title: Lessons learnt from enrolment and follow up of pregnant women and their infants in clinical trials in South Africa, a low-middle income country.
abstract: BACKGROUND
  Infectious causes are a significant contributor to morbidity and mortality in neonates and young infants. Immunization of pregnant women to protect the mother and/or her infant is gaining momentum due to the benefits of this strategy demonstrated in numerous implemented strategies (Maternal and Neonatal Tetanus Elimination Initiative) and clinical trials. Reluctance by regulators, participants and healthcare providers to include pregnant women in clinical trials is considerable, but reducing. Infectious disease burden, and therefore need for interventions to reduce morbidity and mortality in mothers and infants, is highest in low-middle income countries (LMIC), however, reliable background data on adverse pregnancy outcomes and lack of experience in clinical trials and community opinions on immunization during pregnancy are not well documented.
  
  
  METHODS
  We used our experiences in conducting two clinical studies in pregnant women in South Africa to illustrate the challenges experienced and lessons learnt which may benefit others working in the maternal immunization field.
  
  
  RESULTS
  Accurate gestational age assessment, which is essential for clinical trials, is challenging in LMIC due to limited access to early ultrasound examinations, and unreliable assessment by history (last menstrual period date) and physical examination (symphyseal-fundal height). Concomitant administration of recommended vaccines has previously been avoided in clinical trials; however, this limitation could impact the potentially beneficial interventions that participants can access during antenatal care. Women in LMIC have a higher burden of concomitant illnesses (e.g. HIV infection, malaria and anaemia) and adverse pregnancy outcomes (e.g. stillbirth) than pregnant women in higher income countries. Availability of local data is essential for safety monitoring committees to identify vaccine-related adverse event triggers.
  
  
  CONCLUSIONS
  Immunization of pregnant women to reduce disease burden in them and their infants is promising, and women in high-risk settings should be included in trials (Clinical trial registry number: 'Study A': NCT01193920, 'Study B': NCT01888471).
authors.affiliation: Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Johannesburg, South Africa; Department of Science and Technology National Research Foundation, Vaccine Preventable Diseases, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Electronic address: cutlandc@rmpru.co.za.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Cutland
authors.affiliation: GlaxoSmithKline plc, London, United Kingdom.
authors.forename: Marianne
authors.initials: M
authors.lastname: Cunnington
authors.affiliation: GlaxoSmithKline LLC, USA.
authors.forename: Morounfolu
authors.initials: M
authors.lastname: Olugbosi
authors.affiliation: Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Johannesburg, South Africa; Department of Science and Technology National Research Foundation, Vaccine Preventable Diseases, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Johannesburg, South Africa; Department of Science and Technology National Research Foundation, Vaccine Preventable Diseases, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hugo
authors.affiliation: Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Johannesburg, South Africa; Department of Science and Technology National Research Foundation, Vaccine Preventable Diseases, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Karishma
authors.initials: K
authors.lastname: Maharaj
authors.affiliation: GlaxoSmithKline LLC, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Slobod
authors.affiliation: Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Johannesburg, South Africa; Department of Science and Technology National Research Foundation, Vaccine Preventable Diseases, South Africa; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; National Institute for Communicable Diseases, Sandringham, South Africa.
authors.forename: Shabir A
authors.initials: SA
authors.lastname: Madhi
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D055815:Young Adult; D002986:Clinical Trials as Topic; D003906:Developing Countries; D018562:Disease Transmission, Infectious / Q000517:prevention & control; D011251:Pregnancy Complications, Infectious / Q000517:prevention & control; D013019:South Africa; D014612:Vaccines / Q000008:administration & dosage / Q000276:immunology; D064887:Observational Studies as Topic; D016032:Randomized Controlled Trials as Topic
chemical_list: D014612:Vaccines
keywords: GBS: Group B Streptococcus; HIV: human immunodeficiency virus; Immunization in pregnant women; LMIC: low middle income countries; Neonatal morbidity and mortality