"Because the resources aren't there, then we fail. We fail as a society": A Qualitative Analysis of Human Trafficking Provider Perceptions of Child Welfare Involvement among Trafficked Mothers.

BACKGROUND: Little is understood about child welfare involvement (CWI) in cases where the birth mother has experienced human trafficking. OBJECTIVES: The aim of this study was to explore provider perceptions of the impact of CWI for the trafficked mother. METHODS: Participants were selected among providers caring for trafficked birth mothers. Semi-structured interviews were conducted with providers and qualitative content analysis was conducted. RESULTS: Interviewees reported reasons for CWI, positive and negative impacts of CWI and provided recommendations for systems improvement. CONCLUSION FOR PRACTICE: Recommendations from this exploratory study include mechanisms to support trafficked mothers, train hospital social workers, and systems change. During the prenatal period, strategies to support the trafficked mother may include addressing gaps in social determinants of health, ensuring appropriate medical and mental health care, early screening and referral to substance use treatment services, enhancing community support, and working to develop safety plans for survivors and their families. Enhanced engagement of social workers and all providers to improve understanding of the unique complexity of trafficked mothers is needed. Education should include an understanding that judgement of a caretaker's ability to parent should be current and holistic and not reflexive based on history in the electronic medical record. An exploration of the child welfare system itself should also be undertaken to identify and modify discriminatory laws and policies. Finally, efforts to address social determinants of health in the community and enhance the trauma-informed nature of child welfare referrals could improve the lives of trafficked mothers.

Cesarean section in patient with metastatic Ewing sarcoma requiring VA-ECMO support.

A 26-year-old pregnant woman, with multiple metastatic Ewing sarcoma, presented with a sternal mass that began enlarging during pregnancy. Due to high-risk pregnancy, the patient was discussed in a multidisciplinary meeting and intubation was considered too risky without cardiopulmonary support. Computed tomography showed extrinsic tumor compression of the right ventricle outflow tract. Veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) was initiated before general anesthesia, followed by Cesarean section (C-section). VA ECMO was initiated with the patient in the awake position, ECMO support was discontinued when the patient had stable ventilation and hemodynamics. This case represents a unique indication of VA ECMO, during C-section, with maternal and fetal survival.

Placenta Accreta: A Spectrum of Predictable Risk, Diagnosis, and Morbidity.

OBJECTIVE: Placenta accreta is a feared pathology, in part, because prenatal diagnosis is imperfect. It is not known whether clinical risk factors or sonographic features equally predict the entire graded pathological spectrum of placental overinvasion disease nor whether clinical outcomes differ along the spectrum. STUDY DESIGN: We conducted a mixed methods retrospective study of a cohort of women screened sonographically for placenta accreta, cross-referenced against cases identified by pathological diagnosis (N = 416). Demographic, diagnostic, and outcome information were compared across the spectrum of invasive placentation: percreta, increta, accreta, and focal accreta not requiring hysterectomy. The t-test, chi-square, Mann-Whitney, and Kruskal-Wallis tests were used for statistical analysis across groups. RESULTS: As the depth of invasion decreased, risk factors for placental overinvasion were less common, especially placenta previa and previous cesarean. There was also reduced anticipation by sonographic examination of the placenta. Rates of adverse outcomes were lower among women with focal accreta compared with those with deeper invasion. CONCLUSION: As the depth of invasion decreases, clinical risk factors and sonographic evaluation are less reliable in the antenatal prediction of placenta accreta. The potential for unanticipated morbidity underscores the need for improved diagnostic tools for placenta accreta spectrum.

Potassium chloride-induced fetal demise: a retrospective cohort study of efficacy and safety.

OBJECTIVES: Induction of fetal demise before second-trimester termination is performed for a number of reasons. One method for inducing fetal demise is via sonographically guided intracardiac potassium chloride (KCl) injection. We performed a retrospective cohort study to determine the efficacy and safety of intracardiac KCl injection as a method of second-trimester induced fetal demise. METHODS: We reviewed records from patients who were referred for induced fetal demise from October 2002 to October 2011. We excluded patients undergoing selective fetal reduction in multiple gestations. Procedural complications, the dose of KCl, and the number of failed procedures were determined. RESULTS: Of the 192 completed procedures, 191 were successful (99.5%). The median gestational age at termination was 22 weeks (range, 15.4-24.9 weeks), and most terminations were surgical (68.0%). Major indications for termination were fetal anomalies (41.6%), unwanted pregnancy (20.8%), and aneuploidy (15.7%). The median dose of KCl was 10 mL (range, 3-40 mL). We found a significant correlation between the dose of KCl and estimated fetal weight. There was no significant correlation between the dose of KCl and body mass index or gestational age. We had 1 maternal complication of a seizure after needle placement but before KCl injection. CONCLUSIONS: Intracardiac KCl injection is an effective and safe method for induced fetal demise.

Nod1 activation by bacterial iE-DAP induces maternal-fetal inflammation and preterm labor.

There is a strong association between infection and prematurity; however, the underlying mechanisms remain largely unknown. Nod1 and Nod2 are intracellular pattern recognition receptors that are activated by bacterial peptides and mediate innate immunity. We previously demonstrated that human first-trimester trophoblasts express Nod1 and Nod2, which trigger inflammation upon stimulation. This study sought to determine the expression and function of Nod1 and Nod2 in third-trimester trophoblasts, and to characterize the in vivo effects of Nod1 activation on pregnancy outcome. Human term placental tissues and isolated term trophoblast expressed Nod1, but not Nod2. Activation of Nod1 by its agonist, bacterial γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP), in term trophoblast cultures induced a proinflammatory cytokine profile, characterized by elevated levels of secreted IL-6, GRO-α, and MCP-1, when compared with the control. However, these cytokines were not upregulated in response to Nod2 stimulation with bacterial MDP. Administration of high-dose bacterial iE-DAP to pregnant C57BL/6J mice on embryonic day 14.5 triggered preterm delivery within 24 h. iE-DAP at a lower dose that did not induce prematurity, reduced fetal weight, altered the cytokine profile at the maternal-fetal interface, and induced fetal inflammation. Thus, functional Nod1 is expressed by trophoblast cells across gestation and may have a role in mediating infection-associated inflammation and prematurity. This study demonstrates that pattern recognition receptors, other than the TLRs, may be implicated or involved in infection-associated preterm labor.

Pravastatin does not prevent antiphospholipid antibody-mediated changes in human first trimester trophoblast function.

STUDY QUESTION: What is the effect of pravastatin on antiphospholipid antibody (aPL) modulation of human first trimester trophoblast function? SUMMARY ANSWER: Pravastatin does not prevent the effects of aPL on human first trimester trophoblast cell function. WHAT IS KNOWN ALREADY: Antiphospholipid syndrome (APS) is associated with recurrent pregnancy loss and late pregnancy complications, such as pre-eclampsia, owing to direct targeting of the placenta by aPL. While treatment with heparin reduces the rate of pregnancy loss, the risk for severe pre-eclampsia remains high. Thus, there is a need to find alternative treatments for the prenatal management of patients with APS. Statins have recently been shown to prevent aPL-mediated fetal loss in mice but their effects on a human pregnancy model of APS have not yet been studied. DESIGN, DATA COLLECTION, METHODS: The human first trimester trophoblast cell line, HTR8, and human first trimester trophoblast primary cultures were incubated with or without a mouse anti-human beta 2 glycoprotein I (ß(2)GPI) monoclonal antibody in the presence or absence of pravastatin. Cytokine and angiogenic factor secretion were measured by enzyme-linked immunosorbent assay and multiplex analysis. Cell migration was measured using a colorimetric two-chamber migration assay. MAIN FINDINGS: Using the human first trimester trophoblast cell line, HTR8, pravastatin significantly augmented, compared with no treatment, aPL-dependent secretion of interleukin (IL)-8 (P< 0.05), IL-1ß (P< 0.05) and soluble endoglin (P< 0.01) but had no effect on aPL-induced up-regulation of vascular endothelial growth factor, placenta growth factor or growth-related oncogene alpha secretion. Furthermore, pravastatin alone limited basal HTR8 cell migration (P< 0.01), and did not mitigate the adverse effect of aPL on trophoblast migration. Pravastatin also had no impact on the secretion of pro-inflammatory cytokines and angiogenic factors by primary human first trimester trophoblast cells exposed to aPL. LIMITATIONS AND WIDER IMPLICATIONS OF THE FINDINGS: While our in vitro findings suggest that pravastatin may not be effective in preventing pregnancy complications in patients with APS, the in vivo condition may be more complex, and thus, more studies are needed to determine the effectiveness of pravastatin in the prevention of aPL-associated pregnancy complications in humans. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the American Heart Association.

Accreta complicating complete placenta previa is characterized by reduced systemic levels of vascular endothelial growth factor and by epithelial-to-mesenchymal transition of the invasive trophoblast.

OBJECTIVE: We sought to characterize serum angiogenic factor profile of women with complete placenta previa and determine if invasive trophoblast differentiation characteristic of accreta, increta, or percreta shares features of epithelial-to-mesenchymal transition. STUDY DESIGN: We analyzed gestational age-matched serum samples from 90 pregnant women with either complete placenta previa (n = 45) or uncomplicated pregnancies (n = 45). Vascular endothelial growth factor (VEGF), placental growth factor, and soluble form of fms-like-tyrosine-kinase-1 were immunoassayed. VEGF and phosphotyrosine immunoreactivity was surveyed in histological specimens relative to expression of vimentin and cytokeratin-7. RESULTS: Women with previa and invasive placentation (accreta, n = 5; increta, n = 6; percreta, n = 2) had lower systemic VEGF (invasive previa: median 0.8 [0.02-3.4] vs control 6.5 [2.7-10.5] pg/mL, P = .02). VEGF and phosphotyrosine immunostaining predominated in the invasive extravillous trophoblasts that coexpressed vimentin and cytokeratin-7, an epithelial-to-mesenchymal transition feature and tumorlike cell phenotype. CONCLUSION: Lower systemic free VEGF and a switch of the interstitial extravillous trophoblasts to a metastable cell phenotype characterize placenta previa with excessive myometrial invasion.

Utility of routine screening fetal echocardiogram in pregnancies conceived by in vitro fertilization.

OBJECTIVE: To study the incidence and clinical significance of congenital heart defects (CHDs) detected by fetal echocardiography in pregnancies conceived by in vitro fertilization (IVF). DESIGN: Cohort study comparing a prospectively maintained database of all fetal echocardiograms from 2012 to 2018 and pooled data from the Connecticut Birth Defects Registry and statewide hospital discharge data. SETTING: Large tertiary care center. PATIENT(S): A total of 181,749 live births and 9,252 fetal echocardiograms were analyzed. Fetal echocardiograms in patients with a previous child with a CHD, a family history of CHD, medication exposure, diabetes, anomaly in previous pregnancy, cardiac or other abnormality noted on previous ultrasound, or monochorionic twins were excluded from the final analysis. INTERVENTION(S): Treatment with IVF. MAIN OUTCOME MEASURE(S): Incidence of CHD and odds ratios with 95% confidence intervals (CIs). Infant outcomes for cases of CHD were evaluated for clinically significant disease, defined a priori as disease requiring any medical or surgical intervention or continued follow-up with pediatric cardiology. RESULT(S): Fetal echocardiography was performed in 2,230 IVF pregnancies, of which 2,040 were without other known risk factors for CHD. The mean gestational age at the time of fetal echocardiography was 22.2 ± 1.4 weeks. The odds ratio for CHD in the IVF group compared with statewide population rates was 1.4 (95% CI 0.9-2.1). CHD was diagnosed in 26 fetuses, of which 21 were clinically insignificant ventricular septal defects. One fetal echocardiogram was concerning for pulmonary stenosis that was not present at birth. Four defects were clinically significant, indicating that 510 fetal echocardiograms were performed for every diagnosis of one clinically significant CHD in the IVF group. CONCLUSION(S): The incidence of CHD in IVF pregnancies without other risk factors is not significantly different from baseline population rates, and most CHDs diagnosed by fetal echocardiography in this group are clinically insignificant. Routine screening with fetal echocardiography in all IVF pregnancies provides limited utility beyond routine prenatal care and need not be recommended without the presence of other risk factors.

Relationships of maternal serum levels of vascular endothelial growth factor and tensile strength properties of the cervix in a rat model of chronic hypoxia.

OBJECTIVE: It has been shown that hypoxia leads to alterations in maternal serum levels of vascular endothelial growth factor (VEGF). In this study, we sought to test the hypothesis that chronic hypoxia increases maternal serum levels of VEGF, which in turn cause measurable changes in the viscoelastic properties of the rat uterine cervix. STUDY DESIGN: Timed-pregnant adult Sprague-Dawley rats were exposed to hypoxia beginning on day 17 of gestation (term = day 22). The following groups of animals were studied: (1) nonpregnant controls (NP, n = 6); (2) normoxia 21% fraction of inspired oxygen (FiO2) (NMX, n = 6); and (3) severe hypoxia 10% FiO2 (HPX; n = 5). A hypoxic chamber was used to assure consistent hypoxic environment. Animals were killed on day 21 of gestation (before labor). Maternal blood was collected immediately following anesthesia and prior to euthanasia. Free serum levels of VEGF were measured by highly specific immunoassays. Tensile strength properties of the cervix were assessed using a stretching regimen designed to mimic labor. Physical parameters measured were: indicators of viscoelasticity (slope; measure of stiffness), plasticity (yield point [YP]; moment the tissue changes its properties from elastic to plastic), strength (break point [BP]; moment of tissue disruption), and displacement at YP (marks the duration of the viscoelastic phase of the stretching) and BP (a measure of the strength of the material). Data were normalized to the dry weight of the cervix. RESULTS: Hypoxia is associated with increased serum levels of VEGF compared to NP or NMX groups (P = .001). Cervical stiffness was lower in NMX, compared with NP animals (P = .004), and was not significantly influenced by hypoxia (P > .05). Overall there was a significant inverse correlation between slope and maternal serum levels of VEGF (r = -0.85, P < .001). The force required to reach YP was significantly higher for the NP, compared with NMX and HPX groups (P = .004). Hypoxia did not alter the force required to reach the YP (NMX vs HPX, P > .05). Conversely, hypoxia significantly decreased the displacement at YP, indicating a shortening of the elastic phase (NMX vs HPX, P = .021). There was a significant inverse correlation between maternal serum levels of VEGF and the displacement at YP (r = -0.68, P = .002). In vivo, hypoxia decreased the force required to reached the BP (NMX vs HPX, P = .025), but there was no correlation between the levels of maternal serum VEGF and this indicator (r = -0.35, P = .170). CONCLUSION: Chronic hypoxia induces measurable changes in maternal serum levels of VEGF and tensile properties of the rat cervix, specifically a shortening of the elastic phase. Hypoxia decreases the cervical strength to stretch and predisposes to rupture, but this effect seems to be unrelated to maternal serum levels of VEGF.

Ultrasonographic evaluation of myometrial thickness in twin pregnancies.

OBJECTIVE: The objective of the study was to evaluate longitudinally the in vivo changes in myometrial thickness (MT) during gestation in patients carrying twin gestations in relation to pregnancy outcome. STUDY DESIGN: Serial abdominal ultrasounds were performed prospectively in 92 patients carrying twin gestations through each trimester. Ninety-seven patients pregnant with singletons served as controls. For twins, the primary endpoint was spontaneous delivery at less than 35 weeks' gestational age (GA). The myometrium was defined sonographically as the echohomogeneous layer between the serosa and the decidua and was measured at the anterior, fundal, and lower uterine segment (LUS) walls. The estimated fetal weight, maximum vertical pocket of amniotic fluid, and placental thickness were also assessed ultrasonographically at the same time as the MT and served as estimates for the contribution of each to the uterine volume. In twins, cervical length measurements were performed transvaginally, as clinically indicated. Data analysis included 2-way analysis of variance and linear, nonlinear, and multivariate regression. RESULTS: A total of 41.3% of twin pregnancies (38 of 92) delivered preterm (< 35 weeks). There were no significant changes in measurements at the anterior and fundal site over time throughout pregnancy and no differences in these sites between twin and singleton gestations. Conversely, in both twins and singletons, there was a significant and gradual thinning of the LUS myometrium during gestation. In the absence of uterine contractions or symptoms of preterm labor, twins that delivered preterm had a significantly thinner LUS at an earlier gestation, compared with twins that delivered at term (P < .001), suggesting that LUS thinning occurred earlier in these cases. There was a significant correlation between cervical length and LUS thinning during gestation in twins that delivered 35 weeks GA or later (r = 0.352; P < .001) but not in those that delivered preterm (< 35 weeks GA; r = 0.125; P = .326). CONCLUSION: Twin pregnancy is characterized by a significant, selective, and gradual thinning of the LUS during gestation, which does not occur in the anterior and fundal myometrium. Thinning of the LUS occurs earlier in twin pregnancies destined to deliver preterm. These observations suggest that similar to the cervix, the LUS changes dynamically during twin pregnancy and that this too may be assessed through ultrasound imaging.

Cesarean Scar Pregnancy, Incidence, and Recurrence: Five-Year Experience at a Single Tertiary Care Referral Center.

OBJECTIVE: To describe the treatment and subsequent pregnancy outcomes in patients with cesarean scar pregnancies at a single institution over 5 years. METHODS: This is a case series of all cesarean scar pregnancies diagnosed from May 2013 to March 2018 at Yale-New Haven Hospital. Data were collected on each patient using electronic medical record review and included patient demographics; medical, surgical, and obstetric history; pregnancy characteristics; treatment modalities used; response to therapy; complications; and subsequent pregnancy outcomes. RESULTS: Thirty cases of cesarean scar pregnancies were diagnosed in 26 patients, including one recurrence in one patient and three recurrences in another. Forty-six percent of cesarean scar pregnancies were in Hispanic women. The median number of prior cesarean deliveries was two. Mean gestational age at the time of diagnosis was 46 days (SD±10). Fetal cardiac activity was detected in 18 cases. Three patients initially were erroneously diagnosed with a viable intrauterine pregnancy and failed medical termination. Others opted for termination through systemic methotrexate alone (n=4), systemic and local methotrexate (n=12), systemic and local methotrexate with potassium chloride injected into the gestational sac (n=3), potassium chloride injection with laparotomy and wedge resection (n=1), methotrexate with bilateral uterine artery embolization (n=2), or intrauterine balloon (n=4). Five patients who underwent expectant management or methotrexate therapy had retained products of conception and required hysteroscopy and curettage. One patient opted for hysterectomy after failed curettage. After complete resolution of cesarean scar pregnancies, there were 10 subsequent spontaneous conceptions in eight patients, including four recurrent cesarean scar pregnancies, four term pregnancies, and one spontaneous abortion. One viable normally located pregnancy is ongoing. CONCLUSION: There is a wide array of treatment modalities available for cesarean scar pregnancies. Women with a cesarean scar pregnancy are at risk for its recurrence in the future, although normal pregnancy after a cesarean scar pregnancy is also possible. Safe outcomes depend on timely diagnosis and multidisciplinary care by skilled clinicians.

Proteomic profiling of the amniotic fluid to detect inflammation, infection, and neonatal sepsis.

BACKGROUND: Proteomic analysis of amniotic fluid shows the presence of biomarkers characteristic of intrauterine inflammation. We sought to validate prospectively the clinical utility of one such proteomic profile, the Mass Restricted (MR) score. METHODS AND FINDINGS: We enrolled 169 consecutive women with singleton pregnancies admitted with preterm labor or preterm premature rupture of membranes. All women had a clinically indicated amniocentesis to rule out intra-amniotic infection. A proteomic fingerprint (MR score) was generated from fresh samples of amniotic fluid using surface-enhanced laser desorption ionization (SELDI) mass spectrometry. Presence or absence of the biomarkers of the MR score was interpreted in relationship to the amniocentesis-to-delivery interval, placental inflammation, and early-onset neonatal sepsis for all neonates admitted to the Newborn Special Care Unit (n = 104). Women with "severe" amniotic fluid inflammation (MR score of 3 or 4) had shorter amniocentesis-to-delivery intervals than women with "no" (MR score of 0) inflammation or even "minimal" (MR score of 1 or 2) inflammation (median [range] MR 3-4: 0.4 d [0.0-49.6 d] versus MR 1-2: 3.8 d [0.0-151.2 d] versus MR 0: 17.0 d [0.1-94.3 d], p < 0.001). Nonetheless, a "minimal" degree of inflammation was also associated with preterm birth regardless of membrane status. There was a significant association between the MR score and severity of histological chorioamnionitis (r = 0.599, p < 0.001). Furthermore, neonatal hematological indices and early-onset sepsis significantly correlated with the MR score even after adjusting for gestational age at birth (OR for MR 3-4: 3.3 [95% CI, 1.1 to 9.2], p = 0.03). When compared with other laboratory tests routinely used to diagnose amniotic fluid inflammation and infection, the MR score had the highest accuracy to detect inflammation (white blood cell count > 100 cells/mm3), whereas the combination of Gram stain and MR score was best for rapid prediction of intra-amniotic infection (positive amniotic fluid culture). CONCLUSIONS: High MR scores are associated with preterm delivery, histological chorioamnionitis, and early-onset neonatal sepsis. In this study, proteomic analysis of amniotic fluid was shown to be the most accurate test for diagnosis of intra-amniotic inflammation, whereas addition of the MR score to the Gram stain provides the best combination of tests to rapidly predict infection.

Value of placental microbial evaluation in diagnosing intra-amniotic infection.

OBJECTIVE: To evaluate the ability of microbiologic and pathologic examination of the placenta to accurately diagnose intraamniotic infection and inflammation. METHODS: One hundred eighty-three women with a clinically indicated amniocentesis were enrolled prospectively. We applied our analysis to 56 women with evidence of preterm labor or preterm premature rupture of membranes who delivered within 48 hours of amniotic fluid testing results. Twenty-three patients, assessed for fetal lung maturity in the third trimester, served as controls. Amniotic fluid was cultured for aerobic, anaerobic, Ureaplasma, and Mycoplasma species. We used mass spectrometry to assess the degree of intraamniotic inflammation (Mass Restricted scoring). After delivery, microbiologic and histologic studies of the placenta were performed. These results were interpreted in comparison with the direct microbiologic and inflammatory analysis of the amniotic fluid. A sample size of 45 patients was required to show a test accuracy of 80% or more. RESULTS: Ninety-two percent of women with positive amniotic fluid cultures tested with at least one positive placenta culture. Eighty percent of women who had negative amniotic fluid cultures also tested with a positive placenta culture. The accuracy of placental cultures in predicting amniotic fluid infection varied from 44% to 57%. Placental pathology showed an accuracy of only 58% in diagnosing intraamniotic inflammation. CONCLUSION: Placental microbiologic and histologic studies poorly reflect the infectious and inflammatory status of the amniotic fluid. Results of such studies should be interpreted with caution in the management and future counseling of women with preterm labor or preterm premature rupture of membranes. LEVEL OF EVIDENCE: II.

Lactate dehydrogenase isoform activity mapping in patients with intra-amniotic infection.

OBJECTIVE: Five distinct lactate dehydrogenase isoenzymes have been described. We sought to illustrate the specific amniotic fluid lactate dehydrogenase isoenzyme activity profiles in women with intra-amniotic infection. STUDY DESIGN: Amniotic fluid was retrieved from 82 women who were stratified in the following groups: (1) positive amniotic fluid cultures (n = 23 women; gestational age, 26 weeks [range, 21-32 weeks]); (2) negative amniotic fluid cultures (n = 22 women; gestational age, 30 weeks [range, 16-36 weeks]); (3) second trimester control (normal genetic karyotype; n = 17 women; gestational age, 18 weeks [range, 16-22 weeks]); and (4) third trimester control (fetal lung maturity testing; n = 20 women; gestational age, 36 weeks [range, 31-38 weeks]). The optical density of each isoform was determined relative to a standard with 5 known lactate dehydrogenase isoenzyme activities. Total lactate dehydrogenase activity was measured by the clinical laboratory immediately after retrieval and by a kinetic UV spectrophotometric assay at the time of the isoelectric focusing. RESULTS: Infection increased total lactate dehydrogenase activity: positive amniotic fluid cultures (median, 762.4 [range, 169.3-3374.8]) vs negative amniotic fluid cultures (median, 203.7 [range, 57.8-1939.3]; U/L; P < .001]). Lactate dehydrogenase isoform profiling identified significant and specific increases in lactate dehydrogenase isoforms 3, 4 (P < .01), and 5 (P < .05) in positive amniotic fluid cultures compared to the negative amniotic fluid cultures group. A selective up-regulation in lactate dehydrogenase isoform 5 was identified at term in healthy subjects. CONCLUSION: Intra-amniotic infection is characterized by an increase in the activities of lactate dehydrogenase isoforms 3, 4, and 5; advancing gestational age demonstrates an up-regulation of isoform 5 only.

Serum and urine inhibin A but not free activin A are endocrine biomarkers of severe pre-eclampsia.

OBJECTIVE: Elevation of total serum inhibin A and activin A has been interpreted as evidence of placental dysfunction in women who develop pre-eclampsia. We sought to evaluate serum and urine levels of inhibin A and free activin A in normal and hypertensive pregnancies. STUDY DESIGN: Inhibin A and free activin A were measured by immunoassay in simultaneously collected serum and urine samples from 75 women: (1) severe pre-eclampsia (n = 30); (2) mild pre-eclampsia (n = 11); (3) chronic hypertension (n = 9); (4) pregnant control women (n = 16); and (5) nonpregnant control women (n = 9). Urine levels were normalized to milligrams urine creatinine, and fractional excretions were calculated. RESULTS: Serum and urine inhibin A were increased and fractional excretion was decreased in pregnancy. Serum, urine, and fractional excretion of inhibin A were increased in severe pre-eclampsia, compared with other gravidas. The only difference observed in free activin A was a decrease in serum free activin A in chronic hypertension, compared with severe pre-eclampsia and pregnant control women. Urine inhibin A showed the greatest discrimination between severe pre-eclampsia and pregnant control women: a cut-off of 45 pg/mg urine creatinine had 96.8% sensitivity, 87.5% specificity, and 93.6% accuracy. Women with urine inhibin A greater than 90 pg/mg urine creatinine had a 17-fold relative risk (95% confidence interval 9.7-459.5) of a clinically indicated delivery due to pre-eclampsia. CONCLUSION: Serum and urine levels of inhibin A are altered in severe pre-eclampsia. Urine inhibin A may have application in the diagnosis and management of pre-eclampsia. Those with chronic hypertension have lower serum but not urine free activin A levels, compared with severe pre-eclampsia and mild pre-eclampsia.

A low vaginal "pool" amniotic fluid glucose measurement is a predictive but not a sensitive marker for infection in women with preterm premature rupture of membranes.

OBJECTIVE: We sought to identify the use of vaginal amniotic fluid (vAF) glucose measurements in predicting infection of the amniotic fluid retrieved by transabdominal amniocentesis (aAF) in women with preterm premature rupture of the membranes (PPROM). STUDY DESIGN: Fluid was retrieved by aAF was retreived from 35 consecutive women with PPROM on whom an amniocentesis was clinically indicated to rule out intra-amniotic infection/inflammation and successfully completed. aAF was cultured for aerobic, anaerobic bacteria, Ureaplasma and Mycoplasma species. Clinical laboratory analysis for aAF included glucose concentration, Gram stain, lactate dehydrogenase, and white and red blood cell count. vAF was analyzed only for glucose concentration. Glucose concentration for the paired abdominal-vaginal AF samples (aAF-vAF) was determined by using well-established clinical and research laboratory methods. At the end of enrollment we stratified our patients into 2 groups: (1) positive microbial cultures (+)AFC (n = 17, gestational age [GA]: 27.3 +/- 0.7 weeks) or (2) negative microbial cultures (-)AFC (n = 18, GA: 31.3 +/- 0.5 weeks). Cohen kappa measure of concordance and receiver operating characteristic (ROC) curve analysis were used to test the ability of the vaginal "pool" glucose measurements to discriminate between women with positive or negative AF cultures. RESULTS: Women with (+)AFC ruptured and delivered at an earlier GA compared with the (-)AFC group (p < .001). The latency period was similar (P = .35). There was a significant linear correlation between aAF and vAF glucose concentrations (r = 0.783, P < .001). Women with intra-amniotic infection (IAI) had significantly lower aAF [mean +/- SEM (+)AFC: 11.4 +/- 3.2 vs (-)AFC 23.0 +/- 2.8 mg/dL, P = .01] and vAF glucose levels [(+)AFC: 10.1 +/- 2.8 vs (-)AFC: 19.8 +/- 2.9 mg/dL, P = .02] compared with the noninfected group. Cohen kappa measure of concordance indicated "substantial" agreement between aAF and vAF glucose measurements (kappa = 0.719, 95% CI = 0.491-0.947). The sensitivity of the vAF glucose level to detect IAI ranged from 82% to 47%, whereas specificity ranged from 100% to 56% depending on the threshold we used. A vaginal "pool" (vAF) glucose measurement less than 5 mg/dL had 47.1% sensitivity, 100% specificity, 100% positive predictive value, 66.7% negative predictive value, and 74.2% accuracy in identifying women with (+)AFC. CONCLUSION: Vaginal glucose determination is a readily available, inexpensive, rapid AF marker that can be measured practically in any clinical laboratory. vAF glucose measurements less than 5 mg/dL have predictive value, but low sensitivity for detection of IAI.

Mechanisms of progesterone action in inhibiting prematurity.

Progesterone is a steroid hormone that plays an integral role in each step of human pregnancy. In early pregnancy, progesterone produced by the corpus luteum is critical to the maintenance of early pregnancy until the placenta takes over this function at 7 to 9 weeks of gestation, hence its name (pro-gestational steroid hormone). The role of progesterone in later pregnancy, however, is less clear. It has been proposed that progesterone may be important in maintaining uterine quiescence in the latter half of pregnancy by limiting the production of stimulatory prostaglandins and inhabiting the expression of contraction-associated protein genes within the myometrium. Although systemic progesterone withdrawl may not correlate directly with the onset of labour in humans, there is increasing evidence to suggest that progesterone exerts its influence indirectly via a 'functional' withdrawl at the level of the uterus. The molecular mechanisms by which progesterone is able to maintain uterine quiescence and prevent preterm birth in some high-risk women are not clear. Six putative mechanisms have been proposed in the literature by both US and other investigators and are explored in this review.

Uterine didelphys and vaginal birth after cesarean delivery.

BACKGROUND: Müllerian anomalies are associated with adverse pregnancy outcomes. We discuss pregnancy in anomalous uteri, with a focus on uterine didelphys, in the setting of a prior cesarean delivery. CASE(S): A 30-year-old woman, gravida 2 para 1001, presented in latent labor at 40 1/7 weeks of gestation. Her first pregnancy was in the right horn of a didelphic uterus and resulted in a cesarean delivery in the setting of chorioamnionitis remote from delivery. The current pregnancy was in the left horn and resulted in a vacuum-assisted vaginal delivery after spontaneous labor. CONCLUSION: There is sparse literature on a trial of labor after cesarean delivery in a uterine didelphys.

Vitamin D reverses aPL-induced inflammation and LMWH-induced sFlt-1 release by human trophoblast.

PROBLEM: Women with antiphospholipid syndrome (APS) are at increased risk of recurrent pregnancy loss (RPL) and preeclampsia. Antiphospholipid antibodies (aPL) directly alter trophoblast function. Treatment with low molecular weight heparin (LMWH) reduces the risk of RPL but not preeclampsia. Moreover, LMWH stimulates trophoblast sFlt-1 release, an anti-angiogenic factor associated with preeclampsia. Since vitamin D deficiency is associated with APS and preeclampsia, this study sought to determine the effect of vitamin D on trophoblast function in the setting of aPL and LMWH. METHOD OF STUDY: A human first trimester trophoblast cell line (HTR8) and primary trophoblast cultures were treated with or without aPL in the presence and absence of vitamin D, LMWH or both. Trophoblast secretion of inflammatory cytokines and angiogenic factors were measured by ELISA. RESULTS: Vitamin D alone or in combination with LMWH attenuated the aPL-induced trophoblast inflammatory response in the HTR8 cells and primary cultures. While vitamin D did not have any impact on aPL-mediated modulation of angiogenic factors in the primary trophoblast, it significantly inhibited LMWH-induced sFlt-1 release. CONCLUSION: LMWH in combination with vitamin D may be more beneficial than single-agent therapy by preventing aPL-induced trophoblast inflammation and reversing LMWH-induced sFlt-1 secretion.