Yuwen Xu, MD, MS

BACKGROUND: PPROM is the leading cause of preterm birth, occurring in up to 3.5% of all pregnancies. A recent Cochrane review of several smaller studies was unable to show a statistically significant benefit of antibiotic use for PPROM in improving neonatal mortality or morbidity.¹ Another study by these researchers found these antibiotics had no significant effect on outcomes in preterm labor without prelabor rupture of membranes.² The ORACLE Collaborative Group conducted this large multicenter trial to better address the issue.

POPULATION STUDIED: This was a multicenter international study (though it did not include sites in the United States) intended to be reflective of clinical practice. This researchers recruited 4826 pregnant women with PPROM who were at less than 37 weeks’ gestation. Women were excluded if they were previously taking antibiotics, had a known infection requiring antibiotics, or had a contraindication to the study medications. Approximately half of the patients were beyond 32 weeks’ gestation. There were no significant differences between the study groups after randomization in terms of maternal age, gestational age, cervical dilatation, or other medication use.

STUDY DESIGN AND VALIDITY: This was a randomized double-blinded placebo-controlled study. The women were assigned to 1 of 4 treatment groups: erythromycin 250 mg, amoxicillin/clavulanate 250/125 mg, both antibiotics, or placebo. The medications were taken orally 4 times daily for 10 days or until delivery. The strengths of this study include a large sample size, adequate allocation concealment, multiple checks to ensure validity in data collection and treatment assignment, and high follow-up rate (>99.6%). Data were analyzed by intention to treat. This was an overall very well-designed study, though one weakness is its use of a definition of “chronic lung disease” that is simply a neonate’s requirement of oxygen beyond a 36 weeks’ gestational age.

OUTCOMES MEASURED: The composite primary outcome included the overall rate of neonatal death, chronic lung disease, or major cerebral abnormality by ultrasound examination before discharge. Secondary outcomes included delivery within 48 hours, delivery within 7 days, mode of delivery, neonatal infection, number of days in the hospital, and the development of suspected or proven necrotizing enterocolitis.

RESULTS: For the composite primary outcome, there was no statistically significant difference among any of the treatments or placebo. However, there was a nonsignificant trend toward benefit for this outcome in the erythromycin-only group. This outcome may reach statistical significance with a larger sample size. No benefit was found with amoxicillin/clavulanate. In a subgroup analysis of only singleton pregnancies, the researchers found a statistically significant reduction in the composite primary outcome in the erythromycin-only group versus placebo (11.2% vs 14.4%, number needed to treat [NNT]=33).

The important secondary outcomes measured that were of statistical significance included a delay in delivery by at least 7 days (63.3% vs 57.7%, NNT=18) for women taking any antibiotic, as well as reductions in some disease-oriented short-term pulmonary outcomes with erythromycin. However, infants of women receiving amoxicillin/clavulanate were more likely to develop necrotizing enterocolitis (1.8% vs 0.7%, number needed to harm=91), without receiving any benefit from the treatment.

BACKGROUND: PPROM is the leading cause of preterm birth, occurring in up to 3.5% of all pregnancies. A recent Cochrane review of several smaller studies was unable to show a statistically significant benefit of antibiotic use for PPROM in improving neonatal mortality or morbidity.¹ Another study by these researchers found these antibiotics had no significant effect on outcomes in preterm labor without prelabor rupture of membranes.² The ORACLE Collaborative Group conducted this large multicenter trial to better address the issue.

POPULATION STUDIED: This was a multicenter international study (though it did not include sites in the United States) intended to be reflective of clinical practice. This researchers recruited 4826 pregnant women with PPROM who were at less than 37 weeks’ gestation. Women were excluded if they were previously taking antibiotics, had a known infection requiring antibiotics, or had a contraindication to the study medications. Approximately half of the patients were beyond 32 weeks’ gestation. There were no significant differences between the study groups after randomization in terms of maternal age, gestational age, cervical dilatation, or other medication use.

STUDY DESIGN AND VALIDITY: This was a randomized double-blinded placebo-controlled study. The women were assigned to 1 of 4 treatment groups: erythromycin 250 mg, amoxicillin/clavulanate 250/125 mg, both antibiotics, or placebo. The medications were taken orally 4 times daily for 10 days or until delivery. The strengths of this study include a large sample size, adequate allocation concealment, multiple checks to ensure validity in data collection and treatment assignment, and high follow-up rate (>99.6%). Data were analyzed by intention to treat. This was an overall very well-designed study, though one weakness is its use of a definition of “chronic lung disease” that is simply a neonate’s requirement of oxygen beyond a 36 weeks’ gestational age.

OUTCOMES MEASURED: The composite primary outcome included the overall rate of neonatal death, chronic lung disease, or major cerebral abnormality by ultrasound examination before discharge. Secondary outcomes included delivery within 48 hours, delivery within 7 days, mode of delivery, neonatal infection, number of days in the hospital, and the development of suspected or proven necrotizing enterocolitis.

RESULTS: For the composite primary outcome, there was no statistically significant difference among any of the treatments or placebo. However, there was a nonsignificant trend toward benefit for this outcome in the erythromycin-only group. This outcome may reach statistical significance with a larger sample size. No benefit was found with amoxicillin/clavulanate. In a subgroup analysis of only singleton pregnancies, the researchers found a statistically significant reduction in the composite primary outcome in the erythromycin-only group versus placebo (11.2% vs 14.4%, number needed to treat [NNT]=33).

The important secondary outcomes measured that were of statistical significance included a delay in delivery by at least 7 days (63.3% vs 57.7%, NNT=18) for women taking any antibiotic, as well as reductions in some disease-oriented short-term pulmonary outcomes with erythromycin. However, infants of women receiving amoxicillin/clavulanate were more likely to develop necrotizing enterocolitis (1.8% vs 0.7%, number needed to harm=91), without receiving any benefit from the treatment.

BACKGROUND: PPROM is the leading cause of preterm birth, occurring in up to 3.5% of all pregnancies. A recent Cochrane review of several smaller studies was unable to show a statistically significant benefit of antibiotic use for PPROM in improving neonatal mortality or morbidity.¹ Another study by these researchers found these antibiotics had no significant effect on outcomes in preterm labor without prelabor rupture of membranes.² The ORACLE Collaborative Group conducted this large multicenter trial to better address the issue.

POPULATION STUDIED: This was a multicenter international study (though it did not include sites in the United States) intended to be reflective of clinical practice. This researchers recruited 4826 pregnant women with PPROM who were at less than 37 weeks’ gestation. Women were excluded if they were previously taking antibiotics, had a known infection requiring antibiotics, or had a contraindication to the study medications. Approximately half of the patients were beyond 32 weeks’ gestation. There were no significant differences between the study groups after randomization in terms of maternal age, gestational age, cervical dilatation, or other medication use.

STUDY DESIGN AND VALIDITY: This was a randomized double-blinded placebo-controlled study. The women were assigned to 1 of 4 treatment groups: erythromycin 250 mg, amoxicillin/clavulanate 250/125 mg, both antibiotics, or placebo. The medications were taken orally 4 times daily for 10 days or until delivery. The strengths of this study include a large sample size, adequate allocation concealment, multiple checks to ensure validity in data collection and treatment assignment, and high follow-up rate (>99.6%). Data were analyzed by intention to treat. This was an overall very well-designed study, though one weakness is its use of a definition of “chronic lung disease” that is simply a neonate’s requirement of oxygen beyond a 36 weeks’ gestational age.

OUTCOMES MEASURED: The composite primary outcome included the overall rate of neonatal death, chronic lung disease, or major cerebral abnormality by ultrasound examination before discharge. Secondary outcomes included delivery within 48 hours, delivery within 7 days, mode of delivery, neonatal infection, number of days in the hospital, and the development of suspected or proven necrotizing enterocolitis.

RESULTS: For the composite primary outcome, there was no statistically significant difference among any of the treatments or placebo. However, there was a nonsignificant trend toward benefit for this outcome in the erythromycin-only group. This outcome may reach statistical significance with a larger sample size. No benefit was found with amoxicillin/clavulanate. In a subgroup analysis of only singleton pregnancies, the researchers found a statistically significant reduction in the composite primary outcome in the erythromycin-only group versus placebo (11.2% vs 14.4%, number needed to treat [NNT]=33).

The important secondary outcomes measured that were of statistical significance included a delay in delivery by at least 7 days (63.3% vs 57.7%, NNT=18) for women taking any antibiotic, as well as reductions in some disease-oriented short-term pulmonary outcomes with erythromycin. However, infants of women receiving amoxicillin/clavulanate were more likely to develop necrotizing enterocolitis (1.8% vs 0.7%, number needed to harm=91), without receiving any benefit from the treatment.