|Symptoms||Feeling tired, retaining fluid, headache, nausea, upper abdominal pain, blurry vision, seizures|
|Complications||Disseminated intravascular coagulation (DIC), placental abruption, kidney failure, pulmonary edema|
|Usual onset||Last 3 months of pregnancy or shortly after childbirth|
|Risk factors||Preeclampsia, eclampsia, previously having HELLP, mother older than 25 years, white|
|Diagnostic method||Blood tests|
|Differential diagnosis||Viral hepatitis, thrombotic thrombocytopenic purpura, cholangitis, hemolytic uremic syndrome|
|Treatment||Delivery of the baby as soon as possible, management of blood pressure|
|Prognosis||<1% risk of death (mother)|
|Frequency||~0.7% of pregnancies|
HELLP syndrome is a complication of pregnancy characterized by hemolysis, elevated liver enzymes, and a low platelet count. It usually begins during the last three months of pregnancy or shortly after childbirth. Symptoms may include feeling tired, retaining fluid, headache, nausea, upper right abdominal pain, blurry vision, nosebleeds, and seizures. Complications may include disseminated intravascular coagulation, placental abruption, and kidney failure.
The cause is unknown. The condition occurs in association with pre-eclampsia or eclampsia. Other risk factors include previously having the syndrome, a mother older than 25 years, and being white. The underlying mechanism may involve abnormal placental development. Diagnosis is generally based on blood tests finding signs of red blood cell breakdown (lactate dehydrogenase greater than 600 U/l), an aspartate transaminase greater than 70 U/l, and platelets less than 100x109/l. If not all the criteria are present, the condition is incomplete.
Treatment generally involves delivery of the baby as soon as possible. This is particularly true if the pregnancy is beyond 34 weeks of gestation. Medications may be used to decrease blood pressure and blood transfusions may be required. Corticosteroids may be used to speed development of the baby's lungs, if it is early in pregnancy.
HELLP syndrome occurs in about 0.7% of pregnancies and affects about 15% of women with eclampsia or severe pre-eclampsia. Death of the mother is uncommon (< 1%). Outcomes in the babies are generally related to how premature they are at birth. The syndrome was first named in 1982 by American gynaecologist Louis Weinstein.
Signs and symptoms
The first signs of HELLP usually start appearing midway through the third trimester, though the signs can appear in earlier and later stages. Symptoms vary in severity and between individuals and are commonly mistaken with normal pregnancy symptoms, especially if they are not severe.
HELLP syndrome patients suffer from general discomfort followed by severe epigastric pain or right upper abdominal quadrant pain, accompanied by nausea, vomiting, backache, anaemia, and hypertension. Some patients may also suffer from a headache and visual issues. These symptoms may also become more severe at night. As the condition progresses and worsens, a spontaneous hematoma occurs following the rupture of the liver capsule, which occurs more frequently in the right lobe. The presence of any combinations of these symptoms, subcapsular liver hematoma in particular, warrants an immediate check-up due to the high morbidity and mortality rates of this condition.
Elevated body mass index and metabolic disorders, as well as antiphospholipid syndrome, significantly increase the risk of HELLP syndrome in all female patients. Females who have had or are related to a female with previous HELLP syndrome complications tend to be at a higher risk in all their subsequent pregnancies.
The risk of HELLP syndrome is not conclusively associated with a specific genetic variation, but likely a combination of genetic variations, such as FAS gene, VEGF gene, glucocorticoid receptor gene and the tol-like receptor gene, increase the risk.
The pathophysiology is still unclear and an exact cause is yet to be found. However, it shares a common mechanism, which is endothelial cell injury, with other conditions, such as acute kidney injury and thrombotic thrombocytopenic purpura. Increasing the understanding of HELLP syndrome's pathophysiology will enhance diagnostic accuracy, especially in the early stages. This will lead to advancements in the prevention, management, and treatment of the condition, which will increase the likelihood of both maternal and fetal survival and recovery.
Inflammation and coagulation
As a result of endothelial cell injury, a cascade of pathological reactions manifests and become increasingly severe and even fatal as signs and symptoms progress. Following endothelial injury, vasospasms and platelet activation occur alongside the decreased release of the endothelium-derived relaxing factor and increased the release of von Willebrand factor (vWF), leading to general activation of the coagulation cascade and inflammation. Placental components, such as inflammatory cytokines and syncytiotrophoblast particles interact with the maternal immune system and endothelial cells, further promoting coagulation and inflammation. These interactions also elevate leukocyte numbers and interleukin concentrations, as well as increase complement activity.
Low platelet count
vWF degradation in HELLP syndrome is inhibited due to decreased levels of degrading proteins, leading to an increased exposure of platelets to vWF. As a result, thrombotic microangiopathies develop and lead to thrombocytopenia.
As a result of the high number of angiopathies, the erythrocytes fragment as they pass through the blood vessels with damaged endothelium and large fibrin networks, leading to macroangiopathic haemolytic anaemia. As a consequence of hemolysis, lactic acid dehydrogenase (LDH) and hemoglobin are released, with the latter binding to serum bilirubin or haptoglobin.
During the coagulation cascade, fibrin is deposited in the liver and leads to hepatic sinusoidal obstruction and vascular congestion, which increase intrahepatic pressure. Placenta-derived FasL (CD95L), which is toxic to human hepatocytes, leads to hepatocyte apoptosis and necrosis by inducing the expression of TNFα and results in the release of liver enzymes. Hepatic damages are worsened by the disrupted portal and total hepatic blood flow that result as a consequence of the microangiopathies. Collectively, widespread endothelial dysfunction and hepatocellular damage result in global hepatic dysfunction often leading to liver necrosis, haemorrhages, and capsular rupture.
Early and accurate diagnosis, which relies on laboratory tests and imaging exams, is essential for treatment and management and significantly reduces the morbidity rate. However, diagnosis of the syndrome is challenging, especially due to the variability in the signs and symptoms and the lack of consensus amongst healthcare professionals. Similarities to other conditions, as well as normal pregnancy features, commonly lead to misdiagnosed cases or more often, delayed diagnosis.
There is a general consensus regarding the main three diagnostic criteria of HELLP syndrome, which include hepatic dysfunction, thrombocytopenia and microangiopathic haemolytic anaemia in patients suspected to have preeclampsia.
- A blood smear will often exhibit abnormalities, such as schistocytes, bur cells, and helmet cells, which indicate erythrocyte damage.
- Thrombocytopenia, which is the earliest coagulopathy present in all HELLP syndrome patients, is indicated by low platelet count (below 100 x 109 L-1) or by testing the levels of fibrin metabolites and antithrombin III.
- Elevated serum levels of certain proteins, in particular, LDH, alanine transaminase (ALT) and aspartate transaminase (AST), are indicative of hepatic dysfunction. Extremely high serum levels of these proteins, specifically LDH levels > 1,400 IU/L, AST levels > 150 IU/L and ALT levels > 100 IU/L, significantly elevate the risk of maternal mortality.[excessive citations]
A number of other, but less conclusive, clinical diagnostic criteria are also used in diagnosis alongside the main clinical diagnostic criteria for HELLP syndrome.
- De novo manifestation of hypertension with systolic pressure and diastolic pressure above 160mmHg and 110 mmHg, respectively.
- Proteinuria, leucocytosis and elevated uric acid concentrations > 7.8 mg.
- Decreased serum haptoglobin and haemoglobin levels.
- Increased serum bilirubin levels and visual disturbances.
Imaging tests, such as ultrasound, tomography or magnetic resonance imaging (MRI), are instrumental in the correct diagnosis of HELLP syndrome in patients with suspected liver dysfunction. Unurgent cases must undergo MRI, but laboratory tests, such as glucose determination, are more encouraged in mild cases of HELLP syndrome.
A classification system, which was developed in Mississippi, measures the severity of the syndrome using the lowest observed platelet count in the patients alongside the appearance of the other two main clinical criteria. Class I is the most severe, with a relatively high risk of morbidity and mortality, compared to the other two classes.
- Class I HELLP syndrome is characterised by a platelet count below 50,000/µL.
- Class II HELLP syndrome is characterised by a platelet count of 50,000-100,000/µL.
- Class III HELLP syndrome is characterised by a platelet count of 100,000-150,000/µL.
Another classification system, introduced in Memphis, categorises HELLP syndrome based on its expression.
- Partial expression of the condition is characterised by the manifestation of one or two of the main diagnostic criteria.
- The complete expression of the condition is characterised by the manifestation of all three main diagnostic criteria.
The only current recommended and most effective treatment is delivery of the baby, as the signs and symptoms diminish and gradually disappear following the delivery of the placenta. Prompt delivery is the only viable option in cases with multiorgan dysfunction or multiorgan failure, haemorrhage and considerable danger to the fetus. Certain medications are also used to target and alleviate specific symptoms.
With treatment, maternal mortality is about 1 percent, although complications such as placental abruption, acute kidney injury, subcapsular liver hematoma, permanent liver damage, and retinal detachment occur in about 25% of women. Perinatal mortality (stillbirths plus death in infancy) is between 73 and 119 per 1000 babies of woman with HELLP, while up to 40% are small for gestational age. In general, however, factors such as gestational age are more important than the severity of HELLP in determining the outcome in the baby.
HELLP syndrome affects 10-20% of pre-eclampsia patients and is a complication in 0.5-0.9% of all pregnancies. Caucasian women over 25 years of age comprise most of the diagnosed HELLP syndrome cases. In 70% of cases before childbirth, the condition manifests in the third trimester, but 10% and 20% of the cases exhibit symptoms before and after the third trimester, respectively. Postpartum occurrences are also observed in 30% of all HELLP syndrome cases.
HELLP syndrome was identified as a distinct clinical entity (as opposed to severe pre-eclampsia) by Dr. Louis Weinstein in 1982. In a 2005 article, Weinstein wrote that the unexplained postpartum death of a woman who had haemolysis, abnormal liver function, thrombocytopenia, and hypoglycemia motivated him to review the medical literature and to compile information on similar women. He noted that cases with features of HELLP had been reported as early as 1954.
- "HELLP syndrome". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 2018. Retrieved 5 October 2018.
- Haram K, Svendsen E, and Abildgaard U (February 2009). "The HELLP syndrome: clinical issues and management. A Review". BMC Pregnancy Childbirth. 9: 8. doi:10.1186/1471-2393-9-8. PMC 2654858. PMID 19245695.
- Odze, Robert D.; Goldblum, John R. (2009). Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. Elsevier Health Sciences. p. 1240. ISBN 9781416040590.
- Cohen, Hannah; O'Brien, Patrick (2015). Disorders of Thrombosis and Hemostasis in Pregnancy: A Guide to Management. Springer. p. 305. ISBN 9783319151205.
- "Preeclampsia and Eclampsia". Merck Manuals Consumer Version. March 2018. Retrieved 5 October 2018.
- Sibai BM, Taslimi MM, el-Nazer A, Amon E, Mabie BC, Ryan GM (September 1986). "Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia". J Perinat Med. 155 (3): 501–9. doi:10.1016/0002-9378(86)90266-8. PMID 3529964.
- Visser W, Wallenburg HC (February 1995). "Temporising management of severe pre-eclampsia with and without the HELLP syndrome". Br J Obstet Gynaecol. 102 (2): 111–7. doi:10.1111/j.1471-0528.1995.tb09062.x. PMID 7756201.
- Sibai BM (May 2004). "Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count". Obstet Gynecol. 103 (5 Pt 1): 981–91. doi:10.1097/01.AOG.0000126245.35811.2a. PMID 15121574.
- Sibai BM (February 1990). "he HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing?". Am J Obstet Gynecol. 162 (2): 311–6. doi:10.1016/0002-9378(90)90376-i. PMID 2309811.
- Weinstein L (September 2005). "It has been a great ride: The history of HELLP syndrome". Am J Obstet Gynecol. 193 (3 Pt 1): 860–3. doi:10.1016/j.ajog.2005.06.058. PMID 16150288.
- Aarnoudse JG, Houthoff HJ, Weits J, Vellenga E, Huisjes HJ (February 1986). "A syndrome of liver damage and intravascular coagulation in the last trimester of normotensive pregnancy. A clinical and histopathological study". Br J Obstet Gynaecol. 93 (2): 145–55. doi:10.1111/j.1471-0528.1986.tb07879.x. PMID 3511956.
- Araujo AC, Leao MD, Nobrega MH, Bezerra PF, Pereira FV, Dantas EM, Azevedo GD, Jeronimo SM (July 2006). "Characteristics and treatment of hepatic rupture caused by HELLP syndrome". Am J Obstet Gynecol. 1995 (1): 129–33. doi:10.1016/j.ajog.2006.01.016. PMID 16579935.
- Strand S, Strand D, Seufert R, Mann A, Lotz J, Blessing M, Lahn M, Wunsch A, Broering DC, Hahn U, Grischke EM, Rogiers X, Otto G, Gores GJ, Galle PR (March 2004). "Placenta-derived CD95 ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome". Gastroenterology. 126 (3): 849–58. doi:10.1053/j.gastro.2003.11.054. PMID 14988839.
- Rinehart BK, Terrone DA, Magann EF, Martin RW, May WL, Martin JN Jr (March 1996). "Preeclampsia-associated hepatic hemorrhage and rupture: mode of management related to maternal and perinatal outcome". Obstet Gynecol Surv. 54 (3): 196–202. doi:10.1097/00006254-199903000-00024. PMID 10071839.
- Wicke C, Pereira PL, Neeser E, Flesch I, Rodegerdts EA, Becker HD (January 2004). "Subcapsular liver hematoma in HELLP syndrome: Evaluation of diagnostic and therapeutic options--a unicenter study". Am J Obstet Gynecol. 190 (1): 106–12. doi:10.1016/j.ajog.2003.08.029. PMID 14749644.
- Lachmeijer AM, Arngrimsson R, Bastiaans EJ, Frigge ML, Pals G, Sigurdardottir S, Stefansson H, Palsson B, Nicolae D, Kong A, Aarnoudse JG, Gulcher JR, Dekker GA, ten Kate LP, Stefansson K (October 2001). "A genome-wide scan for preeclampsia in the Netherlands". Eur J Hum Genet. 9 (10): 758–64. doi:10.1038/sj.ejhg.5200706. PMID 11781687.
- Habli M, Eftekhari N, Wiebracht E, Bombrys A, Khabbaz M, How H, Sibai B (October 2009). "Long-term maternal and subsequent pregnancy outcomes 5 years after hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome". Am J Obstet Gynecol. 201 (4): 385 e1–5. doi:10.1016/j.ajog.2009.06.033. PMID 19716544.
- Hupuczi P, Rigo B, Sziller I, Szabo G, Szigeti Z, Papp Z (2006). "Follow-up analysis of pregnancies complicated by HELLP syndrome". Fetal Diagn Ther. 21 (6): 519–22. doi:10.1159/000095665. PMID 16969007. S2CID 25427426.
- Sziller I, Hupuczi P, Normand N, Halmos A, Papp Z, Witkin SS (March 2009). "Fas (TNFRSF6) gene polymorphism in pregnant women with hemolysis, elevated liver enzymes, and low platelets and in their neonates". Obstet Gynecol. 107 (3): 582–7. doi:10.1097/01.AOG.0000195824.51919.81. PMID 16507928. S2CID 25044126.
- Nagy B, Savli H, Molvarec A, Varkonyi T, Rigo B, Hupuczi P, Rigo J Jr (2006). "Vascular endothelial growth factor (VEGF) polymorphisms in HELLP syndrome patients determined by quantitative real-time PCR and melting curve analyses". Clin Chim Acta. 389 (1–2): 126–31. doi:10.1016/j.cca.2007.12.003. PMID 18167313.
- Bertalan R, Patocs A, Nagy B, Derzsy Z, Gullai N, Szappanos A (July 2009). "Overrepresentation of BclI polymorphism of the glucocorticoid receptor gene in pregnant women with HELLP syndrome". Clin Chim Acta. 405 (1–2): 148–52. doi:10.1016/j.cca.2009.03.046. PMID 19336230.
- van Rijn BB, Franx A, Steegers EA, de Groot CJ, Bertina RM, Pasterkamp G (April 2008). "Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome". PLOS ONE. 3 (4): e1865. Bibcode:2008PLoSO...3.1865V. doi:10.1371/journal.pone.0001865. PMC 2270909. PMID 18382655.
- Geary M (August 1997). "The HELLP syndrome". Br J Obstet Gynaecol. 104 (8): 877–91. doi:10.1111/j.1471-0528.1997.tb14346.x. PMID 9255078.
- Sibai BM, Kustermann L, Velasco J (July 1994). "DCurrent understanding of severe preeclampsia, pregnancy-associated hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, hemolysis, elevated liver enzymes, and low platelet syndrome, and postpartum acute renal failure: different clinical syndromes or just different names?". Curr Opin Nephrol Hypertens. 3 (4): 436–45. doi:10.1097/00041552-199407000-00010. PMID 8076148.
- Benedetto C, Marozio L, Tancredi A, Picardo E, Nardolillo P, Tavella AM, Salton L (2011). "Biochemistry of HELLP syndrome". Adv Clin Chem. Advances in Clinical Chemistry. 53: 85–104. doi:10.1016/B978-0-12-385855-9.00004-7. ISBN 9780123858559. PMID 21404915.
- Gardiner C, Tannetta DS, Simms CA, Harrison P, Redman CW, Sargent IL (2011). "Syncytiotrophoblast microvesicles released from pre-eclampsia placentae exhibit increased tissue factor activity". PLOS ONE. 6 (10): e26313. Bibcode:2011PLoSO...626313G. doi:10.1371/journal.pone.0026313. PMC 3194796. PMID 22022598.
- Hulstein JJ, van Runnard Heimel PJ, Franx A, Lenting PJ, Bruinse HW, Silence K, de Groot PG, Fijnheer R (December 2006). "Acute activation of the endothelium results in increased levels of active von Willebrand factor in hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome". PLOS ONE. 4 (12): 2569–75. doi:10.1111/j.1538-7836.2006.02205.x. PMID 16968329.
- Terrone DA, Rinehart BK, May WL, Moore A, Magann EF, Martin JN Jr (August 2000). "SLeukocytosis is proportional to HELLP syndrome severity: evidence for an inflammatory form of preeclampsia". South Med J. 93 (8): 768–71. doi:10.1097/00007611-200093080-00005. PMID 10963506.
- Haeger M, Unander M, Norder-Hansson B, Tylman M, Bengtsson A (January 1992). "Complement, neutrophil, and macrophage activation in women with severe preeclampsia and the syndrome of hemolysis, elevated liver enzymes, and low platelet count". Obstet Gynecol. 79 (1): 19–26. PMID 1727579.
- Lattuada A, Rossi E, Calzarossa C, Candolfi R, Mannucci PM (September 2003). "Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome". Haematologica. 88 (9): 1029–34. PMID 12969811.
- Weinstein L (January 1982). "Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy". Am J Obstet Gynecol. 142 (2): 159–67. doi:10.1016/s0002-9378(16)32330-4. PMID 7055180.
- Norwitz ER, Hsu CD, Repke JT (June 2002). "Acute complications of preeclampsia". Clin Obstet Gynecol. 45 (2): 308–29. doi:10.1097/00003081-200206000-00004. PMID 12048392. S2CID 32982061.
- Stevenson JT, Graham DJ (September 1995). "Hepatic hemorrhage and the HELLP syndrome: a surgeon's perspective". Am Surg. 61 (9): 756–60. PMID 7661469.
- Martin JN Jr, Rinehart BK, May WL, Magann EF, Terrone DA, Blake PG (June 1999). "The spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis, elevated liver enzyme levels, and low platelet count) syndrome classification". Am J Obstet Gynecol. 180 (6 Pt 1): 1373–84. doi:10.1016/s0002-9378(99)70022-0. PMID 10368474.
- Martin JN Jr, Rose CH, Briery CM (October 2006). "Understanding and managing HELLP syndrome: the integral role of aggressive glucocorticoids for mother and child". Am J Obstet Gynecol. 195 (4): 914–34. doi:10.1016/j.ajog.2005.08.044. PMID 16631593.
- Martin JN Jr, Blake PG, Perry KG, Jr, McCaul JF, Hess LW, Martin RW (June 1992). "The natural history of HELLP syndrome: patterns of disease progression and regression". Am J Obstet Gynecol. 164 (6 Pt 1): 1500–9, discussion 1509–13. doi:10.1016/0002-9378(91)91429-z. PMID 2048596.
- Catanzarite VA, Steinberg SM, Mosley CA, Landers CF, Cousins LM, Schneider JM (September 1995). "Severe preeclampsia with fulminant and extreme elevation of aspartate aminotransferase and lactate dehydrogenase levels: high risk for maternal death". Am J Perinatol. 12 (5): 310–3. doi:10.1055/s-2007-994482. PMID 8540929.
- Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK (November 1989). "Preeclampsia: an endothelial cell disorder". Am J Obstet Gynecol. 161 (5): 1200–4. doi:10.1016/0002-9378(89)90665-0. PMID 2589440.
- Sibai BM (July 1996). "Treatment of hypertension in pregnant women". N Engl J Med. 335 (45): 257–65. doi:10.1056/NEJM199607253350407. PMID 8657243.
- Weinstein L (November 1985). "Preeclampsia/eclampsia with hemolysis, elevated liver enzymes, and thrombocytopenia". Obstet Gynecol. 66 (5): 657–60. PMID 4058824.
- Martin JN Jr, Blake PG, Lowry SL, Perry KG Jr, Files JC, Morrison JC (November 1990). "Pregnancy complicated by preeclampsia-eclampsia with the syndrome of hemolysis, elevated liver enzymes, and low platelet count: how rapid is postpartum recovery?". Obstet Gynecol. 76 (5 Pt 1): 737–41. doi:10.1097/00006250-199011000-00001. PMID 2216215.
- Audibert F, Friedman SA, Frangieh AY, Sibai BM (August 1996). "Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome". Am J Obstet Gynecol. 175 (2): 460–4. doi:10.1016/s0002-9378(96)70162-x. PMID 8765269.
- Haddad B, Barton JR, Livingston JC, Chahine R, Sibai BM (August 2000). "Risk factors for adverse maternal outcomes among women with HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome". Am J Obstet Gynecol. 183 (2): 444–8. doi:10.1067/mob.2000.105915. PMID 10942484.
- Rath W, Loos W, Kuhn W, Graeff H (August 1990). "The importance of early laboratory screening methods for maternal and fetal outcome in cases of HELLP syndrome". Eur J Obstet Gynecol Reprod Biol. 36 (1–2): 43–51. doi:10.1016/0028-2243(90)90048-6. PMID 2365128.
- Woudstra, DM; Chandra, S; Hofmeyr, GJ; Dowswell, T (8 September 2010). "Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy". The Cochrane Database of Systematic Reviews (9): CD008148. doi:10.1002/14651858.CD008148.pub2. PMC 4171033. PMID 20824872.
- Aloizos S, Seretis C, Liakos N, Aravosita P, Mystakelli C, Kanna E, Gourgiotis (May 2013). "HELLP syndrome: understanding and management of a pregnancy-specific disease". J Obstet Gynaecol. 33 (4): 331–7. doi:10.3109/01443615.2013.775231. PMID 23654309. S2CID 9250437.
- Belfort, Michael A.; Steven Thornton; George R. Saade (2002). Hypertension in Pregnancy. CRC Press. pp. 159–60. ISBN 9780824708276. Retrieved 2012-04-13.
- Stevenson, David Kendal; William E. Benītz (2003). Fetal and Neonatal Brain Injury. Cambridge University Press. p. 260. ISBN 9780521806916. Retrieved 2012-04-13.
- Santema JG, Koppelaar I, Wallenburg HC (January 1995). "Hypertensive disorders in twin pregnancy". Eur J Obstet Gynecol Reprod Biol. 58 (1): 13–9. doi:10.1016/0028-2243(94)01982-d. hdl:1765/61934. PMID 7758654.
- Padden MO (September 1999). "HELLP syndrome: recognition and perinatal management". American Family Physician. 60 (3): 829–36, 839. PMID 10498110.
- Barton JR, Sibai BM (December 2004). "Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome". Clin Perinatol. 31 (4): 807–33. doi:10.1016/j.clp.2004.06.008. PMID 15519429.
- Pritchard JA, Weisman R Jr, Ratnoff OD, Vosburgh GJ (Jan 1954). "Intravascular hemolysis, thrombocytopenia and other hematologic abnormalities associated with severe toxemia of pregnancy". N Engl J Med. 250 (3): 89–98. doi:10.1056/NEJM195401212500301. PMID 13119851.