Maternal Death, Maternal Infections Affecting Fetus or Newborn, Maternal Sepsis During Labor, Neonatal Death, Neonatal SEPSIS, Postpartum Sepsis
Conditions
Keywords
maternal sepsis, maternal death, neonatal sepsis, neonatal death, azithromycin, Democratic Republic of Congo, Zambia, Guatemala, Bangladesh, India, Pakistan, Kenya, COVID-19
Brief 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.
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.
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.
Sponsors
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)
NICHD Global Network for Women's and Children's Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Both the azithromycin and placebo will be procured from the same manufacturer. The packaging will be standardized across sites and will be labeled as: Azithromycin 2 g or Placebo, with the expiration data and a unique identifier. Clinical and research staff as well as the women will be masked to treatment status unless there is a serious adverse event potentially related to the treatment modality that requires unmasking for safety reasons. There will be one pharmacist at each site who will monitor randomization, drug supply, and safety. If concerns about randomization or participant safety are identified, the data coordinating center will authorize and instruct the study pharmacist to apply un-masking procedures.
Intervention model description
Randomized, placebo-controlled, parallel multicenter clinical trial. Women in labor will be randomized with one-to-one ratio to intervention/placebo.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group. | Within 6 weeks (42 days) | Maternal death or sepsis within 6 weeks (42 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 | Within 4 weeks (28 days) post-delivery | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Chorioamnionitis | Between date/time of randomization and date/time of delivery (up to 120 hours before delivery) | 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. |
| Endometritis | Within 42 days post-delivery | 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. |
| Cesarean Wound Infection | Within 42 days post-delivery | 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); |
| Perineal Wound Infection | Within 42 days post-delivery | 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); |
| Other Infections | Within 42 days post-delivery | 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. |
| Use of Subsequent Maternal Antibiotic Therapy | 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. | Use of subsequent maternal antibiotic therapy after randomization to 42 days postpartum for any reason. |
| Maternal Initial Hospital Length of Stay | Time from drug administration (which occurs between onset of labor and delivery) and discharge from delivery hospital (0 to 45 days) | Time from drug administration until initial discharge after delivery (time may vary by site). |
| Maternal Readmissions | After delivery discharge and within 42 days post-delivery | Maternal readmissions after delivery discharge and within 42 days of delivery |
| Maternal Admission to Special Care Units | Within 42 days post-delivery (reported during study) | Maternal admission to special care units |
| Maternal Sepsis | Within 42 days post-delivery | Maternal sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group. |
| Maternal GI Symptoms | Within 42 days post-delivery (reported during study) | Maternal GI symptoms including nausea, vomiting, and diarrhea and other reported side effects. |
| Neonatal Sepsis | Within 28 days post-delivery | 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. |
| Neonatal Death Due to Sepsis | Within 28 days post-delivery | 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. |
| Other Neonatal Infections | Within 28 days post-delivery | 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. |
| Neonatal Initial Hospital Length of Stay | Time from delivery to discharge from delivery hospital (0 to 62 days) | 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. |
| Neonatal Readmissions | After delivery discharge and within 42 days of delivery | 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. |
| Neonatal Admission to Special Care Units | Within 42 days post-delivery (reported during study) | 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. |
| Neonatal Unscheduled Visit for Care | Within 42 days post-delivery (reported during study) | 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. |
| Pyloric Stenosis Within 42 Days of Delivery | Within 42 days post-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. |
| Maternal Unscheduled Visit for Care | Within 42 days post-delivery (reported during study) | Maternal unscheduled visit for care |
| Maternal Death Due to Sepsis | Within 42 days post-delivery | Maternal death due to sepsis using the Global Network algorithm for cause of death |
Countries
Bangladesh, Democratic Republic of the Congo, Guatemala, India, Kenya, Pakistan, Zambia
Participant flow
Recruitment details
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
Pre-assignment details
Participants were randomly assigned (1:1, stratified by site) to receive azithromycin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating center. Mother were randomized and the maternal participant and her baby or babies in the case of multiple pregnancies were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Azithromycin Intervention (Mothers) The study intervention is a single 2 g dose of directly observed oral azithromycin.
Azithromycin: The study intervention is a single 2 g dose of directly observed oral azithromycin, to be administered to maternal participants as four 500 mg pills or tablets directly after randomization which occurs between the onset of labor and delivery. By random allocation, participants will receive 2 g of oral azithromycin. | 14,590 |
| Azithromycin Intervention (Neonates) The study intervention is a single 2 g dose of directly observed oral azithromycin.
Azithromycin: The study intervention is a single 2 g dose of directly observed oral azithromycin, to be administered to maternal participants as four 500 mg pills or tablets directly after randomization which occurs between the onset of labor and delivery. By random allocation, participants will receive 2 g of oral azithromycin. Stillbirths and live births of maternal participants randomized are considered enrolled to the arm which their mother was randomized. | 14,687 |
| Placebo (Mothers) By random allocation, participants will receive four oral placebo pills containing a non-antimicrobial agent directly after randomization.
Placebo: Identical appearing placebo, administered to maternal participants as a single oral dose directly after randomization, which occurs between the onset of labor and delivery. | 14,688 |
| Placebo (Neonates) By random allocation, participants will receive four oral placebo pills containing a non-antimicrobial agent directly after randomization.
Placebo: Identical appearing placebo, administered to maternal participants as a single oral dose directly after randomization, which occurs between the onset of labor and delivery. Stillbirths and live births of maternal participants randomized are considered enrolled to the arm which their mother was randomized. | 14,782 |
| Total | 58,747 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 50 | 15 | 36 | 11 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 14 | 14 | 14 | 14 |
Baseline characteristics
| Characteristic | Azithromycin Intervention (Mothers) | Placebo (Mothers) | Total | Placebo (Neonates) | Azithromycin Intervention (Neonates) |
|---|---|---|---|---|---|
| Age, Continuous | 24 years | 24 years | 24 years | — | — |
| Any maternal condition during pregnancy Missing | 1 Participants | 1 Participants | 2 Participants | — | — |
| Any maternal condition during pregnancy No | 13572 Participants | 13732 Participants | 27304 Participants | — | — |
| Any maternal condition during pregnancy Yes | 1017 Participants | 955 Participants | 1972 Participants | — | — |
| Any maternal infection during pregnancy Missing | 1 Participants | 1 Participants | 2 Participants | — | — |
| Any maternal infection during pregnancy No | 13792 Participants | 13866 Participants | 27658 Participants | — | — |
| Any maternal infection during pregnancy Yes | 797 Participants | 821 Participants | 1618 Participants | — | — |
| Gestational age < 37 weeks Missing | 7 Participants | 4 Participants | 22 Participants | 4 Participants | 7 Participants |
| Gestational age < 37 weeks No | 12742 Participants | 12789 Participants | 51156 Participants | 12834 Participants | 12791 Participants |
| Gestational age < 37 weeks Yes | 1841 Participants | 1895 Participants | 7569 Participants | 1944 Participants | 1889 Participants |
| High risk for sepsis before randomization Missing | 2 Participants | 1 Participants | 3 Participants | — | — |
| High risk for sepsis before randomization No | 13341 Participants | 13404 Participants | 26745 Participants | — | — |
| High risk for sepsis before randomization Yes | 1247 Participants | 1283 Participants | 2530 Participants | — | — |
| Marital status Married | 13729 Participants | 13834 Participants | 27563 Participants | — | — |
| Marital status Missing | 1 Participants | 1 Participants | 2 Participants | — | — |
| Marital status Other | 248 Participants | 253 Participants | 501 Participants | — | — |
| Marital status Single | 612 Participants | 600 Participants | 1212 Participants | — | — |
| Maternal education >= 13 years of schooling | 1798 Participants | 1842 Participants | 3640 Participants | — | — |
| Maternal education 1-6 years of schooling | 2002 Participants | 2022 Participants | 4024 Participants | — | — |
| Maternal education 7-12 years of schooling | 7308 Participants | 7325 Participants | 14633 Participants | — | — |
| Maternal education Missing | 25 Participants | 23 Participants | 48 Participants | — | — |
| Maternal education No formal schooling | 3457 Participants | 3476 Participants | 6933 Participants | — | — |
| Multiple birth Missing | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants |
| Multiple birth No | 14489 Participants | 14592 Participants | 58162 Participants | 14592 Participants | 14489 Participants |
| Multiple birth Yes | 99 Participants | 95 Participants | 582 Participants | 190 Participants | 198 Participants |
| Primiparous Missing | 2 Participants | 1 Participants | 3 Participants | — | — |
| Primiparous No | 8277 Participants | 8311 Participants | 16588 Participants | — | — |
| Primiparous Yes | 6311 Participants | 6376 Participants | 12687 Participants | — | — |
| Prolonged labor >= 18 hours before randomization Missing | 2 Participants | 1 Participants | 3 Participants | — | — |
| Prolonged labor >= 18 hours before randomization No | 13918 Participants | 13989 Participants | 27907 Participants | — | — |
| Prolonged labor >= 18 hours before randomization Yes | 670 Participants | 698 Participants | 1368 Participants | — | — |
| Prolonged rupture of membranes >= 8 hours before randomization Missing | 2 Participants | 1 Participants | 3 Participants | — | — |
| Prolonged rupture of membranes >= 8 hours before randomization No | 13973 Participants | 14055 Participants | 28028 Participants | — | — |
| Prolonged rupture of membranes >= 8 hours before randomization Yes | 615 Participants | 632 Participants | 1247 Participants | — | — |
| Race and Ethnicity Not Collected | — | — | 0 Participants | — | — |
| Region of Enrollment Bangladesh | 1406 Participants | 1441 Participants | 5701 Participants | 1446 Participants | 1408 Participants |
| Region of Enrollment Congo, The Democratic Republic of the | 2181 Participants | 2192 Participants | 8824 Participants | 2231 Participants | 2220 Participants |
| Region of Enrollment Guatemala | 794 Participants | 803 Participants | 3194 Participants | 803 Participants | 794 Participants |
| Region of Enrollment India | 4786 Participants | 4800 Participants | 19206 Participants | 4815 Participants | 4805 Participants |
| Region of Enrollment Kenya | 1829 Participants | 1844 Participants | 7354 Participants | 1846 Participants | 1835 Participants |
| Region of Enrollment Pakistan | 1825 Participants | 1843 Participants | 7371 Participants | 1862 Participants | 1841 Participants |
| Region of Enrollment Zambia | 1769 Participants | 1765 Participants | 7097 Participants | 1779 Participants | 1784 Participants |
| Sex/Gender, Customized Female | 14590 Participants | 14688 Participants | 43591 Participants | 7190 Participants | 7123 Participants |
| Sex/Gender, Customized Male | 0 Participants | 0 Participants | 15154 Participants | 7591 Participants | 7563 Participants |
| Sex/Gender, Customized Missing Sex | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Type of labor onset Induced | 2651 Participants | 2724 Participants | 5375 Participants | — | — |
| Type of labor onset Missing | 9 Participants | 11 Participants | 20 Participants | — | — |
| Type of labor onset Spontaneous | 11930 Participants | 11953 Participants | 23883 Participants | — | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 12 / 14,589 | 291 / 14,686 | 11 / 14,687 | 286 / 14,781 |
| other Total, other adverse events | 1,022 / 14,589 | 8 / 14,686 | 1,110 / 14,687 | 3 / 14,781 |
| serious Total, serious adverse events | 3 / 14,589 | 11 / 14,686 | 3 / 14,687 | 8 / 14,781 |
Outcome results
Primary
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
Population: Intention to treat (ITT)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Intrapartum/Neonatal Death or Sepsis Within 4 Weeks (28 Days) Post-delivery in Intervention vs. Placebo Group | 1,540 Participants |
| Placebo | Intrapartum/Neonatal Death or Sepsis Within 4 Weeks (28 Days) Post-delivery in Intervention vs. Placebo Group | 1,526 Participants |
Comparison: The null hypothesis is there is no treatment effect on the incidence of Intrapartum/Neonatal Death or Sepsis Within 4 Weeks (28 Days) Post-delivery in Intervention vs. Placebo Groupp-value: 0.5695% CI: [0.95, 1.09]Regression, Logistic
Primary
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)
Population: Intention to treat (ITT)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group. | 227 Participants |
| Placebo | Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group. | 344 Participants |
Comparison: The null hypothesis is there is no treatment effect on the incidence of maternal death or sepsis within 6 weeks (42 days) post-deliveryp-value: <0.00195% CI: [0.56, 0.79]Regression, Logistic
Secondary
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
Population: Intention to treat (ITT). This outcome variable is analyzed for the subgroup of women with a cesarean delivery. Numbers differ from the participant flow ITT population due to this subgroup analysis and missing data specific to this secondary outcome. Cesarean wound infection required a diagnosis according to the study algorithm or no diagnosis and follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Cesarean Wound Infection | 77 Participants |
| Placebo | Cesarean Wound Infection | 134 Participants |
95% CI: [0.43, 0.75]
Secondary
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)
Population: Intention to treat (ITT)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Chorioamnionitis | 5 Participants |
| Placebo | Chorioamnionitis | 8 Participants |
Secondary
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
Population: Intention to treat (ITT). Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Endometritis required a diagnosis according to the study algorithm or no diagnosis and follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Endometritis | 191 Participants |
| Placebo | Endometritis | 294 Participants |
95% CI: [0.55, 0.79]
Secondary
Maternal Admission to Special Care Units
Maternal admission to special care units
Time frame: Within 42 days post-delivery (reported during study)
Population: Intention to treat (ITT). Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Maternal admission to special care units required a yes response or a no response on follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Maternal Admission to Special Care Units | 116 Participants |
| Placebo | Maternal Admission to Special Care Units | 130 Participants |
95% CI: [0.7, 1.15]
Secondary
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
Population: Intention to treat (ITT). Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Maternal death due to sepsis required maternal status at 42-days to be included in the denominator.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Maternal Death Due to Sepsis | 4 Participants |
| Placebo | Maternal Death Due to Sepsis | 1 Participants |
95% CI: [0.45, 36.14]
Secondary
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)
Population: Safety population. This is the Treated row of the participant flow.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Maternal GI Symptoms | 119 Participants |
| Placebo | Maternal GI Symptoms | 110 Participants |
95% CI: [0.84, 1.41]
Secondary
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)
Population: Intention to treat (ITT). Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Time from drug administration until initial discharge after delivery required non-missing date and time variables for discharge after delivery.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Maternal Initial Hospital Length of Stay | 1.4 days | Standard Deviation 1.8 |
| Placebo | Maternal Initial Hospital Length of Stay | 1.4 days | Standard Deviation 1.9 |
Secondary
Maternal Readmissions
Maternal readmissions after delivery discharge and within 42 days of delivery
Time frame: After delivery discharge and within 42 days post-delivery
Population: Intention to treat (ITT). Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Maternal readmissions required non-missing date of delivery discharge and a readmission or no indication of a readmission and follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Maternal Readmissions | 124 Participants |
| Placebo | Maternal Readmissions | 192 Participants |
95% CI: [0.52, 0.82]
Secondary
Maternal Sepsis
Maternal sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.
Time frame: Within 42 days post-delivery
Population: Intention to treat (ITT). Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Maternal sepsis required a diagnosis of sepsis according to the study algorithm or no diagnosis and follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Maternal Sepsis | 219 Participants |
| Placebo | Maternal Sepsis | 339 Participants |
95% CI: [0.55, 0.77]
Secondary
Maternal Unscheduled Visit for Care
Maternal unscheduled visit for care
Time frame: Within 42 days post-delivery (reported during study)
Population: Intention to treat (ITT). Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Maternal unscheduled visit for care required a visit for unscheduled care or a no visit reported on follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Maternal Unscheduled Visit for Care | 1,397 Participants |
| Placebo | Maternal Unscheduled Visit for Care | 1,790 Participants |
95% CI: [0.73, 0.84]
Secondary
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)
Population: Intention to treat (ITT) for live births. Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Neonatal admission to special care units is defined among live births so excludes stillbirths. Neonatal admission to special care units required a yes response or a no response on follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Neonatal Admission to Special Care Units | 951 Participants |
| Placebo | Neonatal Admission to Special Care Units | 927 Participants |
95% CI: [0.94, 1.12]
Secondary
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
Population: Intention to treat (ITT) for live births. Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Neonatal death due to sepsis is defined among live births so excludes stillbirths. Neonatal death due to sepsis required status at 28 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Neonatal Death Due to Sepsis | 64 Participants |
| Placebo | Neonatal Death Due to Sepsis | 62 Participants |
95% CI: [0.73, 1.47]
Secondary
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)
Population: Intention to treat (ITT) for live births. Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Neonatal initial hospital length of stay is defined among live births so excludes stillbirths. Neonatal initial hospital length of stay required non-missing date and time of hospital discharge.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention | Neonatal Initial Hospital Length of Stay | 1.5 days | Standard Deviation 2.4 |
| Placebo | Neonatal Initial Hospital Length of Stay | 1.5 days | Standard Deviation 2.1 |
Secondary
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
Population: Intention to treat (ITT)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Neonatal Readmissions | 553 Participants |
| Placebo | Neonatal Readmissions | 518 Participants |
95% CI: [0.96, 1.21]
Secondary
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
Population: Intention to treat (ITT) for live births. Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Neonatal sepsis is defined among live births so excludes stillbirths. Neonatal sepsis required a diagnosis of sepsis according to the study algorithm or no diagnosis and follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Neonatal Sepsis | 1,433 Participants |
| Placebo | Neonatal Sepsis | 1,407 Participants |
95% CI: [0.96, 1.1]
Secondary
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)
Population: Intention to treat (ITT) for live births. Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Neonatal unscheduled visit for care is defined among live births so excludes stillbirths. Neonatal unscheduled visit for care required a reported unplanned care visit or no unplanned care reported on follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Neonatal Unscheduled Visit for Care | 3,223 Participants |
| Placebo | Neonatal Unscheduled Visit for Care | 3,366 Participants |
95% CI: [0.93, 1]
Secondary
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
Population: Intention to treat (ITT). Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Other infections required a diagnosis according to the study algorithm or no diagnosis and follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Other Infections | 149 Participants |
| Placebo | Other Infections | 217 Participants |
95% CI: [0.56, 0.85]
Secondary
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
Population: Intention to treat (ITT) for live births. Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Other neonatal infections is defined among live births so excludes stillbirths. Other neonatal infections required a diagnosis according to the study algorithm or no diagnosis and follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Other Neonatal Infections | 763 Participants |
| Placebo | Other Neonatal Infections | 798 Participants |
95% CI: [0.88, 1.07]
Secondary
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
Population: Intention to treat (ITT). This outcome variable analyzed for the subgroup of women with a vaginal delivery. Numbers differ from the participant flow ITT population due to this subgroup analysis and missing data specific to this secondary outcome. Perineal wound infection required a diagnosis according to the study algorithm or no diagnosis and follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Perineal Wound Infection | 149 Participants |
| Placebo | Perineal Wound Infection | 188 Participants |
95% CI: [0.65, 0.99]
Secondary
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
Population: Safety population for live births. Numbers differ from Treated in the participant flow because they are live births among treated mothers.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Pyloric Stenosis Within 42 Days of Delivery | 8 Participants |
| Placebo | Pyloric Stenosis Within 42 Days of Delivery | 3 Participants |
95% CI: [0.71, 10.1]
Secondary
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.
Population: Intention to treat (ITT). Numbers differ from the participant flow ITT population due to missing data specific to this secondary outcome. Use of subsequent maternal antibiotic therapy required a yes response or a no response on follow-up data on/beyond 7 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention | Use of Subsequent Maternal Antibiotic Therapy | 7,937 Participants |
| Placebo | Use of Subsequent Maternal Antibiotic Therapy | 8,180 Participants |
95% CI: [0.95, 1.01]