Publications by authors named "Carolyn M Salafia"

39 Publications

Histopathology of the fetal inflammatory response to intra-amniotic pathogens.

Semin Fetal Neonatal Med 2020 Aug 28;25(4):101128. Epub 2020 Aug 28.

Department of Epidemiology and Biostatistics, MSU College of Human Medicine, 909 Wilson Road Room B645, East Lansing, MI, 48824, USA. Electronic address:

Obstetric endorsement of the utility of placental histologic examination remains infrequent, especially from obstetricians who do not have a placental pathologist as part of their own local clinical care team. Placental pathologic examinations are viewed as useless if they do not provide answers to urgent clinical questions. Increasingly, however, it is appreciated that while placental analysis should be considered with regard to its longer term value; results can assess lifelong risks of a wide range of diseases that have been tied to prenatal exposures (e.g., [1]), including distinguishing sex-specific differences in those risks. (e.g., [2]) This review will focus solely on acute fetal (?) inflammation, more specifically, the fetal neutrophil responses in umbilical cord, chorionic plate vessels and to some degree, the fetal system as a whole. This histologic fetal inflammatory response is often the most readily accessible aspect of "FIR" piece of FIRS (the fetal inflammatory response syndrome). Some researchers have defined FIRS by a combination of both cytokine (especially IL-6) levels and the histopathologic FIR (Musilova et al., 2018) [3]. As we and others have noted, many histology based FIR cases, even those associated with neurodevelopmental outcomes such as cerebral palsy, are clinically silent.(e.g., [4]) Current clinical diagnostic criteria may have high specificity as they are very good at identifying non-FIR cases. However, that high specificity is coupled with very low specificity, identifying only 10% of FIR (Doty et al., 2018 Jul) [5]. Our aim is to provide a conceptual framework for the readers of the journal to better understand how to answer the following questions: What is a neutrophil and how is it important in FIR? What is the differential diagnosis for histologic FIR? How long has there been FIR? What secondary processes may have been recruited (and when) to contribute to the final pathology and pathophysiology of the given pregnancy?
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http://dx.doi.org/10.1016/j.siny.2020.101128DOI Listing
August 2020

Placental infarcts in the collaborative perinatal project: Variable associations infer variable constructs.

Placenta 2020 09 24;99:1-7. Epub 2020 Jun 24.

Placental Analytics, LLC, New Rochelle, NY, USA; Institute for Basic Research, Staten Island, NY, USA. Electronic address:

Purpose: Reproducible diagnoses of placental infarcts may permit more accurate assessment of their clinical significance. Using data across the 12 study sites of the National Collaborative Perinatal Project, we investigated the consistency of associations between infarct features with birthweight, placental weight and measures of placental "efficiency."

Methods: All delivered infants, live or stillborn, single or multiple, regardless of gestational age, were included. Pathologists scored infarcts by color (tan-white or "old" or pink-red "more recent"), size (cm), location (marginal or central), and total number.

Results: Incidence of any infarcts and distributions of specific features such as size, color (indicating age), locations and total numbers of infarcts were highly variable across sites, as were their associations with birthweight and placental efficiency. The most stable associations (consistent results across sites) of placental infarct scores were with placental size and/or other placental shape variables and with birthweight, but the number of significant associations ranged from 13 to 1.

Conclusion: Given the extremes of infarct incidence within each site plus the variable correlations of infarct features with other placental and birth outcome measures, CPP infarct scores cannot be used as indicative of an underlying shared pathophysiologic construct. However, given the accumulating evidence that intrauterine stressors have the potential for lifelong impact on health, we propose that the infarct features and distinctions proposed are neither complex nor should they be jettisoned. Rather these measures should be clarified and refined. Only then can we understand the reported associations of placental infarcts with child and adult health outcomes.
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http://dx.doi.org/10.1016/j.placenta.2020.06.004DOI Listing
September 2020

Gestational growth trajectories derived from a dynamic fetal-placental scaling law.

J R Soc Interface 2019 10 30;16(159):20190417. Epub 2019 Oct 30.

Placental Analytics, New Rochelle, NY 10538, USA.

Fetal trajectories characterizing growth rates have relied primarily on goodness of fit rather than mechanistic properties exhibited . Here, we use a validated fetal-placental allometric scaling law and a first principles differential equations model of placental volume growth to generate biologically meaningful fetal-placental growth curves. The growth curves form the foundation for understanding healthy versus at-risk fetal growth and for identifying the timing of key events .
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http://dx.doi.org/10.1098/rsif.2019.0417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833314PMC
October 2019

Autism risk classification using placental chorionic surface vascular network features.

BMC Med Inform Decis Mak 2017 Dec 6;17(1):162. Epub 2017 Dec 6.

NIH National Children's Study Placenta Consortium, Bethesda, MD, USA.

Background: Autism Spectrum Disorder (ASD) is one of the fastest-growing developmental disorders in the United States. It was hypothesized that variations in the placental chorionic surface vascular network (PCSVN) structure may reflect both the overall effects of genetic and environmentally regulated variations in branching morphogenesis within the conceptus and the fetus' vital organs. This paper provides sound evidences to support the study of ASD risks with PCSVN through a combination of feature-selection and classification algorithms.

Methods: Twenty eight arterial and 8 shape-based PCSVN attributes from a high-risk ASD cohort of 89 placentas and a population-based cohort of 201 placentas were examined for ranked relevance using a modified version of the random forest algorithm, called the Boruta method. Principal component analysis (PCA) was applied to isolate principal effects of arterial growth on the fetal surface of the placenta. Linear discriminant analysis (LDA) with a 10-fold cross validation was performed to establish error statistics.

Results: The Boruta method selected 15 arterial attributes as relevant, implying the difference in high and low ASD risk can be explained by the arterial features alone. The five principal features obtained through PCA, which accounted for about 88% of the data variability, indicated that PCSVNs associated with placentas of high-risk ASD pregnancies generally had fewer branch points, thicker and less tortuous arteries, better extension to the surface boundary, and smaller branch angles than their population-based counterparts.

Conclusion: We developed a set of methods to explain major PCSVN differences between placentas associated with high risk ASD pregnancies and those selected from the general population. The research paradigm presented can be generalized to study connections between PCSVN features and other maternal and fetal outcomes such as gestational diabetes and hypertension.
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http://dx.doi.org/10.1186/s12911-017-0564-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719902PMC
December 2017

Chorionic vascular "fit" in the human placenta: Relationship to fetoplacental outcomes.

Placenta 2017 Nov 30;59:13-18. Epub 2017 Aug 30.

University of North Carolina Chapel Hill, United States. Electronic address:

Background: Novel measures of the chorionic plate and vessels are used to test the hypothesis that variation in placental structure is correlated with reduced birth weight (BW) independent of placental weight (PW), suggesting functionally compromised placentas.

Methods: 916 mothers recruited to the Pregnancy, Infection and Nutrition Study delivering singleton live born infants at >30 gestational weeks had placentas collected, digitally photographed and weighed prior to formalin fixation. The fetal-placental weight ratio (FPR) was calculated as birthweight/placental weight. Beta (beta) was calculated as ln(PW)/ln(BW). Chorionic disk perimeter was traced and chorionic surface shape (CS) area was calculated. "Fit" was defined as the ratio of the area of the vascular to the full chorionic surface area. The sites at which chorionic vessels dived beneath the chorionic surface were marked to calculate the chorionic surface vessel (CV) area. The centroids of shapes, the distance between centroids and other measures of shape irregularities were calculated. Principal components analysis (PCA) created three independent factors. Factors were used in regression analyses to explore relations to birth weight, trimmed placental weight, FPR, and beta. Specific measures of shape irregularity were also examined in regression analyses for interrelationships and to predict birth weight, placental weight, FPR, and beta.

Results: Variables related to disk size (CS area, perimeter) were correlated with BW, GA, trimmed PW and beta. "Fit" (the ratio of CV area to CS area), measures of shape irregularities, and the distance between the cord insertion and the centroids of surface and vascular areas were also correlated with one or more of the clinical outcome variables. PCA yielded three factors that had independent effects on birth weight, placental weight, the fetal-placental weight ratio, and beta (each p < 0.0001). Addition of GA did not alter the factors' associations with outcomes. Chorionic "fit" (ratio of areas), also included within the factor analysis, was a positive predictor of birth weight (p = 0.005) and FPR (p = 0.002) and a negative predictor of beta (p = 0.01). Fit was statistically significantly associated with greater distances between the umbilical cord insertion site and the CS (p < 0.001) and CV centroids (p < 0.001), and to lesser displacement between CS and CV centroids (p < 0.001).

Conclusions: Measures of CS and CV account for variation in placental efficiency defined by beta, independent of GA. Macroscopic placenta measurements can identify suboptimal placental development.
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http://dx.doi.org/10.1016/j.placenta.2017.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806527PMC
November 2017

Hemodynamic analysis of blood flow in umbilical artery using computational modeling.

Placenta 2017 Sep 28;57:9-12. Epub 2017 May 28.

Placental Analytics, LLC, New Rochelle, NY, USA; Institute for Basic Research, Staten Island, NY, USA. Electronic address:

The umbilical cord is the crucial pathway for blood flow between the fetus and the placenta. Umbilical coiling and length have been separately linked to adverse clinical outcomes; however, the effects of variations of these parameters on umbilical arterial blood flow are not well understood. Using 3D computational model, we studied the individual and combined effects of umbilical coiling index, cord length and arterial diameter on umbilical artery hemodynamics. We found that specific combinations of umbilical coiling index, cord length and arterial diameter yielded pressure and flow drops incompatible with fetal life. Such models are useful as hypothesis-developing tools.
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http://dx.doi.org/10.1016/j.placenta.2017.05.017DOI Listing
September 2017

The association between placental histopathology and autism spectrum disorder.

Placenta 2017 Sep 8;57:183-188. Epub 2017 Jul 8.

Placental Modulation Laboratory, Institute for Basic Research in Developmental Disabilities, 1550 Forest Hill Road, Staten Island, NY 10314, USA; Placental Analytics LLC, 187 Overlook Circle, New Rochelle, NY 10804, USA; Department of Obstetrics and Gynecology, New York Presbyterian Brooklyn Methodist Hospital, 550 6th Street, Brooklyn, NY 11215, USA; Department of Pediatrics, New York Presbyterian Brooklyn Methodist Hospital, 550 6th Street, Brooklyn, NY 11215, USA. Electronic address:

Introduction: Research suggests that autism spectrum disorder (ASD) has its origins in utero. This study examines the association between evidence of placental histopathology and ASD.

Methods: Administrative claims data and medical records data were used to identify ASD cases (N = 55) and matched controls (N = 199) born at New York Methodist Hospital between 2007 and 2014 and subsequently seen in affiliated pediatrics clinics. Placentas from all births during this time period were reviewed as part of routine care. Data were analyzed using conditional logistic regression to account for the matched (gender, gestational age, and birth weight) design.

Results: Acute placental inflammation, regardless of type was associated with an increased risk of ASD (odds ratio [OR] = 3.14, 95% CI = 1.39, 6.95). Chronic uteroplacental vasculitis (OR = 7.13; 95% CI = 1.17, 43.38), the fetal inflammatory response in the chorionic plate vessels (OR = 5.12; 95% CI = 2.02, 12.96), and maternal vascular malperfusion pathology (OR = 12.29; 95% CI = 1.37, 110.69) were associated with an increased risk of ASD. Placental villous edema was associated with a decreased risk of ASD (OR = 0.05; 95% CI = 0.0005, 0.42). In subanalyses among male placentas acute inflammation overall, fetal inflammatory response in the chorionic plate vessels, and maternal vascular malperfusion pathology remained significantly associated with an increased risk of ASD whereas placental villous edema remained associated with a decreased risk of ASD.

Discussion: Histologic evidence of placental inflammation and maternal vascular malperfusion pathology are associated with ASD.
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http://dx.doi.org/10.1016/j.placenta.2017.07.006DOI Listing
September 2017

Correlation Between Placental Matrix Metalloproteinase 9 and Tumor Necrosis Factor-α Protein Expression Throughout Gestation in Normal Human Pregnancy.

Reprod Sci 2018 04 18;25(4):621-627. Epub 2017 Aug 18.

1 Department of Obstetrics and Gynecology, Bronx Lebanon Hospital Center, Bronx, NY, USA.

Matrix metalloproteinases (MMPs), specifically MMP-9 plays a role in human placentation. The enzyme confers an invasive ability to cytotrophoblasts and degrades the endometrial matrix as the cells infiltrate the decidua to keep up with placental growth. Since tumor necrosis factor-α (TNF-α) can induce the synthesis of MMP-9, we investigated the patterns of changes in and correlation between placental villous MMP-9 and TNF-α expressions throughout normal human gestation. Placentas were obtained from 179 normal pregnant women who underwent elective abortion or term delivery. Chorionic villi isolated from placental samples were grouped as first, second, and third trimester (7-13, 13-23, and 37-42 weeks, respectively). Chorionic villous TNF-α and MMP-9 proteins were assayed using enzyme immunoassay kits. There were significant differences in MMP-9 and TNF-α protein expressions among the trimester groups ( P = .001). The MMP-9 protein increased progressively with an increase in gestational age (GA), but TNF-α peaked in the second trimester. Within each trimester group, we searched for the effects of variation of GA in days on the 2 variables. A significant positive correlation between MMP-9 and GA was noted in the first trimester ( r = 0.364, P = .005). No other comparisons were significant. When GA was controlled for, partial correlation revealed a significant positive correlation between TNF-α and MMP-9 only in the second trimester ( r = 0.300, P = .018). We hypothesize that the TNF-α peak and the positive correlation between TNF-α and MMP-9 in the second trimester of normal human gestation could contribute toward a successful pregnancy outcome.
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http://dx.doi.org/10.1177/1933719117725819DOI Listing
April 2018

Urinary Incontinence in Pregnant Young Women and Adolescents: An Unrecognized At-Risk Group.

Female Pelvic Med Reconstr Surg 2018 May/Jun;24(3):232-236

Objectives: The aims of this study were to determine the prevalence of urinary incontinence (UI) in pregnant young women and adolescents, characterize UI subtype, and identify characteristics associated with UI.

Methods: This was a cross-sectional study of pregnant females aged 25 years or below, presenting for routine obstetrical care at a New York City community hospital. Subjects were stratified into 2 groups: adolescents (age, ≤19 years) and young adults (age, >19 years). Demographic and obstetric data were collected. The 3 Incontinence Questions questionnaire was used to screen and evaluate UI symptoms.

Results: A total of 98 young females with a mean age of 20.3 ± 2.6 years were enrolled. Most participants were nulliparous (64%). Of parous women, route of previous obstetric delivery was primarily vaginal (83%). Mean gestational age at recruitment was 34.5 ± 7.5 weeks. The prevalence of UI was 52%. Urinary incontinence was associated with the following conditions: strenuous activity, 73%; urinary urgency, 67%; and absence of either, 20%. However, the most predominant UI subtype was with strenuous activity (63%). There was no statistical difference detected in demographic characteristics (such as age, parity, mode of delivery, race, education, and trimester of pregnancy) between continent and incontinent pregnant females (P > 0.18). No differences were appreciated between pregnant adolescents and young adult females with UI (P > 0.18).

Conclusions: Urinary incontinence was present in 52% of pregnant females aged 25 years or below. By age group, approximately 50% of both adolescents and young adults reported UI during pregnancy. Continent and incontinent patients did not seem to differ demographically. Our study highlights the extent of UI in this segment of the population. This data may support the need for services targeting UI prevention and early intervention in this newly identified at-risk group.
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http://dx.doi.org/10.1097/SPV.0000000000000445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943077PMC
February 2019

The relationship between birth and placental weights changes with placental size.

Early Hum Dev 2017 08 12;111:56-59. Epub 2017 Jun 12.

Department of Obstetrics and Gynecology, Pediatrics, New York Methodist Hospital, Brooklyn, NY, United States.

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http://dx.doi.org/10.1016/j.earlhumdev.2017.05.011DOI Listing
August 2017

Clarification and 3-D visualization of immunolabeled human placenta villi.

Placenta 2017 05 24;53:36-39. Epub 2017 Mar 24.

New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, United States; Placental Analytics, New Rochelle, NY 10804, United States. Electronic address:

We report here the successful 3D visualization of human placenta villous structures on the order of ∼1 mm by a combination of immunolabeling, rapid tissue clarification and laser scanning confocal microscopy. The resultant image sets exhibit a complex arrangement of villi and their contained vasculature that mirrors their arrangement in situ.
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http://dx.doi.org/10.1016/j.placenta.2017.03.015DOI Listing
May 2017

Methods to decrease variability in histological scoring in placentas from a cohort of preterm infants.

BMJ Open 2017 03 31;7(3):e013877. Epub 2017 Mar 31.

Placental Modulation Laboratory, Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA.

Objective: Reliable semiquantitative assessment of histological placental acute inflammation is problematic, even among experts. Tissue samples in histology slides often show variability in the extent and location of neutrophil infiltrates. We sought to determine whether the variability in pathologists' scoring of neutrophil infiltrates in the placenta could be reduced by the use of 'regions of interest' (ROIs) that break the sample into smaller components.

Design: ROIs were identified within stained H&E slides from a cohort of 56 women. ROIs were scored using a semiquantitative scale (0-4) for the average number of neutrophils by at least two independent raters.

Setting: Preterm singleton births at Yale New Haven Hospital.

Participants: This study used stained H&E placental slides from a cohort of 56 women with singleton pregnancies who had a clinically indicated amniocentesis within 24 hours of delivery.

Primary And Secondary Outcome Measures: Interrater agreement was assessed with the intraclass correlation coefficient (ICC) and log-linear regression. Predictive validity was assessed using amniotic fluid protein profile scores (neutrophil defensin-2, neutrophil defensin-1, calgranulin C and calgranulin A).

Results: Excellent agreement by the ICC was found for the average neutrophil scores within a region of interest. Log-linear analyses suggest that even where there is disagreement, responses are positively associated along the diagonal. There was also strong evidence of predictive validity comparing pathologists' scores with amniotic fluid protein profile scores.

Conclusions: Agreement among observers of semiquantitative neutrophil scoring through the use of digitised ROIs was demonstrated to be feasible with high reliability and validity.
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http://dx.doi.org/10.1136/bmjopen-2016-013877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387969PMC
March 2017

First Trimester Detection of Placental Disease: Challenges and Opportunities.

Am J Perinatol 2016 11 4;33(13):1306-1312. Epub 2016 Aug 4.

Division of Predictive Modeling, Placental Analytics, New Rochelle, New York.

It is generally agreed that placental pathology accounts for the majority of perinatal morbidity and mortality. If a placental prodrome could be diagnosed in vivo, risk for maternal or fetal complications could be estimated and acted upon before clinical symptoms are apparent. This is especially relevant in early diagnoses of gestational diabetes mellitus, which can be controlled through carefully monitored diet and activity changes. To meet this important need, there have been increased efforts to identify early gestation biomarkers of placental dysfunction using innovative imaging technologies. Here we outline innovative quantitative markers of placental shape and their relationship to placental function, clinical implications of these quantifiers, and the most recent mathematical models that utilize placental images to delineate at risk from normal pregnancies. We propose that novel contexts of readily available placental measures and routine collection of in vivo placental images in all pregnancies may be all that are needed to advance the identification of early risk determination of complicated pregnancies from placental images.
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http://dx.doi.org/10.1055/s-0036-1586508DOI Listing
November 2016

Placental tumor necrosis factor-α protein expression during normal human gestation.

J Matern Fetal Neonatal Med 2016 Dec 18;29(24):3934-8. Epub 2016 Mar 18.

a Department of Obstetrics & Gynecology , Bronx Lebanon Hospital Center , Bronx , NY , USA.

Objective: Placental tumor necrosis factor-α (TNF-α) is a cell signaling protein. During pregnancy, TNF-α induces synthesis of matrix metalloproteinases (MMPs) which allows cytotrophoblasts to reach the spiral arteries deeper within the uterine decidua. TNF-α also augments apoptosis of vascular smooth muscle cells surrounding these arteries. In this study, chorionic villi TNF-α protein expression throughout normal human gestation were investigated.

Methods: Placental chorionic villi tissues obtained from elective surgical terminations of pregnancy and from uncomplicated term births were assayed using EIA kits (Cayman Chemicals, Ann Arbor, MI, Item # 589201).

Results: The median, 25th percentile and 75th percentile values in the first (N = 99), second (N = 58) and third trimester (N = 42) were: 36.46, 27.25, 45.90 pg/100 mg tissue; 55.43, 40.09, 110.88 pg/100 mg tissue; and 16.63, 9.32, 31.92 pg/100 mg tissue, respectively.

Conclusions: Variations in placental TNF-α protein expression noted at different trimesters may suggest gestational age specific roles for the cytokine. The increase in TNF-α protein expression observed in the second trimester may be involved in upregulating synthesis of MMP and in augmenting apoptosis of vascular smooth muscle cells of the spiral arteries. A failure in this second trimester increase in TNF-α protein could contribute to gestational compromise.
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http://dx.doi.org/10.3109/14767058.2016.1156668DOI Listing
December 2016

Increasing maternal body mass index during pregnancy increases neonatal intensive care unit admission in near and full-term infants.

J Matern Fetal Neonatal Med 2016 Oct 8;29(20):3249-53. Epub 2016 Jan 8.

a Department of Pediatrics , New York Methodist Hospital , Brooklyn, NY , USA .

Background: Obesity is becoming an increasingly commonplace health problem. Obesity during pregnancy is important because the condition adversely affects not only the mother, but also the developing fetus and the newborn.

Objective: The primary objective of this study was to evaluate the association between maternal body mass index (mBMI) at the time of delivery and neonatal intensive care unit (NICU) admission of offspring and to analyze the role of possible confounding variables that are often associated with obesity. Comorbidities, such as gestational diabetes mellitus (DM), hypertension (HT) and/or pre-eclampsia (PEC), are more common in more obese mothers, as is a higher association of obesity among non-Caucasian patients.

Methods: Using a retrospective cohort design, 1736 mothers and their singleton live-born at  ≥35 weeks' gestation were analyzed for mBMI, maternal conditions of DM, HT and/or PEC, and whether NICU care was required and the reason for NICU admission.

Results: NICU admission rate was significantly associated with maternal obesity. In comparing women with mBMI  < 30 versus mBMI ≥ 30, OR was 1.39 (p = 0.045); OR increased to 1.76 (p = 0.006) in comparing patients with mBMI  ≥ 35. mBMI was significantly associated with an increased rate of maternal DM, HT and PEC (p < 0.05 each); however, NICU admission rate was not correlated with DM, HT or PEC. The relationship between NICU admission and mBMI was significant in Caucasian mothers versus a borderline significance in African-American mothers (p = 0.035 versus p = 0.05). After controlling for neonatal hypoglycemia (NH) as the reason for admission to the NICU, no mBMI-NICU association persisted. The rate of infants with NH increased in higher mBMI groups, independent of maternal DM diagnosis.

Conclusion: This study demonstrated a significant association between higher mBMI groups and NICU admissions independent of diagnosis of maternal comorbidities. However, accounting for NH eliminating this association suggests a pre-clinical diabetic pathology in obese women that affects newborn outcome. Despite increased percentage of nonwhite mothers in higher mBMI groups, African-American race does not seem to be a significant contributing factor in the increased rate of NICU admission in our population.
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http://dx.doi.org/10.3109/14767058.2015.1124082DOI Listing
October 2016

Placental Oxidative Status throughout Normal Gestation in Women with Uncomplicated Pregnancies.

Obstet Gynecol Int 2015 1;2015:276095. Epub 2015 Feb 1.

Department of Obstetrics & Gynecology, Bronx Lebanon Hospital Center, 1650 Grand Concourse, Bronx, NY 10457, USA.

The effects of gestational age on placental oxidative balance throughout gestation were investigated in women with uncomplicated pregnancies. Placental tissues were obtained from normal pregnant women who delivered at term or underwent elective pregnancy termination at 6 to 23 + 6 weeks of pregnancy. Placental tissues were analyzed for total antioxidant capacity (TAC) and lipid peroxide (malondialdehyde, MDA) levels using commercially available kits. Two hundred and one placental tissues were analyzed and the mean ± SD MDA (pmol/mg tissue) and TAC (µmol Trolox equivalent/mg tissue) levels for first, second, and third trimester groups were 277.01 ± 204.66, 202.66 ± 185.05, and 176.97 ± 141.61, P < 0.004 and 498.62 ± 400.74, 454.90 ± 374.44, and 912.19 ± 586.21, P < 0.0001 by ANOVA, respectively. Our data reflects an increased oxidative stress in the placenta in the early phase of normal pregnancy. As pregnancy progressed, placental antioxidant protective mechanisms increased and lipid peroxidation markers decreased resulting in diminution in oxidative stress. Our findings provide a biochemical support to the concept of a hypoxic environment in early pregnancy. A decrease in placental oxidative stress in the second and third trimesters appears to be a physiological phenomenon of normal pregnancy. Deviations from this physiological phenomenon may result in placental-mediated disorders.
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http://dx.doi.org/10.1155/2015/276095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333282PMC
February 2015

Induction of labor at 41 weeks of pregnancy among primiparas with an unfavorable Bishop score.

Arch Gynecol Obstet 2013 Nov 24;288(5):989-93. Epub 2013 Aug 24.

Department of Obstetrics and Gynecology, Bronx Lebanon Hospital Center, 1650 Selwyn Avenue Apt 18D, Bronx, NY, 10457, USA,

Objective: To determine the rate and factors associated with the successful Induction of Labor (IOL) in nulliparous patients undergoing scheduled IOL at 41 weeks of gestational age (GA) with an unfavorable cervix.

Design: This was a retrospective analysis that included nulliparous patients who presented to the Labor and Delivery unit at the Bronx Lebanon Hospital Center between 2011 and 2012 for elective IOL at 41 weeks of GA. The Bishop score was assessed upon admission and IOL agents were used in compliance with ACOG guidelines in different combinations, based on the obstetrical team preference.

Setting: Labor and Delivery Unit of the Bronx Lebanon Hospital.

Population: Nulliparous patients with 41 weeks of pregnancy for elective induction of labor.

Sample: Seventy-six patients were included in the study. GA was confirmed using a combination of the last menstrual period and a dating sonogram during pregnancy.

Methods: This was a retrospective chart review that included nulliparous patients who presented to the Labor and Delivery unit at the Bronx Lebanon Hospital Center between October 2011 and October 2012 for elective IOL at 41 weeks of gestational age with an unfavorable cervix defined as a Bishop score of 6 or less.

Main Outcome Measures: The overall successful rate of IOL in a combination of different maternal factors with different agents for induction in nulliparous patients undergoing scheduled IOL with an unfavorable Bishop score at 41 weeks of GA was 51.32 %.

Results: Factors associated with successful IOL were younger age [22.3 years vs. 25.1(p = 0.015)], lower BMI [25 vs. 28.1(p = 0.46)] and lower maternal weight [64.75 kg vs. 74.02 (p = 0.28)]. Maternal height was not a contributing factor; the artificial rupture of membranes, epidural anesthesia and the prostaglandins used did not contribute. Use of cervical balloon and oxytocin was associated with failed IOL.

Conclusions: Patients undergoing IOL at 41 weeks with an unfavorable cervix had a successful rate of 51.32 %. Younger maternal age, lower weight, and lower BMI were associated with successful IOL.
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http://dx.doi.org/10.1007/s00404-013-3006-6DOI Listing
November 2013

Placental morphologic features and chorionic surface vasculature at term are highly correlated with 3-dimensional sonographic measurements at 11 to 14 weeks.

J Ultrasound Med 2011 Sep;30(9):1171-8

Department of Obstetrics and Gynecology, Hospital of University of Pennsylvania, 3400 Spruce St, 2000 Courtyard, Philadelphia, PA 19104, USA.

Objectives: The purpose of this study was to examine the potential for 3-dimensional sonographic measurement of the early placenta in predicting ultimate placental morphologic features at delivery.

Methods: In this prospective cohort study, we collected 3-dimensional sonographic volume sets of placentas at 11 to 14 weeks and then collected the placentas after delivery. The sonographic data were manipulated to obtain various novel measurements of early gross placental morphologic features and the umbilical cord insertion location. The placental weight, chorionic plate area, cord location, and mean chorionic vascular density were obtained from the delivered postpartum placentas. Analyses were performed to identify potential early placental characteristics that were correlated with the ultimate placental morphologic features. The placental weight, cord marginality, and mean chorionic vascular density served as the outcome measures of interest.

Results: Measurements of the early placental volume correlated with the delivered placental weight. An irregular early placental shape, as measured by sonography, was significantly inversely correlated with placental weight (P < .05). The placental morphologic index, a measure of a flatter placenta, was inversely correlated with both the placental weight and chorionic plate area, possibly indicating the importance of placental thickness even in the first trimester before villous arborization. In addition, early sonographic measures of the location of the umbilical cord insertion were significantly correlated with the ultimate marginality of the cord insertion as well as the mean chorionic vascular density (P < .05).

Conclusions: Many important ultimate placental morphologic features are likely predetermined early in pregnancy. Three-dimensional sonography may play an increasing role in the in utero evaluation of the early placenta.
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http://dx.doi.org/10.7863/jum.2011.30.9.1171DOI Listing
September 2011

Impact of fetal versus perinatal hypoxia on sex differences in childhood outcomes: developmental timing matters.

Soc Psychiatry Psychiatr Epidemiol 2012 Mar 17;47(3):455-64. Epub 2011 Feb 17.

Division of Women's Health, Department of Medicine, Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital (BWH), One Brigham Circle, 1620 Tremont Street, Boston, MA 02120, USA.

Purpose: To examine how the timing of hypoxic exposure results in specific childhood outcomes and whether there is a differential effect by sex.

Methods: A sample of 10,879 prospectively followed pregnancies was drawn from the Boston and Providence sites (New England, NE) of the National Collaborative Perinatal Project. Based on placental pathology, we developed and validated a measure of probable chronic placental hypoxia (CHP) and contrasted the effects of acute perinatal hypoxia on age 7 emotional, behavioral, and cognitive outcomes.

Results: Perinatal hypoxia had a significant impact on multiple behavioral and cognitive outcomes in boys and girls by age 7, in contrast to probable CHP which had a differential effect on girls and boys such that there was decreased verbal IQ and increased inhibition in females alone.

Conclusions: Findings underscore the importance of considering the timing of obstetric complications and offspring sex in investigations of the impact of fetal and perinatal hypoxia on offspring's outcomes throughout the life course.
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http://dx.doi.org/10.1007/s00127-011-0353-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715145PMC
March 2012

Centrality of the umbilical cord insertion in a human placenta influences the placental efficiency.

Placenta 2009 Dec 30;30(12):1058-64. Epub 2009 Oct 30.

Department of Mathematics, University of Toronto, Ontario, Canada.

Goal: We assess the effect on placental efficiency of the non-centrality of the umbilical cord insertion and on chorionic vascular distribution to determine if cord centrality measurably affects placental function as reflected in birth weight.

Materials And Methods: 1225 placentas collected from a prospective cohort had digital photographs of the chorionic plate. Of these, 1023 were term, 44 had velamentous cord insertion and 12 had missing clinical data, leaving N=967 (94.5%) cases for analysis. Mathematical tools included a dynamical stochastic growth model of placental vasculature, Fourier analysis of radial parameterization of placental perimeters, and relative chorionic vascular density (a measure of "gaps" in the vascular coverage) derived from manual tracings of the fetal chorionic surface images. Bivariate correlations used Pearson's or Spearman's rank correlation as appropriate, with p<0.05 considered significant.

Results: The correlation of the standard deviation of the placental radius (a measure of non-roundness of the placenta) with cord displacement was negligible (r=0.01). Empirical simulations of the vascular growth model with cord displacement showed no deviation from a normal round-to-oval placental shape for cord displacement of 10-50% of placental radius. The correlation of the metabolic scaling exponent beta with cord displacement measured by Fourier analysis is 0.17 (p<0.001). Analysis of the chorionic vascular density in traced images shows a high correlation of the relative vascular distance with cord displacement: 0.59 in one set of 12 images, and 0.20 in the other set of 28 images.

Conclusion: Non-central cord insertion has little measurable correlation with placental shape in observed or simulated placentas. However, placentas with a displaced cord show a markedly reduced transport efficiency, reflected in a larger value of beta and hence in a smaller birth weight for a given placental weight. Placentas with a non-central cord insertion have a sparser chorionic vascular distribution, as measured by the relative vascular distance. Even if typically a placenta with a non-central insertion is of a normal round shape, its vasculature is less metabolically effective. These findings demonstrate another method by which altered placental structure may affect the fetal environment, influencing birth weight and potentially contributing to later health risks.
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http://dx.doi.org/10.1016/j.placenta.2009.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2790011PMC
December 2009

Gross placental measures and childhood growth.

J Matern Fetal Neonatal Med 2009 Jan;22(1):13-23

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Objectives: We hypothesised that the gross placental measures would be positively associated with childhood growth.

Methods: We analysed data on 23,967 mother-infant pairs enrolled in the Collaborative Perinatal Project. In race-stratified regression models, the main outcomes were birthweight and z-score body-mass index (BMI) at ages 4 and 7.

Results: Some placental measures were significantly associated with z-score BMI at age 7: in Blacks, placental weight (beta = 0.0004/g; 95%CI: 0.0001, 0.0008), chorionic plate area (beta = 0.0007; 95%CI: 0.0001, 0.0012) and largest diameter (beta = 0.013; 95%CI: 0.004, 0.026); and in Whites placental weight (beta = 0.0004/g; 95%CI: 0.0001, 0.0003) and largest diameter (Model 3: beta = 0.020; 95%CI: 0.007, 0.032). Tested as group, placental measures significantly predicted z-score BMI at age 7 (all p values < 0.005).

Conclusions: Placental structure independently predicts birthweight and childhood growth. Strategies to improve placental structure might favourably influence birthweight and childhood development.
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http://dx.doi.org/10.1080/14767050802415728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713228PMC
January 2009

Gross placental structure in a low-risk population of singleton, term, first-born infants.

Pediatr Dev Pathol 2009 May-Jun;12(3):200-10

Center for Cognitive and Decision Sciences, Institute of Psychology, University of Basel, Missionsstrasse 64a, 4055 Basel, Switzerland.

Suboptimal fetal growth has been associated with an increased risk of adult disease, which may be exacerbated by an increased placental weight-to-fetal weight ratio. Placental weight is a summary measure of placental growth and development throughout pregnancy. However, measures of placental structure, including the chorionic disk surface area and thickness and eccentricity of the umbilical cord insertion, have been shown to account for additional variance in birth weight beyond that explained by placental weight. Little is known of the variability of these placental parameters in low-risk populations; their association with maternal, pregnancy, and neonatal characteristics; and the agreement between manual and digital measures. This study used manual and digital image analysis techniques to examine gross placental anatomy in 513 low-risk, singleton, term, first-born infants. Parametric methods compared groups and examined relationships among variables. Maternal birth weight, prepregnancy weight, and body mass index were associated with increased placental and birth weight (all P < 0.005), but only maternal birth weight was associated with increased placental surface area (P < 0.0005) and thickness (P = 0.005). Smoking during pregnancy reduced birth weight and increased the eccentricity of umbilical cord insertion (P = 0.012 and 0.034, respectively). The variability in these placental parameters was consistently lower than that reported in the literature, and correlations between digital and manual measurements were reasonable (r = .87-.71). Detailed analyses of gross placental structure can provide biologically relevant information regarding placental growth and development and, potentially, their consequences.
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http://dx.doi.org/10.2350/08-02-0413.1DOI Listing
September 2009

Maternal risk factors for abnormal placental growth: the national collaborative perinatal project.

BMC Pregnancy Childbirth 2008 Sep 23;8:44. Epub 2008 Sep 23.

From the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Previous studies of maternal risk factors for abnormal placental growth have focused on placental weight and placental ratio as measures of placental growth. We sought to identify maternal risk factors for placental weight and two neglected dimensions of placental growth: placental thickness and chorionic plate area.

Methods: We conducted an analysis of 24,135 mother-placenta pairs enrolled in the National Collaborative Perinatal Project, a prospective cohort study of pregnancy and child health. We defined growth restriction as < 10th percentile and hypertrophy as > 90th percentile for three placental growth dimensions: placental weight, placental thickness and chorionic plate area. We constructed parallel multinomial logistic regression analyses to identify (a) predictors of restricted growth (vs. normal) and (b) predictors of hypertrophic growth (vs. normal).

Results: Black race was associated with an increased likelihood of growth restriction for placental weight, thickness and chorionic plate area, but was associated with a reduced likelihood of hypertrophy for these three placental growth dimensions. We observed an increased likelihood of growth restriction for placental weight and chorionic plate area among mothers with hypertensive disease at 24 weeks or beyond. Anemia was associated with a reduced likelihood of growth restriction for placental weight and chorionic plate area. Pre-pregnancy BMI and pregnancy weight gain were associated with a reduced likelihood of growth restriction and an increased likelihood of hypertrophy for all three dimensions of placental growth.

Conclusion: Maternal risk factors are either associated with placental growth restriction or placental hypertrophy not both. Our findings suggest that the placenta may have compensatory responses to certain maternal risk factors suggesting different underlying biological mechanisms.
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http://dx.doi.org/10.1186/1471-2393-8-44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564930PMC
September 2008

Risk factors for uteroplacental vascular compromise and inflammation.

Am J Obstet Gynecol 2008 Sep;199(3):256.e1-9

Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7516, USA.

Objective: The purpose of this study was to identify potentially modifiable risk factors of placental injury that reflect maternal uteroplacental vascular compromise (UPVC) and acute and chronic placental inflammation.

Study Design: A prospective epidemiologic study was conducted. A total of 1270 placentas were characterized by gross and microscopic examination. Placental pathologic condition was coded for features of amniotic fluid infection syndrome (AFIS), chronic villitis, UPVC, and fetal vascular obstructive lesions. Odds ratios between UPVC, the acute and the chronic inflammatory lesions, and risk factors of interest were calculated.

Results: After adjustment for confounders, we found that women with a history of preterm birth had 1.60 times the odds of chronic inflammation (95% CI, 1.10, 2.55). Women with a previous elective termination had 3.28 times the odds of acute inflammation (95% CI, 1.89, 5.70). The odds of chronic villitis increased with parity; the odds of AFIS decreased with parity.

Conclusion: We have identified several predictors of UPVC, AFIS, and chronic villitis. Further studies are needed to examine whether interventions to alter UPVC, AFIS, and chronic villitis will lead to improved pregnancy outcomes.
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http://dx.doi.org/10.1016/j.ajog.2008.06.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680821PMC
September 2008

Placental characteristics and birthweight.

Paediatr Perinat Epidemiol 2008 May;22(3):229-39

Department of Epidemiology, Mailman School of Public Health, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

Standard gross placental measures capture dimensions relevant to specific placental functions. Our objective was to determine their accountability independent of placental weight for variance in birthweight, an important proxy for intrauterine 'adequacy' in fetal origins studies. The sample consisted of 24 152 singleton liveborn children of the Collaborative Perinatal Project delivered from 34 to 42 completed weeks gestation, with complete data for six placental measures (placental disc shape, umbilical cord length, distance from cord insertion to nearest margin, large diameter, small diameter, placental thickness) and placental weight. Associations between birthweight and placental measures were examined using multiple linear regression. Placental weight alone accounted for 36.6% of birthweight variation; the six other placental measures accounted for 28.1%. Combined, all placental measures accounted for 39.1% of birthweight variation. Seven maternal characteristics (age, height, weight, parity, socio-economic status, cigarette use, and race) were investigated to determine whether their known associations with birthweight were mediated by placental markers. Analysis suggested that the impact of all maternal characteristics except smoking was consistent with mediation by placental characteristics.
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http://dx.doi.org/10.1111/j.1365-3016.2008.00935.xDOI Listing
May 2008

Using proteomic analysis of the human amniotic fluid to identify histologic chorioamnionitis.

Obstet Gynecol 2008 Feb;111(2 Pt 1):403-12

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Objective: To estimate the relationship between histologic chorioamnionitis and four amniotic fluid proteomic biomarkers characteristic of inflammation (defensins 2 and 1, calgranulins C and A).

Methods: One hundred fifty-eight women with singleton pregnancies had a clinically indicated amniocentesis to rule out inflammation and infection in the context of preterm labor or preterm premature rupture of membranes. A proteomic fingerprint (Mass Restricted score) was generated from amniotic fluid using surface-enhanced laser desorption ionization time-of-flight mass spectrometry. The Mass Restricted score ranges from 0 to 4 (none to all four biomarkers present) in direct relationship with severity of intra-amniotic inflammation. Presence or absence of biomarkers was analyzed in relationship to placental pathology. Criteria for severity of histologic chorioamnionitis were 3 stages and 4 grades of inflammation of the amnion, choriodecidua and chorionic plate.

Results: The prevalence of histologic chorioamnionitis was 64% (stage I 12%, stage II 16%, and stage III 37%). The Mass Restricted score significantly correlated with stages of histologic chorioamnionitis (r=0.539, P<.001), grades of choriodeciduitis (r=0.465, P<.001), and amnionitis (r=0.536, P<.001). African-American women were overrepresented in the group with severe inflammation (Mass Restricted score 3-4, P=.022). Of the four biomarkers of the Mass Restricted score, calgranulin C had the strongest relationship with presence of stage III chorioamnionitis, independent of race, amniocentesis-to-delivery interval, and gestational age.

Conclusion: Proteomic analysis of amniotic fluid provides an opportunity for early recognition of histologic chorioamnionitis. This methodology may in the future identify candidates for antenatal therapeutic interventions.

Level Of Evidence: II.
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http://dx.doi.org/10.1097/AOG.0b013e31816102aaDOI Listing
February 2008

Placental growth patterns affect birth weight for given placental weight.

Birth Defects Res A Clin Mol Teratol 2007 Apr;79(4):281-8

Department of Epidemiology, Mailman School of Public Health, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.

Background: An important contributor to fetal growth is growth of the placenta, the fetus' sole source of nutrients and oxygen. Here we use placental growth measures (larger and smaller disk diameters, reflecting the laterally expanding chorionic plate, and disk thickness) to test the hypothesis that placental growth patterns, while associated with placental weight and birth weight, measure placental functional efficiency, and will have independent effects on the feto-placental weight ratio (FPR).

Methods: Placental measures were available from 23,313 participants in the Collaborative Perinatal Project delivered between 34 and 43 completed weeks. Continuous variables were analyzed by regression for associations with placental weight, birth weight, and FPR, to further explore effects of placental growth patterns on the FPR (lateral chorionic plate growth and chorionic disk thickness were grouped as low, normal, and high values). The relationships of the nine resultant combinations of placental growth categories to the FPR using birth weight adjusted for gestational age, infant gender, parity, and African American race were analyzed (ANOVA).

Results: As chorionic disk area and thickness increased, birth weight and placental weight increased, and the FPR decreased (each p < .0001) after adjustment for gestational age, parity, race, and infant gender. Small, thin placental disks had an adjusted FPR of 8.46; the largest, thickest placentas had an adjusted FPR of 6.33. The nine categories of FPRs were significantly different, consistent with chorionic plate area and disk thickness combining to determine the FPR.

Conclusions: Patterns of placental growth, relating to different functional dimensions of the placenta, deliver a different birth weight for a given placental weight.
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http://dx.doi.org/10.1002/bdra.20345DOI Listing
April 2007

Preeclampsia, pregnancy-related hypertension, and breast cancer risk.

Am J Epidemiol 2007 May 6;165(9):1007-14. Epub 2007 Feb 6.

Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.

Pregnancy conditions accompanied by high blood pressure, such as preeclampsia and pregnancy-related hypertension, have been associated with a lower risk of breast cancer in several epidemiologic studies. It is unknown whether length of gestation or multiple occurrence of these conditions alters the association with breast cancer. It is also unknown whether the inverse association between preeclampsia and breast cancer risk is modified by menopausal status at breast cancer diagnosis. Using data from a large, population-based case-control study of breast cancer conducted on Long Island, New York, during 1996-1997, the authors examined these questions among ever-parous women (1,310 cases and 1,385 controls) using multivariate logistic models. Preeclampsia was inversely associated with breast cancer (odds ratio = 0.7, 95% confidence interval: 0.5, 1.0); this association was even stronger among women who had multiple occurrences of preeclampsia (odds ratio = 0.3, 95% confidence interval: 0.1, 0.9). The risk reduction was more pronounced among postmenopausal women. Gestation length did not substantially alter the relation between preeclampsia and breast cancer risk. Pregnancy-related hypertension was also inversely associated with breast cancer risk, but the relations were not statistically significant after adjustment for preeclampsia. These data suggest that pregnancy conditions related to hypertension, particularly preeclampsia, play a role in reducing breast cancer risk. Possible biologic mechanisms underpinning these associations should be further explored.
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http://dx.doi.org/10.1093/aje/kwk105DOI Listing
May 2007

Valproic acid-induced fetal malformations are reduced by maternal immune stimulation with granulocyte-macrophage colony-stimulating factor or interferon-gamma.

Anat Rec A Discov Mol Cell Evol Biol 2006 Dec;288(12):1303-9

Department of Biomedical Science, E. Via Virginia College of Osteopathic Medicine, Blacksburg, Virginia 24060, USA.

Valproic acid, a drug commonly used to treat seizures and other psychiatric disorders, causes neural tube defects (NTDs) in exposed fetuses at a rate 20 times higher than in the general population. Failure of the neural tube to close during development results in exencephaly or anencephaly, as well as spina bifida. In mice, nonspecific activation of the maternal immune system can reduce fetal abnormalities caused by diverse etiologies, including diabetes-induced NTDs. We hypothesized that nonspecific activation of the maternal immune system with interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) could reduce valproic acid (VA)-induced defects as well. Female CD-1 mice were given immune stimulant prebreeding: either IFN-gamma or GM-CSF. Approximately half of the control and immune-stimulated pregnant females were then exposed to 500 mg/kg VA on the morning of gestational day 8. The incidence of developmental defects was determined on gestational day 17 from at least eight litters in each of the following treatment groups: control, VA only, IFN-gamma only, IFN-gamma+VA, GM-CSF only, and GM-CSF+VA. The incidence of NTDs was 18% in fetuses exposed to VA alone, compared to 3.7% and 2.9% in fetuses exposed to IFN-gamma+VA, or GM-CSF+VA respectively. Ocular defects were also significantly reduced from 28.0% in VA exposed groups to 9.8% in IFN-gamma+VA and 12.5% in GM-CSF+VA groups. The mechanisms by which maternal immune stimulation prevents birth defects remain unclear, but may involve maternal or fetal production of cytokines or growth factors which protect the fetus from the dysregulatory effects of teratogens.
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http://dx.doi.org/10.1002/ar.a.20397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567843PMC
December 2006

Elevated maternal serum alpha-fetoprotein, umbilical vein varix, and mesenchymal dysplasia: are they related?

Prenat Diagn 2006 Aug;26(8):659-61

University of Tennessee College of Medicine-Chattanooga Unit Department of OB/GYN, Chattanooga, TN 37403, USA.

Objectives And Methods: Variceal dilatation of the umbilical vein is a rare vascular anomaly of the umbilical cord. We present a patient case where dilatation of the umbilical vein was associated with an elevated maternal serum alpha-fetoprotein on prenatal testing and mesenchymal dysplasia on pathological evaluation of the placenta.

Results: Alterations in the villous structure of the placenta as in mesenchymal dysplasia may lead to increased placental permeability causing an elevated maternal serum alpha-fetoprotein on antenatal testing.

Conclusion: Abnormal testing should be an indication for close evaluation of the placenta and placental structures, as well as the fetus.
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http://dx.doi.org/10.1002/pd.1436DOI Listing
August 2006