Prospective, randomized, double-blind, placebo-controlled evaluation of the Pharmacokinetics, Safety and Efficacy of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia.

BACKGROUND: Despite expectant management, preeclampsia remote from term usually results in preterm delivery. Antithrombin, which displays antiinflammatory and anticoagulant properties, may have a therapeutic role in treating preterm preeclampsia, a disorder characterized by endothelial dysfunction, inflammation, and activation of the coagulation system. OBJECTIVE: This randomized, placebo-controlled clinical trial aimed to evaluate whether intravenous recombinant human antithrombin could prolong gestation and therefore improve maternal and fetal outcomes. STUDY DESIGN: We performed a double-blind, placebo-controlled trial at 23 hospitals. Women were eligible if they had a singleton pregnancy, early-onset or superimposed preeclampsia at 23 0/7 to 30 0/7 weeks' gestation, and planned expectant management. In addition to standard therapy, patients were randomized to receive either recombinant human antithrombin 250 mg loading dose followed by a continuous infusion of 2000 mg per 24 hours or an identical saline infusion until delivery. The primary outcome was days gained from randomization until delivery. The secondary outcome was composite neonatal morbidity score. A total of 120 women were randomized. RESULTS: There was no difference in median gestational age at enrollment (27.3 weeks' gestation for the recombinant human antithrombin group [range, 23.1-30.0] and 27.6 weeks' gestation for the placebo group [range, 23.0-30.0]; P=.67). There were no differences in median increase in days gained (5.0 in the recombinant human antithrombin group [range, 0-75] and 6.0 for the placebo group [range, 0-85]; P=.95). There were no differences between groups in composite neonatal morbidity scores or in maternal complications. No safety issues related to recombinant human antithrombin were noted in this study, despite the achievement of supraphysiological antithrombin concentrations. CONCLUSION: The administration of recombinant human antithrombin in preterm preeclampsia neither prolonged pregnancy nor improved neonatal or maternal outcomes.

Obstetricians' views on the ethics of cardiac surgery for newborns with common aneuploidies.

OBJECTIVE: To examine whether obstetricians think that cardiac surgery is ethical in babies with common aneuploidies and whether insurance companies should be required to pay for these surgeries. STUDY DESIGN: A survey was e-mailed to 2897 OB-GYNs, and 898 (31%) actively practicing obstetricians responded to the survey. Respondents were asked whether it is ethical to offer cardiac surgery for babies with heart defects diagnosed with trisomies 21, 18, and 13 and Turner syndrome and whether insurance companies should be required to pay for such surgeries in cases of trisomy 18 or 13. Chi-square tests were utilized to compare responses by using an alpha level of .05. RESULTS: Most obstetricians thought that offering cardiac surgery was ethical if the baby had trisomy 21 or Turner syndrome (94%), but not trisomy 18 or 13 (75%). Most obstetricians (69%) thought that insurance companies should not be legally required to pay for cardiac surgery for the latter group. CONCLUSION: Obstetricians were more likely to think cardiac surgery was ethical if the prognosis or the outcome was good. Most respondents did not think that insurance companies should be required to subsidize the cost of cardiac surgeries for all babies with trisomy 18 or 13.

Tension compared to no tension on a Foley transcervical catheter for cervical ripening: a randomized controlled trial.

BACKGROUND: Cervical ripening of an unfavorable cervix can be achieved by placement of a transcervical catheter. Advantages of this method include both lower cost and lower risk of tachysystole than other methods. Despite widespread use with varying degrees of applied tension, an unanswered question is whether there is an advantage to placing the transcervical catheter to tension compared with placement without tension. OBJECTIVE: The purpose of this study was to determine whether tension placed on a transcervical balloon catheter that is inserted for cervical ripening results in a faster time to delivery. STUDY DESIGN: This was a prospective, randomized controlled trial; 140 women who underwent cervical ripening (Bishop score, ≤6) were assigned randomly to a balloon catheter with applied tension vs no tension. Tension was created when the catheter was taped to the patient's thigh and tension was reapplied in 30-minute increments. There were 67 patients in the tension group and 73 patients in the no tension group. Low-dose oxytocin (maximum, 6 mU/min) was administered after catheter placement. The primary outcome was time from catheter insertion to delivery. A secondary outcome was time from insertion to catheter expulsion. The Kolmogorov-Smirnov test was used to determine whether the data were distributed normally. Survival curves that used lifetables were constructed from time of catheter insertion to delivery and from time of catheter insertion to catheter expulsion and were compared with the use of the Wilcoxon (Gehan) Breslow statistic. A probability value of <.05 was set to denote statistical significance. RESULTS: Baseline characteristics were similar between groups. The median time from catheter insertion to delivery was not significantly different between the tension group and the no tension group (16.2 vs 16.9 hours; P=.814). The median time from catheter insertion to expulsion, however, was significantly less in the tension group vs the no tension group (2.6 vs 4.6 hours; P<.001), respectively. Vaginal delivery within 24 hours was not significantly different between the tension and no tension groups (41/52 [79%] vs 37/52 [71%]; P=.365) nor were there significant differences in cesarean delivery rates between the tension and no tension groups (17/67 [25%] vs 27/73 [37%]; P=.139). CONCLUSION: Application of tension did not result in faster delivery times but did result in faster times to catheter expulsion.

Transvaginal cervical length and amniotic fluid index: can it predict delivery latency following preterm premature rupture of membranes?

OBJECTIVE: We sought to determine whether transvaginal cervical length (TVCL), amniotic fluid index (AFI), or a combination of both can predict delivery latency within 7 days in women presenting with preterm premature rupture of membranes (PPROM). STUDY DESIGN: This was a prospective observational study of TVCL measurements in 106 singleton pregnancies with PPROM between 23-33 weeks. Delivery latency was defined as the period (in days) from the initial TVCL after PPROM to delivery of the infant, with our primary outcome being delivery within 7 days of TVCL. The independent predictability of significant characteristics for delivery within 7 days was determined using multiple logistic regression. Sensitivity, specificity, and predictive values were used to examine whether the presence of a short TVCL, AFI, or a combination of both affected the risk of delivery within 7 days. RESULTS: Delivery within 7 days occurred in 51/106 (48%) of pregnancies. Median duration (interquartile range) from PPROM to delivery and TVCL to delivery was 8 days (4.0-16.0) and 8 days (3.0-15.0), respectively. Using multiple regression TVCL as a continuous variable (odds ratio, 0.65; 95% confidence interval, 0.44-0.97; P < .05), AFI ≤5 cm (odds ratio, 4.69; 95% confidence interval, 1.58-13.93; P < .01) were determined to be independent predictors of delivery within 7 days. In all, 42 women (40%) had a TVCL ≤2 cm, while 62 (59%) had AFI ≤5 cm. A total of 26 women (25%) had a combination of both TVCL ≤2 cm and AFI ≤5 cm, while 28 women (27%) had neither characteristic. The predictive value of delivery within 7 days for a TVCL ≤2 cm was 62%, and for an AFI ≤5 cm was 58%. Having a combination of low TVCL and low AFI did not increase the predictive value of delivery within 7 days (58%). In contrast, only 3 of 27 women (11%) with neither characteristic delivered within 7 days. The predictive value of delivery >7 days for TVCL >2 cm alone was 61%. This predictive value changed when analyzed in conjunction with an AFI ≤5 cm and >5 cm at 42% and 89%, respectively. CONCLUSION: A shorter TVCL and an AFI ≤5 cm independently predict delivery within 7 days in women presenting with PPROM. The combination of an AFI >5 cm and TVCL >2 cm greatly improved the potential to remain undelivered at 7 days following cervical length assessment. These findings may be helpful for counseling and optimizing maternal and neonatal care in women with PPROM.

Detection of microbial invasion of the amniotic cavity by analysis of cervicovaginal proteins in women with preterm labor and intact membranes.

OBJECTIVE: Microbial invasion of the amniotic cavity (MIAC) is common in early preterm labor and is associated with maternal and neonatal infectious morbidity. MIAC is usually occult and is reliably detected only with amniocentesis. We sought to develop a noninvasive test to predict MIAC based on protein biomarkers in cervicovaginal fluid (CVF) in a cohort of women with preterm labor (phase 1) and to validate the test in an independent cohort (phase 2). STUDY DESIGN: This was a prospective study of women with preterm labor who had amniocentesis to screen for MIAC. MIAC was defined by positive culture and/or 16S ribosomal DNA results. Nine candidate CVF proteins were analyzed by enzyme-linked immunosorbent assay. Logistic regression was used to identify combinations of up to 3 proteins that could accurately classify the phase 1 cohort (N = 108) into those with or without MIAC. The best models, selected by area under the curve (AUC) of the receiver operating characteristic curve in phase 1, included various combinations of interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), alpha fetoprotein, and insulin-like growth factor binding protein-1. Model performance was then tested in the phase 2 cohort (N = 306). RESULTS: MIAC was present in 15% of cases in phase 1 and 9% in phase 2. A 3-marker CVF model using IL-6 plus CXCL1 plus insulin-like growth factor binding protein-1 had AUC 0.87 in phase 1 and 0.78 in phase 2. Two-marker models using IL-6 plus CXCL1 or alpha fetoprotein plus CXCL1 performed similarly in phase 2 (AUC 0.78 and 0.75, respectively), but were not superior to CVF IL-6 alone (AUC 0.80). A cutoff value of CVF IL-6 ≥463 pg/mL (which had 81% sensitivity in phase 1) predicted MIAC in phase 2 with sensitivity 79%, specificity 78%, positive predictive value 38%, and negative predictive value 97%. CONCLUSION: High levels of IL-6 in CVF are strongly associated with MIAC. If developed into a bedside test or rapid laboratory assay, cervicovaginal IL-6 might be useful in selecting patients in whom the probability of MIAC is high enough to warrant amniocentesis or transfer to a higher level of care. Such a test might also guide selection of potential subjects for treatment trials.

Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes.

OBJECTIVE: The purpose of this study was to compare intraamniotic inflammation vs microbial invasion of the amniotic cavity (MIAC) as predictors of adverse outcome in preterm labor with intact membranes. STUDY DESIGN: Interleukin-6 (IL-6) was measured in prospectively collected amniotic fluid from 305 women with preterm labor. MIAC was defined by amniotic fluid culture and/or detection of microbial 16S ribosomal DNA. Cases were categorized into 5 groups: infection (MIAC; IL-6, ≥11.3 ng/mL); severe inflammation (no MIAC; IL-6, ≥11.3 ng/mL); mild inflammation (no MIAC; IL-6, 2.6-11.2 ng/mL); colonization (MIAC; IL-6, <2.6 ng/mL); negative (no MIAC; IL-6, <2.6 ng/mL). RESULTS: The infection (n = 27) and severe inflammation (n = 36) groups had similar latency (median, <1 day and 2 days, respectively) and similar rates of composite perinatal morbidity and mortality (81% and 72%, respectively). The colonization (n = 4) and negative (n = 195) groups had similar outcomes (median latency, 23.5 and 25 days; composite morbidity and mortality rates, 21% and 25%, respectively). The mild inflammation (n = 47) groups had outcomes that were intermediate to the severe inflammation and negative groups (median latency, 7 days; composite morbidity and mortality rates, 53%). In logistic regression adjusting for gestational age at enrollment, IL-6 ≥11.3 and 2.6-11.2 ng/mL, but not MIAC, were associated significantly with composite morbidity and mortality rates (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.2-11.2, OR, 3.1; 95% CI, 1.5-6.4, and OR, 1.8; 95% CI, 0.6-5.5, respectively). CONCLUSION: We confirmed previous reports that intraamniotic inflammation is associated with adverse perinatal outcomes whether or not intraamniotic microbes are detected. Colonization without inflammation appears relatively benign. Intraamniotic inflammation is not simply present or absent but also has degrees of severity that correlate with adverse outcomes. We propose the designation amniotic inflammatory response syndrome to denote the adverse outcomes that are associated with intraamniotic inflammation.

Effect of maternal weight on accuracy of maternal and physician estimate of fetal weight.

OBJECTIVE: To test if maternal and physician clinical fetal weight estimates differ significantly from actual birth weight and if it is affected by maternal weight. STUDY DESIGN: A total of 112 term gravidas who presented for induction or elective cesarean were prospectively observed. Prior to physician evaluation, each subject estimated the weight of her baby. Prepregnancy weight, date of most recent ultrasound that estimated fetal weight, and physician clinical estimation of fetal weight were recorded. Birth weight was recorded and compared to estimates. RESULTS: Maternal and physician mean absolute error (MAE) values did not differ significantly within any body mass index category. Physician MAE values trended higher in class III obese women (477.1 +/- 292.0 g vs. 356.3 +/- 226.8, p = 0.08). Maternal-predicted and birth weight table-predicted MAE did not differ significantly, although table-predicted 50th percentile MAE values trended higher in class II obese women (462.2 +/- 322.4 g vs. 330.8 +/- 275.7, p = 0.07) and in class III obese women (471.5 +/- 363.7 g vs. 356.3 +/- 226.8, p = 0.12). Physician mean percent error trended higher than maternal values in class III obese women (13.6% +/- 9.3 vs. 9.9% +/- 6.4, p = 0.06). CONCLUSION: There was a strong trend showing that women with class III obesity were more accurate than their physician in predicting the actual birth weight of their baby.

"Early" versus "late" 23-week infant outcomes.

OBJECTIVE: To determine whether survival is different in "early" (23(0/7)-23(3/7) weeks) vs "late" (23(4/7)-23(6/7) weeks) infants. STUDY DESIGN: Records of 126 consecutive liveborn infants delivered at 23(0/7) to 23(6/7) weeks' gestation from 2001-2010 were examined using the Vermont Oxford Network database. Infants born at 23 0/7 to 23 3/7 weeks were grouped into "early" and those at 23 4/7 to 23 6/7 weeks were "late." Clinical characteristics were compared between groups and multivariate analyses were used to predict survival. RESULTS: Seventy-two infants were early and 54 were late. Survival was 25% vs 56%, respectively (P < .001). The early group was less likely to receive steroids (43% vs 65%; P = .016) and had a lower mean birthweight (547 g vs 596 g; P < .001). No difference in other factors was seen between groups. No change in survival was observed during the study period in either group. CONCLUSION: Late 23-week infants have improved survival compared with early infants. Delaying delivery as little as 24-96 hours may improve survival for 23-week infants.

Digoxin immune fab treatment for severe preeclampsia.

We evaluated the efficacy, safety, and biological mechanisms of digoxin immune Fab (DIF) treatment of severe preeclampsia. Fifty-one severe preeclamptic patients were randomized in double-blind fashion to DIF ( N = 24) or placebo ( N = 27) for 48 hours. Primary outcomes were change in creatinine clearance (CrCl) at 24 to 48 hours and antihypertensive drug use. Serum sodium pump inhibition, a sequela of endogenous digitalis-like factors (EDLF), was also assessed. CrCl in DIF subjects was essentially unchanged from baseline versus a decrease with placebo (-3 +/- 10 and -34 +/- 10 mL/min, respectively, P = 0.02). Antihypertensive use was similar between treatments (46 and 52%, respectively, P = 0.7). Serum sodium pump inhibition was decreased with DIF compared with placebo at 24 hours after treatment initiation (least squares mean difference, 19 percentage points, P = 0.03). DIF appeared to be well tolerated. These results suggest DIF prevents a decline in renal function in severe preeclampsia by neutralizing EDLF. Sodium pump inhibition was significantly improved. Further research is warranted.

Eczema herpeticum in pregnancy and neonatal herpes infection.

BACKGROUND: Eczema herpeticum is caused by herpes simplex infection of atopic dermatitis. The infection typically causes a vesiculopustular rash, but can disseminate and be life threatening. CASE: A primigravida with a history of eczema and hypogammaglobulinemia presented at 28 weeks of gestation with preterm labor, fever, and extensive rash. After failed tocolysis, she delivered vaginally. Prompt treatment with parenteral acyclovir was initiated for both patients based on a clinical diagnosis of maternal eczema herpeticum. Cultures confirmed the diagnosis of eczema herpeticum and rectal swab of the infant was positive for herpes simplex virus. The mother and infant did well. CONCLUSION: Early diagnosis and treatment of eczema herpeticum is necessary to prevent poor outcomes in pregnancy. Prophylactic acyclovir may help prevent eczema herpeticum in pregnancy.

A new insertion technique for the transcervical Foley catheter used for cervical ripening.

OBJECTIVE: To describe a new placement technique for the transcervical Foley catheter that may succeed when other methods have failed. STUDY DESIGN: Sixteen patients were identified as candidates for placement of a transcervical Foley catheter for cervical ripening, but all had failed attempted placement using the classically described methods. Our new placement technique involved the use of a 5 French rigid catheter guide inserted into the Foley catheter to make the catheter rigid and to ease insertion. RESLLTS: Placement was 100% successful in all 16 patients using the new insertion technique. CONCLUSION: The use of a rigid stylet during insertion increases the chances of success. The ease of insertion using this technique makes the use of a Foley catheter for cervical ripening a valuable option.

Recurrence risk for preterm delivery.

OBJECTIVE: To estimate recurrence risk of preterm delivery in third births. STUDY DESIGN: We conducted a population-based cohort study of Missouri mothers who delivered 3 consecutive singleton live births during 1989-1997. The recurrence risk was computed for 4 cohorts based on prior preterm delivery status and adjusted using Mantel-Haenszel stratified analysis. RESULTS: The study population included 19,025 third births. The recurrence risk ranged from 42% (for women with 2 prior preterm deliveries), through 21% (term/preterm) and 13% (preterm/term), to 5% (term/term). The recurrence risk was highest (57%) for women with 2 prior very preterm deliveries (21-31 weeks) and lowest (33%) for those with 2 prior moderate preterm deliveries (32-36 weeks). The recurrence risk was less pronounced for women with 1 prior very or moderate preterm delivery. CONCLUSION: These data show a strong association between prior preterm delivery and recurrence risk, which is affected by the frequency, order, and severity of prior preterm births.

Expert witness testimony.

One of the most important interfaces between medicine and law occurs in the courtroom. When medical issues are litigated, physicians have potential to make excellent witnesses. This article reviews the proper role, qualifications, and ethical requirements of expert witnesses, the law of professional negligence, and the regulation of unprofessional testimony. Expert witness reform is also briefly discussed.

Standard External Doppler Fetal Heart Tracings versus External Fetal Electrocardiogram in Very Preterm Gestation: A Pilot Study.

Introduction Very preterm babies can be difficult to monitor using standard external Doppler fetal heart tracings (eFHR). External fetal electrocardiogram (fECG) is a potential alternative. Methods This was a prospective observational pilot study of hospitalized patients at 24 to 28 weeks' gestation. A total of 30 women were traced for up to 2 hours using eFHR followed by up to 2 hours using fECG. The percentage of time the fetal heart rate was traced during the 2-hour window for each modality was calculated. Differences of ≥ 60, ≥ 80, and ≥ 90% total time traced were compared between modalities using McNemar's test. Differences were also assessed for each method between nonobese (body mass index [BMI] < 30 kg/m2) and obese (BMI ≥ 30 kg/m2) women using chi-square and Fisher's exact tests. Results Superior performance was found with eFHR at ≥ 60% (93.3 vs. 46.7%, p < 0.001), ≥ 80% (80.0 vs. 30.0%, p < 0.001), and ≥ 90% (60.0 vs. 23.3%, p < 0.01) total time traced. There was a statistically significant finding favoring nonobese women at ≥ 80% total time traced using fECG (7.1 vs. 50.0%, p = 0.017). Conclusion With current technology fECG performance in very preterm gestation was worse than conventional eFHR, although fECG may have a role in nonobese patients.

The effect of cerclage in twin gestations with short cervix: a Bayesian evaluation.

OBJECTIVE: Bayesian inference allows the revision of prior clinical estimates of treatment effectiveness based on current data. We apply it to a published dataset evaluating the effect of cerclage upon preterm delivery in twin gestations with a short cervix. STUDY DESIGN: Prior probability distributions for delivery <35 weeks gestation for the control group and the treatment (cerclage) group were constructed under assumptions ranging from treatment having no effect (prior A) to halving early deliveries (prior C). Likelihood functions were calculated based on a published meta-analysis. Posterior probability densities were derived from which risk ratios for early delivery were computed, with 95% credible intervals and the probability of cerclage benefit. RESULTS: Median posterior risk ratios (95% credible intervals) for delivery <35 weeks with cerclage are 1.51 (1.02-2.33) for prior A and 1.11 (0.72-1.77) for prior C. The probability of cerclage benefit ranged from 2.1% for prior A to 31.4% for prior C. By comparison, the conventional risk ratio (95% confidence interval) for early delivery, based on the data alone, is 2.08 (1.18-3.69). CONCLUSIONS: As might be anticipated, those with low expectation of cerclage benefit remain more convinced of the ineffectiveness (or harm) of the procedure than those with higher expectations.

Risk factors for neonatal mortality among extremely-low-birth-weight infants.

OBJECTIVE: The purpose of this study was to examine characteristics associated with neonatal mortality among extremely low-birth-weight infants (< or = 1000 g). STUDY DESIGN: A population-based, case-control study using linked Missouri birth and death certificates from 1989 to 1997 was conducted. Cases (n = 835) were defined as extremely low-birth-weight infants that died within 28 days of birth. Controls (n = 907) were randomly selected from extremely low-birth-weight infants that were alive at 1 year and were frequency matched to subjects by birth year and birth weight. RESULTS: Infants born with severe congenital anomalies and at the youngest gestational ages were at greatest risk for neonatal mortality. Other significant risk factors included maternal age (< 18 and > 34 years), vaginal delivery, nontertiary hospital care, malpresentation, male gender, and small for gestational age. Black race and preeclampsia were protective against early death. CONCLUSIONS: The risk of neonatal mortality among extremely low-birth-weight infants was associated with several maternal, infant, and obstetric factors, some of which may be preventable.

Review of the professional medical liability insurance crisis: lessons from Missouri.

OBJECTIVE: This study was undertaken to document and generalize the professional liability insurance (PLI) crisis. STUDY DESIGN: Data analysis from physician surveys, Missouri Department of Insurance, and court records. RESULTS: In 2001-2002, many insurers stopped writing new and existing PLI. A survey found 1 in 7 physicians had their PLI terminated and/or application for new insurance denied. Average premiums increased 22% in 2001 and 60% in 2002. Accordingly, 50% of surveyed obstetricians took salary cuts, 18% secured loans, 9% liquidated assets, and 55% significantly limited their clinical services. An adverse court ruling caused insurers to double reserves. Incomplete data led the Missouri Department of Insurance to erroneously conclude a decrease in claim frequency and severity. In contrast, courthouse records and missing data sources revealed increased malpractice filings. PLI premiums continue to rise. CONCLUSION: Many life-saving specialists are being forced out of business. Specialists are less willing to care for emergency and indigent patients for fear of liability exposure. Legislative enactments leading to meaningful tort reform, public support, and judicial restraint must occur to save health care.