Universal premedication and therapeutic drug monitoring for asparaginase-based therapy prevents infusion-associated acute adverse events and drug substitutions.

BACKGROUND: Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs) during PEG infusion are difficult to interpret, representing a mix of drug-inactivating hypersensitivity and noninactivating reactions. Asparaginase Erwinia chrysanthemi (ERW) is approved for PEG hypersensitivity, but is less convenient, more expensive, and yields lower serum asparaginase activity (SAA). We began a policy of universal premedication and SAA testing for PEG, hypothesizing this would reduce aAEs and unnecessary drug substitutions. PROCEDURE: Retrospective chart review of patients receiving asparaginase before and after universal premedication before PEG was conducted, with SAA performed 1 week later. We excluded patients who had nonallergic asparaginase AEs. Primary end point was substitution to ERW. Secondary end points included aAEs, SAA testing, and cost. RESULTS: We substituted to ERW in 21 of 122 (17.2%) patients pre-policy, and 5 of 68 (7.4%) post-policy (RR, 0.427; 95% CI, 0.27-0.69, P = 0.028). All completed doses of PEG yielded excellent SAA (mean, 0.90 units/mL), compared with ERW (mean, 0.15 units/mL). PEG inactivation post-policy was seen in 2 of 68 (2.9%), one silent and one with breakthrough aAE. The rate of aAEs pre/post-policy was 17.2% versus 5.9% (RR, 0.342; 95% CI, 0.20-0.58, P = 0.017). Grade 4 aAE rate pre/post-policy was 15% versus 0%. Cost analysis predicts $125 779 drug savings alone per substitution prevented ($12 402/premedicated patient). CONCLUSIONS: Universal premedication reduced substitutions to ERW and aAE rate. SAA testing demonstrated low rates of silent inactivation, and higher SAA for PEG. A substantial savings was achieved. We propose universal premedication for PEG be standard of care.

Outcome of pregnancies after pelvic artery embolization for postpartum hemorrhage: retrospective cohort study.

OBJECTIVE: The effects of pelvic artery embolization (PAE) for postpartum hemorrhage (PPH) on subsequent pregnancies have been explored in small case series and one case-control study by mailed questionnaire with uncomplicated pregnancies as controls. We conducted a single-center retrospective cohort study using women with PPH without PAE for comparison. STUDY DESIGN: From a cohort of 103 women undergoing PAE for primary PPH between January 1999 and December 2012 (exposed) and 189 pregnancies with PPH not requiring PAE between January 2008 and December 2012 (unexposed), we queried the electronic medical records for readmissions to labor and delivery in subsequent years. Outcomes of subsequent pregnancies continuing past 20 weeks were obtained by chart review. RESULTS: Repeat pregnancies were documented in 17 of 103 exposed women (16.5%) and 18 of 189 unexposed women (9.5%). At delivery complicated by PPH, the groups did not differ in demographics, gestational age, units of blood transfused, or PPH cause. At the time of subsequent deliveries, there was a greater interdelivery interval in women exposed to PAE than those unexposed (1710 ± 938 days vs 904 ± 358 days; P = .002), and the 2 groups were similar in terms of gestational age and birthweight. However, there was a significantly higher rate of placenta accreta in exposed than unexposed women (23.5 % vs 0%; P = .04), with 3 of 17 sustaining total abdominal hysterectomy and 1 requiring repeat PAE for severe PPH. CONCLUSION: Pregnancies following PAE for PPH were more likely than those not receiving PAE for treatment to be complicated by placenta accreta. Pregnancies following PAE should be followed up for imaging evidence of placenta accreta.

Genetic analysis of the ribosome biogenesis factor Ltv1 of Saccharomyces cerevisiae.

Ribosome biogenesis has been studied extensively in the yeast Saccharomyces cerevisiae. Yeast Ltv1 is a conserved 40S-associated biogenesis factor that has been proposed to function in small subunit nuclear export. Here we show that Ltv1 has a canonical leucine-rich nuclear export signal (NES) at its extreme C terminus that is both necessary for Crm1 interaction and Ltv1 export. The C terminus of Ltv1 can substitute for the NES in the 60S-export adapter Nmd3, demonstrating that it is a functional NES. Overexpression of an Ltv1 lacking its NES (Ltv1∆C13) was strongly dominant negative and resulted in the nuclear accumulation of RpS3-GFP; however, export of the pre-40S was not affected. In addition, expression of endogenous levels of Ltv1∆C protein complemented both the slow-growth phenotype and the 40S biogenesis defect of an ltv1 deletion mutant. Thus, if Ltv1 is a nuclear export adapter for the pre-40S subunit, its function must be fully redundant with additional export factors. The dominant negative phenotype of Ltv1∆NES overexpression was suppressed by co-overexpressing RpS3 and its chaperone, Yar1, or by deletion of the RpS3-binding site in Ltv1∆NES, suggesting that titration of RpS3 by Ltv1∆NES is deleterious in yeast. The dominant-negative phenotype did not correlate with a decrease in 40S levels but rather with a reduction in the polysome-to-monosome ratio, indicating reduced rates of translation. We suggest that titration of RpS3 by excess nuclear Ltv1 interferes with 40S function or with a nonribosomal function of RpS3.

Fetal fibronectin for evaluation of preterm labor in the setting of cervical cerclage.

OBJECTIVE: To evaluate the efficacy of fetal fibronectin (fFN) testing in cervical cerclage patients presenting with acute signs or symptoms of preterm labor. METHODS: A total of 71 fFN tests were performed in 48 women between 23 and 34 weeks' gestation who presented at two institutions at risk for imminent delivery with cerclage in situ. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value for delivery within 2 weeks of fFN testing were 100, 77, 28 and 100%, respectively. For delivery before 34 weeks sensitivity, specificity, positive predictive value, and negative predictive value were 91, 78, 56 and 97%, respectively. The relative risk of delivery <34 weeks with positive fFN was 16.7 (P < 0.001). CONCLUSIONS: For patients with cervical cerclage, fFN testing is a valid diagnostic tool in the evaluation of preterm labor.

Perioperative complications of history-indicated and ultrasound-indicated cervical cerclage.

OBJECTIVE: To evaluate perioperative complications of history- and ultrasound-indicated cerclage. METHODS: We performed a retrospective observational study of a cohort of patients who underwent history- (n = 198) or ultrasound-indicated (n = 89) cerclage procedures. We evaluated the rates of perioperative complications based on indication for cerclage. The χ(2) was used for categorical variables and Student t test for continuous data. RESULTS: One patient (0.35%) had an intraoperative complication (unsuccessful regional anesthesia) and 1 patient (0.35%) had a postoperative complication (contractions and bleeding 2 weeks after cerclage placement, delivered a nonviable infant). Peripartum complications included chorioamnionitis (6.2%), preterm premature rupture of membranes (11%), preterm delivery (20%), and delivery before 32 weeks' gestational age (8%), and they were similar in the history-indicated and ultrasound-indicated groups. CONCLUSION: History- and ultrasound-indicated cerclages are associated with a 0.6%; 95% confidence interval, -0.26 to 1.66 risk of perioperative complications. There was no difference in perioperative complications or outcome between the 2 groups.

Importance of timing of gestational exposure to methotrexate for its teratogenic effects when used in setting of misdiagnosis of ectopic pregnancy.

OBJECTIVE: To report a case of embryopathy due to misadministration of methotrexate in the setting of suspected ectopic pregnancy that resulted in a different pattern of malformations than is typically seen with methotrexate. DESIGN: Case report. SETTING: Community hospital. PATIENT(S): A 30-year-old primigravida women exposed to methotrexate (50 mg/m(2)) at 5 6/7 weeks' gestation. INTERVENTION(S): The patient underwent amniocentesis because of abnormal results at the first-trimester genetic screening (low levels of pregnancy associated plasma protein A and hCG) and fetal echocardiogram because of single umbilical artery. MAIN OUTCOME MEASURE(S): Fetal anomalies. RESULT(S): The fetus was found to have a single umbilical artery, tetralogy of Fallot, and a "horseshoe lung," despite administration of high doses of folic acid. The pregnancy ultimately ended with fetal demise at 30 weeks. CONCLUSION(S): As medical management of ectopic pregnancy becomes more common, practitioners should be cautious about the potential teratogenic effects in unrecognized intrauterine pregnancies and be able to diagnose the myriad defects, including cardiac anomalies, that could result from such exposure.

Therapeutic cerclage may be more efficacious in women who develop cervical insufficiency after a term delivery.

OBJECTIVE: Our objective was to determine whether obstetric history affects the efficacy of therapeutic cerclage. STUDY DESIGN: Data were gathered prospectively on patients receiving therapeutic cerclage, defined as midtrimester presentation with a cervical length less than 2.5 cm and prior preterm delivery or cervical dilatation with visible membranes on sterile speculum exam. Delivery outcomes based on cerclage type were compared between women with (n = 31) vs without prior term birth (n = 33). RESULTS: Patients with a history of a term birth were older than those without such history (P = .05) but otherwise similar with regard to ethnicity, body mass index, prior preterm birth, genitourinary infection, prior cervical surgery, gestational age at cerclage placement, and cerclage indication. Women with a therapeutic cerclage and a history of a prior term delivery were significantly more likely to deliver after 35 weeks (90% vs 48%, P < .001) and their babies were significantly larger (2942 +/- 812 g vs 1966 +/- 1069 g, P < .001) than women with no prior term delivery. CONCLUSION: Patients who develop cervical insufficiency after a term delivery may have better perinatal outcomes following therapeutic cerclage than those without a history of term delivery.

Variability in pathologists' detection of placental meconium uptake.

Placental meconium has been associated with poor perinatal outcomes but the reliability of the diagnosis has not been assessed. Our objective was to assess the interobserver variability in detection of placental meconium uptake. Ten pathologists from two community and four university hospitals reviewed 10 hematoxylin and eosin-stained placental slides that included cases of in utero and in vitro meconium uptake as well as negative controls. Pathologists rated amnion denudation, presence, location, and density of meconium. Results were compared using a kappa score measure of concordance. There was fair concordance in samples with > 50% amnion denudation (kappa = 0.42), though overall amnion integrity concordance was poor (kappa = 0.18). Similarly, poor concordance was noted for presence (kappa = 0.13), location (kappa = 0.06), and density of meconium staining (kappa = 0.11). Detection of meconium uptake in placentas is highly variable among a representative group of community and university pathologists. This finding suggests a need for a more objective measure of meconium uptake in placentas.

Earlier gestational age at ultrasound evaluation predicts adverse neonatal outcomes in the preterm appropriate-for-gestational-age fetus with idiopathic oligohydramnios.

Oligohydramnios is related to adverse perinatal outcomes particularly when associated with fetal growth restriction. The purpose of this study was to delineate predictors of adverse perinatal outcomes in cases of preterm idiopathic oligohydramnios associated with appropriate-for-gestational-age (AGA) fetal biometry. A database of preterm AGA fetuses (< 37 weeks) presenting for evaluation of idiopathic oligohydramnios (defined as an amniotic fluid index [AFI] < 10th percentile) in the third trimester with delivery information and uterine artery Doppler indices (average resistance index [RI] and bilateral notching) available was prospectively collected ( N = 90). AFI and birth weight (BW) percentiles were calculated using standard tables. Chi-square and Student T test were used to evaluate for predictors of adverse perinatal outcomes including BW < or = 10th percentile, stillbirth, neonatal intensive care unit admission, 5-minute Apgar score < 7, preterm delivery < 35 weeks, and preeclampsia. Patients destined to experience poor perinatal outcomes (22%) were demographically similar to those experiencing normal outcomes in terms of maternal age ( P = 0.5), ethnicity ( P = 0.9), body mass index ( P = 0.3), and parity ( P = 0.9). However, at-risk patients were more likely to present with oligohydramnios at an earlier gestational age (GA) than those not at risk (33.0 +/- 3.0 versus 34.4 +/- 2.0 weeks; P = 0.02). There were no differences in perinatal outcomes associated with AFI percentile ( P = 0.9), increased average uterine artery RI ( P = 0.5), bilateral notching ( P = 0.4) or a combination of increased uterine artery RI and bilateral notching ( P = 0.2). Patients with preterm AGA fetuses who present with idiopathic oligohydramnios at an earlier GA are at risk for adverse perinatal outcomes compared with those presenting later in gestation. Sonographic indices, particularly uterine artery Doppler findings, were not found to be useful predictors of adverse outcomes.

Cervical length < or = 25 mm in low-risk women: a case control study of cerclage with rest vs rest alone.

OBJECTIVE: The purpose of this study was to evaluate the clinical utility of cerclage in low risk women with cervical length (CL) < or = 25 mm at transvaginal ultrasound (TVU). STUDY DESIGN: This was a retrospective cohort study of women with CL < or = 25 mm identified incidentally at TVU examinations between 16(0/7) to 24(6/7) weeks, with no history of previous preterm birth or midtrimester losses. The primary study outcome was rate of preterm delivery < 35 weeks' gestation. RESULTS: Women undergoing cerclage placement (n = 31) had shorter CL (P < .001) and lower gestational age at presentation (P < .001) than those managed with rest alone (n = 36). Gestational age at delivery was 37.6 +/- 3.6 vs 38.5 +/- 2.1 weeks (P = .17), and delivery at < 35 weeks occurred in 5/31 versus 2/36 cases, respectively (P = .23). The lack of a significant association between cerclage and rate of delivery < 35 weeks persisted after controlling for gestational age at TVU and initial CL (P = .81). CONCLUSION: Cerclage placement does not improve pregnancy outcome in low-risk women with incidental detection of CL < or = 25 mm in the early second trimester.

Good pregnancy outcome with emergent cerclage placed in the presence of intra-amniotic microbial invasion.

Cervical insufficiency with dilation can be associated with amniotic fluid microbial invasion. Cerclage placement in the presence of infection is contraindicated because it is associated with poor fetal and maternal outcome. A 30-year-old gravida 4 para 0 with cervical insufficiency had emergent cervical suture placement at 19 weeks. The patient underwent amniocentesis to screen for infection. After the screen for infection using amniotic fluid glucose and white blood cells had indicated negative results, the patient had cerclage placed. Post cerclage placement, amniotic culture results were positive for KLEBSIELLA PNEUMONIAE, CITROBACTER FREUNDII, and STAPHYLOCOCCUS coagulase negative. The patient was counseled about the need to remove the cerclage and she declined. She was treated with azithromycin and Unasyn and a repeat amniocentesis 7 days later indicated negative results. The patient had a 14 week cerclage to delivery interval, delivery at 33 2/7 weeks. Immediate evaluations of the newborn were negative for infection. Our satisfactory outcome with treatment of very early intra-amniotic infection suggests that this option may be considered in strictly selected patients in similar clinical scenarios as an alternative to cerclage removal and evacuation of the uterus.

Risk factors for cervical insufficiency after term delivery.

OBJECTIVE: Cervical insufficiency can be unexpected in a woman with a previous term birth. Our objective was to determine what risk factors, if any, place women with a term delivery at risk for cervical insufficiency in a subsequent pregnancy. STUDY DESIGN: Demographic characteristics were collected for a cohort of women with at least 1 previous term birth followed by cervical insufficiency (subject group) and for uncomplicated multiparous women (control group). Multiparous women with cervical insufficiency (subjects; n = 49) were compared with multiparous women who were experiencing repeat term birth with no history of cervical insufficiency (control group; n = 49). RESULTS: Patients with cervical insufficiency were similar to control subjects demographically. No difference was noted in previous cervical procedures or spontaneous preterm deliveries. Multivariate logistic regression analysis identified a history of curettage (odds ratio, 4.6; 95% CI, 1.7-12.5), precipitous delivery (odds ratio, 6.8; 95% CI, 1.6-29.6), and prolonged second stage of labor (odds ratio, 24.9; 95% CI, 2.4-253) as independent predictors of cervical insufficiency. CONCLUSION: Multiparous women who experience cervical insufficiency after a term birth are more likely to have had a previous precipitous delivery, a prolonged second stage of labor, or a previous curettage compared with multiparous women who experience a repeat term birth with no cervical insufficiency.

Amniotic fluid index and birth weight: is there a relationship in diabetics with poor glycemic control?

OBJECTIVE: This study was undertaken to evaluate if the previously demonstrated relationship between macrosomia (> 4000 g) and polyhydramnios (> 25 cm) is linear across birth weights (BW) in diabetic patients with poor glycemic control. STUDY DESIGN: Using a prospectively collected database of patients undergoing amniocentesis for fetal lung maturity for various indications with amniotic fluid index (AFI) obtained < or = 7 days before delivery and BWs available (n = 69), we computed gestational age (GA) specific AFI and BW centiles using standard tables. BW and AFI centiles were analyzed in diabetic patients with poor glycemic control using linear regression and ANOVA, with P < .05 significant. RESULTS: In the poorly controlled diabetic population, a linear relationship existed between AFI and BW centiles, with the largest BW centiles having the highest AFI centiles (P < .0001). CONCLUSION: The previously noted relationship between elevated AFI and BW centiles in the general patient population is linear in diabetic patients with poor glycemic control.

Postnatal inflammatory rat model for cerebral palsy: too different from humans.

OBJECTIVE: In humans, cerebral palsy (CP) may originate from inflammation during the second and third trimesters of gestation when preoligodendrocytes (Pre-OL) are most vulnerable to an inflammatory insult. We studied a postnatal CP model to evaluate injury that would correlate with presence of Pre-OL in human pregnancy. STUDY DESIGN: On postnatal (P) days 2, 3, 4, 5 and 6, pups were treated with (lipopolysaccharide [LPS]) (n = 7; 30, 30, 60, 60, 120 microg/Kg) or saline (n = 7). Neonates were tested for motor and cognitive development. Adult offspring performed beam walking and rotarod for motor activity. White matter damage was assessed with immunohistochemical Pre-OL markers (CNP, PLP). Statistical analysis included Mann-Whitney U and analysis of variance. RESULTS: LPS-treated animals performed negative geotaxis (P = .009) and surface righting (P = .01) earlier than controls. No differences were observed for other neonatal tests. Adult LPS-treated offspring performed better in tests of motor control: rotarod (P = .01) and beam walking (P = .02). Pre-OL markers were altered in LPS-treated animals at both P22 (CNP and PLP increased in LPS, P < .01 and P < .001, respectively) and 12 weeks (CNP and PLP decreased in LPS, P < .0001 and P < .03, respectively). CONCLUSION: Neonatal exposure to LPS induced white matter damage in the brain, accelerated neurodevelopment and motor tasks in adulthood. These are similar to findings from a postnatal hypoxic model suggesting that in the rodent, targeting the Pre-OL does not result in a CP phenotype.

Risk of third-trimester amniocentesis: a case-control study.

Risks of third-trimester amniocentesis are considered minimal; however, only case series have been reported. We performed a case-control study in which women undergoing third-trimester amniocentesis were matched with controls undergoing antenatal testing for similar indications to determine adverse outcomes associated with the procedure. Cases undergoing amniocentesis at > 32 weeks for fetal lung maturity assessment followed by antepartum testing with nonstress test and amniotic fluid index determination were matched with controls undergoing only antepartum testing based on gestational age at testing and maternal age. The main outcome variable was a composite occurrence of obstetric complications within 48 hours of testing, including urgent delivery, placental abruption, premature rupture of membranes (PROM), perinatal death, or Apgar score at 5 minutes < 7. Statistical analysis included Fisher's exact test and Student T-test, with P < 0.05 considered significant. A total of 167 matched pairs of patients fulfilled the study criteria. Indications for both amniocentesis and antepartum testing, which included diabetes, preterm labor, and cholestasis, were similar in the two groups. As expected, gestational age at sampling/testing (36.4 +/- 1.4 [mean +/- standard deviation] versus 36.6 +/- 1.7 weeks; P = 0.2) and maternal age (31.4 +/- 5.8 versus 31.5 +/- 6.3 years; P = 0.9) were not different between cases and controls. The rate of the main outcome variable within 48 hours of testing was 0 of 167 among cases and 1 of 167 among controls. Amniocentesis in the third trimester is not associated with increased risk of urgent delivery, placental abruption, PROM, Apgar score at 5 minutes < 7, or perinatal death within 48 hours of the procedure.

Prevention of alcohol-induced learning deficits in fetal alcohol syndrome mediated through NMDA and GABA receptors.

OBJECTIVE: Vasoactive intestinal peptide (VIP)-related peptides prevented the learning deficit in the offspring in a model for fetal alcohol syndrome. We evaluated whether the mechanism of the peptide protection included NR2B, NR2A, and GABAAalpha5. STUDY DESIGN: Timed, pregnant C57BL6/J mice were injected on gestational day 8 with alcohol (0.03 mL/kg), placebo, or alcohol plus peptides. Embryos were harvested after 6 hours, 24 hours, and on gestational day 18. Some of the litters were allowed to deliver, and the adult brains harvested after the offspring were tested for learning. Calibrator-normalized relative real-time polymerase chain reaction (PCR) was performed using primers for NR2B, NR2A, and GABAAalpha5 with GAPDH standardization. Statistic: analysis of variance (ANOVA) and Fisher PLSD, P < .05 was considered significant. RESULTS: In the embryo, the peptides prevented NR2B rise (P < .001) at 6 hours, NR2B down-regulation (P = .002), and GABAAalpha5 decrease (P < .01) on gestational day 18. In the adult, the peptides prevented NR2B down-regulation (P = .01) and NR2A up-regulation (P < .001). CONCLUSION: VIP-related peptides prevented alcohol-induced changes in NR2B, NR2A, and GABAAalpha5. This may explain, at least in part, the peptides' prevention of alcohol-induced learning deficits.

Additional training with an obstetric simulator improves medical student comfort with basic procedures.

OBJECTIVE: To determine if an obstetric birthing simulator can improve medical student understanding of and comfort with basic obstetric procedures. STUDY DESIGN: Medical students were surveyed at the end of their obstetrics rotation regarding their knowledge and comfort with basic obstetric procedures. A group of students was trained on basic procedures utilizing an obstetric simulator. Survey results were compiled and analyzed with the Mann-Whitney U test. RESULTS: In all, 60 untrained students and 18 simulator trained students completed surveys. Trained students were significantly more comfortable with fundal height measurements (P = 0.003), Leopold maneuvers (P < 0.001), fetal scalp electrode placement (P < 0.001), intrauterine pressure catheter placement (P < 0.001), and artificial rupture of membranes (P = 0.001) and reported better understanding of the indications for placement of a fetal scalp electrode (P = 0.01) and intrauterine pressure catheter (P = 0.03). CONCLUSIONS: Additional training with an obstetric simulator improved medical student self-reported comfort with and understanding of basic procedures compared with standard resident and staff-directed instruction.

N-methyl-D-aspartate subunit expression during mouse development altered by in utero alcohol exposure.

OBJECTIVE: Alcohol-related neurodevelopmental disorders are contributors to long-term learning disabilities. By using a model for fetal alcohol syndrome, we have shown that prenatal alcohol exposure results in adult learning deficits of unknown mechanisms. In the developing hippocampus, the N-methyl-D-aspartate (NMDA) receptor subunit NR2B triggers long-term potentiation, fundamental to learning and memory; this is supplemented by the less plastic NR2A subunit in the adult. To understand the mechanism of learning deficits in FAS, we evaluated NR2B and NR2A expression in embryonic and adult mice. STUDY DESIGN: Pregnant C57Bl6/J mice were treated on gestational day 8 with alcohol or control (saline solution). Embryos were harvested at 6 hours, 24 hours, and 10 days, and brains from adult offspring were collected at 3 months (after evaluation for learning deficit). Calibrator-normalized relative real-time polymerase chain reaction was performed for NR2B and NR2A with glyceraldehyde-3-phosphate dehydrogenase standardization. Statistical analysis included analysis of variance. RESULTS: At 6 hours, NR2B expression in the alcohol-exposed embryos was higher than in controls (P < .01). NR2A was not expressed in either group. By 24 hours there was no difference in NR2B (P = .3). However, at 10 days NR2B was lower in alcohol-exposed animals (P = .02). In the adult brains there was a relative decrease in NR2B (P = .03) and an increase in NR2A (P < .01). CONCLUSION: Prenatal alcohol exposure during development induces NR2B expression deregulation in the embryos that persists until adulthood, when a relative increase in the less modifiable subunit NR2A occurs. This alteration in NMDA receptor subunits may underlie the learning abnormalities in fetal alcohol syndrome.