• Cumulative incidence of skin and soft tissue infection, and other infections by 12 months of age in infants [ Time Frame: Birth to 12 Months ]
  To compare intervention and placebo groups with regard to the cumulative incidence of infant infection (meningitis, sepsis, pneumonia, SSTI, fever, diarrhoea, urinary tract infection) up to 12 months of age;
• Cumulative incidence of maternal infection by 6 weeks and 12 months post-delivery [ Time Frame: Delivery to 12 months ]
  To compare intervention and placebo groups with regard to the cumulative incidence of maternal infection (mastitis, sepsis, post-operative wound infections, SSTI, fever, meningitis, pneumonia, abdominal or pelvic abscess, endometritis, urinary tract infection, pyelonephritis) by six weeks post-delivery, and similarly up to 12 months post-delivery
• Cumulative incidence of antibiotic usage by 12 months in infants [ Time Frame: Birth to 12 months ]
  To compare intervention and placebo groups with regard to the cumulative incidence of the number of courses of antibiotics prescribed to the infant up to 12 months of age;
• Cumulative incidence of maternal antibiotic usage by 12 months post-delivery [ Time Frame: Delivery to 12 months ]
  To compare intervention and placebo groups with regard to the cumulative incidence of the number of courses of antibiotics prescribed to the mother up to 12 months post-delivery
• Number of infant participants with adverse events as assessed by adapted version of CTCAE v5.0 and DAID v2.1 [ Time Frame: Birth to 12 months ]
  To compare the number of adverse events including solicited non serious adverse events and all serious adverse events as per study specific definitions throughout the duration of the study.
• Number of maternal participants with adverse events as assessed by adapted version of CTCAE v5.0 and DAID v2.1 [ Time Frame: Delivery to 12 months ]
  To compare the number of adverse events including solicited non serious adverse events and all serious adverse events as per study specific definitions throughout the duration of the study.
• Number of infant and maternal participants with Staphylococcus aureus and/or Group A streptococcus as assessed by real-time quantitative PCR (qPCR) from impetigo swabs [ Time Frame: Delivery/birth to 12 months ]
  The proportion of participants that have Staphylococcus aureus and/or Group A streptoccoccus detected by qPCR from impetigo swabs at key time points throughout the duration of the study, between the two groups
• Number of infant and maternal participants with Staphylococcus aureus and/or Group A streptococcus with azithromycin nonsusceptibility cultured from impetigo swabs. [ Time Frame: Delivery/birth to 12 months ]
  The proportion of participants that have Staphylococcus aureus and/or Group A streptococcus that is non susceptible to azithromycin cultured from impetigo swabs at key time points throughout the duration of the study, between the two groups
• Swab study outcome - Prevalence of bacterial carriage as assessed by real-time quantitative PCR (qPCR) [ Time Frame: Delivery/birth to 12 months ]
  Bacterial carriage, the proportion of participants that have at least one of the following bacterial species including GBS, SA, SPN, GAS or E. coli, assessed by qPCR at key time points throughout the duration of the study, between the two groups
• Swab study outcome - Density of bacterial carriage as assessed by real-time quantitative PCR (qPCR) [ Time Frame: Delivery/birth to 12 months ]
  Density of bacterial carriage, reported as log 10 genome equivalents/ml, of the participants that have at least one of the following bacterial species including GBS, SA, SPN, GAS or E. coli, assessed by qPCR at key time points throughout the duration of the study, between the two groups
• Swab study outcome - Risk of maternal carriage identified through qPCR of common organisms relevant to Sexually Transmitted Infections (STI) [ Time Frame: Delivery/birth to 12 months ]
  Maternal carriage of common organisms relevant to Sexually Transmitted Infections (STI) (including Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma genitalium, HSV-1 and HSV-2) as detected by qPCR at key time points throughout the duration of the study, between the two groups.
• Swab study outcome - Risk of antibiotic nonsusceptibility in culture isolates [ Time Frame: Delivery/birth to 12 months ]
  Antibiotic non susceptibility, based on the proportion of samples from mothers and infants that are non susceptible to antibiotics cultured in the two arms, at key time points throughout the duration of the study
• Swab study outcome - Effects of the intervention on the infant and maternal microbiome of specified body sites [ Time Frame: Delivery/birth to 12 months ]
  To compare the infant and maternal microbiome of specified body sites at key time points in the intervention and placebo groups

• Cumulative incidence of skin and soft tissue infection, and other infections by 12 months of age in infants [ Time Frame: Birth to 12 Months ]
  To compare intervention and placebo groups with regard to the cumulative incidence of infant infection (meningitis, sepsis, pneumonia, SSTI, fever, diarrhoea, urinary tract infection) up to 12 months of age;
• Cumulative incidence of maternal infection by 6 weeks and 12 months post-delivery [ Time Frame: Delivery to 12 months ]
  To compare intervention and placebo groups with regard to the cumulative incidence of maternal infection (mastitis, sepsis, post-operative wound infections, SSTI, fever, meningitis, pneumonia, abdominal or pelvic abscess, endometritis, urinary tract infection, pyelonephritis) by six weeks post-delivery, and similarly up to 12 months post-delivery
• Cumulative incidence of antibiotic usage by 12 months in infants [ Time Frame: Birth to 12 months ]
  To compare intervention and placebo groups with regard to the cumulative incidence of the number of courses of antibiotics prescribed to the infant up to 12 months of age;
• Cumulative incidence of maternal antibiotic usage by 12 months post-delivery [ Time Frame: Delivery to 12 months ]
  To compare intervention and placebo groups with regard to the cumulative incidence of the number of courses of antibiotics prescribed to the mother up to 12 months post-delivery
• Number of infant participants with adverse events as assessed by adapted version of CTCAE v5.0 and DAID v2.1 [ Time Frame: Birth to 12 months ]
  To compare the number of adverse events including solicited non serious adverse events and all serious adverse events as per study specific definitions throughout the duration of the study.
• Number of maternal participants with adverse events as assessed by adapted version of CTCAE v5.0 and DAID v2.1 [ Time Frame: Delivery to 12 months ]
  To compare the number of adverse events including solicited non serious adverse events and all serious adverse events as per study specific definitions throughout the duration of the study.
• Maternal and infant cases of impetigo with detection of SA and/or GAS [ Time Frame: Delivery/birth to 12 months ]
  To describe maternal and infant cases of impetigo in terms of detection of Staphylococcus aureus, Group A streptococcus and azithromycin nonsusceptibility, in the intervention group and the placebo group, at scheduled assessments.
• Swab study outcome - Prevalence of bacterial carriage as assessed by real-time quantitative PCR (qPCR) [ Time Frame: Delivery/birth to 12 months ]
  Bacterial carriage, the proportion of participants that have at least one of the following bacterial species including GBS, SA, SPN, GAS or E. coli, assessed by qPCR at key time points throughout the duration of the study, between the two groups
• Swab study outcome - Density of bacterial carriage as assessed by real-time quantitative PCR (qPCR) [ Time Frame: Delivery/birth to 12 months ]
  Density of bacterial carriage, reported as log 10 genome equivalents/ml, of the participants that have at least one of the following bacterial species including GBS, SA, SPN, GAS or E. coli, assessed by qPCR at key time points throughout the duration of the study, between the two groups
• Swab study outcome - Risk of maternal carriage identified through qPCR of common organisms relevant to Sexually Transmitted Infections (STI) [ Time Frame: Delivery/birth to 12 months ]
  Maternal carriage of common organisms relevant to Sexually Transmitted Infections (STI) (including Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma genitalium, HSV-1 and HSV-2) as detected by qPCR at key time points throughout the duration of the study, between the two groups.
• Swab study outcome - Risk of antibiotic nonsusceptibility in culture isolates [ Time Frame: Delivery/birth to 12 months ]
  Antibiotic non susceptibility, based on the proportion of samples from mothers and infants that are non susceptible to antibiotics cultured in the two arms, at key time points throughout the duration of the study
• Swab study outcome - Effects of the intervention on the infant and maternal microbiome of specified body sites [ Time Frame: Delivery/birth to 12 months ]
  To compare the infant and maternal microbiome of specified body sites at key time points in the intervention and placebo groups

PreYIAL is a Phase III, double-blind, randomised, placebo controlled two arm trial of a single 2g dose of azithromycin or placebo, administered to women who have been admitted for delivery of their baby (either following onset of labour or for caesarean section).

The trial includes an estimated 2110 mothers/infant pairs (1055 per arm), with 12 months of follow-up for the mother/infant pair.

A swab-study within the main study involves 940 of the mother/infant pairs enrolled and involves follow-up for bacterial carriage outcomes, for 12 months.These swab-study participants will also be included in assessments of the infant and maternal microbiome.

• Drug: Azithromycin 500 mg Oral Tablet x 4
  A single prophylactic dose of antibiotic given during labour
• Drug: Matching Placebo
  Matching Placebo

• Experimental: Azithromycin
  A single 2g dose of Azithromycin
  Intervention: Drug: Azithromycin 500 mg Oral Tablet x 4
• Placebo Comparator: Placebo
  Matching Placebo
  Intervention: Drug: Matching Placebo

Inclusion criteria:

1. Pregnant women at least 18 years old intending to deliver at Colonial War Memorial Hospital (CWMH)
2. Women who have been admitted to CWMH for delivery at the time of eligibility assessment
3. Women who expect to be available, with their infant, for the duration of the study, and who agree to adhere to all protocol requirements
4. Women who will have a main place of residence within the Greater Suva area for the follow-up period and within a practical distance of the study site to allow compliance with protocol-required visits and follow-up, including attending follow-up at specified clinics
5. Women who have provided written informed consent prior to study-related procedures being performed

Exclusion criteria:

1. Women who have a known macrolide allergy
2. Women who have taken antibiotics in the week prior to randomisation
3. A women who is unable or unwilling to provide informed consent for her participation in the trial or the participation of her infant
4. Women who decide prior to randomisation that they are no longer willing to participate or to have their infant participate
5. Women who have ever received, or who are anticipated to receive during the study period, any investigational agent other than the study drug
6. Women who are CWMH, Murdoch Children's Research Institute (MCRI) or study site employees who work directly with study staff, or who are working on the study
7. Women taking warfarin due to the potential for drug interactions with azithromycin
8. Women with any cardiac abnormality
9. Women taking other medications known to prolong the QT interval such as antiarrhythmics; antipsychotic agents; antidepressants; and fluoroquinolones;
10. Women with known electrolyte disturbances: including in cases of hypokalaemia and hypomagnesaemia
11. Women who will undergo general anaesthetic for delivery
12. Women carrying a foetus with intrauterine death confirmed before randomisation
13. Women carrying a foetus with a prognosis unlikely to survive
14. Women with known HIV infection and/or taking nelfinavir
15. Women who have participated in the study during a previous pregnancy
16. Women who have been admitted for management of premature labour who have unruptured membranes (This is a temporary exclusion such that the participant may be assessed for eligibility again in the same or a subsequent admission to CWMH).
17. Women with renal impairment
18. Women with hepatic impairment
19. Women with myasthenia gravis
20. Women who are taking any ergot medications