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Screening for small for gestational age using third-trimester ultrasound markers: protocol for a systematic… Gasse, Cédric; Paquette, Kim; Demers, Suzanne; Roberge, Stéphanie; Bujold, Emmanuel; Boutin, Amélie Dec 3, 2018

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PROTOCOL Open AccessScreening for small for gestational ageusing third-trimester ultrasound markers:protocol for a systematic review andmeta-analysis of screening test accuracyCédric Gasse1,2, Kim Paquette1, Suzanne Demers1,3, Stéphanie Roberge4, Emmanuel Bujold1,3 andAmélie Boutin1,5*AbstractBackground: Fetal growth restriction (FGR) is a complication of pregnancy associated with major neonatal morbidityand commonly diagnosed at birth based on birth weight below the 5th or the 10th centile. There is no consensus onthe use of routine third-trimester ultrasound for the detection of FGR in a general population. This systematic reviewaims to estimate the performance of third-trimester ultrasound markers in the screening for babies who are small forgestational age in low-risk or general population.Methods: A systematic review of screening test accuracy will be conducted. The databases MEDLINE, Embase, CochraneLibrary, and Web of Science will be searched from their inception until December 2017, as well as reference lists ofincluded studies and previous related review articles. Studies screening for FGR in a low-risk or general population usingthird-trimester ultrasound markers and reporting low birth weight for gestational age (small for gestational age at birth)as a reference will be eligible. Two reviewers will independently screen references for inclusion, assess the risk of bias, andextract data. The Quality Assessment of Diagnostic Accuracy Study 2 (QUADAS-2) tool will be used to assess themethodological quality and validity of individual studies. The hierarchal summary receiver operating characteristicand random effects hierarchal bivariate models (Bivariate) will be used to estimate the pooled sensitivity andspecificity of each ultrasound marker and to compare the discriminative ability of the different ultrasound markers.Subgroup and sensitivity analyses will be performed to explore the heterogeneity between studies and to assess theeffect of screening tests’ characteristics (e.g., timing) on their discriminative ability.Discussion: This systematic review will determine the relevance of routine third-trimester ultrasound markers in thescreening for FGR in low-risk or general population and their usefulness in standard pregnancy care. Additionally, thisknowledge synthesis represents a step in the optimization of the discriminative ability of third-trimester ultrasoundand predictive tools, allowing for targeted interventions aiming at the reduction of FGR complications and ultimatelyimproving infants’ health.Systematic review registration: This protocol has been registered at PROSPERO: international prospective register ofsystematic reviews. The register number is CRD42018085564.Keywords: Ultrasound, Small for gestational age, Screening, Screening accuracy, Third trimester* Correspondence: amelie.boutin.2@ulaval.ca1Reproduction, Mother and Child Health Unit, CHU de Québec - UniversitéLaval Research Center, Universite Laval, 2705, boul. Laurier, Quebec, QC G1V4G2, Canada5Department of Obstetrics and Gynaecology, Faculty of Medicine, Universityof British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (, which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver( applies to the data made available in this article, unless otherwise stated.Gasse et al. Systematic Reviews           (2018) 7:219 growth restriction (FGR) is a complication thataffects approximately 5 to 10% of all pregnancies [1]. Itis typically defined as an estimated fetal weight or abdominalcircumference below the 5th or the 10th centile accordingto gestational age and sex, with severe cases being below the3rd centile. It can arise from several maternal, fetal, and/orplacental origins, including placental insufficiency orplacental abnormality, a genetic abnormality, or an in-fection during pregnancy [2–5]. FGR is commonly diag-nosed at birth, the affected infants having a low birthweight for their gestational age and sex and being small forgestational age (SGA). FGR is associated with prematurebirths, neurodevelopmental delays in children, and abouthalf of all fetal deaths [6–8]. It is also associated withchronic health problems in adulthood, such as diabetes,obesity, and hypertension [9].Fetal ultrasound is now part of the standard of careduring pregnancy, allowing for the prediction, monitoring,and prevention of many complications, such as fetal andplacental anomalies, fetal anemia, fetal and placental growth,and cervical length [10–16]. Over the last decade, manyultrasound tools (middle cerebral artery [MCA] Dop-pler, uterine arteries [UtA] Doppler, umbilical artery [UA]Doppler, cerebroplacental ratio [CPR], ductus venosus[DV] Doppler, etc.) and markers (e.g., vascularization indi-ces) have been developed to detect growth restrictions andto predict short- and long-term complications relatedto FGR [17–20]. However, there is a clinical equipoiseregarding the use of third-trimester fetal ultrasound asa screening tool for FGR.Despite the potentially significant impact of the newultrasound technologies, the lack of consensus on theclinical value of these new tools and markers and when touse them in clinical practice has led to significant hetero-geneity in clinical guidelines regarding third-trimester ultra-sound recommendations [21–27]. Currently, the Canadian[21] and American [22] obstetrics guidelines recommendthe use of the third-trimester ultrasound to assess fetalgrowth only in women with risk factors of FGR. On theother hand, French obstetrics societies recommend a third-trimester ultrasound systematically to all women formonitoring fetal growth and as part of the preventionof fetal deaths [24–26]. The American [22] and European[23] guidelines state that screening for fetal growth abnor-malities using physical examination alone can identify onlyone third of FGR [27]. A recent meta-analysis showed thatan ultrasound estimation of birth weight is better thanmaternal or clinical (including abdominal palpation,fundal height, and Leopold maneuver) estimations [28].Many experts in the field support the need for thethird-trimester ultrasound to assess fetal and maternalwell-being [29]. A population-based study showed thatantenatally detected FGR was associated with a fivefoldlower risk of perinatal mortality than non-detection ofFGR [30]. Therefore, it is essential to determine theperformance of the third-trimester ultrasound toolsand markers and their optimal parameters in order tomaximize the benefits for the fetuses and the infants.Thus, this study aims to estimate the performance ofthird-trimester ultrasound markers in the screening forFGR in a low-risk or general population of pregnantwomen and to determine the parameters (e.g., timing,thresholds) optimizing the performance of third-trimesterultrasound markers.MethodsA systematic review will be conducted to synthesizeknowledge on the ability of third-trimester ultrasoundmarkers to identify fetuses at risk of low birth weight forgestational age. The guidelines of the Preferred ReportingItems for Systematic Review and Meta-Analysis Protocols(PRISMA-P) were followed to report the methodology(Additional file 1) [31]. The methodology was developedaccording to the recommendations of the CochraneCollaboration for diagnostic test accuracy meta-analyses[32]. The protocol of this systematic review is registeredin PROSPERO [CRD42018085564].Eligibility criteriaPopulationStudies of low-risk or general [unselected] population ofwomen with a singleton pregnancy will be eligible. Therewill be no exclusion based on maternal age. Studies ofmulti-fetal pregnancies, pregnancies complicated by fetalabnormalities, and studies restricted to specific high-riskpopulations will be excluded.Index testAll ultrasound markers (fetal biometrics, MCA Doppler,UtA Doppler, UA Doppler, CPR, DV Doppler, renalDoppler, amniotic fluid volume, placental thickness, etc.)measured at any time over the third trimester (28 weeks’gestation or more) will be eligible. Articles which donot report data on ultrasound markers separately willbe excluded (e.g., predictive model combining ultrasoundand serum biomarkers without information on ultrasoundmarkers only will be excluded).Reference testThe reference will be the diagnosis of SGA at birth,based on any criteria reported in a study.OutcomeThe outcome of interest is the discriminative performanceof third-trimester ultrasound markers in the screening forSGA. Articles which do not report any data on discrim-inative performance [such as a c-statistic, sensitivityGasse et al. Systematic Reviews           (2018) 7:219 Page 2 of 7and specificity, or true positive (TP), false positive (FP),true negative (TN), and false negative (FN)] will beexcluded.Study designPublished clinical trials and cohort studies (prospectiveand retrospective) which estimated the predictive per-formance of any third-trimester ultrasound markers willbe eligible. There will be no language or publication daterestriction. If data from the same sample have been reportedin different publications, only the report with the largeststudy group will be used in the quantitative analyses.Information sourcesMEDLINE (via PubMed), Embase, Cochrane Library,and Web of Science will be searched from their incep-tion until December 2018 for the identification ofeligible studies. Clinical registries (Health Canada’sTrial Registry,,,WHO International Clinical Trials Registry, Cochrane’sCENTRAL) and the grey literature (OpenGrey, TRIP andHealth Canada website) will be searched for potentiallyeligible reports. References of selected articles and previ-ous related review articles will also be screened to identifyadditional potentially eligible references. Co-authors whoare experts in the field will be consulted to review the listof included articles and identify any studies unretrieved byour search of the literature.Search strategiesOur search strategies are presented in Table 1 (MEDLINE),Table 2 (Embase), Table 3 (Cochrane Library), and Table 4(Web of Science). MESH, Emtrees, and free vocabulariesabout the concepts of “pregnant women,” “ultrasound,”“small for gestational age,” and “predictive value” wereused. Terms for specific ultrasound markers and “thirdtrimester” were not included in order to attain a highersensitivity. For instance, many authors may not haveindicated such information in the title or in the abstract orcould have used a different term (e.g., they could haveindicated the gestational age instead of using the “thirdtrimester” expression). All the authors revised and approvedthe search strategies. A filter will be used in Embase toreduce the number of duplicates between the Embase andMEDLINE databases ([embase]/lim NOT [medline]/lim).Selection processThe EndNote X8 software (Thomson Reuters® EndNoteX8 for Mac 1988–2017, version will be usedto manage all the references retrieved from the electronicTable 1 Search strategy for MEDLINE (PubMed)Step Concept Search strategy#1 Population = pregnant women “Pregnancy”[Mesh: NoExp] OR “Pregnancy Outcome”[Mesh: NoExp] OR“Pregnancy, High-Risk”[Mesh] OR “Pregnancy Trimesters”[Mesh] ORpregnant[TIAB] OR pregnanc*[TIAB] OR gestation*[TIAB] OR fetus[Mesh:NoExp] OR fetal[TIAB] OR foetal[TIAB] OR fetus[TIAB] OR foetus[TIAB]OR foetuses[TIAB] OR fetuses[TIAB]#2 Index test = ultrasound “Ultrasonography”[Mesh: NoExp] OR “Ultrasonography, Prenatal”[Mesh:NoExp] OR (“Ultrasonography, Doppler”[Mesh] Not “Echocardiography,Doppler”[Mesh]) OR ultrasonograph*[TIAB] OR ultrasound[TIAB] OR“ultra sound”[TIAB] OR sonograph*[TIAB] OR scan[TIAB] OR Doppler[TIAB]OR echograph*[TIAB]#3 Reference test = small for gestationalage measured by birth weight“Infant, low birth weight”[Mesh] OR “fetal weight”[Mesh] OR “Birthweight”[Mesh: NoExp] OR “Fetal growth retardation”[Mesh] OR “smallfor gestational age”[TIAB] OR “SGA”[TIAB] OR “birth weight”[TIAB] OR“birth-weight”[TIAB] OR “birthweight”[TIAB] OR “IUGR”[TIAB] OR“growth restriction”[TIAB] OR “growth retardation”[TIAB] OR “fetalweight”[TIAB] OR “foetal weight”[TIAB] OR “fetus weight”[TIAB] OR“foetus weight”[TIAB] OR “neonatal weight”[TIAB] OR “newbornweight”[TIAB] OR “infant weight”[TIAB] OR “fetal size”[TIAB] OR“foetal size”[TIAB] OR “fetus size”[TIAB] OR “neonatal size”[TIAB]OR “newborn size”[TIAB] OR “infant size”[TIAB] OR “fetal growth”[TIAB]OR “foetal growth”[TIAB] OR “fetus growth”[TIAB] OR “foetus growth”[TIAB]OR “neonatal growth”[TIAB] OR “newborn growth”[TIAB] OR “infant growth”[TIAB]#4 Outcome = predictive value “Sensitivity and Specificity”[MeSH] OR “Predictive Value of Tests”[MeSH] ORSensitivit*[TIAB] OR specificity[TIAB] OR “predictive value*”[TIAB] OR “predictivemodel*”[TIAB] OR “false-positive rate”[TIAB] OR “detection rate”[TIAB] OR“ROC curve”[TIAB] OR “receiver operating characteristic”[TIAB] OR “AUC”[TIAB] OR“area under the curve”[TIAB] OR “Prenatal Diagnosis”[Mesh: NoExp] OR “NeonatalScreening”[Mesh] OR “Diagnostic imaging”[Subheading] OR screening[TIAB]#5 Human filter Animals[MeSH] NOT Humans[MeSH]#6 Combination of concepts #1 AND #2 AND #3 AND #4 NOT #5Gasse et al. Systematic Reviews           (2018) 7:219 Page 3 of 7databases and to remove duplicates. The remaining refer-ences will be exported to Excel (Microsoft® Excel® for Mac2011, version 14.7.3) to conduct the selection process.Two independent reviewers (CG, KP) will screen the titlesand abstracts to assess the eligibility of studies, followedby a full-text evaluation of the remaining articles’ eligibility.If no consensus is reached between the two reviewersregarding the eligibility of a study, a third independentreviewer with expertise in perinatal epidemiology willbe consulted (EB).Table 2 Search strategy for EmbaseStep Concept Search strategy#1 Population = pregnant women “Pregnancy”/de OR pregnant:TI,AB,kw OR pregnanc*:TI,AB,kw OR gestation*:TI,AB,kwOR fetus/exp. OR fetal:TI,AB,kw OR foetal:TI,AB,kw OR fetus:TI,AB,kw OR foetus:TI,AB,kwOR foetuses:TI,AB,kw OR fetuses:TI,AB,kw#2 Index test = ultrasound “ultrasound”/exp. OR “echography”/de OR “fetus echography”/de OR (“Dopplerultrasonography”/exp. Not “Doppler echocardiography”/exp) ORultrasonograph*:TI,AB,kw OR ultrasound:TI,AB,kw OR “ultra sound”:TI,AB,kw ORscan:TI,AB,kw OR Doppler:TI,AB,kw OR sonograph*:TI,AB,kw OR echograph*:TI,AB,kw#3 Reference test = small for gestationalage measured by birth weight“Birth weight”/exp. OR “fetus weight”/exp. OR “intrauterine growth retardation”/de OR“small for date infant”/exp. OR “small for gestational age”:TI,AB,kw OR “small for ageinfant”:TI,AB,kw OR SGA:TI,AB,kw OR “birth weight”:TI,AB,kw OR birth-weight:TI,AB,kwOR birthweight:TI,AB,kw OR “growth restriction”:TI,AB,kw OR “growth retardation”:TI,AB,kwOR IUGR:TI,AB,kw OR ((fetal OR foetal OR fetus OR foetus OR newborn OR infantOR neonatal) NEAR/2 (weight OR size OR growth)):TI,AB,kw#4 Outcome = predictive value “Sensitivity and Specificity”/exp. OR “Predictive Value”/exp. OR Sensitivit*:TI,AB,kw ORspecificity:TI,AB,kw OR “predictive value*”:TI,AB,kw OR “predictive model*”:TI,AB,kw OR“false-positive rate”:TI,AB,kw OR “detection rate”:TI,AB,kw OR “ROC curve”:TI,AB,kw OR“receiver operating characteristic”:TI,AB,kw OR “AUC”:TI,AB,kw OR “area under thecurve”:TI,AB,kw OR “screening”/de OR “screening test”/exp. OR “Prenatal screening”/exp.OR “Newborn screening”/exp. OR screening:TI,AB,kw#5 Human filter “Animal”/exp. NOT “Human”/exp#6 Filter Embase only [embase]/lim NOT [medline]/lim#7 Combination of concepts #1 AND #2 AND #3 AND #4 AND #6 NOT #5Table 3 Search strategy for Cochrane LibraryStep Concept Search strategy#1 Population = pregnant women “Pregnancy”(MeSH unexploded) OR “Pregnancy Outcome”(MeSH unexploded) OR “Pregnancy,High-Risk”(Mesh) OR “Pregnancy Trimesters”(Mesh) or pregnanc*:ti,ab,kw or gestation*:ti,ab,kwor (MeSH descriptor fetus explode all trees) or fetal:ti,ab,kw or foetal:ti,ab,kw or fetus:ti,ab,kw orfoetus:ti,ab,kw or foetuses:ti,ab,kw or fetuses:ti,ab,kw#2 Index test = ultrasound “Ultrasonography”(MeSH unexploded) OR “Ultrasonography, Prenatal”(MeSH unexploded)OR(“Ultrasonography, Doppler”(MeSH) Not “Echocardiography, Doppler”(MeSH)) ORultrasonograph*:ti,ab,kw OR ultrasound:ti,ab,kw OR “ultra sound”: ti,ab,kw OR scan:ti,ab,kwOR Doppler:ti,ab,kw OR sonograph*:ti,ab,kw OR echograph*:ti,ab,kw#3 Reference test = small for gestationalage measured by birth weight“Infant, low birth weight”(MeSH) OR “fetal weight”(MeSH) OR “Birth weight”(MeSH unexploded)OR “Fetal growth retardation”(MeSH) OR “small for gestational age”:ti,ab,kw OR “small forage infant”:ti,ab,kw OR SGA:ti,ab,kw OR “birth weight”:ti,ab,kw OR birth-weight:ti,ab,kw ORbirthweight:ti,ab,kw OR “growth restriction”:ti,ab,kw OR “growth retardation”:ti,ab,kw ORIUGR:ti,ab,kw OR “fetal weight”:ti,ab,kw OR “foetal weight”:ti,ab,kw OR “fetus weight”:ti,ab,kwOR “foetus weight”:ti,ab,kw OR “neonatal weight”:ti,ab,kw OR “newborn weight”:ti,ab,kw OR“infant weight”:ti,ab,kw OR “fetal size”:ti,ab,kw OR “foetal size”:ti,ab,kw OR “fetus size”:ti,ab,kwOR “neonatal size”:ti,ab,kw OR “newborn size”:ti,ab,kw OR “infant size”:ti,ab,kw OR “fetalgrowth”:ti,ab,kw OR “foetal growth”:ti,ab,kw OR “fetus growth”:ti,ab,kw OR “foetusgrowth”:ti,ab,kw OR “neonatal growth”:ti,ab,kw OR “newborn growth”:ti,ab,kw OR “infantgrowth”:ti,ab,kw#4 Outcome = predictive value “Sensitivity and Specificity”(MeSH) OR “Predictive Value of Tests”(MeSH) OR Sensitivit*:ti,ab,kwOR specificity:ti,ab,kw OR “predictive value*”:ti,ab,kw OR “predictive model*”:ti,ab,kw OR“false-positive rate”:ti,ab,kw OR “detection rate”:ti,ab,kw OR “ROC curve”:ti,ab,kw OR “receiveroperating characteristic”:ti,ab,kw OR “AUC”:ti,ab,kw OR “area under the curve”:ti,ab,kw OR“screening”(MeSH unexploded) OR “screening test”(MeSH) OR “Prenatal screening”(MeSH) OR“Newborn screening”(MeSH) OR screening:ti,ab,kw#5 Human filter “Animal”(MeSH) NOT “Human”(MeSH)#6 Combination of concepts #1 AND #2 AND #3 AND #4 NOT #5Gasse et al. Systematic Reviews           (2018) 7:219 Page 4 of 7Data extractionTwo reviewers (CG, KP) will independently extract datafrom the selected articles using a standardized data collec-tion form and an Excel sheet. The data collection formwill be piloted using three randomly selected articles andwill be corrected to improve completeness, clarity, andusability, as needed. Any discordance between the twodata collections will be resolved by consensus. A thirdindependent reviewer (EB) will be consulted in case ofpersistent disagreement. Authors will be contacted if somedata are missing and needed to conduct the analyses.Extracted data will include (1) study characteristics(authors, study design, year of conduction and publication,country, clinical setting, sample size, participation rate,lost to follow-up rate, number of exclusion), (2) character-istics of participants (maternal age, parity, ethnicity, fetalsex), (3) characteristics of the screening tools (ultrasoundmarkers used, threshold for each ultrasound markers,gestational age at ultrasound exam, type of the deviceused, time between ultrasound exam and delivery, personnelconducting the exam), (4) characteristics of the reference(definition of SGA, number of SGA, reference curve usedfor the classification of SGA), (5) performance data ([TP, FP,TN, and FN; sensitivity, specificity, area under the curve(AUC)]), and (6) other variables (birth weight, gestationalage at birth).Risk of bias in individual studiesUsing the Quality Assessment of Diagnostic AccuracyStudy 2 (QUADAS-2) tool [33], the risk of bias and con-cerns about applicability will be assessed for each includedstudy by two reviews independently. The QUADAS-2assesses four different components of bias, which arerelated to the patient selection, the index test, the referencetest, and the flow and timing. The presence of one domainat high risk of bias will translate in an overall high riskof bias.Statistical analysis and data synthesisThe TP, FP, TN, and FN will be used to compute thesensitivity and specificity of each marker in all studies.The corresponding sensitivity and specificity will be pre-sented in a coupled forest plot.As recommended by the Cochrane Collaboration [32],hierarchal summary receiver operating characteristic(HSROC) [34, 35] and random effects hierarchal bivariatemodels (Bivariate) [36] will be used to pool the results. Asvariation in thresholds and accuracy of the markers acrossstudies are expected, for each SGA definition where therewill be at least three studies with the same definition,HSROC model will be performed to obtain summaryROC curves for each marker. If a study presents morethan one threshold, the most commonly used one amongthe studies included in our meta-analyses will be selected.For each marker with at least three studies with thesame threshold, the Bivariate model will estimate themean sensitivity and specificity for the specific thresholdswith their 95% confidence region and 95% predictionregion.Indirect comparison of each marker will be done usinga HSROC meta-regression model including the differentmarkers as a covariate to compare their screening testaccuracy for SGA.Cochrane Review Manager (version 5.1, The CochraneCollaboration, 2011) and the statistical software packagesSAS (Version 9.3, SAS Institute Inc., Cary, NC, USA) willbe used to complete the analyses.Table 4 Search strategy for Web of ScienceStep Concept Search strategy#1 Population = pregnant women TS=(pregnant OR pregnanc* OR gestation* OR fetal OR foetal OR fetus OR foetusOR foetuses OR fetuses) OR TI=(pregnant OR pregnanc* OR gestation* OR fetalOR foetal OR fetus OR foetus OR foetuses OR fetuses)#2 Index test = ultrasound TS=(ultrasonograph* OR ultrasound OR “ultra sound” OR scan OR DopplerOR sonograph* OR echograph*) OR TI=(ultrasonograph* OR ultrasoundOR “ultra sound” OR scan OR Doppler OR sonograph* OR echograph*)#3 Reference test = small for gestationalage measured by birth weightTS=(“small for gestational age” OR “small for age infant” OR SGA OR “birth weight”OR birth-weight OR birthweight OR “growth restriction” OR “growth retardation”OR IUGR OR ((fetal OR foetal OR fetus OR foetus OR newborn OR infant OR neonatal)NEAR/2 (weight OR size OR growth))) OR TI=(“small for gestational age” OR “small forage infant” OR SGA OR “birth weight” OR birth-weight OR birthweight OR “growthrestriction” OR “growth retardation” OR IUGR OR ((fetal OR foetal OR fetus OR foetusOR newborn OR infant OR neonatal) NEAR/2 (weight OR size OR growth)))#4 Outcome = predictive value TS=(Sensitivit* OR specificity OR “predictive value*” OR “predictive model*”OR “false-positive rate” OR “detection rate” OR “ROC curve” OR “receiver operatingcharacteristic” OR “AUC” OR “area under the curve” OR screening)#5 Human filter TS=(Microorganisms OR Plants OR Invertebrates OR Protochordates OR “NonhumanVertebrates”)#6 Combination of concepts #1 AND #2 AND #3 AND #4 NOT #5Gasse et al. Systematic Reviews           (2018) 7:219 Page 5 of 7Additional analysisSubgroup and sensitivity analyses will be conducted toexplore the possible heterogeneity between studies.Subgroup analyses will be performed to observe theeffect of the screening test characteristics (gestationalage at screening, timing of screening before delivery,type of device used [2D vs 3D ultrasound], study date,ethnicity,) on the discriminative ability of third-trimesterultrasound markers. Also, sensitivity analyses by studydesign and restricted to studies at low risk of bias will bedone.Strength of evidenceThe quality and evidence of this review will be assessedusing the Grading of Recommendations, Assessment,Development and Evaluation (GRADE) domains (studylimitations, consistency of effect, imprecision, indirectness,publication bias, large magnitude of effect, dose-responsegradient, residual confounding effect).DiscussionThere is no consensus on the recommendation of a third-trimester ultrasound for the assessment of fetal growthin a general population. This systematic review willsynthesize the published evidence on the performanceof third-trimester ultrasound markers in the screeningfor FGR in low-risk or general populations. The gatheredknowledge will participate in the evaluation of the useful-ness of a routine third-trimester ultrasound examinationas part of standard antenatal visits schedule, and if anymarker is deemed useful, the review will allow for theoptimization of the third-trimester ultrasound screeningprocess. Thus, this study will help to determine the toolsallowing for the identification of pregnancies at higher riskof SGA which could benefit from closer monitoring andtargeted interventions. Considering the frequency andpotentially serious complications of FGR, this knowledgesynthesis can significantly contribute to the improvementof the health of fetuses and infants.Additional fileAdditional file 1: PRISMA-P. (PDF 100 kb)AbbreviationAUC: Area under the curve; CPR: Cerebroplacental ratio; DV: Ductus venosus;FGR: Fetal growth restriction; FN: False negative; FP: False positive;HSROC: Hierarchal summary receiver operating characteristic; MCA: Middlecerebral artery; QUADAS-2: Quality Assessment of Diagnostic Accuracy Study2; SGA: Small for gestational age; TN: True negative; TP: True positive;UA: Umbilical artery; UtA: Uterine arteriesAcknowledgementsNot applicableFundingDr. Cédric Gasse holds a Doctoral Research Award from the Canadian Institutes ofHealth Research (CIHR). Dr. Amelie Boutin is supported by a Killam PostdoctoralResearch Fellowship and a Fellowship Award from the CIHR. Dr. EmmanuelBujold holds a Clinician Scientist Award from the Fonds de recherche duQuébec – Santé (FRQ-S) and the Jeanne-and-Jean-Louis-Levesque perinatalresearch Chair at Université Laval. The research team is financially supported bythe Jean-Louis-Lévesque Foundation, Montreal, QC, Canada.Availability of data and materialsNot applicableAuthors’ contributionsAB is the guarantor. CG conceived and coordinated this project. CG, EB, andAB contributed to the conception and design of the study. CG developedthe search strategies with the contribution of AB. CG drafted the first versionof the manuscript. All authors participated in the critical review of themanuscript and approved the final version.Ethics approval and consent to participateConsidering data from published studies will be collected and synthesized,this systematic review is exempt from ethics approval.Consent for publicationNot applicableCompeting interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Reproduction, Mother and Child Health Unit, CHU de Québec - UniversitéLaval Research Center, Universite Laval, 2705, boul. Laurier, Quebec, QC G1V4G2, Canada. 2Department of Social and Preventive Medicine, Faculty ofMedicine, Universite Laval, 1050, avenue de la Medecine, Quebec, QC G1V0A6, Canada. 3Department of Gynecology, Obstetrics and Reproduction,Faculty of Medicine, Universite Laval, 1050, avenue de la Médecine, Quebec,QC G1V 0A6, Canada. 4Harris Birthright Research Centre of Fetal Medicine,Fetal Medicine Research Institute, King’s College Hospital, London, UK.5Department of Obstetrics and Gynaecology, Faculty of Medicine, Universityof British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.Received: 19 May 2018 Accepted: 15 November 2018References1. Nardozza LM, Caetano AC, Zamarian AC, Mazzola JB, Silva CP, Marcal VM, etal. Fetal growth restriction: current knowledge. Arch Gynecol Obstet. 2017;295:1061–77.2. American College of Obstetricians and Gynecologists. Practice bulletin no.134: fetal growth restriction. Obstet Gynecol. 2013;121:1122–33.3. 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