The placental component and obstetric outcome in severe preeclampsia with and without HELLP syndrome

Accepted Manuscript The placental component and obstetric outcome in severe preeclampsia with and without HELLP syndrome Eran Weiner, Letizia Schreiber, Ehud Grinstein, Ohad Feldstein, Noa Rymer-Haskel, Jacob Bar, Michal Kovo PII:

S0143-4004(16)30531-8

DOI:

10.1016/j.placenta.2016.09.012

Reference:

YPLAC 3474

To appear in:

Placenta

Received Date: 15 July 2016 Revised Date:

15 September 2016

Accepted Date: 22 September 2016

Please cite this article as: Weiner E, Schreiber L, Grinstein E, Feldstein O, Rymer-Haskel N, Bar J, Kovo M, The placental component and obstetric outcome in severe preeclampsia with and without HELLP syndrome, Placenta (2016), doi: 10.1016/j.placenta.2016.09.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT The placental component and obstetric outcome in severe preeclampsia with and without HELLP syndrome

Eran Weiner, MD 1, Letizia Schreiber, MD 2, Ehud Grinstein, MD 1,

Michal Kovo, MD, PhD1

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Ohad Feldstein, MD 1, Noa Rymer-Haskel, MD 1, Jacob Bar, MD,MSc1,

Departments of Obstetrics & Gynecology1 and Pathology2, the Edith

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Medicine, Tel Aviv University, Tel Aviv, Israel

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Wolfson Medical Center, Holon, Israel affiliated with Sackler Faculty of

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

This study was presented at the 36th annual meeting of the Society for

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Maternal-Fetal Medicine (SMFM) in Atlanta, Georgia, February 1-6, 2016

Corresponding author: Eran Weiner

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Department of Obstetrics & Gynecology The Edith Wolfson Medical Center

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P.O. Box 5, Holon 58100, Israel Phone: 972-3-5028329; Fax: 972-3-5028503 E-mail address: [email protected]

ACCEPTED MANUSCRIPT

ABSTRACT Objective- We aimed to compare obstetric outcome and placental-histopathology in pregnancies complicated by preeclampsia with severe features with and without

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HELLP syndrome.

Methods– Labor, maternal characteristics, neonatal outcome and placental

histopathology of pregnancies complicated with severe preeclampsia during 2008-

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2015 were reviewed. Results were compared between those without signs of HELLP syndrome (severe preeclampsia group) and those with concomitant HELLP syndrome

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(HELLP group). Placental lesions were classified to maternal vascular lesions consistent with malperfusion, fetal vascular lesions consistent with fetal thromboocclusive disease, and inflammatory lesions. Small-for-gestational-age (SGA) was defined as birth-weight ≤10th% and ≤5th%. Composite adverse neonatal outcome was

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defined as one or more early neonatal complications.

Results- Compared to the severe preeclampsia group (n=223), the HELLP group (n=64) was characterized by earlier gestational-age, 34.1±2.7 vs. 35.3±3.4 weeks,

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p=0.010, higher rates of multiple pregnancies (p=0.024), and thrombophilia

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(p=0.028). Placentas in the HELLP group had higher rates of vascular and villous lesions consistent with maternal malperfusion (p=0.023, p=0.037 respectively). By multivariate logistic regression analysis models, vascular and villous lesions of maternal malperfusion were independently associated with HELLP syndrome (aOR 1.9, aOR 1.8, respectively). SGA was also more common in the HELLP group, both below the 10th percentile (p=0.044) and the 5th percentile (p=0.016). Composite adverse neonatal outcome did not differ between the groups.

ACCEPTED MANUSCRIPT Conclusion – Severe preeclampsia and HELLP syndrome have similar placental histopathologic findings. However, HELLP syndrome is associated with higher rates of placental maternal vascular supply lesions and SGA suggesting that the two clinical presentations share a common etiopathogenesis, with higher placental dysfunction in

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HELLP syndrome. Keywords Placental histopathology

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Malperfusion lesions

HELLP syndrome Neonatal outcome Small for gestational age

Abbreviations

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Placental weight

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Severe preeclampsia

HELLP - Hemolysis Elevated Liver enzymes and Low Platelet

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SGA – Small for Gestational Age

NICU - Neonatal Intensive Care Unit

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MIR – Maternal Inflammatory Response FIR – Fetal Inflammatory Response

ACCEPTED MANUSCRIPT INTRODUCTION Preeclampsia is one of the major entities in obstetrics that can have serious consequences for both the infant and the mother due to medically indicated preterm birth, fetal growth restriction (FGR), placental abruption, and maternal end-organ damage. [1]

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Microangiopthic Hemolysis, Elevated Liver enzymes and Low Platelet (HELLP) syndrome is considered as one of the severe forms of preeclampsia, but the relationship between the two entities is controversial. [2, 3]

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Abnormal placentation is known to be significantly associated with preeclampsia [4] and it is expressed through abnormal placental vascular lesions. The placental component in

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preeclampsia has been studied thoroughly in different clinical manifestations as in term and preterm preeclampsia, [5] preeclampsia with and without FGR[6] , or with and without severe features. [7] Studies have shown that abnormal placental morphology is more dominant in early-onset disease [8] and in preeclampsia with severe features, while lesions of fetal

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vascular supply are more common in preeclampsia with than those without FGR.[9] Only three studies investigated the differences in placental histopatholy and neonatal outcome in pregnancies complicated with severe preeclampsia, with and without HELLP syndrome, [10-

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12] using different placental pathological criteria, relatively small samples, and with

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contradictory results and conclusions. We aimed, therefore, to study the obstetric outcome, placental histopathologic lesions

and umbilical cord abnormalities, in pregnancies complicated with preeclampsia with severe features, with and without HELLP syndrome, using the validated placental pathological criteria.

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ACCEPTED MANUSCRIPT MATERIALS AND METHODS

The medical records and pathological reports of all patients who were diagnosed with preeclampsia and delivered at a single university hospital from 2008 to 2015 were reviewed.

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Cases eligible for the study were identified from our computerized data system. The study group included patients who delivered between 24-42 gestational weeks, complicated with preeclampsia with severe features, and their placentas were sent to

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histopathological evaluation, according to our departmental protocol.

Excluded from the study pregnancies complicated by preeclampsia without severe

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features, neonatal chromosomal or structural anomalies, or pregnancies complicated by intrauterine infection.

Preeclampsia was diagnosed according to the current American College of Obstetricians and Gynecologists criteria. [13] Preeclampsia with severe features (severe

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preeclampsia) was defined when systolic blood pressure was ≥ 160 mm Hg and/or diastolic blood pressure was ≥ 110 mm Hg on 2 occasions ≥ 6 hours apart. Blood pressure was measured by well-trained nurses, the cuff was wrapped around the left arm, the position of the

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arm was at heart level, and the patient was in a sitting position. Severe preeclampsia was defined also when there was an evidence of new development of renal insufficiency (elevated

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serum creatinine greater than 1.1 mg/dL, or doubling of serum creatinine in the absence of other renal disease), pulmonary edema, new-onset of cerebral or visual disturbance, or severe persistent right-upper-quadrant/epigastric pain unresponsive to medication. HELLP syndrome was defined on the basis of the following criteria: a. hemolysis

(based on low serum haptoglobin levels, and/or serum bilirubin ≥ 1.2 mg/dL, and/or a suggestive peripheral blood smear), b. elevated liver enzymes (alanine amino transferase or aspartate amino transferase ≥ twice upper level), c. low platelets (platelet count ≤ 100 000

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ACCEPTED MANUSCRIPT /ߤL). In the current study, we included patients complicated by complete or partial HELLP syndrome. Partial HELLP was defined as cases meeting two out of three criteria.[3, 14] All patients were treated with magnesium sulfate for eclampsia prophylaxis, according to current guidelines [13] and with antihypertensive medications as appropriate.

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For the purpose of the study pregnancy outcome and placental pathology reports were compared between pregnancies with severe preeclampsia without HELLP syndrome (severe preeclampsia group) and pregnancies with severe preeclampsia complicated by HELLP

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syndrome (HELLP group).

15-WOMC dated 6.8.2015).

Data collection

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Approval for the study was obtained from the local ethics committee (decision number 0102-

The following data were collected from the patient's medical and surgical files: age,

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gravidity, parity, body mass index (BMI kg/m2), pre-gestational diabetes mellitus, gestational diabetes mellitus, chronic hypertension, history of previous preeclampsia, pre-pregnancy diagnosis of thrombophilia (defined as any thrombophilia , inherited or acquired, that

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necessitated thromboprophylaxis [15, 16]) smoking, pregnancies achieved by assisted

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reproductive techniques (either ovulation induction or in-vitro fertilization), gestational age at delivery, mode of labor (Cesarean delivery vs. vaginal delivery). Gestational age was confirmed by first-trimester ultrasonography. Ultrasound studies before labor were collected. Fetal growth restriction (FGR) was defined as a prenatal ultrasound fetal weight estimation (FWE) <10th percentile.

Laboratory blood studies were collected as well including pre-labor: hemoglobin (Hb) g/dl levels, white blood cells (WBC) 103/µl, platelets (PLT) 103/µl, creatinine mg/dl, bilirubin

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ACCEPTED MANUSCRIPT (total) mg/dl, uric acid mg/dl, lactate dehydrogenase (LDH) U/l, aspartate amino transferase (AST) U/l, and alanine aminotransferase (ALT) U/l. Immediately after birth, all neonates were examined by pediatricians. Birth weight percentiles for gestational age were assigned using the updated local growth charts.[17] Small

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for gestational age (SGA) was defined as actual birth-weight ≤10th percentile or ≤5th

percentile for gestational age. The following data were collected from the neonatal records: Apgar scores, cord blood pH, neonatal intensive care unit (NICU) admissions, sepsis (positive

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blood or cerebrospinal fluid culture), need for blood transfusion, need for phototherapy, respiratory distress syndrome, need for mechanical ventilation or support, necrotizing

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enterocolitis, intraventricular hemorrhage (all grades), hypoxic ischemic encephalopathy, seizures, and death.

Placental examination

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As part of our departmental protocol, in every case of preeclampsia placentas are sent for histopathological evaluation. Placental pathology examinations were performed using our standard protocol, by a single pathologist (author L.S). Placental lesions were classified

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according to the criteria adopted by the Society for Pediatric Pathology [18, 19] and as was

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previously reported by us. [20]

Briefly, placental weight was determined 24 hours after delivery, and the percentile

was determined according to placental weight charts.[21] From each placenta 6 tissue samples were embedded in paraffin blocks for microscopic assessment: one roll of the free membranes, (chorion and amnion with attached deciduas capsularis), and section of umbilical cord. Five full thickness disc samples: one at the cord insertion, one in central tissue that appeared abnormal on gross examination, two from central tissue, and one at the margin, of

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ACCEPTED MANUSCRIPT visible abnormal areas on gross examination. Placentas derived from twin pregnancies were examined and reported separately. Lesions of maternal vascular supply included: placental hemorrhages (marginal, and retro-placental hematoma), vascular changes associated with maternal malperfusion (acute

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atherosis and mural hypertrophy), and villous changes associated with maternal malperfusion (increased syncytial knots, villous agglutination, increased intervillous fibrin deposition, distal villous hypoplasia, and parenchymal infarcts).

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Lesions of fetal vascular supply were defined as findings consistent with fetal

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thrombo-occlusive disease: vascular lesions (thrombosis of the chorionic plate and stem villous vessels) and villous changes (villous stromal-vascular karyorrhexis and avascular villi). Findings consistent with chorioamnionitis were defined according to the structure proposed by the Society for Pediatric Pathology [22]. Maternal inflammatory response (MIR), was divided into three stages and two grades: stage 1 – acute subchorionitis or chorionitis;

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stage 2 – polymorphonuclear (PMN) leukocytes extended into fibrous chorion and /or amnion; stage 3 – necrotizing chorioamnionitis: karyorrhexis of PMN leukocytes, amniocyte

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necrosis and/or amnion basement membrane hypereosinophilia; and grade 1- not severe as defined; grade 2- severe: confluent PMN leukocytes or with subchorionic microabscesses.

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Fetal inflammatory response (FIR) was also divided into 3 stages and 2 grades: stage 1 – umbilical phlebitis; stage 2 involvement of umbilical vein and one or more umbilical arteritis; stage 3 – concentric umbilical perivasculitis (necrotizing funisitis) and grade 1- not severe as defined; grade 2- near confluent intramural PMN leukocytes with attenuation of vascular smooth muscle. The umbilical cord was examined for the detection of hypercoiling and abnormal cord insertion. Umbilical coiling index was calculated by dividing the total number of coils by the length of the cord in centimeters. Hypercoiling was diagnosed in cases of umbilical coiling 5

ACCEPTED MANUSCRIPT index ˃ 0.3 coils/cm.[23] Abnormal cord insertion was defined as either velamentous, or marginal insertion.

Statistical analysis

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Data were analyzed with SPSS software, version 21.0 (SPSS Inc; Chicago, Illinois). Continuous variables are presented as mean ± SD or median and range, as appropriate.

Categorical variables are presented as rate (%). Continuous parameters were compared by

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Student’s t-test and categorical variables by chi-square test or by Fisher exact test, as appropriate. P-value of <0.05 was considered statistically significant.

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To identify independent possible risk factors for vascular placental lesion, multivariate forward logistic regression analyses were performed. The following placental lesions: vascular lesion and villous lesions related to maternal malperfusion served (separately) as dependent variables while, HELLP syndrome, maternal age, gestational age at delivery, DM,

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multiple pregnancy, nulliparity, thrombophilia, BMI , SGA , chronic hypertension, and maternal smoking served as independent variables. Composite adverse neonatal outcome was defined as one or more of the following

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early complications: neonatal sepsis, blood transfusion, phototherapy, respiratory morbidity

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(presence of respiratory distress syndrome, or transient tachypnea of the newborn, or mechanical ventilation, or need for respiratory support) cerebral morbidity (presence of intraventricular hemorrhage, or seizures, or hypoxic-ischemic encephalopathy) necrotizing enterocolitis, or death.

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ACCEPTED MANUSCRIPT RESULTS During the study period 589 out of 25,391 deliveries (2.3%) were complicated with preeclampsia, of them 223 (37.9%) had severe preeclampsia without HELLP syndrome (severe PE group) and 64 (10.9%) had severe PE with HELLP syndrome (HELLP group).

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Table 1 presents maternal characteristics of the study groups. The two groups did not differ in terms of maternal age, nulliparity, BMI, and smoking rate. Patients in the HELLP group were less likely to have chronic hypertension (p=0.025), or previous preeclampsia

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(p=0.025), they had lower gestational age at delivery (34.1 ± 2.7 vs. 35.3 ± 3.4 gestational weeks, p=0.010), higher rate of multiple pregnancy (p=0.024), and higher rate of pre-

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pregnancy diagnosis of thrombophilia (p=0.028) than patients in the severe PE group. Both groups had similar high rate of Cesarean delivery, 81.1% and 88.8%. There were no cases of eclampsia in both groups. There were significant differences in the serum levels of Hb, WBC, PLT, as well as serum creatinine, uric acid, LDH, bilirubin, ALT and AST between the

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groups (Table 2).

Placental characteristics are summarized in Table 3. Mean placental weight was significantly lower in the HELLP group than the severe PE group (p<0.001). In addition, the

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HELLP group had a higher rate of placental weight <10th percentile (p =0.003). The HELLP

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group had a higher rate of vascular lesions related to maternal malperfusion (51.9% vs. 37.0%, p=0.023) and a higher rate of villous lesions related to maternal malperfusion (62.3% vs. 48.6%, p=0.037) than the severe PE group. Using multivariate logistic regression analysis models, vascular lesions of maternal malperfusion, aOR 1.9, 95% CI 1.13-3.53, p= 0.034, and villous lesions of maternal malperfusion, aOR 1.8, 95% CI 1.26-2.93, p= 0.028, were independently associated with HELLP syndrome. Inflammatory lesions did not differ between the severe PE and HELLP group, both MIR (11.1% vs. 14.3%) and FIR (2.5% vs. 5.2%), as well as the different stages and grades of the inflammatory responses. There were also no

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ACCEPTED MANUSCRIPT differences between the groups in the rate of fetal vascular supply lesions and umbilical cord abnormalities.

Neonatal outcome parameters are presented in Table 4. The severe PE group included 36

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out of 243 (14.7%) fetuses (with the pre-labor diagnosis of FGR (FEW <10th %) as compared to 19 out of 77 (24.6%) fetuses in the HELP group , p=0.056. FGR with abnormal Doppler flow indices at the umbilical artery (systolic/diastolic (S/D ratio) were observed in 12 (5%) fetuses in

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the PE group as compared to 9 (11.7%) fetuses in the HELLP group, (p=0.060).

Neonates in the HELLP group were more likely to be SGA both below the 10th percentile

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(32.5% vs. 20.6%, p=0.044) and below the 5th percentile (15.6% vs. 6.2%, p=0.016) compared to the severe PE group. In addition, neonates in the HELLP group had longer hospitalization (8.2 ± 5.5 vs 6.1 ± 4.3 days, p<0.001), higher rates of NICU admission (80.5% vs. 62.1%, p=0.003), and higher rate of 5-minute Apgar score ≤ 7 (6.5% vs. 1.2%, p=0.021),

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between the groups.

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as compared to the severe PE group. Composite adverse neonatal outcome did not differ

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ACCEPTED MANUSCRIPT DISCUSSION The present study shows that placentas retrieved from pregnancies complicated with HELLP syndrome, were associated with a significantly higher rate of placentas weighing below the 10th percentile and more placental vascular and villous lesions related to maternal

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malperfusion, than placentas from severe preeclampsia without HELLP syndrome.

Additionally, pregnancies with HELLP syndrome were also associated with higher rate of neonates that were SGA.

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The relationship between HELLP syndrome and severe preeclampsia has been studied with conflicting results. Several studies have suggested that HELLP syndrome differs from

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preeclampsia by its ethnical and clinical manifestations. HELLP syndrome is more frequent in white women, [24] about 20% of the affected patients with HELLP syndrome do not have antecedent hypertension or proteinuria, [25] while coagulopathy is observed more often in HELLP patients than in preeclampsia. [26] Moreover, it has been suggested that pregnancies

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complicated with HELLP syndrome have less effect on fetal growth than pregnancies complicated with severe preeclampsia without HELLP syndrome. [10]

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Studies on placental lesions and preeclampsia tried to establish a relationship between

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placental morphologic lesions and the clinical severity of the disease. The current study suggests that preeclampsia and HELLP syndrome have similar underlying pathophysiology with a continuum course of a disease, with HELLP syndrome representing a severe phenotype of it. The specific pathogenesis of preeclampsia is still explored. The most cited hypothesis on the etiology of preeclampsia is based on an inadequate remodeling of uterine spiral arteries in the placental bed due to superficial trophoblast invasion followed by placental hypoxia.[4, 27] The main placental features of preeclampsia are small placentas with increased placental

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ACCEPTED MANUSCRIPT maternal malperfusion lesions, [28, 29] which we observed more common in the HELLP syndrome group than in the severe preeclampsia group. Our findings are contradictory to a previous study by Vinnars et al. [10] who found higher rates of infarction, intervillous thrombosis (villous lesions related to maternal

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malperfusion), and abruption, as well as higher placental weight in cases of severe

preeclampsia than in HELLP syndrome, suggesting that different pathogenetic mechanisms participate in the development of preeclampsia and HELLP syndrome. On the other hand,

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they have not found a significant difference in the rate of decidual arteriopathy, vascular

lesion related to maternal malperfusion, between the groups. Moreover, Smulian et al. [12]

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and Mehrabian et al. [11] who studied placental lesions in pregnancies complicated by severe preeclampsia and HELLP syndrome could not demonstrate any differences in histopathology lesions except for higher frequency of abruption in the severe preeclampsia group. The differences between the studies could be attributed to different criteria defining severe

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preeclampsia or HELLP syndrome and different placental pathology criteria. In addition, the studies by Smulian et al. [12] and Mehrabian et al. [11] also included considerable smaller study cohorts than the current one.

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An additional finding of the current study is the increased rate of SGA neonates, below

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the 10th and the 5th percentiles in HELLP syndrome compared with severe preeclampsia. This finding is in the same line of our hypothesis that HELLP syndrome is a more severe form of the same etiopathogenesis of the disease, with increased placental dysfunction that affect the developing fetus. It has been shown that increased decidual vasculopathy or vascular lesions related to maternal malperfusion are correlated with placental dysfunction and adverse perinatal outcome.[30] Our findings are in concordant with Haddad et al. [31] who demonstrated, as well, a higher rate of growth restricted neonates in HELLP syndrome as compared to preeclampsia (37% vs. 17%), but in contrast to Vinnars et al. [10] who found a

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ACCEPTED MANUSCRIPT higher rate of SGA infants in the severe preeclampsia as compared to HELLP syndrome (72% vs. 23%). The characteristics of the study population differed between the groups. In fact, the relationship between the two disorders is controversial. In the current study, patients in the

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HELLP syndrome group had lower gestational age at delivery, with higher rates of multiple pregnancies and thrombophilia than the severe preeclampsia group, as also described in

previous studies.[32-36] Yet, maternal and composite neonatal outcome were similar in the

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two groups.

The present study is unique in several aspects. First, we applied the definitions of

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preeclampsia with severe features according to the updated guidelines of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. [13] Second, we used the validated placental pathological criteria adopted by the Society for Pediatric Pathology. [18] A single pathologist (author L.S) performed all the pathological

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reports, and was blinded to the occurrence of HELLP syndrome and neonatal outcome. Thirdly, we included in the HELLP group patients who met at least two out of three criteria for HELLP syndrome. [3, 14]

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The current study is not without limitations. First, by it's the retrospective nature.

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Second, data on neonatal long-term follow up were not available. Third, the pathologist was not blinded to the diagnosis of preeclampsia, but only to the presence or absence of associated HELLP syndrome. This could potentially influence diagnoses in the same spectrum of lesions.

It is important that future studies should use strict definitions of severe preeclampsia and HELLP syndrome and accepted criteria of placental pathology evaluation to further establish the relationship between severe preeclampsia and HELLP syndrome.

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ACCEPTED MANUSCRIPT In conclusion, HELLP syndrome and severe preeclampsia have similar histopathological placental lesions. However, HELLP syndrome is characterized by increased rate of placental maternal malperfusion lesions and a higher rate of SGA, than preeclampsia with severe features. Lesions seen with maternal malperfusion are considered to be a consequence of early

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developmental events. These probably indicate that similar early pathogenic mechanisms

participate in the development of these two clinical presentations, with an exacerbation of a more

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severe form of placental dysfunction that is manifested in HELLP syndrome.

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Berks, D., et al., Associations between phenotypes of preeclampsia and thrombophilia. Eur J Obstet Gynecol Reprod Biol, 2015. 194: p. 199-205. Tufano, A., et al., HELLP syndrome and its relation with the antiphospholipid syndrome.

RI PT

35.

Blood Transfus, 2014. 12(1): p. 114-8.

Le Thi Thuong, D., et al., The HELLP syndrome in the antiphospholipid syndrome:

EP

TE D

M AN U

SC

retrospective study of 16 cases in 15 women. Ann Rheum Dis, 2005. 64(2): p. 273-8.

AC C

36.

16

ACCEPTED MANUSCRIPT Table 1: Maternal characteristics of the study groups

HELLP

n=223

n=64

Maternal age (years)

31.1 ± 5.8

31.3 ± 6.0

0.302

Gestational age at delivery (weeks)

35.3 ±3.4

34.1 ± 2.7

0.010

Early onset < 34 weeks

91 (40.1)

40 (63.4)

0.002

Nulliparity (%)

129 (57.8)

37 (58.7)

0.886

BMI (kg/m2)

27.6 ± 2.9

28.2 ± 3.8

0.387

20 (9.0)

13 (20.3)

0.024

34 (15.2)

4 (6.3)

0.025

42 (18.8)

10 (15.6)

0.7123

34 (15.2)

4 (6.3)

0.025

6 (2.7)

6 (9.3)

0.028

19 (8.5)

4 (6.3)

0.794

15 (6.7)

5 (7.9)

0.780

181 (81.1)

56 (88.8)

0.186

SC

Previous preeclampsia (%)

TE D

DM (%) Chronic hypertension (%)

Smoking (%)

AC C

ART (%)

EP

Thrombophilia (%)

M AN U

Multiple pregnancy (%)

Cesarean delivery (%)

p-value

RI PT

Sever PE

Continuous variables are presented as mean ±SD and categorical variables as n (%). DMdiabetes mellitus including PGDM and GDM; BMI- body mass index; ART – assisted reproduction technology (ovulation induction or in-vitro fertilization)

ACCEPTED MANUSCRIPT

Table 2: Hematological and biochemical parameters in the two groups

HELLP

RI PT

Severe PE

p-value

n=223 White blood cells (103/µl)

11.1 ± 1.6

Hemoglobin (g/dl)

10.9 ± 1.1

10.1 ± 0.9

<0.001

M AN U

n=64

142.3 ± 63

89.8 ± 47.6

<0.001

6.5 ± 1.2

7.6 ± 2.1

<0.001

0.69 ± 0.1

0.76 ± 0.3

0.002

0.4 ± 0.1

0.8 ± 0.3

<0.001

SC

11.6 ± 1.4

Platelets (103/µl) Uric acid (mg/dl)

TE D

Creatinine (mg/dl) Bilirubin-total (mg/dl)

EP

Lactate dehydrogenase (U/l)

AC C

Aspartate aminotransferase (U/l) Alanine aminotransferase (U/l)

439.1 ± 161.9

0.014

736.3 ± 268.3

<0.001

29.1 ± 6.3

73.2 ± 6.9

<0.001

28.6 ± 5.9

71.6 ± 5.1

<0.001

ACCEPTED MANUSCRIPT Table 3: Placental characteristics of the study groups

HELLP

n=243

n=77

459 ± 107

406 ± 102

<0.001

22 (28.5)

0.003

7 (9.1)

0.544

Placental weight (gr) Placental weight < 10th %

34 (14)

Maternal vascular supply lesions 31 (12.8)

SC

Placental hemorrhage

p-value

RI PT

Sever PE

90 (37)

40 (51.9)

0.023

Villous changes related to maternal mal-perfusion

118 (48.6)

48 (62.3)

0.037

24 (9.9)

4 (5.2)

0.252

33 (13.6)

7 (9.1)

0.429

27 (11.1)

11 (14.3)

0.427

6 (2.5)

4 (5.2)

0.260

34 (14)

12 (15.6)

0.712

Hypocoiling

15 (6.2)

4 (5.2)

1

Abnormal cord insertion

5 (2.1)

4 (5.2)

0.227

Fetal vascular supply lesions Vascular lesions consistent with FTOD Villous lesions consistent with FTOD

MIR stages 1-3, grade 1-2 FIR stages 1-3, grade 1-2

TE D

Inflammatory lesions

M AN U

Vascular lesions related to maternal mal-perfusion

AC C

Hyprecoiling

EP

Umbilical cord abnormalities

Continuous variables are presented as mean ±SD and categorical variables as n (%). FTOD- fetal thrombo-occlusive disease; MIR - maternal inflammatory response; FIR - fetal inflammatory response

ACCEPTED MANUSCRIPT Table 4: Neonatal outcome in the study groups

HELLP

n=243

n=77

2498 ± 436

< 0.001

SGA ≤ 10th percentile

50 (20.6)

25 (32.5)

0.044

SGA ≤ 5th percentile

15 (6.2)

12 (15.6)

0.016

Neonatal hospitalization (days)

6.1 ± 4.3

8.2 ± 5.5

< 0.001

151 (62.1)

62 (80.5)

0.003

5 (2.1)

4 (5.2)

0.227

3 (1.2)

5 (6.5)

0.021

46 (20.6)

17 (22.1)

0.621

Cerebral morbidity **

4 (1.6)

2 (2.6)

0.633

Neonatal sepsis

7 (2.9)

5 (6.5)

0.169

Necrotizing enterocolitis

0

1 (1.3)

0.241

9 (3.7)

5 (6.5)

0.337

33 (13.6)

9 (11.7)

0.847

0

0

1

90 (37.0)

35 (45.5)

0.228

Umbilical cord pH ≤ 7.1 5-minute Apgar score ≤ 7

EP

TE D

Respiratory morbidity *

Blood transfusions Phototherapy

Neonatal death

Composite adverse neonatal outcome

M AN U

NICU admission

SC

2210 ± 280

AC C

Birth Weight (grams)

p-value

RI PT

Severe PE

ACCEPTED MANUSCRIPT Continuous variables are presented as mean ±SD and categorical variables as n (%). NICUneonatal intensive care unit. *Respiratory morbidity includes- presence of respiratory distress syndrome, or mechanical ventilation or need for respiratory support. **Cerebral morbidity includes- presence of intra-ventricular hemorrhage (all grades), or seizures or hypoxic-ischemic

AC C

EP

TE D

M AN U

SC

RI PT

encephalopathy.

ACCEPTED MANUSCRIPT Highlights

Obstetric outcome and placental histopathology in severe preeclampsia ± HELLP

RI PT

syndrome were compared

HELLP had an earlier gestational age and higher rates of multiple pregnancies, and

SC

thrombophilia

Placentas in HELLP had higher rates of vascular and villous lesions consistent with

M AN U

maternal malperfusion

These lesions were associated with HELLP syndrome independent of all background

TE D

factors

AC C

EP

SGA was more common in the HELLP group, both below the 10th and 5th percentiles