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Keywords:

  • Hypertensive disorders;
  • pregnancy;
  • premature delivery

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Rationale for prenatal AT to treat preeclampsia
  5. AT therapy in preeclampsia
  6. PRESERVE-1 overview
  7. References

Problem

Antithrombin (AT) replacement has been described in patients with hereditary AT deficiency undergoing delivery; however, the kinetics of AT replacement in preeclampsia is not adequately understood. Therefore, the Prospective Randomized Evaluation of the Safety and Efficacy of Recombinant Antithrombin in Very Preterm Preeclampsia (PRESERVE-1) study has been proposed.

Methods

Sixty women aged ≥18 years at 24 0/7–28 0/7 weeks' gestation and with hypertension and proteinuria will be enrolled and randomly assigned to receive recombinant human AT or placebo until fetal and/or maternal indications cause cessation of expectant management or until 34 0/7 weeks' gestation. The primary endpoint is the increase in gestational age from randomization to delivery. Safety assessments and laboratory assays will also be performed.

Results

PRESERVE-1 study enrollment will begin during the second half of 2013.

Conclusion

The PRESERVE-1 study will provide further insight into the pharmacokinetic activity and safety of AT therapy in preeclampsia.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Rationale for prenatal AT to treat preeclampsia
  5. AT therapy in preeclampsia
  6. PRESERVE-1 overview
  7. References

Preeclampsia, a pregnancy-specific disorder affecting 3–5% of all pregnancies, is characterized by hypertension and proteinuria.[1] Although preeclampsia is a leading cause of maternal and perinatal morbidity and mortality, its precise etiopathogenesis, ideal detection strategy, prophylaxis, and treatment remain elusive.[2, 3] Delivery is the only effective cure; however, significant prematurity sequelae can complicate the scenario when delivery is remote from term gestation.[4]

Recently, digoxin immune Fab has been proposed as a treatment for severe preeclampsia.[5] Aspirin or aspirin-like agents demonstrate minimal to modest decreases in the occurrence of preeclampsia.[6] In a limited number of studies, heparin has been associated with a reduction in recurrence of placenta-mediated complications, including preeclampsia.[7, 8] At present, however, routine prenatal administration of heparin to prevent placenta-mediated complications (e.g., preeclampsia, fetal loss, fetal growth restriction, abruption) is considered experimental.[9]

Current treatment paradigms for severe, preterm preeclampsia consist of expectant management. Haddad and colleagues conducted a prospective observational study of 239 women with severe preeclampsia after prenatal steroid administration to prevent prematurity-related complications.[10] The authors reported perinatal mortality rates (gestational age in weeks at admission) of 67% (24 weeks), 40% (25 weeks), 0% (26 weeks), 3.6% (27 weeks), and 7% (28 weeks). Rates of chronic lung disease, which has important long-term health implications for the neonate, were similarly high: 100% (24 weeks), 67% (25 weeks), 57% (26 weeks), 33% (27 weeks), and 15% (28 weeks).[10]

Hall and colleagues investigated perinatal outcomes after expectant management of severe preterm preeclampsia[11] and reported survival rates of 20 and 72% at 27 and 28 weeks, respectively. Witlin and colleagues reported that rates of newborn respiratory distress syndrome were 100 and 90.9% and survival rates of 61.5 and 93.9% for gestational age ranges of 24 0/7–26 6/7 weeks and 27 0/7–28 6/7 weeks, respectively.[12]

Abramovici and colleagues examined whether different variants of the severe preeclamptic syndrome known as hemolysis, elevated liver enzymes, and low platelet count (HELLP) influenced perinatal outcome.[13] For early gestational age, there were no differences in the rates of perinatal complications associated with HELLP syndrome, its variants, or severe preeclampsia. Specifically, for neonates born at <28 weeks' gestation, mortality rates for HELLP syndrome, partial HELLP syndrome, or severe preeclampsia, respectively, were 22, 27, and 21%, respectively; rates of respiratory distress syndrome were 78, 67 and 71%, respectively; rates of grade 3/4 intracranial hemorrhage were 0, 13 and 7%, respectively; rates of necrotizing enterocolitis were 0, 13 and 7%, respectively; rates of bronchopulmonary dysplasia were 56, 53 and 21%, respectively; and use of mechanical ventilation was 83, 87 and 93%, respectively. Visser and Wallenburg reported the following perinatal mortality rates in 254 consecutive patients with preeclampsia that was managed expectantly[14]: <26 weeks, 84% (95% confidence interval [CI], 64–95%); 26 weeks, 44% (95% CI, 22–69%); 27 weeks, 30% (95% CI, 15–49%); and 28 weeks, 17% (95% CI, 7–31%).

Previous studies by Sibai and colleagues have highlighted the extraordinarily high complication rates associated with expectant management of severe preeclampsia in the second trimester, largely as a consequence of prematurity. In 1985, Sibai and colleagues reported on 60 patients with severe preeclampsia, who were conservatively managed between 18 and 27 weeks' gestation[15]; the perinatal outcome for these pregnancies was exceptionally poor, with 31 of 60 pregnancies resulting in a stillborn infant. In a subsequent study, Sibai and colleagues reported on 95 patients with severe preeclampsia at 28–32 weeks of gestation.[16] Forty-six patients were randomly assigned to aggressive treatment and 49 to conservative treatment. Compared with the aggressively managed group, the conservatively managed group showed a significant prolongation of pregnancy (mean, 15.4 days; range, 4–36 days), lower incidence of admission to a neonatal intensive care unit (76% versus 100%), decreased time in the neonatal intensive care unit (20.2 days versus 36.6 days), reduced incidence of respiratory distress syndrome (22.4% versus 50.0%), a lower incidence of necrotizing enterocolitis (0% versus 11%), a nonsignificant reduction in bronchopulmonary dysplasia (4.1% versus 8.7%), and a lower rate of neonatal cerebral hemorrhage (2.0% versus 6.5%).

In 2008, Bombrys et al. performed a retrospective analysis of 46 patients (51 fetuses) with severe preeclampsia at <27 weeks of gestation.[17] Rates of fetal death, neonatal death, severe respiratory distress syndrome, chronic lung disease, intraventricular hemorrhage, and necrotizing enterocolitis were 27, 16, 65, 24, 3 and 8%, respectively. Prolongations of pregnancy by 7–15 days and by 10–14 days were reported for the randomized and non-randomized trials evaluating expectant management of preeclampsia, respectively.[17] Thus, despite advances in perinatal and newborn care in the past 25 years, perinatal complication rates during the periviable period in newborns of preeclamptic mothers remain substantial. The current management of preterm preeclampsia is outlined in Fig. 1.[18] The lack of an effective treatment has lead us to consider a different approach to treat preterm preeclampsia, which is based upon key aspects of its pathology, decreased maternal serum levels of antithrombin (AT), and favorable preliminary clinical experience regarding AT replacement in preeclampsia.

image

Figure 1. Clinical algorithm for the management of suspected severe preeclampsia at <34 weeks' gestation. Figure 1 is adapted from Sibai [18]. Figure adapted with permission. Copyright©, 2012. Elsevier.

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Rationale for prenatal AT to treat preeclampsia

  1. Top of page
  2. Abstract
  3. Introduction
  4. Rationale for prenatal AT to treat preeclampsia
  5. AT therapy in preeclampsia
  6. PRESERVE-1 overview
  7. References

Hallmarks of preeclampsia include aberrant trophoblast invasion, endothelial cell dysfunction, and activation of the coagulation cascade[3]; decreased AT levels have also been noted.[19] Weiner et al. measured AT levels near term in hypertensive patients[19](i.e., those with chronic hypertensive preeclampsia or chronic hypertension with superimposed preeclampsia) and reported that mean ± S.E. AT activity level was 60 ± 15% in preeclamptic patients, 68 ± 16% in patients with superimposed preeclampsia, and 85 ± 15% in control patients. With a cutoff of ≥70%, the negative predictive value for preeclampsia was 89%, and with a cutoff of <70%, the positive predictive value for preeclampsia was 80%.

Antithrombin possesses a number of properties that make it a potentially attractive therapy for preeclampsia. As a therapeutic agent, it has potent anticoagulant and anti-inflammatory properties.[20] Plasma-derived AT (e.g., Thrombate® and Talecris® Grifols, Research Triangle Park, NC, USA) and recombinant AT (ATryn®; GTC Biotherapeutics, Framingham, MA, USA) are available for consideration in future clinical trials, given their approval by the United States Food and Drug Administration for other indications in pregnancy. Plasma-derived AT has been administered as a treatment for preeclampsia in several small clinical trials, with success in improving both perinatal and maternal outcomes. There are no studies of recombinant human antithrombin (rhAT) in the treatment of preeclampsia.

AT therapy in preeclampsia

  1. Top of page
  2. Abstract
  3. Introduction
  4. Rationale for prenatal AT to treat preeclampsia
  5. AT therapy in preeclampsia
  6. PRESERVE-1 overview
  7. References

Investigation of AT replacement in preeclampsia is limited to a few studies and case reports. In a study by Buller et al., a dose of 2000 units of AT concentrate administered to an AT-deficient patient with severe preeclampsia improved blood pressure, proteinuria, and coagulation parameters.[21] The patient had an uneventful cesarean delivery.

Terao et al. reported on 40 patients with preeclampsia (37 with severe disease), most of whom were between 32 and 39 weeks' gestation.[22] Twenty-seven patients were treated with AT at doses of 1000–2000 units per day for 7 days. Hypertensive patients were scored using the gestosis index (GI), which consists of edema, proteinuria, and systolic and diastolic blood pressure criteria. An efficacy rate of 40% as measured by GI improvement was noted in the AT-treated group versus 0% in the untreated group; a correlation between GI and AT activity was also observed.

Nakabayashi and colleagues compared AT replacement with heparin treatment in early-onset severe preeclampsia with intrauterine fetal growth restriction under 32 weeks' gestation.[23] Fifteen patients received an AT dose of 1500 units per day for 7 days. Compared with heparin, the AT infusion was associated with improved systolic blood pressure levels and sonographic estimation of fetal weight. The authors concluded that AT replacement therapy was useful for improving maternal hypertension and fetal weight in severe preeclampsia.

Kobayashi and colleagues performed a phase 2 trial to assess the efficacy of AT concentrate in 29 patients with severe preeclampsia (GI ≥6) at 24–36 weeks of gestation.[24] Treatment with AT at 1500 units plus heparin at 5000 units daily was compared with treatment with heparin only (5000 units per day × 7 days). Both the GI and biophysical profile indicating fetal well-being were significantly improved with AT replacement (= 0.46 and = 0.022, respectively). When the authors compared coagulation parameters, AT replacement was associated with improved levels of plasmin–plasmin inhibitor complex, D-dimer, and platelet counts; however, none of these changes were statistically significant. Thus, the addition of AT was superior to use of heparin alone with respect to improving maternal and fetal outcomes. Other studies have reported improved uteroplacental circulation after AT administration.[25, 26] The optimal dose of AT replacement was 3000 units per day, which was efficacious and safe for both mother and fetus.[25, 26]

Maki and colleagues performed a placebo-controlled double-blind phase 3 trial in 133 patients with severe preeclampsia and gestational ages ranging from 24 to 35 weeks and a GI ≥6.[27] Sixty-six patients received AT replacement at 3000 units per day and 67 received intravenous placebo for 7 days; patients were observed for 14 days and followed up until delivery. A significant prolongation (mean ± S.D.) of pregnancy was found with AT replacement versus placebo (16.8 ± 2.0 days versus 10.2 ± 1.2 days, respectively; = 0.007) along with a significantly greater gestational age at delivery (34.1 ± 3.2 versus 33.0 ± 2.7 weeks, respectively; = 0.007). A significant mean increase in gestational age of 6.5 days was noted in the AT replacement group. Both AT antigen and AT activity levels increased significantly (= 0.001) in the AT replacement group, compared with the placebo group. Thus, AT replacement in addition to conventional therapy improved maternal symptoms and biophysical profile scores, prolonged pregnancy, and decreased the prevalence of very low-birthweight infants.

Paternoster and colleagues compared two different dosing regimens of AT replacement in patients with severe preeclampsia between 24 and 33 weeks of gestation.[28] The high-dose AT group (n = 10) received 3000 units of AT per day for 5 days (mean cumulative dose, 12,600 units per patient). The standard-dose AT group (n = 13) received AT replacement to maintain 80% AT activity (mean dose, 3370 units per patient); the high-dose group ultimately received a dose that was 3.7 times higher than that of the standard-dose group. Pregnancies in the high-dose group were prolonged by a mean of 6 days, compared with 3.5 days in the standard-dose group (= 0.03). The high-dose group also had greater birthweights (1185 g versus 1005 g, respectively), but this difference was not significant (= 0.3). It was concluded that standard-dose AT replacement corrects a hemostatic abnormality, whereas high-dose AT replacement also corrects an inflammatory state.

In summary, the published studies suggest a benefit to AT replacement in preeclampsia. However, these studies have significant limitations and are unlikely to change practice patterns. Most notably, data from the disproportionate number of Japanese studies are confounded by a preeclamptic classification that is not used by the rest of the developed world. A high-quality, prospective, randomized clinical trial of AT replacement in preeclampsia is therefore required. Hence, we propose the following study: A Prospective Randomized Evaluation of the Safety and Efficacy of Recombinant Antithrombin in Very Preterm Preeclampsia (PRESERVE-1).

PRESERVE-1 overview

  1. Top of page
  2. Abstract
  3. Introduction
  4. Rationale for prenatal AT to treat preeclampsia
  5. AT therapy in preeclampsia
  6. PRESERVE-1 overview
  7. References

The goal of this phase 2 study is to assess the pharmacokinetic properties and safety of rhAT in preterm severe preeclampsia. Approval will be obtained from the institutional review board prior to initiation of the multicenter study, and a data safety monitoring board will oversee the study. This study will provide data concerning the population pharmacokinetics of rhAT as well as safety and efficacy data.

Sixty ≥18-year-old women at 24 0/7–28 0/7 weeks' gestation with hypertension and proteinuria (blood pressure ≥140/≥90 mm Hg and urine protein collection ≥0.3 g per 24 hr or blood pressure ≥160/≥110 mm Hg and urine protein dipstick value ≥+1) will be enrolled. In addition to standard care, patients will be randomly assigned to receive rhAT (twice-daily bolus infusions or a 24-hr continuous infusion) or placebo until fetal and/or maternal indications cause cessation of expectant management or until 34 0/7 weeks' gestation.

Antithrombin activity levels and potential interaction of AT with other drugs that are routinely administered in severe preterm preeclampsia will be assessed. Common medications used in the severe preterm preeclampsia setting include (i) magnesium sulfate to prevent seizures (typically given for 24 hr upon diagnosis of preeclampsia and in the peridelivery period for 24 hr after delivery), (ii) betamethasone or dexamethasone (given for 24 hr for 1 or 2 courses to prevent prematurity complications), and (iii) antihypertensive therapy (typically consisting of labetalol or hydralazine). Antithrombin is not thought to cross the placenta, but cord blood levels of AT will be assessed. Short-term follow-up assessment of the newborn will also be conducted.

The primary aim of this proposed phase 2 study is to assess pharmacokinetic parameters and safety. However, the study will also provide preliminary evidence as to whether prenatal administration of rhAT reduces the rate of adverse fetal/neonatal outcomes by prolonging pregnancy. Neonatal and fetal outcome variables that will be assessed include grade 3/4 intraventricular hemorrhage, severe respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and perinatal death. Another secondary aim of the phase 2 study is to provide preliminary evidence on prenatal administration of rhAT to reduce the rate of adverse maternal outcomes, specifically pulmonary edema, eclampsia, HELLP, clinically apparent disseminated intravascular coagulation, acute renal failure, stroke, and death. Safety assessments comprising adverse events (AEs), serious AEs, and specific maternal and fetal/neonatal complications will be studied. Laboratory assays will monitor AT activity, coagulation, urine protein, and other biomarkers. Maternal and neonatal assessments will continue through the postpartum period. If the results of this phase 2 study are favorable, a larger pivotal trial of AT replacement in preeclampsia will be conducted.

Important considerations regarding AT administration in this proposed trial include the rationale for dosing with respect to physiologic versus pharmacologic levels of AT and monitoring of AT levels. A focus on these issues in the phase 2 study will provide useful data for a larger clinical trial of rhAT dosing.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Rationale for prenatal AT to treat preeclampsia
  5. AT therapy in preeclampsia
  6. PRESERVE-1 overview
  7. References
  • 1
    Duley L: The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009; 33:130137.
  • 2
    Sibai BM: Maternal and uteroplacental hemodynamics for the classification and prediction of preeclampsia. Hypertension 2008; 52:805806.
  • 3
    Roberts JM, Cooper DW: Pathogenesis and genetics of pre-eclampsia. Lancet 2001; 357:5356.
  • 4
    Goldenberg RL, Culhane JF, Iams JD, Romero R: Epidemiology and causes of preterm birth. Lancet 2008; 371:7584.
  • 5
    FDA grants fast track review to Glenveigh Digoxin Immune Fab. Pharmaceutical Business Review. November 13, 2012. http://regulatoryaffairs.pharmaceutical-business-review.com/news/fda-grants-fast-track-review-to-glenveigh-digoxin-immune-fab-131112 Accessed December 14, 2012.
  • 6
    Duley L, Henderson-Smart DJ, Meher S, King JF: Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2007;2: CD004659.
  • 7
    Urban G, Vergani P, Tironi R, Ceruti P, Vertemati E, Sala F, Pogliani E, Triche EW, Lockwood CJ, Paidas MJ: Antithrombotic prophylaxis in multiparous women with preeclampsia or intrauterine growth retardation in an antecedent pregnancy. Int J Fertil Womens Med 2007; 52:5967.
  • 8
    Rey E, Garneau P, David M, Gauthier R, Leduc L, Michon N, Morin F, Demers C, Kahn SR, Magee LA, Rodger M: Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost 2009; 7:5864.
  • 9
    Rodger MA, Paidas M, McLintock C, Middeldorp S, Kahn S, Martinelli I, Hague W, Rosene Montella K, Greer I: Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol 2008; 112:320324.
  • 10
    Haddad B, Deis S, Goffinet F, Paniel BJ, Cabrol D, Siba BM: Maternal and perinatal outcomes during expectant management of 239 severe preeclamptic women between 24 and 33 weeks' gestation. Am J Obstet Gynecol 2004; 190:15901595. Discussion 1595–1597.
  • 11
    Hall DR, Odendaal HJ, Kirsten GF, Smith J, Grové D: Expectant management of early onset, severe pre-eclampsia: perinatal outcome. BJOG 2000; 107:12581264.
  • 12
    Witlin AG, Saade GR, Mattar F, Sibai BM: Predictors of neonatal outcome in women with severe preeclampsia or eclampsia between 24 and 33 weeks' gestation. Am J Obstet Gynecol 2000; 182:607611.
  • 13
    Abramovici D, Friedman SA, Mercer BM, Audibert F, Kao L, Sibai BM: Neonatal outcome in severe preeclampsia at 24 to 36 weeks' gestation: does the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome matter? Am J Obstet Gynecol 1999; 180:221225.
  • 14
    Visser W, Wallenburg HC: Maternal and perinatal outcome of temporizing management in 254 consecutive patients with severe pre-eclampsia remote from term. Eur J Obstet Gynecol Reprod Biol 1995; 63:147154.
  • 15
    Sibai BM, Taslimi M, Abdella TN, Brooks TF, Spinnato JA, Anderson GD: Maternal and perinatal outcome of conservative management of severe preeclampsia in midtrimester. Am J Obstet Gynecol 1985; 152:3237.
  • 16
    Sibai BM, Mercer BM, Schiff E, Friedman SA: Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks' gestation: a randomized controlled trial. Am J Obstet Gynecol 1994; 171:818822.
  • 17
    Bombrys AE, Barton JR, Nowacki EA, Habli M, Pinder L, How H, Sibai BM: Expectant management of severe preeclampsia at less than 27 weeks' gestation: maternal and perinatal outcomes according to gestational age by weeks at onset of expectant management. Am J Obstet Gynecol 2008;199:247 e16.
  • 18
    Sibai BM: Evaluation and management of severe preeclampsia before 34 weeks' gestation. Am J Obstet Gynecol 2011; 205:191198.
  • 19
    Weiner CP, Kwaan HC, Xu C, Paul M, Burmeister L, Hauck W: Antithrombin III activity in women with hypertension during pregnancy. Obstet Gynecol 1985; 65:301306.
  • 20
    Maclean PS, Tait RC: Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007; 67:14291440.
  • 21
    Buller HR, Weenink AH, Treffers PE, Kahlé LH, Otten HA, ten Cate JW: Severe antithrombin III deficiency in a patient with pre-eclampsia. observations on the effect of human AT III concentrate transfusion. Scand J Haematol 1980; 25:8186.
  • 22
    Terao T, Kobayashi T, Imai N, Oda H, Karasawa T: Pathological state of the coagulatory and fibrinolytic system in preeclampsia and the possibility of its treatment with AT III concentrate. Asia-Oceania J Obstet Gynaecol 1989; 15:2532.
  • 23
    Nakabayashi M, Asami M, Nakatani A: Efficacy of antithrombin replacement therapy in severe early-onset preeclampsia. Semin Thromb Hemost 1999; 25:463466.
  • 24
    Kobayashi T, Terao T, Ikenoue T, Sameshima H, Nakabayashi M, Kajiwara Y, Maki M: Treatment of severe preeclampsia with antithrombin concentrate: results of a prospective feasibility study. Semin Thromb Hemost 2003; 29:645652.
  • 25
    Kobayashi T, Terao T, Ikenoue T, Kajiwara Y, Maki M: Antithrombin therapy for preeclampsia. Biomed Prog 2003; 16:7277.
  • 26
    Kobayashi T: Antithrombin abnormalities and perinatal management. Curr Drug Targets 2005; 6:559566.
  • 27
    Maki M, Kobayashi T, Terao T, Ikenoue T, Satoh K, Nakabayashi M, Sagara Y, Kajiwara Y, Urata M: Antithrombin therapy for severe preeclampsia: results of a double-blind, randomized, placebo-controlled trial. BI51.017 Study Group. Thromb Haemost 2000; 84:583590.
  • 28
    Paternoster DM, Fantinato S, Manganelli F, Milani M, Nicolini U, Girolami A: Efficacy of AT in pre-eclampsia: a case-control prospective trial. Thromb Haemost 2004; 91:283289.