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.

Placental growth factor predicts time to delivery in women with signs or symptoms of early preterm preeclampsia: a prospective multicenter study.

BACKGROUND: There is a robust association between altered angiogenic factor concentrations, which includes placental growth factor and clinically recognized preeclampsia. Alterations in concentrations of angiogenic factors precede the clinical onset of preeclampsia by several weeks. The temporal relationship between the measured angiogenic factors and the time to delivery in women with suspected preeclampsia at <35 weeks gestation, however, remains to be clarified. OBJECTIVE: The purposes of this study were to examine the relationship between placental growth factor and time to delivery in women at <35 weeks gestation with signs or symptoms of preeclampsia and to compare the performance of placental growth factor to other clinical markers for prediction of time to delivery in preeclampsia. STUDY DESIGN: Women with signs or symptoms of preeclampsia between 20.0 and 35.0 weeks gestation were enrolled in a prospective, observational study at 24 centers. Blood was collected at presentation for placental growth factor, and subjects were evaluated and treated according to local protocols. Clinical outcomes were obtained, and all final diagnoses were adjudicated by an independent expert panel according to 2013 American College of Obstetricians and Gynecologists' Hypertension in Pregnancy criteria. Placental growth factor was measured retrospectively on the Alere, Inc, triage platform. A normal placental growth factor was defined as >100 pg/mL; the assay's limit of detection is 12 pg/mL. Two-by-2 tables were constructed for comparison of test outcomes that included negative predictive value; time-to-delivery was analyzed by survival curves and Cox regression. RESULTS: Seven hundred fifty-three subjects were enrolled; 538 (71%) had a final diagnosis of preeclampsia; 542 (72%) delivered at <37 weeks gestation, and 358 (47%) delivered at <34 weeks gestation. Among the 279 women (37%) with a normal placental growth factor at presentation, the negative predictive value for preeclampsia delivered within 14 days or within 7 days was 90% and 93%, respectively. Compared with women with normal placental growth factor, women with placental growth factor ≤100 pg/mL have a hazard ratio of 7.17 (confidence interval, 5.08-10.13) in Cox regression for time to delivery after adjustment for both gestational age at enrollment and the final diagnosis of preeclampsia. The placental growth factor levels of normal (>100 pg/mL), low (12-100 pg/mL), and very low (<12 pg/mL) have well-separated distributions of time to delivery, with median values of 45, 10, and 2 days, respectively. Subjects with placental growth factor ≤100 pg/mL have a perinatal death rate of 5.7% and a small-for-gestational-age rate of 51.7%; subjects with placental growth factor >100 pg/mL have a perinatal death rate of 0% (no observations in this cohort) and an a small-for-gestational-age rate of 16.8%. CONCLUSION: In women with suspected preeclampsia at <35.0 weeks gestation, a low placental growth factor was correlated strongly with preterm delivery independent of a diagnosis of preeclampsia or gestational age at presentation, whereas a normal placental growth factor was associated with pregnancy prolongation, even in patients who ultimately had a final diagnosis of preeclampsia. This suggests that placental growth factor levels are superior to clinical markers in the prediction of adverse pregnancy in women with suspected preeclampsia.

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.

Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length.

OBJECTIVE: The objective of the study was to assess cerclage to prevent recurrent preterm birth in women with short cervix. STUDY DESIGN: Women with prior spontaneous preterm birth less than 34 weeks were screened for short cervix and randomly assigned to cerclage if cervical length was less than 25 mm. RESULTS: Of 1014 women screened, 302 were randomized; 42% of women not assigned and 32% of those assigned to cerclage delivered less than 35 weeks (P = .09). In planned analyses, birth less than 24 weeks (P = .03) and perinatal mortality (P = .046) were less frequent in the cerclage group. There was a significant interaction between cervical length and cerclage. Birth less than 35 weeks (P = .006) was reduced in the less than 15 mm stratum with a null effect in the 15-24 mm stratum. CONCLUSION: In women with a prior spontaneous preterm birth less than 34 weeks and cervical length less than 25 mm, cerclage reduced previable birth and perinatal mortality but did not prevent birth less than 35 weeks, unless cervical length was less than 15 mm.

Preterm labor biomarker discovery in serum using 3 proteomic profiling methodologies.

OBJECTIVE: The aim of this study was to identify changes in protein expression in normal pregnancy compared with preterm labor by using 3 proteomic methods. STUDY DESIGN: Serum was collected from 25 nonpregnant (n = 5) and pregnant women at 24-40 weeks' gestation (n = 20) who had preterm labor resulting in preterm delivery (n = 5), preterm labor with term delivery (n = 5), term labor resulting in delivery (n = 5), or at term with contractions (n = 5). Undepleted serum was used for surface-enhanced laser desorption ionization and immune-depleted serum for matrix-assisted laser desorption ionization and 2-dimensional electrophoresis. RESULTS: Surface-enhanced laser desorption ionization identified significantly different peaks between preterm labor resulting in preterm delivery vs term labor resulting in delivery and preterm labor resulting in preterm delivery vs preterm labor with term delivery using 4 surfaces. In preterm labor resulting in preterm delivery vs preterm labor with term delivery, a peak of 7783.2 m/z was significantly up-regulated and at 3164 m/z down-regulated on 3 surfaces. By using 2-dimensional electrophoresis, protein 5364 was significantly different between preterm labor resulting in preterm delivery and term labor resulting in delivery. In preterm labor resulting in preterm delivery, 6 proteins showed decreasing trend and 1 showed increasing trend vs preterm labor with term delivery. Matrix-assisted laser desorption ionization showed a striking difference at 55,000 m/z between preterm labor resulting in preterm delivery and term labor resulting in delivery. CONCLUSION: Surface-enhanced laser desorption ionization identified 2 proteins fulfilling the criteria of putative biomarkers. Biomarker identification may aid in identifying women with preterm labor who will deliver preterm.

Progesterone for the prevention of preterm birth: indications, when to initiate, efficacy and safety.

Preterm birth is the leading cause of neonatal mortality and morbidity and long-term disability of non-anomalous infants. Previous studies have identified a prior early spontaneous preterm birth as the risk factor with the highest predictive value for recurrence. Two recent double blind randomized placebo controlled trials reported lower preterm birth rate with the use of either intramuscular 17 alpha-hydroxyprogesterone caproate (IM 17OHP-C) or intravaginal micronized progesterone suppositories in women at risk for preterm delivery. However, it is still unclear which high-risk women would truly benefit from this treatment in a general clinical setting and whether socio-cultural, racial and genetic differences play a role in patient's response to supplemental progesterone. In addition the patient's acceptance of such recommendation is also in question. More research is still required on identification of at risk group, the optimal gestational age at initiation, mode of administration, dose of progesterone and long-term safety.

Indications for delivery and short-term neonatal outcomes in late preterm as compared with term births.

OBJECTIVE: The objective of the study was to evaluate the indications for late preterm birth and compare outcomes by gestational age among late preterm (34-36 weeks) and term (> or = 37 weeks) neonates at our institution. STUDY DESIGN: This was a retrospective analysis of delivery indications and short-term neonatal outcomes in women who delivered at the University Hospital between January 1, 2005 and Dec. 31, 2006. Data were analyzed using chi(2), Student's t-test, analysis of variance, and post hoc Tukey tests. RESULTS: One hundred forty-nine late preterm (n = 49 for 34, n = 50 for 35, n = 50 for 36 weeks) and 150 term infants (n = 50 for 37, n = 50 for 38, n = 50 for 39 weeks or longer) were evaluated. Differences among groups (ie, 34 vs 35 vs 36 vs 37, etc) as well as combinations of differences between 2 groups (ie, 34-36 weeks vs > or = 37 or > or = 38 weeks) were analyzed. Spontaneous labor and/or rupture of membranes were the most common indications for late preterm delivery (92%). Compared with term, late preterm infants had longer hospital stays (5 days vs 2.4 days; P < .001) and higher rates of neonatal intensive care unit (NICU) admissions (56% vs 4%; P < .001), feeding problems (36% vs 5%; P < .001), hyperbilirubinemia (25% vs 3%; P < .001), and respiratory complications (20% vs 5%; P < .001). Neonatal complications were minimal at 38 weeks or longer. CONCLUSION: Rates of neonatal intensive care unit admission, length of stay, and neonatal morbidities are significantly higher in late preterm as compared with term births.

Cervical dilatation on presentation for preterm labor and subsequent preterm birth.

We sought to determine the risk of preterm (< 32 weeks) delivery as it relates to cervical dilatation at presentation of an initial preterm labor admission episode. We retrospectively reviewed the records of all patients presenting with preterm contractions at 22 to 32 weeks' gestation. Multiple regression was used to analyze the relationship between the interval from initial preterm labor admission episode to delivery and cervical dilatation at presentation. Logistic regression analysis was used to identify variables associated with preterm birth. Mean gestational age on admission for preterm labor episode was 28.1 +/- 2.9 weeks. With a cervical dilatation of 0 to 1 cm, 6% of the women delivered within 48 hours, 20% delivered at < 32 weeks, and 38% delivered at < 35 weeks. With cervical dilatation of 6 to 10 cm, 89% delivered in < 24 hours, 11% between 24 and 48 hours, 94% delivered at < 32 weeks, and 100% delivered at < 35 weeks. Time from admission for initial preterm labor episode to delivery was inversely associated with cervical dilatation. Variables associated with preterm birth at < 32 weeks' gestation were cervical dilatation ( P < 0.0001), gestational age ( P < 0.0001), and effacement ( P < 0.0001) at presentation. In women who experience preterm contractions, cervical dilatation on admission is inversely related to interval to delivery. However, women with cervical dilatation of 0 to 1 cm are still at significant risk for preterm delivery: 19/94 (20%) at < 32 weeks' gestation and 40/104 (38%) at < 35 weeks' gestation.

Prophylaxis with 17 alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery: does gestational age at initiation of treatment matter?

OBJECTIVE: The purpose of this study was to determine effectiveness of 17 alpha-hydroxyprogesterone caproate (17 P) prophylaxis by gestational age (GA) at 17 P initiation. STUDY DESIGN: Singleton gestations with > or = 1 preterm birth (PTB) treated with 17 P prophylaxis for recurrent preterm birth before 27 weeks were identified from a data base. Data were stratified by GA at 17 P initiation (16-20.9 [n = 599] weeks and 21-26.9 [n = 307] weeks) and number of PTB (1, 2, > 2). Outcome variables were PTB at < 37, < 35, and < 32 weeks. RESULTS: No significant differences were found in gestational age at delivery or rates of recurrent PTB < 37, < 35, and < 32 weeks between those women initiating 17 P at 16-20.9 weeks or 21-26.9 weeks, or when stratified by number of prior preterm deliveries. CONCLUSION: Initiation of 17 P prophylaxis at 21-26.9 weeks is as effective as initiation at 16-20.9 weeks of gestation.

Does peripartum infection increase the incidence of cerebral palsy in extremely low birthweight infants?

OBJECTIVES: This study was undertaken to determine the perinatal predictors of cerebral palsy in extremely low birthweight infants (<1000 g). STUDY DESIGN: A case control study of infants with birthweight of less than 1000 g (19 with cerebral palsy and 38 controls) who survived beyond 18-22 months of corrected age was performed. Outcome variables included maternal demographics, obstetric complications, and neonatal outcome (gestational age at delivery, birthweight, Apgar scores, intrauterine growth restriction, respiratory distress syndrome, intraventricular hemorrhage, and neonatal sepsis). Data analysis consisted of t tests, chi2, and analysis of variance when appropriate. RESULTS: There were no significant differences between cerebral palsy and control groups with regard to mode of delivery, Apgar scores, preeclampsia, antenatal vaginal bleeding, or the use of magnesium sulfate. However, male gender (odds ratio 3.70; 95% CI 1.05-12.5), primigravid status (odds ratio 5.52; 95% CI 1.67-18.3), early neonatal sepsis (odds ratio 12.9; 95% CI 2.94-57.2) and chorioamnionitis, both clinical and histologic (odds ratio 3.71; 95% CI 1.16-11.9) were significantly associated with the development of cerebral palsy. The strong association between cerebral palsy and chorioamnionitis, as well as early neonatal sepsis, remain significant after adjustment for primigravid status and male gender. CONCLUSION: In extremely low birthweight infants, cerebral palsy was strongly associated with chorioamnionitis, early neonatal sepsis, male gender, and primigravid status.

Postpartum headache: is your work-up complete?

OBJECTIVE: Headache is a common finding in the postpartum period, and there are limited data describing the cause and treatment of women with postpartum headache. Our objective was to describe our experience with women who were hospitalized for postpartum headache and to develop a management algorithm for these women. STUDY DESIGN: Data for 95 women with headache >24 hours after delivery from 2000-2005 were reviewed retrospectively. Maternal assessment included an evaluation for benign and serious causes of headache that included preeclampsia, dural puncture, and neurologic lesions. Neurologic imaging were performed on the basis of initial neurologic findings and clinical course. Outcomes that were studied included cause, a need for cerebral imaging, neurologic findings, maternal complications, and long-term follow-up evaluations. RESULTS: The mean onset of headache was 3.4 days (range, 2-32 days) after delivery. Tension-type/migraine headache was the most common cause (47%). Preeclampsia/eclampsia and spinal headache comprised 24% and 16% of cases, respectively. Anesthesia evaluation was required in 15 patients because of suspected spinal headache; blood patch was required in 12 of these patients. Cerebral imaging was performed in 22 patients because of focal neurologic deficits and/or failure to respond to initial therapy; 15 of these women (68%) had abnormal findings. Ten patients had serious cerebral pathologic findings, such as hemorrhage, thrombosis, or vasculopathy. There were no deaths; 2 women had minor residual neurologic damage on follow-up evaluation. CONCLUSION: The evaluation of persistent headaches that develop >24 hours after delivery must be performed in a stepwise fashion and requires a multidisciplinary approach. Preeclampsia should be considered initially in women with hypertension and proteinuria. Normotensive women should be evaluated initially for tension-type/migraine headache or spinal headache. Patients with headache that is refractory to usual therapy and patients with neurologic deficit require cerebral imaging to detect the presence of life-threatening causes.

Thrombophilia and adverse maternal-perinatal outcome: controversies in screening and management.

A recent review of the literature on thrombophilia and adverse pregnancy outcome reveals contradictory findings. There are retrospective and prospective studies that recommend testing for genetic and acquired markers of thrombophilia for those with the enumerated adverse pregnancy outcome. Based on our review, routine screening for thrombophilias in women with a history of adverse pregnancy outcome (preeclampsia, abruptio placenta, intrauterine growth restriction, and fetal loss) is not justified. Based on data from observational studies and few randomized trials with inadequate number of subjects, there is consensus that women with true antiphospholipid antibody syndrome should receive low-dose aspirin plus adjusted-dose heparin in subsequent pregnancies. Some authors also recommend heparin prophylaxis in subsequent pregnancies in women with genetic thrombophilia with previous adverse pregnancy outcome. However, this recommendation is not based on randomized trials. Hence, a randomized double-blind, controlled trial is urgently needed to evaluate the benefit of heparin during pregnancy in women with a history of adverse pregnancy outcome in association with genetic thrombophilia.

Tocolysis in women with preterm labor between 32 0/7 and 34 6/7 weeks of gestation: a randomized controlled pilot study.

OBJECTIVE: The purpose of this study was to determine whether intravenous magnesium sulfate (MgSO4) followed by oral nifidepine tocolysis in women with preterm labor between 32 0/7 and 34 6/7 weeks' gestation reduces neonatal hospital stay. STUDY DESIGN: Fifty-four women between 32 0/7 and 34 6/7 weeks with preterm labor were randomized to receive either MgSO4 and oral nifidepine (n = 24) or no tocolysis (n = 30). All women received betamethasone and prophylactic antibiotics. The primary outcome was total neonatal hospital stay. Data were analyzed using Chi-square and Mann Whitney U test. RESULTS: The 2 groups had similar mean cervical dilation and gestational age at enrollment. There were no statistically significant differences in total neonatal hospital stay (5.8 +/- 7.2 days; median of 3 days in the no tocolysis vs. 7.5 +/- 8.6 days; median of 3 days in the tocolysis group), rate of preterm delivery (57% vs. 75%) or need for oxygen supplementation (7% vs. 21%, p < 0.23). The neonatal complications were similar in each group. CONCLUSION: Tocolysis after 32 weeks gestation does not reduce neonatal hospital stay.

Is early-pregnancy proteinuria associated with an increased rate of preeclampsia in women with pregestational diabetes mellitus?

OBJECTIVE: The purpose of this study was to determine whether the rate of preeclampsia in pregnant diabetic women is increased in those women with early-pregnancy proteinuria of 190 to 499 mg/24 hours compared with women with proteinuria of <190 mg/24 hours. STUDY DESIGN: Secondary analysis was performed with relevant data from 194 pregnant women with type 1 and type 2 diabetes mellitus whose condition required insulin and who were enrolled previously in a multicenter trial of low-dose aspirin for the prevention of preeclampsia. The women were assigned to 1 of 3 groups, based on the level of proteinuria at enrollment (13-26 weeks of gestation). Group 1 comprised women with <190 mg protein/24 hours (n=94); group 2 comprised women with 190 to 499 mg protein/24 hours (n=35); and group 3 comprised women with >/=500 mg protein/24 hours (n=65). The rate of preeclampsia, according to strict predefined criteria, was then determined. RESULTS: The rate of preeclampsia was not increased statistically significantly in patients with early-pregnancy proteinuria of 190 to 499 mg/24 hours (7/35 women; 20%) when compared with women with proteinuria of <190 mg/24 hours (16/94 women; 17%). CONCLUSION: We did not find an increased rate of preeclampsia in women with pregestational diabetes mellitus with early-pregnancy proteinuria of 190 to 499 mg/24 hours when compared with women with pregestational diabetes mellitus with proteinuria of <190 mg/24 hours.

The pattern of change in the lecithin/sphingomyelin ratio in patients with preterm premature rupture of membranes between 24 and 34 weeks' gestation.

OBJECTIVE: To report the pattern of change in the lecithin/sphingomyelin (L/S) ratio in patients with preterm premature rupture of membranes (PPROM) between 24 and 34 weeks' gestation. STUDY DESIGN: L/S was determined prospectively using transvaginally and transabdominally collected amniotic fluid from patients with PPROM between 24 and 34 weeks' gestation. Samples were collected prospectively on admission and every 48 to 96 hours until L/S was > or =2.0. All patients received intramuscular betamethasone weekly. RESULTS: Fifty-five patients were included in the study. One hundred twenty-seven samples were collected transvaginally and nine were collected transabdominally. Cox regression analysis showed that a higher initial L/S value and more advanced gestational age were associated with accelerated lung maturation. Among patients at > or =29 weeks' gestation with an initial L/S of > or =1.5 and <2.0 (n=17), 15 of 17 (88%) reached L/S > or = 2 at a mean of 3.1 +/- 1.7 days (range 1.0 to 7.0 days). With an initial L/S of > or =1.0 and <1.5 (n=16), 14 of 16 (88%) patients reached L/S > or =2 at a mean of 4.1 +/- 1.9 days (range 1.7 to 7.0 days). With an initial L/S of <1.0 (n=11), 6 of 11 (54%) patients reached L/S > or =2 at a mean of 5.0 +/- 1.6 days (range 4.7 to 6.8 days). CONCLUSION: Our data document a dramatic acceleration of fetal lung maturation among patients with PPROM at > or = 29 weeks.