Original Research
Risk Factors, Management, and Outcomes of Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome and Elevated Liver Enzymes, Low Platelets Syndrome Kathryn E. Fitzpatrick, BA, MSc, Kim Hinshaw, and Marian Knight, MBChB, DPhil
MB BS, FRCOG,
OBJECTIVE: To describe the risk factors, management and outcomes of hemolysis, elevated liver enzymes, and low platelets (HELLP) and elevated liver enzymes, low platelets (ELLP) syndrome in the United Kingdom. METHODS: A case–control study was conducted using the U.K. Obstetric Surveillance System between June 2011 and May 2012, including 129 women diagnosed with HELLP, 81 diagnosed with ELLP, and 476 control women. RESULTS: Women with HELLP were more likely than those in the control group to be 35+ years old (33% compared with 22%, adjusted odds ratio [OR] 1.85, 95% confidence interval [CI] 1.12–3.06), nulliparous (67% compared with 43%, adjusted OR 4.16, 95% CI 2.48–6.98), have had a previous gestational hypertensive disorder (9% compared with 7%, adjusted OR 3.47, 95% CI 1.49–8.09), and have a multiple pregnancy (7% compared with 2%, adjusted OR 4.51, 95% CI 1.45–14.06). Women with ELLP were more likely than those in the From the National Perinatal Epidemiology Unit, University of Oxford, Oxford, and Sunderland Royal Hospital, Sunderland, United Kingdom. This article presents independent research funded by the National Institute for Health Research (NIHR) under the “Beyond maternal death: Improving the quality of maternity care through national studies of ‘near-miss’ maternal morbidity” program (Programme Grant RP-PG-0608-10038). Marian Knight is funded by a NIHR Professorship. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank the United Kingdom Obstetric Surveillance System reporting clinicians who notified cases and completed data collection forms. Corresponding author: Kathryn E. Fitzpatrick, BA, MSc, National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, UK; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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Jennifer J. Kurinczuk,
MD, MSc,
control group to be nulliparous (79% compared with 43%, adjusted OR 8.35, 95% CI 3.88–17.95), and have had a previous gestational hypertensive disorder (7% compared with 7%, adjusted OR 4.66, 95% CI 1.37– 15.89). Of the women diagnosed antenatally with HELLP or ELLP, 51% (71/138) had planned management of immediate delivery, 43% (60/138) had delivery planned within 48 hours, and 5% (7/138) had planned expectant (conservative) management. No differences were found between women who had delivery planned within 48 hours and those who had planned immediate delivery in terms of the proportion who received blood products (37% compared with 33%, P5.681); were admitted to the intensive care unit (57% compared with 61%, P5.652); experienced severe morbidity (10% compared with 4%, P5.300); or had a neonate with major complications (6% compared with 11%, P5.342). CONCLUSION: A short delay in the delivery of women diagnosed antenatally with HELLP or ELLP syndrome may be considered. However, the rarity of the condition limits study power. (Obstet Gynecol 2014;123:618–27) DOI: 10.1097/AOG.0000000000000140
LEVEL OF EVIDENCE: II
H
emolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is a serious complication of pregnancy that usually occurs in women who have signs of preeclampsia.1 In the absence of hemolysis, the condition has been called elevated liver enzymes, low platelets (ELLP) syndrome.2,3 Incidence estimates vary from five to 76 per 10,000 deliveries4,5 and between 8% and 24% of women with severe preeclampsia or eclampsia.5,6 There has been no comprehensive study of the risk factors for this complication. There is also
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debate over the optimal management of the syndrome, particularly with regard to women who develop the condition remote from term.3,7 The aims of this study were to investigate the risk factors for HELLP syndrome and ELLP syndrome in the United Kingdom and to describe the management and outcomes to inform future practice guidelines.
MATERIALS AND METHODS A population-based nationwide case–control study was conducted. The London Research Ethics Committee approved the study (reference 10/H0717/20). Cases were defined as any pregnant women meeting the criteria outlined in Box 1. Cases with hemolysis were classified as HELLP syndrome and those without hemolysis were classified as ELLP syndrome. Controls were defined as the women delivering just before the reported case in the same hospital who did not have HELLP or ELLP syndrome. The U.K. Obstetric Surveillance System was used to identify cases on a national basis between June 1, 2011, and May 31, 2012.8 Every month, up to four nominated
Box 1. Case Definition of Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome or Elevated Liver Enzymes, Low Platelets Syndrome Any pregnant women identified as having new onset of the following: Elevated liver enzymes, defined as: Serum aspartate aminotransferase 70 international units/L or greater OR Gamma-glutamyltransferase 70 international units/L or greater OR Alanine aminotransferase 70 international units/L or greater AND Low platelets, defined as platelet count less than 1003109/L AND EITHER Hemolysis, defined by abnormal (fragmented or contracted red cells) peripheral blood smear or serum lactate dehydrogenase levels 600 international units/L or greater or total bilirubin 20.5 micromole/L or greater OR Hypertension, defined as a systolic blood pressure 140 mm Hg or greater or a diastolic blood pressure 90 mm Hg or greater OR Proteinuria, defined as 1+ (0.3 g/L) or more on dipstick testing, a protein:creatinine ratio of 30 mg/mmol or more on a random sample, or a urine protein excretion of 300 mg or more/24 h Case definition adapted from Sibai et al, references 3 and 16.
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clinicians in each of the U.K.’s obstetrician-led maternity units were sent a card requesting the number of patients with HELLP or ELLP syndrome they had seen that month. Clinicians who reported a case were asked to complete a data collection form for the case and up to two control women, detailing putative risk factors, management, outcomes. All data requested were anonymous. If complete forms were not returned, up to five reminders were sent. Data were double-entered into a customized database. Information on the women’s year of birth and expected date of delivery were used to detect duplicate reports. Women in the case group were checked to ensure they fulfilled the case definition and women in the control group were reviewed to confirm they had been appropriately selected. If data were missing or a validity check highlighted an issue with the data, the reporting clinician was asked to verify the information provided. All statistical analysis was performed using STATA 11 software. Incidence rates with exact Poisson 95% confidence intervals (CIs) were calculated using the number of maternities reported in the most recent national birth data (2011)9–11 as the denominator. Odds ratios (ORs) and 95% CIs were estimated using unconditional logistic regression. Parsimonious regression models were developed by including in a core model factors that have previously been thought to be associated with HELLP or ELLP syndrome. Factors with a very low prevalence (less than 5%) were excluded from the full models where there was no evidence (P..10) in the univariable or evidence (P,.10) in the univariable but no evidence (P..10) in the multivariable analysis that they were associated with HELLP or ELLP syndrome. Continuous variables were tested for evidence of departure from linearity by the addition of first-order fractional polynomials to the model and Notified cases N=302
Data collection forms received n=243
Excluded: n=59 No data received: 34; 11% Case record lost: 2; 1% Subsequently reported by clinician as not a case: 23; 8% Excluded (did not meet case definition): n=33
Confirmed cases n=210
Fig. 1. Case reporting and completeness of data collection. Fitzpatrick. HELLP Syndrome and ELLP Syndrome. Obstet Gynecol 2014.
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Table 1. Risk Factors for Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome or Elevated Liver Enzymes, Low Platelets Syndrome HELLP Syndrome
Risk Factor Sociodemographic factors Age (y) Younger than 35 35 or older Ethnic group White Black or other minority ethnic group Socioeconomic group Managerial and professional occupations Other BMI (kg/m2) Less than 25 25–29.9 30 or more Smoking status Never smoked or former smoker Smoked during pregnancy Previous obstetric and medical history Nulliparous No Yes Essential hypertension No Yes Gestational hypertensive disorder in previous ‡ pregnancy No Yes Preexisting diabetes mellitus No Yes Preexisting autoimmune disease No Yes Preexisting renal problems No Yes Current pregnancy Multiple pregnancy No Yes Interval between last delivery or termination or miscarriage and last menstrual period (y) Less than 5 5–9.9 10 or more Assisted reproductive technologies used No Yes
No. (%)* of Women in the Control Group (n5476)
No. (%)* of Women With HELLP Syndrome (n5129)
Unadjusted OR (95% CI)
372 (78) 103 (22)
87 (67) 42 (33)
1 1.74 (1.14–2.68)
376 (80) 96 (20)
96 (76) 31 (24)
1 1.26 (0.80–2.01)
125 (30) 295 (70)
45 (39) 71 (61)
1 0.67 (0.44–1.03)
234 (50) 130 (28) 101 (22)
68 (54) 30 (24) 27 (22)
1 0.79 (0.49–1.28) 0.92 (0.56–1.52)
394 (83) 80 (17)
117 (92) 10 (8)
1 0.42 (0.21–0.84)
272 (57) 204 (43)
42 (33) 87 (67)
1 2.76 (1.83–4.16)
455 (96) 21 (4)
118 (91) 11 (9)
1 2.02 (0.95–4.31)
444 (93) 32 (7)
117 (91) 12 (9)
1 1.42 (0.71–2.85)
471 (99) 3 (1)
127 (99) 1 (1)
1 1.24 (0.13–11.99)
472 (99) 3 (1)
124 (98) 3 (2)
1 3.81 (0.76–19.09)
474 (100) 1 (0)
124 (98) 3 (2)
1 11.47 (1.18–111.20)
467 (98) 9 (2)
120 (93) 9 (7)
1 3.89 (1.51–10.02)
243 (82) 38 (13) 16 (5)
42 (75) 9 (16) 5 (9)
1 1.37 (0.62–3.04) 1.81 (0.63–5.20)
475 (100) 0 (0)
125 (98) 2 (2)
1 9.09 (0.71–infinity)
HELLP, hemolysis, elevated liver enzymes, and low platelets syndrome; ELLP, elevated liver enzymes, low platelets syndrome; OR, odds ratio; CI, confidence interval; BMI, body mass index. * Percentage of women with complete data. † Adjusted for all factors in the table apart from preexisting diabetes mellitus, autoimmune disease, and renal problems, interval between last delivery or termination or miscarriage, and last menstrual period and assisted reproductive technologies. When adjusted for age and body mass index, these variables have been treated as a continuous linear term in the analysis. ‡ Includes pregnancy induced hypertension, preeclampsia, eclampsia, or HELLP syndrome.
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HELLP Syndrome
ELLP Syndrome
Adjusted OR (95% CI)
No. (%)* of Women With ELLP Syndrome (n581)
Unadjusted OR (95% CI)
Adjusted OR (95% CI)
1 1.85 (1.12–3.06)
57 (70) 24 (30)
1 1.52 (0.90–2.57)
1 1.66 (0.87–3.20)
1 1.19 (0.70–2.03)
71 (88) 10 (12)
1 0.55 (0.27–1.11)
1 0.42 (0.19–0.95)
1 0.92 (0.56–1.49)
31 (42) 43 (58)
1 0.59 (0.35–0.98)
1 0.86 (0.47–1.58)
1 0.71 (0.41–1.22) 1.02 (0.57–1.82)
45 (58) 22 (29) 10 (13)
1 0.88 (0.51–1.53) 0.51 (0.25–1.06)
1 0.94 (0.51–1.76) 0.52 (0.23–1.21)
1 0.62 (0.28–1.35)
78 (96) 3 (4)
1 0.19 (0.06–0.62)
1 0.15 (0.03–0.63)
1 4.16 (2.48–6.98)
17 (21) 64 (79)
1 5.02 (2.85–8.83)
1 8.35 (3.88–17.95)
1 1.69 (0.70–4.06)
77 (95) 4 (5)
1 1.13 (0.38–3.37)
1 2.21 (0.62–7.90)
1 3.47 (1.49–8.09)
75 (93) 6 (7)
1 1.11 (0.45–2.75)
1 4.66 (1.37–15.89)
79 (98) 2 (2)
1 3.97 (0.65–24.17)
81 (100) 0 (0)
1 1.52 (0–14.28)
80 (99) 1 (1)
1 5.92 (0.37–95.69)
75 (93) 6 (7)
1 4.15 (1.44–12.00)
26 (87) 4 (13) 0 (0)
1 0.98 (0.33–2.98)
79 (98) 2 (2)
1 14.30 (1.11–infinity)
†
1 4.51 (1.45–14.06)
subsequent likelihood ratio testing. Continuous variables that showed evidence of nonlinearity were treated and presented as categorical in the analysis, whereas those showing evidence of linearity were treated as continuous linear terms in the analysis but presented as
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†
1 3.31 (0.79–13.84)
categorical for ease of interpretation. Potential interactions between variables in the full model were tested by adding interaction terms and subsequent likelihood ratio testing. To allow for multiple testing, a P value of ,.01 was considered sufficient evidence of significant
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interaction. Assuming putative risk factors have a prevalence of between 40% and 5%, the analysis to investigate risk factors for HELLP syndrome had 80% power at the 5% significance level to detect ORs ranging between 1.8 and 2.9. Making the same assumption, for ELLP syndrome, the analysis had 80% power at the 5% significance level to detect ORs in the range of 2.1 and 3.3. The x2 test, Fisher’s exact test, or Wilcoxon rank sum test, as appropriate, was used to compare groups. Logistic regression using robust standard errors to allow for the nonindependence of neonates from multiple births was used when comparing neonate outcomes. Small for gestational age (birth weight less than the 10th centile) was calculated by comparing birth weight with British 1990 reference data using the Microsoft Excel add-in LMSgrowth.12,13
RESULTS Throughout the study period, all 214 eligible U.K. hospitals contributed data to the U.K. Obstetric Surveillance System (100% response) and notified 302 cases. Excluding those subsequently reported as not cases, data collection forms were obtained for 87% of cases (Fig. 1 ) and data were received for 476 control women. There were 210 women who met the case definition in an estimated 799,003 maternities9–11; 129 of the women had hemolysis and were considered to have HELLP syndrome, giving an incidence of 1.6 per 10,000 maternities (95% CI 1.3–1.9); a further 81 of the women met the case definition, but either did not have hemolysis (n579) or it is unknown whether they had hemolysis (n52); these women were considered to have ELLP syndrome, giving an incidence of one per 10,000 maternities (95% CI 0.8–1.3). The characteristics of the women with HELLP syndrome and ELLP syndrome compared with the control women are shown in Table 1. The odds of having both HELLP and ELLP syndrome were significantly raised in nulliparous women and women who had a gestational hypertensive disorder in a previous pregnancy. Older women and women who had a multiple pregnancy also had significantly raised odds of having HELLP but not ELLP syndrome noting the limited power of the analysis. There was also evidence that women of black or other minority ethnic groups and women who smoked during pregnancy had significantly reduced odds of ELLP, although no such association was apparent for HELLP, again noting the limited power of the analysis. The only significant interaction found was between essential hypertension and parity for HELLP syndrome; women who had essential hypertension had a raised odds of having HELLP syndrome if they were nulliparous but not if they were multiparous
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(adjusted OR 6.46, 95% CI 1.62–25.83 in nulliparous women; adjusted OR 0.23, 95% CI 0.01–1.95 in multiparous women). Although an unadjusted analysis directly comparing women with HELLP syndrome with those with ELLP syndrome suggested that women with HELLP syndrome were more likely to be of black or other minority ethnic group (unadjusted OR 2.29, 95% CI 1.06–4.98); this difference disappeared after adjusting for maternal age, socioeconomic status, body mass index (calculated as weight (kg)/[height (m)]2), smoking status, nulliparity, essential hypertension, gestational hypertensive disorder in a previous pregnancy, and multiple pregnancy. No other differences in characteristics were found between the women with HELLP syndrome and those with ELLP syndrome. Of the women with HELLP syndrome, 64% (83/129) were diagnosed antenatally at a median gestation of 34.5 weeks (range 21–41 weeks), 10% (13/129) were diagnosed intrapartum at a median gestation of 37 weeks (range 23–40 weeks), and 26% (33/129) were diagnosed postnatally. The women diagnosed with HELLP syndrome postnatally delivered at a median gestation of 36 weeks (range 25–41 weeks), and all were diagnosed within 3 days of delivery. The women with ELLP syndrome were diagnosed at a similar time to the women with HELLP syndrome: 72% (57/79) of ELLP cases were diagnosed antenatally at a median gestation of 34 weeks (range 24–39 weeks); 5% (4/79) were diagnosed intrapartum at a median gestation of 38 weeks (range 34–41 weeks); and 23% (18/79) were diagnosed postnatally within 2 days of delivery with the postnatally diagnosed women delivering at a median gestation of 36 weeks (range 29–42 weeks). Compared with the women with ELLP syndrome, those with HELLP syndrome had a lower median lowest platelet count recorded and higher median highest aspartate aminotransferase, alanine transaminase, lactate dehydrogenase, and total bilirubin level recorded (Table 2). Women with HELLP syndrome were also more likely than the women with ELLP syndrome to have a lowest recorded platelet count of less than 503109/L (50% [65/129] compared with 25% [20/81], P,.001). The presenting symptoms and signs of the women with both HELLP and ELLP syndrome were similar (Table 3). Women with HELLP syndrome were significantly more likely than those with ELLP syndrome to have received magnesium sulfate (76% [98/129] compared with 62% [50/81], P5.028). No other significant differences in management were seen between the women with either HELLP or ELLP syndrome (data not shown) and therefore the management of these women has been presented together. Of the women diagnosed
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Table 2. Laboratory Values of Women With Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome or Elevated Liver Enzymes, Low Platelets Syndrome Women With HELLP Syndrome (n5129)
Women With ELLP Syndrome (n581)
No. of Women With Median Highest* No. of Women With Median Highest* or Lowest† Value or Lowest† Value Value Outside of Value Outside of Normal Range/n (%) Recorded (Range) Normal Range/n (%) Recorded (Range) Platelet count Aspartate aminotransferase Gammaglutamyltransferase Alanine aminotransferase
129/129 (100) 41/43 (95) 16/45 (36) 123/124 (99)
Lactate dehydrogenase
54/61 (89)
Total bilirubin
99/129 (77)
Abnormal (fragmented or contracted red cells) peripheral blood smear
34/51 (67)
493109/L (12–99)† 379 international units/L (32–3269)* 59 international units/L (6–349)* 320 international units/L (37–5860)* 981 international units/L (148– 5282)* 28 micromole/L (6–305)* N/A
81/81 (100) 32/32 (100) 10/31 (32) 71/75 (95) 0/6 (0)
P‡
683109/L (23–99)† ,.001 178 international .014 units/L (75–873)* 32 international .083 units/L (12–110)* 181 international ,.001 units/L (33–674)* 466 international .001 units/L (256–591)*
0/79 (0)
13 micromole/L (4–20)* N/A
0/8 (0)
,.001 N/A
HELLP, hemolysis, elevated liver enzymes, and low platelets syndrome; ELLP, elevated liver enzymes, low platelets syndrome; N/A, Not applicable. * International units per liter. † Per liter. ‡ P value of difference between median highest or lowest value recorded for HELLP compared with ELLP syndrome cases.
antenatally with HELLP or ELLP syndrome: 51% (71/138) had a planned management of immediate delivery and delivered a median of 3 hours 41 minutes after diagnosis (range 38 minutes to 32 hours 22 minutes) at a median gestation of 35 weeks (range 22–41 weeks), 91% (63/69) by cesarean delivery; 43% (60/138) had a planned management of delivery within 48 hours and delivered a median of 11 hours 40 minutes after diagnosis (range 1 hour 28 minutes to 95 hours 56 minutes) at a median gestation of 35 weeks (range 22–40 weeks), 68% (40/59) by cesarean delivery; only seven of 138 (three had HELLP and four had ELLP syndrome) had a planned attempt at expectant
(conservative) management; these women were diagnosed at a median of 29 weeks of gestation (range 24–39 weeks) and delivered a median of 3 days after diagnosis (range 1–12 days), all by cesarean delivery (indication maternal compromise). Women who had a planned management of delivery within 48 hours were more likely than those who had planned immediate delivery to be nulliparous (83% [50/60] compared with 68% [48/71], P5.039), but no other differences in characteristics were found between these women. Overall, 47% (99/209) of the women with HELLP or ELLP syndrome received corticosteroids (only three for maternal indications, two of whom were diagnosed
Table 3. Presenting Symptoms and Signs of Women With Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome or Elevated Liver Enzymes, Low Platelets Syndrome Symptoms and Signs Epigastric or abdominal pain Nausea or vomiting Headache Visual changes New-onset hypertension New-onset proteinuria New-onset hypertension and newonset proteinuria
No. (%)* of Women With HELLP Syndrome (n5129) 78 52 38 13 101 90 76
(60) (40) (29) (10) (81) (70) (60)
No. (%)* of Women With ELLP Syndrome (n581) 46 24 30 10 74 61 55
(57) (30) (37) (12) (91) (75) (68)
P .598 .117 .253 .608 .05 .385 .191
HELLP, hemolysis, elevated liver enzymes, and low platelets syndrome; ELLP, elevated liver enzymes, low platelets syndrome. * Percentage of women with complete data.
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postpartum) and 80% (166/208) were given antihypertensive medication. Table 4 summarizes the main maternal outcomes of women with both HELLP and ELLP syndrome. Compared with the women with ELLP syndrome, those with HELLP syndrome were more likely to have a blood transfusion and were more likely to have severe morbidity, although the proportion admitted to level 2 or level 3 critical care14 (which we will refer to as intensive care unit [ICU]), the duration of stay in ICU and proportion with eclampsia did not significantly differ. Although there were no maternal deaths among the women diagnosed with ELLP syndrome, one woman with HELLP syndrome died (case fatality 0.8%, 95% CI 0.02–4.2%). No significant differences were found between the women who had a planned management of delivery within 48 hours of diagnosis and those who had a planned management of immediate delivery in terms of the proportion who received blood products (37% [21/57] compared with 33% [23/69], P5.681); were admitted to the ICU (57% [34/60] compared with 61% [43/71], P5.652); or experienced severe morbidity (10% [6/60] compared with 4% [3/71], P5.300). Of the seven women who had a planned attempt at expectant management, two received blood products, five were admitted to the ICU, but none experienced severe morbidity or died. No significant differences were found between the women with HELLP syndrome who were given blood products and those who were not in terms of their median lowest platelet count recorded (463109/L, range 12–96 compared with 553109/L, range 20– 99, P5.0.62) or the proportion with a lowest recorded platelet count of less than 503109/L (56% [32/57] compared with 44% [30/68], P5.181). There were also no significant differences apparent between the women with HELLP syndrome who were admitted
to the ICU and those who were not in terms of their median lowest platelet count recorded (493109/L, range 20–99 compared with 503109/L, range 12– 96, P5.912) or the proportion with a lowest recorded platelet count of less than 503109/L (51% [42/82] compared with 49% [23/47], P5.803). Similarly, no significant differences were seen between the women with HELLP syndrome who experienced severe morbidity and those who did not in terms of their median lowest platelet count recorded (463109/L, range 22–80 compared with 513109/L, range 12–99, P5.48) or the proportion with a lowest recorded platelet count of less than 503109/L (59% [10/17] compared with 49% [55/112], P5.455). Of the women with HELLP syndrome, two had late fetal demises and two had their pregnancy terminated because of HELLP syndrome before 24 weeks of gestation. The remaining 125 women with HELLP syndrome gave birth to a total of 135 neonates (116 singleton, eight twin, and one triplet pregnancy), whereas the 81 women with ELLP syndrome gave birth to a total of 87 neonates (75 singleton, six twin pregnancies). There were two stillbirths, no early neonatal deaths, two late neonatal deaths, and one post neonatal death among the 135 neonates born to women with HELLP syndrome, equating to a perinatal morality rate of 15 per 1,000 total births (95% CI 2–53); a late neonatal mortality rate of 15 per 1,000 live births (95% CI 2–53); and a postneonatal mortality rate of eight per 1,000 live births (95% CI 0.2–41). Of the 87 neonates born to women with ELLP syndrome, there were no stillbirths, one early neonatal death, and one postneonatal death, equating to a perinatal mortality rate of 12 per 1,000 total births (95% CI 0.3–62) and a postneonatal mortality rate of 12 per 1,000 live births (95% CI 0.3–62). There were no statistically significant differences in these rates between HELLP syndrome and ELLP syndrome but note the low statistical power of
Table 4. Maternal Outcomes of Women With Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome or Elevated Liver Enzymes, Low Platelets Syndrome Maternal Outcomes
Women With HELLP (n5129)*
Blood products given Admission to ICU Duration of stay in ICU (d) Eclampsia Severe morbidity†
57 82 2 8 17
(46) (64) (1–10) (6) (13)
Women With ELLP (n581)* 17 43 2 4 1
(21) (53) (1–7) (5) (1)
P ,.001 .132 .321 .770 .003
HELLP, hemolysis, elevated liver enzymes, and low platelets syndrome; ELLP, elevated liver enzymes, low platelets syndrome; ICU, intensive care unit. Data are n (%) or median (range). * Percentage of women with complete data. † Includes renal impairment or failure, pulmonary edema, subarachnoid hemorrhage, sepsis, subcapsular liver hematoma, hepatic encephalopathy.
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this comparison. All of the neonates who died apart from one were born very preterm (less than 28 weeks of gestation). Women with HELLP syndrome and those with ELLP syndrome both had a similarly high preterm (less than 37 weeks of gestation) birth rate (59% [74/125] compared with 72% [58/81], respectively, P5.070), mainly iatrogenic (95% [126/132]). The proportion of neonates with major complications such as respiratory distress syndrome, chronic lung disease, severe infection, and necrotizing enterocolitis was also similar between the neonates born to women with both HELLP and ELLP syndrome (10% [13/131] compared with 7% [6/86], P5.453) and higher than the rate reported in the control neonates (1% [6/480], P,.001), although this difference disappeared after controlling for gestational age at delivery. Having controlled for maternal age, ethnicity, socioeconomic status, body mass index, smoking status, and parity, the proportion of neonates who were small for gestational age was similar between the neonates born to women with both HELLP and ELLP syndrome (26% [35/135] compared with 30% [26/86], P5.701) and significantly higher than the proportion seen in the control infants (8% [41/483], P,.001). There were no significant differences between the neonates born to women who had a planned management of delivery within 48 hours of diagnosis and those born to women who had a planned management of immediate delivery in terms of the proportion that were born preterm (67% [43/64] compared with 71% [52/73], P5.626); were small for gestational age (20% [13/64] compared with 26% [19/73], P5.431), had major complications (6% [4/64] compared with 11% [8/73], P5.342), or who died perinatally (zero of 64 compared with one of 72, P51.000). Of the seven neonates born to the women who had a planned attempt at expectant management, none died, but two had major complications relating to preterm birth and three were small for gestational age.
DISCUSSION Our incidence estimates indicate the rarity of HELLP syndrome and ELLP syndrome and are lower than frequently quoted rates.7,15 There may be a number of reasons for this difference, including variable and inconsistent diagnostic criteria3; we used a case definition comparable to the strict criteria proposed by Sibai et al.3,16 Other methodologic differences may also explain our lower incidence estimates. The existing literature is dominated by retrospective studies undertaken in single tertiary referral centers. Such studies tend to underestimate the denominator population, leading to an overestimate of incidence. They
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also tend to rely on coded data from routine hospital administrative systems, which may lead to inaccurate case ascertainment.17 As a result of the rarity of HELLP and ELLP syndrome, we had limited power to analyze risk factors. Nevertheless, consistent with the hypothesis that the syndrome is part of the spectrum of hypertensive disorders of pregnancy, the factors our study found to be associated with HELLP or ELLP syndrome are the same as many of the reported risk factors for preeclampsia.18–20 It is possible that there has been a decrease in the incidence of the syndrome in the United Kingdom, perhaps because progression from preeclampsia to HELLP syndrome is being more effectively prevented by improved management practices, similar to the decrease in incidence that has been reported for eclampsia.17 We also cannot rule out the possibility that our lower incidence estimates are the result of underreporting of cases, although we have taken steps to minimize this. There are three main options for the management of women who develop the syndrome antenatally: immediate delivery, delivery within 48 hours, and prolonging pregnancy (expectant management). We found that expectant management is rarely used in the United Kingdom and therefore cannot provide clear evidence of the risks or benefits of this approach. However, we were able to compare the maternal and neonatal outcomes of planned delivery within 48 hours compared with planned immediate delivery, finding no significant differences. This suggests that a short delay in delivery may be considered if the maternal and fetal status is reassuring, although we acknowledge that even in this national study, the analysis may not have sufficient power to detect real differences as statistically significant. A short delay is important to consider in situations where fetal lung maturation can be enhanced by the administration of corticosteroids.21 Current U.K. guidelines recommend two main situations where this is the case: when a woman is at risk of preterm birth up to 34+6 weeks of gestation and when a cesarean delivery is planned before 38+6 weeks of gestation.22 Our study suggests that currently corticosteroids are rarely used in the United Kingdom to improve maternal outcome in HELLP syndrome. In keeping with other studies,23–26 we found that women with HELLP syndrome were more likely than those with ELLP syndrome to experience severe morbidity and require blood transfusion. This finding supports Sibai et al’s26 assertion of the importance of using strict diagnostic criteria for reporting and managing women with HELLP syndrome. Nevertheless, it is important to note that both groups experienced severe complications including admission to the ICU, emphasizing that both should be considered as serious
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pregnancy complications. The occurrence of eclampsia in both groups also highlights the importance of considering seizure prophylaxis in these women. Consistent with other studies,27,28 we found that women with both HELLP and ELLP syndrome have a similarly increased risk of adverse infant outcomes. Although this appears primarily to be associated with iatrogenic preterm birth, our study suggests that women with both HELLP and ELLP syndrome also have an increased risk of having a small-for-gestational-age neonate; this should be taken into account when considering further research on expectant management. In summary, where there are sound reasons that a delay in delivery of women with HELLP or ELLP syndrome may be beneficial, eg, to allow administration of corticosteroids for fetal lung maturation, this study suggests that a short delay, of up to 48 hours, may be considered. Current U.K. guidelines recommend corticosteroids when there is a risk of delivery before 35 completed weeks of gestation or planned cesarean delivery at less than 39 completed weeks of gestation. Although we cannot comment on whether ELLP cases proceed to HELLP or whether they are different entities, it is clear that women with ELLP as well as HELLP have severe additional complications, and thus ELLP should not be managed as a less severe form of HELLP. In particular, there is a high rate of eclampsia among both women with ELLP and HELLP; thus, obstetricians should consider magnesium sulfate prophylaxis alongside delivery planning. REFERENCES 1. 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.
8. Knight M, Kurinczuk JJ, Tuffnell D, Brocklehurst P. The UK Obstetric Surveillance System for rare disorders of pregnancy. BJOG 2005;112:263–5. 9. Northern Ireland Statistics and Research Agency. Registrar general annual report 2011. Belfast (UK): Northern Ireland Statistics and Research Agency; 2012. 10. General Register Office for Scotland. Vital events reference tables 2011. Edinburgh (UK): General Register Office for Scotland; 2012. 11. Office for National Statistics. Birth summary tables, England and Wales 2011. Newport (UK): Office for National Statistics; 2012. 12. Cole TJ, Williams AF, Wright CM; RCPCH Growth Chart Expert Group. Revised birth centiles for weight, length and head circumference in the UK-WHO growth charts. Ann Hum Biol 2011;38:7–11. 13. Pan H, Cole TJ. LMSgrowth, a Microsoft Excel add-in to access growth referencs based on the LMS method. Version 2.77. Available at: http://www.healthforallchildren.co.uk/. 2012. Retrieved on July 1, 2013. 14. Department of Health. Comprehensive critical care: a review of adult critical care services. London (UK): Department of Health; 2000. 15. Aloizos S, Seretis C, Liakos N, Aravosita P, Mystakelli C, Kanna E, et al. HELLP syndrome: understanding and management of a pregnancy-specific disease. J Obstet Gynaecol 2013; 33:331–7. 16. 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. 17. Knight M. Studies using routine data versus specific data collection: what can we learn about the epidemiology of eclampsia and the impact of changes in management of gestational hypertensive disorders? Pregnancy Hypertens An Int J Women’s Cardiovasc Health 2011;1:109–16. 18. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005; 365:785–99. 19. Dekker GA. Risk factors for preeclampsia. Clin Obstet Gynecol 1999;42:422–35.
2. Sibai BM. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing? Am J Obstet Gynecol 1990;162:311–6.
20. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005;330:565.
3. Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol 2004;103:981–91.
21. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. The Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004454. doi: 10.1002/14651858.CD004454. pub2.
4. Waterstone M, Bewley S, Wolfe C. Incidence and predictors of severe obstetric morbidity: case-control study. BMJ 2001;322: 1089–93. 5. Martin JN Jr, Rinehart BK, May WL, Magann EF, Terrone DA, Blake PG. The spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis, elevated liver enzyme levels, and low platelet count) syndrome classification. Am J Obstet Gynecol 1999;180:1373–84. 6. Gasem T, Al Jama FE, Burshaid S, Rahman J, Al Suleiman SA, Rahman MS. Maternal and fetal outcome of pregnancy complicated by HELLP syndrome. J Matern Fetal Neonatal Med 2009;22:1140–3. 7. Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and management. A Review. BMC Pregnancy Childbirth 2009;9:8.
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22. Royal College of Obstetricians and Gynaecologists. Green-top guideline no. 7: antenatal corticosteroids to reduce neonatal morbidity and morality. London (UK): RCOG; 2010. 23. van Pampus MG, Wolf H, Ilsen A, Treffers PE. Maternal outcome following temporizing management of the (H)ELLP syndrome. Hypertens Pregnancy 2000;19:211–20. 24. Roelofsen AC, van Pampus MG, Aarnoudse JG. The HELLPsyndrome; maternal-fetal outcome and follow up of infants. J Perinat Med 2003;31:201–8. 25. 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.
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26. Martin JN Jr, Brewer JM, Wallace K, Sunesara I, Canizaro A, Blake PG, et al. HELLP syndrome and composite major maternal morbidity: importance of Mississippi classification system. J Matern Fetal Neonatal Med 2013;26:1201–6. 27. Abramovici D, Friedman SA, Mercer BM, Audibert F, Kao L, Sibai BM. Neonatal outcome in severe preeclampsia at 24 to 36 weeks’ gestation: does the HELLP (hemolysis, elevated liver
enzymes, and low platelet count) syndrome matter? Am J Obstet Gynecol 1999;180:221–5. 28. van Pampus MG, Wolf H, Westenberg SM, van der Post JA, Bonsel GJ, Treffers PE. Maternal and perinatal outcome after expectant management of the HELLP syndrome compared with pre-eclampsia without HELLP syndrome. Eur J Obstet Gynecol Reprod Biol 1998;76:31–6.
Standards for Different Types of Articles Guidelines for five different types of articles have been adopted by Obstetrics & Gynecology: 1. CONSORT (Consolidated Standards of Reporting Trials) standards for reporting randomized trials 2. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for metaanalyses and systematic reviews of randomized controlled trials 3. MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines for meta-analyses and systematic reviews of observational studies 4. STARD (Standards for Reporting of Diagnostic Accuracy) standards for reporting studies of diagnostic accuracy 5. STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for the reporting of observational studies Investigators who are planning, conducting, or reporting randomized trials, meta-analyses of randomized trials, meta-analyses of observational studies, studies of diagnostic accuracy, or observational studies should be thoroughly familiar with these sets of standards and follow these guidelines in articles submitted for publication. NOW AVAILABLE ONLINE - http://ong.editorialmanager.com
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Risk Factors, Management, and Outcomes of Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome and Elevated Liver Enzymes, Low Platelets Syndrome Kathryn E. Fitzpatrick, BA, MSc, Kim Hinshaw, and Marian Knight, MBChB, DPhil
MB BS, FRCOG,
OBJECTIVE: To describe the risk factors, management and outcomes of hemolysis, elevated liver enzymes, and low platelets (HELLP) and elevated liver enzymes, low platelets (ELLP) syndrome in the United Kingdom. METHODS: A case–control study was conducted using the U.K. Obstetric Surveillance System between June 2011 and May 2012, including 129 women diagnosed with HELLP, 81 diagnosed with ELLP, and 476 control women. RESULTS: Women with HELLP were more likely than those in the control group to be 35+ years old (33% compared with 22%, adjusted odds ratio [OR] 1.85, 95% confidence interval [CI] 1.12–3.06), nulliparous (67% compared with 43%, adjusted OR 4.16, 95% CI 2.48–6.98), have had a previous gestational hypertensive disorder (9% compared with 7%, adjusted OR 3.47, 95% CI 1.49–8.09), and have a multiple pregnancy (7% compared with 2%, adjusted OR 4.51, 95% CI 1.45–14.06). Women with ELLP were more likely than those in the From the National Perinatal Epidemiology Unit, University of Oxford, Oxford, and Sunderland Royal Hospital, Sunderland, United Kingdom. This article presents independent research funded by the National Institute for Health Research (NIHR) under the “Beyond maternal death: Improving the quality of maternity care through national studies of ‘near-miss’ maternal morbidity” program (Programme Grant RP-PG-0608-10038). Marian Knight is funded by a NIHR Professorship. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank the United Kingdom Obstetric Surveillance System reporting clinicians who notified cases and completed data collection forms. Corresponding author: Kathryn E. Fitzpatrick, BA, MSc, National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, UK; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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Jennifer J. Kurinczuk,
MD, MSc,
control group to be nulliparous (79% compared with 43%, adjusted OR 8.35, 95% CI 3.88–17.95), and have had a previous gestational hypertensive disorder (7% compared with 7%, adjusted OR 4.66, 95% CI 1.37– 15.89). Of the women diagnosed antenatally with HELLP or ELLP, 51% (71/138) had planned management of immediate delivery, 43% (60/138) had delivery planned within 48 hours, and 5% (7/138) had planned expectant (conservative) management. No differences were found between women who had delivery planned within 48 hours and those who had planned immediate delivery in terms of the proportion who received blood products (37% compared with 33%, P5.681); were admitted to the intensive care unit (57% compared with 61%, P5.652); experienced severe morbidity (10% compared with 4%, P5.300); or had a neonate with major complications (6% compared with 11%, P5.342). CONCLUSION: A short delay in the delivery of women diagnosed antenatally with HELLP or ELLP syndrome may be considered. However, the rarity of the condition limits study power. (Obstet Gynecol 2014;123:618–27) DOI: 10.1097/AOG.0000000000000140
LEVEL OF EVIDENCE: II
H
emolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is a serious complication of pregnancy that usually occurs in women who have signs of preeclampsia.1 In the absence of hemolysis, the condition has been called elevated liver enzymes, low platelets (ELLP) syndrome.2,3 Incidence estimates vary from five to 76 per 10,000 deliveries4,5 and between 8% and 24% of women with severe preeclampsia or eclampsia.5,6 There has been no comprehensive study of the risk factors for this complication. There is also
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debate over the optimal management of the syndrome, particularly with regard to women who develop the condition remote from term.3,7 The aims of this study were to investigate the risk factors for HELLP syndrome and ELLP syndrome in the United Kingdom and to describe the management and outcomes to inform future practice guidelines.
MATERIALS AND METHODS A population-based nationwide case–control study was conducted. The London Research Ethics Committee approved the study (reference 10/H0717/20). Cases were defined as any pregnant women meeting the criteria outlined in Box 1. Cases with hemolysis were classified as HELLP syndrome and those without hemolysis were classified as ELLP syndrome. Controls were defined as the women delivering just before the reported case in the same hospital who did not have HELLP or ELLP syndrome. The U.K. Obstetric Surveillance System was used to identify cases on a national basis between June 1, 2011, and May 31, 2012.8 Every month, up to four nominated
Box 1. Case Definition of Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome or Elevated Liver Enzymes, Low Platelets Syndrome Any pregnant women identified as having new onset of the following: Elevated liver enzymes, defined as: Serum aspartate aminotransferase 70 international units/L or greater OR Gamma-glutamyltransferase 70 international units/L or greater OR Alanine aminotransferase 70 international units/L or greater AND Low platelets, defined as platelet count less than 1003109/L AND EITHER Hemolysis, defined by abnormal (fragmented or contracted red cells) peripheral blood smear or serum lactate dehydrogenase levels 600 international units/L or greater or total bilirubin 20.5 micromole/L or greater OR Hypertension, defined as a systolic blood pressure 140 mm Hg or greater or a diastolic blood pressure 90 mm Hg or greater OR Proteinuria, defined as 1+ (0.3 g/L) or more on dipstick testing, a protein:creatinine ratio of 30 mg/mmol or more on a random sample, or a urine protein excretion of 300 mg or more/24 h Case definition adapted from Sibai et al, references 3 and 16.
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clinicians in each of the U.K.’s obstetrician-led maternity units were sent a card requesting the number of patients with HELLP or ELLP syndrome they had seen that month. Clinicians who reported a case were asked to complete a data collection form for the case and up to two control women, detailing putative risk factors, management, outcomes. All data requested were anonymous. If complete forms were not returned, up to five reminders were sent. Data were double-entered into a customized database. Information on the women’s year of birth and expected date of delivery were used to detect duplicate reports. Women in the case group were checked to ensure they fulfilled the case definition and women in the control group were reviewed to confirm they had been appropriately selected. If data were missing or a validity check highlighted an issue with the data, the reporting clinician was asked to verify the information provided. All statistical analysis was performed using STATA 11 software. Incidence rates with exact Poisson 95% confidence intervals (CIs) were calculated using the number of maternities reported in the most recent national birth data (2011)9–11 as the denominator. Odds ratios (ORs) and 95% CIs were estimated using unconditional logistic regression. Parsimonious regression models were developed by including in a core model factors that have previously been thought to be associated with HELLP or ELLP syndrome. Factors with a very low prevalence (less than 5%) were excluded from the full models where there was no evidence (P..10) in the univariable or evidence (P,.10) in the univariable but no evidence (P..10) in the multivariable analysis that they were associated with HELLP or ELLP syndrome. Continuous variables were tested for evidence of departure from linearity by the addition of first-order fractional polynomials to the model and Notified cases N=302
Data collection forms received n=243
Excluded: n=59 No data received: 34; 11% Case record lost: 2; 1% Subsequently reported by clinician as not a case: 23; 8% Excluded (did not meet case definition): n=33
Confirmed cases n=210
Fig. 1. Case reporting and completeness of data collection. Fitzpatrick. HELLP Syndrome and ELLP Syndrome. Obstet Gynecol 2014.
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Table 1. Risk Factors for Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome or Elevated Liver Enzymes, Low Platelets Syndrome HELLP Syndrome
Risk Factor Sociodemographic factors Age (y) Younger than 35 35 or older Ethnic group White Black or other minority ethnic group Socioeconomic group Managerial and professional occupations Other BMI (kg/m2) Less than 25 25–29.9 30 or more Smoking status Never smoked or former smoker Smoked during pregnancy Previous obstetric and medical history Nulliparous No Yes Essential hypertension No Yes Gestational hypertensive disorder in previous ‡ pregnancy No Yes Preexisting diabetes mellitus No Yes Preexisting autoimmune disease No Yes Preexisting renal problems No Yes Current pregnancy Multiple pregnancy No Yes Interval between last delivery or termination or miscarriage and last menstrual period (y) Less than 5 5–9.9 10 or more Assisted reproductive technologies used No Yes
No. (%)* of Women in the Control Group (n5476)
No. (%)* of Women With HELLP Syndrome (n5129)
Unadjusted OR (95% CI)
372 (78) 103 (22)
87 (67) 42 (33)
1 1.74 (1.14–2.68)
376 (80) 96 (20)
96 (76) 31 (24)
1 1.26 (0.80–2.01)
125 (30) 295 (70)
45 (39) 71 (61)
1 0.67 (0.44–1.03)
234 (50) 130 (28) 101 (22)
68 (54) 30 (24) 27 (22)
1 0.79 (0.49–1.28) 0.92 (0.56–1.52)
394 (83) 80 (17)
117 (92) 10 (8)
1 0.42 (0.21–0.84)
272 (57) 204 (43)
42 (33) 87 (67)
1 2.76 (1.83–4.16)
455 (96) 21 (4)
118 (91) 11 (9)
1 2.02 (0.95–4.31)
444 (93) 32 (7)
117 (91) 12 (9)
1 1.42 (0.71–2.85)
471 (99) 3 (1)
127 (99) 1 (1)
1 1.24 (0.13–11.99)
472 (99) 3 (1)
124 (98) 3 (2)
1 3.81 (0.76–19.09)
474 (100) 1 (0)
124 (98) 3 (2)
1 11.47 (1.18–111.20)
467 (98) 9 (2)
120 (93) 9 (7)
1 3.89 (1.51–10.02)
243 (82) 38 (13) 16 (5)
42 (75) 9 (16) 5 (9)
1 1.37 (0.62–3.04) 1.81 (0.63–5.20)
475 (100) 0 (0)
125 (98) 2 (2)
1 9.09 (0.71–infinity)
HELLP, hemolysis, elevated liver enzymes, and low platelets syndrome; ELLP, elevated liver enzymes, low platelets syndrome; OR, odds ratio; CI, confidence interval; BMI, body mass index. * Percentage of women with complete data. † Adjusted for all factors in the table apart from preexisting diabetes mellitus, autoimmune disease, and renal problems, interval between last delivery or termination or miscarriage, and last menstrual period and assisted reproductive technologies. When adjusted for age and body mass index, these variables have been treated as a continuous linear term in the analysis. ‡ Includes pregnancy induced hypertension, preeclampsia, eclampsia, or HELLP syndrome.
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HELLP Syndrome
ELLP Syndrome
Adjusted OR (95% CI)
No. (%)* of Women With ELLP Syndrome (n581)
Unadjusted OR (95% CI)
Adjusted OR (95% CI)
1 1.85 (1.12–3.06)
57 (70) 24 (30)
1 1.52 (0.90–2.57)
1 1.66 (0.87–3.20)
1 1.19 (0.70–2.03)
71 (88) 10 (12)
1 0.55 (0.27–1.11)
1 0.42 (0.19–0.95)
1 0.92 (0.56–1.49)
31 (42) 43 (58)
1 0.59 (0.35–0.98)
1 0.86 (0.47–1.58)
1 0.71 (0.41–1.22) 1.02 (0.57–1.82)
45 (58) 22 (29) 10 (13)
1 0.88 (0.51–1.53) 0.51 (0.25–1.06)
1 0.94 (0.51–1.76) 0.52 (0.23–1.21)
1 0.62 (0.28–1.35)
78 (96) 3 (4)
1 0.19 (0.06–0.62)
1 0.15 (0.03–0.63)
1 4.16 (2.48–6.98)
17 (21) 64 (79)
1 5.02 (2.85–8.83)
1 8.35 (3.88–17.95)
1 1.69 (0.70–4.06)
77 (95) 4 (5)
1 1.13 (0.38–3.37)
1 2.21 (0.62–7.90)
1 3.47 (1.49–8.09)
75 (93) 6 (7)
1 1.11 (0.45–2.75)
1 4.66 (1.37–15.89)
79 (98) 2 (2)
1 3.97 (0.65–24.17)
81 (100) 0 (0)
1 1.52 (0–14.28)
80 (99) 1 (1)
1 5.92 (0.37–95.69)
75 (93) 6 (7)
1 4.15 (1.44–12.00)
26 (87) 4 (13) 0 (0)
1 0.98 (0.33–2.98)
79 (98) 2 (2)
1 14.30 (1.11–infinity)
†
1 4.51 (1.45–14.06)
subsequent likelihood ratio testing. Continuous variables that showed evidence of nonlinearity were treated and presented as categorical in the analysis, whereas those showing evidence of linearity were treated as continuous linear terms in the analysis but presented as
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†
1 3.31 (0.79–13.84)
categorical for ease of interpretation. Potential interactions between variables in the full model were tested by adding interaction terms and subsequent likelihood ratio testing. To allow for multiple testing, a P value of ,.01 was considered sufficient evidence of significant
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interaction. Assuming putative risk factors have a prevalence of between 40% and 5%, the analysis to investigate risk factors for HELLP syndrome had 80% power at the 5% significance level to detect ORs ranging between 1.8 and 2.9. Making the same assumption, for ELLP syndrome, the analysis had 80% power at the 5% significance level to detect ORs in the range of 2.1 and 3.3. The x2 test, Fisher’s exact test, or Wilcoxon rank sum test, as appropriate, was used to compare groups. Logistic regression using robust standard errors to allow for the nonindependence of neonates from multiple births was used when comparing neonate outcomes. Small for gestational age (birth weight less than the 10th centile) was calculated by comparing birth weight with British 1990 reference data using the Microsoft Excel add-in LMSgrowth.12,13
RESULTS Throughout the study period, all 214 eligible U.K. hospitals contributed data to the U.K. Obstetric Surveillance System (100% response) and notified 302 cases. Excluding those subsequently reported as not cases, data collection forms were obtained for 87% of cases (Fig. 1 ) and data were received for 476 control women. There were 210 women who met the case definition in an estimated 799,003 maternities9–11; 129 of the women had hemolysis and were considered to have HELLP syndrome, giving an incidence of 1.6 per 10,000 maternities (95% CI 1.3–1.9); a further 81 of the women met the case definition, but either did not have hemolysis (n579) or it is unknown whether they had hemolysis (n52); these women were considered to have ELLP syndrome, giving an incidence of one per 10,000 maternities (95% CI 0.8–1.3). The characteristics of the women with HELLP syndrome and ELLP syndrome compared with the control women are shown in Table 1. The odds of having both HELLP and ELLP syndrome were significantly raised in nulliparous women and women who had a gestational hypertensive disorder in a previous pregnancy. Older women and women who had a multiple pregnancy also had significantly raised odds of having HELLP but not ELLP syndrome noting the limited power of the analysis. There was also evidence that women of black or other minority ethnic groups and women who smoked during pregnancy had significantly reduced odds of ELLP, although no such association was apparent for HELLP, again noting the limited power of the analysis. The only significant interaction found was between essential hypertension and parity for HELLP syndrome; women who had essential hypertension had a raised odds of having HELLP syndrome if they were nulliparous but not if they were multiparous
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(adjusted OR 6.46, 95% CI 1.62–25.83 in nulliparous women; adjusted OR 0.23, 95% CI 0.01–1.95 in multiparous women). Although an unadjusted analysis directly comparing women with HELLP syndrome with those with ELLP syndrome suggested that women with HELLP syndrome were more likely to be of black or other minority ethnic group (unadjusted OR 2.29, 95% CI 1.06–4.98); this difference disappeared after adjusting for maternal age, socioeconomic status, body mass index (calculated as weight (kg)/[height (m)]2), smoking status, nulliparity, essential hypertension, gestational hypertensive disorder in a previous pregnancy, and multiple pregnancy. No other differences in characteristics were found between the women with HELLP syndrome and those with ELLP syndrome. Of the women with HELLP syndrome, 64% (83/129) were diagnosed antenatally at a median gestation of 34.5 weeks (range 21–41 weeks), 10% (13/129) were diagnosed intrapartum at a median gestation of 37 weeks (range 23–40 weeks), and 26% (33/129) were diagnosed postnatally. The women diagnosed with HELLP syndrome postnatally delivered at a median gestation of 36 weeks (range 25–41 weeks), and all were diagnosed within 3 days of delivery. The women with ELLP syndrome were diagnosed at a similar time to the women with HELLP syndrome: 72% (57/79) of ELLP cases were diagnosed antenatally at a median gestation of 34 weeks (range 24–39 weeks); 5% (4/79) were diagnosed intrapartum at a median gestation of 38 weeks (range 34–41 weeks); and 23% (18/79) were diagnosed postnatally within 2 days of delivery with the postnatally diagnosed women delivering at a median gestation of 36 weeks (range 29–42 weeks). Compared with the women with ELLP syndrome, those with HELLP syndrome had a lower median lowest platelet count recorded and higher median highest aspartate aminotransferase, alanine transaminase, lactate dehydrogenase, and total bilirubin level recorded (Table 2). Women with HELLP syndrome were also more likely than the women with ELLP syndrome to have a lowest recorded platelet count of less than 503109/L (50% [65/129] compared with 25% [20/81], P,.001). The presenting symptoms and signs of the women with both HELLP and ELLP syndrome were similar (Table 3). Women with HELLP syndrome were significantly more likely than those with ELLP syndrome to have received magnesium sulfate (76% [98/129] compared with 62% [50/81], P5.028). No other significant differences in management were seen between the women with either HELLP or ELLP syndrome (data not shown) and therefore the management of these women has been presented together. Of the women diagnosed
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Table 2. Laboratory Values of Women With Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome or Elevated Liver Enzymes, Low Platelets Syndrome Women With HELLP Syndrome (n5129)
Women With ELLP Syndrome (n581)
No. of Women With Median Highest* No. of Women With Median Highest* or Lowest† Value or Lowest† Value Value Outside of Value Outside of Normal Range/n (%) Recorded (Range) Normal Range/n (%) Recorded (Range) Platelet count Aspartate aminotransferase Gammaglutamyltransferase Alanine aminotransferase
129/129 (100) 41/43 (95) 16/45 (36) 123/124 (99)
Lactate dehydrogenase
54/61 (89)
Total bilirubin
99/129 (77)
Abnormal (fragmented or contracted red cells) peripheral blood smear
34/51 (67)
493109/L (12–99)† 379 international units/L (32–3269)* 59 international units/L (6–349)* 320 international units/L (37–5860)* 981 international units/L (148– 5282)* 28 micromole/L (6–305)* N/A
81/81 (100) 32/32 (100) 10/31 (32) 71/75 (95) 0/6 (0)
P‡
683109/L (23–99)† ,.001 178 international .014 units/L (75–873)* 32 international .083 units/L (12–110)* 181 international ,.001 units/L (33–674)* 466 international .001 units/L (256–591)*
0/79 (0)
13 micromole/L (4–20)* N/A
0/8 (0)
,.001 N/A
HELLP, hemolysis, elevated liver enzymes, and low platelets syndrome; ELLP, elevated liver enzymes, low platelets syndrome; N/A, Not applicable. * International units per liter. † Per liter. ‡ P value of difference between median highest or lowest value recorded for HELLP compared with ELLP syndrome cases.
antenatally with HELLP or ELLP syndrome: 51% (71/138) had a planned management of immediate delivery and delivered a median of 3 hours 41 minutes after diagnosis (range 38 minutes to 32 hours 22 minutes) at a median gestation of 35 weeks (range 22–41 weeks), 91% (63/69) by cesarean delivery; 43% (60/138) had a planned management of delivery within 48 hours and delivered a median of 11 hours 40 minutes after diagnosis (range 1 hour 28 minutes to 95 hours 56 minutes) at a median gestation of 35 weeks (range 22–40 weeks), 68% (40/59) by cesarean delivery; only seven of 138 (three had HELLP and four had ELLP syndrome) had a planned attempt at expectant
(conservative) management; these women were diagnosed at a median of 29 weeks of gestation (range 24–39 weeks) and delivered a median of 3 days after diagnosis (range 1–12 days), all by cesarean delivery (indication maternal compromise). Women who had a planned management of delivery within 48 hours were more likely than those who had planned immediate delivery to be nulliparous (83% [50/60] compared with 68% [48/71], P5.039), but no other differences in characteristics were found between these women. Overall, 47% (99/209) of the women with HELLP or ELLP syndrome received corticosteroids (only three for maternal indications, two of whom were diagnosed
Table 3. Presenting Symptoms and Signs of Women With Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome or Elevated Liver Enzymes, Low Platelets Syndrome Symptoms and Signs Epigastric or abdominal pain Nausea or vomiting Headache Visual changes New-onset hypertension New-onset proteinuria New-onset hypertension and newonset proteinuria
No. (%)* of Women With HELLP Syndrome (n5129) 78 52 38 13 101 90 76
(60) (40) (29) (10) (81) (70) (60)
No. (%)* of Women With ELLP Syndrome (n581) 46 24 30 10 74 61 55
(57) (30) (37) (12) (91) (75) (68)
P .598 .117 .253 .608 .05 .385 .191
HELLP, hemolysis, elevated liver enzymes, and low platelets syndrome; ELLP, elevated liver enzymes, low platelets syndrome. * Percentage of women with complete data.
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postpartum) and 80% (166/208) were given antihypertensive medication. Table 4 summarizes the main maternal outcomes of women with both HELLP and ELLP syndrome. Compared with the women with ELLP syndrome, those with HELLP syndrome were more likely to have a blood transfusion and were more likely to have severe morbidity, although the proportion admitted to level 2 or level 3 critical care14 (which we will refer to as intensive care unit [ICU]), the duration of stay in ICU and proportion with eclampsia did not significantly differ. Although there were no maternal deaths among the women diagnosed with ELLP syndrome, one woman with HELLP syndrome died (case fatality 0.8%, 95% CI 0.02–4.2%). No significant differences were found between the women who had a planned management of delivery within 48 hours of diagnosis and those who had a planned management of immediate delivery in terms of the proportion who received blood products (37% [21/57] compared with 33% [23/69], P5.681); were admitted to the ICU (57% [34/60] compared with 61% [43/71], P5.652); or experienced severe morbidity (10% [6/60] compared with 4% [3/71], P5.300). Of the seven women who had a planned attempt at expectant management, two received blood products, five were admitted to the ICU, but none experienced severe morbidity or died. No significant differences were found between the women with HELLP syndrome who were given blood products and those who were not in terms of their median lowest platelet count recorded (463109/L, range 12–96 compared with 553109/L, range 20– 99, P5.0.62) or the proportion with a lowest recorded platelet count of less than 503109/L (56% [32/57] compared with 44% [30/68], P5.181). There were also no significant differences apparent between the women with HELLP syndrome who were admitted
to the ICU and those who were not in terms of their median lowest platelet count recorded (493109/L, range 20–99 compared with 503109/L, range 12– 96, P5.912) or the proportion with a lowest recorded platelet count of less than 503109/L (51% [42/82] compared with 49% [23/47], P5.803). Similarly, no significant differences were seen between the women with HELLP syndrome who experienced severe morbidity and those who did not in terms of their median lowest platelet count recorded (463109/L, range 22–80 compared with 513109/L, range 12–99, P5.48) or the proportion with a lowest recorded platelet count of less than 503109/L (59% [10/17] compared with 49% [55/112], P5.455). Of the women with HELLP syndrome, two had late fetal demises and two had their pregnancy terminated because of HELLP syndrome before 24 weeks of gestation. The remaining 125 women with HELLP syndrome gave birth to a total of 135 neonates (116 singleton, eight twin, and one triplet pregnancy), whereas the 81 women with ELLP syndrome gave birth to a total of 87 neonates (75 singleton, six twin pregnancies). There were two stillbirths, no early neonatal deaths, two late neonatal deaths, and one post neonatal death among the 135 neonates born to women with HELLP syndrome, equating to a perinatal morality rate of 15 per 1,000 total births (95% CI 2–53); a late neonatal mortality rate of 15 per 1,000 live births (95% CI 2–53); and a postneonatal mortality rate of eight per 1,000 live births (95% CI 0.2–41). Of the 87 neonates born to women with ELLP syndrome, there were no stillbirths, one early neonatal death, and one postneonatal death, equating to a perinatal mortality rate of 12 per 1,000 total births (95% CI 0.3–62) and a postneonatal mortality rate of 12 per 1,000 live births (95% CI 0.3–62). There were no statistically significant differences in these rates between HELLP syndrome and ELLP syndrome but note the low statistical power of
Table 4. Maternal Outcomes of Women With Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome or Elevated Liver Enzymes, Low Platelets Syndrome Maternal Outcomes
Women With HELLP (n5129)*
Blood products given Admission to ICU Duration of stay in ICU (d) Eclampsia Severe morbidity†
57 82 2 8 17
(46) (64) (1–10) (6) (13)
Women With ELLP (n581)* 17 43 2 4 1
(21) (53) (1–7) (5) (1)
P ,.001 .132 .321 .770 .003
HELLP, hemolysis, elevated liver enzymes, and low platelets syndrome; ELLP, elevated liver enzymes, low platelets syndrome; ICU, intensive care unit. Data are n (%) or median (range). * Percentage of women with complete data. † Includes renal impairment or failure, pulmonary edema, subarachnoid hemorrhage, sepsis, subcapsular liver hematoma, hepatic encephalopathy.
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this comparison. All of the neonates who died apart from one were born very preterm (less than 28 weeks of gestation). Women with HELLP syndrome and those with ELLP syndrome both had a similarly high preterm (less than 37 weeks of gestation) birth rate (59% [74/125] compared with 72% [58/81], respectively, P5.070), mainly iatrogenic (95% [126/132]). The proportion of neonates with major complications such as respiratory distress syndrome, chronic lung disease, severe infection, and necrotizing enterocolitis was also similar between the neonates born to women with both HELLP and ELLP syndrome (10% [13/131] compared with 7% [6/86], P5.453) and higher than the rate reported in the control neonates (1% [6/480], P,.001), although this difference disappeared after controlling for gestational age at delivery. Having controlled for maternal age, ethnicity, socioeconomic status, body mass index, smoking status, and parity, the proportion of neonates who were small for gestational age was similar between the neonates born to women with both HELLP and ELLP syndrome (26% [35/135] compared with 30% [26/86], P5.701) and significantly higher than the proportion seen in the control infants (8% [41/483], P,.001). There were no significant differences between the neonates born to women who had a planned management of delivery within 48 hours of diagnosis and those born to women who had a planned management of immediate delivery in terms of the proportion that were born preterm (67% [43/64] compared with 71% [52/73], P5.626); were small for gestational age (20% [13/64] compared with 26% [19/73], P5.431), had major complications (6% [4/64] compared with 11% [8/73], P5.342), or who died perinatally (zero of 64 compared with one of 72, P51.000). Of the seven neonates born to the women who had a planned attempt at expectant management, none died, but two had major complications relating to preterm birth and three were small for gestational age.
DISCUSSION Our incidence estimates indicate the rarity of HELLP syndrome and ELLP syndrome and are lower than frequently quoted rates.7,15 There may be a number of reasons for this difference, including variable and inconsistent diagnostic criteria3; we used a case definition comparable to the strict criteria proposed by Sibai et al.3,16 Other methodologic differences may also explain our lower incidence estimates. The existing literature is dominated by retrospective studies undertaken in single tertiary referral centers. Such studies tend to underestimate the denominator population, leading to an overestimate of incidence. They
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also tend to rely on coded data from routine hospital administrative systems, which may lead to inaccurate case ascertainment.17 As a result of the rarity of HELLP and ELLP syndrome, we had limited power to analyze risk factors. Nevertheless, consistent with the hypothesis that the syndrome is part of the spectrum of hypertensive disorders of pregnancy, the factors our study found to be associated with HELLP or ELLP syndrome are the same as many of the reported risk factors for preeclampsia.18–20 It is possible that there has been a decrease in the incidence of the syndrome in the United Kingdom, perhaps because progression from preeclampsia to HELLP syndrome is being more effectively prevented by improved management practices, similar to the decrease in incidence that has been reported for eclampsia.17 We also cannot rule out the possibility that our lower incidence estimates are the result of underreporting of cases, although we have taken steps to minimize this. There are three main options for the management of women who develop the syndrome antenatally: immediate delivery, delivery within 48 hours, and prolonging pregnancy (expectant management). We found that expectant management is rarely used in the United Kingdom and therefore cannot provide clear evidence of the risks or benefits of this approach. However, we were able to compare the maternal and neonatal outcomes of planned delivery within 48 hours compared with planned immediate delivery, finding no significant differences. This suggests that a short delay in delivery may be considered if the maternal and fetal status is reassuring, although we acknowledge that even in this national study, the analysis may not have sufficient power to detect real differences as statistically significant. A short delay is important to consider in situations where fetal lung maturation can be enhanced by the administration of corticosteroids.21 Current U.K. guidelines recommend two main situations where this is the case: when a woman is at risk of preterm birth up to 34+6 weeks of gestation and when a cesarean delivery is planned before 38+6 weeks of gestation.22 Our study suggests that currently corticosteroids are rarely used in the United Kingdom to improve maternal outcome in HELLP syndrome. In keeping with other studies,23–26 we found that women with HELLP syndrome were more likely than those with ELLP syndrome to experience severe morbidity and require blood transfusion. This finding supports Sibai et al’s26 assertion of the importance of using strict diagnostic criteria for reporting and managing women with HELLP syndrome. Nevertheless, it is important to note that both groups experienced severe complications including admission to the ICU, emphasizing that both should be considered as serious
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pregnancy complications. The occurrence of eclampsia in both groups also highlights the importance of considering seizure prophylaxis in these women. Consistent with other studies,27,28 we found that women with both HELLP and ELLP syndrome have a similarly increased risk of adverse infant outcomes. Although this appears primarily to be associated with iatrogenic preterm birth, our study suggests that women with both HELLP and ELLP syndrome also have an increased risk of having a small-for-gestational-age neonate; this should be taken into account when considering further research on expectant management. In summary, where there are sound reasons that a delay in delivery of women with HELLP or ELLP syndrome may be beneficial, eg, to allow administration of corticosteroids for fetal lung maturation, this study suggests that a short delay, of up to 48 hours, may be considered. Current U.K. guidelines recommend corticosteroids when there is a risk of delivery before 35 completed weeks of gestation or planned cesarean delivery at less than 39 completed weeks of gestation. Although we cannot comment on whether ELLP cases proceed to HELLP or whether they are different entities, it is clear that women with ELLP as well as HELLP have severe additional complications, and thus ELLP should not be managed as a less severe form of HELLP. In particular, there is a high rate of eclampsia among both women with ELLP and HELLP; thus, obstetricians should consider magnesium sulfate prophylaxis alongside delivery planning. REFERENCES 1. 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.
8. Knight M, Kurinczuk JJ, Tuffnell D, Brocklehurst P. The UK Obstetric Surveillance System for rare disorders of pregnancy. BJOG 2005;112:263–5. 9. Northern Ireland Statistics and Research Agency. Registrar general annual report 2011. Belfast (UK): Northern Ireland Statistics and Research Agency; 2012. 10. General Register Office for Scotland. Vital events reference tables 2011. Edinburgh (UK): General Register Office for Scotland; 2012. 11. Office for National Statistics. Birth summary tables, England and Wales 2011. Newport (UK): Office for National Statistics; 2012. 12. Cole TJ, Williams AF, Wright CM; RCPCH Growth Chart Expert Group. Revised birth centiles for weight, length and head circumference in the UK-WHO growth charts. Ann Hum Biol 2011;38:7–11. 13. Pan H, Cole TJ. LMSgrowth, a Microsoft Excel add-in to access growth referencs based on the LMS method. Version 2.77. Available at: http://www.healthforallchildren.co.uk/. 2012. Retrieved on July 1, 2013. 14. Department of Health. Comprehensive critical care: a review of adult critical care services. London (UK): Department of Health; 2000. 15. Aloizos S, Seretis C, Liakos N, Aravosita P, Mystakelli C, Kanna E, et al. HELLP syndrome: understanding and management of a pregnancy-specific disease. J Obstet Gynaecol 2013; 33:331–7. 16. 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. 17. Knight M. Studies using routine data versus specific data collection: what can we learn about the epidemiology of eclampsia and the impact of changes in management of gestational hypertensive disorders? Pregnancy Hypertens An Int J Women’s Cardiovasc Health 2011;1:109–16. 18. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005; 365:785–99. 19. Dekker GA. Risk factors for preeclampsia. Clin Obstet Gynecol 1999;42:422–35.
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4. Waterstone M, Bewley S, Wolfe C. Incidence and predictors of severe obstetric morbidity: case-control study. BMJ 2001;322: 1089–93. 5. Martin JN Jr, Rinehart BK, May WL, Magann EF, Terrone DA, Blake PG. The spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis, elevated liver enzyme levels, and low platelet count) syndrome classification. Am J Obstet Gynecol 1999;180:1373–84. 6. Gasem T, Al Jama FE, Burshaid S, Rahman J, Al Suleiman SA, Rahman MS. Maternal and fetal outcome of pregnancy complicated by HELLP syndrome. J Matern Fetal Neonatal Med 2009;22:1140–3. 7. Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and management. A Review. BMC Pregnancy Childbirth 2009;9:8.
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22. Royal College of Obstetricians and Gynaecologists. Green-top guideline no. 7: antenatal corticosteroids to reduce neonatal morbidity and morality. London (UK): RCOG; 2010. 23. van Pampus MG, Wolf H, Ilsen A, Treffers PE. Maternal outcome following temporizing management of the (H)ELLP syndrome. Hypertens Pregnancy 2000;19:211–20. 24. Roelofsen AC, van Pampus MG, Aarnoudse JG. The HELLPsyndrome; maternal-fetal outcome and follow up of infants. J Perinat Med 2003;31:201–8. 25. 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.
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26. Martin JN Jr, Brewer JM, Wallace K, Sunesara I, Canizaro A, Blake PG, et al. HELLP syndrome and composite major maternal morbidity: importance of Mississippi classification system. J Matern Fetal Neonatal Med 2013;26:1201–6. 27. Abramovici D, Friedman SA, Mercer BM, Audibert F, Kao L, Sibai BM. Neonatal outcome in severe preeclampsia at 24 to 36 weeks’ gestation: does the HELLP (hemolysis, elevated liver
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