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ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-029467 Article Type: Protocol Date Submitted by the 28-Jan-2019 Author: Complete List of Authors: Bettiol, Alessandra; Universita degli Studi di Firenze Dipartimento di Neuroscienze Psicologia Area del Farmaco e Salute del Bambino Lombardi, Niccolò; Universita degli Studi di Firenze Dipartimento di Neuroscienze Psicologia Area del Farmaco e Salute del Bambino Crescioli, Giada; Universita degli Studi di Firenze Dipartimento di Neuroscienze Psicologia Area del Farmaco e Salute del Bambino Ravaldi, Claudia; Universita degli Studi di Firenze, Department of Health Sciences,; Charity for Healthy Pregnancy, Stillbirth and Perinatal Loss Support Vannacci, Alfredo; Florence University, Department of Pharmacology Fetal medicine < OBSTETRICS, Maternal medicine < OBSTETRICS, http://bmjopen.bmj.com/ Keywords: PREVENTIVE MEDICINE, CLINICAL PHARMACOLOGY, PERINATOLOGY on September 23, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 18 BMJ Open 1 2 3 Pharmacological interventions for the prevention of foetal growth restriction: protocol for a 4 BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from 5 systematic review and network meta-analysis. 6 7 8 9 Alessandra Bettiol1, Niccolò Lombardi1, Giada Crescioli1, Claudia Ravaldi2,3, Alfredo Vannacci1,2 10 11 12 13 14 1. Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmacology and 15 16 Toxicology, University of Florence; Tuscan Regional Centre of Pharmacovigilance and Phytovigilance, 17 18 Florence, Italy For peer review only 19 20 2. CiaoLapo, Charity for Healthy Pregnancy, Stillbirth and Perinatal Loss Support, Prato, Italy 21 22 3. Department of Health Sciences, University of Florence, Florence, Italy 23 24 25 26 Email: Alessandra Bettiol [email protected]; Niccolò Lombardi [email protected]; Giada 27 28 Crescioli [email protected]; Claudia Ravaldi [email protected]; Alfredo Vannacci 29 30 31 [email protected] 32 33 34 35 Corresponding author 36 http://bmjopen.bmj.com/ 37 Prof. Alfredo Vannacci 38 39 Department of Neurosciences, Psychology, Drug Research and Child Health 40 41 University of Florence 42 43 Viale G. Pieraccini, 6 - 50139 - Florence, Italy 44 on September 23, 2021 by guest. Protected copyright. 45 Phone number: +39 055 27 58 206 46 47 Email address: [email protected] 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 18 1 2 3 ABSTRACT 4 BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from 5 Introduction: Foetal growth restriction (FGR) includes different conditions in which a foetus fails to reach 6 7 the full growth, and accounts for 28-45% of non-anomalous stillbirths. The management of FGR is based on 8 9 the prolongation of pregnancy long enough for foetal organs to mature. As for pharmacological management, 10 11 12 most guidelines recommend treatment with low-dose aspirin, while use of heparin is controversial and 13 14 innovative promising therapies are under investigation. As no firm evidence exists to guide clinicians 15 16 towards the most effective therapeutic intervention, this protocol describes methods for a systematic review 17 18 and network meta-analysisFor of pharmacological peer treatmentsreview for FGR onlyprevention. 19 20 Methods and analysis: We will search MEDLINE and Embase for clinical trials and observational studies 21 22 performed on singleton-gestating women with clinically-diagnosed risk of FGR and/or preeclampsia. 23 24 Experimental interventions will include heparin and low-molecular-weight heparin, acetylsalicylic acid, 25 26 antiplatelet agents, phosphodiesterase type 5 inhibitors, maternal VEGF gene therapy, nanoparticles, 27 28 microRNA, statins, nitric oxide donors, hydrogen sulphite, proton pump inhibitors, melatonin, creatine and 29 30 31 N-acetylcysteine, compared between each other or to placebo or no treatment. Primary efficacy outcome is 32 33 FGR. Secondary efficacy outcomes will be preeclampsia, placental abruption, and foetal or neonatal death. 34 35 For the safety outcome, all adverse events reported in included studies and experienced by either mothers or 36 http://bmjopen.bmj.com/ 37 newborns will be considered. 38 39 Two review authors will independently screen title, abstract and full paper text, and will independently 40 41 extract data from included studies. Where possible and appropriate, for primary and secondary efficacy 42 43 outcomes, a network meta-analysis will be performed using a random-effects model within a frequentist 44 on September 23, 2021 by guest. Protected copyright. 45 framework. Adverse events will be narratively described. 46 47 Ethics and dissemination: Results will be disseminated through a peer-reviewed scientific journal, and by 48 49 scientific congresses and meetings. 50 51 52 PROSPERO registration number: CRD42019122831 53 54 55 56 STRENGTHS AND LIMITATIONS OF THIS STUDY 57 58 Both clinical trials and observational studies will be included. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 18 BMJ Open 1 2 3 Where possible, results will be synthetized using a network meta-analysis, thus allowing to 4 BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from 5 simultaneously combine both direct and indirect evidence. 6 7 The study team includes clinicians, pharmacologists, and experts in the field of pregnancy 8 9 10 complications and related therapeutic interventions. 11 12 13 14 Word count: 2508 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43 44 on September 23, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 18 1 2 3 INTRODUCTION 4 BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from 5 Foetal growth restriction (FGR), also known as intrauterine growth restriction (IUGR), includes different 6 7 conditions in which a foetus fails to reach the full growth. The most common parameter used to measure 8 9 FGR is small for gestational age (SGA) [1] , and is usually defined as an infant with a birthweight for 10 11 12 gestational age <10th centile for a population or customized standard [1]. 13 14 Suboptimal foetal growth is important as SGA babies comprise 28-45% of non-anomalous stillbirths [2,3]. 15 16 Causes of FGR and SGA can be foetus- or mother-related: among the former, there are chromosomal 17 18 anomalies, genetic syndromes,For and peer infection. Among review maternal conditions, only the most common are: exposition 19 20 to environmental toxins (ex. cigarette smoking), or uteroplacental insufficiency. The mechanism leading to 21 22 FGR involves an abnormal trophoblast invasion of the maternal spiral arteries during pregnancy, which 23 24 results in an incomplete remodelling of these vessels and in the persistence of a high-resistance and low-flow 25 26 uteroplacental circulation, which on its turn determines and insufficient gaseous and nutrient exchange for 27 28 optimal foetal growth [4]. 29 30 31 This results in a cascade of events, including reduced placental perfusion, imbalance in angiogenic factors, 32 33 and in vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), and may lead to 34 35 placenta-mediated complications of pregnancy such as FGR, preeclampsia, placental abruption, and late 36 http://bmjopen.bmj.com/ 37 pregnancy loss [5,6]. 38 39 The management of FGR is based on the prolongation of pregnancy long enough for foetal organs to mature 40 41 while avoiding irreversible foetus’ sufferance [7]. As for pharmacological management, most guidelines 42 43 recommend treatment with low-dose aspirin – in preference by gestational week 16 - for prevention of SGA 44 on September 23, 2021 by guest. Protected copyright. 45 [8–11]. Use of heparin is instead controversial: the Canadian guideline recommends that heparin should be 46 47 offered in selected women [8], although recent evidence indicates that enoxaparin is not effective in 48 49 preventing FGR in women with previous severe or early-onset FGR, or in those with thrombophilia, and can 50 51 52 therefore not be recommended for this purpose [1,12].