title: Sulphadoxine-pyrimethamine plus azithromycin for the prevention of low birthweight in Papua New Guinea: a randomised controlled trial.
abstract: BACKGROUND
  Intermittent preventive treatment in pregnancy has not been evaluated outside of Africa. Low birthweight (LBW, <2,500 g) is common in Papua New Guinea (PNG) and contributing factors include malaria and reproductive tract infections.
  
  
  METHODS
  From November 2009 to February 2013, we conducted a parallel group, randomised controlled trial in pregnant women (≤ 26 gestational weeks) in PNG. Sulphadoxine-pyrimethamine (1,500/75 mg) plus azithromycin (1 g twice daily for 2 days) (SPAZ) monthly from second trimester (intervention) was compared against sulphadoxine-pyrimethamine and chloroquine (450 to 600 mg, daily for three days) (SPCQ) given once, followed by SPCQ placebo (control). Women were assigned to treatment (1:1) using a randomisation sequence with block sizes of 32. Participants were blinded to assignments. The primary outcome was LBW. Analysis was by intention-to-treat.
  
  
  RESULTS
  Of 2,793 women randomised, 2,021 (72.4%) were included in the primary outcome analysis (SPCQ: 1,008; SPAZ: 1,013). The prevalence of LBW was 15.1% (305/2,021). SPAZ reduced LBW (risk ratio [RR]: 0.74, 95% CI: 0.60-0.91, P = 0.005; absolute risk reduction (ARR): 4.5%, 95% CI: 1.4-7.6; number needed to treat: 22), and preterm delivery (0.62, 95% CI: 0.43-0.89, P = 0.010), and increased mean birthweight (41.9 g, 95% CI: 0.2-83.6, P = 0.049). SPAZ reduced maternal parasitaemia (RR: 0.57, 95% CI: 0.35-0.95, P = 0.029) and active placental malaria (0.68, 95% CI: 0.47-0.98, P = 0.037), and reduced carriage of gonorrhoea (0.66, 95% CI: 0.44-0.99, P = 0.041) at second visit. There were no treatment-related serious adverse events (SAEs), and the number of SAEs (intervention 13.1% [181/1,378], control 12.7% [174/1,374], P = 0.712) and AEs (intervention 10.5% [144/1,378], control 10.8% [149/1,374], P = 0.737) was similar. A major limitation of the study was the high loss to follow-up for birthweight.
  
  
  CONCLUSIONS
  SPAZ was efficacious and safe in reducing LBW, possibly acting through multiple mechanisms including the effect on malaria and on sexually transmitted infections. The efficacy of SPAZ in the presence of resistant parasites and the contribution of AZ to bacterial antibiotic resistance require further study. The ability of SPAZ to improve pregnancy outcomes warrants further evaluation.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01136850 (06 April 2010).
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Post Office Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia. hwunger@doctors.org.uk.|Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. hwunger@doctors.org.uk.
authors.forename: Holger W
authors.initials: HW
authors.lastname: Unger
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. marai.kaius@gmail.com.
authors.forename: Maria
authors.initials: M
authors.lastname: Ome-Kaius
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. wangnapi.regina@yahoo.com.
authors.forename: Regina A
authors.initials: RA
authors.lastname: Wangnapi
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Post Office Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia. alex.umbers@gmail.com.|Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. alex.umbers@gmail.com.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Umbers
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Post Office Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia. shanieh@unimelb.edu.au.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hanieh
authors.affiliation: Walter and Eliza Hall Institute (WEHI), Parkville, Victoria, 3052, Australia. liwaisuen@wehi.edu.au.
authors.forename: Connie S N Li Wai
authors.initials: CS
authors.lastname: Suen
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. robinson@wehi.edu.au.|Walter and Eliza Hall Institute (WEHI), Parkville, Victoria, 3052, Australia. robinson@wehi.edu.au.
authors.forename: Leanne J
authors.initials: LJ
authors.lastname: Robinson
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. arosanas@itg.be.|Institute of Tropical Medicine, Nationalestraat 155, 2000, Antwerpen, Belgium. arosanas@itg.be.
authors.forename: Anna
authors.initials: A
authors.lastname: Rosanas-Urgell
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. jo.wapling@gmail.com.
authors.forename: Johanna
authors.initials: J
authors.lastname: Wapling
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. elvinlufele@gmail.com.
authors.forename: Elvin
authors.initials: E
authors.lastname: Lufele
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. charliekongs@gmail.com.
authors.forename: Charles
authors.initials: C
authors.lastname: Kongs
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. samol.jppaula@gmail.com.
authors.forename: Paula
authors.initials: P
authors.lastname: Samol
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. sui.desmond0@gmail.com.
authors.forename: Desmond
authors.initials: D
authors.lastname: Sui
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. marai.kaius@gmail.com.
authors.forename: Dupain
authors.initials: D
authors.lastname: Singirok
authors.affiliation: Barcelona Centre for International Health Research (CRESIB), Hospital Clínic-Universitat de Barcelona, Rossello, 132, 7th floor, 08036, Barcelona, Spain. abardaji@clinic.ub.es.
authors.forename: Azucena
authors.initials: A
authors.lastname: Bardaji
authors.affiliation: Walter and Eliza Hall Institute (WEHI), Parkville, Victoria, 3052, Australia. schofield@wehi.edu.au.|Australian Institute of Tropical Health and Medicine, Faculty of Medicine, Health, and Molecular Sciences, James Cook University, Townsville, Queensland, 4811, Australia. schofield@wehi.edu.au.
authors.forename: Louis
authors.initials: L
authors.lastname: Schofield
authors.affiliation: Barcelona Centre for International Health Research (CRESIB), Hospital Clínic-Universitat de Barcelona, Rossello, 132, 7th floor, 08036, Barcelona, Spain. menendez@clinic.ub.es.
authors.forename: Clara
authors.initials: C
authors.lastname: Menendez
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. ibetuela@gmail.com.
authors.forename: Inoni
authors.initials: I
authors.lastname: Betuela
authors.affiliation: Papua New Guinea Institute of Medical Research, PO Box 60, Goroka, Eastern Highlands Province, 441, Papua New Guinea. pmaxsiba@gmail.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Siba
authors.affiliation: Walter and Eliza Hall Institute (WEHI), Parkville, Victoria, 3052, Australia. mueller@wehi.edu.au.|Barcelona Centre for International Health Research (CRESIB), Hospital Clínic-Universitat de Barcelona, Rossello, 132, 7th floor, 08036, Barcelona, Spain. mueller@wehi.edu.au.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, 3010, Australia. mueller@wehi.edu.au.
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Post Office Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia. sroger@unimelb.edu.au.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Rogerson
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage*; D017963:Azithromycin / Q000008:administration & dosage*; D002738:Chloroquine / Q000008:administration & dosage; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D008288:Malaria / Q000150:complications / Q000517:prevention & control*; D010219:Papua New Guinea; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000517:prevention & control*; D011739:Pyrimethamine / Q000008:administration & dosage*; D016037:Single-Blind Method; D013413:Sulfadoxine / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D017963:Azithromycin; D013413:Sulfadoxine; D002738:Chloroquine; D011739:Pyrimethamine