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HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome: The benefit of corticosteroids
HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome: The benefit of corticosteroids Matthew J. Tompkins, MD, and Siva Thiagarajah, MD Charlottesville, Virginia OBJECTIVE: The purpose of this study was to determine the effect of corticosteroids on platelet counts and liver functions in women with pregnancies complicated by the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. STUDY DESIGN: The study group consisted of 93 patients between 24 and 34 weeks’ gestation diagnosed with HELLP syndrome. All were given intramuscular injections of either betamethasone or dexamethasone. The 3 most common regimens used were 12 mg of intramuscular betamethasone administered twice 12 hours apart, 12 mg of intramuscular betamethasone administered twice 24 hours apart, and 6 mg of intramuscular dexamethasone administered 4 times 6 hours apart. Precorticosteroid and postcorticosteroid platelet counts and liver function test results were compared. The differences in improvement in hematologic abnormalities among the 3 corticosteroid regimens were also analyzed. RESULTS: The hematologic abnormalities seen in the 93 patients with HELLP syndrome improved after the administration of corticosteroids. The platelet count increased by 23.3 × 103/µL (P < .001). A statistically significant decrease was seen in liver enzyme levels. The alanine aminotransferase decreased by 31.6 IU/L, the aspartate aminotransferase decreased by 52.1 IU/L, and the alkaline phosphatase decreased by 7.6 IU/L. Of the 3 regimens used, 2 doses of 12 mg of intramuscular betamethasone given every 12 hours improved the liver function to the greatest degree. CONCLUSIONS: This study demonstrates that corticosteroids produce a significant improvement in the hematologic abnormalities associated with HELLP syndrome. Two doses of betamethasone given 12 hours apart was the most effective corticosteroid regimen. (Am J Obstet Gynecol 1999;181:304-9.)
Key words: HELLP syndrome, corticosteroids, severe preeclampsia, anesthesia, growth restriction
The HELLP syndrome is a form of severe preeclampsia that is characterized by hemolysis, elevated liver functions, and low platelet counts.1 It is a disease isolated to pregnancy and is associated with an increased risk of perinatal morbidity and mortality.2-4 The etiology of HELLP syndrome is unknown and, apart from delivery, few treatment strategies have been found to be beneficial in stabilizing or improving the disease. Conservative management with bed rest, plasma expansion, and intensive maternal and fetal monitoring have provided temporary stabilization.5 Several small studies and case reports have observed that the administration of corticosteroids, given with the primary objec-
From the Department of Obstetrics and Gynecology, University of Virginia. Presented at the Sixty-first Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, White Sulfur Springs, West Virginia, January 23-26, 1999. Reprint requests: Matthew J. Tompkins, MD, 213 Wiggington Rd, Lynchburg, VA 24502. Copyright © 1999 by Mosby, Inc. 0002-9378/99 $8.00 + 0 6/6/99899
304
tive of accelerating fetal lung maturity, produced improvement in some of the laboratory abnormalities associated with HELLP syndrome.2, 6-9 The beneficial effect of corticosteroids in HELLP syndrome was first published in 1984 by Thiagarajah et al2 at the University of Virginia. They observed improvement in laboratory abnormalities in 5 patients with HELLP syndrome who received corticosteroids. Since 1984, research on this aspect of preeclampsia has been limited. In 1993, Magann et al10 published the largest study to date. They studied 27 patients with HELLP syndrome and reported that a larger percentage of those who received corticosteroids had improvement in hematologic abnormalities, compared with those who did not receive corticosteroids. However, the degree of improvement was not quantified. Several smaller case studies also demonstrated the benefits of corticosteroids in HELLP syndrome.6-8, 11 Additionally, corticosteroids given to these patients in the postpartum period have accelerated their recovery.12, 15 The purpose of this study was to quantify the beneficial effects of corticosteroids in patients with HELLP syn-
Tompkins and Thiagarajah 305
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Fig 1. Effect of corticosteroids on HELLP syndrome. Average precorticosteroid and postcorticosteroid hematologic values are shown for all patients (n = 93). PLT, Platelet count (×103/µL); ALT, alanine aminotransferase (international units per liter); AST, aspartate aminotransferase (international units per liter); ALP, alkaline phosphatase (international units per liter); LDH, lactate dehydrogenase (international units per liter × 10).
Fig 2. Effect of corticosteroids on HELLP syndrome. Precorticosteroid and postcorticosteroid hematologic values for patients with diagnosis of HELLP before administration of corticosteroids are shown (n = 52). PLT, Platelet count (×103/µL); ALT, alanine aminotransferase (international units per liter); AST, aspartate aminotransferase (international units per liter); ALP, alkaline phosphatase (international units per liter); LDH, lactate dehydrogenase (international units per liter × 10).
drome and to determine which corticosteroid regimen improves the laboratory abnormalities to the greatest degree.
after completion of the entire corticosteroid regimen. Samples for determination of the laboratory values designated before administration of corticosteroids were drawn within the 12 hours preceding the administration of corticosteroids, and samples for the postcorticosteroid values were drawn between 6 and 18 hours after completion of the particular corticosteroid regimen. Statistical analyses were performed with the SPSS statistics program. Precorticosteroid and postcorticosteroid platelet counts and liver function test results were compared by using the paired samples t test. The different corticosteroid regimens were compared by using analysis of variance. A comparison of 2 variables with a P value of < .05 and a 95% confidence interval that did not include the numeral 1 was considered statistically significant. Anesthesia type and anesthesia-related complications were analyzed. The type of anesthesia used was selected by the attending anesthesiologist on the basis of the maternal platelet count. The complications related to anesthesia were recorded.
Material and methods The study group consisted of 93 patients with HELLP syndrome, as defined by The American College of Obstetricians and Gynecologists,1 who were managed between 24 and 36 weeks’ gestation. All patients were given intramuscular injections of corticosteroids to enhance fetal lung maturity, and all infants were delivered within 48 hours of completion of the corticosteroid therapy. The 3 corticosteroid regimens used were as follows: (1) 2 doses of 12 mg of intramuscular betamethasone given 24 hours apart (n = 27), (2) 2 doses of 12 mg of intramuscular betamethasone given 12 hours apart (n = 44), and (3) 4 doses of 6 mg of intramuscular dexamethasone given 6 hours apart (n = 12). The remaining 10 patients received 1 dose of 12 mg of betamethasone or 1, 2, or 3 doses of 6 mg of dexamethasone. The selection of the corticosteroid regimen was determined by the attending obstetrician and in accordance with the availability of the corticosteroids. Fifty-two patients had laboratory evidence of HELLP syndrome before the administration of corticosteroids. The other 41 patients had preeclampsia with borderline hematologic values before they were given corticosteroids. These patients later met the criteria for HELLP syndrome, either before or after delivery. On admission, all patients were started on bed rest, given intravenous fluids, and started on magnesium sulfate. Management included fluid boluses for decreased urine output and antihypertensive agents for diastolic blood pressures >105 mm Hg. Platelet counts and liver function test results were obtained before the administration of corticosteroids and
Results The demographic data are displayed in Table I. The majority of the patients were young, white, and primiparous and were delivered of their infants by cesarean. The gestational ages ranged from 24 to 34 weeks. The majority of the patients received 12 mg of intramuscular betamethasone given twice 12 hours apart. Fig 1 shows the improvement in hematologic abnormalities in HELLP syndrome after the administration of corticosteroids. The platelet counts increased by an average of 23.3 × 103/µL (P < .001; confidence interval, 14.532.0). The liver function test results also improved, with the alanine aminotransferase decreasing by 31.6 IU/L (P = .002; confidence interval, 11.6-51.6), the aspartate
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Table I. Study group characteristics (N = 93)
Fig 3. Effect of different corticosteroid regimens on hematologic abnormalities in patients with HELLP syndrome (n = 83). PLT, Platelet count (×103/µL); ALT, alanine aminotransferase (international units per liter); AST, aspartate aminotransferase (international units per liter); ALP, alkaline phosphatase (international units per liter); LDH, lactate dehydrogenase (international units per liter × 10).
aminotransferase decreasing by 52.1 IU/L (P < .001; confidence interval, 29.1-75.1), the alkaline phosphatase decreasing by 7.6 IU/L (P = .004; confidence interval, 2.512.7), and the lactate dehydrogenase decreasing by 46.2 IU/L (not statistically significant). Fig 2 compares the precorticosteroid and postcorticosteroid values in the subgroup of patients who had the diagnosis of HELLP syndrome at admission. The improvement in laboratory abnormalities was even more evident in this group. The platelet counts increased by 32.8 × 103/µL (P < .001; confidence interval, 23.2-42.4), the alanine aminotransferase decreased by 80.4 IU/L (P = .001; confidence interval, 36.2-124.5), the aspartate aminotransferase decreased by 104.2 IU/L (P < .001; confidence interval, 65.3-143.0), the alkaline phosphatase decreased by 11.3 IU/L (P = .003; confidence interval, 4.1-18.4), and the lactate dehydrogenase decreased by 146 IU/L (not statistically significant). Of the 52 patients diagnosed with HELLP syndrome on admission, 45 had improvement in platelet counts after the administration of corticosteroids. This increase ranged from 2 × 103/µL to 128 × 103/µL. Only 7 patients did not benefit. The platelet counts of 22 of these patients completely normalized (>150 × 103/µL) after receiving corticosteroids. Despite not having the laboratory abnormalities necessary for the diagnosis of HELLP syndrome, 31 of the 41 patients with preeclampsia on admission had an increase in platelet counts after the administration of corticosteroids. The maximum increase in this group was 123 × 103/µL. These patients later met the laboratory criteria for HELLP syndrome, either before (n = 28) or after (n = 13) delivery.
Demographics Average age (y) Average parity Average length of stay (d) Average gestational age (wk) Race White African American Asian Other Mode of delivery Cesarean Vaginal Corticosteroid regimen Betamethasone: 2 doses, 12 mg, 12 h apart Betamethasone: 2 doses, 12 mg, 24 h apart Dexamethasone: 4 doses, 6 mg, 6 h apart Other
25.0 1.3 9.3 29.7 71 19 1 2 88 5 44 27 12 10*
*Includes 1 dose of betamethasone and 1, 2, or 3 doses of dexamethasone.
Table II. Anesthesia-related complications Anesthesia type
No.
Complications
General Regional Platelet count >150 × 103/µL Platelet count 100-150 × 103/µL Platelet count 50-100 × 103/µL Platelet count <50 × 103/µL
43 51 17 23 9 2
5 1 0 1* 0 0
*Maternal hypotension and subsequent fetal bradycardia after the intravascular injection of anesthetic.
The changes in hematologic abnormalities were compared among the 3 corticosteroid regimens. The precorticosteroid to postcorticosteroid change in the laboratory values for each of the regimens is depicted in Fig 3. The increase in platelet count was statistically significant with each corticosteroid schedule. Although dexamethasone appears to improve platelet counts to a greater extent than either betamethasone regimen, statistical analysis showed the improvement was equal among the 3 regimens. The improvement in liver function test results was only statistically significant with the 2 betamethasone regimens. Betamethasone given every 12 hours for 2 doses was the most beneficial at improving the liver enzymes. With this regimen, the alanine aminotransferase decreased by 37.6 IU/L (P = .016; confidence interval, 7.567.7), the aspartate aminotransferase decreased by 61.4 IU/L (P = .003; confidence interval, 22.8-100.0), and the alkaline phosphatase decreased by 11.8 IU/L (P = .003; confidence interval, 4.3-19.4). Birth weights were recorded and compared to the table of the standards of growth for each gestational age of Brenner et al.16 The percentage of newborns found to be growth-restricted, as defined by a weight of
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26.8% of the newborns of the patients with HELLP syndrome. In 63.4% the weights were <25th percentile. Anesthesia-related complications are listed in Table II. The majority of the complications occurred with general anesthesia. The complications in the 5 patients included maternal hypotension, pulmonary edema, maternal hypoxia, and admission to the intensive care unit for respiratory complications. Epidural and spinal anesthesia, which was achieved in patients with maternal thrombocytopenia, is also illustrated. A total of 34 patients with a platelet count of <150,000 received regional anesthesia. Only 1 patient in this group had a complication. This was an episode of maternal hypotension with subsequent fetal bradycardia immediately after the placement of an epidural. No patients had epidural or spinal site bleeding, hematomas, or abscesses. The bleeding times were recorded in 25 patients. Fifteen of these patients had at least one abnormal value (>7.5 minutes). There was no correlation between the bleeding times and platelet counts in these patients. Of the 52 patients admitted with HELLP syndrome, 40 had prothrombin times and partial thromboplastin times measured on admission. Despite abnormal platelet counts, all of the prothrombin times and partial thromboplastin times were normal. Comment Corticosteroids clearly improve the hematologic abnormalities associated with HELLP syndrome.2, 8, 10 Our results have quantified this improvement in platelet counts and liver functions and have confirmed the qualitative improvement reported in other studies. The improvement in the laboratory values in the 52 patients who were diagnosed with HELLP syndrome at the time of admission is most clinically relevant if corticosteroids were to be used for the treatment of HELLP. The remaining 41 patients were admitted with the diagnosis of preeclampsia, and although HELLP eventually developed in these patients during their hospital stay, most of them had an increase in platelet count after the administration of corticosteroids as well. Our patients were delivered of their infants within 48 hours of completion of corticosteroid therapy. This approach was adopted because the abnormalities in platelet counts and liver functions were noted to recur after completion of therapy. The platelet counts decreased by a mean of 46.3 × 103/µL (P < .001) within 48 hours after the completion of the corticosteroid regimen. It is yet to be determined whether extended use of corticosteroids would be beneficial in maintaining a stable state to allow prolongation of the pregnancy. Corticosteroids do not improve alkaline phosphatase and lactate dehydrogenase to as great a degree as the transaminases (alanine aminotransferase and aspartate aminotransferase). The smaller decrease in alkaline phos-
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phatase may be accounted for by the fact that half of the serum alkaline phosphatase is produced by the placenta during the last trimester. Lactate dehydrogenase is nonspecific and may not be the most accurate means of assessing the effects of corticosteroids on HELLP syndrome. Of the 3 corticosteroid regimens studied, 12 mg of betamethasone given every 12 hours was the most effective in reversing the laboratory abnormalities associated with HELLP syndrome. This may be accounted for by the fact that betamethasone is 1.25 times more potent than dexamethasone.17 Although dexamethasone did not appear to produce as significant an improvement as betamethasone, the number of patients who received dexamethasone was relatively small. Further studies may be designed to compare larger, more frequent, and prolonged dosages of corticosteroids, including corticosteroids that cross the placenta less efficiently, such as prednisone. Although fetal lung maturity may not be a problem in patients presenting after 34 weeks’ gestation, the use of corticosteroids may be valuable in stabilizing the maternal condition before delivery in these patients as well. The improvement in HELLP syndrome seen with corticosteroids may prove beneficial in many ways. It may allow the time required for corticosteroids to accelerate fetal lung maturity; delay delivery to achieve maternal hemodynamic stabilization through volume expansion, blood pressure control, or central monitoring, which would potentiate a safer delivery or transportation to a tertiary care center; and increase platelet counts to allow the possible use of regional anesthesia. Anecdotal reports exist in the literature supporting the use of general anesthesia in patients with severe preeclampsia and HELLP syndrome.18, 19 Our study illustrates the safe use of regional anesthesia in patients with HELLP syndrome. When the platelet count rose above 100 × 103/µL in response to the corticosteroids, regional anesthesia was used safely. Although there were only 11 patients with platelet counts <100 × 103/µL, no complications were noted in this group. The type of anesthesia was selected on the basis of the maternal platelet count. The lack of a correlation between platelet counts and bleeding times that we observed has also been reported by others.20, 21 Therefore the bleeding time should not be used in the selection of the type of anesthesia. In summary, corticosteroids improve the laboratory abnormalities associated with HELLP syndrome. Twelve milligrams of intramuscular betamethasone given every 12 hours is the most effective regimen to be used for the treatment of HELLP. The utilization of corticosteroids in patients with HELLP syndrome confers maternal benefits in addition to accelerating lung maturity in the fetus. For this purpose, consideration should be given to the use of corticosteroids even in patients presenting after 34 weeks’ gestation.
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REFERENCES
1. American College of Obstetricians and Gynecologists. Hypertension in pregnancy. Washington: The College; 1996. Technical Bulletin No.: 219. 2. Thiagarajah S, Bourgeois FJ, Harbert GM, Caudle MR. Thrombocytopenia in preeclampsia: associated abnormalities and management principles. Am J Obstet Gynecol 1984;150:1-7. 3. Geary M. The HELLP syndrome. Br J Obstet Gynaecol 1997;104:887-91. 4. Romero R, Mazor M, Lockwood CJ, Emamian M, Belanger KP, Hobbins JC, et al. Clinical significance, prevalence and natural history of thrombocytopenia in pregnancy-induced hypertension. Am J Perinat 1989;6:32-8. 5. Sibai BM, Frangieh AY. Management of severe preeclampsia. Curr Opin Obstet Gynecol 1996;8:110-3. 6. Clark SL, Phelan JR, Allen SH, Golde SR. Antepartum reversal of hematologic abnormalities associated with the HELLP syndrome. J Reprod Med 1986;31:70-2. 7. Heyborne KD, Burke MS, Porreco RP. Prolongation of premature gestation in women with hemolysis, elevated liver enzymes and low platelets. J Reprod Med 1990;35:53-7. 8. Magann EF, Martin RW, Isaacs JD, Blake PG, Morrison JC, Martin JN. Corticosteroids for the enhancement of fetal lung maturity: impact on the gravida with preeclampsia and HELLP syndrome. Aust N Z J Obstet Gynaecol 1993;33:127-30. 9. Magann EF, Graves GR, Roberts WE, Blake PG, Morrison JC, Martin JN. Corticosteroids for enhanced fetal lung maturation in patients with HELLP syndrome: impact on Neonates. Aust N Z J Obstet Gynaecol 1993;33:131-5. 10. Magann EF, Bas D, Chauhan SP, Sullivan DL, Martin RW, Martin JN. Antepartum corticosteroids: disease stabilization in patients with the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP). Am J Obstet Gynecol 1994;171:1148-53. 11. Martin JN, Blake PG, Perry KG, McCaul JF, Hess LW, Martin RW. The natural history of HELLP syndrome: patterns of disease progression and regression. Am J Obstet Gynecol 1991;164:1500-11. 12. Magann EF, Perry KG, Meydrech EF, Harris RL, Chauhan SP, Martin JN. Postpartum corticosteroids: accelerated recovery from the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP). Am J Obstet Gynecol 1994;171:11548. 13. Martin JN, Perry KG, Blake PG, May WA, Moore A, Robinette L. Better maternal outcomes are achieved with dexamethasone therapy for postpartum HELLP (hemolysis, elevated liver enzymes, and thrombocytopenia) syndrome. Am J Obstet Gynecol 1997;177:1011-7. 14. Vigil-De Gracia P, Garcia-Caceres E. Dexamethasone in the postpartum treatment of HELLP syndrome. Int J Gynaecol Obstet 1997;59:217-21. 15. Yalcin OT, Sener T, Hassa H, Ozalp S, Okur A. Effects of postpartum corticosteroids in patients with HELLP syndrome. Int J Gynaecol Obstet 1998;61:141-8. 16. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth of the United States of America. Am J Obstet Gynecol 1976;126:555-64. 17. American Medical Association. Drug evaluations: annual 1992. Chicago: American Medical Association; 1992. p. 1715. 18. Donner A, Ullrich R, Kneifel W, Urak G, Hartmann T, Zimpfer M, et al. The HELLP syndrome. Acta Anaesth Scand 1997;111:165-7. 19. Grambling DR, Douglas MJ. Obstetric anesthesia and uncommon disorders. Philadelphia: WB Saunders; 1998. p. 321-2. 20. Ramanathan J, Sibai BM, Vu T, Chauhan D. Correlation between bleeding times and platelet counts in women with preeclampsia undergoing cesarean section. Anesthesiology 1989;71:188-91. 21. Schindler M, Gatt S, Isert P, Morgans D, Cheung A. Thrombocytopenia and platelet functional defects in preeclampsia: implications for regional anesthesia. Anaesth Intensive Care 1990;18:169-74.
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Discussion DR NORMAN GANT, Dallas, Texas. First, how many of the 52 patients admitted with HELLP syndrome and the 41 patients in whom it later developed did not improve with corticosteroid administration? What are the minimum and maximum values of improvement? Second, please comment on the conclusion made about the use of regional anesthesia in these patients. Subdivide the 9 patients with platelet counts <100 × l03 who underwent regional anesthesia. DR LARRY DEVOE, Augusta, Georgia. Would you comment on the fetal outcome of these pregnancies? Did you look at the neonatal outcome as a function of time from admission until delivery, and did this adversely effect the ultimate outcome? How did you measure the benefit of the corticosteroids, and what was the mechanism of action of the benefit? Do you think this benefit is at the microangiopathic level or is this due to change in endothelial activity? DR RANDALL FALLS, Roanoke, Virginia. Did you notice any difference in the clinical outcomes of the mothers in this study? Were there decreased hospital days or transfusions? Is there clinical evidence that the therapy helped the mother? DR JOHN MARSTON, Tampa, Florida. Did you notice an increased rate of infection in the mothers after cesarean delivery? Did you use your normal prophylactic antibiotics, or did you vary this in these patients? DR RAMEZ AZOURY, Norfolk, Virginia. The American College of Anesthesia has strict contraindications for epidural anesthesia, and it appears that epidural anesthesia might have been contraindicated in your patients. Would you comment on how safe you believe the use of epidural anesthesia is in patients with HELLP syndrome. DR GENE BURKETT, Miami, Florida. In our experience we have seen patients initially get better only to become worse later. Did you find that patients initially improved only to get worse? Specifically, did you see a decrease in platelet counts and an increase in liver function results after initial improvement? DR TOMPKINS (Closing). In response to Dr Gant’s first point, of the 52 patients diagnosed with HELLP syndrome on admission, 45 had improvement in the platelet count after the administration of corticosteroids. This increase ranged from 2 × 103/µL to 128 × 103/µL. Only 7 patients failed to benefit. The platelet counts of 22 of these patients completely normalized (>150 × 103/µL) after receiving corticosteroids. Despite not having the laboratory abnormalities necessary for the diagnosis of HELLP syndrome, 31 of the 41 patients with preeclampsia on admission had an increase in platelet counts after the administration of corticosteroids. The maximum increase in this group was 123 × 103/µL. These patients later met the laboratory criteria for HELLP syndrome, either before (n = 28) or after (n = l3) delivery. As to Dr Gant’s second point, this study illustrates the safe use of regional anesthesia in patients with HELLP
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syndrome. The group consisted of 23 patients with platelet counts between 100 and 150 × 103, 5 with platelet counts between 75 and 100 × 103, 4 with platelet counts between 50 and 100 × 103, and 2 with platelet counts of <50 × 103. None of these patients had complications, such as epidural site hematomas or abscesses, which have been a concern in the literature in patients with decreased platelet counts. I agree with Dr Gant that larger studies are needed to confirm the safety of regional anesthesia in patients with severe thrombocytopenia. In response to Dr Devoe, specific fetal outcomes were not addressed in this study; however, the vast majority of fetuses were admitted to the neonatal intensive care unit after delivery. The benefit of the corticosteroids was measured strictly by the improvement observed in the laboratory abnormalities associated with HELLP syndrome. The mechanism of action may be related to an increase in the prostacyclin/thromboxane ratio, which has been observed in vitro after the administration of corticosteroids. This shift may lower platelet aggregation and subsequently raise the platelet count. In response to Dr Falls, the objective of this study was to quantify the improvement in hematologic abnormalities after the administration of corticosteroids. Because
Tompkins and Thiagarajah 309
this was not a placebo-controlled trial, the clinical benefit in terms of maternal outcome, transfusions, and hospital days could not be ascertained. In response to Dr Marston, we used routine prophylactic antibiotics in these patients, typically Ancef. An increase in endometritis above baseline was not observed. The specific contraindication that was questioned by Dr Azoury dealt with use of regional anesthesia in patients with abnormal bleeding times. The type of anesthesia used was determined on the basis of platelet counts alone. Therefore all instances of regional anesthesia were in compliance with the recommendations of the American College of Anesthesia. Finally, in response to Dr Burkett, although the initial improvement was quite striking, the abnormalities in platelet counts and liver functions were noted to recur after completion of therapy. The platelet counts decreased by a mean of 46.3 × 103/µL (P < .001) within 48 hours after the completion of the corticosteroid regimen, prompting delivery. It is yet to be determined whether extended use of corticosteroids would be beneficial in maintaining a stable state to allow prolongation of the pregnancy.
Key words: HELLP syndrome, corticosteroids, severe preeclampsia, anesthesia, growth restriction
The HELLP syndrome is a form of severe preeclampsia that is characterized by hemolysis, elevated liver functions, and low platelet counts.1 It is a disease isolated to pregnancy and is associated with an increased risk of perinatal morbidity and mortality.2-4 The etiology of HELLP syndrome is unknown and, apart from delivery, few treatment strategies have been found to be beneficial in stabilizing or improving the disease. Conservative management with bed rest, plasma expansion, and intensive maternal and fetal monitoring have provided temporary stabilization.5 Several small studies and case reports have observed that the administration of corticosteroids, given with the primary objec-
From the Department of Obstetrics and Gynecology, University of Virginia. Presented at the Sixty-first Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, White Sulfur Springs, West Virginia, January 23-26, 1999. Reprint requests: Matthew J. Tompkins, MD, 213 Wiggington Rd, Lynchburg, VA 24502. Copyright © 1999 by Mosby, Inc. 0002-9378/99 $8.00 + 0 6/6/99899
304
tive of accelerating fetal lung maturity, produced improvement in some of the laboratory abnormalities associated with HELLP syndrome.2, 6-9 The beneficial effect of corticosteroids in HELLP syndrome was first published in 1984 by Thiagarajah et al2 at the University of Virginia. They observed improvement in laboratory abnormalities in 5 patients with HELLP syndrome who received corticosteroids. Since 1984, research on this aspect of preeclampsia has been limited. In 1993, Magann et al10 published the largest study to date. They studied 27 patients with HELLP syndrome and reported that a larger percentage of those who received corticosteroids had improvement in hematologic abnormalities, compared with those who did not receive corticosteroids. However, the degree of improvement was not quantified. Several smaller case studies also demonstrated the benefits of corticosteroids in HELLP syndrome.6-8, 11 Additionally, corticosteroids given to these patients in the postpartum period have accelerated their recovery.12, 15 The purpose of this study was to quantify the beneficial effects of corticosteroids in patients with HELLP syn-
Tompkins and Thiagarajah 305
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Fig 1. Effect of corticosteroids on HELLP syndrome. Average precorticosteroid and postcorticosteroid hematologic values are shown for all patients (n = 93). PLT, Platelet count (×103/µL); ALT, alanine aminotransferase (international units per liter); AST, aspartate aminotransferase (international units per liter); ALP, alkaline phosphatase (international units per liter); LDH, lactate dehydrogenase (international units per liter × 10).
Fig 2. Effect of corticosteroids on HELLP syndrome. Precorticosteroid and postcorticosteroid hematologic values for patients with diagnosis of HELLP before administration of corticosteroids are shown (n = 52). PLT, Platelet count (×103/µL); ALT, alanine aminotransferase (international units per liter); AST, aspartate aminotransferase (international units per liter); ALP, alkaline phosphatase (international units per liter); LDH, lactate dehydrogenase (international units per liter × 10).
drome and to determine which corticosteroid regimen improves the laboratory abnormalities to the greatest degree.
after completion of the entire corticosteroid regimen. Samples for determination of the laboratory values designated before administration of corticosteroids were drawn within the 12 hours preceding the administration of corticosteroids, and samples for the postcorticosteroid values were drawn between 6 and 18 hours after completion of the particular corticosteroid regimen. Statistical analyses were performed with the SPSS statistics program. Precorticosteroid and postcorticosteroid platelet counts and liver function test results were compared by using the paired samples t test. The different corticosteroid regimens were compared by using analysis of variance. A comparison of 2 variables with a P value of < .05 and a 95% confidence interval that did not include the numeral 1 was considered statistically significant. Anesthesia type and anesthesia-related complications were analyzed. The type of anesthesia used was selected by the attending anesthesiologist on the basis of the maternal platelet count. The complications related to anesthesia were recorded.
Material and methods The study group consisted of 93 patients with HELLP syndrome, as defined by The American College of Obstetricians and Gynecologists,1 who were managed between 24 and 36 weeks’ gestation. All patients were given intramuscular injections of corticosteroids to enhance fetal lung maturity, and all infants were delivered within 48 hours of completion of the corticosteroid therapy. The 3 corticosteroid regimens used were as follows: (1) 2 doses of 12 mg of intramuscular betamethasone given 24 hours apart (n = 27), (2) 2 doses of 12 mg of intramuscular betamethasone given 12 hours apart (n = 44), and (3) 4 doses of 6 mg of intramuscular dexamethasone given 6 hours apart (n = 12). The remaining 10 patients received 1 dose of 12 mg of betamethasone or 1, 2, or 3 doses of 6 mg of dexamethasone. The selection of the corticosteroid regimen was determined by the attending obstetrician and in accordance with the availability of the corticosteroids. Fifty-two patients had laboratory evidence of HELLP syndrome before the administration of corticosteroids. The other 41 patients had preeclampsia with borderline hematologic values before they were given corticosteroids. These patients later met the criteria for HELLP syndrome, either before or after delivery. On admission, all patients were started on bed rest, given intravenous fluids, and started on magnesium sulfate. Management included fluid boluses for decreased urine output and antihypertensive agents for diastolic blood pressures >105 mm Hg. Platelet counts and liver function test results were obtained before the administration of corticosteroids and
Results The demographic data are displayed in Table I. The majority of the patients were young, white, and primiparous and were delivered of their infants by cesarean. The gestational ages ranged from 24 to 34 weeks. The majority of the patients received 12 mg of intramuscular betamethasone given twice 12 hours apart. Fig 1 shows the improvement in hematologic abnormalities in HELLP syndrome after the administration of corticosteroids. The platelet counts increased by an average of 23.3 × 103/µL (P < .001; confidence interval, 14.532.0). The liver function test results also improved, with the alanine aminotransferase decreasing by 31.6 IU/L (P = .002; confidence interval, 11.6-51.6), the aspartate
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Table I. Study group characteristics (N = 93)
Fig 3. Effect of different corticosteroid regimens on hematologic abnormalities in patients with HELLP syndrome (n = 83). PLT, Platelet count (×103/µL); ALT, alanine aminotransferase (international units per liter); AST, aspartate aminotransferase (international units per liter); ALP, alkaline phosphatase (international units per liter); LDH, lactate dehydrogenase (international units per liter × 10).
aminotransferase decreasing by 52.1 IU/L (P < .001; confidence interval, 29.1-75.1), the alkaline phosphatase decreasing by 7.6 IU/L (P = .004; confidence interval, 2.512.7), and the lactate dehydrogenase decreasing by 46.2 IU/L (not statistically significant). Fig 2 compares the precorticosteroid and postcorticosteroid values in the subgroup of patients who had the diagnosis of HELLP syndrome at admission. The improvement in laboratory abnormalities was even more evident in this group. The platelet counts increased by 32.8 × 103/µL (P < .001; confidence interval, 23.2-42.4), the alanine aminotransferase decreased by 80.4 IU/L (P = .001; confidence interval, 36.2-124.5), the aspartate aminotransferase decreased by 104.2 IU/L (P < .001; confidence interval, 65.3-143.0), the alkaline phosphatase decreased by 11.3 IU/L (P = .003; confidence interval, 4.1-18.4), and the lactate dehydrogenase decreased by 146 IU/L (not statistically significant). Of the 52 patients diagnosed with HELLP syndrome on admission, 45 had improvement in platelet counts after the administration of corticosteroids. This increase ranged from 2 × 103/µL to 128 × 103/µL. Only 7 patients did not benefit. The platelet counts of 22 of these patients completely normalized (>150 × 103/µL) after receiving corticosteroids. Despite not having the laboratory abnormalities necessary for the diagnosis of HELLP syndrome, 31 of the 41 patients with preeclampsia on admission had an increase in platelet counts after the administration of corticosteroids. The maximum increase in this group was 123 × 103/µL. These patients later met the laboratory criteria for HELLP syndrome, either before (n = 28) or after (n = 13) delivery.
Demographics Average age (y) Average parity Average length of stay (d) Average gestational age (wk) Race White African American Asian Other Mode of delivery Cesarean Vaginal Corticosteroid regimen Betamethasone: 2 doses, 12 mg, 12 h apart Betamethasone: 2 doses, 12 mg, 24 h apart Dexamethasone: 4 doses, 6 mg, 6 h apart Other
25.0 1.3 9.3 29.7 71 19 1 2 88 5 44 27 12 10*
*Includes 1 dose of betamethasone and 1, 2, or 3 doses of dexamethasone.
Table II. Anesthesia-related complications Anesthesia type
No.
Complications
General Regional Platelet count >150 × 103/µL Platelet count 100-150 × 103/µL Platelet count 50-100 × 103/µL Platelet count <50 × 103/µL
43 51 17 23 9 2
5 1 0 1* 0 0
*Maternal hypotension and subsequent fetal bradycardia after the intravascular injection of anesthetic.
The changes in hematologic abnormalities were compared among the 3 corticosteroid regimens. The precorticosteroid to postcorticosteroid change in the laboratory values for each of the regimens is depicted in Fig 3. The increase in platelet count was statistically significant with each corticosteroid schedule. Although dexamethasone appears to improve platelet counts to a greater extent than either betamethasone regimen, statistical analysis showed the improvement was equal among the 3 regimens. The improvement in liver function test results was only statistically significant with the 2 betamethasone regimens. Betamethasone given every 12 hours for 2 doses was the most beneficial at improving the liver enzymes. With this regimen, the alanine aminotransferase decreased by 37.6 IU/L (P = .016; confidence interval, 7.567.7), the aspartate aminotransferase decreased by 61.4 IU/L (P = .003; confidence interval, 22.8-100.0), and the alkaline phosphatase decreased by 11.8 IU/L (P = .003; confidence interval, 4.3-19.4). Birth weights were recorded and compared to the table of the standards of growth for each gestational age of Brenner et al.16 The percentage of newborns found to be growth-restricted, as defined by a weight of
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26.8% of the newborns of the patients with HELLP syndrome. In 63.4% the weights were <25th percentile. Anesthesia-related complications are listed in Table II. The majority of the complications occurred with general anesthesia. The complications in the 5 patients included maternal hypotension, pulmonary edema, maternal hypoxia, and admission to the intensive care unit for respiratory complications. Epidural and spinal anesthesia, which was achieved in patients with maternal thrombocytopenia, is also illustrated. A total of 34 patients with a platelet count of <150,000 received regional anesthesia. Only 1 patient in this group had a complication. This was an episode of maternal hypotension with subsequent fetal bradycardia immediately after the placement of an epidural. No patients had epidural or spinal site bleeding, hematomas, or abscesses. The bleeding times were recorded in 25 patients. Fifteen of these patients had at least one abnormal value (>7.5 minutes). There was no correlation between the bleeding times and platelet counts in these patients. Of the 52 patients admitted with HELLP syndrome, 40 had prothrombin times and partial thromboplastin times measured on admission. Despite abnormal platelet counts, all of the prothrombin times and partial thromboplastin times were normal. Comment Corticosteroids clearly improve the hematologic abnormalities associated with HELLP syndrome.2, 8, 10 Our results have quantified this improvement in platelet counts and liver functions and have confirmed the qualitative improvement reported in other studies. The improvement in the laboratory values in the 52 patients who were diagnosed with HELLP syndrome at the time of admission is most clinically relevant if corticosteroids were to be used for the treatment of HELLP. The remaining 41 patients were admitted with the diagnosis of preeclampsia, and although HELLP eventually developed in these patients during their hospital stay, most of them had an increase in platelet count after the administration of corticosteroids as well. Our patients were delivered of their infants within 48 hours of completion of corticosteroid therapy. This approach was adopted because the abnormalities in platelet counts and liver functions were noted to recur after completion of therapy. The platelet counts decreased by a mean of 46.3 × 103/µL (P < .001) within 48 hours after the completion of the corticosteroid regimen. It is yet to be determined whether extended use of corticosteroids would be beneficial in maintaining a stable state to allow prolongation of the pregnancy. Corticosteroids do not improve alkaline phosphatase and lactate dehydrogenase to as great a degree as the transaminases (alanine aminotransferase and aspartate aminotransferase). The smaller decrease in alkaline phos-
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phatase may be accounted for by the fact that half of the serum alkaline phosphatase is produced by the placenta during the last trimester. Lactate dehydrogenase is nonspecific and may not be the most accurate means of assessing the effects of corticosteroids on HELLP syndrome. Of the 3 corticosteroid regimens studied, 12 mg of betamethasone given every 12 hours was the most effective in reversing the laboratory abnormalities associated with HELLP syndrome. This may be accounted for by the fact that betamethasone is 1.25 times more potent than dexamethasone.17 Although dexamethasone did not appear to produce as significant an improvement as betamethasone, the number of patients who received dexamethasone was relatively small. Further studies may be designed to compare larger, more frequent, and prolonged dosages of corticosteroids, including corticosteroids that cross the placenta less efficiently, such as prednisone. Although fetal lung maturity may not be a problem in patients presenting after 34 weeks’ gestation, the use of corticosteroids may be valuable in stabilizing the maternal condition before delivery in these patients as well. The improvement in HELLP syndrome seen with corticosteroids may prove beneficial in many ways. It may allow the time required for corticosteroids to accelerate fetal lung maturity; delay delivery to achieve maternal hemodynamic stabilization through volume expansion, blood pressure control, or central monitoring, which would potentiate a safer delivery or transportation to a tertiary care center; and increase platelet counts to allow the possible use of regional anesthesia. Anecdotal reports exist in the literature supporting the use of general anesthesia in patients with severe preeclampsia and HELLP syndrome.18, 19 Our study illustrates the safe use of regional anesthesia in patients with HELLP syndrome. When the platelet count rose above 100 × 103/µL in response to the corticosteroids, regional anesthesia was used safely. Although there were only 11 patients with platelet counts <100 × 103/µL, no complications were noted in this group. The type of anesthesia was selected on the basis of the maternal platelet count. The lack of a correlation between platelet counts and bleeding times that we observed has also been reported by others.20, 21 Therefore the bleeding time should not be used in the selection of the type of anesthesia. In summary, corticosteroids improve the laboratory abnormalities associated with HELLP syndrome. Twelve milligrams of intramuscular betamethasone given every 12 hours is the most effective regimen to be used for the treatment of HELLP. The utilization of corticosteroids in patients with HELLP syndrome confers maternal benefits in addition to accelerating lung maturity in the fetus. For this purpose, consideration should be given to the use of corticosteroids even in patients presenting after 34 weeks’ gestation.
308 Tompkins and Thiagarajah
REFERENCES
1. American College of Obstetricians and Gynecologists. Hypertension in pregnancy. Washington: The College; 1996. Technical Bulletin No.: 219. 2. Thiagarajah S, Bourgeois FJ, Harbert GM, Caudle MR. Thrombocytopenia in preeclampsia: associated abnormalities and management principles. Am J Obstet Gynecol 1984;150:1-7. 3. Geary M. The HELLP syndrome. Br J Obstet Gynaecol 1997;104:887-91. 4. Romero R, Mazor M, Lockwood CJ, Emamian M, Belanger KP, Hobbins JC, et al. Clinical significance, prevalence and natural history of thrombocytopenia in pregnancy-induced hypertension. Am J Perinat 1989;6:32-8. 5. Sibai BM, Frangieh AY. Management of severe preeclampsia. Curr Opin Obstet Gynecol 1996;8:110-3. 6. Clark SL, Phelan JR, Allen SH, Golde SR. Antepartum reversal of hematologic abnormalities associated with the HELLP syndrome. J Reprod Med 1986;31:70-2. 7. Heyborne KD, Burke MS, Porreco RP. Prolongation of premature gestation in women with hemolysis, elevated liver enzymes and low platelets. J Reprod Med 1990;35:53-7. 8. Magann EF, Martin RW, Isaacs JD, Blake PG, Morrison JC, Martin JN. Corticosteroids for the enhancement of fetal lung maturity: impact on the gravida with preeclampsia and HELLP syndrome. Aust N Z J Obstet Gynaecol 1993;33:127-30. 9. Magann EF, Graves GR, Roberts WE, Blake PG, Morrison JC, Martin JN. Corticosteroids for enhanced fetal lung maturation in patients with HELLP syndrome: impact on Neonates. Aust N Z J Obstet Gynaecol 1993;33:131-5. 10. Magann EF, Bas D, Chauhan SP, Sullivan DL, Martin RW, Martin JN. Antepartum corticosteroids: disease stabilization in patients with the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP). Am J Obstet Gynecol 1994;171:1148-53. 11. Martin JN, Blake PG, Perry KG, McCaul JF, Hess LW, Martin RW. The natural history of HELLP syndrome: patterns of disease progression and regression. Am J Obstet Gynecol 1991;164:1500-11. 12. Magann EF, Perry KG, Meydrech EF, Harris RL, Chauhan SP, Martin JN. Postpartum corticosteroids: accelerated recovery from the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP). Am J Obstet Gynecol 1994;171:11548. 13. Martin JN, Perry KG, Blake PG, May WA, Moore A, Robinette L. Better maternal outcomes are achieved with dexamethasone therapy for postpartum HELLP (hemolysis, elevated liver enzymes, and thrombocytopenia) syndrome. Am J Obstet Gynecol 1997;177:1011-7. 14. Vigil-De Gracia P, Garcia-Caceres E. Dexamethasone in the postpartum treatment of HELLP syndrome. Int J Gynaecol Obstet 1997;59:217-21. 15. Yalcin OT, Sener T, Hassa H, Ozalp S, Okur A. Effects of postpartum corticosteroids in patients with HELLP syndrome. Int J Gynaecol Obstet 1998;61:141-8. 16. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth of the United States of America. Am J Obstet Gynecol 1976;126:555-64. 17. American Medical Association. Drug evaluations: annual 1992. Chicago: American Medical Association; 1992. p. 1715. 18. Donner A, Ullrich R, Kneifel W, Urak G, Hartmann T, Zimpfer M, et al. The HELLP syndrome. Acta Anaesth Scand 1997;111:165-7. 19. Grambling DR, Douglas MJ. Obstetric anesthesia and uncommon disorders. Philadelphia: WB Saunders; 1998. p. 321-2. 20. Ramanathan J, Sibai BM, Vu T, Chauhan D. Correlation between bleeding times and platelet counts in women with preeclampsia undergoing cesarean section. Anesthesiology 1989;71:188-91. 21. Schindler M, Gatt S, Isert P, Morgans D, Cheung A. Thrombocytopenia and platelet functional defects in preeclampsia: implications for regional anesthesia. Anaesth Intensive Care 1990;18:169-74.
August 1999 Am J Obstet Gynecol
Discussion DR NORMAN GANT, Dallas, Texas. First, how many of the 52 patients admitted with HELLP syndrome and the 41 patients in whom it later developed did not improve with corticosteroid administration? What are the minimum and maximum values of improvement? Second, please comment on the conclusion made about the use of regional anesthesia in these patients. Subdivide the 9 patients with platelet counts <100 × l03 who underwent regional anesthesia. DR LARRY DEVOE, Augusta, Georgia. Would you comment on the fetal outcome of these pregnancies? Did you look at the neonatal outcome as a function of time from admission until delivery, and did this adversely effect the ultimate outcome? How did you measure the benefit of the corticosteroids, and what was the mechanism of action of the benefit? Do you think this benefit is at the microangiopathic level or is this due to change in endothelial activity? DR RANDALL FALLS, Roanoke, Virginia. Did you notice any difference in the clinical outcomes of the mothers in this study? Were there decreased hospital days or transfusions? Is there clinical evidence that the therapy helped the mother? DR JOHN MARSTON, Tampa, Florida. Did you notice an increased rate of infection in the mothers after cesarean delivery? Did you use your normal prophylactic antibiotics, or did you vary this in these patients? DR RAMEZ AZOURY, Norfolk, Virginia. The American College of Anesthesia has strict contraindications for epidural anesthesia, and it appears that epidural anesthesia might have been contraindicated in your patients. Would you comment on how safe you believe the use of epidural anesthesia is in patients with HELLP syndrome. DR GENE BURKETT, Miami, Florida. In our experience we have seen patients initially get better only to become worse later. Did you find that patients initially improved only to get worse? Specifically, did you see a decrease in platelet counts and an increase in liver function results after initial improvement? DR TOMPKINS (Closing). In response to Dr Gant’s first point, of the 52 patients diagnosed with HELLP syndrome on admission, 45 had improvement in the platelet count after the administration of corticosteroids. This increase ranged from 2 × 103/µL to 128 × 103/µL. Only 7 patients failed to benefit. The platelet counts of 22 of these patients completely normalized (>150 × 103/µL) after receiving corticosteroids. Despite not having the laboratory abnormalities necessary for the diagnosis of HELLP syndrome, 31 of the 41 patients with preeclampsia on admission had an increase in platelet counts after the administration of corticosteroids. The maximum increase in this group was 123 × 103/µL. These patients later met the laboratory criteria for HELLP syndrome, either before (n = 28) or after (n = l3) delivery. As to Dr Gant’s second point, this study illustrates the safe use of regional anesthesia in patients with HELLP
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syndrome. The group consisted of 23 patients with platelet counts between 100 and 150 × 103, 5 with platelet counts between 75 and 100 × 103, 4 with platelet counts between 50 and 100 × 103, and 2 with platelet counts of <50 × 103. None of these patients had complications, such as epidural site hematomas or abscesses, which have been a concern in the literature in patients with decreased platelet counts. I agree with Dr Gant that larger studies are needed to confirm the safety of regional anesthesia in patients with severe thrombocytopenia. In response to Dr Devoe, specific fetal outcomes were not addressed in this study; however, the vast majority of fetuses were admitted to the neonatal intensive care unit after delivery. The benefit of the corticosteroids was measured strictly by the improvement observed in the laboratory abnormalities associated with HELLP syndrome. The mechanism of action may be related to an increase in the prostacyclin/thromboxane ratio, which has been observed in vitro after the administration of corticosteroids. This shift may lower platelet aggregation and subsequently raise the platelet count. In response to Dr Falls, the objective of this study was to quantify the improvement in hematologic abnormalities after the administration of corticosteroids. Because
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this was not a placebo-controlled trial, the clinical benefit in terms of maternal outcome, transfusions, and hospital days could not be ascertained. In response to Dr Marston, we used routine prophylactic antibiotics in these patients, typically Ancef. An increase in endometritis above baseline was not observed. The specific contraindication that was questioned by Dr Azoury dealt with use of regional anesthesia in patients with abnormal bleeding times. The type of anesthesia used was determined on the basis of platelet counts alone. Therefore all instances of regional anesthesia were in compliance with the recommendations of the American College of Anesthesia. Finally, in response to Dr Burkett, although the initial improvement was quite striking, the abnormalities in platelet counts and liver functions were noted to recur after completion of therapy. The platelet counts decreased by a mean of 46.3 × 103/µL (P < .001) within 48 hours after the completion of the corticosteroid regimen, prompting delivery. It is yet to be determined whether extended use of corticosteroids would be beneficial in maintaining a stable state to allow prolongation of the pregnancy.