Contents lists available at ScienceDirect Placenta journal homepage: www.elsevier.com/locate/placenta Asymmetric dimethylarginine levels in preeclampsia – Systematic review and meta-analysis Balázs Németh a,* , Edit Murányi a , Péter Hegyi b , Péter Mátrai b , Zsolt Szakács b , Péter Varjú b , Szilárd Hamvas c , Benedek Tinusz b , Ferenc Budán a , József Czimmer d , Bálint Bérczi a , Bálint Erőss b , Zoltán Gyöngyi a , István Kiss a a Department of Public Health Medicine, Medical School, University of Pécs, Szigeti str. 12. H-7624, Pécs, Hungary b Institute for Translational Medicine, Medical School, University of Pécs, Szigeti str. 12. H-7624, Pécs, Hungary c Faculty of Health Science, University of Pécs, Mária str. 7. H-7621, Pécs, Hungary d 1st Department of Internal Medicine, Medical School, University of Pécs, Ifjúság str. 13. H-7624, Pécs, Hungary ARTICLE INFO Keywords: Preeclampsia Asymmetric dimethylarginine meta-Analysis Systematic review ABSTRACT Objective: Preeclampsia (PE) is the leading cause of maternal and perinatal mortality around the world. The impaired function of fetal–placental vasculature is a key factor in PE. Several studies have investigated the connection between PE and endothelial dysfunction. Also, many authors have examined the changes in asym- metric dimethylarginine (ADMA) as a prominent marker of endothelial dysfunction. Our study aim is to review and analyse the connections between PE and ADMA levels. Methods: To obtain data we performed a comprehensive literature search in Pubmed, Embase and Web of Science. Standardized mean differences were used to estimate the differences in ADMA levels. Results: The quantitative analysis included 10 studies reporting a total number of 631 PE and 498 healthy pregnant individuals. We found significantly higher ADMA levels in PE patients compared to controls, when comparing the ADMA levels of the patients to the ADMA levels of the controls (z = 5.93, p < 0.001). This difference was present regardless of the measurement method. Regarding the onset of PE, we found significantly higher ADMA levels in patients suffering from early-onset PE when comparing the ADMA levels of the early- onset PE patients to that of the controls (z = 2.82, p = 0.005). However, we did not find such difference when we compared late-onset PE patients' ADMA levels to controls. Conclusion: ADMA is significantly higher in PE patients than in the controls. Elevated ADMA levels can play a major role in the development of PE, but more research is needed to clarify the connection between the two. 1. Introduction Preeclampsia (PE) is the leading cause of maternal and perinatal mortality around the world. It is estimated to occur in 3–5% of all pregnancies [1,2]. According to the latest guideline of the International Society for the Study of Hypertension in Pregnancy (ISSHP), PE is characterized by the de-novo onset of hypertension (> 140 mmHg systolic or > 90 mmHg diastolic) after 20 weeks gestation and at least one of the following: proteinuria (> 300 mg/day or at least 1 g/L, “2 +” on dipstick testing), maternal organ dysfunction and uteroplacental dysfunction [3]. There are two categories of PE according to the onset of the disease: early-onset before gestation age of 34 weeks; late onset after gestation age of 34 weeks [4]. Numerous factors increase the risk of developing PE: antipho- spholipid syndrome, previous PE, diabetes mellitus, multiple preg- nancy, nulliparity, obesity, age > 40, pre-existing hypertension, ect [5]. The onset of PE has harmful short-term and long-term effects both on the infant and the mother [6–8]. The exact pathomechanism of PE is still unclear. Nevertheless, the impaired build up and function of the fetal–placental vasculature play a key role in the development of the https://doi.org/10.1016/j.placenta.2018.07.010 Received 26 April 2018; Received in revised form 20 June 2018; Accepted 17 July 2018 Abbreviations: ADMA, asymmetric dimethylarginine; BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; ELISA, enzyme-linked im- munosorbent assay; HPLC, high performance liquid chromatography; ISSHP, International Society for the Study of Hypertension in Pregnancy; IQR, inter quartile range; NO, nitric oxide; NOS, nitric oxide synthases; PE, preeclampsia; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis; SBP, systolic blood pressure; SMD, standardized mean differences * Corresponding author. E-mail address: balazs.nemeth@aok.pte.hu (B. Németh). Placenta 69 (2018) 57–63 0143-4004/ © 2018 Elsevier Ltd. All rights reserved. T