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1475

Severe preeclampsia, including the HELLP (hemolysis,


elevated liver enzymes, and low platelet count) syn-
drome, has been shown to increase maternal and neona-
tal morbidity and mortality rates,
1
particularly if occur-
ring in the second trimester.
2, 3
The usual management of
severe preeclampsia remote from term has been the de-
livery of the fetus, regardless of gestational age.
1
Recently,
expectant management of women with severe pre-
eclampsia but without the HELLP syndrome between 28
and 32 weeks gestation has been shown to reduce neona-
tal complications and neonatal stay in the intensive care
unit.
4
In the second trimester, expectant management
with aggressive monitoring of the status of both mother
and fetus improves perinatal outcomes.
5
The success of
this management, however, is limited by adverse maternal
outcomes occurring in women with severe preeclampsia
at the mid trimester.
2
An increased risk of maternal morbidity and death is
reported in women with the HELLP syndrome, particu-
larly in those with a platelet count <100,000 cells/L.
6
From the Division of Maternal-Fetal Medicine, University of Tennessee,
a
the Perinatal Diagnostic Center, Central Baptist Hospital,
b
and the De-
partment of Obstetrics and Gynecology, University of Cincinnati College
of Medicine.
c
Received for publication December 1, 1999; revised January 27, 2000;
accepted March 4, 2000.
Reprint requests: Baha M. Sibai, MD, Department of Obstetrics and Gy-
necology, University of Cincinnati College of Medicine, 231 Bethesda
Ave, PO Box 670526, Cincinnati, OH 45267.
Copyright 2000 by Mosby, Inc.
0002-9378/2000 $12.00 + 0 6/1/106975
doi:10.1067/mob.2000.106975
HELLP (hemolysis, elevated liver enzymes, and low platelet
count) syndrome versus severe preeclampsia: Onset at 28.0
weeks gestation
Bassam Haddad, MD,
a
John R. Barton, MD,
b
Jeffrey C. Livingston, MD,
a
Rabih Chahine, MD,
a
and Baha M. Sibai, MD
c
Memphis, Tennessee, Lexington, Kentucky, and Cincinnati, Ohio
OBJECTIVE: Our purpose was to determine whether the onset of the HELLP (hemolysis, elevated liver
enzymes, and low platelet count) syndrome in women at 28.0 weeks gestation is associated with an in-
creased risk of adverse maternal and perinatal outcomes in comparison with the risk for women with severe
preeclampsia but without the HELLP syndrome at a similar gestational age.
STUDY DESIGN: Sixty-four patients with either the HELLP syndrome (n = 32) or severe preeclampsia but
absent HELLP syndrome laboratory test results (n = 32), admitted at 28.0 weeks gestation between July 1,
1992, and April 30, 1999, were studied. Maternal and perinatal outcomes were compared between the 2
groups. Statistical analysis was performed by the Student t test and the Fisher exact test.
RESULTS: There were no significant differences between the 2 groups regarding African-American race
(59% vs 75%), nulliparity (50% vs 56%), or the use of corticosteroids (59% vs 78%). There were no maternal
deaths. One woman with the HELLP syndrome had a liver hematoma. The rate at which transfusion of blood
products was required was significantly greater in women with the HELLP syndrome than in those with se-
vere preeclampsia only (25% vs 3%; P < .05). There were no significant differences between the 2 groups
with respect to eclampsia (16% vs 13%), abruptio placentae (6% vs 9%), disseminated intravascular coagu-
lopathy (13% vs 0%), pulmonary edema (13% vs 6%), acute renal failure (3% vs 0%), pleural effusion
(3% vs 3%), or ascites (6% vs 16%). No significant differences were found between the 2 groups with
respect to neonatal death (11% vs 17%), respiratory distress syndrome (78% vs 86%), or composite
neonatal morbidity.
CONCLUSIONS: Except for the need for transfusion of blood products in women with the HELLP syndrome,
onset at 28.0 weeks gestation is not associated with an increased risk of adverse maternal or neonatal out-
comes in comparison with the risk for women with severe preeclampsia but without the HELLP syndrome at
a similar gestational age. (Am J Obstet Gynecol 2000;183:1475-9.)
Key words: HELLP syndrome, severe preeclampsia, second trimester, maternal outcome, neonatal
outcome
Obstetrics
In addition, women with the HELLP syndrome were re-
ported to have an increased risk of adverse maternal out-
come in comparison with those who had severe pre-
eclampsia but not the HELLP syndrome.
7, 8
However, the
differences in the outcomes observed in these studies
may be related to earlier gestation in women with the
HELLP syndrome than in women with severe preeclamp-
sia alone and may also reflect a greater severity of the dis-
ease process. To clarify this hypothesis, we conducted this
study to determine whether onset of the HELLP syn-
drome at 28.0 weeks gestation is associated with an in-
creased risk of maternal and perinatal morbidity in com-
parison with the risk associated with severe preeclampsia
without the HELLP syndrome at a similar gestational age.
Material and methods
We reviewed the medical records of women with the
HELLP syndrome and of those with severe preeclampsia
but without the HELLP syndrome who were admitted to
the E.H. Crump Womens Hospital, Memphis, Tennessee
(between July 1, 1992, and April 30, 1999) and to the
Central Baptist Hospital, Lexington, Kentucky (between
March 1, 1994, and April 30, 1999). Women with a history
of hematologic or liver diseases were excluded from
analysis.
The HELLP syndrome was defined by using the strict
criteria of Sibai
9
to avoid any misinterpretation of the re-
sults regarding different diagnostic criteria for the
HELLP syndrome or incomplete HELLP syndrome. The
diagnosis was made by the presence of all 3 of the follow-
ing criteria: hemolysis (characteristic peripheral blood
smear and serum lactate dehydrogenase >600 U/L or
serum total bilirubin 1.2 mg/dL), elevated liver en-
zymes (serum aspartate aminotransferase 70 U/L), and
low platelet counts (<100,000 cells/L).
9
Women with
class 3 HELLP syndrome (eg, platelet count of 100-150
l0
3
/L), as defined by Martin et al,
7
and those with in-
complete HELLP syndrome, as described by Audibert
et al,
8
were therefore excluded from this study. Women
were considered to have severe preeclampsia if they met
one or more of the following criteria of The American
College of Obstetricians and Gynecologists
1
: systolic
blood pressure >160 mm Hg or diastolic blood pressure
>110 mm Hg, headache, visual disturbances, epigastric or
right-upper-quadrant pain, eclampsia, pulmonary edema,
and proteinuria (urinary protein level >5 g/24 h). Women
with severe preeclampsia selected for analysis also met all
the following laboratory criteria: platelet count 150,000
cells/L, serum lactate dehydrogenase <600 U/L, serum
total bilirubin <1.2 mg/dL, and serum aspartate amino-
transferase <70 U/L. All women routinely received intra-
venous magnesium sulfate to prevent and control convul-
sions. Blood products were used to correct severe anemia
or coagulation abnormalities, as needed.
Gestational age was determined by using the best ob-
stetric criteria, including either last menstrual period or
ultrasonography (where available) at <20 weeks gesta-
tion, or both. Only those women admitted at 28.0 weeks
gestation were included in the analysis. Maternal vari-
ables studied included age, race (African-American or
white), parity, previous preeclampsia, chronic hyperten-
sion, gestational stage at diagnosis, mean arterial blood
pressure, headache, visual change, nausea and vomiting,
epigastric or right-upper-quadrant pain, and adverse ma-
ternal outcome. Maternal outcomes included eclampsia,
abruptio placentae, disseminated intravascular coagu-
lopathy (DIC), acute renal failure, pulmonary edema,
pleural effusion, ascites, the need for transfusion, and
liver hematoma. DIC was defined as the presence of 3 of
the following criteria: low platelet count (<100,000
cells/L), low fibrinogen level (<300 mg/dL), positive
D-dimers (40 mg/dL), or prolonged prothrombin time
(14 seconds) and partial thromboplastin times (40 sec-
onds). Acute renal failure was diagnosed in the presence
of oligouria or anuria in association with creatinine clear-
ance 20 mL/min and an elevated serum creatinine level
2 mg/dL. Pulmonary edema and pleural effusion were
assessed on the basis of clinical findings and radiography
of the chest. The diagnosis of severe ascites was made by
estimation during ultrasonographic examination, com-
puted tomography, or cesarean delivery or laparotomy
(1000 mL of fluid measured by suction apparatus).
The neonatal medical records were reviewed for the
following outcomes as diagnosed by the attending pedia-
trician: respiratory distress syndrome, bronchopul-
monary dysplasia, intraventricular hemorrhage (grade
III/IV), necrotizing enterocolitis (grade 2/3), duration
of stay in an intensive care unit, and neonatal death.
Data are presented as mean SD, median and range,
or frequency, as appropriate. Categoric data were com-
pared by the Fisher exact test. Continuous variables were
analyzed by the Student t test. A P value < .05 was consid-
ered significant.
Results
During the study period, 32 women met the criteria of
the HELLP syndrome and were compared with 32
women who had severe preeclampsia but not the hema-
tologic and hepatic abnormalities. The findings in these
women are shown in Table I. Rates of nausea and vomit-
ing and of epigastric pain were significantly higher in the
women with the HELLP syndrome. Laboratory results are
shown in Table II.
Complications are presented in Table III. The overall
rate of adverse maternal outcomes for women with the
HELLP syndrome was statistically similar to that for
women with severe preeclampsia only (44% vs 38%, re-
spectively). However, significantly more women with the
HELLP syndrome needed transfusion of blood products
than did those without the HELLP syndrome (25% vs
1476 Haddad et al December 2000
Am J Obstet Gynecol
3%; odds ratio, 10.3; 95% confidence interval, 1.2-88.4;
P < .05). No statistical differences were found between
the 2 groups for all other adverse maternal outcomes
studied.
The perinatal mortality rate for both groups was 250 of
1000 women. The stillbirth rates for women with the
HELLP syndrome and for those without the HELLP cri-
teria were statistically similar (16% vs 9%; odds ratio, 1.8;
confidence interval, 0.4-8.3; P = .70). Neonatal mortality
and morbidity rates are presented in Table IV. No statisti-
cal differences were found in the neonatal outcomes be-
tween the 2 groups.
Volume 183, Number 6 Haddad et al 1477
Am J Obstet Gynecol
Table I. Clinical findings in 2 study groups
HELLP syndrome (n = 32) Preeclampsia without HELLP syndrome (n = 32)
Age (y, mean SD)* 24.4 4.7 21.9 4.7
Gestational age at diagnosis (wk, mean SD) 25.8 2.5 26.2 1.5
Arterial blood pressure (mm Hg, mean SD) 130 18 132 11
Maternal stay (d, mean SD) 7.8 2.7 9.5 8.1
African-American (No.) 19 (59%) 24 (75%)
Nulliparity (No.) 16 (50%) 18 (56%)
Previous preeclampsia (No.) 14 (44%) 18 (56%)
Chronic hypertension (No.) 4 (13%) 10 (31%)
Headache (No.) 9 (28%) 14 (44%)
Visual change (No.) 6 (19%) 6 (19%)
Nausea and vomiting (No.) 13 (41%) 2 (6%)
Epigastric or right-upper-quadrant pain (No.) 19 (59%) 3 (9%)
Corticosteroid prophylaxis (No.) 18 (67%) 24 (83%)ll
*P < .05.
P < .01.
P < .0001.
Five stillbirths excluded from analysis.
llThree stillbirths excluded from analysis.
Table II. Laboratory findings in 2 study groups
HELLP syndrome (n = 32) Preeclampsia without HELLP syndrome (n = 32)
Platelet count nadir (10
3
/L)* 57 (17-95) 195 (153-292)
Lactate dehydrogenase (U/L)* 1347 (407-5720) 228 (152-431)
Aspartate aminotransferase (U/L)* 182 (71-2924) 29 (12-56)
Serum creatinine (mg/dL) 0.9 (0.5-10.4) 0.9 (0.6-5.3)
Serum uric acid (mg/dL) 7.3 (2.8-20) 7 (4.5-12.3)
Values are expressed as median and range.
*P < .001.
Table III. Maternal complications in 2 study groups
HELLP syndrome Preeclampsia without
(n = 32) HELLP (n = 32)
No. % No. % Odds ratio and 95% confidence interval
Eclampsia 5 16 4 13 1.3 (0.3-5.3)
Abruptio placentae 2 6 3 9 0.6 (0.1-4.1)
DIC 4 13 0 NA
Transfusion of blood products* 8 25 1 3 10.3 (1.2-88.4)
Acute renal failure 1 3 0 NA
Ascites 2 6 5 16 0.4 (0.1-2)
Pulmonary edema 4 13 2 6 2.1 (0.4-12.6)
Pleural effusion 1 3 1 3 1
Cesarean delivery 25 93 29 100 NA
Cesarean delivery for fetal distress 4 16 8 28 0.5 (0.1-1.9)
NA, Not applicable.
*P < .05.
Five stillbirths excluded from analysis.
Three stillbirths excluded from analysis.
Comment
The ultimate goal of any protocol for management of
severe preeclampsia is to reduce maternal mortality and
morbidity rates, followed by delivery of a healthy and ma-
ture baby. Seven percent of the cases of severe pre-
eclampsia occur in the second trimester, and the gesta-
tional age has a critical influence on perinatal outcome.
2
The optimal management in the second trimester usually
depends on balancing the risks to the mother and fetus
resulting from expectant management against the risks of
extreme prematurity in the event of immediate delivery.
3
Severe preeclampsia occurring in the second trimester
has been reported to be associated with an increased in-
cidence of adverse maternal outcomes, with a high rate of
abruptio placentae (22%), HELLP syndrome (17%),
eclampsia (17%), and DIC (8%).
2
Under these adverse
maternal conditions, expeditious delivery has been rec-
ommended because the risks resulting from a delayed de-
livery outweigh the possible benefits of pregnancy pro-
longation.
10
The overall rate of adverse maternal outcomes ob-
served in women with the HELLP syndrome (44%) was
similar to that observed in those with severe preeclampsia
but not the HELLP syndrome (38%) during the second
trimester. Except for hematologic changes, the inci-
dences of all other adverse maternal outcomes studied
among women with the HELLP syndrome and those with
severe preeclampsia but not the HELLP syndrome were
not statistically different. Our finding of similar rates of
eclampsia in women with the HELLP syndrome and in
those with severe preeclampsia only is not in agreement
with that of Martin et al,
11
who reported that eclampsia
was more frequent in women with the HELLP syndrome
than in those without the HELLP syndrome at 24 to 32
weeks gestation. This may be related to a bias in their re-
cruitment, because 13 (93%) of the 14 women with
eclampsia before 28 weeks had the HELLP syndrome.
11
Although the rate of DIC in our study appeared to be
higher in women with the HELLP syndrome (13%) than
in those with severe preeclampsia (0%), this difference
was not statistically significant. We cannot, however, ex-
clude a type II statistical error because the estimated
power analysis is 0.54. Moreover, these findings are in
agreement with those of Martin et al,
7
who reported DIC
rates of 12% in women with the HELLP syndrome, classes
1 and 2 (eg, platelet count <100 10
3
cells/L) and 1%
in those with severe preeclampsia but without the HELLP
syndrome.
In the management of patients with severe preeclamp-
sia developing before 28 weeks gestation, the presence of
the HELLP syndrome was considered to be an indication
for delivery within 48 hours of the start of corticosteroid
treatment for enhancing fetal lung maturity.
10
In our
study perinatal and neonatal mortality and morbidity
rates were statistically similar between the women with
the HELLP syndrome and those with severe preeclamp-
sia. These findings are similar to those of other investiga-
tors,
12-14
who found that neonatal morbidity and death
were related to gestational age at delivery rather than to
the severity of the HELLP syndrome or preeclampsia.
The HELLP syndrome is associated with an increased
risk of adverse maternal outcomes, in comparison with
the risks associated with other forms of severe pre-
eclampsia. However, the HELLP syndrome usually has an
earlier onset than other forms of severe preeclampsia.
8, 11
This aspect is of interest because it suggests that the ges-
tational age at which the disease is diagnosed might cor-
relate with severity. Indeed, studies comparing expectant
management in women with severe preeclampsia with
and without the HELLP syndrome but matched for ges-
tational age failed to demonstrate any differences in ad-
verse maternal outcomes, except for transfusion of blood
products.
14, 15
Because expectant management in women
with severe preeclampsia but without the HELLP syn-
drome at <32 weeks gestation improves neonatal out-
come,
4, 5
the results of this study raise the issue regarding
expectant management in women with the HELLP syn-
drome developing before 28.0 weeks gestation. We
1478 Haddad et al December 2000
Am J Obstet Gynecol
Table IV. Neonatal findings in 2 study groups
HELLP syndrome Preeclampsia without HELLP Odds ratio and
(n = 27) (n = 29) 95% confidence interval
Gestational age at delivery (wk, mean SD) 26.7 1.3 27.3 1.4
Delivery weight (g, mean SD) 740 224 825 167
Small for gestational age (No.)* 10 (37%) 5 (17%) 3.4 (1-11.3)
Neonatal death (No.) 3 (11%) 5 (17%) 0.6 (0.1-2.8)
Respiratory distress syndrome (No.) 21 (78%) 25 (86%) 0.6 (0.1-2.3)
Bronchopulmonary dysplasia (No.) 15 (56%) 9 (31%) 2.8 (0.9-8.3)
Intraventricular hemorrhage, grade III/IV (No.) 1 (4%) 2 (7%) 0.5 (0-6.1)
Necrotizing enterocolitis grade 2/3 (No.) 2 (7%) 2 (7%) 1.1 (0.1-8.3)
Mechanical ventilation (No.) 25 (93%) 27 (93%) 0.9 (0.1-7.1)
Time in neonatal intensive care unit (d, mean SD) 74 41 55 29
Stillbirths excluded from analysis.
*Defined as delivery weight at <10th percentile.
P = .05.
should, however, caution that women with DIC should
not be managed expectantly.
Magann et al,
16
in a randomized study, analyzed the
usefulness of dexamethasone (20 mg/d) administered
until delivery to 25 women with the HELLP syndrome.
They found a significantly increased entry-to-delivery
interval in treated women in comparison with nontreated
women (41 15 vs 15 4.5 hours, P < .01). This, in turn,
should have a beneficial effect on neonatal outcome. Re-
cently, Tompkins and Thiagarajah,
17
in a retrospective
study, reported a beneficial effect of corticosteroid treat-
ment given to enhance fetal lung maturity on laboratory
parameters of women with the HELLP syndrome.
17
The
number of patients admitted before 28 weeks gestation,
their clinical course, and the neonatal outcome, however,
were not provided in either study.
16, 17
On the basis of our results and the data reported in the
literature,
14-17
expectant management may be beneficial
in some women with the HELLP syndrome at or before
28 weeks gestation, as reported for women with severe
preeclampsia in the second trimester in the absence of
the HELLP syndrome.
5
The ideal approach to answer this
important clinical question would be a randomized trial
comparing outcomes for women managed expectantly by
means of high-dose corticosteroid therapy with outcomes
for those managed by immediate delivery.
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