Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from Pharmacological interventions for the prevention of fetal growth restriction: protocol for a systematic review and network meta-analysis Alessandra Bettiol,1 Niccolò Lombardi,1 Giada Crescioli,1 Laura Avagliano,2 Alessandro Mugelli,1 Claudia Ravaldi,3,4 Alfredo Vannacci 1,4 To cite: Bettiol A, ABSTRACT Strengths and limitations of this study Lombardi N, Crescioli G, et al. Introduction Fetal growth restriction (FGR) includes Pharmacological interventions different conditions in which a fetus fails to reach for the prevention of fetal ► Both clinical trials and observational studies will be growth restriction: protocol for a the own full growth, and accounts for 28%–45% of included. systematic review and network non-anomalous stillbirths. The management of FGR is ► Where possible, results will be synthetised using a meta-analysis. BMJ Open based on the prolongation of pregnancy long enough network meta-analysis, thus allowing to simultane- 2019;9:e029467. doi:10.1136/ for fetal organs to mature while preventing starvation. ously combine both direct and indirect evidence. bmjopen-2019-029467 As for pharmacological management, most guidelines ► The study team includes clinicians, pharmacologists ► Prepublication history and recommend treatment with low-dose aspirin and/or with and experts in the field of pregnancy complications additional material for this heparin, although this approach is still controversial and and related therapeutic interventions. paper are available online. To innovative promising therapies are under investigation. view these files, please visit As no firm evidence exists to guide clinicians towards the journal online (http:// dx. doi. INTRODUCTION org/ 10. 1136/ bmjopen- 2019- the most effective therapeutic intervention, this protocol 029467). describes methods for a systematic review and network Fetal growth restriction (FGR), also known meta-analysis (NetMA) of pharmacological treatments for as intrauterine growth restriction, includes Received 28 January 2019 FGR prevention. different conditions in which a fetus fails to Revised 15 May 2019 Methods and analysis We will search MEDLINE and reach its own growth potential. For many Accepted 21 May 2019 Embase for clinical trials and observational studies years, the most common parameter used http://bmjopen.bmj.com/ performed on gestating women with clinically diagnosed to measure FGR was small for gestational risk of FGR. Experimental interventions will include heparin age (SGA),1 although the two terms are not and low-molecular-weight heparin, acetylsalicylic acid, synonymous. Recently, an international clin- antiplatelet agents, phosphodiesterase type 3 and 5 ical consensus was obtained about the defi- © Author(s) (or their inhibitors, maternal vascular endothelial growth factor nition of FGR2; therefore, works aimed to employer(s)) 2019. Re-use gene therapy, nanoparticles, microRNA, statins, nitric study the risk of growth-related adverse fetal permitted under CC BY-NC. No oxide donors, hydrogen sulphide, proton pump inhibitors, outcome should focus on true FGR. Namely, commercial re-use. See rights melatonin, creatine and N-acetylcysteine, and insulin- on October 2, 2021 by guest. Protected copyright. and permissions. Published by SGA is usually defined by a fetal size <10th BMJ. like growth factors, compared between each other or to centile for a population or customised stan- 1 1Department of Neurosciences, placebo or no treatment. Primary efficacy outcome is FGR. dard. However, this definition includes also Psychology, Drug Research Secondary efficacy outcomes will be preterm birth, fetal or a proportion of constitutionally small but and Child Health, University of neonatal death and neonatal complications. For the safety health fetuses while excluding a group of Florence, Florence, Italy outcome, all adverse events reported in included studies 2 fetuses with biometry >10th percentile but Department of Health Sciences, and experienced by either mothers, fetuses or newborns San Paolo Hospital Medical not meeting their own growth potential. On will be considered. Two review authors will independently School, Università degli Studi di the other hand, the concept of FGR applies Milano, Milano, Italy screen title, abstract and full paper text, and will only to non-healthy fetuses that failed to 3 Department of Health Sciences, independently extract data from included studies. Where reach their growth potential and thus are at University of Florence, Florence, possible and appropriate, for primary and secondary increased risk of adverse outcomes.2 Italy efficacy outcomes, a NetMA will be performed using a 4CiaoLapo - Charity for Healthy According to the definition identified random-effects model within a frequentist framework. 2 Pregnancy, Stillbirth and through a Delphi consensus procedure, early Adverse events will be narratively described. Perinatal Loss Support, Prato, FGR (ie, at gestational age <32 weeks), in the Ethics and dissemination Results will be disseminated Italy absence of congenital anomalies, is defined through a peer-reviewed scientific journal, and by scientific by fetal abdominal circumference (AC)/ Correspondence to congresses and meetings. estimated fetal weight (EFW) <3rd centile or Dr Alfredo Vannacci; PROSPERO registration number CRD42019122831. alfredo. vannacci@ unifi. it umbilical artery (UA) absent end-diastolic Bettiol A, et al. BMJ Open 2019;9:e029467. doi:10.1136/bmjopen-2019-029467 1 Open access flow, or by the co-presence of AC (EFW <10th centile meta-analysis (NetMA) of clinical trials and observational BMJ Open: first published as 10.1136/bmjopen-2019-029467 on 26 July 2019. Downloaded from and uterine artery pulsatility index (PI) >95th centile, studies conducted on gestating women at diagnosed risk alone or in combination with UA-PI >95th centile. On the of FGR, with the primary objective of estimating the effect other hand, late FGR (ie, at gestational age of 32 weeks of different pharmacological treatments on the incidence of more), is defined, in the absence of congenital anom- of FGR. alies, by AC/EFW <3rd centile or by the co-presence of at Secondary efficacy objectives include the evaluation of least two parameters among (i) AC/EFW <10th centile, the effect of different therapeutic strategies on the inci- (ii) AC/EFW crossing centiles >2 quartiles on growth dence of (i) preterm birth; (ii) fetal or neonatal death centiles or (iii) cerebroplacental ratio <5th centile or and (iii) neonatal complications related to the abnormal UA-PI >95th centile. growth. Safety objective includes the evaluation of adverse Suboptimal fetal growth accounts for 28%–45% of cases events involving treated women, fetuses or newborns. of non-anomalous stillbirth.3 4 Causes of FGR can be fetus-related or mother-related: among the former, there are chromosomal anomalies, genetic syndromes and infections. Among maternal METHODS AND ANALYSIS conditions, the most common are clinically relevant This protocol has been written according to the Preferred Reporting Items for Systematic Review and Meta-Analysis conditions such as autoimmune disorders, clinically rele- 15 vant conditions such as autoimmune disorders, hypox- Protocols guidance. emic conditions (such as severe anaemia, congenital cyanotic heart diseases), cardiovascular diseases (such as Eligibility criteria hypertension) or the exposition to environmental toxins. Studies will be selected according to the eligibility criteria The mechanism leading to FGR involves an abnormal outlined below. trophoblast invasion of the maternal spiral arteries during pregnancy, which results in an incomplete remodelling of Study designs these vessels and in the persistence of a high-resistance We will consider for inclusion both clinical trials and and low-flow uteroplacental circulation, which on its observational cohort studies, either prospective or retro- turn determines and insufficient gaseous and nutrient spective. Observational cross-sectional studies or case– exchange for optimal fetal growth.5 control studies will be excluded. Similarly, we will exclude This results in a cascade of events, including reduced reviews and meta-analyses, letters to the editor, case placental perfusion, imbalance in angiogenic factors, reports, case series and expert opinions. and in vascular endothelial growth factor (VEGF) and placental growth factor, and may lead to placen- Participants ta-mediated complications of pregnancy such as FGR, We will include studies performed on gestating women at http://bmjopen.bmj.com/ preeclampsia, placental abruption and late pregnancy diagnosed risk of FGR, including16 the following: 6 7 loss. ► History of late pregnancy loss or FGR. The management of FGR is based on the prolongation ► History of recurrent pregnancy loss (define by three of pregnancy long enough for fetal organs to mature or more consecutive first trimester spontaneous while avoiding irreversible fetus’ sufferance.8 As for phar- abortions). macological management, most guidelines recommend ► Hypertensive diseases. treatment with low-dose aspirin—in preference by gesta- ► Pre-eclampsia (in the current or previous tional week 16—for prevention of FGR,9–12 although pregnancies). on October 2, 2021 by guest. Protected copyright. 13 this approach is not universally accepted. The use of ► Diabetes mellitus. heparin is also controversial: the Canadian guideline ► Congenital cyanotic heart diseases.