Preterm premature rupture of membranes (PROM) complicates more than 130,000 pregnancies in the United States every year and is associated with at least one third of preterm births.1 Although the latency period is inversely proportional to gestational age, 70–80% of women with preterm PROM, overall, will deliver within 1 week of membrane rupture.2 Infant morbidity in these cases is related primarily to gestational age at delivery. However, neonatal sepsis remains an important cause of morbidity and mortality at all gestational ages.
When remote from term, the fetus of a patient with preterm PROM can benefit from expectant treatment. Adjunctive treatments to reduce neonatal morbidity in this setting include tocolysis and maternal administration of corticosteroids and antibiotics. Whereas tocolysis and corticosteroid therapy are controversial, several trials of antibiotic therapy have shown prolongation of the latency period,3–12 reduction in neonatal morbidity,5,6,9,10,12,13 and decreased incidence of maternal infection.6,9,12–15
Although those trials show a benefit of antibiotic therapy, the optimal drug or combination of drugs, route of administration, and duration of therapy are yet to be determined. Because of the variety of potential pathogens colonizing the vagina (and possibly the amnion after membrane rupture), broad-spectrum antibiotics offer some theoretic advantages over more narrow-spectrum agents. A potential pitfall of broad-spectrum agents is the emergence of resistant organisms in gravidas and their neonates. To investigate this phenomenon, we reviewed the records of women treated at Shands Hospital at the University of Florida. We compared maternal infection rates, neonatal sepsis rates, and bacterial resistance rates associated with three antibiotic protocols for women with preterm PROM.
Materials and Methods
Infants at Shands Hospital at the University of Florida with positive blood cultures within the first 7 days of life from January 1, 1988 to February 28, 1998, were identified from the microbiology laboratory database. The medical records of these neonates were reviewed to identify those who had been born to mothers with preterm PROM who were treated expectantly. The charts of the mothers also were reviewed. In addition, our computerized obstetrics database was used to obtain demographic and outcome data on all patients with preterm PROM treated at our institution during that period.
Before March 1991, the protocol for patients expectantly treated for preterm PROM did not include antibiotic administration. From March 1991 until September 1993, intravenous ampicillin, 2 g every 6 hours, was administered for 48 hours, followed by oral amoxicillin, 500 mg three times daily. The protocol from October 1993 to February 1998 was intravenous ticarcillin-clavulanic acid, 3.1 g every 6 hours for 48 hours, followed by oral amoxicillin-clavulanic acid, 500 mg three times daily. During each of the latter two protocols, the oral agent was continued until the results of cervical cultures for gonorrhea and chlamydia and vaginal and perianal culture for group B streptococcus were available. If these culture results were negative, antibiotics were discontinued. Patients who tested positive for gonorrhea received a single oral dose of cefixime (400 mg), and any other antibiotic was discontinued. Patients who tested positive for chlamydia were treated with either oral erythromycin (500 mg four times daily for 7 days) or a single oral dose of azithromycin (1 g); other antibiotics were discontinued. Patients who tested positive for group B streptococci were continued on amoxicillin or amoxicillin-clavulanate for 7 days.
We measured rates of chorioamnionitis, endometritis, and neonatal sepsis. The resistance patterns of organisms causing neonatal sepsis also were compared. Statistical analysis was done using Epistat software (Epistat Services, Richardson, TX). We used the uncorrected χ2, Fisher exact, and log-likelihood ratio tests where appropriate. The log-likelihood ratio test is a way of testing a null hypothesis against an alternative hypothesis and is described elsewhere.16 The Bonferroni correction was used for multiple comparisons. For all statistical analyses, P < .05 was considered statistically significant.
During the study period, 1695 women with preterm PROM were treated at our institution. There were 465 cases during the first period, 510 received ampicillin during the second period, and 720 received ticarcillin-clavulanic acid during the third period. Demographic data are presented in Table 1. The gestational age given is the gestational age at delivery. The latency period, ie, the time from PROM to delivery, is not included in our database and is not available for this group of patients. There was a statistically significant shift toward fewer black patients, more nulliparas, and older gravidas during the study period.
Maternal infection rates and neonatal sepsis rates for each protocol period are presented in Table 2. The rate of chorioamnionitis was unaffected by antibiotic treatment. The endometritis rate progressively decreased when antibiotic treatment was implemented and when the spectrum was broadened. The rate of neonatal sepsis was halved with the addition of antibiotic treatment. The overall difference in neonatal sepsis rate between groups approached, but did not reach, statistical significance. However, when the ampicillin and ticarcillin-clavulanic acid groups were combined, the neonatal sepsis rate was significantly lower compared with the no antibiotics group (P = .04).
Also included in Table 2 are the rates of chorioamnionitis and endometritis for the different subgroups of race, parity, age, and gestational age. Similar to the total comparison, the subgroups showed no significant change in the rate of chorioamnionitis according to antibiotic treatment. The exception to this is the group of patients who were parous; they showed a statistically significant decrease in the rate of chorioamnionitis with the addition of antibiotic therapy. The decrease in the rate of endometritis during the periods when antibiotics were utilized was maintained when subgroup analysis was done for race, parity, maternal age, and gestational age. The small total number of cases of neonatal sepsis precluded subgroup analysis.
The organisms causing neonatal sepsis are presented in Table 3. Two neonates with sepsis who were born during the ticarcillin-clavulanic acid protocol were delivered to mothers with a history of penicillin allergy. Accordingly, these patients received clindamycin rather than ticarcillin-clavulanic acid. Excluding those two cases, zero of ten cases of sepsis during the no antibiotic protocol were caused by gram-negative organisms in contrast to two of three and two of six during the ampicillin and ticarcillin-clavulanic acid protocols, respectively. This overall difference is statistically significant (P = .02). Additionally, the antibiotic resistance patterns of organisms causing neonatal sepsis differed among the groups: three of ten, three of three, and three of six cases of sepsis were caused by ampicillin-resistant organisms during the no antibiotics, ampicillin, and ticarcillin-clavulanic acid protocols, respectively. The overall differences between these groups was statistically significant (P = .04). Resistance to other antibiotics was not more likely during any period. Two neonates with sepsis whose mothers received no antibiotics died. Although none of the septic neonates died during the other periods, this difference in mortality rates was not statistically significant.
The results of this study show a significantly lower rate of postpartum endometritis with antibiotic therapy for women with expectantly treated preterm PROM and a further reduction in this rate when a broader-spectrum agent was used. This result is not surprising given the polymicrobial nature of endometritis. What is surprising is that the rate of chorioamnionitis during the study period was decreased by antibiotic therapy only in the parous subgroup of patients, because both postpartum endometritis and chorioamnionitis are thought to be caused by ascension of organisms from the vagina. In any event, decreased postpartum maternal morbidity alone supports the use of broad-spectrum antibiotics for expectant treatment of preterm PROM.
There was a trend in this study toward fewer cases of neonatal sepsis when antepartum antibiotics were administered. When the antibiotic protocols collectively were compared with no antibiotics, the difference achieved statistical significance. This decrease in neonatal morbidity also supports the use of antibiotics for preterm PROM. The proportion of neonatal sepsis cases caused by gram-negative organisms and ampicillin-resistant organisms was significantly higher during the periods when antibiotics were utilized. Ampicillin resistance is important because pediatricians typically use ampicillin and gentamicin to treat neonatal sepsis, and this result represents a disadvantage of antibiotic therapy for the expectant treatment of preterm PROM.
We acknowledge that the study's time-series design spanning several years creates potential bias, especially considering the demographic differences (Table 1). The differences in treatments might have been confounded with changes in our population over time. However, when the demographic subgroups were analyzed independently, the significant decrease in endometritis with antibiotic therapy persisted. As in the overall group, there was no difference in the rate of chorioamnionitis in the subgroups over these periods, except for the parous subgroup. In that group, antibiotic therapy for expectantly treated preterm PROM was associated with a statistically significant decrease in the rate of chorio-amnionitis.
Repeat pregnancies for the same subject during the study period affected the assumption that each pregnancy is independent. However, the effect of repeat pregnancies on our results is quite small, as only 41 subjects had two pregnancies and six had three pregnancies with preterm PROM treated at our institution during the study period. Furthermore, although this rate cannot be quantified, it is possible that the intrinsic infection rate, without regard to demographic changes, might have been changing during the study period.
One concern regarding the use of broad-spectrum antibiotics is that it might predispose mothers and neonates to infection with resistant organisms. There was one case of Candida sepsis and one case of sepsis caused by an anaerobic streptococcus, both occurring in neonates whose mothers received ticarcillin-clavulanic acid. The case of yeast sepsis might have been acquired nosocomially, as the culture was obtained on day 7 of life. One question that cannot be answered by our data is whether the antibiotic resistance was the result of selection pressure in each case or in our obstetric population in general because of the increased overall use of antibiotics both for patients with preterm PROM and for those who had gonorrhea, chlamydia, bacterial vaginosis, or group B streptococcal colonization.
Although our data support the use of antibiotics to expectantly treat patients with preterm PROM, the optimal drug regimen is yet to be determined. Although we agree with others17 that the most narrow-spectrum agents possible should be used for prophylaxis, more broad-spectrum regimens could benefit patients with preterm PROM. In this study at least, a broad-spectrum agent was not associated with adverse sequelae. Although the proportion of gram-negative and ampicillin-resistant organisms causing neonatal sepsis increased with antibiotic administration, the percentage relative to preterm PROM cases remained relatively the same. Further research evaluating the nature of the organisms causing neonatal sepsis with preterm PROM is warranted.
1. Meis PJ, Ernest JM, Moore ML. Causes of low birth weight births in public and private patients. Am J Obstet Gynecol 1987;156:1165–8.
2. Mercer BM. Antibiotic therapy for preterm premature rupture of membranes. Clin Obstet Gynecol 1998;41:461–8.
3. Mercer BM, Moretti ML, Prevost RR, Sibai BM. Erythromycin therapy in preterm premature rupture of the membranes: A prospective, randomized trial of 220 patients. Am J Obstet Gynecol 1992;166:794–802.
4. McGregor JA, French JI, Seo K. Antimicrobial therapy in preterm premature rupture of membranes: Results of a prospective, double-blind, placebo-controlled trial of erythromycin. Am J Obstet Gynecol 1991;165:632–40.
5. Amon E, Lewis SV, Sibai BM, Villar MA, Arheart KL. Ampicillin prophylaxis in preterm premature rupture of the membranes: A prospective randomized study. Am J Obstet Gynecol 1988;159:539–43.
6. Owen J, Groome LJ, Hauth JC. Randomized trial of prophylactic antibiotic therapy after preterm amnion rupture. Am J Obstet Gynecol 1993;169:976–81.
7. McCaul JF, Perry KG, Moore JL, Martin RW, Bucovaz ET, Morrison JC. Adjunctive antibiotic treatment of women with preterm rupture of membranes or preterm labor. Int J Gynecol Obstet 1992;38:19–24.
8. Lockwood CJ, Costigan K, Ghidini A, Wein R, Chien D, Brown BL, et al. Double-blind, placebo-controlled trial of piperacillin prophylaxis in preterm membrane rupture. Am J Obstet Gynecol 1993; 169:970–6.
9. Johnston MM, Sanchez-Ramos L, Vaughn AJ, Todd MW, Benrubi GI. Antibiotic therapy in preterm premature rupture of membranes: A randomized, prospective, double-blind trial. Am J Obstet Gynecol 1990;163:743–7.
10. Lovett SM, Weiss JD, Diogo MJ, Williams PT, Garite TJ. A prospective, double-blind, randomized, controlled clinical trial of ampicillin-sulbactam for preterm premature rupture of membranes in women receiving antenatal corticosteroid therapy. Am J Obstet Gynecol 1997;176:1030–8.
11. Christmas JT, Cox SM, Andrews W, Dax J, Leveno KJ, Gilstrap LC. Expectant management of preterm ruptured membranes: Effects of antimicrobial therapy. Obstet Gynecol 1992;80:759–62.
12. Mercer BM, Miodovnik M, Thurnau GR, Goldenberg RL, Das AF, Ramsey RD, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes: A randomized controlled trial. JAMA 1997;278:989–95.
13. Morales WJ, Angel JL, O'Brien WF, Knuppel RA. Use of ampicillin and corticosteroids in premature rupture of membranes: A randomized study. Obstet Gynecol 1989;73:721–6.
14. Ernest JM, Givner LB. A prospective, randomized, placebo-controlled trial of penicillin in preterm premature rupture of membranes. Am J Obstet Gynecol 1994;170:516–21.
15. Kurki T, Hallman M, Zilliacus R, Teramo K, Ylikorkala O. Premature rupture of the membranes: Effect of penicillin prophylaxis and long-term outcome of the children. Am J Perinatol 1992;9:11–6.
16. Agresti A. Inference for two-way contingency tables. In: Agresti A. Categorical data analysis. New York: John Wiley & Sons, 1990:36–78.
17. Towers CV, Carr MH, Padilla G, Asrat T. Potential consequences of widespread antepartal use of ampicillin. Am J Obstet Gynecol 1998;179:879–83.