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Open Letter

Azithromycin in labour to reduce maternal and newborn sepsis and associated deaths: the need for a harmonized approach

[version 1; peer review: 1 approved, 1 approved with reservations]
PUBLISHED 16 May 2023
Author details Author details

Abstract

Maternal and newborn infections are a major contributor to mortality and morbidity globally.  Lost-cost, effective and safe interventions are needed to address these.  Based on promising findings, azithromycin has been identified as potentially effective antibiotic to reduce maternal and newborn infections in low- and middle-income countries (LMICs).  However, robust randomized clinical trials in a range of settings are needed to confirm these findings as well as to understand the implications for antimicrobial resistance.  To better understand the impact of azithromycin on maternal and newborn health, at least three clinical trials are being conducted to evaluate azithromycin in LMICs.  We describe these trials, the importance of harmonizing study measures and the potential public health impact of azithromycin in LMICs.

Keywords

stillbirth, MITS, azithromycin, pathology

Background and rationale

While under-5 childhood mortality has decreased over the last two decades, the proportion of neonatal deaths has increased during this period1. Infection during pregnancy and the puerperium account for approximately 15% of newborn deaths3,4. Maternal sepsis and infections represent about 10% of the global burden of maternal deaths2. In such context, there is a need for innovative, context specific interventions to reduce intrapartum sepsis in countries with the highest burden. However, to be sustainable, these interventions should be amenable to scale up in these settings to reduce the burden of both maternal and neonatal mortality.

Based on several studies, treatment with azithromycin, a low-cost antibiotic with immunomodulatory properties, has been identified as a novel approach to reduce maternal, neonatal and child mortality associated with infections57. Azithromycin can target organisms that may be very frequent pathogens but that historically have not been the target of antimicrobial preventive treatment8. Whether there are additional benefits beyond the antimicrobial effects remains to be determined.

During recent years, azithromycin has been delivered at pre-specified intervals through mass drug administration to African children under 5 years of age with the aim to reduce child mortality911. While these trials showed heterogenic results, the most apparent benefit has been observed among young infants911. Azithromycin has also been used in randomized clinical trials during pregnancy to reduce preterm birth11,12. One meta-analysis of 14 trials of azithromycin in pregnancy, primarily used in conjunction with other treatments, showed reduced risk of preterm birth and low-birth weight, but not significant reductions in other adverse perinatal outcomes13.

More recently, there has been a growing interest in using azithromycin prophylaxis during labour. One multicenter randomized clinical trial (RCT) of 500 mg azithromycin orally added to the standard prophylactic regimen for women who underwent cesarean delivery following labour or membrane rupture in the US showed that maternal infection was reduced by about 50%7. Use of this intervention was reported to be highly cost-saving14. A single center test-of-concept RCT in The Gambia including all women in labour found in a post hoc analysis that treatment with 2 g of intra-partum azithromycin reduced maternal infections by more than 50% and neonatal infections by more than 25%16.

These promising results have been tempered by several concerns of risks. One recurrent concern regarding the prophylactic use of azithromycin is the potential for developing macrolide resistance1720. This is a particular consideration for widespread use of azithromycin in populations. In the MORDOR study from sub-Saharan Africa, antimicrobial resistance was associated with mass distribution of azithromycin to preschool children twice yearly for two years21, though levels returned to baseline in later studies. The individual-randomized trial from The Gambia found that macrolide resistance increases appeared to be transient, at least in populations with low baseline resistance21. These studies evaluated resistance through surveillance activities, and it is unclear this translates to resistant infections22.

A second important concern is the risk of adverse events, that may be rare, but with scale-up to large populations, could result in significant deaths. Azithromycin was associated with cardiac deaths in an observational study of an elderly population with medical comorbidities but not in a younger, healthy population similar to women of reproductive age23. Macrolides administered to neonates have been associated with infantile hypertrophic pyloric stenosis in some observational studies24, while were not reported in infants following a single dose of azithromycin to women in labour in randomized trials in The Gambia where daily active case detection was conducted by study nurses followed by weekly home visits for eight weeks22. A recent study administering azithromycin during the neonatal period to more than 10,000 neonates did not show an association between the use of azithromycin and infantile hypertrophic pyloric stenosis23.

Given the potential public health benefit, balanced with potential risks of population-based interventions in vulnerable populations, a thorough evaluation of the impact of intrapartum azithromycin prophylaxis is needed. Evidence for a new strategy is strengthened when the direction of the findings can be replicated in multiple studies conducted independently in different settings and population. However, when trials of the same intervention result in contradicting findings, policy makers, clinicians and others have a dilemma about how to translate the research findings into policy, delaying the implementation of potentially promising, life-saving interventions.

To explore optimal delivery strategies, dosing frequency, and target population for azithromycin administration to benefit pregnant women and their infants, a variety of approaches have been undertaken. Thus, while evaluating interventions in diverse settings is critical for generalizability, in order to facilitate the interpretation of results, prospective harmonization of data collection and methods is important2426.

In the case of intrapartum azithromycin, to date there have been positive results but no definitive RCT from LMICs, where the intervention is most urgently needed. To address this concern, at least three independent groups have launched trials with harmonization of the critical metrics to evaluate the impact of azithromycin given during pregnancy and/or labour on maternal and newborn outcomes in different LMIC settings2729. The BMGF-funded Sauver avec l’Azithromycine en Traitant les Femmes Enceintes et les Enfants (SANTE) trial uses a factorial design to randomize pregnant women in Mali to receive antenatal and intrapartum azithromycin or placebo, with their infants randomized to receive azithromycin or placebo at routine 6- and 14-week immunization visits29. ThePregnAnZI-2, SANTE and the Azithromycin in Labor Study (A-PLUS) include ancillary studies to address the effect of the intervention on macrolide resistance and the newborn’s microbiome. These trials also include secondary objectives to determine additional potential benefits of the intervention in non-severe infection and infant’s growth. The protocols for these trials are published, as part of an intention to harmonize methods, where possible, and to define the trial differences so that the findings ultimately can be better interpreted.

Methods

The trials are being conducted in The Gambia and Burkina Faso (the PregnAnZI-2 Trial), Mali (the SANTE Trial) and within the Global Network for Women’s and Children’s Health Research, a multi-site research network conducting research in 8 sites in 7 LMICs including Democratic Republic of Congo, Kenya, Zambia, Guatemala, Bangladesh, India and Pakistan (the A-PLUS Trial). Table 1 summarizes the population, intervention, comparator, and outcomes (PICO) features of these trials. In addition, Table 2 summarizes the secondary outcomes.

Table 1. Population, intervention, comparator, outcomes (PICO) comparison.

PregnAnZI-2A-PLUSSANTE
PopulationPregnant women in labourPregnant women in labourPregnant women seeking routine
antenatal care
Intervention2 g of oral intrapartum azithromycin2 g of oral intrapartum azithromycin2 g of oral azithromycin, twice during
pregnancy and once intrapartum
Infants receive 20mg/kg
azithromycin or placebo alongside
the first and third doses of
pentavalent vaccine
ComparatorPlaceboPlaceboPlacebo
Primary
Outcomes
•    Composite of neonatal sepsis or
neonatal death, excluding deaths
from severe birth asphyxia,
very low birth weight or severe
congenital malformations.
•    Incidence of maternal death or
sepsis within 42 days post-delivery in
the intervention vs. placebo group.
•    Incidence of intrapartum/neonatal
death or sepsis within 28 days post-
delivery
•    Composite of stillbirth and infant
death through 6–12 months of
age (maternal intervention)
•    Infant death from the time of first
dose through 6–12 months of
age (infant intervention)
Sample Size12,00034,00033,600
Study SitesThe Gambia; Burkina FasoIndia; Bangladesh, Pakistan, DRC,
Kenya, Zambia and Guatemala
Mali

Table 2. Trial inclusion and exclusion criteria.

PregnAnZI-2A-PLUSSANTE
Main
Inclusion
Criteria
Pregnant women in labour ≥16 years
who signed consent during Antenatal
Care (ANC) and oral consent to
continue participation during labour
Pregnant women in labour ≥28 weeks who
plan to deliver vaginally at health facility

Presence of one or more live fetus confirmed
via a fetal heart rate by Doptone

Age ≥ 18 years of age (14–17 years per local
standards)
Pregnant women estimated to be
≥14 weeks gestation according
to the study algorithm and
presenting at a study facility for
routine antenatal care

Intend to reside in the study area
for at least 6 months post-delivery
Main
Exclusion
Criteria
Known HIV infection;
any chronic or acute conditions;
planned caesarean section or know
n required referral; known severe
congenital malformation, intrauterine
death or allergy to macrolides; and
drugs known to prolong QT interval
taken during the last 2 weeks, such
as chloroquine, quinine, piperaquine,
and erythromycin.
Evidence of chorioamnionitis or other
infection requiring antibiotic therapy
Arrhythmia or history of cardiomyopathy
Allergy to azithromycin or other macrolides
Use of azithromycin, erythromycin, or other
macrolide within 3 days of randomization.
Planned Cesarean delivery
Preterm labour with no plan to proceed to
delivery
Advanced stage of labour and pushing or too
distressed to give informed consent
Incapable of consenting
Medical conditions considered a
contraindication per clinical judgement
In active labour

Known allergy to macrolide
antibiotics.

Current treatment with
azithromycin for a medical
condition (this can be a temporary
exclusion if the drug is later
discontinued)

Discussion

There are several important commonalities of these trials that will facilitate meta-analyses to address gaps in the current research. First, the intrapartum intervention, including the dosage, was carefully considered. Given the success with a single oral dose of 2 g in The Gambian trial, an oral azithromycin dose of 2 g was selected for the proposed interventions. The PregnAnZI-2 and the A-PLUS trials administered a single 2 g dose of azithromycin during labour, while SANTE administered a single 2 g dose at an antenatal care visit in the second and/or third trimester and during labour or within 24 hours thereafter. The administration of the azithromycin within 24 hours after delivery is justified by the high concentration of azithromycin arriving to the newborns through the breast milk. All three trials utilized a double-blind, placebo-controlled RCT design, selected as the optimal trial methodology.

Second, the important outcomes were prospectively harmonized. Each trial is examining core outcomes, including mortality. The PregnAnZI-2 and the A-PLUS trials are also assessing maternal and newborn infections, and hospitalization rates. Therefore, an individual participant meta-analysis will be possible as the protocols including outcomes were harmonized as much as possible.

The primary neonatal outcome is intrapartum/neonatal death or sepsis within 28 days after birth. For the A-PLUS trial, the primary maternal outcome is maternal death or sepsis within 28 to 42 days after delivery and PregnAnZI-2 maternal sepsis. The primary aim of the antenatal and intrapartum dosing in SANTE is a composite outcome of stillbirths and infant mortality through 6–12 months. SANTE’s co-primary aim will assess the efficacy of azithromycin for the prevention of infant deaths from the time of the first infant dose, administered alongside the first dose of pentavalent vaccine, through 6 to 12 months of age.

In addition, the sample size for each of the trials is substantial, allowing cumulatively, full evaluation of potentially rare adverse events. For example, concerns have been raised about potential adverse effects of intra and antepartum azithromycin on the pulmonary and gastrointestinal systems. Altogether, these trials will provide a comprehensive picture of the potential of short-term adverse events associated with azithromycin given during in labour.

Furthermore, several factors mitigate concerns about antibiotic resistance. The design of each of the trials use a single prophylactic intrapartum dose of antibiotic/placebo rather than multiple prophylactic dose administration. Both have also included women at both high- and low-risk for infection. The prophylactic use of azithromycin, if effective, will reduce the risk of infection and in turn reduce the overall use of antibiotics to treat infection as already shown in other trials6,14. To better assess this, all 3 trials are monitoring for resistant infection. In addition, the trials are conducting in-depth investigations that will inform on the impact of azithromycin use on potential changes to the microbiome.

Besides the similarities, there are several important differences in the trials, including secondary outcomes (Table 3) as well as among prospectively planned ancillary studies to assess important research questions. PregnAnZi-2 is assessing the impact of the intervention on growth. One of the main areas is the concern about AMR. To address this, the A-PLUS and SANTE trials have a sub-study to assess AMR of those randomized to azithromycin vs. placebo while the PregnAnZI-2 trial has several secondary endpoints to determine the extent of the impact on macrolide resistance in both mothers and babies.

Table 3. Trial secondary maternal, neonatal and child outcomes.

PregnAnZI-2A-PLUSSANTE
Maternal
Outcomes
•    Post-partum sepsis: maternal hospitalizations within 28 days
of delivery for endometritis or culture-confirmed infection of
sterile site or wound infection;
•    Endometritis;
•    Wound infection: perineal or caesarean wound infection
•    Mastitis: breast pain, redness, tenderness and localised
mass with or without fluctuance;
•    Malaria: clinical suspicion confirmed by either positive blood
film test for malaria or a RDT for malaria;
•    Fever: axillary temperature ≥38.0 C of two readings with 10
min interval;
•    Antibiotic use during the post-partum follow-up
•    Hospitalizations: any hospital admission;
•    Mortality up to 4 wks.
•    The primary maternal outcome in a high-
risk for infection population
•    Incidence of maternal infections
•    Subsequent maternal antibiotic therapy
after randomization to 42 days postpartum
•    Time from drug administration until initial
discharge after delivery
•    Maternal readmissions and admissions
to special care units within 42 days
postpartum or unscheduled care
•    Maternal gastrointestinal symptoms or
other reported side effects
•    Maternal death due to sepsis
•    A composite outcome of maternal mortality and
hospitalization (for events other than planned surgery or
trauma) while pregnant or within 42 days of termination of
pregnancy
•    Spontaneous abortions and early stillbirths occurring before
22 weeks gestational age
•    14-day period prevalence of malaria, pneumonia, or diarrheal
illness reported at follow up visits (ANC follow up, delivery,
and 6 weeks postpartum visits)
Neonatal
Outcomes
•    Neonatal sepsis and neonatal mortality
•    Culture-confirmed sepsis;
•    Fever
•    Clinical bacterial skin infections
•    Clinical bacterial conjunctivitis
•    Infection (omphalitis)
•    Malaria
•    Use of any prescribed antibiotics
•    All cause neonatal hospitalization excluding those due to
injuries.
•    Neonatal deaths due to sepsis and all-cause neonatal death
•    Other neonatal infections
•    Neonatal readmissions and admissions
to special care units within 42 days
postpartum
•    Neonatal initial hospital length of stay
•    Neonatal unscheduled visit for care
•    Neonatal death due to sepsis
•    Incidence of pyloric stenosis
•    Death within 24 hours (all-cause)
•    Early neonatal death, 0-6 days (all-cause)
•    Late neonatal death, 7-28 days
•    Neonatal death, 0-28 days (all-cause)
•    Gestational age at birth
•    Birth weight
Infant/child
Outcomes
•    All-cause hospitalization during follow up
•    Infant mortality: all-cause mortality
•    Malnutrition (measured by z-scores): anthropometric
measurements at 6 and 12 months of age.
Neurologic (BSID) outcomes at 24-mos
postpartum for sub-set of infants
•    7-day period prevalence of malaria, pneumonia, or diarrheal
illness reported at follow up visits (at approximately 6 weeks,
14 weeks, 6 months and 12 months of age
•    Anthropometric parameters (weight-for-age z-score,
length-for-age z-score, weight-for-length z-score, head
circumference, MUAC
Microbiologic
secondary
outcomes
(and others)
For infants: S. pneumoniae and Klebsiella spp in the
nasopharynx; E. coli, Pseudomonas spp, Klebsiella spp from
rectal swab and S. aureus, GBS, GAS in the oropharynx.
For mothers: prevalence of S. aureus, GBS, GAS, E. coli,
Pseudomonas spp, Klebsiella in BM; S. pneumoniae, Klebsiella spp
in the nasopharynx and S. aureus, GBS, GAS in the oropharynx.
Resistance to AZI, oxacillin and amoxicillin.
Microbiome analysis in nasopharyngeal samples, rectal swabs
(babies) and breast milk (women)
Testing of antimicrobial resistance by
culture at 7, 42 days and up to 3 months
for all dyads and between 6 and 12 after
randomization for culture of maternal and
infant samples (nasopharyngeal and rectal)
to test for antimicrobial resistance by culture,
microbiome and the effects on the resistome
Streptococcus pneumoniae in the nasopharynx (pregnant
women and infants)

Escherichia coli in the rectum (pregnant women and infants)

Genetic determinants of antimicrobial resistance in the gut and
nasopharyngeal microbiomes (pregnant women and infants)

Stool and serum biomarkers of environmental enteric
dysfunction and/or improved growth hormone axis function
(infants)

Composition of the vaginal (maternal), gut (maternal and infant)
and nasopharyngeal (maternal and infant) microbiome

Malaria infection (pregnant women and infants)
Safety
endpoints
SAEs in mothers and infants
Infantile hypertrophic pyloric stenosis
SAEs in mothers and infants
Infantile hypertrophic pyloric stenosis
SAEs in mothers and infants
Infantile hypertrophic pyloric stenosis

There have been concerns about the impact of azithromycin on the microbiome. The PregnAnZI-2, A-PLUS and SANTE trials will conduct detailed microbiome assessments for a sub-set of participants (mothers and newborns). Future studies might correlate differences in microbiome due to antibiotics with longer-term outcomes of the child and mother.

As with other interventions administered during pregnancy, assessing the potential for long-term neurological effects on children is another public health concern. To help address this issue, the PregnAnZI-2 study will be following infants until 36 months after birth to assess neurodevelopmental outcomes. The A-PLUS trial will also evaluate neurodevelopmental outcomes among a subset of children at 24 months of age.

Conclusions

Azithromycin is an inexpensive macrolide that shows promise for improving health in LMICs. To date, numerous clinical trials have assessed the effect of azithromycin on maternal, newborn, and child survival as well as health for a range of conditions and using a range of outcomes. Since the puerperal period is the time with the highest risk of sepsis for women and their newborns, assessing the potential effect of this intervention during the time of highest risk is a necessity. With the public health concerns of increasing antimicrobial resistance globally, it is of special importance that these trials definitively address potential of antimicrobial resistance associated with azithromycin, and various approaches will be studied across the trials.

RCTs provide the strongest evidence needed to weigh the benefits and safety of interventions to improve health outcomes. Given the time and costs involved, prospective harmonization of trial outcomes is important whenever possible to allow for meaningful comparisons across trials and meta-analyses to evaluate outcomes among sub-groups. The three trials on azithromycin described here represent an opportunity to gain substantial, high-quality data across diverse populations to inform the use of azithromycin in pregnancy to reduce sepsis and other adverse pregnancy outcomes.

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McClure EM, Roca A, Kotloff K et al. Azithromycin in labour to reduce maternal and newborn sepsis and associated deaths: the need for a harmonized approach [version 1; peer review: 1 approved, 1 approved with reservations]. Gates Open Res 2023, 7:72 (https://doi.org/10.12688/gatesopenres.14214.1)
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Version 1
VERSION 1 PUBLISHED 16 May 2023
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Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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