170 Am J Exp Clin Res, Vol. 3, No. 3, 2016 http://www.ajecr.org American Journal of Experimental and Clinical Research Am J Exp Clin Res 2016;3(3):170-174 Original Article HELLP Syndrome a severe form of preeclampsia: A comparative study of clinical and laboratorial parameters Campos A, Goncalves A, Massa A, Amaral P, Silva P, Aguilar S 1Obstetric Department, Maternal Fetal Unit, Nova Doctoral Medical School, Lisbon, Portugal Abstract. The objective of this study was to compare clinical, laboratorial, maternal and perinatal results between HELLP Syndrome and severe Preeclampsia. An observational study comparing women with HELLP Syndrome (n=71) to women with severe preeclampsia (n=253) was done. The authors analyzed the early course of the pathologies and the outcomes in both groups. HELLP syndrome occurred in 28% of all the cases and was more frequent at gestational age before 32 weeks (n=39 – 55%) than severe preeclampsia (n=108 - 42%), with more newborns weighting less than 1500g (27 – 38.6% vs 65 – 25.6%; p=0.036). Thrombocytopenia below 100 000/µL (aOR, 2.14; 95% CI, 1.49 – 3.06) and LDH>1 000 UI/L (aOR: 5.17; 95% CI 2.19 – 12.16) were risk factors for HELLP. Maternal morbidity (eclampsia, abruptio placentae, and acute renal failure) was similar in both cohorts; eight stillbirths (6 in severe preeclampsia and 2 in HELLP Syndrome) occurred. There were no maternal deaths. In conclusion, in this study the authors confirmed that HELLP Syndrome is a severe form of preeclampsia with an earlier presentation in pregnancy, worst laboratorial findings and more prematurity rates. Keywords: Preeclampsia, thrombocytopenia, maternal and perinatal morbidity, HELLP syndrome Introduction Although being a leading cause of great maternal and perinatal morbidity and mortality, even in developed countries, preeclampsia is present in only 2 to 8% of all pregnancies [1]. It has higher prevalence in nulliparous and is present as a maternal syndrome, characterized by arterial hypertension generally with proteinuria, and a fetal syndrome, with fetal growth restriction and amniotic fluid reduction. It may have several systemic manifestations, variable degrees of severity and either an early onset with maternal and fetal morbidity, or a late onset, near term, with less severity and reduced fetal compromise. Preeclampsia is characterized by hypertension (systolic and diastolic blood pressure of ≥ 140 and 90 mm Hg, respectively, on two occasions, at least 6 hours apart) and proteinuria (protein excretion of ≥ 300 mg in a 24 h urine collection, or a dipstick of ≥ 1+), developing after 20 weeks of gestation in previously normotensive women[1] . The analysis of the physio-pathological process shows that its origins are related to an immunological process associated with a defective and insufficient placentation [1, 2]. Although the placental origins of the disease are largely accepted maternal or fetal predisposing factors are also considered when an early onset or a high severity are present [3]. The syndrome characterized by micro-angiophatic hemolysis, liver enzymes elevation and thrombocytopenia (HELLP syndrome) was individualized in 1982 by Weinstein and is considered a severe form of preeclampsia, occurring in 0.5% to 0.9% of all pregnancies and complicating 10% to 20% of severe preeclampsia cases [4- 6]. It may have a sudden aggravation and even though some clinical aspects may be similar to preeclampsia, in HELLP syndrome the blood pressure can be normal, the proteinuria is not always present and there is more expression of inflammation markers [6-8]. Additional characteristics of HELLP syndrome include higher platelet and coagulation activation, with thrombocytopenia, coagulation disorders and disseminated intravascular coagulation (DIC) [8]. The Tennessee classification defines as characteristics of the disease the presence of hemolysis, with total serum lactic dehydrogenase greater than or equal to 600 IU/L, serum aminotransferases greater than or equal to 70 IU/L and platelets less than or equal to 100 000/µL [6]. The Mississippi classification proposes the existence of categories according to platelet count: class 1 stands for less than 50 000/ µL, class 2 for less than 100 000/ µL and class 3 for a platelet count less than 150 000/µL [9]. Hemolysis is the main finding of this syndrome and can be documented by an elevation of serum lactic dehydrogenase (LDH), anemia with presence of schistocytes in peripheral smear and low haptoglobin concentration. The elevation of both aspartate aminotrans- ___________________________________________________________ * Corresponding author: Ana Campos, MD (anacampos.campos87@gmail.com) . http://www.ajecr.org/ mailto:anacampos.campos87@gmail.com 171 Am J Exp Clin Res, Vol. 3, No. 3, 2016 http://www.ajecr.org ferase (AST) and alanine aminotransferase (ALT) are mainly due to a hepatic lesion. Low platelet count is a result of a higher consumption: activated platelets adhere to endothelial cells with a reduced life-span [9, 10]. Perinatal morbidity and mortality are greater in HELLP syndrome and are related to gestational age of the onset of the clinical situation [7]. Excluding cases with no doubts in the classification of HELLP syndrome, when there is an hepatic involvement and coagulation disorders, sometimes the distinction with severe preeclampsia is difficult [8, 9]. The aim of this study was to identify factors that can distinguish preeclampsia from HELLP syndrome. We analyzed the early or late onset of the disease, based in clinical features and laboratorial findings, and the results in terms of maternal and fetal morbidity. Materials and Methods We reviewed the medical records of women diagnosed with severe preeclampsia or HELLP syndrome between January 1, 2008 and December 31, 2013 in a tertiary perinatal care center in Lisbon, Portugal. Socio-demographic, clinical and laboratorial data were analyzed. Classification criteria for preeclampsia diagnosis were defined according to guidelines of the International Society for the Study of Hypertension in Pregnancy (ISSHP) [11] and from the American College of Obstetrics and Gynecology (ACOG) [12]. According to ACOG criteria (2013) we classified as severe preeclampsia cases with a systolic arterial pressure (SAP) greater than or equal to 160 mm Hg and a diastolic arterial pressure (DAP) greater than or equal to 110mm Hg on two occasions 4 hours apart and the occurrence of any of these findings: impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes, significant proteinuria (≥300 mg/dL) per 24 hour urine collection, severe and persistent right upper quadrant or epigastric pain, headaches or visual disturbances, serum creatinine concentration values greater than 1.1mg/dL or pulmonary edema. Fetal compromise due to maternal placental insufficiency may be presented as fetal growth restriction, oligo-hydramnios, disturbed Doppler velocimetry with absent or reversed end diastolic flow in umbilical artery or other fetal vessels. If established before 34 weeks, preeclampsia was classified as of early onset and as of late onset if the diagnose was done only after 34 weeks. According to the ACOG we defined fetal growth restriction as an estimated fetal growth at ultrasound < 10th percentile or an abdominal circumference < the 10th percentile for a given gestational age [12]. We defined low birth weight as a newborn weight lesser than 2,500g and extremely low birth weight as a newborn weight lesser than 1,500g. The management during pregnancy consisted in symptomatic treatment, maternal condition stabilization, and eventually pregnancy termination when the risks of pregnancy continuation outweighed the benefits for either the mother or the fetus. The Mississippi criteria were applied for HELLP syndrome classification [10,13,14], with the categories’ TABLE 1 PREECLAMPSIA AND HELLP: SOCIO-DEMOGRAPHIC DATA AND CLINICAL EVALUATION PE: preeclampsia; BMI: body mass index; CH: chronic hy- pertension; AH: Arterial hypertension; GA: gestational age; UAD: Umbicial artery Doppler; FGR: fetal growth restric- tion; MgSO4: Magnesium sulfate; * Fisher exact test. division according to the number of platelet count, impaired liver function (AST or ALT) and lactate dehydrogenase (LDH) always under 600 IU/L. We also considered this syndrome as early or late onset, if the disease criteria were established before or after 34 weeks. For a complete evaluation, clinical and laboratorial parameters were associated with fetal status study, by ultra-sonographic assessment of fetal growth and Doppler velocimetry of uterine, umbilical and middle cerebral arteries and ductus venoso, for evaluation of fetal adaptation to an insufficient placental perfusion. We used anti-hypertensive therapy to stabilize maternal hypertension and to prevent cerebrovascular events, when arterial pressure was equal or greater than 160/100 mm Hg or with lower values associated with other symptoms, such as headaches or epigastric pain. Magnesium Sulfate was used for convulsions prophylaxis. When gestational age was lesser than 34 weeks 6 days, antenatal corticosteroid therapy was used for fetal lung maturation. When maternal platelet count was lesser than 80,000/ µL we started corticosteroid therapy, according to Missi- P E HELLP Adjust ed OR (n = 253) (n = 71) (95% CI) Age Median 30.5/6.6 31.3/6.7 1,009 (0.969 – 1.051) 0.65 Min-Max. 14 – 45 17 – 45 ≥35 years 81(30.9%) 24(33.3%) 0.895 (0.513 – 1.560) 0.696 Et hnicit y Caucasian 156 (63.0%) 44 (64.7%) Afro-American 66 (26.7%) 17 (25.0%) 0.813 (0.548 – 1,206) 0.303 Asiat ic 3 (1.2%) P arit y Nulliparous 164 (68.6%) 41 (68.3%) 1,088 (0.792-1.496) 0.602 Mult iparous 75 (31.4%) 19 (31.7) BMI Median/SD 25.7/5.6 25.0/4.5 0.968 (0.888 -1.056) 0.464 ≥25 59 (53.6%) 11 (44%) 0.384 ≥30 25 (22.7%) 5 (20%) 0.767 CH/HT in previous pregnancy 67 (26%) 8 (11.1%) 1.122 (1.008-1.249) 0.034* Diabet es 27 (10.7%) 6 (8.4%) 0.993 (0.885 – 1.115) 0.907 HT T herapy Labet alol 64(24.5%) 17 (23.6%) Nifedipine 41(15.7%) 9 (12.5%) Associat ion 78 (29.9%) 17 (23.6%) No t herapy 39(14.9) 22(30.6%) 0.804 (0.672 – 0.962) 0.017 GA at incoming Median/SD 33.3/4.1 33.07/ 4.4 IG <32s 81 (32%) 32 (45.1%) 1.988 (1.168-3.384) 0.011 IG <34s 108 (42.2%) 39 (54.9%) 1.670 (0.984-2.835) 0.057 UAD alt ered <34s 54 (56%) 17 (51,5%) 0.969 (0.606-1.549) 0.896 FGR 101 (41.1%) 22 (31.4%) 0.741 (0.427 – 1.287) 0.288 T herapy MgSO4 153 (58.6%) 50 (70.4%) 0.976 (0.628 – 1.518) 0.915 Fet al cort icot herapy 102 (94.4%) 36 (92,3%) 1.417 (0.337 – 5.962) 0.635 Mat ernal cort icot herapy 13 (5.2%) 35 (50%) 16.688 (8.196-33.982) >0.001 Variable p http://www.ajecr.org/ 172 Am J Exp Clin Res, Vol. 3, No. 3, 2016 http://www.ajecr.org TABLE 2 LABORATORIAL DATA AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDH: lactate dehydrogenase. ssippi protocol [10]. The data was registered in an informatics database. To compare categorical variables between the study groups, Qui-square test or extension to exact Fisher test were used; to analyze continuous variables the non-parametrical test of Mann-Whitney was used. Univariate analysis was used to assess differences in baseline demographic and pregnancy characteristics and in the outcome among the 2 groups. Unadjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to quantify the risk of severe preeclampsia and HELLP syndrome. Multivariate logistic regression was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (95% CI) for the outcome of HELLP syndrome. All statistical analysis was performed with Statistical Package for Social Sciences (SPSS) version 20.0 (SPSS Inc., Chicago, IL). Tests with probability values of α < 0.05 were considered significant. Results In the period in a total of 33 620 deliveries, 324 cases In the period of the study, in a total of 33620 deliveries, 324 cases of severe preeclampsia occurred, representing a prevalence of 0.9%. According to clinical and laboratory parameters the diagnosis of severe preeclampsia was present in 253 cases while HELLP syndrome in 71, resulting in a HELLP syndrome prevalence of 28% among all cases of severe preeclampsia and of 0.2% among all deliveries. The median maternal age was similar in both groups (30.5 years in severe preeclampsia and 31.3 years in HELLP syndrome) (p = 0.65); 30.9% of the women were older than 35 years in severe preeclampsia and 33.3% in HELLP syndrome (p = 0.69). Most of the women were nulliparous (68.6% in preeclampsia and 68.3% in HELLP syndrome), without differences between the two groups (p = 0.60). A history of hypertension was more frequent in preeclampsia group (aOR, 1.12; CI, 1.01-1.25); there were no differences in ethnicity and body mass index (BMI) (Table 1). Gestational age at the diagnosis was the same in both groups (33 weeks); no differences were found in doppler flow velocimetry (p = 0.34) or fetal growth restriction (FGR) (p = 0.29) (Table 1). The clinical classification and differences in severe preeclampsia and HELLP syndrome were based on laboratory tests results: elevated aspartate aminotransferase (AST) (p < 0.001), elevation in alanine aminotransferase (ALT) (p <0.001), lactate dehydrogenase (LDH) >1 000UI/L (p <0.001) and platelet count <100 000/µL (p <.001). HELLP syndrome class 1 or 2 was present, according to Mississippi criteria when platelet count <100 000/ µL (41% of HELLP cases) or <50 000/ µL (24% of HELLP cases) (Table 2). There were no differences in other laboratorial results, such as hemoglobin (p=0.4), hematocrit (p = 0.57), uric acid (p = 0.37) or proteinuria (p = 0.84), but haptoglobin <20 g/L was significantly more frequent in HELLP syndrome (p = 0.04) (Table 2). The early onset of the disease (<34 weeks) was more frequent in HELLP syndrome cases (55% vs 42%). Compared with the late onset cases, arterial pressure was higher when the disease established before 34 weeks, with higher need for anti-hypertensive drugs in association (p = 0.002). Fetal growth restriction was more frequent (p< 0.001) as well as elevated pulsatility index (IP) doppler velocimetry (p < .001) (Table 3). The newborn median weight was similar in preeclampsia and HELLP cases (2027g vs 1861g) (p = 0.104), although the HELLP syndrome group had more newborns under 1500g (a OR 1.82; CI, 1.10 – 3.18) (p = 0.036) (Table 4). Antenatal glucocorticoid for fetal lung maturation was used in 94% of preeclampsia and in 92% of HELLP syndrome cases (Table 1). Corticosteroids were administered for maternal severe or moderate thrombocytopenia in 50% of HELLP cases and only in 5.2% of preeclampsia cases (p > 0.001) (Table 1). No differences were found in severe preeclampsia cases and in class 3 of HELLP cases, in pregnancy results or in newborn morbidity (Table 3). There were 6 stillbirths (2.5%) in preeclampsia and 2 (3.3%) in HELLP syndrome. Three occurred between 31 and 35 weeks after placental P reeclampsia HELLP syndrome Adjust ed OR (n = 253) (n = 71) (95% CI) Hemat ocrit Med/DP 3.,7/4.8 36/4.3 0.572 Mín-Max 22-49 28-46 Hemoglobin ≥13g 68 (27.0%) 18 (25.4%) 0.4 ≥10-<13g 157 (62.3%) 42 (59.2%) <10g 25 (9.9%) 11 (15.5%) Uric Acid Med/DP 6.3/1.6 5.9/1.4 0.368 Mín-Máx 3.1-11.8 2.0-9.2 AST Normal 151 (60.6%) 12 (16.9%) 3.341 (2.371-4.707) <0.001 Alt ered 51 (20.5%) 15 (21.1%) Duplicat ed 44 (17.7%) 43 (60.6%) ALT Normal 161 (64.7%) 16 (22.5%) 3.112 (2.253-4.300) <0.001 Alt ered 39 (15.7%) 9 (12.7%) Duplicat ed 45 (18.1%) 45 (63.4%) LDH Normal 120 (47.6%) 11 (15.5%) 3.811 (2.592-5.604) <0.001 Alt ered 93 (36.9%) 15 (21.1%) >1000 IU/L 29 (11.5%) 43 (60.6%) P lat elet s ≥100 000 µL 212 (83.8%) 20 (28.2%) 2.885 (2.077-4.009) <0.001 <100 000 µL 22 (8.7%) 29 (40.8%) <50 000 µL 2 (0.8) 17 (23.9%) Hapt oglobin <20 g 15 (6.0%) 27 (38.0%) 1.246 (1.011- 1.536) 0.039 P rot einuria <100 89 (35.4%) 29 (41.4%) 0.844 ≥100-<500 64 (25.4%) 15 (21.4%) ≥500 61 (24.2%) 17 (37.2%) Variable p http://www.ajecr.org/ 173 Am J Exp Clin Res, Vol. 3, No. 3, 2016 http://www.ajecr.org TABLE 3 DIAGNOSIS BEFORE AND AFTER 34 WEEKS PE: Preeclampsia; AUD: Arterial uterine Doppler; FGR: Fetal growth restriction. abruption; five occurred between 24 and 26 weeks with an early and severe fetal growth restriction (table 4). There were no maternal deaths but there were two cases of eclampsia, six of coagulopathy after placental abruption, two cases of renal acute failure. Post-partum HELLP syndrome was diagnosed in 21% of the cases (table 4). After using multivariate logistic regression we identified thrombocytopenia <100 000/µL (aOR: 2.14; p <.01) and ALT >1000 UI/L(aOR:5.17; p <.001) as factors influencing HELLP syndrome diagnosis(table 5). Discussion In this comparative study, we tried to identify specific characteristics of HELLP syndrome. In the studied period, in a total of 33 620 deliveries, 324 cases of severe hypertensive disease were verified, with a prevalence of 0.9%. The prevalence of HELLP syndrome was 0.2% and complicated 27% of the cases of severe preeclampsia, results similar to other studies [10, 12, 13]. We didn’t find any differences in socio-demographic aspects nor in parity, in contrast to other studies, where multiparous and advanced maternal age are is more frequent in HELLP syndrome [6]. These results may be related to a greater prevalence of nulliparity in women with advanced age and with a reduced representation of multiparous women in our studied women, which may be an expression of delaying childbearing age. History of hypertensive disease was more frequent in severe preeclampsia cases than in HELLP syndrome. Arterial pressure values were greater, with higher need of anti-hypertensive drugs in severe preeclampsia cases, which is also present in other studies [6, 8, 14, 15]. Early onset of the disease, and extremely low birth weight, were more frequent in HELLP syndrome, supporting a more severe clinical picture in these cases, which is similar to other reports [8, 15]. An expectant attitude before 34 weeks was more frequent in severe preeclampsia than in HELLP syndrome cases, because in the latter there was a more frequent deterioration of clinical situation, determining an urgent pregnancy termination. TABLE 4. PREGNANCY OUTCOME* *Univariate analysis; PE: preeclampsia; PA: Placental abruption; ARF: Acute renal failure; GA: gestational age; NB: newborn. TABLE 5. HELLP SYNDROME: MULTIVARIATE ANALYSIS LDH: Lactate dehydrogenase. Nevertheless, in 92% of HELLP syndrome cases, it was possible to administrate antenatal corticosteroid for fetal lung maturation. In the presence of moderate or severe thrombo- cytopenia Dexametasone was used, according to Mississippi protocol, for a faster mother recovery [14]. There was an elevation of platelet count, allowing not only HELLP 39 (54.9%) P E 108 (42.2%) HELLP 32 (45.1%) P E 148 (57.8%) Ant ihypert ensive t herapy associat ion 1.78 (1.21-2.31) 0.002 AUD alt ered 4.21 (2.92-6.06) <0.001 FGR 2.72 (1.71-4.32) <0.001 Cesarean sect ion 3.93 (2.24-6.95) <0.001 FGR 0.698 Cesarean sect ion 0.772 AUD alt ered 0.876 Delivery <34s 0.19 Newborn weight <1500g 0.313 p 71 (49.3%) 73 (52.5%) 52 (28.9%) 112 (62.2%) Adjust ed OR (95% CI) 37 (20.7%) 18 (10.3%) 58 (26.5%) <34w (n = 147) ≥34w (n = 180) 52 (35.4%) 26(17.2%) 93 (42.3%) 14 (56%) 88 (40%) 162 (73.3%) 9 (36%) Variable Severe P E (n = 226) HELLP (n = 25) 9 (36%) 3 (15.8%) 19 (76%) 123 (86.6%) Obst et ric out come P lat elet s≥100 000 P E HELLP Adjust ed OR (n = 253) (n = 71) (95% CI) P A 4 (1.7%) 2 (2.8%) Eclampsia 2 (0.8%) 1 (1.4%) Fet al deat h 6 (2.4%) 2 (2.8%) ARF 2 (0.8%) 2 (2.8%) HELLP aft er birt h 15 (21.1%) GA at delivery (median) 35weeks 33weeks 0.329 <34weeks 108(42.2%) 39 (54.9%) 0.50 (0.29 – 0.85) 0.057 <32weeks 81 (32%) 32 (45.1%) 0.011 At t it ude Delivery 160 (61.1%) 42(58.3%) 0.675 Expect ant <34 weeks 61 (56.5%) 19 (48.7%) 0.404 Labour induct ion 120 (46.5%) 27 (37.5%) 0.601 Vaginal birt h 70(27.2%) 18 (25.0%) 0.92 Cesarean 187 (72.5%) 54 (75.0%) NB weight Median/DP 2027g /837 1861g/836 1.82 (1.04-3.18) <1500g 65(25.6%) 27 (38.6%) <2500g 182 (71.7%) 50 (71.4%) pVariable Variable Adjust ed OR (CI 95%) p Plat elet s <100 000/ µL 2.14 (1.49 – 3.06) <.001 LDH >1000IU/L 5.17 (2.19 – 12.16) <.001 http://www.ajecr.org/ 174 Am J Exp Clin Res, Vol. 3, No. 3, 2016 http://www.ajecr.org epidural anesthesia, but also a reduction of transfusion needs. The length of hospital staying was similar to severe preeclampsia cases and we maintain this protocol, even if there is not an evidence supporting this attitude. The Mississippi classification proposes the existence of classes according to platelet count. The class 3 with a platelets count less than 150 000/ µL is very similar to severe preeclampsia cases, when compared to clinical and laboratorial results. The early and sudden onset, the elevation of liver enzymes and thrombocytopenia are characteristic of HELLP syndrome severity. In this study, thrombocytopenia < 100 000/µL, and elevation of the liver function tests, were the identification factors of this syndrome. When multivariate analysis was done, thrombocytopenia < 100 000/µL and lactate dehydrogenase more than 1000UI/L, are the significant risk factors for this syndrome. 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