 inner-city women enrolled in the Urban Environment and Childhood Asthma (URECA) study. We tested for associations between atopy and asthma status and cytokine responses in peripheral blood mononuclear cells incubated ex vivo with a panel of innate and adaptive immune stimulants. Atopic subjects had heightened Th2 cytokine responses (IL-4, IL-5, IL-13) to cockroach and dust mite antigens, tetanus toxoid, and phytohemagglutinin (P < 0.05 for all). Differences in cytokine responses were greatest in response to stimulation with cockroach and dust mite. In a multivariate analysis, atopy was broadly related to increased Th2-like responses to all antigens and PHA, while asthma was only weakly related to mitogen-induced IL-4 and IL-5 responses. There were few asthma or allergy-related differences in responses to innate stimuli, including IFN-α and IFN-γ responses. In this inner-city adult female population, atopy is associated with enhanced Th2 responses to allergens and other stimuli, and there was little or no additional signal attributable to asthma. In particular, these data indicate that altered systemic interferon and innate immune responses are not associated with allergies and/or asthma in inner-city women.

Cord Blood Methylmercury and Fetal Growth Outcomes in Baltimore Newborns: Potential Confounding and Effect Modification by Omega-3 Fatty Acids, Selenium, and Sex.

BACKGROUND: Methylmercury (MeHg) may affect fetal growth; however, prior research often lacked assessment of mercury speciation, confounders, and interactions. OBJECTIVE: Our objective was to assess the relationship between MeHg and fetal growth as well as the potential for confounding or interaction of this relationship from speciated mercury, fatty acids, selenium, and sex. METHODS: This cross-sectional study includes 271 singletons born in Baltimore, Maryland, 2004-2005. Umbilical cord blood was analyzed for speciated mercury, serum omega-3 highly unsaturated fatty acids (n-3 HUFAs), and selenium. Multivariable linear regression models controlled for gestational age, birth weight, maternal age, parity, prepregnancy body mass index, smoking, hypertension, diabetes, selenium, n-3 HUFAs, and inorganic mercury (IHg). RESULTS: Geometric mean cord blood MeHg was 0.94 µg/L (95% CI: 0.84, 1.07). In adjusted models for ponderal index, ßln(MeHg) = -0.045 (g/cm(3)) × 100 (95% CI: -0.084, -0.005). There was no evidence of a MeHg × sex interaction with ponderal index. Contrastingly, there was evidence of a MeHg × n-3 HUFAs interaction with birth length [among low n-3 HUFAs, ßln(MeHg) = 0.40 cm, 95% CI: -0.02, 0.81; among high n-3 HUFAs, ßln(MeHg) = -0.15, 95% CI: -0.54, 0.25; p-interaction = 0.048] and head circumference [among low n-3 HUFAs, ßln(MeHg) = 0.01 cm, 95% CI: -0.27, 0.29; among high n-3 HUFAs, ßln(MeHg) = -0.37, 95% CI: -0.63, -0.10; p-interaction = 0.042]. The association of MeHg with birth weight and ponderal index was affected by n-3 HUFAs, selenium, and IHg. For birth weight, ßln(MeHg) without these variables was -16.8 g (95% CI: -75.0, 41.3) versus -29.7 (95% CI: -93.9, 34.6) with all covariates. Corresponding values for ponderal index were -0.030 (g/cm(3)) × 100 (95% CI: -0.065, 0.005) and -0.045 (95% CI: -0.084, -0005). CONCLUSION: We observed an association of increased MeHg with decreased ponderal index. There is evidence for interaction between MeHg and n-3 HUFAs; infants with higher MeHg and n-3 HUFAs had lower birth length and head circumference. These results should be verified with additional studies.

Recognition of Streptococcus pseudoporcinus Colonization in Women as a Consequence of Using Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Group B Streptococcus Identification.

During a 14-month period of using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for group B streptococcus (GBS) identification, we recovered 32 (1%) Streptococcus pseudoporcinus isolates from 3,276 GBS screening cultures from female genital sources (25 isolates from pregnant women and 7 from nonpregnant women). An additional two S. pseudoporcinus isolates were identified from a urine culture and a posthysterectomy wound culture. These isolates were found to cross-react with three different GBS antigen agglutination kits, PathoDx (Remel) (93%), Prolex (Pro-Lab Diagnostics) (38%), and Streptex (Remel) (53%). New approaches to bacterial identification in routine clinical microbiology laboratories may affect the prevalence of S. pseudoporcinus.

Prenatal mercury concentration is associated with changes in DNA methylation at TCEANC2 in newborns.

BACKGROUND: Human exposure to the widespread environmental contaminant mercury is a known risk factor for common diseases such as cancer, cardiovascular disease and neurological disorders through poorly characterized mechanisms. Evidence suggests mercury exposure may alter DNA methylation levels, but to date, the effects in early life on a genome-wide scale have not been investigated. METHODS: A study sample of 141 newborns was recruited in Baltimore, MD, USA and total mercury and methylmercury were measured in cord blood samples. We quantified genome-wide DNA methylation data using CHARM 2.0, an array-based method, and used region-finding analyses to identify concentration-associated differentially methylated regions (DMRs). To test for replication of these identified DMRs in the pilot, or Vanguard, phase of the National Children's Study (NCS), we compared bisulfite-pyrosequenced DNA at candidate regions from 85 whole cord blood samples with matched first trimester maternal mercury concentration measures. RESULTS: Total mercury concentration was associated with methylation at DMRs inside ANGPT2 and near PRPF18 genes [false discovery rate (FDR) < 0.05], as well as DMRs near FOXD2 and within TCEANC2 (FDR< 0.1) genes. Methylmercury concentration was associated with an overlapping DMR within TCEANC2 (FDR< 0.05). In NCS replication analyses, methylation levels at three of four cytosine-guanine DNA dinucleotides (CpG sites) within the TCEANC2 DMR were associated with total mercury concentration (P < 0.05), and this association was diminished after adjusting for estimated cell proportions. CONCLUSIONS: Evidence for an association between mercury and DNA methylation at the TCEANC2 region was found, which may represent a mercury-associated shift in cord blood cell composition or a change in methylation within blood cell types. Further confirmatory studies are needed.

Elucidating the molecular basis of adverse health effects from exposure to anthropogenic polyfluorinated compounds using toxicoproteomic approaches.

Linear, short-chain polyfluorinated and perfluorinated alkyl compounds, often referred to as PFCs, have been in worldwide use as surfactants and polymer precursors for decades, and environmental dispersal of these highly persistent compounds represents a public health threat. Whereas ubiquitous low-level exposure to these compounds has been demonstrated in human populations from around the world, the exact mechanisms of toxicity and their toxic potency remain subject to investigation and scientific dispute. As with other environmental exposures, a major hurdle for gaining a better understanding of their human health impacts is the limited utility of cell culture and animal models serving as convenient, yet imperfect proxies to human physiology and disease. The present communication provides a brief overview of the current understanding of potential health effects of PFC exposure and examines how new toxicoproteomic methodologies can provide insight into the molecular mechanism of PFC exposure. Furthermore, we showcase an exemplary data set to illustrate how toxicoproteomic, population-wide studies might overcome limitations of animal models to more fully understand the metabolism and effects of PFCs and other environmental stressors where it matters most, in human populations experiencing real-world, chronic, low-level exposures.

A potential method to lower risk for surgical site infection during cesarean birth.

It's common practice to use a preparation containing chlorhexidine to prepare the surgical site before cesarean birth. We observed an interaction between ultrasound gel, used for electronic fetal heart monitoring before birth, and chlorhexidine. This interaction creates the potential for surgical site infection. Using isopropyl alcohol to thoroughly remove all gel before application of chlorhexidine was associated with reduced rates of postsurgical infection at our institution.

Diagnostic accuracy of fetal heart rate monitoring in the identification of neonatal encephalopathy.

OBJECTIVE: To estimate the diagnostic accuracy of electronic fetal heart rate abnormalities in the identification of neonates with encephalopathy treated with whole-body hypothermia. METHODS: Between January 1, 2007, and July 1, 2013, there were 39 neonates born at two hospitals within our system treated with whole-body hypothermia within 6 hours of birth. Neurologically normal control neonates were matched to each case by gestational age and mode of delivery in a two-to-one fashion. The last hour of electronic fetal heart rate monitoring before delivery was evaluated by three obstetricians blinded to outcome. RESULTS: The differences in tracing category were not significantly different (neonates in the case group 10.3% I, 76.9% II, 12.8% III; neonates in the control group 9.0% I, 89.7% II, 1.3% III; P=.18). Bivariate analysis showed neonates in the case group had significantly increased late decelerations, total deceleration area 30 (debt 30) and 60 minutes (debt 60) before delivery and were more likely to be nonreactive. Multivariable logistic regression showed neonates in the case group had a significant decrease in early decelerations (P=.03) and a significant increase in debt 30 (.01) and debt 60 (P=.005). The area under the receiver operating characteristic curve, sensitivity, and specificity were 0.72, 23.1%, and 94.9% for early decelerations; 0.66, 33.3%, and 87.2% for debt 30, and 0.68, 35.9%, and 89.7% for debt 60, respectively. CONCLUSION: Abnormalities during the last hour of fetal heart rate monitoring before delivery are poorly predictive of neonatal hypoxic-ischemic encephalopathy qualifying for whole-body hypothermia treatment within 6 hours of birth. LEVEL OF EVIEDENCE: II.

Decreasing cesarean section surgical site infection: an ongoing comprehensive quality improvement program.

This report illustrates how the "plan-do-study-act" method of continuous quality improvement can be effective in reducing surgical site infection after cesarean delivery.

Reductions in heel bone quality across gestation are attenuated in pregnant adolescents with higher prepregnancy weight and greater increases in PTH across gestation.

Few studies have examined the effect of maternal calcium intake and vitamin D status on bone health across gestation in pregnant adolescents. This study aimed to characterize maternal bone quality and determinants of bone-quality change across gestation in pregnant adolescents. Healthy pregnant adolescents (n = 156; aged 13 to 18 years) with singleton pregnancies and at 12 to 30 weeks gestation at enrollment were recruited from two urban maternity clinics in Baltimore, MD, and Rochester, NY, for this prospective longitudinal study. Maternal serum was collected at midgestation and at delivery for assessment of bone biomarkers and calcitropic hormones. Maternal bone quality (assessed by heel ultrasound) and sonographic fetal biometry were measured up to three times across pregnancy. Racially diverse teens (64.7% African American, 35.3% white) were followed from 21.0 (interquartile range [IQR] 17.3, 27.0) weeks of gestation until delivery at 40.0 (IQR 39.0, 40.7) weeks. Significant decreases in calcaneal speed of sound (SOS), broadband ultrasound attenuation (BUA), and quantitative ultrasound index (QUI) (-9.2 ± 16.1 m/s, -3.2 (-8.0, 2.1) dB/MHz and -5.3 ± 8.8, respectively) were evident across pregnancy. Multivariate analysis controlling for baseline measures and measurement intervals was used to identify independent predictors of normalized (per week) calcaneal bone loss. Weekly decreases in bone quality were not significantly associated with maternal calcium intake or 25(OH)D concentration. Greater weekly reductions in calcaneal bone quality were evident in teens with lower prepregnancy weight (BUA, p = 0.006 and QUI, p = 0.012) and among those with lower weekly increase in PTH (SOS, p = 0.046). Overall, significant decreases in calcaneal bone quality occurred across pregnancy in adolescents, but the magnitude of this loss was attenuated in those with greater prepregnancy weight and weekly increases in PTH. Further studies are needed to understand the role of elevated PTH and greater prepregnancy weight in preserving adolescent bone during pregnancy.

Prioritization of biomarker targets in human umbilical cord blood: identification of proteins in infant blood serving as validated biomarkers in adults.

BACKGROUND: Early diagnosis represents one of the best lines of defense in the fight against a wide array of human diseases. Umbilical cord blood (UCB) is one of the first easily available diagnostic biofluids and can inform about the health status of newborns. However, compared with adult blood, its diagnostic potential remains largely untapped. OBJECTIVES: Our goal was to accelerate biomarker research on UCB by exploring its detectable protein content and providing a priority list of potential biomarkers based on known proteins involved in disease pathways. METHODS: We explored cord blood serum proteins by profiling a UCB pool of 12 neonates with different backgrounds using a combination of isoelectric focusing and liquid chromatography coupled with matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS) and by comparing results with information contained in metabolic and disease databases available for adult blood. RESULTS: A total of 1,210 UCB proteins were identified with a protein-level false discovery rate of ~ 5% as estimated by naïve target-decoy and MAYU approaches, signifying a 6-fold increase in the number of UCB proteins described to date. Identified proteins correspond to 138 different metabolic and disease pathways and provide a platform of mechanistically linked biomarker candidates for tracking disruptions in cellular processes. Moreover, among the identified proteins, 38 were found to be approved biomarkers for adult blood. CONCLUSIONS: The results of this study advance current knowledge of the human cord blood serum proteome. They showcase the potential of UCB as a diagnostic medium for assessing infant health by detection and identification of candidate biomarkers for known disease pathways using a global, nontargeted approach. These biomarkers may inform about mechanisms of exposure-disease relationships. Furthermore, biomarkers approved by the U.S. Food and Drug Administration for screening in adult blood were detected in UCB and represent high-priority targets for immediate validation.

DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth.

BACKGROUND: Gestational age at birth strongly predicts neonatal, adolescent and adult morbidity and mortality through mostly unknown mechanisms. Identification of specific genes that are undergoing regulatory change prior to birth, such as through changes in DNA methylation, would increase our understanding of developmental changes occurring during the third trimester and consequences of pre-term birth (PTB). METHODS: We performed a genome-wide analysis of DNA methylation (using microarrays, specifically CHARM 2.0) in 141 newborns collected in Baltimore, MD, using novel statistical methodology to identify genomic regions associated with gestational age at birth. Bisulphite pyrosequencing was used to validate significant differentially methylated regions (DMRs), and real-time PCR was performed to assess functional significance of differential methylation in a subset of newborns. RESULTS: We identified three DMRs at genome-wide significance levels adjacent to the NFIX, RAPGEF2 and MSRB3 genes. All three regions were validated by pyrosequencing, and RAGPEF2 also showed an inverse correlation between DNA methylation levels and gene expression levels. Although the three DMRs appear very dynamic with gestational age in our newborn sample, adult DNA methylation levels at these regions are stable and of equal or greater magnitude than the oldest neonate, directionally consistent with the gestational age results. CONCLUSIONS: We have identified three differentially methylated regions associated with gestational age at birth. All three nearby genes play important roles in the development of several organs, including skeletal muscle, brain and haematopoietic system. Therefore, they may provide initial insight into the basis of PTB's negative health outcomes. The genome-wide custom DNA methylation array technology and novel statistical methods employed in this study could constitute a model for epidemiologic studies of epigenetic variation.

Selenium and maternal blood pressure during childbirth.

Evidence suggests selenium concentrations outside the nutritional range may worsen cardiovascular health. This paper examines the relationship between selenium and maternal blood pressure (BP) among 270 deliveries using umbilical cord serum as a proxy for maternal exposure levels. Multivariable models used linear splines for selenium and controlled for gestational age, maternal age, race, median household income, parity, smoking, and prepregnancy body mass index. Non-parametric analysis of this dataset was used to select spline knots for selenium at 70 and 90 µg/l. When selenium was <70 µg/l, increasing selenium levels were related to a non-statistically significant decrease in BP. For selenium 70-90 µg/l, a 1 µg/l increase was related to a 0.37 mm Hg (95% confidence interval (CI): 0.005, 0.73) change in systolic and a 0.35 mm Hg (0.07, 0.64) change in diastolic BP. There were very few selenium values >90 µg/l. Other studies indicate that the maternal/cord selenium ratio is 1.46 (95% CI: 1.28, 1.65). This u-shaped relationship between selenium and BP is consistent with a dual role of selenium as an essential micronutrient that is nonetheless a toxicant at higher concentrations; however, this needs to be studied further.

Lupus and pregnancy.

Systemic lupus erythematosus (SLE) disproportionately affects women in their reproductive age years. Pregnancy in this systemic autoimmune disease has long been associated with poor obstetric outcomes. However, the frequency of pregnancy loss in lupus has dropped to a level commensurate with that of the general US population. The outcomes of lupus pregnancies are better if conception is delayed until the disease has been inactive for at least 6 months, and the medication regimen has been adjusted in advance. Pregnancy in lupus is prone to complications, including flares of disease activity during pregnancy or in the postpartum period, preeclampsia, miscarriage, stillbirth, intrauterine growth retardation, and preterm birth. Active lupus nephritis poses the greatest risk. The recognition of a lupus flare during pregnancy may be difficult because the signs and symptoms may mimic those of normal pregnancy. Monitoring should include baseline and monthly laboratory tests, serial ultrasonography, fetal surveillance tests, and fetal m-mode echocardiography for mothers with SS-A (Ro) or SS-B (La) antibodies. In the absence of any signs or symptoms of active SLE, affected patients require no specific treatment during pregnancy. If hydroxychloroquine was in use before conception, it should be maintained throughout pregnancy. If a woman with SLE has antiphospholipid antibodies, prophylactic treatment with aspirin and/or low-molecular weight heparin is indicated to prevent fetal loss. Lupus flares during pregnancy are generally treated with hydroxychloroquine, low-dose prednisone, pulse intravenous methylprednisolone, and azathioprine. High-dose prednisone and cyclophosphamide are reserved for severe lupus complications but are associated with significant pregnancy-related complications and poor obstetrical outcomes.