title: Identifying late-onset fetal growth restriction by measuring circulating placental RNA in the maternal blood at 28 weeks' gestation.
abstract: BACKGROUND
  Late-onset fetal growth restriction (FGR) is often undetected prior to birth, which puts the fetus at increased risk of adverse perinatal outcomes including stillbirth.
  
  
  OBJECTIVE
  Measuring RNA circulating in the maternal blood may provide a noninvasive insight into placental function. We examined whether measuring RNA in the maternal blood at 26-30 weeks' gestation can identify pregnancies at risk of late-onset FGR. We focused on RNA highly expressed in placenta, which we termed "placental-specific genes."
  
  
  METHODS
  This was a case-control study nested within a prospective cohort of 600 women recruited at 26-30 weeks' gestation. The circulating placental transcriptome in maternal blood was compared between women with late-onset FGR (<5th centile at >36+6 weeks) and gestation-matched well-grown controls (20-95th centile) using microarray (n = 12). TaqMan low-density arrays, reverse transcription-polymerase chain reaction (PCR), and digital PCR were used to validate the microarray findings (FGR n = 40, controls n = 80).
  
  
  RESULTS
  Forty women developed late-onset FGR (birthweight 2574 ± 338 g, 2nd centile) and were matched to 80 well-grown controls (birthweight 3415 ± 339 g, 53rd centile, P < .05). Operative delivery and neonatal admission were higher in the FGR cohort (45% vs 23%, P < .05). Messenger RNA coding 137 placental-specific genes was detected in the maternal blood and 37 were differentially expressed in late-onset FGR. Seven were significantly dysregulated with PCR validation (P < .05). Activating transcription factor-3 messenger RNA transcripts were the most promising single biomarker at 26-30 weeks: they were increased in fetuses destined to be born FGR at term (2.1-fold vs well grown at term, P < .001) and correlated with the severity of FGR. Combining biomarkers improved prediction of severe late-onset FGR (area under the curve, 0.88; 95% CI 0.80-0.97). A multimarker gene expression score had a sensitivity of 79%, a specificity of 88%, and a positive likelihood ratio of 6.2 for subsequent delivery of a baby <3rd centile at term.
  
  
  CONCLUSIONS
  A unique placental transcriptome is detectable in maternal blood at 26-30 weeks' gestation in pregnancies destined to develop late-onset FGR. Circulating placental RNA may therefore be a promising noninvasive test to identify pregnancies at risk of developing FGR at term.
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynecology, University of Melbourne, Mercy Hospital for Women, Melbourne, Australia. Electronic address: clarew@unimelb.edu.au.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Whitehead
authors.affiliation: Department of Obstetrics and Gynecology, University of Melbourne, Royal Women's Hospital, Parkville, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: McNamara
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynecology, University of Melbourne, Mercy Hospital for Women, Melbourne, Australia.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Walker
authors.affiliation: Hudson Institute of Medical Research, Monash Health, Clayton, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Alexiadis
authors.affiliation: Hudson Institute of Medical Research, Monash Health, Clayton, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Fuller
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynecology, University of Melbourne, Mercy Hospital for Women, Melbourne, Australia.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Vickers
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynecology, University of Melbourne, Mercy Hospital for Women, Melbourne, Australia.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Hannan
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynecology, University of Melbourne, Mercy Hospital for Women, Melbourne, Australia.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Hastie
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynecology, University of Melbourne, Mercy Hospital for Women, Melbourne, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Tuohey
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynecology, University of Melbourne, Mercy Hospital for Women, Melbourne, Australia.
authors.forename: Tu'uhevaha J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
authors.affiliation: Translational Obstetrics Group, Department of Obstetrics and Gynecology, University of Melbourne, Mercy Hospital for Women, Melbourne, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
mesh_terms: D051700:Activating Transcription Factor 3 / Q000097:blood / Q000235:genetics; D053607:Adrenomedullin / Q000097:blood / Q000235:genetics; D000328:Adult; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002585:Cesarean Section / Q000706:statistics & numerical data; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000097:blood / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000097:blood* / Q000175:diagnosis*; D015686:Gene Products, env / Q000097:blood / Q000235:genetics; D005865:Gestational Age; D006760:Hospitalization; D006801:Humans; D007231:Infant, Newborn; D059648:Kisspeptins / Q000097:blood / Q000235:genetics; D046228:Microarray Analysis; D015287:Neurokinin B / Q000097:blood / Q000235:genetics; D021041:Placental Circulation; D016133:Polymerase Chain Reaction; D011247:Pregnancy / Q000097:blood; D011257:Pregnancy Proteins / Q000097:blood / Q000235:genetics; D011266:Pregnancy-Associated Plasma Protein-A / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000097:blood*
chemical_list: D051700:Activating Transcription Factor 3; D015415:Biomarkers; D004268:DNA-Binding Proteins; D015686:Gene Products, env; C106628:KISS1 protein, human; D059648:Kisspeptins; C104382:PLAG1 protein, human; D011257:Pregnancy Proteins; D012333:RNA, Messenger; C000601382:TAC3 protein, human; C405335:syncytin; D053607:Adrenomedullin; D015287:Neurokinin B; C430889:PAPPA2 protein, human; D011266:Pregnancy-Associated Plasma Protein-A
keywords: activating transcription factor-3; circulating RNA; fetal growth restriction