For more than a decade, it has been known that maternally administered dexamethasone to enhance fetal lung function in patients with severe preeclampsia diagnosed as hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome has unexpected benefits for the amelioration of maternal disease.1–3 The first prospective randomized clinical trial of this intervention in postpartum patients with HELLP syndrome was undertaken during 1991–1992 at the University of Mississippi Medical Center in Jackson.2 Patients who received intravenous dexamethasone had a more rapid puerperal normalization of HELLP syndrome disease parameters than control patients, including platelet count, aspartate aminotransferase (AST), serum lactate dehydrogenase (LDH), blood pressure, and urinary output. On the basis of these findings from randomized clinical trials for antepartum and postpartum patients in 1993, practice guidelines for patients with HELLP syndrome in our tertiary care center were revised to routinely incorporate high-dose potent glucocorticoids in patient management. Our clinical experience and that of other maternal–fetal medicine units with similar protocols has been reviewed recently.4 Most recently, we have shown that since 1993 significant maternal morbidity is reduced and disease progression arrested if high-dose intravenous dexamethasone is administered antepartum and postpartum to patients with HELLP syndrome.5,6
If high-dose intravenous dexamethasone is a beneficial therapy for mothers with severe preeclampsia/HELLP syndrome, could these benefits be realized similarly in postpartum patients with severe preeclampsia that is not expressed as HELLP syndrome? Anticipated benefits of potent glucocorticoids as part of the therapeutic armamentarium include better blood pressure control with less need for antihypertensive agents, more rapid onset of diuresis, a shorter time of intensive surveillance, less risk to develop delayed HELLP syndrome, less frequent and less severe cardiopulmonary or renal compromise, shorter hospitalization, and less hospital cost.
Consequently, the present randomized and blinded clinical trial was undertaken to estimate whether high-dose intravenous dexamethasone given adjunctively postpartum to patients with severe preeclampsia absent evidence of HELLP syndrome, compared with control patients not receiving this intervention, could be shown to have a global maternal benefit with less disease severity, less hypertension and need for antihypertensive therapy, and more rapid maternal recovery without causing adverse consequences.
MATERIALS AND METHODS
All patients diagnosed with severe preeclampsia or eclampsia admitted to the University of Mississippi Medical Center/Wiser Hospital for Women and Infants in Jackson between April 2000 and January 2003 were evaluated for inclusion in this randomized, double-blinded placebo-controlled clinical trial that was approved by the University's Institutional Review Board. The American College of Obstetricians and Gynecologists criteria were required for the diagnosis of severe preeclampsia7; patients were excluded if their pregnancies were complicated by insulin-dependent diabetes mellitus, if they had recent or current use of corticosteroids for maternal disease such as systemic lupus erythematosus, they had evidence of acute renal failure or renal insufficiency caused by renal or obstetric causes, or if they exhibited complete criteria for HELLP syndrome (platelet count 100,000/μL, AST and/or alanine transaminase ≥70 IU/L, and LDH ≥600 IU/L).
After written informed consent was obtained, patients meeting inclusion criteria were randomly assigned to receive either intravenous dexamethasone sodium phosphate or an equal volume of placebo. Randomization via computer-generated randomization sequence and assignment to treatment group was performed via personnel in the University Pharmacy Research Group. Once a study candidate was identified and approved by the physician in the labor/delivery unit, a phone call to the University Pharmacy Research Group was placed and the assignment made by their staff. Clinical staff was blinded to patient group assignment; infusion sets sent by the University Pharmacy Research Group were identical for treatment and control patients. Patients assigned to the dexamethasone group by the University Pharmacy Research Group received 2 doses of 10 mg followed by 2 doses of 5 mg every 12 hours for 4 total doses at 0, 12, 24, and 36 hours postpartum. A comparable volume of saline in an identical infusion set was sent by the University Pharmacy Research Group for administration to controls on an identical infusion schedule.
Study subjects remained in the labor/delivery/recovery unit for the first 48 hours postpartum to assure timely receipt of study drug and to complete study assessments. Vital signs, including blood pressure, hourly urine output, hourly assessment of symptoms and cardiopulmonary status, and twice-daily evaluations of laboratory parameters (urinary protein, platelet count, AST, alanine transaminase, total serum LDH, total bilirubin, uric acid, blood urea nitrogen, and creatinine) were recorded for analysis. All patients, regardless of group assignment or clinical parameters, received magnesium sulfate by continuous infusion for the first 24 hours postpartum. Antihypertensive therapy was given postpartum to a patient in either group if there was recorded a single systolic (>160 mm Hg) and/or diastolic (>110 mm Hg) blood pressure elevation, or if systolic blood pressure was greater than 150 mm Hg and/or a diastolic blood pressure was greater than 100 mm Hg on 2 or more occasions, especially if accompanied by headache or sign of persisting severe disease.
Disease severity and duration were compared. Disease severity was assessed by extent of laboratory abnormalities (parameters of renal function, platelet count depression, elevations in LDH and transaminases, peak serum uric acid), clinical parameters (urinary output, blood pressure), need for antihypertensive therapy, development of any maternal morbidity, and length of hospitalization.
Indicated antihypertensive therapy was used as the primary parameter of disease severity to estimate the size of the study population. Power analysis indicated a need for 38 patients to be enrolled into each group to observe a 30% difference assuming the incidence of patients requiring antihypertensive medications to be 40% (total patients = 76). Although the power analysis was based on a single primary end point, we considered the sample size too small for some of the secondary end points of interest (urine output, blood pressure, changes in laboratory values, length of hospitalization, so the number was doubled, ie, total patients = 152). Study data were analyzed using the χ2 and Student t tests and analysis of variance. For statistical analysis, the 2 groups of patients were compared with the alpha controlled at .05 with P < .05 considered significant.
Data from 157 patients with severe preeclampsia who met inclusion and exclusion criteria and were properly consented to participate in this investigation are reported. Seventy-seven women constitute the group randomized to receive dexamethasone; 80 others, ie, the control group, received placebo.
No significant differences existed between the control and dexamethasone groups with regard to demographic parameters, diagnostic criteria for severe preeclampsia, and pre-enrollment laboratory abnormalities (Table 1). Although patients receiving dexamethasone had fewer returns to labor/delivery/recovery for uncontrolled hypertension compared with control patients, overall no significant differences existed in the primary outcome variable of need for additional antihypertensive therapy or any of the listed secondary outcome variables between groups, as shown in Table 2.
Although statistically significant differences in laboratory values were observed between groups at various times during the trial (lower LDH at 12 hours in the dexamethasone group, lower AST at 24 hours and higher platelet count at 36 and 48 hours in the dexamethasone group), these difference were not clinically significant. No differences in blood urea nitrogen, serum creatinine, or serum uric acid were noted between groups. Finally, as shown in Figures 1 and 2, no evidence was found to indicate that dexamethasone had any consistent beneficial or adverse effect on urine output or mean arterial blood pressure.
Two study subjects in the control group subsequently developed complicated HELLP syndrome. Consequently, they were withdrawn from the trial, unblinded, found to be receiving placebo, and emergently intervened upon successfully with high-dose intravenous dexamethasone. The first patient was a primipara who underwent classical cesarean delivery at 30 weeks of gestation. Approximately 18–24 hours postpartum, she reported the sudden onset of severe epigastric pain; laboratory analysis revealed LDH greater than 10,000 IU/L, AST greater than 900 IU/L, and a platelet count of 36,000/μL. The second patient developed HELLP syndrome associated with significant thrombocytopenia and incisional bleeding. Both patients were eliminated from the data analysis for the control group. No patient in the dexamethasone group developed HELLP syndrome.
In contrast to the reported experience in patients with HELLP syndrome,2,5 a significant and consistently beneficial impact of dexamethasone on 1 or more parameters of severe preeclampsia disease severity was not observed in this investigation. This was unexpected because several lines of evidence give reasonable foundation to the possibility that intravenous dexamethasone might be an effective adjunct for the treatment of patients with severe preeclampsia because it is a condition with inflammatory dysfunction of the endothelium.8,9 Human glucocorticosteroid receptors in endothelial cells have been shown to regulate leukocyte adhesion to endothelial cells and expression of certain adhesion molecules.10 Dexamethasone has been shown to repress the production of certain vasoactive prostaglandins11 and enhance vasodilatory prostaglandin12 production in other systems. In addition, dexamethasone appears to suppress cytokine production in the placenta13 and could decrease plasma catecholamines11 and/or suppress sympathetic activation.14
The lack of a clearly demonstrable impact of dexamethasone on mean arterial pressure and urinary output in postpartum patients with severe preeclampsia, although reported to occur in patients with HELLP syndrome, could be secondary to differences in pathophysiology such as a qualitative and/or quantitative differences in placental or peripheral cytokine activation,15 probably in combination with cellular activation and cell-mediated injury.16,17 Recently, patients with preeclampsia were shown to have elevated placental soluble fms-like tyrose kinase 1 (sFlt1), which antagonizes vascular endothelial growth factor (VEGF) and platelet growth factor (PGF).18 Decreases in maternal serum concentrations of both VEGF and PGF have been demonstrated in mothers with severe preeclampsia.19 A decrease in the systemic levels of VEGF and PGF has been shown in vitro to result in endothelial dysfunction, and administration of sFlt1 to pregnant rats has been shown to induce hypertension, proteinuria, and glomerular endotheliosis.18
An effective therapy to restore systemic VEGF and PGF concentrations to their high pregnancy levels might be beneficial for patients with severe preeclampsia. Dexamethasone can increase VEGF, but the action may take some time to occur inasmuch as its administration to preterm neonates required more than 72 hours to produce an increase in VEGF levels as measured from deep pulmonary lavage samples compared with control patients.20 Thus, it is possible that the dose and duration of dexamethasone administration in the present investigation was insufficient to produce a measurable change in maternal blood pressure or urinary output or that dexamethasone does not work pathophysiologically to induce a positive VEGF response at all in patients with preeclampsia.
Not all of the patients with preeclampsia in the study by Maynard and collaborators18 had significantly elevated sFlt1 levels, leading the authors to postulate that other factors likely are involved in the pathogenesis of some patients with preeclampsia. Thrombocytopenia was not observed in the sFlt1-treated animals from the studies of Maynard and collaborators, yet it was invariably present in patients with HELLP syndrome. Thus, it is possible that other factors than sFlt1 are involved in the pathogenesis of HELLP syndrome and that dexamethasone impacts these factor(s) to exert its beneficial affects. The unavailability of serum samples from the patients involved in our investigation prevents assay of VEGF, PlGF, sFlt1, and potential others to further study this issue. If excess sFlt1 plays a causative role in most patients with severe preeclampsia, we speculate that it likely is not responsive to dexamethasone administration. Fischer and colleagues21 have shown that vasodilatory reactivity is reduced in preeclampsia but not in HELLP syndrome, which suggests different alterations of the vasculature that might respond differently to interventions such as dexamethasone.
The finding in the present study that neither urine output nor mean arterial pressure was favorably impacted by dexamethasone, coupled with the observations in the Maynard study that infused sFlt1 to pregnant rats caused both hypertension and renal dysfunction,18 suggests that the 2 parameters of preeclampsia are closely related as to pathophysiology and would be expected to respond similarly. Both were improved in a prior investigation of patients with HELLP syndrome.2 Qiu and Baylis22 recently summarized evidence in rat studies in which higher blood pressure and renal dysfunction resulted from dexamethasone administration to unstressed conscious rats.
Standardization of the dose of dexamethasone for the patient to receive either 10 mg or 5 mg as 4 consecutive intravenous doses might have prevented us witnessing a reduction in mean arterial blood pressure with a lower dose. In the reduced uterine artery perfusion pressure (RUPP) animal model (rat) of preeclampsia, dexamethasone has been shown to have a variable effect on blood pressure depending upon dosage (Rose C, Bennett W, Thigpen B, Cockrell K, Morrison J, Martin J, et al. Effects of repeated steroid dosing protocols in a rat model of preeclampsia [abstract]. Am J Obstet Gynecol 2003;189:S94). However, the same dosages were used in this investigation as were administered to patients with HELLP in an earlier investigation during which a blood pressure reduction and an increase in urine output was recorded.2
Only 2 patients in the trial developed HELLP syndrome, both of whom were in the control group. One of these patients became seriously ill very quickly with severe, progressively worsening, writhing epigastric pain associated with a dramatic elevation in total serum LDH and aspartate aminotransferase. Intravenously infused magnesium sulfate was administered continuously during this episode; narcotic analgesics given systemically failed to substantially improve her pain. Because of our concern that this patient would develop hepatic hematomas and/or rupture her liver given the grossly abnormal laboratory indices suggesting hemolysis, hepatic dysfunction, and thrombocytopenia, the patient was pulled from the trial and immediately infused with 10 mg of intravenous dexamethasone followed by 3 subsequent administrations. Dramatic and rapid resolution of symptomatology and laboratory abnormalities followed quickly thereafter. The other patient's course was less dramatic, with increased bleeding associated with progressively worse thrombocytopenia, both of which quickly responded similarly to the initiation of dexamethasone rescue therapy.
We conclude that postpartum dexamethasone administration to patients with severe preeclampsia absent HELLP syndrome does not have an apparent positive effect on maternal outcome or hasten resolution of the disease process. The relatively infrequent development of delayed postpartum HELLP syndrome in a small number of patients with severe preeclampsia does not warrant routine prevention via prophylactic high-dose corticosteroid administration.
1. Magann EF, Martin RW, Isaacs JD, Blake PG, Morrison JC, Martin JN Jr. Corticosteroids for the enhancement of fetal lung maturity: impact on the gravida with preeclampsia and HELLP syndrome. Aust NZ J Obstet Gynaecol 1993;33:127–31.
2. Magann EF, Perry KG Jr, Meydrech EF, Harris RL, Chauhan SP, Martin JN Jr. Postpartum corticosteroids: accelerated recovery from HELLP syndrome. Am J Obstet Gynecol 1994;171:1154–8.
3. Martin JN Jr, Rinehart BK, May WL, Magann EF, Terrone DA, Blake PG. The spectrum of severe preeclampsia: comparative analysis by HELLP syndrome classification. Am J Obstet Gynecol 1999;180:1373–84.
4. Martin JN Jr, Magann EF, Isler CM. HELLP syndrome: the scope of disease and treatment. In: Belfort MA, Thornton S, Saade GRM, editors. Hypertension in pregnancy. New York (NY): Marcel Dekker; 2003. p. 141–88.
5. Martin JN Jr, Perry KG Jr, Blake PG, May WA, Moore A, Robinette L. Better maternal outcomes are achieved with dexamethasone therapy for postpartum HELLP syndrome. Am J Obstet Gynecol 1997;177:1011–7.
6. Martin JN Jr, Thigpen BD, Rose CH, Cushman J, Moore A, May WL. Maternal benefit of high-dose intravenous corticosteroid therapy for HELLP syndrome. Am J Obstet Gynecol 2003;189:830–4.
7. Diagnosis and management of preeclampsia and eclampsia. ACOG Practice Bulletin No. 33. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002;99:159–67.
8. Roberts JM. Endothelial dysfunction in preeclampsia [review]. Semin Reprod Endocrinol 1998;16:5–15.
9. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia [review]. Lancet 2001;357:53–56.
10. Cronstein BN, Kimmel SC, Levin RI, Martiniuk F, Weissmann G. A mechanism for the anti-inflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci USA 1992;89:9991–5.
11. Kallio J, Karlsson R, Toppari J, Helminen T, Scheinin M, Kero P. Antenatal dexamethasone treatment decreases plasma catecholamine levels in preterm infants. Pediatr Res USA 1998;43:801–7.
12. Zakar T, Hirst JJ, Mijovic JE, Olson DM. Glucocorticoids stimulate the expression of prostaglandin endoperoxide H synthase-2 in amnion cells. Endocrinology 1995;136:1610–9.
13. Rosen T, Krikun G, Ma Y, Wang EY, Lockwood CJ, Guller S. Chronic antagonism of nuclear factor-kappa B activity in cytotrophoblasts by dexamethasone: a potential mechanism for anti-inflammatory action of glucocorticoids in human placenta. J Clin Endocrinol Metab 1998;83:3647–52.
14. Randin D, Vollenweider P, Tappy L, Jequier E, Nicod P, Scherrer U. Suppression of alcohol-induced hypertension by dexamethasone. N Engl J Med 1995;332:1733–7.
15. Conrad KP, Benyo DF. Placental cytokines and the pathogenesis of preeclampsia [review]. Am J Reprod Immunol 1997;37:240–9.
16. Haeger M, Unander M, Norder-Hansson B, Tylman M, Bengtsson A. Complement, neutrophil and macrophage activation in women with severe preeclampsia and the syndrome of hemolysis, elevated liver enzymes and low platelet count. Obstet Gynecol 1992;79:19–26.
17. Halim A, Kanayama N, El Maradny E, Maehara K, Takahashi A, Nosaka K, et al. Immunohistological study in cases of HELLP syndrome (hemolysis, elevated liver enzymes and low platelets) and acute fatty liver of pregnancy. Gynecol Obstet Invest 1996;41:106–12.
18. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension and proteinuria in preeclampsia. J Clin Invest 2003;111:649–58.
19. Livingston JC, Chin R, Haddad B, McKinney ET, Ahokas R, Sibai BM. Reductions of vascular endothelial growth factor and placental growth factor concentrations in severe preeclampsia. Am J Obstet Gynecol 2000;183:1554–7.
20. D'Angio CT, Maniscalco WM, Ryan RM, Avissar NE, Basevegowda K, Sinkin RA. Vascular endothelial growth factor in pulmonary lavage fluid from premature infants: effect of age and postnatal dexamethasone. Biol Neonate 1999;76:266–73.
21. Fischer T, Schneider MP, Schobel HP, Heusser K, Langenfeld M, Schmieder RE. Vascular reactivity in patients with preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Am J Obstet Gynecol 2000;183:1489–94.
22. Qiu C, Baylis C. Dexamethasone worsens nitric oxide inhibition-induced hypertension and renal dysfunction. Am J Hypertens 2000;13:1097–102.