Obstetrics

Pregnancies complicated by HELLP syndrome (hemolysis,

elevated liver enzymes, and low platelets): Subsequent
pregnancy outcome and long-term prognosis
Baha M. Sibai, MD, Mohammed K. Ramadan, MD, Radha S. Chari, MD, and
Steven A. Friedman, MD
Memphis, Tennessee

OBJECTIVE: Our purpose was to describe subsequent pregnancy outcome and long-term maternal
prognosis in women with HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) during
the index pregnancy.
STUDY DESIGN: This is a descriptive and analytic study of women with HELLP syndrome admitted to
E.H. Crump Women’s Hospital between August 1977 and July 1992. HELLP syndrome was defined by
previously published laboratory criteria. Only patients who were delivered > 2 years ago were included
(median 4 years, range 2 to 14 years). Data on these patients were obtained from our obstetric clinics,
local physicians, local health departments, and hospital records.
RESULTS: Adequate follow-up data were available on 341 patients. One hundred fifty-two women
subsequently became pregnant. One hundred thirty-nine normotensive women had 192 subsequent
pregnancies. Complications included preeclampsia (19%), preterm delivery (21%) intrauterine growth
restriction (12%) abruptio placentae (2%), perinatal death (4%) and HELLP syndrome (3%). Seven of the
113 women with at least 5 years’ follow-up (6.2%) had chronic hypertension, and 98 received oral
contraceptive pills without complications. Thirteen women with preexisting chronic hypertension had 20
subsequent pregnancies. These women had a higher rate of preeclampsia (75%) preterm delivery (80%),
intrauterine growth restriction (45%), abruptio placentae (20%) and perinatal death (40%) but a low rate
of recurrent HELLP syndrome (5%).
CONCLUSIONS: Women with HELLP syndrome have an increased risk of obstetric complications in
future pregnancies but a low risk for recurrent HELLP syndrome. Oral contraceptive pills should not be
contraindicated in normotensive women. (AM J OBSTET GYNECOL 1995;i 72: 125-9.)

Key words: HELLP syndrome, recurrence, remote prognosis

The HELLP syndrome (hemolysis, elevated liver en- athy, pulmonary edema, adult respiratory distress syn-
zymes, and low platelets) is a well-recognized complica- drome, acute renal failure, ruptured liver hematomas,
tion of severe preeclampsia-eclampsia.’ The incidence and a variety of hemorrhagic complications.4~‘1
of this syndrome in preeclamptic pregnancies ranges The development of HELLP syndrome, particularly
from 4% to 14%.’ Pregnancies complicated by the when it is associated with poor maternal-perinatal out-
HELLP syndrome are usually associated with increased come, is a frightening experience for both the patient
maternal and perinatal mortality.‘-’ In addition, such and her family. In addition to offering advice about the
pregnancies are associated with life-threatening mor- current pregnancy, the managing physician must be
bidities, including disseminated intravascular coagulop- prepared to answer questions regarding long-term ma-
ternal prognosis, outcome of future pregnancies, and
the risk of using oral contraceptive pills. The purpose of
From the Division of Maternal-Fetal Medicine, Department of Ob- this study is to report subsequent pregnancy outcome
stetrics and Gynecology, University of Tennessee, Memphis.
Received for publication July 25, 1994; revised September 19, 1994; and long-term maternal prognosis of 341 women who
accepted October 11, 1994. had HELLP syndrome in the index pregnancy.
Reprint requests: Baha M. Sibai, MD, Department of Obstetrics and
Gynecoloa\ University of Tennessee, Memphis, 853 Jefferson Ave., Material and methods
Suite E-I 02, Memphis, TN 38103.
Copyright 0 1995 by Mosby-Year Book, Inc. The E.H. Crump Women’s Hospital and Perinatal
0002-9378/95 $3.00 f 0 6/l/61243 Center in Memphis serves as a tertiary referral center

125
126 Sibai et al. January 1995
Am J Obstet Gynecol

Table I. Subsequent pregnancy outcome after HELLP syndrome in index pregnancy

Normotensive (n = 139) Hypertensive (n = 13) Signzjicance

Pregnancies (No.) 192 20

Normotensive (%)* 73 -
Hypertension only (%) 8 25 p = 0.09
Preeclai$sia.(%) 19 75 p < 0.001
Mild (%) 11 15 p = 0.48
Severe (%) 6 55 p -c 0.001
HELLP (%) 3 5 p = 0.45
Delivery < 37 wk (%) 21 80 p < 0.001
Intrauterine growth restriction 12 45 p < 0.001
(IUGR) (< 10th percentile) (%)
Abruptio placentae (%) 2 20 p = 0.002
Perinatal death (%) 4 40 p < 0.001
-
*Percentage of pregnancies.

for an area that includes five states: Tennessee, Arkan- 6 hours apart) plus proteinuria ( 2 300 mg per 24 hours
sas, Mississippi, Missouri, and Kentucky. Between Au- or urine dipstick 2 I+ on two occasions at least 6 hours
gust 1977 to July 1992, 442 pregnancies managed at apart). Women without proteinuria were considered to
this center were complicated by HELLP syndrome. The have hypertension only. Preeclampsia was diagnosed as
diagnosis, management, and maternal-perinatal out- severe by The American College of Obstetricians and
come of these patients were described previously.4 Gynecologists criteria.” The laboratory criteria for
These 442 pregnancies occurred in 437 women (five HELLP syndrome were abnormal peripheral smear
women each had two pregnancies complicated by plus either total bilirubin ZY1.2 mgidl or lactic dehydro-
HELLP). For the purpose of this study only the first genase 2 600 U/L, aspartate aminotransferase 2 70
pregnancy complicated by HELLP will be considered as U/L, and platelet count < 100,000/mm3.
the index pregnancy in these five women. Four women All data pertaining to blood pressure measurements
died during the acute episode of HELLP syndrome, during subsequent physical examinations or pregnancy
and one woman died of pulmonary embolism 8 to 9 were obtained and reviewed by the authors. The diag-
weeks post parturn.* Fifty-three of the 432 surviving nosis of chronic hypertension was based on the pres-
women were lost to follow-up, and 38 were delivered ence of documented hypertension (either before the
within the past 2 years. The remaining 341 women had index pregnancy or on follow-up) for which the patient
adequate medical follow-up data for at least 2 years received antihypertensive therapy. This diagnosis was
after having HELLP syndrome. This latter cohort usually made when the patient had persistent elevations
served as the study population for this report. of diastolic pressure of 2 90 mm Hg on two occasions at
Early postpartum follow-up (first 6 weeks) was per- least 6 months apart. Data were compared using x2
formed at our obstetric clinics. Subsequent follow-up analysis or Fisher exact test, as appropriate.
data were obtained from our clinics, local physicians,
local health departments, and hospital records. In the Results
majority of cases (> 90%), the women were given regu- Adequate follow-up data for at least 2 years (median
lar appointments to be seen and examined by one of 4 years, range 2 to 14 years) were available on 341
the authors (B.M.S.) or a research nurse. Maternal patients, of whom 292 (86%) were normotensive and 49
evaluation included an interval history with special (14%) had preexisting chronic hypertension during the
emphasis on the use of oral contraceptive pills, history index pregnancy. One hundred thirty-nine normoten-
of convulsions and use of anticonvulsant drugs (for sive women and 13 hypertensive women had subse-
eclamptic women), use of antihypertensive drugs, car- quent pregnancies beyond the first trimester.
diovascular complications, and subsequent pregnancy Normotensive women. A total of 292 women were
outcome. Outcome in subsequent pregnancies was re- normotensive before the index pregnancy. Ninety-nine
viewed with regard to gestational age at delivery, fetal (34%) were multiparous, and 193 (66%) were nullipa-
growth, occurrence of preeclampsia, preterm birth, rous. One hundred sixty-one (55%) were black, and 131
abruptio placentae, and perinatal outcome. Only preg- (45%) were white. The median age at onset of HELLP
nancies delivered beyond the first trimester were in- syndrome was 23 years (range 13 to 39 years), and the
cluded in the analysis of the above outcomes. median duration of follow-up was 4 years (range 2 to 14
Preeclampsia was diagnosed in the presence of hy- years). One hundred forty-three women had no subse-
pertension (systolic blood pressure 2 140 mm Hg or quent pregnancies, 10 women had miscarriages or
diastolic pressure 2 90 mm Hg on two occasions at least abortions only, and the remaining 139 had a total of
 Volume 172, Number 1, Part 1 Sibai et al. 127
Am J Obstet Gynecol

Table II. Subsequent perinatal outcome in normotensive women after HELLP syndrome in
index pregnancy
Normotensive pregnancy (n = 140) Hypertensive pregnancy (n = 52) Sign$xnce

Infants (No.) 141 55

Delivery < 37 wk (%)* 14 40 p < 0.001
IUGR (< 10th percentile) (%) 8 24 p = 0.003
Abruptio placentae (%) 1 4 p = 0.18
Perinatal death (%) 3 6 p = 0.39

*Percentage of infants.

192 subsequent pregnancies beyond the first trimester. index pregnancy or subsequently. Two women had
Fifty-eight of these 139 women were white, and 8 1 were secondary infertility because of Sheehan’s syndrome.
black; 95 were nulliparous, and 44 were parous during Women with preexisting chronic hypertension.
the index pregnancy. Table I describes the frequency of Forty-nine women had preexisting chronic hyperten-
hypertensive disorders during subsequent pregnancies. sion (with or without renal disease) before the index
Ninety-one of these 139 women (65%) had only nor- pregnancy. Seventeen (35%) were nulliparous, and 32
motensive pregnancies, 35 (25%) had at least one sub- (65%) were multiparous. Thirty (61%) were black and
sequent preeclamptic pregnancy, and the remaining 13 19 (39%) were white. The median age at onset of
women (10%) had subsequent pregnancies complicated HELLP syndrome in these women was 28 years (range
by hypertension only. Five women had another preg- 17 to 40 years), and the median duration of follow-up
nancy complicated by HELLP syndrome, giving a re- was 4 years (range 2 to 13 years). Thirty-four of the 49
currence rate of 4%. Two women who had ruptured women had no subsequent pregnancies, two women
liver hematomas had three subsequent term normoten- had miscarriages only, and the remaining 13 had a total
sive pregnancies. of 20 subsequent pregnancies (Table I). Eight of these
If only the next subsequent pregnancy (rather than 13 women were black, and five were white; five were
all subsequent pregnancies) is considered, 97 (70%) of nulliparous, and eight were parous during the index
these 139 women had a normotensive pregnancy, 32 pregnancy.
(23%) had preeclampsia, and 10 (7%) had hypertension If only the next subsequent pregnancy (rather than
only. all subsequent pregnancies) is considered, nine (69%)
The 192 pregnancies resulted in 196 births (four sets had preeclampsia and four (31%) had hypertension
of twins). Table I summarizes perinatal outcome in only. One of the 13 subsequent pregnancies was com-
these pregnancies. Table II compares perinatal out- plicated by HELLP syndrome, giving a recurrence rate
come in women who had subsequent hypertensive preg- of 8%.
nancies and those who had subsequent normotensive The median maternal age at last follow-up in these
pregnancies. Not surprisingly, women who had subse- 49 women was 32 years (range 21 to 44 years). Four
quent hypertensive pregnancies had significantly women (8%) died during the follow-up period. One
higher incidences of preterm birth and IUGR than woman died from massive intracerebral hemorrhage
those who had subsequent normotensive pregnancies. and adult respiratory distress syndrome after an over-
The median maternal age at time of last follow-up dose of cocaine after 3.5 years of follow-up. Another
was 26 years (range 17 to 45 years). No woman died woman died of cardiovascular complications after 13
during the follow-up period. During follow-up 280 years of follow-up. In addition, two women died of renal
women (95.9%) remained normotensive, and 12 women failure complications after 2 and 9.5 years of follow-up.
(4.1%) had chronic hypertension. Among the 280 nor- Both required long-term dialysis, and one had multiple
motensive women the median systolic blood pressure complications from systemic lupus erythematosus.
was 116 mm Hg (range 80 to 138 mm Hg), and the Twenty-three women had bilateral tubal ligatiofi, and
median diastolic blood pressure was 70 mm Hg (range two had hysterectomy either during the index preg-
50 to 88 mm Hg). Of 113 women with ~5 years of nancy or on follow-up.
follow-up, seven (6%) had chronic hypertension. Two
women had diabetes, and one had new-onset systemic Comment
lupus erythematosus. We reported previously that women who have severe
Ninety-eight women received oral contraceptive pills preeclampsia-eclampsia are at increased risk for having
for 4 months to 6 years, and none had any complica- preeclampsia in subsequent pregnancies.13M’5 In addi-
tions. In addition, 78 women had bilateral tubal liga- tion, we found that the risk of preeclampsia in subse-
tion, and four had hysterectomy, either during the quent pregnancies was markedly increased in those
128 Sibai et al. January 1995
Am J Obstet Gym01

women who had preexisting chronic hypertension and to the preexisting hypertension (with or without renal
in those who developed severe preeclampsia in the disease) rather than to HELLP syndrome per se. Nev-
second trimester.14, I5 Moreover, for women who were ertheless, such women should be informed of the high
normotensive before the index pregnancy, the risk of likelihood of severe preeclampsia and adverse perinatal
having chronic hypertension on follow-up ranged from outcome in subsequent pregnancies. Moreover, they
10% to 15%.‘3, I5 However, none of these studies de- should be informed of the increased long-term mater-
scribed the risks for women with HELLP syndrome. nal morbidity and counseled regarding close medical
There are minimal data describing subsequent preg- follow-up.
nancy outcome and safety of oral contraceptives in Thrombotic thrombocytopenic purpura and hemo-
women’with HELLP syndrome.‘, I6 In addition, there lytic uremic syndrome are life-threatening syndromes
are no data describing the long-term prognosis for characterized by thrombocytopenia, microangiopathic
these women. The findings of this study indicate that hemolytic anemia, hepatic dysfunction, and neurologic
women. who have had HELLP syndrome have a high abnormalities. Indeed, both of these syndromes share
risk of obstetric complications in subsequent pregnan- many clinical and laboratory findings with HELLP syn-
cies (Table I). drome.* In addition, thrombotic thrombocytopenic
For women who were normotensive before the onset purpura and hemolytic uremic syndrome have been
of HELLP syndrome, the risk of recurrence in subse- reported to develop in women taking oral contracep-
quent pregnancies was 19% for preeclampsia, 27% for tives.“, I8 In this study 98 women received oral contra-
all hypertensive disorders, and only 3% for HELLP ceptives for varying periods of time, but none had
syndrome. If the rate in women, rather than in preg- clinical or labortory findings consistent with thrombotic
nancies, is considered, then the recurrence rate of thrombocytopenic purpura, hemolytic uremic syn-
HELLP syndrome in this study was 4%. This finding is drome, or HELLP syndrome. Thus there is no evidence
in contrast to the 25% recurrence risk reported by /that oral contraceptives should be contraindicated after
Sullivan et a1.16 The difference in recurrence risk of HELLP syndrome.
HELLP syndrome between the two studies could in part In summary, women who have had HELLP syndrome
be attributed to differences in definitions of the syn- should be considered at increased risk for obstetric
drome or in the populations studied. Moreover, in complications in subsequent pregnancies. Their risk of
these normotensive women, the risk of preterm deliv- recurrent HELLP syndrome is only 4%.
ery, IUGR, and abruptio placentae were more than
twofold higher than the expected incidence for these REFERENCES
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hospital. However, the majority of these complications evated liver enzymes, and thrombocytopenia. Obstet Gy-
necol 1985;66:657-60.
were encountered in women who had subsequent hy- 2. Barton JR, Sibai BM. Care of the pregnancy complicated
pertensive pregnancies (Table II). In addition, two of by HELLP syndrome. Obstet Gynecol Clin North Am
these women who had ruptured liver hematomas had 1991;18:165-79.
3. Sibai BM, Taslimi MM, El-Nazer A, Amon E, Mabie BC,
three subsequent pregnancies without complications. Ryan GM. Maternal-perinatal outcome associated with the
These findings should be used in counseling patients syndrome of hemolysis, elevated liver enzymes, and low
who are considering future pregnancies. platelets in severe preeclampsia-eclampsia. AM J OBSTET
GYNECOL 1986;155:501-9.
The long-term effects of HELLP syndrome on ma- 4. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM,
ternal blood pressure have not been studied previously. Friedman SA. Maternal morbidity and mortality in 442
The results of this study show that women without pregnancies with hemolysis, elevated liver enzymes, and
low platelets (HELLP syndrome). AM J OBSTET GIWXOL
evidence of chronic hypertension before HELLP syn- 1993;169:1000-6.
drome have a 4% incidence of chronic hypertension on 5. Van Dam PA, Reiner M, Baeklandt M, Buytaert P, Uytten-
follow-up. This incidence is less than half the expected broeck F. Disseminated intravascular coagulation and the
syndrome of hemolysis, elevated liver enzymes, and low
incidence of 10% during a similar follow-up period in platelets in severe preeclampsia. Obstet Gynecol 1989;73:
women with eclampsia managed at our institution.” 97-102.
Future obstetric complications are particularly in- 6. Martin JN Jr, Blake PG, Perry KG Jr, McCaul JF, Hess LW,
Martin RW. The natural history of HELLP syndrome:
creased in those who had preexisting chronic hyperten- patterns of disease progression and regression. AM J
sion before the onset of HELLP syndrome in the index OBSTET GYNECOL 1991;164:1500-13.
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RW, Meeks GR. Postpartum eclampsia: a recurring peri-
subsequent pregnancies was 75% (5% for recurrent natal dilemma. Obstet Gynecol 1990;76:328-31.
HELLP syndrome). The risks of preterm delivery, 8. Woods JB, Blake PG, Perry KG Jr, Magann EF, Martin RW,
IUGR, abruptio placentae, and perinatal death were Martin JN Jr. Ascites: a portent of cardiopulmonary com-
plications in the preeclamptic patient with the syndrome
markedly increased in subsequent pregnancies. How- of hemolysis, elevated liver enzymes, and low platelets.
ever, it is important to note that these risks are related Obstet Gynecol 1992;80:87-91.
Volume 172, Number 1, Part 1 Sanchez-Ramos et al.
Am J Obstet Gynecol

9. Martin JN Jr, Files JC, Blake PG, et al. Plasma exchange come and remote prognosis. AI J OBSTET GYNECOL 1986;
for preeclampsia. I. Postpartum use for persistently severe 155:1011-6.
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young prim&-avid women: subsequent pregnancy out-

Pyelonephritis in pregnancy: Once-a-day ceftriaxone versus

multiple doses of cefazolin
A randomized, double-blind trial

Luis Sanchez-Ramos, MD, Kenneth J. McAlpine, MD, C. David Adair, MD,

Andrew M. Kaunitz, MD, Isaac Delke, MD, and Donna K. Briones, RNC, MS
Jachonville, Florida

OBJECTIVE: The purpose of this study was to compare the efficacy of a single daily dose of intravenous
ceftriaxone with that of multiple-dose cefazolin in the treatment of acute pyelonephritis in pregnancy.
STUDY DESIGN: This was a double-blind, randomized, clinical trial. Patients admitted to the hospital with
the diagnosis of acute pyelonephritis in pregnancy were enrolled and randomized according to a
computer-generated randomization schedule. The study group received a single daily 1 gm dose of
ceftriaxone intravenously along with two additional doses of normal saline solution. The comparison
group received three daily 2 gm doses of cefazolin intravenously. All infusions were given on an b-hour
schedule. Treatments were continued until the patient became afebrile. Each patient was discharged from
the hospital on a regimen of appropriate oral antibiotics as directed by urine culture and sensitivities. At
follow-up visits test-of-cure cultures were obtained.
RESULTS: During the 2-year study period, 178 patients were randomized: 88 received cefazolin and 90
ceffriaxone. Patient demographics and presenting signs and symptoms were similar in both groups. No
differences were noted between the groups regarding days of febrile morbidity, length of hospital stay, or
treatment failures.
CONCLUSIONS: Daily single-dose intravenous ceftriaxone is as effective as multiple-dose cefazolin in the
treatment of patients with acute pyelonephritis during pregnancy. (AM J OBSTET GYNECOL 1995;172:129-33.)

Key words: Ceftriaxone, pyelonephritis

From the Division of Maternal-Fetal Medicine, Department of Ob- Acute pyelonephritis is one of the most frequent seri-
stetrics and Gynecology, University of Florida Health Science Center. ous medical complications of pregnancy, occurring in 1%
Received for publication March 8, 1994; revised May IO, 1994;
accepted June I, 1994. to 2% of obstetric patients.’ Although ampicillin repre-
Reprint requests: Luti Sanchez-Ramos, MD, Department of Obstetrics sented a standard therapy for pyelonephritis in preg-
and Gynecology, University of Florida Health Science Center, 653-I nancy for many years, the current high prevalence of
West 8th St., Jackonville, FL 32209-6561.
Copyright 0 1994 by Mosby-Year Book, Inc. uropathogens resistant to ampicillin supports the use of
0002.9378/94 $3.00 f 0 6/l/58075 cephalosporins.’ Ceftriaxone, the first broad-spectrum

129