Intensive Care Med (1992) 18:274-277

IntensiveCare Medicine 9 Springer-Verlag 1992

Hellp syndrome: incidence and maternal-fetal outcome a prospective study F. Abroug 1, R. Boujdaria 1, S. Nouira 1, S. Abroug 3, M. Souissi 2, M.F. Najjar 4, J.F. Secourgeon 2 and S. Bouchoucha 1 Intensive Care Unit, 2Department of Obstetrics and Gynecology, 3Department of Pediatrics, 4Biochemistry Laboratory, H6pital Universitaire Fattouma Bourguiba, Monastir 5000, Tunisia Received: 16 August 199i; accepted: 25 May 1992

Abstract. Objective: to determine the incidence of Hellp

syndrome (HS) and the maternal fetal outcome associated with its occurrence. Design: a prospective study during a 6-month period. Setting: the department of obstetrics and gynecology and the Intensive Care Unit of a 700 bed teaching hospital. Patients: Sixty-two consecutive preeclamptic and eclamptic women. Measurements and results: all patients were systematically investigated for the biological markers of HS. The effects of the occurrence of HS on maternal and fetal prognosis were evaluated by comparing for prognosis indicators usually assessed in gravidic hypertension, pre-eclamptic and eclamptic women who exhibited HS (HS+ subgroup) with HS free patients ( H S - subgroup). HS was found in 12 out of the 62 pre-eclamptic and eclamptic women (19.3~ Its occurrence was associated with higher maternal mortality (16.7~ vs 0~ p = 0.03), a greater incidence of eclamptic crisis (50070 vs 20070; p = 0.03), severe hypertension (33070 vs 8~ p = 0.03) and episodes of acute renal failure (66~ vs 30o70; p = 0.02). Mean proteinuria was also higher in H S + patients (4.6___3.3 vs 2.2+2.5g/day; p = 0.001). However, fetal outcome was not significantly altered. Conclusion: Pre-eclampsia and eclampsia may be more severe in the presence of HS with a worsening of maternal prognosis while fetal outcome seems not altered. Key words: Pre-eclampsia natal outcome

Hellp syndrome -

Peri-

Hellp Syndrome (HS) refers to a biological syndrome occurring in pre-eclamptic and eclamptic women, characterized by hemolysis, elevated liver enzymes and low platelets [1-3]. Since the first description of HS by Weinstein in 1982 [1], a persisting controversy has arisen regarding its incidence and prognosis. Hellp Syndrome has been estimated to occur at a rate of 4~ - 12070 in preeclamptic and eclamptic women [4-7] with predilection to the white and multiparous patients [5]. In addition, HS is considered as a worsening factor of maternal and

perinatal outcome with an increased risk for mortality and morbidity [1, 5, 8]. However, all these descriptions have been reported by retrospective and often small-scale studies on HS. Moreover, most of these studies failed in dissociating the specific maternal-fetal consequences of HS from those of pre-eclampsia and eclampsia making their results not totally conclusive. The aim of this prospective study is to determine the actual incidence of Hellp Syndrome and to evaluate the maternal-perinatal outcome associated with its occurrence. Patients and methods

Patients Sixty-two consecutive pre-eclamptic and eclamptic women (of whom 33 were primigravidas) referred to the department of obstetrics and gynecology and the intensive care unit of the University Hospital of Monastir daring a 6-month period (January-June 1989) were included in the study. Diagnosis of pre-eclampsia and eclampsia was made according to the definition of the American College of Obstetricians and Gynecologists [9] on the association of Hypertension and Proteinuria in each patient. The mean diastolic arterial pressure and proteinuria were t25+_ 12 mm Hg and 2.64_+ 1.8 g/day respectively.

Study design Diagnosis of Hellp Syndrome and incidence. All patients were systematically investigated for the syndrome. Diagnosis of HS was based on the association in each patient of hemolysis, increased liver enzymes and thrombocytopenia. On admission, each patient had the following biological examinations for the diagnosis of: (i) Hemolysis: based mainly on the decrement of the haptoglobin Ievel below 0.7 g/1 (Radial Immunodiffusion Assay. NOR-Partigen, Behring; Germany. Normal range: 0.7-3.2 g/l). A decreased hemoglobin level below 10 g/100 ml and increased bilirubin level over 17 ixmol/1 were also considered as accessory contributive criteria of hemolysis. (ii) The increase in the level of hepatic enzymes namely the Aspartate Aminotransferase (AST) and the Alanine Aminotransferase (ALT) over the normal values of our laboratory (30 IU/I and 35 IU/I respectively). (iii) Thrombocytopenia defined as a platelet count below 150000/mm 3 [4, 10]

275

Maternal-perinatal outcome associated with Hellp syndrome. Two subsets of patients were identified according to the presence (subgroup HS +) or absence (subgroup HS-) of Hellp Syndrome. Prognosis indicators usually assessed in pre-eclampsia and eclampsia were then statistically compared in both subgroups: 9 maternal prognosis: was assessed on the comparison in both subgroups of the mortality rate and the incidence of eclampsia and cardiovascular complications (pulmonary edema and severe hypertension defined as a diastolic blood pressure > 110 mmHg on two or more consecutive occasions [11]). The respective incidence of the hemorrhagic episodes (cerebral hemorrhage, peritoneal bleeding, retroplacentar hematoma, subcapsular hematoma of the liver or Disseminated Intravascular Coagulation (DIC)), were compared too. The evaluation of maternal prognosis also involvedthe incidence of acute renal failure (diagnosed on an increased creatinine level over 160 ~tmol/1 [12, 13]), and the severity of glomerular impairment evaluated on the level of proteinuria. The effects of HS on the pregnancy course was also assessed by comparison of the gestational age at delivery and the cesarean section rate. 9 Fetal prognosis: both subgroups of patients were compared in relation to intrauterine fetal deaths, neonatal deaths, fetal distress diagnosed on the decrease of fetal cardiac rhythm and intrauterine growth retardation [14]. All neonates were investigated for thrombocytopenia (platelet count < 150000/mrn3) or leucopenia (leucocytes< 500/mm3). 9 Patient's management. All patients were managed in order to stabilize blood pressure while fetal vital signs were closely monitored. Prompt delivery was indicated in patients with evidence of worsening pre-eclampsia (uncontrolled hypertension, deterioration in neurological status...), in cases of fetal distress and when there was evidence of fetal maturity. Statistics Data are presented as means_+standard deviation (SD). Differences in the means and the rates between subgroups (HS+ and HS-) were analyzed by Student's ttest, the ~2 test and Fisher's exact test used when appropriate. A p value of less than 0.05 was considered significant.

Table 1. Clinical characteristics of subgroups HS + and H S -

(n)

HS+ (12)

H S - (50)

p

Mean age (years) Mean gravidity (n) Gestational age on admission (weeks)

31.2 + 9.8 5 _+4.5

28.9 _+6.3 3.4+ 3.5

NS NS

37 _+2.4

37.2 + 2.1

NS

Table 2. Laboratory values of subgroups HS + and H S -

Haptoglobin (g/l) a Bilirubin 0smol/1) Hemoglobin (g/100 ml) AST (IU/1) ALT (IU/1) Platelets ( • 1000/mm3)

HS+

HS-

p

0.27 _+0.24 18.8 +_4.3 10.8 + 2.2 230 _+80 325 + 52 89 + 33

1.8 • 1.1 5.6 _+3.9 10.8 + 1.9 42 +_27 42 + 14 190 _+50

0.0001 0.001 NS 0.0001 0.0001 0.01

a Haptoglobin was undetectable in 3 out of the 12 patients with HS. The reported mean is calculated on the basis of the remaining 9 patients Table 3. Effects of HS on maternal prognosis

Deaths Eclamptic crisis Severe hypertension Acute renal failure Proteinuria (g/24 h) mean (SD) Cesarean sections Gestational age at delivery (weeks) mean (SD)

HS + n (%)

HS n (%)

p

2 (16.7) 6 (50) 4 (33) 8 (66) 4.5 (3.3) 7 (58) 37.2 (0.8)

0 10 (20) 4 (8) 15 (30) 2.2 (2.5) 15 (30) 37.4 (1.2)

0.03 0.03 0.03 0.02 0.001 NS NS

Results

Hellp S y n d r o m e was detected in 12 pre-eclamptic a n d eclamptic w o m e n (19.3%). At the time o f a d m i s s i o n to the hospital, n o n e from these patients c o m p l a i n e d o f the s y m p t o m s u s u a l l y associated with the occurrence o f H S (epigastric pain, nausea, v o m i t i n g . . . ) . Table 1 s u m m a r i z e s the clinical a n d obstetric characteristics of b o t h subgroups. N o significant differences could be detected with respect to the items analyzed. There was a trend toward a higher gravidity a n d age, which was n o t statistically significant, in the H S + subgroup. O n l y the l a b o r a t o r y tests involved in the diagnosis of H S (haptoglobin, b i l i r u b i n , liver enzymes a n d platelet c o u n t ) were statistically different (Table 2). Platelet c o u n t ranged i n the patients with H S from 40000 to 1 4 0 0 0 0 / m m 3. There was n o difference in the hemoglob i n level between subgroups. Peripheral b l o o d smear cont r i b u t e d in o n l y one p a t i e n t to the diagnosis o f hemolysis by showing schizocytes.

E f f e c t s o f H S on m a t e r n a l o u t c o m e C o m p a r i s o n s between subgroups H S + a n d H S - with regard to the indicators of m a t e r n a l prognosis are reported in Table 3. There was a singificantly higher m o r t a l i t y in subg r o u p H S + (16.7% v s 0 % ; p = 0 . 0 3 ) ; two deaths oc-

curred secondary to cerebral h e m o r r h a g e in the first patient a n d p u l m o n a r y e d e m a in the second who died o n a d m i s s i o n in the emergency r o o m prior to a n y therapeutic intervention. S u b g r o u p H S + patients also exhibited a greater incidence o f eclamptic crisis (50% v s 2 0 % ; p = 0.03) a n d severe h y p e r t e n s i o n episodes (33% vs 807o; p = 0.03). Acute renal failure was more frequent i n HS + patients (66% vs 30%; p = 0.02) who also h a d a greater a m o u n t of p r o t e i n u r i a (4.5_+3.3 vs 2.2_+2.5g/day; p = 0 . 0 0 1 ) . Two patients, one in each group, had p u l m o n a r y edema. There was one m e t e r n a l bleeding episode (peritoneal h e m o r r h a g e ) in H S + subgroup. Two H S + patients a n d o n e H S - p a t i e n t h a d DIC. The media n interval between a d m i s s i o n a n d delivery was 1.3 _+1.2 days in H S + patients a n d 1 . 8 + l . l d a y s in s u b g r o u p H S - patients (difference n o t significant). N o difference i n the rate of C a e s a r e a n section could be detected.

E f f e c t s o f H S on f e t a l o u t c o m e 50 pregnancies o f s u b g r o u p H S - patients resulted i n 53 births (one set o f twins a n d one set o f triplets). There were two fetal deaths i n s u b g r o u p H S + a n d 6 in subgroup H S - (difference n o t significant). Table 4 summarizes the consequences o f HS o n fetal outcome. N o significant differences could be detected between b o t h subgroups.

276 Table 4. Effects o f HS on fetal prognosis

Intrauterine fetal demise Fetal distress Intrauterine growth retardation Neonatal deaths Neonatal thrombopenia Neonatal leucopenia

HS +

HS -

n (%)

n a (%)

2 4 3 2 5 0

6 13 12 8 24 4

(i6) (40) (30) (20) b (50) (0)

(11) (28) (25) (17) c (51) (8)

p

NS NS NS NS NS NS

a Considering one set of twins and one set of triplets b From neonatal hemorrhage (n = 1) and hypoglycemia (n = 1) c From sepsis (n = 4) and neonatal hemorrhage (n = 4)

Discussion The current study shows an incidence of 19.3 %0 of HS in pre-eclampsia and eclampsia. The occurrence of HS represented a high risk for maternal mortality and morbidity in patients with pre-eclampsia. The perinatal prognosis was, however, not significantly altered. The incidence of HS we have found in pre-eclamptic and eclamptic patients is higher than the 4 % - 1 2 % reported so far [4- 7]. The prospective design of our study may have accounted, at least in part, for this higher incidence. Indeed all the patients included in the present study were systematically investigated for HS prior to any of the symptoms generally associated with it. Besides, the diagnostic criteria for HS are likely to contribute to this descrepancy. These criteria are, in fact, still widely debated particularly those permitting the diagnosis of hemolysis and thrombocytopenia. The degree of laboratory abnormalities needed to diagnose HS are controversial too. Sibai et al. [5] required a platelet count below 100000/mm 3 for the diagnosis of thrombocytopenia. This limit seems to be very restrictive and may have resulted in the low incidence mentioned in their report: 9.7% [5]. Bearing in mind Sibai et al's. findings, only 18 out of the 29 patients in Weinstein's initial study would have responded to this criterion [1]. Therefore, the limit of 150000/mm 3 for thrombocytopenia we have used in our study, seems to be more widely recognized [4, 10]. Moreover, it is worth noting that in the studies of Weinstein [81, McKenna [41 and Ellart [101, several patients were reported to have HS though they did not demonstrate clear evidence of hemolysis. Only 62% of Weinstein's patients had hyperbilirubinemia eventhough abnormal peripheral blood smear was found in up to 84~ of them [8]. In McKenna's study only 4 out of 27 patients had hyperbilirubinemia [4]. In 4 out of the 9 patients of Ellart's study [10] there was no haptoglobin dosage while the amount of hemoglobin decrease was not specified. In the present study, the diagnosis of hemolysis was based, mainly on the decrease of haptoglobin [15] in association with concordant criteria such as the hyperbilirubinemia and an abnormal low level of hemoglobin. The lack of daily investigation for HS in our patients might have been the source of underestimation of the actual incidence of the syndrome. However, the time elapsed between admission and delivery (1.8 _+1.1 days in H S -

subgroup) was too short to expect a significant change in the incidence reported herein. Although a worsening of the maternal and fetal prognosis was ascribed to the occurrence of Hellp Syndrome in previous studies [1, 5, 8], we have found that the latter failed to dissociate the specific effects of HS from those of pre-eclampsia-eclampsia since they did not compare with series of pre-eclamptic-eclamptic patients without HS. Most of the patients of these uncontrolled series had, in fact, severe forms of pre-eclampsia and eclampsia which entails a poor maternal-fetal prognosis. The present study was designed to specify whether HS was associated with further deterioration of the maternal-fetal condition and prognosis in the setting of pre-ecIampsia and eclampsia and compared two groups of pre-eclamptic and eclamptic women where the sole difference was the presence of HS. The current study suggests that preeclampsia and eclampsia may be more severe in the presence of HS and is associated with a higher risk of mortality and more frequent eclamptic crises, renal failure and severe hypertension episodes. However, the mechanisms of death in our patients (cerebral hemorrhage and pulmonary edema) are common complications of severe preeclampsia too and, therefore should not be considered as specific consequences of Hellp Syndrome. Conversely, our data suggest that HS is not associated with further deterioration of the fetal prognosis with respect to the indicators analyzed in the study namely the fetal growth, distress of demise, the neonatal deaths and the hematological distubances. Nevertheless, any conclusions on fetal prognosis are seriously hampered by the small number of patients with HS in our series and studies on larger sample sizes of patients with Hellp Syndrome are needed to clearly assess fetal prognosis. In conclusion, the current study emphasizes the importance of dosing bilirubinemia, haptoglobin, liver enzymes, platelets and coagulation in all patients with preeclampsia even in the absence of abdominal symptoms. The high risk of mortality and mobidity associated with Hellp Syndrome recommands optimal management of patients in whom HS is detected with close monitoring of physiologic signs (especially cardiovascular, cerebral and renal parameters). An emergency cesarean section should be performed as soon as fetal maturity as achieved [1, 2, 4, 5].

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sion gravidique. Prise en charge de Ia m~re en r6animation. In: R~animation et m~decine d'urgence. Expansion Scientifique Fran9aise, Paris, pp 279-296 13. Sibai BM, Anderson GD, McCubbin JH (1982) Eclampsia IL Clinical significance of laboratory findings. Obstet Gynecol 59:153 - 157 14. Lubchenco LO (1976) The estimation of gestational age. Major problems in clinical pediatrics, vol 14. The high risk infant. Saunders, Philadelphia 15. Poldre PA (1987) Haptoglobin helps diagnose the Hellp syndrome. Am J Obstet Gynecol 157:1267

Dr. E Abroug Service de R6animation Polyvalente H6pital Universitaire Monastir 5000 Tunisia