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CompletedNCT03871491Updated Oct 24, 2024Results posted

Azithromycin-Prevention in Labor Use Study (A-PLUS)

A Phase 3 interventional study of Azithromycin and Placebo in Maternal Death, Maternal Infections Affecting Fetus or Newborn and Neonatal SEPSIS, sponsored by NICHD Global Network for Women's and Children's Health. Completed at 8 sites in 7 countries. Open to female participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-10-24.

Sponsored by NICHD Global Network for Women's and Children's Health · Phase 3, Interventional, and Prevention

Phase
Phase 3
Study type
Interventional
Enrollment
58,747
Allocation
Randomized
Ages
18 Years to 45 Years
Sex
Female
01

Study summary

Maternal and neonatal infections are among the most frequent causes of maternal and neonatal deaths, and current antibiotic strategies have not been effective in preventing many of these deaths. Recently, a randomized clinical trial conducted in a single site in The Gambia showed that treatment with oral dose of 2 g azithromycin vs. placebo for all women in labor reduced selected maternal and neonatal infections. However, it is unknown if this therapy reduces maternal and neonatal sepsis and mortality. The A-PLUS trial includes two primary hypotheses, a maternal hypothesis and a neonatal hypothesis. First, a single, prophylactic intrapartum oral dose of 2 g azithromycin given to women in labor will reduce maternal death or sepsis. Second, a single, prophylactic intrapartum oral dose of 2 g azithromycin given to women in labor will reduce intrapartum/neonatal death or sepsis.

Read the detailed description

The A-PLUS Trial is a randomized, placebo-controlled, parallel multicenter clinical trial. The study intervention is a single, prophylactic intrapartum oral dose of 2 g azithromycin, with a comparison with a single intrapartum oral dose of an identical appearing placebo. For the A-PLUS randomized control trial (RCT), a total of 34,000 laboring women from eight research sites in sub-Saharan Africa, South Asia, and Latin America will be randomized with one-to-one ratio to intervention/placebo. In response to the global coronavirus pandemic, research sites will also collect data on COVID-19 signs/symptoms, diagnosis, and treatment in order to estimate the incidence of infection and evaluate the impact of the pandemic on the target population.

Prior to the initiation of the A-PLUS RCT, research sites will conduct an observational pilot study using the RCT's planned infrastructure in order to characterize the current practices at participating research facilities and optimize the identification of suspected infection for the RCT. The information obtained in the pilot study will be used to validate estimates of intrapartum deaths, maternal sepsis, and neonatal sepsis used in the sample size calculations for the RCT. Finally, the pilot study will allow the research sites to inventory and upgrade local capacity to conduct routine cultures during the RCT.

A maximum of 16,000 women, separate from the sample for the main trial, will be enrolled in the pilot, across all eight research sites, with no more than 2000 women enrolled at any individual site. Research sites will be eligible to transition to the RCT when a minimum of 600 participants have been enrolled in the pilot study with evidence of (a) high rates of follow-up; (2) acceptable data quality and completeness; and (3) there are no concerns about identification and reporting of infection.

Given the clinical benefits of intrapartum azithromycin so far reported in two trials and the likelihood that it may become the usual practice if the investigator's large RCT confirms the reported benefits, it is important to monitor antibiotic resistance to determine the safety of azithromycin prophylaxis. Therefore, the RCT will also include an ancillary study (referred to as the antimicrobial resistance (AMR) sub-study) to monitor antimicrobial resistance and maternal and newborn microbiome effects of the single dose of prophylactic azithromycin using the following methodology

  1. For all mothers enrolled in the RCT and their infants:

    a. Routine clinical monitoring at baseline and three post-partum time points (3 days, 7 days, and 42 days), with culture and sensitivity testing in cases of suspected bacterial infections;

  2. Among a subset of 1000 randomly selected maternal-infant dyads:

    1. Serial susceptibility monitoring of antimicrobial resistance patterns (including azithromycin resistance) from selected maternal and newborn flora through culture and sensitivity testing. Serial monitoring will be conducted at baseline and three post-partum time points (1 week, 6 weeks, and 3 months).
    2. Serial microbiome collection and storage of specimens for future testing to monitor maternal and newborn microbiome status of selected sites.
02

Conditions studied

  • Maternal Death
  • Maternal Infections Affecting Fetus or Newborn
  • Neonatal SEPSIS
  • Maternal Sepsis During Labor
  • Neonatal Death
  • Postpartum Sepsis

Keywords

  • maternal sepsis
  • maternal death
  • neonatal sepsis
  • neonatal death
  • azithromycin
  • Democratic Republic of Congo
  • Zambia
  • Guatemala
  • Bangladesh
  • India
  • Pakistan
  • Kenya
  • COVID-19
03

Who can participate

Ages eligible
18 Years to 45 Years
Sexes eligible
Female
Accepts healthy volunteers
Yes

Inclusion criteria

  • Pregnant women in labor ≥28 weeks Gestational Age (GA) (by best estimate) with a pregnancy with one or more live fetuses who plan to deliver vaginally in a facility.
  • Admitted to health facility with clear plan for spontaneous or induced delivery.
  • Live fetus must be confirmed via a fetal heart rate by Doptone prior to randomization.
  • ≥18 years of age or minors 14-17 years of age in countries where married or pregnant minors (or their authorized representatives) are legally permitted to give consent.
  • Have provided written informed consent.
  • Pregnant women in labor ≥28 weeks GA (by best estimate) with a pregnancy with one or more live fetuses who plan to deliver vaginally in a facility.
  • Admitted to health facility with clear plan for spontaneous or induced delivery.
  • Live fetus must be confirmed via presence of a fetal heart rate prior to randomization.
  • ≥18 years of age or minors 14-17 years of age in countries where married or pregnant minors (or their authorized representatives) are legally permitted to give consent.
  • Have provided written informed consent [Note: written informed consent may be obtained during antenatal care, but verbal re-confirmation may be needed (per local regulations) at the time of randomization].

Exclusion criteria

Exclusion Criteria:

  • Non-emancipated minors (as per local regulations)
  • Evidence of chorioamnionitis or other infection requiring antibiotic therapy at time of eligibility (however, women given single prophylactic antibiotics with no plans to continue after delivery should not be excluded).
  • Arrhythmia or known history of cardiomyopathy.
  • Allergy to azithromycin or other macrolides that is self-reported or documented in the medical record.
  • Any use of azithromycin, erythromycin, or other macrolide in the 3 days or less prior to randomization.
  • Plan for cesarean delivery prior to randomization.
  • Preterm labor undergoing management with no immediate plan to proceed to delivery.
  • Advanced stage of labor (>6 cm or 10 cm cervical dilation per local standards) and pushing or too distressed to understand, confirm, or give informed consent regardless of cervical dilation.
  • Are not capable of giving consent due to other health problems such as obstetric emergencies (for example, antepartum hemorrhage) or mental disorder.
  • Any other medical conditions that may be considered a contraindication per the judgment of the site investigator.
  • Previous randomization in the trial.
04

Study design

Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Care provider, Investigator)
Enrollment
58,747 participants (actual)

Study arms

  • Experimental
    Intervention

    The study intervention is a single 2 g dose of directly observed oral azithromycin.

    Drug: Azithromycin

  • Placebo comparator
    Placebo

    By random allocation, participants will receive four oral placebo pills containing a non-antimicrobial agent directly after randomization.

    Drug: Placebo

Interventions

  • DrugAzithromycin

    The study intervention is a single 2 g dose of directly observed oral azithromycin, to be administered as four 500 mg pills or tablets directly after randomization. By random allocation, participants will receive 2 g of oral azithromycin.

  • DrugPlacebo

    Identical appearing placebo, administered as a single oral dose directly after randomization.

05

What researchers measure

Primary outcomes

  1. Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group.

    Maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.

    Time frame: Within 6 weeks (42 days)

  2. Intrapartum/Neonatal Death or Sepsis Within 4 Weeks (28 Days) Post-delivery in Intervention vs. Placebo Group

    Intrapartum/neonatal death or sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group. This outcome is measured among stillbirths and neonates with 28-day status available born to women randomized. The study includes multiple births so there are more stillbirths and neonates than participants enrolled.

    Time frame: Within 4 weeks (28 days) post-delivery

Secondary outcomes

  1. Maternal Sepsis

    Maternal sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.

    Time frame: Within 42 days post-delivery

  2. Maternal Death Due to Sepsis

    Maternal death due to sepsis using the Global Network algorithm for cause of death

    Time frame: Within 42 days post-delivery

  3. Chorioamnionitis

    Fever (\>100.4°F/38°C) in addition to one or more of the following: fetal tachycardia ≥160 bpm, maternal tachycardia \>100 bpm, tender uterus between contractions, or purulent/foul smelling discharge from uterus prior to delivery.

    Time frame: Between date/time of randomization and date/time of delivery (up to 120 hours before delivery)

  4. Endometritis

    Fever (\>100.4°F/38°C) in addition to one or more of maternal tachycardia \>100 bpm, tender uterine fundus, or purulent/foul smelling discharge from uterus after delivery.

    Time frame: Within 42 days post-delivery

  5. Cesarean Wound Infection

    Wound infection (Purulent infection of a Cesarean wound with or without fever. In the absence of purulence, requires presence of fever \>100.4°F/38°C and at least one of the following signs of local infection: pain or tenderness, swelling, heat, or redness around the incision/laceration);

    Time frame: Within 42 days post-delivery

  6. Perineal Wound Infection

    Wound infection (Purulent infection of a perineal wound with or without fever. In the absence of purulence, requires presence of fever \>100.4°F/38°C and at least one of the following signs of local infection: pain or tenderness, swelling, heat, or redness around the incision/laceration);

    Time frame: Within 42 days post-delivery

  7. Other Infections

    Abdominopelvic abscess (Evidence of pus in the abdomen or pelvis noted during open surgery, interventional aspiration or imaging); Pneumonia (Fever \>100.4°F/38°C and clinical symptoms suggestive of lung infection including cough and/or tachypnea \>24 breaths/min or radiological confirmation); Pyelonephritis (Fever \>100.4°F/38°C and one or more of the following: urinalysis/dip suggestive of infection, costovertebral angle tenderness, or confirmatory urine culture); Mastitis/breast abscess or infection (Fever \>100.4°F/38°C and one or more of the following: breast pain, swelling, warmth, redness, or purulent drainage). Other bacterial infection.

    Time frame: Within 42 days post-delivery

  8. Use of Subsequent Maternal Antibiotic Therapy

    Use of subsequent maternal antibiotic therapy after randomization to 42 days postpartum for any reason.

    Time frame: After randomization to 42 days post-delivery. Randomization occurs between labor onset and delivery (0 to 120 hours before delivery). 42 participants were randomized >120 hours before delivery due to false labor.

  9. Maternal Initial Hospital Length of Stay

    Time from drug administration until initial discharge after delivery (time may vary by site).

    Time frame: Time from drug administration (which occurs between onset of labor and delivery) and discharge from delivery hospital (0 to 45 days)

  10. Maternal Readmissions

    Maternal readmissions after delivery discharge and within 42 days of delivery

    Time frame: After delivery discharge and within 42 days post-delivery

  11. Maternal Admission to Special Care Units

    Maternal admission to special care units

    Time frame: Within 42 days post-delivery (reported during study)

  12. Maternal Unscheduled Visit for Care

    Maternal unscheduled visit for care

    Time frame: Within 42 days post-delivery (reported during study)

  13. Maternal GI Symptoms

    Maternal GI symptoms including nausea, vomiting, and diarrhea and other reported side effects.

    Time frame: Within 42 days post-delivery (reported during study)

  14. Neonatal Sepsis

    Neonatal sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

    Time frame: Within 28 days post-delivery

  15. Neonatal Death Due to Sepsis

    Neonatal death due to sepsis using the Global Network algorithm for causes of death. This outcome is measured among neonates with 28-day status available born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

    Time frame: Within 28 days post-delivery

  16. Other Neonatal Infections

    Other neonatal infections (e.g. eye infection, skin infection). This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

    Time frame: Within 28 days post-delivery

  17. Neonatal Initial Hospital Length of Stay

    Neonatal initial hospital length of stay, defined as time of delivery until initial discharge (time may vary by site). This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

    Time frame: Time from delivery to discharge from delivery hospital (0 to 62 days)

  18. Neonatal Readmissions

    Neonatal readmissions to facility after delivery discharge and within 42 days of delivery. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

    Time frame: After delivery discharge and within 42 days of delivery

  19. Neonatal Admission to Special Care Units

    Neonatal admission to special care units. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

    Time frame: Within 42 days post-delivery (reported during study)

  20. Neonatal Unscheduled Visit for Care

    Neonatal unscheduled visit for care. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

    Time frame: Within 42 days post-delivery (reported during study)

  21. Pyloric Stenosis Within 42 Days of Delivery

    Pyloric stenosis within 42 days of delivery, defined as clinical suspicion based on severe vomiting leading to death, surgical intervention (pyloromyotomy) as verified from medical records, or radiological confirmation. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

    Time frame: Within 42 days post-delivery

06

Results

Posted Oct 24, 2024

Participant flow

Randomized, multi-country, double-masked, placebo-controlled trial of azithromycin (single 2g oral dose) initiated during labor, in women who were in labor at 28 weeks' gestation or more and who were planning a vaginal delivery

Participant flow — Overall Study
MilestoneAzithromycin Intervention (Mothers)Azithromycin Intervention (Neonates)Placebo (Mothers)Placebo (Neonates)
Started14590146871468814782
Treated14589146861468714781
Included in intention to treat (itt) analysis14590146871468814782
Completed14526146581463714756
Not completed64295126
Withdrew: Withdrawal by subject14141414
Withdrew: Physician decision0011
Withdrew: Lost to follow-up50153611

Outcome measures

PrimaryMaternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group.

Maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.

Time frame:
Within 6 weeks (42 days)
Reported as:
Count of participants · Participants
Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group.
ParticipantsInterventionPlacebo
Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group.227344
Statistical analysis
  • Placebo · Regression, Logistic · p = <0.001 (We calculated P values to test each of the primary hypotheses at an alpha level of 0.05 overall, with a nominal alpha level of 0.0001 at the interim analysis.) · Risk ratio (rr): 0.67 · 95% CI 0.56 to 0.79Used multiple imputation for missing outcomes by means of logistic regression imputation.
PrimaryIntrapartum/Neonatal Death or Sepsis Within 4 Weeks (28 Days) Post-delivery in Intervention vs. Placebo Group

Intrapartum/neonatal death or sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group. This outcome is measured among stillbirths and neonates with 28-day status available born to women randomized. The study includes multiple births so there are more stillbirths and neonates than participants enrolled.

Time frame:
Within 4 weeks (28 days) post-delivery
Reported as:
Count of participants · Participants
Intrapartum/Neonatal Death or Sepsis Within 4 Weeks (28 Days) Post-delivery in Intervention vs. Placebo Group
ParticipantsIntervention ArmPlacebo Arm
Intrapartum/Neonatal Death or Sepsis Within 4 Weeks (28 Days) Post-delivery in Intervention vs. Placebo Group1,5401,526
Statistical analysis
  • Placebo Arm · Regression, Logistic · p = 0.56 (We calculated P values to test each of the primary hypotheses at an alpha level of 0.05 overall, with a nominal alpha level of 0.0001 at the interim analysis.) · Risk ratio (rr): 1.02 · 95% CI 0.95 to 1.09Used multiple imputation for missing outcomes by means of logistic regression imputation.
SecondaryMaternal Sepsis

Maternal sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.

Time frame:
Within 42 days post-delivery
Reported as:
Count of participants · Participants
Maternal Sepsis
ParticipantsIntervention ArmPlacebo Arm
Maternal Sepsis219339
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 0.65 · 95% CI 0.55 to 0.77
SecondaryMaternal Death Due to Sepsis

Maternal death due to sepsis using the Global Network algorithm for cause of death

Time frame:
Within 42 days post-delivery
Reported as:
Count of participants · Participants
Maternal Death Due to Sepsis
ParticipantsIntervention ArmPlacebo Arm
Maternal Death Due to Sepsis41
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 4.04 · 95% CI 0.45 to 36.14
SecondaryChorioamnionitis

Fever (\>100.4°F/38°C) in addition to one or more of the following: fetal tachycardia ≥160 bpm, maternal tachycardia \>100 bpm, tender uterus between contractions, or purulent/foul smelling discharge from uterus prior to delivery.

Time frame:
Between date/time of randomization and date/time of delivery (up to 120 hours before delivery)
Reported as:
Count of participants · Participants
Chorioamnionitis
ParticipantsIntervention ArmPlacebo Arm
Chorioamnionitis58
SecondaryEndometritis

Fever (\>100.4°F/38°C) in addition to one or more of maternal tachycardia \>100 bpm, tender uterine fundus, or purulent/foul smelling discharge from uterus after delivery.

Time frame:
Within 42 days post-delivery
Reported as:
Count of participants · Participants
Endometritis
ParticipantsIntervention ArmPlacebo Arm
Endometritis191294
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 0.66 · 95% CI 0.55 to 0.79
SecondaryCesarean Wound Infection

Wound infection (Purulent infection of a Cesarean wound with or without fever. In the absence of purulence, requires presence of fever \>100.4°F/38°C and at least one of the following signs of local infection: pain or tenderness, swelling, heat, or redness around the incision/laceration);

Time frame:
Within 42 days post-delivery
Reported as:
Count of participants · Participants
Cesarean Wound Infection
ParticipantsIntervention ArmPlacebo Arm
Cesarean Wound Infection77134
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 0.57 · 95% CI 0.43 to 0.75
SecondaryPerineal Wound Infection

Wound infection (Purulent infection of a perineal wound with or without fever. In the absence of purulence, requires presence of fever \>100.4°F/38°C and at least one of the following signs of local infection: pain or tenderness, swelling, heat, or redness around the incision/laceration);

Time frame:
Within 42 days post-delivery
Reported as:
Count of participants · Participants
Perineal Wound Infection
ParticipantsIntervention ArmPlacebo Arm
Perineal Wound Infection149188
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 0.8 · 95% CI 0.65 to 0.99
SecondaryOther Infections

Abdominopelvic abscess (Evidence of pus in the abdomen or pelvis noted during open surgery, interventional aspiration or imaging); Pneumonia (Fever \>100.4°F/38°C and clinical symptoms suggestive of lung infection including cough and/or tachypnea \>24 breaths/min or radiological confirmation); Pyelonephritis (Fever \>100.4°F/38°C and one or more of the following: urinalysis/dip suggestive of infection, costovertebral angle tenderness, or confirmatory urine culture); Mastitis/breast abscess or infection (Fever \>100.4°F/38°C and one or more of the following: breast pain, swelling, warmth, redness, or purulent drainage). Other bacterial infection.

Time frame:
Within 42 days post-delivery
Reported as:
Count of participants · Participants
Other Infections
ParticipantsIntervention ArmPlacebo Arm
Other Infections149217
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 0.69 · 95% CI 0.56 to 0.85
SecondaryUse of Subsequent Maternal Antibiotic Therapy

Use of subsequent maternal antibiotic therapy after randomization to 42 days postpartum for any reason.

Time frame:
After randomization to 42 days post-delivery. Randomization occurs between labor onset and delivery (0 to 120 hours before delivery). 42 participants were randomized >120 hours before delivery due to false labor.
Reported as:
Count of participants · Participants
Use of Subsequent Maternal Antibiotic Therapy
ParticipantsIntervention ArmPlacebo Arm
Use of Subsequent Maternal Antibiotic Therapy7,9378,180
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 0.98 · 95% CI 0.95 to 1.01
SecondaryMaternal Initial Hospital Length of Stay

Time from drug administration until initial discharge after delivery (time may vary by site).

Time frame:
Time from drug administration (which occurs between onset of labor and delivery) and discharge from delivery hospital (0 to 45 days)
Reported as:
Mean · days
Maternal Initial Hospital Length of Stay
daysIntervention ArmPlacebo Arm
Maternal Initial Hospital Length of Stay1.4 ± 1.81.4 ± 1.9
SecondaryMaternal Readmissions

Maternal readmissions after delivery discharge and within 42 days of delivery

Time frame:
After delivery discharge and within 42 days post-delivery
Reported as:
Count of participants · Participants
Maternal Readmissions
ParticipantsIntervention ArmPlacebo Arm
Maternal Readmissions124192
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 0.65 · 95% CI 0.52 to 0.82
SecondaryMaternal Admission to Special Care Units

Maternal admission to special care units

Time frame:
Within 42 days post-delivery (reported during study)
Reported as:
Count of participants · Participants
Maternal Admission to Special Care Units
ParticipantsIntervention ArmPlacebo Arm
Maternal Admission to Special Care Units116130
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 0.90 · 95% CI 0.70 to 1.15
SecondaryMaternal Unscheduled Visit for Care

Maternal unscheduled visit for care

Time frame:
Within 42 days post-delivery (reported during study)
Reported as:
Count of participants · Participants
Maternal Unscheduled Visit for Care
ParticipantsIntervention ArmPlacebo Arm
Maternal Unscheduled Visit for Care1,3971,790
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 0.79 · 95% CI 0.73 to 0.84
SecondaryMaternal GI Symptoms

Maternal GI symptoms including nausea, vomiting, and diarrhea and other reported side effects.

Time frame:
Within 42 days post-delivery (reported during study)
Reported as:
Count of participants · Participants
Maternal GI Symptoms
ParticipantsIntervention ArmPlacebo Arm
Maternal GI Symptoms119110
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 1.09 · 95% CI 0.84 to 1.41
SecondaryNeonatal Sepsis

Neonatal sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

Time frame:
Within 28 days post-delivery
Reported as:
Count of participants · Participants
Neonatal Sepsis
ParticipantsIntervention ArmPlacebo Arm
Neonatal Sepsis1,4331,407
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 1.03 · 95% CI 0.96 to 1.1
SecondaryNeonatal Death Due to Sepsis

Neonatal death due to sepsis using the Global Network algorithm for causes of death. This outcome is measured among neonates with 28-day status available born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

Time frame:
Within 28 days post-delivery
Reported as:
Count of participants · Participants
Neonatal Death Due to Sepsis
ParticipantsIntervention ArmPlacebo Arm
Neonatal Death Due to Sepsis6462
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 1.04 · 95% CI 0.73 to 1.47
SecondaryOther Neonatal Infections

Other neonatal infections (e.g. eye infection, skin infection). This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

Time frame:
Within 28 days post-delivery
Reported as:
Count of participants · Participants
Other Neonatal Infections
ParticipantsIntervention ArmPlacebo Arm
Other Neonatal Infections763798
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 0.97 · 95% CI 0.88 to 1.07
SecondaryNeonatal Initial Hospital Length of Stay

Neonatal initial hospital length of stay, defined as time of delivery until initial discharge (time may vary by site). This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

Time frame:
Time from delivery to discharge from delivery hospital (0 to 62 days)
Reported as:
Mean · days
Neonatal Initial Hospital Length of Stay
daysIntervention ArmPlacebo Arm
Neonatal Initial Hospital Length of Stay1.5 ± 2.41.5 ± 2.1
SecondaryNeonatal Readmissions

Neonatal readmissions to facility after delivery discharge and within 42 days of delivery. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

Time frame:
After delivery discharge and within 42 days of delivery
Reported as:
Count of participants · Participants
Neonatal Readmissions
ParticipantsIntervention ArmPlacebo Arm
Neonatal Readmissions553518
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 1.08 · 95% CI 0.96 to 1.21
SecondaryNeonatal Admission to Special Care Units

Neonatal admission to special care units. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

Time frame:
Within 42 days post-delivery (reported during study)
Reported as:
Count of participants · Participants
Neonatal Admission to Special Care Units
ParticipantsIntervention ArmPlacebo Arm
Neonatal Admission to Special Care Units951927
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 1.03 · 95% CI 0.94 to 1.12
SecondaryNeonatal Unscheduled Visit for Care

Neonatal unscheduled visit for care. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

Time frame:
Within 42 days post-delivery (reported during study)
Reported as:
Count of participants · Participants
Neonatal Unscheduled Visit for Care
ParticipantsIntervention ArmPlacebo Arm
Neonatal Unscheduled Visit for Care3,2233,366
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 0.96 · 95% CI 0.93 to 1.0
SecondaryPyloric Stenosis Within 42 Days of Delivery

Pyloric stenosis within 42 days of delivery, defined as clinical suspicion based on severe vomiting leading to death, surgical intervention (pyloromyotomy) as verified from medical records, or radiological confirmation. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.

Time frame:
Within 42 days post-delivery
Reported as:
Count of participants · Participants
Pyloric Stenosis Within 42 Days of Delivery
ParticipantsIntervention ArmPlacebo Arm
Pyloric Stenosis Within 42 Days of Delivery83
Statistical analysis
  • Placebo Arm · Risk ratio (rr): 2.68 · 95% CI 0.71 to 10.1

Adverse events

Collected over Adverse events were monitored continuously throughout the study from time of randomization (between onset of labor and delivery) through 6-weeks post delivery.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Azithromycin Intervention (Mothers)12/14,589 (0.1%)3/14,589 (0%)1,022/14,589 (7%)
Azithromycin Intervention (Neonates)291/14,686 (2%)11/14,686 (0.1%)8/14,686 (0.1%)
Placebo (Mothers)11/14,687 (0.1%)3/14,687 (0%)1,110/14,687 (7.6%)
Placebo (Neonates)286/14,781 (1.9%)8/14,781 (0.1%)3/14,781 (0%)
Most frequent serious events
Most frequent serious events
EventAzithromycin Intervention (Mothers)Azithromycin Intervention (Neonates)Placebo (Mothers)Placebo (Neonates)
Neonatal deathPregnancy, puerperium and perinatal conditions—9/14627—5/14725
Maternal deathPregnancy, puerperium and perinatal conditions3/14589—1/14687—
Other maternal serious adverse eventPregnancy, puerperium and perinatal conditions0/14589—2/14687—
Other neonatal serious adverse eventPregnancy, puerperium and perinatal conditions—1/14627—2/14725
StillbirthPregnancy, puerperium and perinatal conditions—1/14686—1/14781
Most frequent other events
Most frequent other events
EventAzithromycin Intervention (Mothers)Azithromycin Intervention (Neonates)Placebo (Mothers)Placebo (Neonates)
Severe vaginal painGeneral disorders309/14589—329/14687—
Vomited within 15 minutes after study drug administrationGastrointestinal disorders311/14589—279/14687—
Feeling faint or dizzyCardiac disorders241/14589—309/14687—
Severe abdominal or uterine painGeneral disorders170/14589—208/14687—
GI symptoms and other reported side effectsGastrointestinal disorders119/14589—110/14687—
Foul-smelling vaginal dischargeGeneral disorders37/14589—83/14687—
Diarrhea/loose stoolsGastrointestinal disorders76/14589—66/14687—
Nausea/vomitingGastrointestinal disorders45/14589—48/14687—
Pyloric stenosisGastrointestinal disorders—8/14627—3/14726

Baseline characteristics

Women who were eligible according to the intention-to-treat (ITT) criteria and included in the ITT analysis. Includes baseline data for neonates of randomized maternal participants. Baseline data was not collected for the 115 stillbirths. The number of neonates is larger than the number of maternal participants randomized due to multiple births.

Age, Continuous
Age, Continuous(years)Azithromycin Intervention (Mothers)Azithromycin Intervention (Neonates)Placebo (Mothers)Placebo (Neonates)Total
Median24 (21 to 28)—24 (21 to 28)—24 (21 to 28)
Sex/Gender, Customized
Sex/Gender, Customized(Participants)Azithromycin Intervention (Mothers)Azithromycin Intervention (Neonates)Placebo (Mothers)Placebo (Neonates)Total
Female14590712314688719043591
Male075630759115154
Missing Sex01012
Race and Ethnicity Not Collected
Race and Ethnicity Not Collected(Participants)Azithromycin Intervention (Mothers)Azithromycin Intervention (Neonates)Placebo (Mothers)Placebo (Neonates)Total
Count of participants————0
Region of Enrollment
Region of Enrollment(Participants)Azithromycin Intervention (Mothers)Azithromycin Intervention (Neonates)Placebo (Mothers)Placebo (Neonates)Total
Bangladesh14061408144114465701
Pakistan18251841184318627371
Congo, The Democratic Republic of the21812220219222318824
Guatemala7947948038033194
Zambia17691784176517797097
Kenya18291835184418467354
India478648054800481519206
Marital status
Marital status(Participants)Azithromycin Intervention (Mothers)Azithromycin Intervention (Neonates)Placebo (Mothers)Placebo (Neonates)Total
Married13729—13834—27563
Single612—600—1212
Other248—253—501
Missing1—1—2
Maternal education
Maternal education(Participants)Azithromycin Intervention (Mothers)Azithromycin Intervention (Neonates)Placebo (Mothers)Placebo (Neonates)Total
No formal schooling3457—3476—6933
1-6 years of schooling2002—2022—4024
7-12 years of schooling7308—7325—14633
>= 13 years of schooling1798—1842—3640
Missing25—23—48
Primiparous
Primiparous(Participants)Azithromycin Intervention (Mothers)Azithromycin Intervention (Neonates)Placebo (Mothers)Placebo (Neonates)Total
Yes6311—6376—12687
No8277—8311—16588
Missing2—1—3
Multiple birth
Multiple birth(Participants)Azithromycin Intervention (Mothers)Azithromycin Intervention (Neonates)Placebo (Mothers)Placebo (Neonates)Total
Yes9919895190582
No1448914489145921459258162
Missing20103

7 further baseline measures are reported on the registry.

07

Study locations

8 sites
  • ICDDRB
    Dhaka, 1212, Bangladesh
  • Kinshasa School of Public Health
    Kinshasa, Congo, The Democratic Republic of the
  • Institute for Nutrition of Central America and Panama (INCAP)
    Guatemala City, 01011, Guatemala
  • Jawaharlal Nehru Medical College
    Belagam, 590 010, India
  • Lata Medical Research Foundation
    Nagpur, India
  • Moi University School of Medicine
    Eldoret, 30100, Kenya
  • The Aga Khan University
    Karachi, 74800, Pakistan
  • University Teaching Hospital
    Lusaka, Zambia
08

References and documents

Publications

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  • Gyte GM, Dou L, Vazquez JC. Different classes of antibiotics given to women routinely for preventing infection at caesarean section. Cochrane Database Syst Rev. 2014 Nov 17;2014(11):CD008726. doi: 10.1002/14651858.CD008726.pub2. PubMed 25402227 ↗
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  • Tita AT, Szychowski JM, Boggess K, Saade G, Longo S, Clark E, Esplin S, Cleary K, Wapner R, Letson K, Owens M, Abramovici A, Ambalavanan N, Cutter G, Andrews W; C/SOAP Trial Consortium. Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. N Engl J Med. 2016 Sep 29;375(13):1231-41. doi: 10.1056/NEJMoa1602044. PubMed 27682034 ↗
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  • Harper LM, Kilgore M, Szychowski JM, Andrews WW, Tita ATN. Economic Evaluation of Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. Obstet Gynecol. 2017 Aug;130(2):328-334. doi: 10.1097/AOG.0000000000002129. PubMed 28697108 ↗
  • Andrews WW, Hauth JC, Cliver SP, Savage K, Goldenberg RL. Randomized clinical trial of extended spectrum antibiotic prophylaxis with coverage for Ureaplasma urealyticum to reduce post-cesarean delivery endometritis. Obstet Gynecol. 2003 Jun;101(6):1183-9. doi: 10.1016/s0029-7844(03)00016-4. PubMed 12798523 ↗
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  • Tita AT, Owen J, Stamm AM, Grimes A, Hauth JC, Andrews WW. Impact of extended-spectrum antibiotic prophylaxis on incidence of postcesarean surgical wound infection. Am J Obstet Gynecol. 2008 Sep;199(3):303.e1-3. doi: 10.1016/j.ajog.2008.06.068. PubMed 18771992 ↗
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  • Emmons SL, Krohn M, Jackson M, Eschenbach DA. Development of wound infections among women undergoing cesarean section. Obstet Gynecol. 1988 Oct;72(4):559-64. PubMed 3419735 ↗
  • Roberts S, Maccato M, Faro S, Pinell P. The microbiology of post-cesarean wound morbidity. Obstet Gynecol. 1993 Mar;81(3):383-6. PubMed 8437791 ↗
  • Rosene K, Eschenbach DA, Tompkins LS, Kenny GE, Watkins H. Polymicrobial early postpartum endometritis with facultative and anaerobic bacteria, genital mycoplasmas, and Chlamydia trachomatis: treatment with piperacillin or cefoxitin. J Infect Dis. 1986 Jun;153(6):1028-37. doi: 10.1093/infdis/153.6.1028. PubMed 3701114 ↗
  • Andrews WW, Shah SR, Goldenberg RL, Cliver SP, Hauth JC, Cassell GH. Association of post-cesarean delivery endometritis with colonization of the chorioamnion by Ureaplasma urealyticum. Obstet Gynecol. 1995 Apr;85(4):509-14. doi: 10.1016/0029-7844(94)00436-H. PubMed 7898825 ↗
  • Keski-Nisula L, Kirkinen P, Katila ML, Ollikainen M, Suonio S, Saarikoski S. Amniotic fluid U. urealyticum colonization: significance for maternal peripartal infections at term. Am J Perinatol. 1997 Mar;14(3):151-6. doi: 10.1055/s-2007-994117. PubMed 9259918 ↗
  • Yoon BH, Romero R, Park JS, Chang JW, Kim YA, Kim JC, Kim KS. Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol. 1998 Nov;179(5):1254-60. doi: 10.1016/s0002-9378(98)70142-5. PubMed 9822511 ↗
  • Ledger WJ. Prophylactic antibiotics in obstetrics-gynecology: a current asset, a future liability? Expert Rev Anti Infect Ther. 2006 Dec;4(6):957-64. doi: 10.1586/14787210.4.6.957. PubMed 17181412 ↗
  • Guideline: Managing Possible Serious Bacterial Infection in Young Infants When Referral Is Not Feasible. Geneva: World Health Organization; 2015. Available from http://www.ncbi.nlm.nih.gov/books/NBK321136/ PubMed 26447263 ↗
  • Sutton AL, Acosta EP, Larson KB, Kerstner-Wood CD, Tita AT, Biggio JR. Perinatal pharmacokinetics of azithromycin for cesarean prophylaxis. Am J Obstet Gynecol. 2015 Jun;212(6):812.e1-6. doi: 10.1016/j.ajog.2015.01.015. Epub 2015 Jan 13. PubMed 25595580 ↗
  • Eberly MD, Eide MB, Thompson JL, Nylund CM. Azithromycin in early infancy and pyloric stenosis. Pediatrics. 2015 Mar;135(3):483-8. doi: 10.1542/peds.2014-2026. PubMed 25687145 ↗
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  • Svanstrom H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013 May 2;368(18):1704-12. doi: 10.1056/NEJMoa1300799. PubMed 23635050 ↗
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  • Goldenberg RL, Saleem S, Ali S, Moore JL, Lokangako A, Tshefu A, Mwenechanya M, Chomba E, Garces A, Figueroa L, Goudar S, Kodkany B, Patel A, Esamai F, Nsyonge P, Harrison MS, Bauserman M, Bose CL, Krebs NF, Hambidge KM, Derman RJ, Hibberd PL, Liechty EA, Wallace DD, Belizan JM, Miodovnik M, Koso-Thomas M, Carlo WA, Jobe AH, McClure EM. Maternal near miss in low-resource areas. Int J Gynaecol Obstet. 2017 Sep;138(3):347-355. doi: 10.1002/ijgo.12219. Epub 2017 Jun 13. PubMed 28513837 ↗
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  • Albright CM, Has P, Rouse DJ, Hughes BL. Internal Validation of the Sepsis in Obstetrics Score to Identify Risk of Morbidity From Sepsis in Pregnancy. Obstet Gynecol. 2017 Oct;130(4):747-755. doi: 10.1097/AOG.0000000000002260. PubMed 28885400 ↗
  • Bowyer L, Robinson HL, Barrett H, Crozier TM, Giles M, Idel I, Lowe S, Lust K, Marnoch CA, Morton MR, Said J, Wong M, Makris A. SOMANZ guidelines for the investigation and management sepsis in pregnancy. Aust N Z J Obstet Gynaecol. 2017 Oct;57(5):540-551. doi: 10.1111/ajo.12646. Epub 2017 Jul 3. PubMed 28670748 ↗

Study documents

  • Protocol, analysis plan and consent form · Oct 13, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Deidentified participant data will be made available through the NICHD Data and Specimen Hub (N-DASH) system, a publicly accessible online archive, following publication of the primary paper.

Supporting information: Study protocol, Sap

09

Registry details

Key details

Study ID
NCT03871491
Lead sponsor
NICHD Global Network for Women's and Children's Health
Collaborators
University of Alabama at Birmingham, University Teaching Hospital, Lusaka, Zambia, University of North Carolina, Chapel Hill, Kinshasa School of Public Health, University of Colorado, Denver, Institute of Nutrition of Central America and Panama, University of Virginia, International Centre for Diarrhoeal Disease Research, Bangladesh, Thomas Jefferson University, Columbia University, Aga Khan University, Boston University, Lata Medical Research Foundation, Nagpur, Indiana University School of Medicine, Moi Univeristy, RTI International, Bill and Melinda Gates Foundation, Jawaharlal Nehru Medical College, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Responsible party
Sponsor
First posted
Mar 12, 2019
Start date
Sep 1, 2020
Primary completion
Sep 30, 2022
Completion
Sep 30, 2022
Results posted
Oct 24, 2024
Last update
Oct 24, 2024

Study contacts

Marion Koso-Thomas, MD
study director · Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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