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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Florida Health Science Center, Jacksonville, Florida.
Address reprint requests to: Luis Sanchez-Ramos, MD, Department of Obstetrics and Gynecology, University of Florida Health Science Center, 653-1 West 8th Street, Jacksonville, FL 32209; E-mail: luis.sanchez{at}jax.ufl.edu.
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ABSTRACT |
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METHODS: This double-masked, placebo-controlled randomized trial included patients of at least 24 weeks’ gestation undergoing cesarean deliveries for various indications. Patients were randomized to receive either 5 g of metronidazole gel intravaginally or matching placebo before the initiation of the cesarean. All patients underwent surgical cleansing of the abdomen, and most received prophylactic antibiotics after cord clamping. Patients with chorioamnionitis and/or suspected allergy to metronidazole were excluded. For a two-sided 
of 0.05 and ß of 0.20 (80% power), 120 subjects were required in each group. The main outcome variable was the incidence of postcesarean endometritis. Secondary outcome variables included presence of febrile morbidity, wound infection, days on antibiotics, and length of postpartum hospitalization. Neonatal outcomes included birth weight, Apgar scores less than 7 at 5 minutes, umbilical arterial pH less than 7.16, admission and length of stay in the neonatal intensive care unit, and length of hospital stay.
RESULTS: Of 112 patients receiving metronidazole, eight (7%) developed postcesarean endometritis, compared with 19 of 112 (17%) of those receiving placebo gel (relative risk 0.42, 95% confidence interval 0.19, 0.92). No significant differences were noted between treatment groups with respect to the other outcome variables.
CONCLUSION: The preoperative administration of 5 g of intravaginal metronidazole gel appears to reduce the incidence of postcesarean endometritis.
Peripartal maternal infections represent common complications of childbirth. The morbidity associated with such infections often leads to increased length of hospital stay, multiple antimicrobial drug use, and increased costs.1,2 These infections include, but are not limited to, intrapartum amnionitis, postpartum endometritis, and wound and urinary tract infections. The incidence of postcesarean endometritis ranges from as low as 5% to as high as 85%, depending on the practice setting and the patient population.3,4 This broad range makes it difficult to identify risk factors responsible for the infectious process.
Hawrylshyn et al showed that the infection rates for endometritis varied by mode of delivery: vaginal, 3.6%; elective repeat cesarean delivery, 6.0%; nonurgent primary cesarean delivery, 22.2%; and emergency cesarean, 38.4%.5 To reduce the incidence of endometritis, antibiotic prophylaxis at the time of cesarean delivery has become a common practice. The incidence of post-cesarean infection is 30–35% without antibiotic prophylaxis and 15–20% with prophylaxis.6,7 Our challenge as obstetricians is to further reduce the occurrence of this common cause of postpartum morbidity. Currently, the standard of care is to administer a first-generation cephalosporin intraoperatively, after cord clamping. This strategy may not provide optimal anaerobic coverage. Moreover, this approach differs from prophylaxis used in other major gynecologic procedures, where antimicrobials are given before the initiation of the procedure. Thus, it becomes important to better understand risk factors, limit exposure to infectious organisms, and discover which antimicrobials work best to prevent disease and when they should be given.
Endometritis appears to result from ascending vaginal flora bacteria, with anaerobes playing an important role. The microbes endogenous to the vagina change throughout the course of pregnancy and parturition. Larsen and Galask8 noted that anaerobic species located in the vagina increase dramatically by the third postpartum day. In addition, women with bacterial vaginosis diagnosed by Gram stain criteria are six times more likely to develop postpartum endometritis after cesarean delivery.9
When metronidazole was used as the sole agent in treating culture-proven, anaerobically driven endometritis, a clinical cure was achieved at a rate of 84%.10 A recent study of intravaginal 0.75% metronidazole gel resulted in a clinical cure in 87% of women with bacterial vaginosis.11 These observations suggest that local administration of metronidazole before delivery might reduce the prevalence of vaginal anaerobes, thereby reducing the incidence of postpartum endometritis. The objective of this randomized, double-masked, placebo-controlled clinical trial was to assess whether preoperative administration of vaginal metronidazole gel reduces the incidence of postcesarean endometritis.
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MATERIALS AND METHODS |
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Of 261 women randomized, 224 had outcomes assessed (Figure 1
). Subjects randomized to the treatment group received one 5-g application of metronidazole gel (0.75%) administered intravaginally; the placebo group received a similar amount of placebo gel. A single 5-g dose of 0.75% metronidazole gel contains 37.5 mg of metronidazole. The clinically indistinguishable intravaginal metronidazole gel and placebo were prepared by the hospital pharmacy and maintained in the labor and delivery suite. The randomization order was generated through a computer program and the medications maintained in serially numbered sealed bags in the labor and delivery area. After enrollment of each subject, these bags were opened in sequential order. Resident physicians in obstetrics and gynecology performed the enrollment of patients, administration of intravaginal gel, cesarean delivery, and postpartum care.
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The primary study outcome was postcesarean endometritis, defined as an oral temperature 38C or greater on any 2 postoperative days (excluding the first 24 hours after delivery). In addition, the diagnosis required at least one of the following signs: uterine tenderness to palpation, maternal tachycardia (at least 100 beats/minute), foul-smelling vaginal discharge, or maternal leukocytosis (greater than 12,000/mm3). Other maternal outcomes assessed included febrile morbidity, presence of wound infection, sepsis (positive blood cultures), length of hospital stay, and number of days on antibiotics. Febrile morbidity was defined as a persistent fever of at least 38C for at least 24 hours after surgery and not associated with lower abdominal or pelvic tenderness and no signs of infection elsewhere. Wound infection was diagnosed when a wound drained purulent material or serosanguineous fluid, associated with induration, warmth, and tenderness. Neonatal outcomes including need for admission to the neonatal intensive care unit, Apgar score less than 7 at 5 minutes, umbilical cord pH less than 7.16, birth weight, and hospital length of stay were obtained by reviewing each newborn’s medical record.
Based on previously published collected information from our institution,12 we estimated that the placebo group would have a postcesarean endometritis rate of 30% and reasoned that a 50% reduction in this rate would be clinically significant (30–15%). For a two-sided of 0.05 and ß of 0.20 (80% power), a sample size of 120 patients in each group would be required.
Statistical analysis was performed on an intention-to-treat basis and was conducted with the use of Statview 4.0 (Abacus Concepts, Berkeley, CA). The unpaired Student t or Mann-Whitney U tests, as indicated, analyzed continuous variables. Dichotomous variables were analyzed by Fisher exact test or 
2 analyses. We also calculated relative risks and 95% confidence intervals for certain rates or proportions. A P value of <.05 was considered statistically significant.
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RESULTS |
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). Although no patient was left out intentionally, some patients were not included secondary to failure to obtain informed consent, refusal to participate, or the urgent nature of surgery for fetal heart rate abnormalities.
The treatment groups did not significantly differ with respect to age, weight, height, body mass index, race, gravidity, or gestational age at delivery (Table 1). In addition, the groups were similar with respect to presence of diabetes, human immunodeficiency virus, and group B streptococcus carrier status. Likewise, the two groups did not differ significantly as to whether labor occurred before delivery and, if so, whether it was spontaneous, augmented, or induced. The groups were likewise comparable with respect to number of digital examinations, time between first examination and delivery, status of membranes on admission, presence of fever or antibiotic treatment during labor, prolonged rupture of membranes greater than 12 hours, and meconium fluid characteristics (Table 2). The two groups were similar with respect to indication for cesarean, type of cesarean, type of anesthesia, associated tubal ligation, and antibiotic prophylaxis (Tables 3A and 3B).
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DISCUSSION |
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Previous studies have employed local vaginal irrigation or solutions with the aim of reducing the rate of postpartum infectious morbidity.13–16 Vaginal solutions of chlorhexidine gluconate and povidone-iodine have been shown to markedly decrease the total number of aerobes and anaerobes in the vagina. Studies of the use of these agents before cesarean delivery have had mixed results in reducing postcesarean infectious morbidity.13,14 Several studies have shown that chlorhexidine significantly reduces peripartum infectious morbidity (chorioamnionitis and/or endometritis); however, the timing of the vaginal douche with this agent varied among studies.15,16 In a placebo-controlled randomized trial, 1024 patients were enrolled and allocated to receive a single 200-mL irrigation of 0.2% chlorhexidine or sterile water. Although a nonsignificant reduction in peripartal infections after cesarean delivery was noted, the use of chlorhexidine lacked efficacy in the overall prevention of maternal peripartal infection.13 More recently, Reid et al,14 in a randomized trial, concluded that administration of a vaginal preparation of povidone-iodine before cesarean had no effect on the incidence of postoperative fever, endometritis, or wound infection. These vaginal preparations appear to have limited effect on anaerobic vaginal flora.
Metronidazole, administered intravenously or rectally, has been used as a prophylactic agent for postcesarean endometritis and wound infection with mixed results.17–22 Vaughn,17 in a nonmasked study, showed a significant reduction of wound sepsis and endometritis with intravenous metronidazole with or without cephadrine compared with placebo. In that study, 500-mg metronidazole was given preoperatively followed by three additional 8-hourly doses postoperatively. In two similar randomized clinical trials, Gerstner et al18 and Ruiz-Moreno et al19 showed that intravenously administered metronidazole significantly reduced postcesarean endometritis, wound infection, and overall postoperative febrile morbidity. In contrast, Gummerus,20 in a randomized, placebo-controlled trial, was unable to show a significant reduction in overall infectious morbidity after the perioperative intravenous infusion of 500-mg metronidazole. It appears that a single 500-mg dose of metronidazole affords inadequate anaerobic suppression for the prevention of endometritis.
Two trials assessed the efficacy of rectally administered metronidazole in preventing postcesarean endometritis. DeBoer and Thornton21 randomized 182 subjects to receive two 1-g doses of metronidazole rectal suppositories or matching placebo. The initial metronidazole dose was administered 10–45 minutes before starting the cesarean; the second dose was administered 8 hours later. Patients allocated to receive metronidazole had a significant reduction in wound infection, febrile morbidity, and length of hospitalization. Interestingly, in a non-randomized trial, Rosler and Kulz22 were unable to show a reduction in postcesarean infectious morbidity in 96 patients who received 2.5 g of metronidazole rectal suppositories. In several of the trials showing benefit, metronidazole was administered before the start of the surgical procedure, and in most cases, multiple doses were administered. The current study found that a single 5-g vaginal dose, administered before starting the cesarean delivery, is effective in reducing postcesarean endometritis.
We wish to clarify that the dominant antibacterial effect of metronidazole vaginal gel is local. The mean peak serum concentration after intravaginal administration of a single 5-g dose of metronidazole gel is less than 2% of that achieved after a single 500-mg oral dose.23
The reduction in the risk of postcesarean endometritis with intravaginal metronidazole gel was more robust than the reduction noted with other infectious outcomes, underscoring the local effect of the gel. Consistent with similar studies,13,15,16 we did not include atelectasis or pneumonia as outcomes. Our primary finding was that intravaginal metronidazole gel reduced the incidence of postcesarean endometritis, minimizing the impact of this omission.
There are several limitations to our study and the application of the study drugs in patients undergoing cesarean delivery. Approximately two-thirds of cesarean delivery patients meeting inclusion criteria were not approached and therefore not randomized into this study. This proportion of missed patients is similar to that noted in other recently published randomized controlled trials of topical agents for the prevention of postpartum infection.13,14 This underscores the challenges faced by investigators performing interventional studies in intrapartum patients. Because our study was not funded, the investigators relied entirely on the initiative of housestaff, faculty physicians, and nursing personnel, all of whom faced numerous competing responsibilities. Neither demographic or outcome data were collected on eligible candidates not approached for this study.
Intravaginal placement of prophylactic agents is not always feasible, especially in cases where emergency intervention is required. In addition, the time interval from placement of the agent to time of delivery was difficult to control, as some cesareans were performed as an emergency and others experienced delays secondary to physician, nursing, or anesthesia availability. Unfortunately, this interval was not consistently documented.
Some subjects did not receive intravenous antibiotic prophylaxis at the time of cord clamping. Results of a subanalysis limited to these participants did not differ from our overall findings.
The vaginal/cervical epithelial surface coated by the gel may vary. Arrest of descent at a low station, for instance, may reduce the surface area to which the gel may be applied. However, such factors are unlikely to have impacted our results because the distribution of indications for cesarean delivery was similar in both treatment groups. Finally, it is common practice at our institution to place manual pressure on the uterine fundus to expel clots after completion of a cesarean delivery. Although this practice may reduce gel absorption, its occurrence should have been evenly distributed between the two study groups.
Although our study population represented a group of patients heterogeneous with respect to risk of postcesarean endometritis, we found that use of intravaginal metronidazole gel significantly reduced the risk of this outcome. A recent systematic overview concluded that the prophylactic use of antibiotics reduces the risk of post-cesarean endometritis even in the population at lowest risk.24
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Footnotes |
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Received February 13, 2001. Received in revised form June 12, 2001. Accepted June 21, 2001.
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REFERENCES |
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2. Henderson E, Love EJ. Incidence of hospital-acquired infections associated with caesarean section. J Hosp Infect 1995;29:245–55.[Medline]
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7. Polk BF. Antimicrobial prophylaxis to prevent mixed bacterial infection. J Antimicrob Chemother 1981;8:115–29.
8. Larsen B, Galask RP. Vaginal microbial flora: Practical and theoretic relevance. Obstet Gynecol 1980;55: 100s–13s.[Medline]
9. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. Bacterial vaginosis as a risk factor for post-cesarean endometritis. Obstet Gynecol 1990;75:52–8.
10. Platt LD, Yonekura ML, Ledger WJ. The role of anaerobic bacteria in postpartum endomyometritis. Am J Obstet Gynecol 1979;135:814–7.[Medline]
11. Hillier SL, Lipinski C, Briselden AM, Eschenbach DA. Efficacy of intravaginal 0.75% metronidazole gel for the treatment of bacterial vaginosis. Obstet Gynecol 1993;81: 963–7.
12. Probst J, Benrubi GI, Sanchez-Ramos L, Todd M. Comparison of one dose cefazolin versus one dose cefotetan for cesarean section prophylaxis. J Fla Med Assoc 1989;76: 1027–9.
13. Rouse DJ, Hauth JC, Andrews WW, Mills BB, Maher JE. Chlorhexidine vaginal irrigation for the prevention of peripartal infection: A placebo-controlled randomized clinical trial. Am J Obstet Gynecol 1997;176:617–22.[Medline]
14. Reid VC, Hartmann KE, McMahon M, Fry EP. Vaginal preparation with povidone iodine and postcesarean infectious morbidity: A randomized controlled trial. Obstet Gynecol 2001;97:147–52.
15. Stray-Pedersen B, Bergan T, Hafstad A, Normann E, Grogaard J, Vangdal M. Vaginal disinfection with chlorhexidine during childbirth. Int J Antimicrob Agents 1999; 12:245–51.[Medline]
16. Sweeten KM, Eriksen NL, Blanco JD. Chlorhexidine versus sterile water vaginal wash during labor to prevent peripartum infection. Am J Obstet Gynecol 1997;176: 426–30.[Medline]
17. Vaughn JE. Comparison of metronidazole and cephadrine in the prevention of wound sepsis following caeserean section. Roy Soc Med Int Congr Symp Ser 1979;18:203–5.
18. Gerstner G, Kofler E, Huber J. Perioperative metronidazole prophylaxis for cesarean section. Z Geburtshilfe Perinatol 1980;184:418–23.[Medline]
19. Ruiz-Moreno JA, Garcia-Rojas JM, Lozada-Leon JD. Prevention of postcesarean infectious morbidity with a single dose of intravenous metronidazole. Int J Gynaecol Obstet 1991;34:217–20.[Medline]
20. Gummerus M. Perioperative short-term prevention of puerperal infections following cesarean section with metronidazole. Geburtshilfe Frauenheilkd 1984;44:570–2.[Medline]
21. DeBoer CN, Thornton JG. Prophylactic short course rectal metronidazole for cesarean section. A double-blind controlled trial of a simple low cost regimen. Int J Gynaecol Obstet 1989;28:103–7.[Medline]
22. Rosler EM, Kulz T. Perioperative chemoprevention with metronidazole in cesarean section. Zentralbl Gynakol 1986;108:1066–9.[Medline]
23. Cunningham FE, Kraus DM, Brubaker L, Fischer JH. Pharmacokinetics of intravaginal metronidazole gel. J Clin Pharmacol 1994;34:1060–5.[Abstract]
24. Chelmow D, Ruehli MS, Huang E. Prophylactic use of antibiotics for nonlaboring patients undergoing cesarean delivery with intact membranes: A meta-analysis. Am J Obstet Gynecol 2001;184:656–61.[Medline]
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