Comparison of Two Antibiotic Prophylactic Protocols in Preterm Premature Rupture of the Membranes

Premature Rupture of Membrane Clinical Trial

Official title:

Comparison of Two Antibiotic Prophylactic Protocols in Preterm Premature Rupture of the Membranes. A Randomized Prospective, Open Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02819570
• Other study ID #: 0149-15-NHR
• Status: Recruiting
• Phase: Phase 4
• First received: June 2, 2016
• Last updated: December 28, 2016
• Start date: November 2015
• Est. completion date: December 2017

Study information

• Verified date: December 2016
• Source: Western Galilee Hospital-Nahariya
• Contact: Maya Wolf, MD
• Phone: 972-507887800
• Email: homesickid[@]yahoo.com
• Is FDA regulated: No
• Health authority: Israel: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The objective of the study is to compare a new antibiotic protocol with the current prophylactic treatment in routine use and to evaluate obstetric and neonatal outcome: preterm labor, chorioamnionitis and early onset sepsis

Description:

Preterm premature rupture of membranes (PPROM) occurs in approximately 3% of all pregnancies and is associated with approximately one-third of preterm births. The incidence of chorioamnionitis in women with premature rupture of membranes (PROM) at < 27, 28 to 36, and > 37weeks' gestation is 41, 15, and 2%, respectively. Intra-amniotic infection is usually polymicrobial, comprised vaginal or enteric flora including aerobic and anaerobic bacteria and atypical agents, such as Mycoplasma. Group B streptococcus (GBS) has been a frequent pathogen. The American College of Obstetricians and Gynecologists approach to PPROM consists of recommending induction of labor in all women > 34 weeks' gestation. In the absence of intrauterine infection, placental abruption or non-reassuring fetal heart rate, management of women with PPROM < 34 weeks consists of hospitalization from the time of diagnosis until delivery, administration of antenatal corticosteroids, and a 7-day course of antibiotic prophylactic therapy to prolong the latency period. Antibiotic therapy has been associated with significant reductions in chorioamnionitis, deliveries within 48 hours, and early-onset (within 3 days of delivery) neonatal sepsis (EOS). The antibiotic regimen in PPROM usually consists of ampicillin intravenously for 48 hours, followed by oral amoxicillin for 5 days (specifically targeting GBS), and a macrolide targeting atypical agents.

An increase in EOS due to gram negative Enterobacteriaceae have been reported lately with a relative decrease in GBS related EOS . These data may have an impact on the antibiotic regimen used for PPROM. The Local pathogens distribution in cases of EOS and their antibiotic sensitivity profiles in Northern Israel have been explored in a multicenter study There were 27 neonates diagnosed with EOS with positive blood cultures. Aerobic Enterobacteriaceae accounted for 14 cases (52%) and group B streptococcus for 7 cases (26%). Of the Escherichia coli and Klebsiella sp.,only 38% were sensitive to ampicillin. As a result the most effective antibiotic protocol to cover those pathogens is required. The purpose of the current study is to compare a new antibiotic protocol with the current prophylactic treatment in use and to evaluate pregnancy and neonatal outcome.

The diagnosis of preterm premature rupture of membranes (PPROM) is clinical, and is based on visualization of amniotic fluid in the vagina of a woman who presents with a history of leaking fluid. Laboratory tests as "Amniosure" can be used to confirm the clinical diagnosis when it is uncertain.

Women who meet the study criteria and have signed inform consent will be randomly divided in two groups to receive prophylactic antibiotic treatment as follow:

1. I.V ampicillin 2 gram x4/d for 2 days followed by P.O moxypen 500 mgx3/d for additional 5 days+ P.O roxithromycin 150 mg*2/d for 7 days

2. I.V cefuroxime 750 mg*3/d for 2days followed by P.O cefuroxime 500 mgx2/d + P.O roxithromycin 150 mg*2/d for 7 days

A course of corticosteroids will be given to all women participating in the study

Expectant management:

1. Vital signs *3/day

2. Uterine tenderness evaluation

3. Complete Blood Count + C-reactive protein every second day

4. Urine culture and GBS recto-vaginal swab

5. Fetal heart monitoring*6 /d

6. Sonography evaluation every 2-3 days

7. Vaginal swab once a week

8. Fetal movements follow up

Labor induction will be conducted at 34 weeks of gestation If chorioamnionitis is suspected amniocentesis should be considered or expeditious delivery

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: December 2017
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• Women with PPROM between 24+0 and 34+0 weeks of gestation who are suitable for conservative management

Exclusion Criteria:

• P-PROM>34 weeks of gestation

• Suspected fetal distress or chorioamnionitis

• Active labor

• Drug allergy to one of the study regiments

• Immune deficiency

• Multiple pregnancy

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Fetal Membranes, Premature Rupture
• Premature Birth
• Premature Rupture of Membrane
• Rupture

Intervention

Drug:
• I.V cefuroxime 750 mg*3/d for 2 days

• I.V ampicillin 2 gram x4/d for 2 days

• P.O cefuroxime 500 mgx2/d for 5 days

• P.O roxithromycin 150 mg*2/d for 7 days

• P.O moxypen 500 mgx3/d for 5 days

Locations

Country	Name	City	State
Israel	Galil Medical Center	Nahariyya

Sponsors (1)

Lead Sponsor	Collaborator
Western Galilee Hospital-Nahariya

Country where clinical trial is conducted

Israel, 

References & Publications (13)

Carlan SJ, O'Brien WF, Parsons MT, Lense JJ. Preterm premature rupture of membranes: a randomized study of home versus hospital management. Obstet Gynecol. 1993 Jan;81(1):61-4. — View Citation

Grigsby PL, Novy MJ, Sadowsky DW, Morgan TK, Long M, Acosta E, Duffy LB, Waites KB. Maternal azithromycin therapy for Ureaplasma intraamniotic infection delays preterm delivery and reduces fetal lung injury in a primate model. Am J Obstet Gynecol. 2012 Dec;207(6):475.e1-475.e14. doi: 10.1016/j.ajog.2012.10.871. — View Citation

Harding JE, Pang J, Knight DB, Liggins GC. Do antenatal corticosteroids help in the setting of preterm rupture of membranes? Am J Obstet Gynecol. 2001 Jan;184(2):131-9. — View Citation

Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev. 2013 Dec 2;(12):CD001058. doi: 10.1002/14651858.CD001058.pub3. Review. — View Citation

Mercer BM, Miodovnik M, Thurnau GR, Goldenberg RL, Das AF, Ramsey RD, Rabello YA, Meis PJ, Moawad AH, Iams JD, Van Dorsten JP, Paul RH, Bottoms SF, Merenstein G, Thom EA, Roberts JM, McNellis D. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. A randomized controlled trial. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. JAMA. 1997 Sep 24;278(12):989-95. — View Citation

Mercer BM. Preterm premature rupture of the membranes: current approaches to evaluation and management. Obstet Gynecol Clin North Am. 2005 Sep;32(3):411-28. Review. — View Citation

Newton ER. Chorioamnionitis and intraamniotic infection. Clin Obstet Gynecol. 1993 Dec;36(4):795-808. Review. — View Citation

Practice bulletins No. 139: premature rupture of membranes. Obstet Gynecol. 2013 Oct;122(4):918-30. doi: 10.1097/01.AOG.0000435415.21944.8f. — View Citation

Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004454. Review. — View Citation

Sperling RS, Newton E, Gibbs RS. Intraamniotic infection in low-birth-weight infants. J Infect Dis. 1988 Jan;157(1):113-7. — View Citation

Turnbull DA, Wilkinson C, Gerard K, Shanahan M, Ryan P, Griffith EC, Kruzins G, Stamp GE. Clinical, psychosocial, and economic effects of antenatal day care for three medical complications of pregnancy: a randomised controlled trial of 395 women. Lancet. 2004 Apr 3;363(9415):1104-9. — View Citation

Wolf MF, Miron D, Peleg D, Rechnitzer H, Portnov I, Salim R, Keness Y, Reich D, Ami MB, Peretz A, Koshnir A, Shachar IB. Reconsidering the Current Preterm Premature Rupture of Membranes Antibiotic Prophylactic Protocol. Am J Perinatol. 2015 Nov;32(13):1247-50. doi: 10.1055/s-0035-1552935. — View Citation

Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC).. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010 Dec 17;59(RR-12):1-110. Erratum in: MMWR Recomm Rep. 2011 Jan 14;60(1):18. Dosage error in article text. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of participants with adverse events as assessed by umbilical cord acid-based analysis<7	cord ph analysis at delivery (units of moles per liter)	at delivery	No
Other	Neonatal intensive care unit (NICU) admission duration	days from admission until rerelease from NICU assessed up to 6 month	days since delivery until rerelease from NICU, assessed up to 6 month	No
Primary	EARLY NEONATAL SEPSIS - positive blood culture	Number of Participants with early neonatal sepsis	within 3 days of delivery	No
Primary	latency period	time in days	from date of randomization until the date of delivery assessed up to 10 weeks	No
Primary	Chorioamnionitis rate	rate of positive cultures	from day of randomization until date of clinical/laboratory chorioamnionitis diagnosis assessed up to 10 weeks	No
Secondary	Neonatal weight	grams	at delivery	No
Secondary	Apgar score	score from 0 to 10	1 minute 5 minute	No