Long-Term Postpartum Cardiac Function and Its Association With Preeclampsia.

Background Preeclampsia is a prominent risk factor for long-term development of cardiovascular disease. Although existing studies report a strong correlation between preeclampsia and heart failure, the underlying mechanisms are poorly understood. One possibility is the glycoprotein growth factor activin A. During pregnancy, elevated activin A levels are associated with impaired cardiac global longitudinal strain at 1 year, but whether these changes persist beyond 1 year is not known. We hypothesized that activin A levels would remain increased more than 1 year after a preeclamptic pregnancy and correlate with impaired cardiac function. Methods and Results To test our hypothesis, we performed echocardiograms and measured activin A levels in women approximately 10 years after an uncomplicated pregnancy (n=25) or a pregnancy complicated by preeclampsia (n=21). Compared with women with a previously normal pregnancy, women with preeclampsia had worse global longitudinal strain (-18.3% versus -21.3%, P=0.001), left ventricular posterior wall thickness (0.91 mm versus 0.80 mm, P=0.003), and interventricular septal thickness (0.96 mm versus 0.81 mm, P=0.0002). Women with preeclampsia also had higher levels of activin A (0.52 versus 0.37 ng/mL, P=0.02) and activin/follistatin-like 3 ratio (0.03 versus 0.02, P=0.04). In a multivariable model, the relationship between activin A levels and worsening global longitudinal strain persisted after adjusting for age at enrollment, mean arterial pressure, race, and body mass index (P=0.003). Conclusions Our findings suggest that both activin A levels and global longitudinal strain are elevated 10 years after a pregnancy complicated by preeclampsia. Future studies are needed to better understand the relationship between preeclampsia, activin A, and long-term cardiac function.

Risk factors for cervical ectopic pregnancy.

OBJECTIVE: To evaluate risk factors for cervical ectopic pregnancies. METHODS: Retrospective, quasi-experimental case-control study of cervical ectopic pregnancy (CEP) cases from 2000-2013. Two groups were selected as controls, patients with tubal ectopic (TEP) and intrauterine pregnancies (IUP) without a history of TEP, matched by year of pregnancy and randomly sampled in a 1:3 case-control ratio per each study group. RESULTS: 21 cases were identified and 126 controls included, 63 TEP and IUP each. A binary logistic regression model was used to analyze whether statistically significant preceding factors from a bivariate analysis could predict CEP. Compared to patients with IUP, CEP patients had a higher history of elective abortions, D&C and cervical excisional procedures, with a high effect size (>0.7). Compared to patients with TEP, CEP patients had a higher history of D&C and cervical excisional procedures, with a high effect size (>.7). The risk of CEP was significantly higher with a prior history of D&C compared to an IUP (aOR 1.4; 95% CI, 1.1-9.1; p=0.04) and a TEP (aOR 6.1; 95% CI, 1.8-21.2; p=0.04). CONCLUSION: D&C is a strong risk factor for CEP when compared to pregnancies in other locations. These findings confirm previous associations described in case series.

Outcomes in subsequent pregnancies after wedge resection for interstitial ectopic pregnancy: a retrospective cohort study.

OBJECTIVE: The objective of this study is to evaluate pregnancy outcomes in patients with a history of wedge resection for interstitial ectopic pregnancy (WRIEP). METHODS: Retrospective cohort study of pregnancies with a history of WRIEP from 2000 to 2013 at two inner city hospitals in Detroit, MI. Pregnant-matched controls (1:3) were selected and included patients with history of surgically treated tubal ectopic pregnancy and delivered patients without history of ectopic pregnancy. Pregnancy outcomes, including a composite, were compared among the groups. RESULTS: Eighty-three cases of interstitial pregnancy were identified. Sixty-three (75.9%) underwent WRIEP from which 19 (30.2%) had a subsequent pregnancy and 11 (57.9%) carried it ≥20 weeks. No difference in subsequent pregnancy outcomes including the composite was found among patients with prior WRIEP and patients with history of surgically treated tubal ectopic pregnancy except for a longer interpregnancy interval. Compared with delivered patients without a history of ectopic pregnancy, no difference in late obstetric outcomes was found including the composite, gestational age at delivery in weeks (38.2 versus 38.1, p = .955), preterm delivery rate (30% versus 21%, p = .674), and proportion of term vaginal (40% versus 52%, p = .721) or cesarean deliveries (60% versus 30%, p = .137). The most common indication for cesarean among patients with a history of WRIEP was a history of such (5/6, 83.3%) and there were no cases of abnormal placentation. CONCLUSION: Findings suggest that a history of WRIEP is not associated with increased risk of adverse pregnancy outcomes.

Rosiglitazone augments antioxidant response in the human trophoblast and prevents apoptosis†.

Insufficient perfusion of the trophoblast by maternal blood is associated with an increased generation of reactive oxygen species and complications of the placenta. In this study, we first examined whether rosiglitazone, an agonist of the peroxisome proliferator-activated receptor-γ (PPARγ), protects the human trophoblast from oxidative injury by regulating key antioxidant proteins, catalase (CAT) and the superoxide dismutases (SOD1 and SOD2). In first trimester placental explants, localization of CAT was limited to cytotrophoblasts, whereas SOD1 was expressed in both the cyto- and syncytiotrophoblasts. In first trimester placental explants, hypoxia decreased the expression of both SOD1 and SOD2, and increased apoptosis. Treatment with rosiglitazone dose-dependently upregulated anti-oxidative CAT and SOD2, and rescued hypoxic injury in first trimester villous explants and JEG-3 cells, strongly suggesting the involvement of the PPARγ in regulating their expressions. Rosiglitazone facilitated transcription activity of PPARγ, and enhanced promotor binding, increased transcriptional activity at the CAT promoter, and elevated protein expression/activity. Treatment of hypoxic JEG-3 cells with rosiglitazone resulted in mitochondrial membrane potential increase and a reduction of caspase 9 and caspase 3 activity which is consistent with improved cell survival. To complement PPARγ activation data, we also utilized the antagonist (SR-202) and siRNA to suppress PPARγ expression and demonstrate the specific role of PPARγ in reducing ROS and oxidative stress. Ex vivo examination of term human placenta revealed lower expression of antioxidant proteins in pathologic compared to healthy placental tissues, which could be rescued by rosiglitazone, indicating that rosiglitazone can improve survival of the trophoblast under pathological conditions. These findings provide evidence that the PPARγ pathway directly influences cellular antioxidants production and the pathophysiology of placental oxidative stress.

Sonographic Measurement of Cervical Volume in Pregnant Women at High Risk of Preterm Birth Using a Geometric Formula for a Frustum Versus 3-Dimensional Automated Virtual Organ Computer-Aided Analysis.

OBJECTIVES: To compare cervical volume measurements by 3-dimensional (3D) sonography using Virtual Organ computer-aided analysis (VOCAL; GE Healthcare, Milwaukee, WI) versus a manual method using a geometric formula for a frustum. METHODS: We included 142 asymptomatic pregnant women at 16 to 24 weeks gestation at high risk for preterm birth. With a Voluson 730 Expert system (GE Healthcare), they underwent 2-dimensional (2D) transvaginal sonographic cervical length measurements and 3D cervical volume acquisition. The stored volumes were processed by VOCAL on a surface tablet. Cervical volume was manually calculated from the 2D images by using the formula V = 1/3 × π × h × (r12 + r22 + r1 × r2), where V represents cervical volume; π was approximated as 3.14159; h, cervical length; r1, radius at the internal os; and r2, radius at the external os. RESULTS: Cervical volume was lower when obtained manually than by VOCAL, with a coefficient of variation of 30%, a mean difference of 10.1 ± 14.9 cm3 (P < .0001), and a poor interclass correlation coefficient of 0.62 (95% confidence interval [CI], 0.31 to 0.78). Both methods had good reproducibility; however, VOCAL had wider limits of agreement. A positive correlation was found between both methods (r = 0.63; P < .0001). No correlation was found between cervical length by 2D transvaginal ultrasound and cervical volume by the VOCAL technique (r = 0.06; 95% CI, -0.10 to 0.22) or cervical volume by the manual method (r = 0.2; 95% CI, 0.08 to 0.39). CONCLUSIONS: The cervix represents a frustum (truncated cone, r1 is not equal to r2) in shape rather than a cylinder. Both methods are reproducible; VOCAL is less reliable but provides higher values of cervical volume.

Morbid obesity and outcome of ectopic pregnancy following capped single-dose regimen methotrexate.

PURPOSE: Evaluate whether morbid obesity influenced resolution, number of doses or ultimately surgical management of tubal ectopic pregnancy (TEP) when treated with single-dose regimen methotrexate (SDR-MTX) capped at 100 mg. METHODS: Retrospective cohort study of patients with a diagnosis of TEP who underwent MTX treatment from 2000 to 2013. Patients were excluded if initial ß-hCG <1000 mIU/mL, did not have ß-hCG follow-up or were not treated with SDR-MTX. Per protocol, dose was administered at 50 mg/m2 with a capped maximum of 100 mg. Patients were divided based on their BMI (<40 and ≥40 kg/m2). Demographic variables, ß-hCG before treatment, maximum diameter of ectopic size, embryonic heart tones, decrease of ß-hCG, need for additional MTX doses and surgery despite treatment were recorded and compared among the groups. RESULTS: 151 women were included in the study, 89.4% (135/151) non-morbidly obese and 10.6% (16/151) morbidly obese. No differences in age distribution, ethnicity, pre-treatment presence of embryonic heart tones, maximum diameter of ectopic size ≥35 mm and ß-hCG ≥5000 mIU/ml were found. Following treatment, the proportion of patients with at least an 80% decrease in their ß-hCG levels or need for surgery were similar, however, morbidly obese patients were significantly more likely [11/134 vs. 5/16, OR 5.1 (1.5-17.3, p = 0.015)] to require an additional MTX dose. CONCLUSION: Among patients with TEP, morbidly obese patients were five times more likely to require an additional dose compared to non-morbidly obese when SDR-MTX capped at 100 mg was used for medical management.

Reduced homeobox protein MSX1 in human endometrial tissue is linked to infertility.

STUDY QUESTION: Is protein expression of the muscle segment homeobox gene family member MSX1 altered in the human secretory endometrium by cell type, developmental stage or fertility? SUMMARY ANSWER: MSX1 protein levels, normally elevated in the secretory phase endometrium, were significantly reduced in endometrial biopsies obtained from women of infertile couples. WHAT IS KNOWN ALREADY: Molecular changes in the endometrium are important for fertility in both animals and humans. Msx1 is expressed in the preimplantation mouse uterus and regulates uterine receptivity for implantation. The MSX protein persists a short time, after its message has been down-regulated. Microarray analysis of the human endometrium reveals a similar pattern of MSX1 mRNA expression that peaks before the receptive period, with depressed expression at implantation. Targeted deletion of uterine Msx1 and Msx2 in mice prevents the loss of epithelial cell polarity during implantation and causes infertility. STUDY DESIGN, SIZE DURATION: MSX1 mRNA and cell type-specific levels of MSX1 protein were quantified from two retrospective cohorts during the human endometrial cycle. MSX1 protein expression patterns were compared between fertile and infertile couples. Selected samples were dual-labeled by immunofluorescence microscopy to localize E-cadherin and ß-catenin in epithelial cells. PARTICIPANTS/MATERIALS, SETTING METHODS: MSX1 mRNA was quantified by PCR in endometrium from hysterectomies (n = 14) determined by endometrial dating to be in the late-proliferative (cycle days 10-13), early-secretory (cycle days 14-19) or mid-secretory (cycle days 20-24) phase. MSX1 protein was localized using high-throughput, semi-quantitative immunohistochemistry with sectioned endometrial biopsy tissues from fertile (n = 89) and infertile (n = 89) couples. Image analysis measured stain intensity specifically within the luminal epithelium, glands and stroma during the early-, mid- and late- (cycle days 25-28) secretory phases. MAIN RESULTS AND THE ROLE OF CHANCE: MSX1 transcript increased 5-fold (P < 0.05) between the late-proliferative and early secretory phase and was then down-regulated (P < 0.05) prior to receptivity for implantation. In fertile patients, MSX1 protein displayed strong nuclear localization in the luminal epithelium and glands, while it was weakly expressed in nuclei of the stroma. MSX1 protein levels accumulated throughout the secretory phase in all endometrial cellular compartments. MSX1 protein decreased (P < 0.05) in the glands between mid- and late-secretory phases. However, infertile patients demonstrated a broad reduction (P < 0.001) of MSX1 accumulation in all cell types throughout the secretory phase that was most pronounced (∼3-fold) in stroma and glands. Infertility was associated with persistent co-localization of E-cadherin and ß-catenin in epithelial cell junctions in the mid- and late-secretory phases. LIMITATIONS, REASONS FOR CAUTION: Details of the infertility diagnoses and other patient demographic data were not available. Therefore, patients with uterine abnormalities (Mullerian) could not be distinguished from other sources of infertility. Antibody against human MSX2 is not available, limiting the study to MSX1. However, both RNAs in the human endometrium are similarly regulated. In mice, Msx1 and Msx2 are imperative for murine embryo implantation, with Msx2 compensating for genetic ablation of Msx1 through its up-regulation in a knockout model. WIDER IMPLICATIONS OF THE FINDINGS: This investigation establishes that the MSX1 homeobox protein accumulation is associated with the secretory phase in endometrium of fertile couples, and is widely disrupted in infertile patients. It is the first study to examine MSX1 protein localization in the human endometrium, and supported by genetic findings in mice, suggests that genes regulated by MSX1 are linked to the loss of epithelial cell polarity required for uterine receptivity during implantation. STUDY FUNDING/COMPETING INTERESTS: This research was supported by the NICHD National Cooperative Reproductive Medicine Network grant HD039005 (M.P.D.), NIH grants HD068524 (S.K.D.), HD071408 (D.R.A., M.P.D.), and HL128628 (S.D.), the Intramural Research Program of the NICHD, March of Dimes (S.K.D., S.D.) and JSPS KAKENHI grant 26112506 (Y.H.). There were no conflicts or competing interests.

Uso del balón sos bakri en atonía uterina: serie de casos en un hospital universitario de tercer nivel / SOS bakri balloon use in uterine inertia. number of cases in a university tertiary hospital

Objetivo: Describir el uso del balón SOS Bakri en el tratamiento de la hemorragia posparto vaginal por atonía uterina después de la falla del tratamiento médico. Métodos: Se presenta una serie de 15 pacientes con hemorragia posparto vaginal por atonía uterina, tratadas satisfactoriamente con taponamiento uterino con balón SOS Bakri luego de no responder a tratamiento médico ni a masaje uterino. Resultados: La edad promedio de las pacientes fue 22,7 (± 6,8) años. La edad gestacional promedio fue 36,3 (± 2,6) semanas. El balón se insertó en los primeros 30 minutos del diagnóstico de la atonía uterina. El tiempo total que permaneció el balón en útero fue de 13,6 (± 6,1) horas. La pérdida hemática posterior a la colocación del balón fue en total 265,3 (± 258,1) cm3. El balón SOS Bakri fue efectivo en 100 % de las pacientes. Ninguna de las pacientes ameritó histerectomía. Conclusiones: El balón SOS Bakri es una alternativa eficaz mínimamente invasiva, económica y de fácil acceso en la terapéutica de la AU que no responde al tratamiento médico.

Objective: To describe the use of SOS Bakri Balloon in the treatment of postpartum hemorrhage after unsuccessful medical treatment of uterine atony. Method: We describe a case series of 15 patients with severe uterine atony after vaginal delivery that were successfully managed with SOS Bakri balloon after failed uterine massage and medical treatment. Results: The mean patient age was 22.7 (± 6.8) years. The mean gestational age was 36.3 (± 2.6) weeks. The balloon was inserted within 30 minutes of diagnosis of uterine atony. The mean length of balloon placement was 13.6 (± 6.1) hours. The mean total blood loss post balloon insertion was of 265.3 (± 258.1) cm3. The SOS Bakri balloon was effective 100 % of the time. None of the patient required hysterectomy. Conclusion: Insertion of SOS Bakri balloon is a simple conservative live saving alternative in the management of postpartum uterine atony.