Pregnancy Outcomes in Women with Arrhythmias following Surgical Repair of Cardiac Defects.

OBJECTIVE: The goal of this study was to investigate whether preexisting cardiac arrhythmias are associated with adverse obstetrical outcomes in women with a history of open cardiac surgery. STUDY DESIGN: This was a retrospective cohort study of women with a history of open cardiac surgery who delivered at MedStar Washington Hospital Center (Washington, DC) from January 2007 through December 2018. Women with the isolated percutaneous cardiac surgical repair were excluded. Maternal and neonatal outcomes were compared between patients with preexisting cardiac arrhythmias and patients without preexisting cardiac arrhythmias. Maternal outcomes studied were intensive care unit admission, postpartum blood loss greater than 1,000 mL, congestive heart failure development, preeclampsia with severe features, postpartum readmission, postpartum cardiac events, and postpartum length of stay >5 days. Neonatal outcomes investigated were low birth weight <2,500 g, Apgar's scores <7 at 5 minutes, and neonatal intensive care unit admission. Multivariate logistic regression model was used to calculate the adjusted odds ratio (aOR) and 95% confidence intervals. RESULTS: The outcomes for 69 deliveries from 56 women with a history of open cardiac surgery were examined. Thirty-three women (48%) had arrhythmias after cardiac surgery with fourteen (20%) requiring implantable cardioverted defibrillators. Two women (6%) with preexisting arrhythmias after cardiac surgery developed postpartum volume overload requiring readmission (p = 0.06). After controlling for age, gestational age at delivery, and BMI, preeclampsia with severe features (p = 0.02) and low birth weight neonates (p = 0.02, aOR = 2.26 [0.56-9.03]) remained statistically more like to occur in patients with preexisting cardiac arrhythmias than in patients without preexisting arrhythmias. CONCLUSION: Women with a history of open cardiac surgery and preexisting cardiac arrhythmias prior to pregnancy are more likely to develop preeclampsia with severe features and have low birth weight neonates compared with women with a history of open cardiac surgery without preexisting cardiac arrhythmias. KEY POINTS: · Preexisting arrhythmias after cardiac surgery was associated with a risk of preeclampsia.. · Neonates of women with preexisting cardiac arrhythmias are more likely to be low birth weight.. · Forty-seven percent of women with open cardiac surgery developed subsequent arrhythmias..

Association of Inadvertent 9-Valent Human Papillomavirus Vaccine in Pregnancy With Spontaneous Abortion and Adverse Birth Outcomes.

Importance: The 9-valent human papillomavirus (9vHPV) vaccine is recommended for individuals through age 26 years and may be administered to women up to age 45 years. Data on 9vHPV vaccine exposures during pregnancy are limited. Objective: To evaluate the associations between 9vHPV vaccine exposures during pregnancy or peripregnancy and selected pregnancy and birth outcomes (spontaneous abortion [SAB], preterm birth, small-for-gestational age [SGA] birth, and major structural birth defect). Design, Setting, and Participants: This cohort study analyzed data from 7 participating health systems in the Vaccine Safety Datalink. The cohort comprised pregnancies among girls and women aged 12 to 28 years that ended between October 26, 2015, and November 15, 2018. Singleton pregnancies that ended in a live birth, stillbirth, or SAB were included. Exposures: Vaccine exposure windows were distal (9vHPV or 4vHPV vaccine administered from 22 to 16 weeks before last menstrual period [LMP]), peripregnancy (9vHPV vaccine administered from 42 days before LMP until LMP), and during pregnancy (9vHPV vaccine administered from LMP to 19 completed weeks' gestation). Primary comparisons were (1) girls and women with 9vHPV vaccine exposures during pregnancy vs those with 4vHPV or 9vHPV distal vaccine exposures, (2) girls and women with vaccine exposures peripregnancy vs those with 4vHPV or 9vHPV distal vaccine exposures, and (3) girls and women with 9vHPV vaccine exposures during pregnancy or peripregnancy vs those with 4vHPV or 9vHPV distal vaccine exposure. Main Outcomes and Measures: Spontaneous abortions were confirmed based on medical record review and adjudication. Preterm and SGA births were identified from electronic health record and birth data. Major structural birth defects were based on diagnostic codes using a validated algorithm. Inverse probability weighting was used to balance the covariates. Time-dependent covariate Cox proportional hazards regression models and Poisson regression were used to estimate the associations between 9vHPV vaccine exposures and pregnancy and birth outcomes. Results: The final cohort included 1493 pregnancies among girls and women with a mean (SD) maternal age of 23.9 (2.9) years. Of these pregnancies, 445 (29.8%) had exposures to the 9vHPV vaccine during pregnancy, 496 (33.2%) had exposures to the 9vHPV vaccine peripregnancy, and 552 (37.0%) had 4vHPV or 9vHPV distal vaccine exposures. The 9vHPV vaccine administered during pregnancy was not associated with increased risk for SAB (hazard ratio, 1.12; 95% CI, 0.66-1.93) compared with distal vaccine exposures. Findings were similar for 9vHPV vaccine exposures peripregnancy (relative risk [RR], 0.72; 95% CI, 0.42-1.24). Among live births (n = 1409), 9vHPV vaccine exposures during pregnancy were not associated with increased risks for preterm birth (RR, 0.73; 95% CI, 0.44-1.20) or SGA birth (RR, 1.31; 95% CI, 0.78-2.20). Results were similar regarding the association between 9vHPV vaccine exposures peripregnancy and preterm birth (RR, 0.72; 95% CI, 0.45-1.17) and SGA birth (RR, 1.10; 95% CI, 0.65-1.88). Birth defects were rare in all exposure groups, occurring in about 1% of live births with available infant data. Conclusions and Relevance: This study found that 9vHPV vaccine exposures during or around the time of pregnancy were uncommon and not associated with SABs or selected adverse birth outcomes. These findings can inform counseling for inadvertent 9vHPV vaccine exposures.

Intramuscular progesterone in women with twins and a prior singleton spontaneous preterm birth.

BACKGROUND: Although the use of 17-alpha-hydroxyprogesterone caproate is one of the most commonly used strategies to reduce the risk of preterm birth since its approval by the Food and Drug Administration in 2011, there has been controversy recently that there may be no benefit associated with its use in singleton pregnancies in women with a prior history of spontaneous preterm birth. However, very few of these investigations evaluated the use of intramuscular progesterone in twin pregnancies. A few studies that used 17-alpha-hydroxyprogesterone caproate in twin pregnancies had mainly included unselected twin pregnancies. Although a twin pregnancy is independently associated with an increased likelihood of preterm birth, the primary indication for the use of supplemental progesterone in pregnancy is prior history of spontaneous preterm birth. Therefore, our investigation of weekly intramuscular progesterone in twin pregnancies with this birth history best addresses this question using a selected cohort. OBJECTIVE: To assess whether weekly 17-alpha-hydroxyprogesterone caproate prevents recurrent preterm birth in women with a current twin pregnancy and a prior singleton spontaneous preterm birth. STUDY DESIGN: This was a retrospective cohort study of women with twin pregnancy and a prior singleton spontaneous preterm birth in 2 institutions between January 2005 and December 2016. One group (intervention group) consisted of women who received weekly 17-alpha-hydroxyprogesterone caproate, whereas the other (control group) did not. The primary outcome was twin spontaneous preterm birth <34 weeks compared with odds ratio and adjusted odds ratio, adjusting for potential confounders. Secondary outcomes included composite neonatal morbidity such as respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, admission to the neonatal intensive care nursery, and fetal or neonatal death before hospital discharge. RESULTS: A total of 79 patients were included; 27 women received weekly 17-alpha-hydroxyprogesterone caproate and 52 did not. There were no statistically significant differences in maternal demographics except for age. Spontaneous preterm birth <34 weeks occurred in 16 patients (59%) in the intervention group vs 24 (46%) in the control group (odds ratio, 1.69; 95% confidence interval, 0.68-4.54). Composite neonatal morbidity occurred in 20 pregnancies (74%) in the intervention group and 41 pregnancies (79%) in the control group (odds ratio, 0.76; 95% confidence interval, 0.27-2.12). There remained no differences in outcomes after adjusting for potential confounders. CONCLUSION: In our study, weekly 17-alpha-hydroxyprogesterone caproate did not prevent spontaneous preterm birth or neonatal morbidity in women with twins and a prior singleton spontaneous preterm birth; however, further research with larger numbers and prospective design is needed.

Commercial quality "awards" are not a strong indicator of quality surgical care.

BACKGROUND: This study aimed to determine whether publicized hospital rankings can be used to predict surgical outcomes. METHODS: Patients undergoing one of nine surgical procedures were identified, using the Healthcare Cost and Utilization Project State Inpatient Database for Florida and New York 2011-2013 and merged with hospital data from the American Hospital Association Annual Survey. Nine quality designations were analyzed as possible predictors of inpatient mortality and postoperative complications, using logistic regression, decision trees, and support vector machines. RESULTS: We identified 229,657 patients within 177 hospitals. Decision trees were the highest performing machine learning algorithm for predicting inpatient mortality and postoperative complications (accuracy 0.83, P<.001). The top 3 variables associated with low surgical mortality (relative impact) were Hospital Compare (42), total procedure volume (16) and, Joint Commission (12). When analyzed separately for each individual procedure, hospital quality awards were not predictors of postoperative complications for 7 of the 9 studied procedures. However, when grouping together procedures with a volume-outcome relationship, hospital ranking becomes a significant predictor of postoperative complications. CONCLUSION: Hospital quality rankings are not a reliable indicator of quality for all surgical procedures. Hospital and provider quality must be evaluated with an emphasis on creating consistent, reliable, and accurate measures of quality that translate to improved patient outcomes.

Suberoylanilide hydroxamic acid (SAHA) potentiates paclitaxel-induced apoptosis in ovarian cancer cell lines.

OBJECTIVES: To determine if SAHA, a histone deacetylase inhibitor, decreases ovarian cancer cell viability when combined with paclitaxel in vitro, and to explore molecular alterations of combined paclitaxel+SAHA treatment. METHODS: SKOV3 and Hey ovarian cancer cell lines were treated for 24 h with paclitaxel, then re-treated with SAHA or paclitaxel for an additional 48 h. Protein extracts were prepared at 48 h for western blot analysis. Cell viability was assessed at 72 h using the ApoAlert Annexin V Apoptosis Kit. RESULTS: SAHA causes G1 and G2 cell cycle arrest in ovarian cancer cell lines. Cell viability was significantly reduced by combined paclitaxel+SAHA treatment. In Hey cells, viability was reduced to 67% with paclitaxel, and to 48% with paclitaxel+SAHA (p<0.001). In the SKOV3 cell line, viability was reduced to 70% with continuous paclitaxel treatment, and was further reduced to 57% in the combined treatment group (p<0.05). Increased PARP cleavage was noted in the paclitaxel+SAHA groups. SAHA increased expression of p21cip1/waf1 and p27Kip1, down regulated cyclins A and B, and suppressed CDK1. Paclitaxel induced expression of survivin, an inhibitor of apoptosis protein, was reduced to baseline control levels with the addition of SAHA. The pro-apoptotic protein, Bad, was also increased with SAHA. CONCLUSIONS: Paclitaxel+SAHA reduces cell viability in excess of either agent alone in ovarian cancer cell lines. Cell death is mediated via several mechanisms including G1/G2 arrest from CDK1 downregulation, inhibition of paclitaxel-induced survivin accumulation, and from increased Bad expression.

In vitro and in vivo histone deacetylase inhibitor therapy with suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer.

OBJECTIVE: To determine effects of suberoylanilide hydroxamic acid (SAHA) with and without paclitaxel in ovarian cancer cells and a nude mouse model. METHODS: Cell viability and apoptosis of ovarian cancer cells (2774) were measured following exposure to control, SAHA, paclitaxel, or SAHA in combination with paclitaxel. Nude mice were injected intraperitoneally (IP) with cancer cells and then groups received variable SAHA doses (25-100 mg/kg/day). In a second experiment, mice were inoculated with cancer and treated IP with vehicle injection, SAHA, paclitaxel, paclitaxel followed by SAHA, or SAHA followed by paclitaxel. Survival, tumor weight, and ascites were evaluated. RESULTS: SAHA decreased viability and increased apoptosis similarly to paclitaxel, but the combination was not statistically significantly different from the single agents. The only significant difference in the SAHA alone mouse study was decreased survival in the 50 mg/kg/daily group. In the combination groups, SAHA followed by paclitaxel, paclitaxel alone, and paclitaxel followed by SAHA improved survival compared with control (p=0.0358, 0.0006, and 0.0001), but SAHA alone did not (p=0.524). The paclitaxel followed by SAHA group had improved survival compared to SAHA followed by paclitaxel (p=0.0002) but not compared to paclitaxel alone (p=0.166). CONCLUSIONS: In vitro, SAHA alone decreased viability and increased apoptosis similarly to paclitaxel. In vivo, paclitaxel followed by SAHA and paclitaxel alone increased survival compared with SAHA alone or SAHA followed by paclitaxel. This suggests adding SAHA to ovarian cancer chemotherapy could increase efficacy and that sequencing of agents is important.

Paclitaxel induces the phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1 through a Cdk1-dependent mechanism.

Initial chemotherapeutic treatment triggers a stress-related response, which can lead to an increase in the expression of survival proteins. In this study we examine whether paclitaxel (PTX) alters the expression and/or phosphorylation of the translation initiation proteins, eukaryotic initiation factor 4E (eIF-4E) and 4E-binding protein (4E-BP1), a suppressor of eIF-4E in the dephosphorylated state. We found that PTX induced the hyperphosphorylation of 4E-BP1 in the breast cancer cell line, MDA MB 231, which reduced its association with eIF-4E, but did not alter the expression and phosphorylation of eIF-4E. The hyperphosphorylation of 4E-BP1 correlated with G2/M accumulation and with an increase in the phosphorylation of cdk1 substrates. Cotreatment with a histone deacetylase inhibitor (an indirect inhibitor of cdk activity), purvalanol A and roscovitine (direct cdk inhibitors), and the reduction of cyclin B expression using RNA interference decreased the hyperphosphorylation of 4E-BP1 in PTX treated cells. The hyperphosphorylation of 4E-BP1 by PTX increased the association of eIF-4E with eIF-4G, whereas cotreatment with purvalanol A inhibited the association of eIF-4E with eIF-4G in PTX treated cells. Taken together, our data suggest that PTX-increases the functional level of eIF-4E by promoting the hyperphosphorylation and release of 4E-BP1 through a cdk1-dependent mechanism.

Histone deacetylase inhibitors enhance paclitaxel-induced cell death in ovarian cancer cell lines independent of p53 status.

BACKGROUND: Recurrence of drug-resistant disease contributes to the high mortality of ovarian cancer patients, which necessitates the identification of additional chemotherapeutic drugs. Histone deacetylase inhibitors (HDAIs) induce apoptosis in a number of malignant cell types and may represent a new class of drugs clinically relevant in the treatment of ovarian cancer. MATERIALS AND METHODS: Ovarian cancer cells were treated with various combinations of a HDAI and paclitaxel (PTX). Cell death was measured using annexin V/propidium iodide exclusion. RESULTS: The PTX/HDAI drug combination was as efficient in inducing cell death as continuous PTX treatment and superior to continuous HDAI treatment. Reversing the sequence of drug exposure reduced the cytotoxic efficacy of the drug combination. The p53 status of the cell lines did not alter the cytotoxic efficacy of the treatment protocols. CONCLUSION: These results suggest that HDAIs possess possible clinical applications as an adjuvant therapy in the treatment of ovarian cancer.