Ampicillin and gentamicin prophylaxis is superior to ampicillin alone in patients with prelabor rupture of membranes at term: the results of a randomized clinical trial - 31/03/25

Doi : 10.1016/j.ajog.2025.03.011

Raneen Abu Shqara, MD ^a,^b, Daniel Glikman, MD ^b,^c, Gabriela Goldinfeld, MD ^b, Olga Braude, MD ^b, Silas Assy, MD ^b, Dunia Hassan, MD ^a,^b, Inshirah Sgayer, MD ^a,^b, Nadir Ganem, MD ^a,^b, Hadas Shasha-Lavsky, MD ^b, Enav Yefet, MD ^b,^c, Marian Matanis, MD ^b,^c, Lior Lowenstein, MD ^a,^b, Maya Frank Wolf, MD ^a,^b,^⁎
^a Department of Obstetrics & Gynecology, Galilee Medical Center, Nahariya, Israel
^b Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel
^c Tzafon Medical Center, Poriya, Israel

^∗Corresponding author: Maya Frank Wolf, MD.

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Abstract

Background

Prelabor rupture of membranes is a risk factor for maternal and neonatal infectious morbidity. Ampicillin is indicated for patients with unknown group B Streptococcus status and prelabor rupture of membranes ≥18 hours. Although ampicillin-resistant Enterobacteriaceae contribute to maternal and neonatal infectious morbidity, current guidelines on intrapartum antibiotic prophylaxis primarily target group B Streptococcus and do not adequately cover Enterobacteriaceae.

Objective

To compare maternal and neonatal infectious morbidity between 2 antibiotic regimens: ampicillin and gentamicin vs ampicillin alone.

Study Design

This randomized controlled trial was conducted between November 2022 and March 2024 in a tertiary university-affiliated hospital. Inclusion criteria were a term singleton pregnancy ≥37 0/7, vertex presentation, unknown group B Streptococcus status, and prelabor rupture of membranes without active labor. Exclusion criteria included penicillin/gentamicin allergy, contraindications for vaginal delivery, and current antibiotic treatment. The participants were randomized at 12 to 18 hours post prelabor rupture of membranes to receive ampicillin and gentamicin (n=102) or ampicillin alone (n=102). They were blinded from the allocation until antibiotics initiation at 18 hours post prelabor rupture of membranes. The antibiotics were administered until delivery. The primary outcome was clinical chorioamnionitis. Secondary maternal outcomes were puerperal endometritis, peripartum infections, intrapartum fever, and a composite of postpartum maternal morbidity, defined as the presence of puerperal endometritis, postpartum antibiotic treatment exceeding 24 hours, wound infection, or infection-related hospitalization >5 days. A neonatal composite adverse outcome included culture-proven neonatal sepsis, admission to the neonatal intensive care unit, empiric antibiotic treatment in the neonatal intensive care unit, performance of a sepsis workup, and infection-related hospitalization >5 days. Microbiologic findings were assessed from chorioamniotic swab cultures. An intention-to-treat analysis was performed. The number needed to treat was calculated for the primary outcome. Multivariate logistic regression was conducted to predict clinical chorioamnionitis, after controlling for antibiotic regimen, prelabor rupture of membranes duration, delivery number, body mass index, delivery week, maternal age, meconium staining, and diabetes mellitus.

Results

Ampicillin and gentamicin treatment was associated with lower rates of clinical chorioamnionitis (1/102 [1.0%] vs 8/102 [7.8%], P=.035), intrapartum fever (8/102 [8.0%] vs 18/102 [18.0%], P=.036), and overall peripartum infections (1/102 [1.0%] vs 10/102 [9.8%], P=.005). The number needed to treat to prevent 1 case of clinical chorioamnionitis was 14.7 (95% confidence interval, 10.2–27.0). The rate of the composite postpartum maternal complications was also lower in the ampicillin and gentamicin group (0/102 [0%] vs 6/102 [5.9%], P=.029). Ampicillin and gentamicin treatment was associated with lower rates of the composite neonatal adverse outcome (11/102 [10.8%] vs 22/102 [21.6%], P=.036) and sepsis workups (8/102 [7.8%] vs 18/102 [17.6%], P=.036) and a shorter median neonatal intensive care unit stay (3.0 vs 3.5 days, P=.047). The frequency of positive Enterobacteriaceae cultures in chorioamniotic swab samples was lower following ampicillin and gentamicin (17/85 [20%] vs ampicillin alone 45/89 [51%], P<.001).

Conclusion

In term prelabor rupture of membranes, ampicillin and gentamicin prophylaxis, compared to ampicillin alone, resulted in lower rates of clinical chorioamnionitis, maternal postpartum complications, and neonatal adverse outcomes. It is time to reconsider the antimicrobial prophylactic regimen in term prelabor rupture of membranes.

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Key words : ampicillin resistance, chorioamniotic membrane cultures, clinical chorioamnionitis, endometritis, Enterobacteriaceae, gentamicin, maternal infectious morbidity, neonatal outcomes, neonatal sepsis, prelabor rupture of membranes, prophylactic antibiotics

Plan

	L.L. and M.F.W. contributed equally to this work.
	The authors report no conflict of interest.
	This research study received no funding.
	The paper was presented as an oral presentation on September 26, 2024, during the SMFM 2024 Congress Meeting, at the Auditorium Parco della Musica, Rome, Italy.
	Cite this article as: Abu Shqara R, Glikman D, Goldinfeld G, et al. Ampicillin and gentamicin prophylaxis is superior to ampicillin alone in patients with prelabor rupture of membranes at term: the results of a randomized clinical trial. Am J Obstet Gynecol 2025;XXX:XX–XX.
	Reasonable requests for data that do not identify the patient will be shared by the corresponding author.
	Trial registration number: ClinicalTrials.gov identifier: NCT05469984, NCT05469984.
	Date of registration: July 22, 2022.
	Date of initial participant enrollment: November 27, 2022.