Pregnancy Hypertension- An International Journal of Women's Cardiovascular Health Volume 12 issue 2018 [doi 10.1016%2Fj.preghy.2018.02.001] Weiner, Eran; Feldstein, Ohad; Tamayev, Lili.pdf

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Pregnancy Hypertension 12 (2018) 6–10 Contents lists available at ScienceDirect Pregnancy Hypertension journal homepage: www.elsevier.com/locate/preghy Placental histopathological lesions in correlation with neo
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  Contents lists available at ScienceDirect Pregnancy Hypertension  journal homepage: www.elsevier.com/locate/preghy Placental histopathological lesions in correlation with neonatal outcome inpreeclampsia with and without severe features Eran Weiner a,1, ⁎ , Ohad Feldstein a,1 , Liliya Tamayev a , Ehud Grinstein a , Elad Barber a , Jacob Bar a ,Letizia Schreiber b , Michal Kovo a a  Department of Obstetrics & Gynecology, The Edith Wolfson Medical Center, Holon, Israel a  ffi liated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel b  Department of Pathology, The Edith Wolfson Medical Center, Holon, Israel a  ffi liated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel A B S T R A C T Objective:  We aimed to compare pregnancy outcome and placental histopathology in women with preeclampsia(PE) with and without severe features.  Methods:  The medical records and placental pathology reports of all pregnancies complicated by PE during2008 – 2016, were reviewed. Results were compared between those with and without severe features (severe PEvs. mild PE groups), according to current ACOG guidelines. Placental lesions were classi 󿬁 ed to maternal/fetalvascular supply lesions, and maternal/fetal in 󿬂 ammatory responses. Small for gestational age (SGA) was de 󿬁 nedas neonatal birth-weight  ≤ 10th%. Composite adverse neonatal outcome was de 󿬁 ned as one or more of thefollowing: sepsis, transfusion, phototherapy, respiratory morbidity, cerebral morbidity, NEC, or death.  Results:  The severe PE group (n=284) was characterized by lower gestational age at delivery (p < 0.001), andhigher rates of antenatal corticosteroid use (p=0.003), and cesarean deliveries (p < 0.001) as compared to themild PE group (n=151). More placentas<10th% and more composite maternal vascular malperfusion (MVM)lesions were observed in the severe PE group as compared to the mild PE group (p < 0.001 for both). Inmultivariate analysis, composite placental MVM lesions were independently associated with severe PE(aOR=1.75, 95%CI 1.4 – 4.9).Higher rates of SGA (p=0.016), and composite adverse neonatal outcome (p=0.002) characterized thesevere PE group. In multivariate analysis, adverse neonatal outcome was independently associated with gesta-tional age (aOR=0.54, 95%CI 0.49 – 0.68), SGA (aOR=1.75, 95%CI=1.15 – 3.59), severe PE (aOR=1.8,95%CI=1.13 – 3.54) and placental MVM lesions (aOR=2.13, 95%CI=1.05 – 4.39). Conclusion:  More pronounced placental pathology and higher rate of adverse neonatal outcome characterizepreeclampsia with severe features as compared with the milder form of the disease. 1. Introduction Preeclampsia (PE) is a multi-system disorder of pregnancy [1] thatcould lead to immediate and long-term detrimental maternal andneonatal consequences. Maternal complications include eclampsia,placental abruption, renal and hepatic failure during pregnancy, as wellas increased risk of chronic hypertension, cardiovascular disease,stroke, and metabolic syndrome later in life [2 – 4]. Neonatal compli-cations include prematurity related consequences, compromised motordevelopment [5], intra uterine fetal growth restriction (FGR) with in-creased risk of diabetes and cardiovascular morbidity in adulthood [6].PE has two main clinical presentations, PE with and without severefeatures [1]. The severe form of the disease includes severehypertension and symptoms of end-organ injury. In comparison to PEwithout severe features, severe PE was shown to be associated withadverse neonatal outcomes, including higher rates of preterm birth andsmall for gestational age (SGA) [7,8].The etiology and pathophysiology of PE have not been fully eluci-dated yet [9]. Studies suggest that endothelial dysfunction, systemicin 󿬂 ammation or infection, genetic and immunologic aberrations areinvolved in the development of PE [10,11]. It is generally accepted thatabnormal placentation plays a central role in the pathophysiology of PE[12,13]. This abnormality leads to the release of circulating anti-angiogenic factors that in turn cause systemic endothelial dysfunction,resulting in hypertension, proteinuria, and numerous systemic mani-festations [14]. https://doi.org/10.1016/j.preghy.2018.02.001Received 6 September 2017; Received in revised form 19 January 2018; Accepted 6 February 2018 ⁎ Corresponding author at: Department of Obstetrics and Gynecology, The Edith Wolfson Medical Center, P.O. Box 5, Holon 58100, Israel. 1 Authors EW and OF equally contributed to this manuscript.  E-mail address:  masolbarak@gmail.com (E. Weiner). Pregnancy Hypertension 12 (2018) 6–10Available online 07 February 20182210-7789/ © 2018 Published by Elsevier B.V. on behalf of International Society for the Study of Hypertension in Pregnancy.    The association between ischemic placental diseases, such as PE andFGR, and placental histopathology lesions, mostly of maternal vascularmalperfusion (MVM) lesions, has been studied in di ff  erent clinicalpresentations [15]. These presentations include early and late onset of PE [16], severe PE with and without HELLP syndrome [17,18] as well as early vs. late FGR [19,20]. Only few studies investigated the asso-ciation between the severity of PE and placental histopathology  󿬁 nd-ings [21 – 23], and none of these studies looked for a correlation withneonatal outcomes.Therefore, we aimed to  󿬁 ll this gap and to examine the associationbetween neonatal outcome and placental histopathologic lesions, inpregnancies complicated by PE, with and without severe features. 2. Materials and methods The medical records and pathological reports of all patients whowere diagnosed with PE and delivered at a single university hospitalfrom 2008 to 2017 were reviewed. Cases eligible for the study wereidenti 󿬁 ed from our computerized data system. The study group in-cluded singleton pregnancies complicated by preeclampsia, deliveredbetween 24 and 42 gestational weeks, and who had placental histo-pathological evaluation, according to our departmental protocol.Excluded from the study multiple pregnancies, pregnancies complicatedby neonatal chromosomal, structural anomalies, and intrauterine in-fection, as well as cases that underwent termination of pregnancy.PE was diagnosed according to the current American College of Obstetricians and Gynecologists criteria [1], which were fully adaptedby our institution for preeclampsia diagnosis and management. PE withsevere features (severe PE) was de 󿬁 ned by the presence of any of thefollowing  󿬁 ndings: systolic blood pressure was  ≥ 160mm Hg, or dia-stolic blood pressure was  ≥ 110mm Hg on 2 occasions  ≥ 6h apart,thrombocytopenia (platelet count  ≤ 100,000/  μ L), severe persistentright-upper-quadrant/epigastric pain unresponsive to medication, ele-vated liver enzymes (alanine amino transferase or aspartate aminotransferase ≥ twice upper level), hemolysis (based on low serum hap-toglobin levels, and/or serum bilirubin ≥ 1.2mg/dL, and/or a sugges-tive peripheral blood smear), renal insu ffi ciency (elevated serumcreatinine greater than 1.1mg/dL, or doubling of serum creatinine inthe absence of other renal disease), pulmonary edema, or new-onset of cerebral/visual disturbance. All patients with severe features weretreated with magnesium sulfate for eclampsia prophylaxis, according tothe current guidelines and with antihypertensive medications as ap-propriate [1].For the purpose of the study, pregnancy outcome and placentalpathology reports were compared between pregnancies complicated byPE with (severe PE group) and without severe features (mild PE group).Approval for the study was obtained from the local ethics committee(decision number 0102-15-WOMC dated 6.8.2015).  2.1. Data collection The following data were collected from the patient's medical andsurgical  󿬁 les: age, gravidity, parity, body mass index (BMI kg/m 2 ), pre-gestational diabetes mellitus, gestational diabetes mellitus, chronichypertension, history of previous PE, thrombophilia (de 󿬁 ned as anythrombophilia, inherited or acquired, that necessitated thrombopro-phylaxis [24,25], maternal smoking, gestational age at delivery, an-tenatal corticosteroid administration, Magnesium Sulfate administra-tion, and mode of labor (cesarean delivery vs. vaginal delivery).Gestational age was con 󿬁 rmed by  󿬁 rst-trimester ultrasonography.Women were considered to receive antenatal corticosteroids if theyreceived two dose of intramuscular Betamethasone 12mg, 24h apart,prior to delivery [26].Immediately after birth, all neonates were examined by pediatri-cians. Birth weight percentiles for gestational age were assigned usingthe updated local growth charts [27]. SGA was de 󿬁 ned as actual birth-weight ≤ 10th percentile for gestational age. The following data werecollected from the neonatal records: Apgar scores, cord blood pH,neonatal intensive care unit (NICU) admissions, sepsis (positive bloodor cerebrospinal  󿬂 uid culture), need for blood transfusion, need forphototherapy, respiratory distress syndrome, need for mechanicalventilation or support, necrotizing enterocolitis, intraventricular he-morrhage (all grades), hypoxic ischemic encephalopathy, seizures, anddeath.  2.2. Placental examination As part of our departmental protocol, in every case of pregnancycomplications placentas are sent for histopathological evaluation.Placental pathology examinations were performed using our standardprotocol, by a single pathologist (author L.S) Placental lesions wereclassi 󿬁 ed according to the criteria adopted by the Society for PediatricPathology [28,29] and as was previously reported by us [18,30]. Brie 󿬂 y, placental weight was determined 24h after delivery, andthe percentile was determined according to placental weight charts[31]. Each placenta was  󿬁 xed in formalin, and at least 5 samples wereembedded in para ffi n blocks for microscopic assessment.Lesions of maternal vascular supply included: placental hemor-rhages (marginal, and retro-placental hematoma), vascular changesassociated with maternal malperfusion (acute atherosis and mural hy-pertrophy), and villous changes associated with maternal malperfusion(increased syncytial knots, villous agglutination, increased intervillous 󿬁 brin deposition, distal villous hypoplasia, and villous infarcts).Lesions of fetal vascular supply were de 󿬁 ned as  󿬁 ndings consistentwith fetal thrombo-occlusive disease: vascular lesions (thrombosis of the chorionic plate and stem villous vessels) and villous changes (hy-povascular,  󿬁 brotic and avascular villi).Findings consistent with chorioamnionitis were de 󿬁 ned by thepresence of an in 󿬂 ammatory neutrophil in 󿬁 ltrate at two or more siteson the chorionic plate and extra-placental membrane. Maternal in- 󿬂 ammatory response (MIR), was divided into three stages; stage 1  – characterized by the presence of a few scattered neutrophils in the sub-chorionic space; stage 2  –  characterized by many neutrophils (11 – 30per HPF) in the lower half of the chorionic plate; and stage 3  –  char-acterized by dense in 󿬁 ltrates of neutrophils (>30 per HPF) throughoutthe chorionic plate. Fetal in 󿬂 ammatory response (FIR) was also dividedinto 3 stages: stage 1  –  early, umbilical phlebitis; stage 2  –  intermediate,umbilical arteritis; and stage 3  –  concentric umbilical perivasculitis(necrotizing funisitis). Villitis of unknown etiology or chronic villitis,de 󿬁 ned as lymphohistiocytic in 󿬂 ammation localized to the stroma of terminal villi but often extending to the small vessels of upstream villi,was recorded separately.The umbilical cord was examined for the detection of hypercoilingand abnormal cord insertion. Umbilical coiling index was calculated bydividing the total number of coils by the length of the cord in cen-timeters. Hypercoiling was diagnosed in cases of umbilical coilingindex> 0.3coils/cm [32]. Abnormal cord insertion was de 󿬁 ned aseither velamentous, or marginal insertion.  2.3. Statistical analysis Data were analyzed with SPSS software, version 21.0 (SPSS Inc;Chicago, Illinois). Continuous variables are presented as median [IQR].Categorical variables are presented as rate (%). Continuous parameterswere compared by Mann – Whitney ’ s  U   test and categorical variables bychi-square test or by Fisher exact test, as appropriate. P-value of<0.05was considered statistically signi 󿬁 cant.Composite placental maternal vascular malperfusion lesions wasde 󿬁 ned as the presence of one or more of maternal vascular supplyabnormalities, and composite placental fetal vascular malperfusion le-sions was de 󿬁 ned as the presence of one or more fetal vascular supplyabnormalities.  E. Weiner et al.  Pregnancy Hypertension 12 (2018) 6–10 7  Composite adverse neonatal outcome was de 󿬁 ned as one or more of the following early complications: neonatal sepsis, blood transfusion,phototherapy, respiratory morbidity (presence of respiratory distresssyndrome, or transient tachypnea of the newborn, or mechanical ven-tilation, or need for respiratory support) cerebral morbidity (presenceof intra-ventricular hemorrhage, or seizures, or hypoxic-ischemic en-cephalopathy), necrotizing enterocolitis, or death.In order to identify factors that are independently associated withcomposite maternal vascular malperfusion (MVM) lesions a regressionanalysis model was designed. Composite maternal vascular malperfu-sion lesions served as a dependent variable and the following factors,gestational age, mode of delivery, mild/severe PE, smoking, BMI, dia-betes, and chronic hypertension, served as independent variables.To identify independent possible risk factors for composite adverseneonatal outcome, another multivariate logistic regression analysis wasperformed. Composite neonatal outcome served as dependent variableswhile composite maternal malperfusion lesions, gestational age at de-livery, DM, BMI, maternal smoking, thrombophilia, chronic hyperten-sion, antenatal corticosteroids, Magnesium Sulfate administration, SGA,and severe PE, served as independent variables. 3. Results In total, 435 pregnancies complicated with PE were eligible for thestudy, of them 284 (65.3%) had PE with severe features, (severe PEgroup), and 151 (34.7%) had PE without severe features (mild PE group).Table 1 presents maternal characteristics of the study groups. Therewere no between group di ff  erences in maternal age, nulliparity, BMI,maternal diseases as diabetes, thrombophilia, chronic hypertension andsmoking rate. Compared to the mild PE group, the severe PE group hada lower median gestational age at delivery (35.0 vs. 36.6weeks,p < 0.001), and higher rates of previous PE (p=0.006), antenatalcorticosteroid use (31.7% vs. 18.5%, p=0.003), and of cesarean de-liveries (p < 0.001). There were no cases of eclampsia in both groups.Placental and cord characteristics are summarized in Table 2. Thesevere PE group was characterized by lower placental weights andhigher rate of placental weights below the 10th percentile, as comparedto the mild PE group (p=0.004, p < 0.001, respectively). Ad-ditionally, placentas from the severe PE group had a higher rate of vascular lesions related to maternal malperfusion (p < 0.001) and ahigher rate of villous lesions related to maternal malperfusion(p=0.001), as compared to placentas from the mild PE group. Therewere no di ff  erences between the groups in the rate of fetal vascularsupply lesions, maternal or fetal in 󿬂 ammatory responses or umbilicalcord abnormalities. By a multivariable regression analysis model, aftercontrolling for gestational age, mode of delivery, mild/severe PE,smoking, BMI, diabetes, and chronic hypertension, composite maternalvascular malperfusion (MVM) lesions was found to be independentlyassociated with severe preeclampsia, aOR 1.75, 95% CI 1.4 – 4.9,p < 0.001.Neonatal outcome parameters are presented in Table 3. Neonates inthe severe PE group had a lower median birth weight (2269 vs. 2552g,p=0.002) and a higher rate of SGA (26.1% vs. 15.9%, p=0.016) ascompared to the mild PE group. Furthermore, neonates in the severe PEgroup had longer hospitalization (p=0.011), higher rates of NICUadmission (p=0.019) and higher rate of phototherapy treatment(p=0.001), as compared to the mild PE group. Composite adverse Table 1 Maternal demographics of the study groups DM- diabetes mellitus including PGDM andGDM; BMI- body mass index; Continuous variables are presented as median [IQR] andcategorical variables as n (%). Values in bold are statistically signi 󿬁 cant (p < 0.05).Mild PE Severe PE  p -valuen=151 n=284Maternal age (years) 31.4 (6.2) 32.1 (5.8) 0.316Gestational age at delivery (weeks) 36.6 (2.1) 35 (4.1)  <0.001 Nulliparity (%) 100 (66.2) 162 (57.0) 0.065BMI (kg/m 2 ) 28.3 (7) 27.1 (7.4) 0.184DM (%) 31 (20.5) 48 (16.9) 0.363Thrombophilia (%) 2 (1.3) 8 (2.8) 0.505Chronic hypertension (%) 16 (10.6) 38 (13.4) 0.448Previous preeclampsia (%) 10 (6.6) 45 (15.8)  0.006 Smoking (%) 17 (11.3) 23 (8.1) 0.298Cesarean delivery (%) 108 (71.5) 242 (85.2)  <0.001 Antenatal corticosteroids 28 (18.5) 90 (31.7)  0.003Table 2 Placental characteristics and umbilical cord abnormalities.Mild PEn=151Severe PEn=284  p- valuePlacental weight (gr) 438 (107) 392 (151)  0.004 Placental weight < 10th percentile (%) 25 (16.6) 90 (31.7)  <0.001  Maternal vascular supply lesions Retro-placental hemorrhage (%) 13 (8.6) 36 (12.7) 0.265Vascular lesions related to maternalmalperfusion (%)25 (16.6) 114 (40.1)  <0.001 Villous changes related to maternalmalperfusion (%)61 (40.4) 161 (56.7)  0.001 Composite maternal vascular malperfusionlesions (%)78 (51.7) 226 (79.6)  <0.001  Fetal vascular supply lesions Vascular lesions consistent with FTOD (%) 11 (7.3) 24 (8.5) 0.716Villous lesions consistent with FTOD (%) 23 (15.2) 42 (14.8) 0.889Composite fetal vascular malperfusionlesions (%)31 (20.5) 51 (17.9) 0.522  In  󿬂 ammatory lesions MIR stages 1 – 3 (%) 13 (8.6) 24 (8.5) 1.000FIR stages 1 – 3 (%) 9 (6.0) 12 (4.2) 0.483Chronic villitis of unknown etiology (%) 4 (2.6) 8 (2.8) 1.000 Umbilical cord abnormalities Hypercoiling (%) 15 (9.9) 47 (16.5) 0.063Hypocoiling (%) 8 (5.3) 19 (6.7) 0.679Abnormal insertion (%) 15 (9.9) 32 (11.3) 0.747FTOD  –  fetal thrombo-occlusive disease; MIR  –  maternal in 󿬂 ammatory response; FIR  – fetal in 󿬂 ammatory response; Continuous variables are presented as median [IQR] andcategorical variables as n (%). Values in bold are statistically signi 󿬁 cant (p < 0.05). Table 3 Neonatal outcome.Mild PE Severe PE  p -valuen=151 n=284Birth weight (grams) 2552 (742) 2269 (801)  0.002 SGA ≤ 10th percentile (%) 24 (15.9) 74 (26.1)  0.016 Neonatal hospitalization (days) 11.8 (10) 16.3 (19)  0.011 NICU admission (%) 51 (33.8) 130 (45.8)  0.019 Umbilical cord pH ≤ 7.1 (%) 5 (3.3) 5 (1.8) 0.3265-minute Apgar score ≤ 7 4 (2.6) 12 (4.2) 0.594Respiratory morbidity * (%) 11 (7.3) 39 (13.7) 0.058Cerebral morbidity ** (%) 1 (0.7) 3 (1.1) 1.000Neonatal sepsis (%) 0 4 (1.4) 0.303Necrotizing enterocolitis (%) 0 1 (0.4) 1.000Blood transfusions (%) 6 (4.0) 16 (5.6) 0.501Phototherapy (%) 26 (17.2) 89 (31.3)  0.001 Neonatal death (%) 2 (1.3) 7 (2.5) *** 0.725Composite adverse neonatal outcome (%) 31 (20.5) 99 (34.9)  0.002 NICU-neonatal intensive care unit; Continuous variables are presented as median [IQR]and categorical variables as n (%). Values in bold are statistically signi 󿬁 cant (p < 0.05).* Respiratory morbidity includes-presence of respiratory distress syndrome, or me-chanical ventilation or need for respiratory support.** Cerebral morbidity includes-presence of intra-ventricular hemorrhage (all grades),or seizures or hypoxic-ischemic encephalopathy.*** Two cases of neonatal death were due to withdraw of care.  E. Weiner et al.  Pregnancy Hypertension 12 (2018) 6–10 8  neonatal outcome was higher in the severe PE group compared to themild PE group (p=0.002).Maternal, placental, and neonatal characteristics of the entire cohortwas strati 󿬁 ed to groups according to the presence (n=130) or absence(n=305) of composite adverse neonatal outcome (Table 4). The groupwith adverse neonatal outcome was characterized by lower gestationalage, higher rate of SGA, and increased rate of placentas with maternalvascular malperfusion lesions, as compared to the group without adverseneonatal outcome (p < 0.001, p < 0.001, p=0.003, respectively)In order to identify independent risk factors for composite adverseneonatal outcome a multivariate logistic regression analysis model wasperformed (Table 5). In this analysis composite adverse neonatal out-come was found to be associated with gestational age at delivery(aOR=0.54), SGA (aOR=1.75), severe PE (aOR=1.8), and compo-site maternal vascular malperfusion lesions (aOR=2.13) independentof other background confounders. 4. Discussion The present study shows that placental malperfusion lesions andadverse neonatal outcome were signi 󿬁 cantly more common in preg-nancies complicated with PE with severe features, as compared to PEwithout severe features.Placental abnormalities, particularly inadequate remodeling of uterine spiral arteries in the placental bed, play a major etiological rolein PE [33,34]. Such abnormalities can lead to placental histopatholo-gical changes, including placental parenchymal infarcts, decidualarteriopathy and other placental features considered to be indicative of maternal vascular malperfusion (MVM) lesions [28,35,36]. Previousstudies demonstrated that placental malperfusion lesions were morecommon in early severe PE [37], as well as in PE cases requiring de-livery before 34weeks of gestation, than in mild cases of PE [38]. Our 󿬁 ndings, showing higher rate of placental MVM lesions (vascular andvillous changes) in severe PE are consistent with a previous studyshowing that the prevalence and extent of placental infarction weregreater in severe than in mild PE, regardless of the gestational age [21].The correlation between the clinical severity of PE and the degree of placental malperfusion lesions points to a di ff  erent maternal responsewhich is not dependent on gestational age. Thus, it is probably a re-sponse to a more prominent change in vascular modi 󿬁 cation and de-velopment of the maternal spiral arteries [39].The second interesting  󿬁 nding of the current study is the associationbetween adverse neonatal outcome, severity of PE and placental ma-ternal malperfusion lesions. Lower birth weights, increased rate of SGAand adverse neonatal outcome characterized the severe PE group ascompared to the mild PE group. The association between SGA, gesta-tional age and adverse neonatal outcome has been reported previously[40]. Moreover, the presence of placental decidual arteriopathy in PEpredicted the need for neonatal care [41]. However, these studies didnot assess the severity of PE and its relation to neonatal outcome. In thecurrent study, we demonstrate for the  󿬁 rst time that adverse neonataloutcome was independently associated with severe PE (OR 1.8 95% CI1.13 – 3.54, p=0.029), and with placental maternal vascular mal-perfusion lesions (OR 2.13, 95% CI 1.05 – 4.39, p=0.041). The pre-sence of placental malperfusion lesions has an important impact onneonatal outcome, especially in the presence of SGA, with higherneonatal morbidity as well as late neurological developmental sequels[40,42 – 44]. The mechanisms underlying the association between pla-cental malperfusion lesions and adverse neonatal outcome are not clear.It could be hypothesized that adverse neonatal outcome is a result of suboptimal placental function and decreased oxygen delivery to thedeveloping fetus. Alternatively, it may be a result of underlying pro-cesses that independently a ff  ect placental development (causing mal-perfusion lesions), and fetal brain development (causing late neurolo-gical sequela) [45].The present study is unique in several aspects. First, this is a rela-tively large cohort study, and we applied the de 󿬁 nitions of PE, with andwithout severe features, according to the updated guidelines of theAmerican College of Obstetricians and Gynecologists' Task Force onHypertension in Pregnancy [1]. Second, a single pathologist (authorL.S) performed all placental histopathology evaluations using the vali-dated placental pathological criteria adopted by the Society for Pedia-tric Pathology [28]. Although there are many studies about placentalpathology in PE, this is the  󿬁 rst study that focuses on the di ff  erences inmild vs. severe PE in relation to neonatal outcome.The current study is not without limitations. First, because of itsretrospective design, which forced us to conduct it only on patientswhose placentas were initially sent for pathological examination, un-intended selection bias may have occurred. Second, neonatal long-termfollow up was not available. Third, by applying the current ACOGguidelines (1) over a time period of 8years, bias is introduced as di-agnosis and management has signi 󿬁 cantly changed throughout thistime period. Lastly, due to the nature of the study design, the pathol-ogist was not blinded to the diagnosis of PE or to the presence of severefeatures, all could have led to an observer bias.In conclusion, PE with severe features is associated with higher ratesof placental maternal malperfusion lesions as compared to mild disease.The pathology is similar but more substantial in pregnancies compli-cated with severe PE. Adverse neonatal outcome was found to be in-dependently associated with severe PE and with the presence of ma-ternal vascular malperfusion lesions. The association between placentallesions and neonatal outcome does not necessarily re 󿬂 ect a causal re-lation and the etiopathogenesis mechanisms need to be further studied. Table 4 Maternal, placental, and neonatal characteristics of the entire cohort, strati 󿬁 ed accordingto the presence or absence of adverse neonatal outcome DM- diabetes mellitus includingPGDM and GDM; BMI- body mass index; SGA- small for gestational age; Continuousvariables are presented as median [IQR] and categorical variables as n (%). Values in boldare statistically signi 󿬁 cant (p < 0.05).Adverseneonataloutcomen=130No adverseneonatal outcomen=305p-valueGestational age at delivery(weeks)33.6 (3.2) 37.3 (2.4) <0.001BMI (kg/m 2 ) 26.1 (7) 26.9 (7.3) 0.226DM (%) 19 (14.6) 60 (19.7) 0.225Thrombophilia (%) 5 (3.8) 5 (1.6) 0.173Chronic hypertension (%) 17 (13.1) 37 (12.1) 0.753Previous preeclampsia (%) 18 (13.8) 37 (12.1) 0.638Smoking (%) 10 (7.7) 30 (9.8) 0.588SGA ≤ 10 th percentile (%) 46 (35.4) 52 (17.0)  <0.001 Composite maternalmalperfusion lesions (%)103 (79.2) 201 (65.9)  0.003Table 5 Results of a multivariate logistic regression analysis model to identify independent pos-sible risk factors for composite adverse neonatal outcome.Adjusted OR * 95% con 󿬁 denceinterval  p -valueGestational age at delivery 0.54 0.49 – 0.68 <0.001BMI (kg/m 2 ) 0.98 0.92 – 1.07 0.835DM 0.49 0.17 – 1.05 0.089SGA ≤ 10th percentile (%) 1.75 1.15 – 3.59 0.026Severe PE 1.8 1.13 – 3.54 0.029Composite maternalmalperfusion lesions2.13 1.05 – 4.39 0.041Values in bold are statistically signi 󿬁 cant (p < 0.05).* Adjusted for composite maternal malperfusion lesions, gestational age at delivery,DM (diabetes mellitus), PE- preeclampsia, BMI (body mass index), smoking, thrombo-philia, chronic hypertension, antenatal corticosteroids, Magnesium Sulfate administra-tion, SGA (small for gestational age), and severe PE (preeclampsia).  E. Weiner et al.  Pregnancy Hypertension 12 (2018) 6–10 9
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