The HELLP syndrome. Clinical course, underlying disorders and long-term follow-up - Chapter 1: Introduction

UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

The HELLP syndrome. Clinical course, underlying disorders and long-term

follow-up

van Pampus, M.G.

Publication date

1999

Link to publication

Citation for published version (APA):

van Pampus, M. G. (1999). The HELLP syndrome. Clinical course, underlying disorders and

long-term follow-up.

General rights

It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)

and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open

content license (like Creative Commons).

Disclaimer/Complaints regulations

If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please

let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material

inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter

to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You

will be contacted as soon as possible.

C h a p t e r

1

Chapter 1

Introduction

The HELLP syndrome is defined as a combination of Hemolysis, Elevated Liver enzymes

and Low Platelet count in pregnancy and is currently thought to be a variant of preeclampsia.

Between 1954 and 1976 several authors described a number of (pre) eclamptic patients

with thrombocytopenia, hemolysis and abnormal liver enzymes.

In 1976 Goodlin reported

28 patients with severe preeclampsia, thrombocytopenia and abnormal liver enzymes.

These cases had all been misdiagnosed as disorders unrelated to pregnancy.

In 1982 Weinstein introduced the term HELLP syndrome for this seemingly unique group

of preeclamptic or eclamptic patients with Hemolysis (microangiopatic hemolytic anemia),

Elevated Liver function tests and Low Platelet count.

Hemolysis may be revealed by

examination of a peripheral blood smear in which burr cells are visible (crenated, contracted

red blood cells with spiny projections along the periphery), schistocytes (small, irregularly

shaped red blood cell fragments) and polychromasia. The pathogenesis of microangiopathic

hemolytic anemia is secondary to passage of red cells through small blood vessels with

intimai damage and fibrin deposition. Obstruction of blood flow in the hepatic sinusoids

due to intravascular fibrin deposition is a probable cause of the cellular damage and

distension of the liver resulting in right upper-quadrant or epigastric pain and elevation of

liver enzymes.

The decrease in circulating platelets is secondary to an increased

consumption. In the most severe cases low fibrinogen and positive fibrin degradation split

products will co-exist with the hemolytic anemia.

In 1986 Sibai described the laboratory

criteria: hemolysis is defined by an abnormal peripheral blood smear, bilirubin > 1.2 mg/dl

and LDH > 600 U/L. Elevated liver enzymes were defined as SGOT > 70 U/L, low platelet

count as < 100x10

. In 1990 he introduced the term ELLP for those patients with elevated

liver enzymes and low platelet count without overt hemolysis.

The expression of the disease

may vary largely from malaise for a few days or viral syndrome-like symptoms, to severe

epigastric and right-upper-quadrant pain.

Disorders that are confused with HELLP

syndrome include gastroenteritis, peptic ulcer disease, viral or toxic hepatitis, gall bladder

disease, pyelonephritis, nephrolithiasis, idiopathic thrombocytopenic purpera, and hemolytic

uremic syndrome.

Fifteen percent of HELLP syndrome patients present with only mild

hypertension or even no hypertension and without significant proteinuria.

In these cases

a nonobstetric diagnosis of their complaints may often be made.

The variety in reported prevalence of the HELLP syndrome is related to the lack of

consensus on the definition of the laboratory abnormalities and to differences in reference

values and assay techniques.

The HELLP syndrome occurs in 4 to 35% of pregnancies

complicated by preeclampsia.

The incidence is highest among older, white and

intravascular coagulation, cerebral hemorrhage, abruptio placentae, acute renal failure,

pulmonary edema and ruptured liver hematoma.

The reported maternal mortality of the

HELLP syndrome ranges from 0% to 24%.

Sibai reported 2 maternal deaths in a

group of 112 patients with HELLP syndrome (1.6%).

Two later studies documented a

maternal mortality rate of 1.1 %.

The perinatal mortality ranges from 8% to 37%.3,e,io,i7,2o,2i

Most of the perinatal deaths are related to fetal growth retardation, placental insufficiency,

asphyxia, extreme preterm birth and abruptio placentae. Thirty percent of the newborns

are small for gestational age.

Many different opinions on the causes of the HELLP syndrome and its treatment have

been expressed. Goodlin

considered hypovolemia to be the cause of this syndrome and

hence recommended plasma volume expansion using 5% albumin. He reported a 10%

success rate in prolonging pregnancies in such patients. In addition, he reported

improvement in laboratory findings following the use of prednisone and plasma expansion.

Thiagarajah

reported an increase in platelet count and improvement in liver enzyme

levels in five patients treated with prednisone or betamethasone. Mackenna et al.

treated

patients with the HELLP syndrome conservatively by bed rest and intravenous magnesium

sulfate. In the past treatment of patients with thrombocytopenia, hemolysis and abnormal

liver enzymes in pregnancy was expectant. In 1982 Weinstein advised an aggressive

strategy in HELLP patients to prevent maternal and neonatal death.

Later many other

authors agreed that immediate termination of pregnancy was necessary to prevent serious

maternal morbidity and death

-

-

-

-

'

, while others

recommended a more conservative

approach to prolong pregnancies at less than 32 weeks of gestation. This conservative

management was restricted to 24 hours following the last corticosteroid administration.

Data on the effectiveness of early termination of pregnancy are scarce. In 1996 Sibai

compared maternal outcome of pregnancies complicated by HELLP, partial HELLP (ELLP)

syndrome and severe preeclampsia.

Partial HELLP syndrome was defined by the presence

of one or two features of HELLP but not the complete syndrome. He used strict diagnostic

criteria and managed patients with ELLP syndrome conservatively and patients with HELLP

syndrome more agressively. Women with HELLP syndrome had significantly more serious

complications than those in the other two groups. Although a number of case reports

demonstrate severe maternal complications and deaths resulting from the HELLP syndrome,

only few studies actually report on a consecutive cohort of patients.

One case-control

study compares outcome in HELLP and preeclampsia patients.

This study demonstrated

that the course and outcome of pregnancy in patients with severe preeclampsia, who

received temporizing hemodynamic treatment with invasive monitoring on an intensive

care unit, does not depend on the presence of the HELLP syndrome. Until recently the

Chapter 1

clinical course of the HELLP syndrome following temporizing management strategy without

using volume expanders has only been described in case reports. New developments in

management of HELLP syndrome suggest using low-dose aspirin and corticosteroids to

improve the severity of the HELLP syndrome.

All these proposed therapies have not

been evaluated by large randomised studies.

Recently many studies demonstrated that endothelial cell dysfunction and damage is very

likely the first step in the pathogenesis of preeclampsia and HELLP syndrome.

A study

without control subjects described the association of severe early-onset preeclampsia with

hemostatic abnormalities, associated with an increased risk of thrombosis

. Women with

inherited thrombophilia are at increased risk of preeclampsia and of fetal loss.

Prothrombin 20210 G-A mutation and factor V Leiden mutation are the most prevalent

thrombotic genetic risk factors, together they can be found in up to 60% of the families

with inherited thrombophilia.

Both factors are more frequently co-inherited in patients

with venous thrombophilia.

'

Several publications report a relation between factor V

Leiden mutation and preeclampsia or pregnancy loss.

-

'

'

Until now only two reports

have been published about prothrombin 20210 G-A mutation in relation to obstetric

complications.

Several reports demonstrate an increased risk of cardiovascular disease

in women with these mutations.

Hyperhomocysteinemia, which is associated with an enhanced risk of arterial and venous

thrombosis, has also been described as a risk factor in women with preeclampsia, as well

as those with unexplained recurrent early pregnancy loss or abruptio placentae.

Since

the 1980s the presence of anticardiolipin antibodies has been associated with adverse

perinatal outcome.

Until recently It was unclear whether these hemostatic abnormalities

are indeed found more frequently in patients with a history of preeclampsia as compared

with a control group of women with a history of uncomplicated pregnancies only. Treatment

aimed at correcting underlying abnormalities could have implications for future pregnancies

and for public health.

The induction of endothelial cell dysfunction is probably multifactorial.

'

Lipoprotein

(a) consists of a low density lipoprotein (LDL) particle to which a long polypeptide chain is

attached (the apo(a)polypeptide chain). Several studies showed an association between

high levels of lipoprotein (a) and vessel wall changes. This resulted in the hypothesis that

lipoprotein (a) may induce atherosclerosis.

This may be mediated by the influence of

lipoprotein (a) on the fibrinolytic process, plaque formation, endothelial function and function

of mononucleated cells.

Atheroma has been observed in spiral arteries in both preeclamptic

and normal pregnancies, although in preeclampsia it is much more common, especially in

the decidual segments.

High levels of lipoprotein (a) may interfere with placental circulation

and cause fetal growth retardation.

Only case reports prior to 1997 were available. Leerink

et al. detected no difference in lipoprotein (a) levels between women with a history of

preeclampsia and control subjects with a history of normal pregnancies.

Wang et al. found

elevated levels of lipoprotein (a) in women with preeclampsia as compared to pregnant

women with uncomplicated pregnancies.

Whether women with a history of severe

preeclampsia have higher levels of lipoprotein (a) than women with a history of uncomplicated

pregnancies only has never been described.

Various studies reach different conclusions about the risk of recurrence of the HELLP

syndrome, varying from 3% to 25%.

Women with a history of preeclampsia developing

in the second trimester should be considered at increased risk of severe preeclampsia in

subsequent pregnancies and at increased risk of chronic hypertension.

Long-term problems

of the HELLP syndrome are not only related to the risk of recurrence, but also to the

development of hypertension, diabetes mellitus and cardiovascular disease in later life.

The clinical course of the HELLP syndrome after temporizing management without plasma

volume expansion has scarcely been described. Little is known about risk factors,

long-term problems and the risk of recurrence of the HELLP syndrome.

Aim of the thesis

The aim of this thesis is to answer the following questions regarding the HELLP syndrome:

1. What is the clinical course of the (H)ELLP syndrome during temporizing management?

Does this management increase maternal risk?

2. Which factors contribute to adverse perinatal outcome after severe preeclampsia and

HELLP pregnancy?

3. Is hemodynamic temporizing treatment with plasma volume expansion preferable to

temporizing treatment without plasma volume expansion in severe preeclampsia?

4. Is the prevalence of risk factors for venous and arterial disease increased in women

with a history of severe preeclampsia and/or HELLP syndrome?

5. What is the risk of recurrence in subsequent pregnancies of women with a history of

(H)ELLP syndrome and what are the consequences later in life?

Chapter 1

References

1. Pritchard JA, Weisman R, Ratnoff OD, Vosburgh GJ. Intravascular hemolysis, thrombocytopenia and other hematologic abnormalities associated with severe toxemia of preqnancv N Enal J Med 1954;250:89-98.

2. McKay DG. Hematologic evidence of disseminated intravascular coagulation in eclampsia Obstet Gynecol Surv 1972;27:399-417.

3. Killam AP, Dillard SH, Patton RC, Pederson PR. Pregnancy-induced hypertension complicated by acute liver disease and disseminated intravascular coagulation Am J Obstet Gynecol 1975;123:823-8.

4. Goodlin RC. Severe pre-eclampsia:another great imitator. Am J Obstet Gynecol 1976;125:747-53.

5. Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: A severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982; 142:159-67. 6. Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low

platelets)-Much ado about nothing? Am J Obstet Gynecol 1990;162:311-6.

7. Barton JR, Riely CA, Adamec TA, Shanklin DR, Khoury AD, Sibai BM. Hepatic histopathologic condition does not correlate with laboratory abnormalities in HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) Am J Obstet Gynecol 1992; 167-1538-43 8. Sibai BM, Taslimi MM, El-Nazer A, Amon E, Mabie BC, Ryan GM. Maternal-perinatal outcome

associated with the syndrome of hemolysis, elevated liver enzymes and low platelets in severe pre-eclampsia-eclampsia. Am J Obstet Gynecol 1986;155:501-9.

9. Tomsen TR. HELLP syndrome (helolysis, elevated liver enzymes, and low platelets) presenting as generalized malaise. Am J Obstet Gynecol 1995;172:1876-80.

10. Goodlin RC. Beware the great imitator-severe preeclampsia. ContempObGyn 1982-20215 11. Aarnoudse JG, Houthoff HJ, Weits J, Vellenga E, Huisjes HJ. A syndrome of liver damage and intravascular coagulation in the last trimester of normotensive pregnancy. A clinical and histopathological study. Br J Obstet Gynaecoi 1986;93:145-55.

12. Weinstein L. Preeclampsia/eclampsia with hemolysis, elevated liver enzymes and thrombocytopenia. Obstet Gynecol 1985;66:657-60.

13. Chandran R, Serra-Serra V, Redman CWG. Spontaneous resolution of pre-eclampsia related thrombocytopenia. Br J Obstet Gynecol 1992;99:887-90.

14. Martin JN jr, 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;164:1500-13.

15. Geary M. The HELLP syndrome. Br J Obstet Gynaecol 1997;104:887-91.

16. Barton JR, Sibai BM. Hepatic imaging in HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). Am J Obstet Gynecol 1996;174:1820-7.

17. Reubinoff BE, Schenker JG. HELLP syndrome- a syndrome of hemolysis, elevated liver enzymes and low platelet count- complicating pre-eclampsia-eclampsia. Int J Gynecol Obstet 1991;36:95-102.

18. Martin JN jr, Perry KG, Miles JF, Blake PG, Magann EF, Roberts WE, Martin RW. The interrelationship of eclampsia, HELLP syndrome, and prematurity: cofactors for significant maternal and perinatal risk. Br J Obstet Gynecol 1993;100:1095-1100.

19. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes and low platelets (HELLP syndrome). Am J Obstet Gynecol 1993;169:1000-6.

20. Thiagarajah S, Bourgeois FJ, Harbert GM, Caudle MR. Thrombocytopenia in preeclampsia: Associated abnormalities and management principles. Am J Obstet Gynecol 1984-150-1 -7 21. Mackenna J, Dover NL, Brame RG. Preeclampsia associated with hemolysis, elevated liver

22. van Dam PA, Renier M, Baekelandt M, Buytaert P, Uyttenbroeck F. Disseminated Intravascular Coagulation and the Syndrome of Hemolysis, Elevated Liver Enzymes, and Low Platelets in Severe Preeclampsia. Obstet Gynecol 1989;73:97-102.

23. Schwartz ML, Brenner WE. Pregnancy-induced hypertension presenting with life-threatening thrombocytopenia. Am J Obstet Gynecol 1983;146:756-9.

24. Audibert F, Friedman SA, Frangieh AY, Sibai BM. Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 1996;175:460-4.

25. Visser W, Wallenburg HCS. Temporising management of severe pre-eclampsia with and without the HELLP syndrome. Br J Obstet Gynaecol 1995;102:111-7.

26. Heyborne KD, Burke MS. Porreco RP Prolongation of premature gestation in women with hemolysis, elevated liver enzymes, and low platelets. J Reprod Med 1990;35:53-57. 27. Magann EF, Bass D, Chauhan SP, Sullivan DL, Martin RW, Martin JN jr. Antepartum

corticosteroids: Disease stabilisation in patients with the syndrome of haemolysis, elevated liver enzymes and low platelets (HELLP). Am J Obstet Gynecol 1994;171:1148-1153. 28. Roberts JM, Redman CW. Pre-eclampsia: more than pregnancy-induced hypertension. The

Lancet 1993;341:1447-54.

29. Dekker GA, de Vries JIP, Doelitzsch PM, Huijgens PC, von Blomberg BME, Jakobs C, van Geijn HP. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995;173:1042-8.

30. Preston FE, Rosendaal FR, Walker ID, Brief E, Berntorp E, Conard J, FontcubertaJ, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJM. Increased fetal loss in women with heritable thrombophilia. The Lancet 1996;348:913-6.

31. Sanson BJ, Friederich PW, Simioni P, Zanardi S, Hilsman MV, Girolami A, ten Cate JW, Prins MH. The risk of abortion and stillbirth in antithrombin, protein C and protein S deficient women. Thromb Haemostas 1996;75:387-8.

32. Lindoff C, Ingemarsson G, Segelmark M, Thysell H, Astedt B. Preeclampsia is associated with a reduced response to activated protein C. Am J Obstet Gynecol 1997;176:457-60. 33. Dizon-Townson DS, Nelson LM, Easton K, Ward K. The factor V Leiden mutation may

predispose women to severe preeclampsia. Am J Obstet Gynecol 1996;175:902-5. 34. Bertina RM. Factor V and other coagulation factor mutations affecting thrombotic risk.

(Review) (42 refs). Clinical Chemistry 1997;43:1678-83.

35. Howard TE, Marusa M, Boisza J, Young A, Seqeira J, Channell C, Guy C, Benson E, Duncan A. The prothrombin gene 3'-untranslated region mutation is frequently associated with factor V Leiden in thrombophilia patients and shows ethnic-specific variation in allele frequency (letter). Blood 1998;91:1092.

36. Ehrenforth S, Ludwig G, Klinke S, Krause M, Scharrer I, Nowak-Göttl U. The prothrombin 20210 A allele is frequently coinherited in young carriers of the factor V Arg 506 to Gin mutation with venous thrombophilia (letter). Blood 1998;91:2209-10.

37. Brenner B, Mandel H, Lanir N, Younis J, Rothbart H, Ohel G, Blumenfeld Z. Activated protein C resistance can be associated with recurrent loss. Br J Haematol 1997;97:551-4. 38. Rotmensch S, Liberati M, Mittelmann M, Ben-Rafael Z. Activated protein C resistance and

adverse pregnancy outcome. Am J Obstet Gynecol 1997;177:170-3.

39. Dizon-Townson DS, Meline L, Nelson LM, Varner M, Ward K. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 1997;177:402-5.

40. Grandone E, Margaglione M, Colaizzo D, d'Addedda M, Cappucci G, Vecchione G, Sciannamé N, Pavone G, Di Minno G. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997;77:822-4.

41. Kupfermine MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB. Increased Frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9-13.

Chapter 1 42. Gris J, Quéré I, Monpeyroux F, Mercier E, Ripart-Neveu S, Tailland M, Hoffet M, Berlan J, Daurès J, Mares M. Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent. Thromb Haemost 1999;81:891 -9. 43. Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos HL. A common

prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood 1997;90:1747-50.

44. Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth jr WT, Raghunathan TE, KoepsellTD, ReitsmaPH. Factor V Leiden (Resistance to activated Protein C) increases the risk of myocardial infarction in young women. Blood 1997;89:2817-21. 45. Doggen CJM, Manger Cats VM, Bertina RM, and Rosendaal FR. Interaction of coagulation

defects and cardiovascular risk factors: increased risk of myocard infarction associated with factor V Leiden or prothrombin 20210A. Circulation 1998;97:1037-41.

46. Arruda VR, Siquiera LH, Chiaparini LC, Coelho OR, Mansur AP, Ramires A, Annichino-Bizzacchi JM. Prevalence of the prothrombin gene variant 20210 G-A among patients with myocardial infarction. Cardiovascular Research 1998;37:42-5.

47. Wouters MGAJ, Boers GHJ, Blom HJ, Trijbels FJM, Thomas CMG, Borm GF, Steegers-Theunissen RPM, Eskes TKAB. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent pregnancy loss. Fertility and Sterility 1993;60:820-5.

48. Steegers-Theunissen RPM, Boers GHJ, Blom HJ, Trijbels FJM, Eskes TKAB. Hyperhomocysteinemia and recurrent spontaneous abortion or abruptio placentae. Lancet 1992;339:1122-3.

49. Pattison NS, Birdsall MA, Chamley LW. Recurrent fetal loss and the antiphospholipid syndrome. Recent Adv Obstet Gynaecol 1994;18:23-50.

50. de Groot CJM, Davidge ST, Friedman SA, Mclaughlin MK, Roberts JM, Taylor RN. Plasma from preeclamptic women increases human endothelial cell prostacyclin production without changes in cellular enzyme activity or mass. Am J Obstet Gynecol 1995;172:977-84. 51. Hubel CA, Mclaughlin MK, Evans RW, Hauth BA, Sims CJ, Roberts JM. Fasting serum

triglycerides, free fatty acids, and malondialdehyde are increased in preeclampsia, are positively correlated, and decrease within 48 hours post partum. Am J Obstet Gynecol 1996;174:975-82.

52. Sattar N, Bendomir A, Berry C, Shepherd J, Greer IA, Packard CJ. Lipoprotein Subfraction Concentrations in Preeclampsia: Pathogenic Parallels to Atherosclerosis. Obstet and Gynecol 1997;89:403-7.

53. Redman CWG. Immunological aspects of pre-eclampsia. Bailieres Clin Obstet Gynaecol 1992;6(3):601-15.

54. Endresen MJR. Preeclampsia and endothelial cell function. Acta Obstet Gynecol Scand 1995;74:667-69.

55. Scanu AM. Lipopotein (a) and atherosclerosis. Ann Intern Med 1991;115:209-18.

56. Miles LA, Fless GM, Levin EG, Scanu AM, Plow EF. A potential basis for the thrombotic risks associated with lipoprotein (a). Nature (London) 1989;339:301-5.

57. Heinrich J, Sandkamp M, Kokott R, Schulte H, Assmann G. Relationship of lipoprotein (a) to variables of coagulation and fibrinolysis in a healthy population. Clin Chem. (Winston-Salem, NC) 1991;37:1950-4.

58. van den Ende A, van der Hoek YY, Kastelein JJP, Koschinsky ML, Labeur C, Rosseneu M. Lipoprotein (a). In: Spiegel H, editor. Volume 32: Advances in Clinical Chemistry; 1996:74-135.

59. Meekins JW, Pijnenborg R, Hanssens M, Assche van A, Mcfadyen IR. Immunohistochemical Detection of Lipoprotein (a) in the Wall of Placental Bed Spiral Arteries in normal and Severe Preeclamptic Pregnancies. Placenta 1994;15:511-24.

60. Berg K, Roald B, Sande H. High lipoprotein level in maternal serum may interfere with placental circulation and cause fetal growth retardation. Clin Genet 1994;46:52-6.

61. Leerink CB, de Vries CV, van der Klis FR. Elevated levels of serum lipoprotein (a) and apolipoprotein (a) phenotype are not related to pre-eclampsia. Acta Obstet Gynecol Scand 1997;76:625-8.

62. Wang J, Mimuro S, Lahoud R, Trudinger B, Li Wang X. Elevated levels of lipoprotein (a) in women with preeclampsia. Am J Obstet Gynecol 1998;178:146-9.

63. Sibai BM, Ramadan MK, Chari RS, Friedman SA. Pregnancies complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): Subsequent preganancy outcome and long-term prognosis. Am J Obstet Gynecol 1995;172:125-9.

64. Sullivan CA, Magann EF, Perry KG Jnr, Roberts EW, Blake PG, Martin JN jr. The recurrence risk of the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP ) in subsequent gestations. Am J Obstet Gynecol 1994;171:940-3.

65. Sibai BM, Mercer B, Sarinoglu C. Severe preeclampsia in the second trimester: Recurrence risk and long-term prognosis. Am J Obstet Gynecol 1991;165:1408-12.

66. Ness RB, Roberts JM. Heterogeneous causes constituting the single syndrome of preeclamspia: A hypothesis and its implications. Am J Obstet Gynecol 1996;175:1365-70. 67. Sibai BM, El-Nazer A, Gonzalez-Ruiz. Severe preeclampsia-eclampsia in young primigravid women: Subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 1986;155:1011-6.