Obstetricians & Gynecologists
16 years of experience
Video profile
Accepting new patients
Washington Square West
800 Spruce St
Philadelphia, PA 19107
215-829-2346
Locations and availability (7)

Education ?

Medical School Score Rankings
Yeshiva University (1994)
  • Currently 3 of 4 apples
Top 50%

Awards & Distinctions ?

Appointments
University of Pennsylvania
Assistant Professor of Obstetrics and Gynecology Director, Maternal Fetal Medicine Fellowship Program
Associations
American Board of Obstetrics and Gynecology

Affiliations ?

Dr. Elovitz is affiliated with 6 hospitals.

Hospital Affilations

Score

Rankings

  • Chestnut Hill Hospital
    8835 Germantown Ave, Philadelphia, PA 19118
    • Currently 4 of 4 crosses
    Top 25%
  • Chester County Hospital
    701 E Marshall St, West Chester, PA 19380
    • Currently 4 of 4 crosses
    Top 25%
  • Graduate Hospital
    1800 Lombard St, Philadelphia, PA 19146
    • Currently 1 of 4 crosses
  • Pennsylvania Hospital University PA Health System
  • Clinical Practices of the University of Pennsylvania
  • Hospital of the University of PA
  • Publications & Research

    Dr. Elovitz has contributed to 37 publications.
    Title A Mouse Model of Term Chorioamnionitis: Unraveling Causes of Adverse Neurological Outcomes.
    Date January 2012
    Journal Reproductive Sciences (thousand Oaks, Calif.)
    Excerpt

    Maternal fever and/or chorioamnionitis at term are associated with an increased prevalence of adverse neurobehavioral outcomes in exposed offspring. Since the mechanisms of such injury are currently unknown, the objectives of this study were to elucidate whether intrauterine inflammation at term results in fetal brain injury. Specifically, we assessed brain injury by investigating the cytokine response, white matter damage, and neuronal injury and viability. A mouse model of intrauterine inflammation at term was utilized by injecting lipopolysaccharide (LPS), or normal saline into uterine horn. Compared to saline-exposed, LPS-exposed fetal brains had significantly increased IL-1β and IL-6 messenger RNA (mRNA) expression (P < .05 for both) and IL-6 protein levels by enzyme-linked immunosorbent assay (ELISA; P < 0.05). Fetal neurons were affected by the intrauterine and fetal brain inflammation, as demonstrated by significantly decreased microtubule-associated protein 2 (MAP2) mRNA expression and a decrease in immunocytochemical staining (a marker of neuronal cytoskeleton development; P < .05), altered neuronal morphology (P < 0.05), and delayed neurotoxicity (P < .05). These fetal neuronal changes occurred without overt changes in white matter damage markers. Marker of astrocyte development and astrogliosis (glial fibrillary acidic protein [GFAP]) did not show an increase; pro-oligodendrocyte marker (PLP1/DM20) was not significantly changed (P > .05). These studies may provide a critical mechanism for the observed long-term adverse neurobehavioral outcomes after exposure to chorioamnionitis at term.

    Title Fetal Erap2 Variation is Associated with Preeclampsia in African Americans in a Case-control Study.
    Date August 2011
    Journal Bmc Medical Genetics
    Excerpt

    Preeclampsia affects 3-8% of pregnancies and is a major cause of maternal and perinatal morbidity and mortality worldwide. This complex disorder is characterized by alterations in the immune and vascular systems and involves multiple organs. There is strong evidence for a genetic contribution to preeclampsia. Two different single nucleotide polymorphisms (SNPs) in the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene were recently reported to be associated with increased risk for preeclampsia in two different populations. ERAP2 is expressed in placental tissue and it is involved in immune responses, inflammation, and blood pressure regulation; making it is an attractive preeclampsia candidate gene. Furthermore, ERAP2 expression is altered in first trimester placentas of women destined to develop preeclampsia.

    Title Pregnancy in Women with Congenital Heart Disease: the Impact of a Systemic Right Ventricle.
    Date July 2011
    Journal Congenital Heart Disease
    Excerpt

    Individuals with a systemic right ventricle develop cardiac complications earlier in life. Limited data exists regarding the effect of a maternal systemic right ventricle on cardiac events during pregnancy. We sought to assess the effect of a systemic right ventricle on cardiac events and pregnancy outcomes.

    Title Inflammation-induced Preterm Birth Alters Neuronal Morphology in the Mouse Fetal Brain.
    Date September 2010
    Journal Journal of Neuroscience Research
    Excerpt

    Adverse neurological outcome is a major cause of long-term morbidity in ex-preterm children. To investigate the effect of parturition and inflammation on the fetal brain, we utilized two in vivo mouse models of preterm birth. To mimic the most common human scenario of preterm birth, we used a mouse model of intrauterine inflammation by intrauterine infusion of lipopolysaccharide (LPS). To investigate the effect of parturition on the immature fetal brain, in the absence of inflammation, we used a non-infectious model of preterm birth by administering RU486. Pro-inflammatory cytokines (IL-10, IL-1beta, IL-6 and TNF-alpha) in amniotic fluid and inflammatory biomarkers in maternal serum and amniotic fluid were compared between the two models using ELISA. Pro-inflammatory cytokine expression was evaluated in the whole fetal brains from the two models. Primary neuronal cultures from the fetal cortex were established from the different models and controls in order to compare the neuronal morphology. Only the intrauterine inflammation model resulted in an elevation of inflammatory biomarkers in the maternal serum and amniotic fluid. Exposure to inflammation-induced preterm birth, but not non-infectious preterm birth, also resulted in an increase in cytokine mRNA in whole fetal brain and in disrupted fetal neuronal morphology. In particular, Microtubule-associated protein 2 (MAP2) staining was decreased and the number of dendrites was reduced (P < 0.001, ANOVA between groups). These results suggest that inflammation-induced preterm birth and not the process of preterm birth may result in neuroinflammation and alter fetal neuronal morphology.

    Title The Effects of a Preterm Labor Episode Prior to 34 Weeks Are Evident in Late Preterm Outcomes, Despite the Administration of Betamethasone.
    Date August 2010
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    We sought to assess whether betamethasone (BETA) <34 weeks reduces adverse outcomes in late preterm infants.

    Title N-terminal Pro-brain Natriuretic Peptide As a Biomarker for Hypertensive Disorders of Pregnancy.
    Date June 2010
    Journal American Journal of Perinatology
    Excerpt

    We tested the hypothesis that the cardiac biomarker N-terminal pro-brain natriuretic peptide would be elevated in hypertensive disorders of pregnancy, with an increase in levels of this biomarker across increasing gradations of disease severity. We performed a case-controlled study of women admitted to labor and delivery at the Hospital of the University of Pennsylvania between 24 and 42 weeks of gestation. Cases had hypertension that developed after 20 weeks of gestation, and controls were normotensive women presenting for delivery. N-terminal pro-brain natriuretic peptide levels were compared between cases ( N = 83) and controls ( N = 290). Cases were subclassified into gestational hypertension ( N = 20) and mild ( N = 15) and severe preeclampsia ( N = 48), and N-terminal pro-brain natriuretic peptide levels were compared between these subgroups. N-terminal pro-brain natriuretic peptide levels were higher in cases than in controls (81 pg/mL versus 37 pg/mL, P < 0.001), with a graded increase in levels from gestational hypertension (64 pg/mL) to preeclampsia (89 pg/mL) to severe preeclampsia (157 pg/mL; P < 0.001). Each log increase in N-terminal pro-brain natriuretic peptide doubled the risk of preeclampsia (odds ratio = 2.10 P < 0.001). N-terminal pro-brain natriuretic peptide levels were increased in hypertensive disorders of pregnancy and discriminate between subcategories of disease.

    Title Evidence of a Gene-environment Interaction That Predisposes to Spontaneous Preterm Birth: a Role for Asymptomatic Bacterial Vaginosis and Dna Variants in Genes That Control the Inflammatory Response.
    Date April 2010
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    We determined whether an environmental exposure to bacterial vaginosis (BV) modified genetic susceptibilities for spontaneous preterm delivery within genes that regulate the inflammatory response.

    Title Do Neonatal Outcomes Differ Depending on the Cause of Preterm Birth? A Comparison Between Spontaneous Birth and Iatrogenic Delivery for Preeclampsia.
    Date April 2010
    Journal American Journal of Perinatology
    Excerpt

    We compared short-term neonatal outcomes between premature infants with spontaneous preterm birth (s-PTB) and those delivered due to preeclampsia (PEC). Data were collected from women with singleton pregnancies admitted with spontaneous preterm labor (PTL) (2002 to 2005) and PEC (2005 to 2007). Patients delivering 24 to 36(6/7) weeks were analyzed. The incidence of adverse outcomes was compared. Chi-square and Fisher exact tests compared outcomes between neonates of varying gestational ages, and Poisson regression was used to control for confounders. Data describing 368 infants are included (PTL: n = 224; PEC: n = 144). Overall, s-PTB infants had less favorable outcomes at earlier gestational ages, and at later gestational ages those born preterm secondary to PEC (pec-PTB) had less favorable outcomes. s-PTB infants 24 to 27(6/7) weeks were 21% more likely to stay in the neonatal intensive care unit (NICU) > or = 8 days than pec-PTB infants (incident rate ratios [IRR] 0.79, P = 0.002, 95% confidence interval [CI] 0.68 to 0.92). Pec-PTB infants 32 to 33(6/7) weeks were 6 times more likely to stay in the NICU > or = 31 days than s-PTB infants (IRR 5.82, P = 0.03, 95% CI 1.20 to 28.31). Short-term neonatal outcomes differ by the etiology of preterm birth. These data can help facilitate proper patient counseling and allocation of resources. Future studies should address mechanisms by which the etiology of PTB leads to specific adverse outcomes, thus allowing for more direct interventional strategies.

    Title Preterm and Term Cervical Ripening in Cd1 Mice (mus Musculus): Similar or Divergent Molecular Mechanisms?
    Date January 2010
    Journal Biology of Reproduction
    Excerpt

    Premature cervical ripening is believed to contribute to preterm birth (PTB). Preterm cervical ripening may be due to an aberrant regulation in timing of the same processes that occur at term, or may result from unique molecular mechanisms. Using mouse models of PTB, this study sought to investigate if the molecular mechanisms that govern cervical ripening were similar between preterm and term. Lipopolysaccharide (LPS) is infused into the uterine horn to create a mouse model of inflammation-induced PTB. For a noninfectious model of PTB, RU486 was administered. Both models result in delivery of pups in 8-24 h. Cervical tissues were collected from these models, as well as throughout gestation. Cervical tissues from E15 (preterm), E15 LPS (preterm inflammation), and E18.5 (term) were used for microarray analysis (n = 18). Additional experiments using gestational time course specimens were performed to confirm microarray results. Specific gene pathways were differentially expressed between the groups. Genes involved in immunity and inflammation were increased in the cervix in inflammation-induced PTB; term labor was not associated with differential expression of immune pathways. Cytokine expression was not increased in cervices during term labor, but was increased in the pospartum period. Epithelial cell differentiation pathway was significantly altered in term, but not preterm, labor. Activation of immune pathways may be sufficient for cervical ripening, but does not appear necessary. Differential expression of the epithelial cell differentiation pathway appears necessary in the process of cervical repair. Our results indicate that the molecular mechanisms governing preterm and term cervical ripening are distinctly different.

    Title Limitations of Ultrasound in Diagnosing Intrauterine Growth Restriction in Severe Preeclampsia.
    Date December 2009
    Journal The Journal of Maternal-fetal & Neonatal Medicine : the Official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians
    Excerpt

    The objective of this study was to determine test characteristics of ultrasound in detecting intrauterine growth restriction (IUGR) in severe preeclampsia (S-PEC).

    Title Beyond White Matter Damage: Fetal Neuronal Injury in a Mouse Model of Preterm Birth.
    Date October 2009
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    The purpose of this study was to elucidate possible mechanisms of fetal neuronal injury in inflammation-induced preterm birth.

    Title The Negative Regulators of the Host Immune Response: an Unexplored Pathway in Preterm Birth.
    Date October 2009
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Toll-like receptors (TLRs) are essential mediators of host immunity. TLR activation must be tightly regulated to prevent an exaggerated immune response from devastating the host. These studies assessed the expression of negative regulators (interleukin receptor-associated kinase [IRAK]-3, IRAK-1, Fas-associated protein with death domain) during pregnancy and in preterm birth (PTB).

    Title Periodontal Disease and Adverse Pregnancy Outcomes: is There an Association?
    Date May 2009
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    We assessed the risk of adverse pregnancy outcomes (preterm birth [PTB], preeclampsia [PRE], fetal growth restriction [FGR], or perinatal death) in women with periodontal disease (PD) compared to those without.

    Title Maternal Mortality from Systemic Illness: Unraveling the Contribution of the Immune Response.
    Date April 2009
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Maternal morbidity and/or mortality (MM) is increased in pyelonephritis and influenza. Alterations in the immune response could account for the increase MM. We sought to determine whether the immune response is functionally different during pregnant and nonpregnant (NP) states.

    Title Medroxyprogesterone Acetate Modulates Remodeling, Immune Cell Census, and Nerve Fibers in the Cervix of a Mouse Model for Inflammation-induced Preterm Birth.
    Date April 2009
    Journal Reproductive Sciences (thousand Oaks, Calif.)
    Excerpt

    To determine whether a progestational agent can modify inflammation-induced preterm cervical ripening, mice on day 15 of gestation were given an intrauterine injection of (1) saline, (2) lipopolysaccharide, (3) an intramuscular injection of medroxyprogesterone acetate alone prior to lipopolysaccharide, or (4) medroxyprogesterone acetate alone. Cervices were obtained 6 hours later, then fixed, sectioned, and processed to stain collagen structure or to identify immune cells or nerve fibers. Cervical remodeling was induced by lipopolysaccharide treatment compared with that in saline controls, an effect blocked by medroxyprogesterone acetate pretreatment. Moreover, lipopolysaccharide reduced macrophages and enhanced neutrophils in the cervix, effects also forestalled by medroxyprogesterone acetate pretreatment. Although the density of nerve fibers was not altered by lipopolysaccharide, medroxyprogesterone acetate reduced innervation in the cervix. Thus, progestational treatment forestalls the inflammation-induced reduction in collagen structure and immune cell traffic through a mechanism that is independent of nerve fiber density. These findings raise the possibility that progestational treatment may regulate ripening of the cervix early in the process leading to preterm birth.

    Title Adverse Neonatal Outcomes: Examining the Risks Between Preterm, Late Preterm, and Term Infants.
    Date November 2008
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: There is a relative paucity of data regarding neonatal outcomes in the late preterm cohort (34 to 36 6/7 weeks). This study sought to assess differences in adverse outcomes between infants delivering 32 to 33 6/7, 34 to 36 6/7 weeks, and 37 weeks or later. STUDY DESIGN: Data were collected as part of a retrospective cohort study of preterm labor patients (2002-2005). Patients delivering 32 weeks or later were included (n = 264). The incidence of adverse outcomes was assessed. Significant associations between outcomes and gestational age at delivery were determined using chi(2) analyses and Poisson regression modeled cumulative incidence and controlled for confounders. RESULTS: Late preterm infants have increased risk of adverse outcomes, compared with term infants. Controlling for confounders, there was a 23% decrease in adverse outcomes with each week of advancing gestational age between 32 and 39 completed weeks (relative risk 0.77, P < .001, 95% confidence interval, 0.71-0.84). CONCLUSION: Further investigation regarding obstetrical management and long-term outcomes for this cohort is warranted.

    Title Can Placental Pathology Explain Second-trimester Pregnancy Loss and Subsequent Pregnancy Outcomes?
    Date November 2008
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: This study sought to determine whether specific placental pathology may provide further insight into the mechanisms of second-trimester pregnancy loss, particularly in cases without inflammation. STUDY DESIGN: A blinded pathologist examined placentas from 90 patients with spontaneous second-trimester pregnancy loss and 17 controls who presented for induction of labor for fetal indications. Inflammation was staged and evidence of other vascular pathology recorded. Significant associations were determined by chi(2) analysis and Fisher's exact test. A secondary analysis examined losses without inflammation. Twelve patients with a subsequent pregnancy were also evaluated. RESULTS: Acute inflammation was more prevalent in cases than controls (P < .001). Sixty-seven percent of all cases and none of the controls showed a stage 2-3 inflammatory response. Histologic abruption was also more prevalent in cases than controls (P = .05). CONCLUSION: Second-trimester pregnancy loss is strongly associated with placental inflammation. Histologic abruption is likely another etiology. Future research should focus on subsequent pregnancy outcomes in these women based on initial placental pathology to help determine etiology and recurrence risk.

    Title Medroxyprogesterone Acetate Modulates the Immune Response in the Uterus, Cervix and Placenta in a Mouse Model of Preterm Birth.
    Date October 2008
    Journal The Journal of Maternal-fetal & Neonatal Medicine : the Official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians
    Excerpt

    OBJECTIVE: These studies sought to determine whether a progestational agent, specifically medroxyprogesterone acetate (MPA) prevents inflammation-induced preterm birth, in a mouse model, through modulation of the host immune response. STUDY DESIGN: Using an established mouse model of inflammation-induced preterm birth, the activation of the immune response in maternal serum, uterus, cervix and placenta was assessed. In addition, the ability of MPA to modulate this response was investigated. Message RNA and protein expression were assessed by quantitative PCR and ELISAs respectively. RESULTS: Intrauterine inflammation promotes a significant up-regulation of both TH1 and TH2 mediators in all tissues studies though the response is divergent by time and tissue studied. MPA significantly differentially regulates this immune response in the uterus, cervix and placenta. CONCLUSIONS: In the setting of inflammation-induced preterm birth, the host immune response is activated and not limited to a traditional TH1 bias. The ability of MPA to modulate the immune response may be a critical mechanism by which progestins prevent preterm birth.

    Title Is Routine Infectious and Toxicologic Screening in Preterm Labor Effective in Predicting Preterm Birth?
    Date May 2008
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Our objective was to evaluate whether a significant association exists between cocaine use, cervical, urine, and/or Group B streptococcus (GBS) infections and preterm birth (PTB) in patients admitted with active preterm labor (PTL). STUDY DESIGN: A retrospective cohort study of PTL patients < 34 weeks (n = 400) admitted to a large, urban tertiary care hospital (2002-2005) was performed. Pertinent history and screening test results were collected. The prevalence of a positive result for each test was determined. Pearson chi-square and Poisson regression were used to evaluate the significance of associations between screening tests and PTB and to control for confounders. RESULTS: The percentage of patients that delivered at < 37 and < 34 weeks was 63.5% (n = 254) and 44.5% (n = 178), respectively. Only cocaine use was significantly associated with PTB at < 34 weeks (RR 1.86, 95%CI 1.03, 2.08). CONCLUSION: This laboratory test panel is not an effective adjunctive means to predict PTB in PTL patients.

    Title Preventing Cervical Ripening: the Primary Mechanism by Which Progestational Agents Prevent Preterm Birth?
    Date April 2008
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Recent clinical trials suggest that progestational agents may prevent preterm birth, specifically in women with short cervices. These studies sought to assess novel pathways by which progestational agents (PAs) may modify signal transduction pathways that are involved in cervical ripening. STUDY DESIGN: A microarray analysis was performed on pregnant mouse cervix that was exposed to a MPA. Appropriate microarray and cluster analyses were performed. Target genes of interest were investigated in both PA- and inflammation-exposed cervices by quantitative polymerase chain reaction and immunohistochemistry. RESULTS: Microarray analysis identified both the previously recognized and novel pathways that are involved in cervical ripening. PAs differentially regulate expression of claudin-2, hyaluronan synthase 2, and lipocalin 2. Claudin expression is significantly decreased by inflammation, which is prevented by PAs. CONCLUSION: PAs significantly modulate gene expression in the cervix in the presence and absence of inflammation. The regulation of these pathways, specifically claudin proteins, may be a critical mechanism by which PAs prevent preterm birth, especially in women with premature cervical shortening.

    Title Hyperosmolar Hyperglycemic State of Pregnancy with Intrauterine Fetal Demise and Preeclampsia.
    Date January 2008
    Journal American Journal of Perinatology
    Excerpt

    Hyperosmolar hyperglycemic state (HHS) is a serious complication of uncontrolled hyperglycemia. Paralleling the obesity epidemic, the incidence of type 2 diabetes is increasing in a younger population. Therefore, obstetricians must be prepared to deal with the complications of this disease. We present a unique case of new-onset diabetes resulting in HHS. A 21-year-old G1P0 presented at 32 weeks 2 days with an intrauterine fetal demise. At presentation, she was noted to have hyperglycemia, hypertension, proteinuria, altered sensorium, and negative serum ketones. Management included an insulin drip, rehydration, and magnesium. Labor was induced without complications. HHS secondary to undiagnosed type 2 diabetes may become a more common entity in the pregnant population as obesity reaches epidemic proportions. The practitioner should have a high index of suspicion for HHS in obese patients presenting with hyperglycemia.

    Title Second-trimester Loss and Subsequent Pregnancy Outcomes: What is the Real Risk?
    Date December 2007
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: This study was performed to determine whether second-trimester pregnancy loss was associated with an increased risk for spontaneous preterm birth or recurrent second-trimester loss in a subsequent pregnancy. STUDY DESIGN: A retrospective cohort study was conducted. Patients with a second-trimester pregnancy loss (n = 38), a spontaneous preterm birth (n = 76), and a full term delivery (n = 76) were identified from 2002 to 2005 (index pregnancy). Computerized medical records were used to obtain demographic and obstetrical histories. RESULTS: Frequencies of subsequent second-trimester loss were 27%, 3%, and 1% in the second-trimester loss, spontaneous preterm birth, and full-term delivery cohorts, respectively. Frequencies of subsequent spontaneous preterm birth were 33%, 39.5%, and 9% in the same 3 cohorts. Patients with a prior second-trimester loss were 10.8 times more likely to have recurrent second-trimester loss or spontaneous preterm birth, compared with those with prior full-term delivery (confidence interval 3.6 to 32.1, P < .0001). CONCLUSION: Patients with a prior second-trimester loss are at significantly increased risk for spontaneous preterm birth and recurrent second-trimester loss in their next pregnancy.

    Title Metabolic Score As a Novel Approach to Assessing Preeclampsia Risk.
    Date November 2007
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Clinical trials have confirmed the association of metabolic syndrome with cardiovascular disease (CVD) in women. Because recent evidence suggests that preeclampsia is a risk factor for future CVD, we sought to determine whether metabolic syndrome was associated with preeclampsia. STUDY DESIGN: As part of a large case-control study, women were prospectively identified with preeclampsia. Controls were patients presenting for delivery at term without preeclampsia. Two pregnancy-based metabolic scores (0, 1, or 2 or more) were created using initial or final pregnancy body mass index, chronic hypertension, and diabetes. Stratified analysis and logistic regression were used to evaluate the association of metabolic score with preeclampsia and disease severity. RESULTS: For initial metabolic score, 44.1%, 42.3%, and 13.5% of cases (n = 259) and 61.5%, 33.2%, and 5.3% of controls (n = 297) had scores of 0, 1 (odds ratio [OR] 1.91, P = .002), and 2 or more (OR 2.65, P = .001), respectively. CONCLUSION: Metabolic score appears to be associated independently with developing preeclampsia, particularly severe disease.

    Title Toll-like Receptors in the Uterus, Cervix, and Placenta: is Pregnancy an Immunosuppressed State?
    Date September 2007
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: These studies were performed to elucidate the expression of Toll-like receptors (TLRs) in the uterus, cervix, and placenta in pregnancy and across gestation. STUDY DESIGN: Message expressions of TLR-2, -3, -4, and -9 were investigated in nonpregnant mice and across gestation in CD-1 mice. Uterine, cervical, and placental tissues were harvested, and RNA was extracted. Quantitative polymerase chain reaction was performed. RESULTS: Messenger RNA expression of TLRs is significantly upregulated in pregnant uterine and cervical tissues. There is differential TLR messenger RNA expression between the uterus, cervix, and placenta. In the placenta, TLR 4 is significantly downregulated. CONCLUSION: These findings suggest that the innate immune system is a dynamic system during gestation. The concept of immunosuppression during pregnancy appears to be valid in the placenta only in regard to TLR expression. Research is warranted to determine whether the upregulation in the uterus and cervix during pregnancy is associated with an increased likelihood of responding to a pathogen or serve as a protective mechanism or both.

    Title Anti-inflammatory Interventions in Pregnancy: Now and the Future.
    Date February 2007
    Journal Seminars in Fetal & Neonatal Medicine
    Excerpt

    A growing body of evidence implicates inflammatory pathways in adverse reproductive outcomes. This expanding evidence suggests that anti-inflammatory interventions may hold promise in reducing the maternal and neonatal morbidities and mortalities associated with these obstetrical complications. Preterm birth, preeclampsia, pregnancy loss and adverse neonatal outcomes have all been associated with the activation of inflammatory pathways during pregnancy. Because of the number of observational human studies, as well as animal models of preterm birth, the mechanisms by which inflammation may promote preterm parturition and adverse effects on the fetus are beginning to be elucidated. Although the future use of anti-inflammatory interventions in this context holds significant promise, much research is still warranted. Only when the pathogenesis of obstetrical complications is more fully understood can meaningful therapeutic interventions become a realistic goal.

    Title The Use of Progestational Agents for Preterm Birth: Lessons from a Mouse Model.
    Date October 2006
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: On the basis of the recent Maternal Fetal Medicine Unit Networks clinical trial, the American College of Obstetricians and Gynecologists supports the administration of 17-alpha hydroxyprogesterone caproate to high-risk patients. Because inflammation/infection is believed to be a contributing factor in many cases of preterm birth, it is imperative to understand the effect of 17-alpha hydroxyprogesterone caproate treatment in this clinical situation. STUDY DESIGN: Using a mouse model of localized intrauterine inflammation, we investigated the ability of progestational agents to prevent preterm birth. On gestational day 15 (E15), dams were assigned randomly to treatment with 17-alpha hydroxyprogesterone caproate, medroxyprogesterone acetate, or vehicle before intrauterine infusion of lipopolysaccharide. All dams were monitored for morbidity and preterm birth. Three separate sets of experiments were performed to assess different outcomes at 6, 24, and 96 hours. At 6 and 24 hours, C-reactive protein, interleukin-6, and interleukin-10 levels were measured in maternal serum by enzyme-linked immunosorbent assay. RESULTS: Pretreatment with 17-alpha hydroxyprogesterone caproate or medroxyprogesterone acetate before intrauterine lipopolysaccharide treatment significantly decreased the preterm birth rate, compared with lipopolysaccharide treatment alone. Medroxyprogesterone acetate treatment was more effective than 17-alpha hydroxyprogesterone caproate treatment in the prevention of preterm birth and resulted in live pups at term. Treatment with 17-alpha hydroxyprogesterone caproate was associated with significant maternal morbidity. CONCLUSION: In the setting of intrauterine inflammation, progestational agents decrease the preterm birth rate but can result in maternal morbidity. 17-Alpha hydroxyprogesterone caproate should not be used in patients who are suspected of having subclinical infection and/or acute preterm labor. The mechanisms by which progestational agents inhibit preterm birth warrants further investigations so that the use of this drug to appropriate populations could be pursued without undue fetal or maternal harm.

    Title Placental Inflammation and Viral Infection Are Implicated in Second Trimester Pregnancy Loss.
    Date October 2006
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Second trimester pregnancy loss continues to be a poorly understood adverse obstetric outcome. A case control study was performed to determine if: (1) similar to early spontaneous preterm birth, second trimester loss is associated with histologic chorioamnionitis (HCA); and (2) if HCA is present, which organisms may mediate this placental inflammation. STUDY DESIGN: Cases were patients with a spontaneous second trimester loss. Controls were patients who presented for induction of labor for fetal or maternal indications. Nested polymerase chain reaction (PCR) was performed on placental tissues to detect the presence of viruses and pathogenic and atypical bacteria. Chi-square and Fisher exact test were used to determine if HCA and/or the presence of virus or bacteria were significantly associated with second trimester loss. The associations of interest were adjusted for possible confounders using multivariable logistic regression. RESULTS: HCA was more prevalent in cases (67%) than controls (16%) (P < .001). Seventy-nine percent (66/84) of cases and 44% (7/16) of controls were positive for any virus (P = .01). The rate of bacterial infection was similar in both cases and controls (P = .35). In multivariable logistic regression models, HCA (odds ratio [OR] 14.58, 2.62-81.15) and the presence of any virus (OR 6.62, 1.56-28.07) were independently associated with second trimester loss. CONCLUSION: These studies demonstrate that spontaneous second trimester loss is strongly associated with HCA and viral infections.

    Title Transcytosis of Human Immunodeficiency Virus 1 Across the Placenta is Enhanced by Treatment with Tumour Necrosis Factor Alpha.
    Date September 2006
    Journal The Journal of General Virology
    Excerpt

    The human placenta is relatively resistant to Human immunodeficiency virus 1 (HIV-1), but obstetric complications associated with inflammatory processes, including chorioamnionitis and spontaneous preterm delivery, are associated with increased rates of vertical transmission. It was hypothesized that the pro-inflammatory mediator tumour necrosis factor alpha (TNF-alpha), which promotes HIV-1 transmission across endothelial membranes, increases HIV-1 transmission across the placenta. Flow cytometry and immunostaining studies were performed, which demonstrated that the HIV-1 receptors CD4, CCR5 and CXCR4 were not expressed by villous trophoblast cells. Consequently, primary villous trophoblast cells were not infected with cell-free HIV-1 isolates, as measured by in situ PCR and quantitative PCR, but villous trophoblast cells were infected by HIV-1-infected peripheral blood mononuclear cells (PBMC). HIV-1 from infected PBMC was rapidly transported across confluent transformed trophoblast cell monolayers by transcytosis, and TNF-alpha significantly upregulated transcytosis of HIV-1 across the trophoblast layer without disrupting cell viability or confluency. Inhibitors of TNF-alpha (antibodies against TNF-alpha and TNF-alpha receptors) and an anti-inflammatory drug (tenidap) significantly reduced transcytosis rates. It was concluded that the villous trophoblast is resistant to infection by cell-free HIV-1 but susceptible to transcytosis of HIV-1 from infected PBMC, and inflammatory mediators such as TNF-alpha may play a critical role in promoting maternal-fetal transmission of HIV-1.

    Title Nausea, Emesis, and Muscle Weakness in a Pregnant Adolescent.
    Date April 2006
    Journal Obstetrics and Gynecology
    Excerpt

    BACKGROUND: Gitelman syndrome is a rare autosomal recessive disorder that presents in early adulthood with fatigue, muscle cramps and electrolyte abnormalities. CASE: A 17-year-old African-American woman presented at 17 weeks of pregnancy with nausea, emesis, profound lower extremity proximal muscle weakness, hypokalemia, and hypomagnesemia. After a thorough evaluation, Gitelman syndrome was diagnosed. The patient was maintained on high levels of potassium and magnesium supplementation throughout the rest of her pregnancy and delivered a healthy infant. CONCLUSION: In pregnancy, nausea and emesis is most commonly attributed to hyperemesis gravidarum. However, an atypical presentation of these symptoms and/or the coexistence of less common complaints warrant further investigation.

    Title Elucidating the Early Signal Transduction Pathways Leading to Fetal Brain Injury in Preterm Birth.
    Date January 2006
    Journal Pediatric Research
    Excerpt

    Adverse neurologic outcome, including cerebral palsy, is a significant contributor to long-term morbidity in preterm neonates. However, the mechanisms leading to brain injury in the setting of a preterm birth are poorly understood. In the last decade, there has been a growing body of evidence correlating infection or inflammation with preterm birth. The presence of intrauterine inflammation significantly increases the risk for adverse neurologic outcome in the neonate. These studies were performed to elucidate the early signal transduction pathways activated in the fetal brain that may result in long-term neurologic injury. Using our mouse model of localized intrauterine inflammation, the activation of TH1/TH2 pathways in the placenta, fetus corpus, fetal liver, and fetal brain was investigated. Additional studies determined whether activation of TH1/TH2 pathways could promote cell death and alter glial development. Real-time PCR studies demonstrated that a robust TH1/TH2 response occurs rapidly in the fetal brain after exposure to intrauterine inflammation. The cytokine response in the fetus and placenta was not significantly correlated with the response in the fetal brain. Along with an immune response, cell death pathways were activated early in the fetal brain in response to intrauterine LPS. Implicating TH1/TH2 and cell death pathways in permanent brain injury are our findings of an increase in GFAP mRNA and protein as well as a loss of pro-oligodendrocytes. With increased understanding of the mechanisms by which inflammation promotes brain injury in the preterm neonate, identification of potential targets to limit adverse neonatal outcomes becomes possible.

    Title Can Medroxyprogesterone Acetate Alter Toll-like Receptor Expression in a Mouse Model of Intrauterine Inflammation?
    Date October 2005
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Activation of the innate immune receptors, Toll-like receptors 2 and 4, are critical for a host inflammatory response to both Gram-positive and Gram-negative organisms. These receptors can initiate and modulate the inflammatory response. Differential regulation of Toll-like receptors may be one of the mechanisms by which intrauterine inflammation signals parturition. Likewise, progestational agents may have the ability to modify this effect. These studies were performed to elucidate the effect of intrauterine inflammation and medroxyprogesterone acetate on Toll-like receptor expression in the uterus, cervix, and placenta in a mouse model of intrauterine inflammation. STUDY DESIGN: On day 15 of gestation, CD-1 mice were randomized to pretreatment with medroxyprogesterone acetate or vehicle before intrauterine infusion with lipopolysaccharide or sterile saline solution. Six hours after intrauterine infusion, uterine, cervical, and placental tissues were harvested. RNA and protein were extracted. Quantitative polymerase chain reaction was performed for Toll-like receptor 2 and 4 messenger RNA. Western blot analysis was performed with Toll-like receptor 4-specific antibodies. RESULTS: Intrauterine inflammation up-regulated Toll-like receptor 2 and 4 messenger RNA in uterus, cervix, and placenta. Pretreatment with medroxyprogesterone acetate decreased the lipopolysaccharide-induced up-regulation of Toll-like receptor 2 and 4 messenger RNA in the cervix and placenta. Medroxyprogesterone acetate treatment, in the presence of lipopolysaccharide, was unable to prevent the lipopolysaccharide-induced increase in Toll-like receptor 4 messenger RNA and protein in the uterus. Medroxyprogesterone acetate treatment alone in pregnant mice significantly increased Toll-like receptor 4 messenger RNA expression in the uterus. CONCLUSION: Intrauterine inflammation has a differential effect on Toll-like receptor 2 and 4 expression. The observed up-regulation of Toll-like receptor 2 in the uterus in response to intrauterine lipopolysaccharide may be a mechanism to augment the inflammatory response and may serve to promote parturition in the setting of inflammation. Consequently, the ability of medroxyprogesterone acetate to suppress lipopolysaccharide-induced up-regulation of Toll-like receptor 2 messenger RNA may be one of the mechanisms by which progestins are able to decrease preterm birth.

    Title Animal Models of Preterm Birth.
    Date February 2005
    Journal Trends in Endocrinology and Metabolism: Tem
    Excerpt

    Preterm birth continues to pose a significant clinical dilemma and contributes to both acute and long-term neonatal morbidity. Despite efforts, the incidence of preterm birth has not decreased, partly because of our lack of understanding of the mechanisms that trigger parturition. Animal models are essential research tools for investigating the pathways that promote preterm parturition and for testing therapeutic interventions. Growing evidence correlates infection or inflammation with preterm birth. Consequently, many investigators have created animal models that reflect these findings. Current models of preterm parturition include diverse species, varying means of inducing an inflammatory or infectious state, and different routes of administration. Although each of these models can advance our knowledge, it is important to understand their advantages, disadvantages and unique characteristics. An understanding of such models will hopefully promote continued research that will ultimately lead to a decrease in preterm birth and an improvement in neonatal outcome.

    Title A New Model for Inflammation-induced Preterm Birth: the Role of Platelet-activating Factor and Toll-like Receptor-4.
    Date December 2003
    Journal The American Journal of Pathology
    Excerpt

    Preterm birth is a leading cause of neonatal morbidity and mortality. Despite a growing body of evidence correlating inflammation with preterm birth, the signal transduction pathways responsible for the emptying of the uterus in the setting of intrauterine inflammation has not been elucidated. We now report a unique, reproducible mouse model of localized intrauterine inflammation. This model results in 100% preterm delivery with no maternal mortality. Using our model, we also show that platelet-activating factor is a crucial mediator of both inflammation-induced preterm birth and fetal demise. Using C3H/HeJ mice, we demonstrate that toll-like receptor-4 (TLR-4) plays a role in lipopolysaccharide-induced preterm birth but not in inflammation-induced fetal death. Immunohistochemistry studies demonstrate the presence of the platelet-activating factor receptor in both endometrial glands and smooth muscle in uterine tissues. Molecular studies demonstrate the differential expression of platelet-activating factor receptor and TLR-4 in uterine and cervical tissue throughout gestation. Quantitative polymerase chain reaction revealed an up-regulation of TLR-4 in the fundal region of the uterus in response to intrauterine inflammation. The use of this model will increase our understanding of the significant clinical problem of inflammation-induced preterm birth and will elucidate signal transduction pathways involved in an inflammatory state.

    Title The Role of Thrombin in Preterm Parturition.
    Date December 2001
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Previous reports from our laboratory have shown that thrombin is a potent uterotonic agonist; those studies have suggested a role for thrombin during parturition, especially with regard to intrauterine bleeding. Thrombin activation can be quantified in peripheral blood by measurement of thrombin-antithrombin III (TAT) complex levels. This study sought to determine whether thrombin activation, as measured by thrombin-antithrombin III levels, is associated with premature labor. STUDY DESIGN: Thrombin-antithrombin III levels were measured in patients and control subjects with preterm labor. Quantitative TAT levels were determined by use of an enzyme-linked immunoassay with a working range from 0 to 60 ng/mL. All patients were monitored for pregnancy outcome. Receiver operating curve analysis was performed to determine the optimal TAT cutoff values. Further statistical analyses with one-way ANOVA, the chi2 test, or the Fisher exact test were performed to determine statistical significance (P <.05). RESULTS: Patients admitted with preterm labor who were subsequently delivered within 3 weeks had significantly higher mean TAT levels (7.80 +/- 2.86 ng/mL; P <.05) than control subjects (5.77 +/- 1.43 mL) or patients with preterm labor who were not delivered within 3 weeks of presentation with preterm labor (5.57 +/- 1.69 ng/mL; P <.05). Given a diagnosis of preterm labor, a TAT level of 8.0 ng/mL had a positive predictive value of 80% for delivery within 3 weeks of enrollment. CONCLUSIONS: This study showed that TAT levels are elevated in patients with preterm labor who are destined to deliver before term. These results suggest that preterm labor resulting in premature delivery is associated with the activation of thrombin. Future studies will further elucidate the role of thrombin in preterm parturition and confirm whether tests for thrombin activation can accurately identify those patients destined for preterm delivery.

    Title Effects of Thrombin on Myometrial Contractions in Vitro and in Vivo.
    Date November 2000
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: A previous report from our laboratory demonstrated that thrombin stimulates myometrial contractions by activating the phosphatidylinositol signaling pathway in a dose-dependent fashion. The studies described in this report sought to determine whether thrombin and blood stimulate myometrial contractions both in vivo and in vitro and whether these uterotonic effects could be suppressed or prevented with thrombin inhibitors. STUDY DESIGN: In vitro contraction studies were performed with proestrus and estrus rat myometrial tissue. In vivo contraction studies were performed with nonpregnant and timed-pregnant Sprague-Dawley rats. RESULTS: Pretreatment of thrombin with hirudin suppressed the uterotonic effects of thrombin in vitro. Fresh whole blood stimulated myometrial contractions in a dose-dependent fashion in vitro, and thrombin inhibitors decreased the myometrial response seen with blood alone. Thrombin increased the frequency, intensity, and tone of myometrial contractions in vivo in a dose-related manner. In pregnant animals increasing doses of whole blood increased the frequency and tone of myometrial contractions. In both pregnant and nonpregnant animals whole blood significantly stimulated myometrial contractions, whereas heparinization of the blood significantly suppressed this in vivo uterotonic effect. CONCLUSION: Thrombin is a potent uterotonic agent both in vitro and in vivo; furthermore, the uterotonic effects of blood appeared to be related to thrombin production during coagulation. These studies provide a possible mechanistic explanation for the observed increase in myometrial contractions in the presence of intrauterine bleeding and may also provide an insight into preterm labor associated with vaginal bleeding.

    Title The Mechanisms Underlying the Stimulatory Effects of Thrombin on Myometrial Smooth Muscle.
    Date October 2000
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: The mechanisms underlying the stimulation of uterine contractions in the presence of intrauterine hemorrhage have not been well defined. Thrombin, a blood coagulation factor, activates membrane receptors to result in the stimulation of the phosphatidylinositol signaling pathway and the mobilization of cytosolic calcium in platelets. Our studies sought to determine whether thrombin stimulates similar events in myometrial smooth muscle. STUDY DESIGN: Cytosolic calcium imaging and in vitro contraction studies were performed with rat myometrial tissue. RESULTS: At a concentration range of 1 to 100 U/mL thrombin produced phasic myometrial contractions, which were comparable in intensity to those produced by oxytocin and prostaglandin F(2)(alpha). Thrombin-induced cytosolic calcium concentration oscillations were similar to those produced by oxytocin. Contractions stimulated by thrombin were significantly suppressed in response to inhibitors of the phosphatidylinositol signaling pathway. These studies also confirmed that membrane receptor-Gq protein coupling events play a more important role than tyrosine kinase-mediated events during thrombin stimulation of myometrial smooth muscle. CONCLUSION: Thrombin is a potent uterotonic agonist, and its effects in myometrium are mediated by intracellular signaling events comparable to those activated by classic uterotonic agents. The physiologic importance of thrombin appears to be related to its potential role in the stimulation of uterine contractions in the presence of intrauterine hemorrhage.

    Title Biomarkers of Inflammation and Placental Dysfunction Are Associated with Subsequent Preterm Birth.
    Date
    Journal The Journal of Maternal-fetal & Neonatal Medicine : the Official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians
    Excerpt

    Objective. To assess whether the analysis of high sensitivity C-Reactive Protein (hsCRP), a biomarker of inflammation, and placental growth factor (PlGF), a biomarker of placental dysfunction, could help identify patients at risk for preterm birth (PTB). Methods. We performed a prospective cohort study of women with symptoms of preterm labor (22-33 6/7 weeks). Maternal serum was analyzed for hsCRP and PlGF. Median biomarker values were used as analytic cut-points. We performed chi-square tests of association between biomarkers and PTB, nonparametric tests to compare medians, and logistic regression to determine the odds of PTB associated with biomarker values. Test characteristics of each biomarker were calculated. Results. 56.3% of the cohort (N = 96) delivered preterm. Median hsCRP (N = 78) was 4.34 mg/L, and median PlGF (N = 86) was 558.25 mg/l. In the setting of inflammation (high hsCRP), women with low PlGF had a 6.84-fold (95%CI: 1.57-29.80) increased risk of PTB. In the setting of placental dysfunction (low PlGF), women with high hsCRP had a 5.97-fold (95%CI: 1.52-23.43) increased risk of PTB. Conclusions. Our results suggest an interplay between inflammation and placental dysfunction in the pathogenesis of PTB. Analyzing biomarkers that reflect different pathways of PTB may hold promise for identifying patients at greatest risk.

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