title: Effects of Plasmodium falciparum infection on umbilical artery resistance and intrafetal blood flow distribution: a Doppler ultrasound study from Papua New Guinea.
abstract: Doppler velocimetry studies of umbilical artery (UA) and middle cerebral artery (MCA) flow help to determine the presence and severity of fetal growth restriction. Increased UA resistance and reduced MCA pulsatility may indicate increased placental resistance and intrafetal blood flow redistribution. Malaria causes low birth weight and fetal growth restriction, but few studies have assessed its effects on uteroplacental and fetoplacental blood flow.
  
  
  
  Colour-pulsed Doppler ultrasound was used to assess UA and MCA flow in 396 Papua New Guinean singleton fetuses. Abnormal flow was defined as an UA resistance index above the 90th centile, and/or a MCA pulsatility index and cerebroplacental ratio (ratio of MCA and UA pulsatility index) below the 10th centile of population-specific models fitted to the data. Associations between malaria (peripheral infection prior to and at ultrasound examination, and any gestational infection, i.e., 'exposure') and abnormal flow, and between abnormal flow and birth outcomes, were estimated.
  
  
  
  Of 78 malaria infection episodes detected before or at the ultrasound visit, 62 (79.5%) were Plasmodium falciparum (34 sub-microscopic infections), and 16 were Plasmodium vivax. Plasmodium falciparum infection before or at Doppler measurement was associated with increased UA resistance (adjusted odds ratio (aOR) 2.3 95% CI 1.0-5.2, P = 0.047). When assessed by 'exposure', P. falciparum infection was significantly associated with increased UA resistance (all infections: 2.4, 1.1-4.9, P = 0.024; sub-microscopic infections 2.6, 1.0-6.6, P = 0.051) and a reduced MCA pulsatility index (all infections: 2.6, 1.2-5.3, P = 0.012; sub-microscopic infections: 2.8, 1.1-7.5, P = 0.035). Sub-microscopic P. falciparum infections were additionally associated with a reduced cerebroplacental ratio (3.64, 1.22-10.88, P = 0.021). There were too few P. vivax infections to draw robust conclusions. An increased UA resistance index was associated with histological evidence of placental malaria (5.1, 2.3-10.9, P < 0.001; sensitivity 0.26, specificity 0.93). A low cerebroplacental Doppler ratio was associated with concurrently measuring small-for-gestational-age, and with low birth weight.
  
  
  
  Both microscopic and sub-microscopic P. falciparum infections impair fetoplacental and intrafetal flow, at least temporarily. Increased UA resistance has high specificity but low sensitivity for the detection of placental infection. These findings suggest that interventions to protect the fetus should clear and prevent both microscopic and sub-microscopic malarial infections. Trial Registration ClinicalTrials.gov NCT01136850. Registered 06 April 2010.
authors.affiliation: Papua New Guinea Institute of Medical Research (PNG IMR), Madang, Papua New Guinea.
authors.forename: Maria
authors.initials: M
authors.lastname: Ome-Kaius
authors.affiliation: Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research (WEHI), 1G Royal Parade, Parkville, 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Stephan
authors.initials: S
authors.lastname: Karl
authors.affiliation: Papua New Guinea Institute of Medical Research (PNG IMR), Madang, Papua New Guinea.
authors.forename: Regina Alice
authors.initials: RA
authors.lastname: Wangnapi
authors.affiliation: Department of Obstetrics and Gynaecology, Modilon General Hospital, Madang, Papua New Guinea.
authors.forename: John Walpe
authors.initials: JW
authors.lastname: Bolnga
authors.affiliation: Department of Obstetrics and Gynaecology, University of Papua New Guinea, Port Moresby, Papua New Guinea.
authors.forename: Glen
authors.initials: G
authors.lastname: Mola
authors.affiliation: Department of Radiology, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Walker
authors.affiliation: Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research (WEHI), 1G Royal Parade, Parkville, 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.|Institut Pasteur, 28 Rue de Dr. Roux, 75015, Paris, France.
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.affiliation: Department of Obstetrics and Gynaecology, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, UK.|Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Post Office Royal Melbourne Hospital, Parkville, VIC, 3050, Australia.
authors.forename: Holger Werner
authors.initials: HW
authors.lastname: Unger
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Post Office Royal Melbourne Hospital, Parkville, VIC, 3050, Australia. sroger@unimelb.edu.au.
authors.forename: Stephen John
authors.initials: SJ
authors.lastname: Rogerson
mesh_terms: D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D005317:Fetal Growth Retardation / Q000175:diagnosis* / Q000469:parasitology; D005333:Fetus / Q000503:physiopathology; D006801:Humans; D016778:Malaria, Falciparum / Q000503:physiopathology*; D008875:Middle Aged; D020768:Middle Cerebral Artery / Q000503:physiopathology*; D010219:Papua New Guinea; D010963:Plasmodium falciparum / Q000502:physiology*; D018608:Ultrasonography, Doppler; D016216:Ultrasonography, Prenatal; D014469:Umbilical Arteries / Q000503:physiopathology*; D055815:Young Adult
keywords: Cerebroplacental ratio; Doppler; Fetal growth; Middle cerebral artery pulsatility; Sub-microscopic; Umbilical artery resistance