Antimicrobial therapy in expectant management of preterm premature rupture of the membranes

therapy in expectant management of preterm premature rupture of the membranes

Antimicrobial

Summary

Introduction

We review the impact of antimicrobial treatment on maternal and fetal outcome during expectant management of preterm premature rupture of the membranes. Relevant studies were retrieved from Medline (1966 to August, 1994) with the search term fetal-membrane-prematurerupture and antibiotics or antimicrobial, Excerpta Medica (1972 to August, 1994) with the search term premature fetus, membrane rupture, and antibiotic or antimicrobial therapy, and the Cochrane database of systemic reviews with the criterion antibiotics and prelabour rupture of membranes. We also obtained unpublished data from a randomised clinical trial of ceftizoxime versus placebo. The selected studies were randomised controlled trials of systemic antimicrobial therapy for prolongation of gestation in non-labouring women after preterm premature rupture of the membranes. Data extraction was done by a single reviewer. Studies were evaluated for postrandomisation exclusion and other confounding variables that might introduce analytical bias. Analysis was done with SAS statistical software by a blinded investigator. Antimicrobial therapy after preterm premature rupture of the membranes is associated with a reduced number of women delivering within 1 week (62 vs 76%; OR 0·51, 95% Cl 0·41-0·68), and reduced diagnosis of maternal morbidity including chorioamnionitis (12 vs 23%; 0·45, 0·33-0·60) and postpartum infection (8 vs 12%; 0·63, 0·41-0·97). Fetal morbidity, including confirmed sepsis (5

Premature rupture of the membranes before 37 weeks’ gestation (pPROM) puts.both the mother and her unborn child at risk. Accounting for about one-third of all preterm births, pPROM is associated with short latency and frequent infectious morbidity. Although the cause of pPROM is multifactorial, infection appears to have an important role. 18 Placentitis and chorioamnionitis have been associated with prematurity and pPROM, and are

vs

9%; 0·57, 0·36-0·88), pneumonia (1

vs

3%; 0·32,

0·11-0·96), and intraventricular haemorrhage (9 vs 14%; 0·65, 0·45-0·92) were less often diagnosed after antimicrobial therapy. Separate analysis of the six placebocontrolled trials revealed similar or improved odds of pregnancy prolongation, chorioamnionitis, neonatal sepsis, postpartum infection, positive infant blood cultures, and pneumonia. Antimicrobial

when

used

in

the expectant therapy, management of preterm premature rupture of the membranes is associated with prolongation of pregnancy and a reduction in the diagnosis of maternal and infant morbidity. Further study should be directed towards determination of optimal antimicrobial therapy, increasing and enhancement of pregnancy prolongation, corticosteroid therapy for induction of pulmonary maturity after preterm premature rupture of the membranes.

Lancet 1995; 346: 1271-79 Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology (B M Mercer MD), and Division of Biostatistics, Department of Preventive Medicine (K L Arheart EdD), University of Tennessee, Memphis, Tennessee, USA

Correspondence to: Dr Brian M Mercer, E H Crump Women’s Hospital, Room E102, 853 Jefferson Avenue, Memphis, TN 38103, USA

frequently seen in pregnancies delivering before term. ‘-3 Ascending infection may result in weakening of the amniotic membranes and subclinical contractions leading to pPROM, or may occur secondary to membrane rupture. Ascending infection may lead to occult deciduitis, frank intra-amniotic infection, or fetal infection including pneumonia and bacteraemia. Unfortunately, risk assessment protocols have not been sensitive in the prediction or prevention of prematurity due to spontaneous preterm labour and pPROM.6,9 Because it is not possible to identify accurately patients destined to develop pPROM, attention has focused on the management of women subsequent to this complication. Isolated case reports suggest that antimicrobial therapy might be useful in treating intrauterine infection after pPROM."," However, such treatment has not been evaluated prospectively. Over the past 3 decades, a number of clinical trials have evaluated antimicrobial therapy in the management of pPROM. The purpose of this review is to study the available prospective clinical trials with regard to the impact of antimicrobial treatment and fetal outcome during expectant management of more

pPROM. Methods In August, 1994, a literature search was done to identify all published clinical trials that evaluated the use of antimicrobial agents to improve pregnancy outcome after pPROM. Three databases were searched. Medline was searched for all years from 1966 to present with the search term fetal-membrane-prematurerupture and antibiotics or antimicrobial. A similar search was done of Excerpta Medica (Embase) from 1972 to the present, with the search term premature fetus, membrane rupture, and antibiotic or antimicrobial therapy. Third, the Cochrane database of systemic reviews was searched for antibiotics and prelabour rupture of membranes." Finally, references of all reviewed articles were screened for additional relevant articles, and we attempted to obtain information from two unpublished trials. 13,14 Only randomised controlled clinical trials of women receiving systemic antimicrobial therapy after the onset of pPROM were included for the purpose of statistical analysis. To obtain the most homogeneous group of studies possible, only those studies in which the authors intended to pursue a course destined to prolong the gestation (ie, expectant management) were included. Studies that included women with PROM at term (S=37 weeks’ gestation) but did not sub-analyse those with pPROM were excluded from further analysis. Additionally, studies that enrolled women who were in labour, and those in which intrapartum antimicrobial treatment was given solely for group B streptococcus prophylaxis, were excluded. Studies that

1271

demonstrated

NK=not known *Placebo controlled.

tGroup B streptococcus. *Included m factonal design. clinical trials of antimicrobial prospective therapy after pPROM

IV/]M=intravenous/intramuscular, Table: Evaluated

bias-such as those that used ill-defined study outcomes, excessive postretrospective controls, randomisation exclusion (>15%), and confounding treatments to one applied only study group-were excluded from further reasons for trial exclusion are presented in the analysis. Explicit results section. The evaluated maternal morbidities included latency, chorioamnionitis, caesarean section, and postpartum febrile morbidity. Fetal and infant outcomes included stillbirth, birthweight, respiratory distress, intraventricular haemorrhage, necrotising enterocolitis, proven sepsis, group B streptococcal sepsis, positive blood cultures, pneumonia, infant death, death from sepsis, and overall survival. All enrolled mothers were included in analysis denominators regardless of whether they were subsequently lost to follow-up. Stillbirths and overall infant survival were calculated based on the total number of fetuses present at the time of study enrolment. All live births were included in the analysis when specific infant morbidities were evaluated. Data abstraction was done by a single author (BM) with a computerised data-collection form. Entered data was subsequently exported to SAS statistical software for analysis. Statistical analysis included descriptive statistics and odds ratio with 95% confidence intervals for individual studies. The MantelHaenszel test and weighted 95% CIs were calculated to compare outcomes between treatment and control groups. The MantelHaenszel test for heterogeneity of odds ratios was used to evaluate variability in outcomes between the clinical trials.

potential

Results 24 clinical trials of antimicrobial therapy for pPROM identified. 11of these studies were excluded from

were

further

1272

analysis.

Excluded trials A large multicentre placebo-controlled trial by Lebherz et al’S that evaluated dechlormethyltetracycline after preterm and term PROM was excluded. The population was analysed based on a birthweight limit of 2500 g rather than on gestational age at membrane rupture. This procedure introduced evaluation bias since those with pPROM who had prolonged latency after treatment might have been included in the term group, negating a potential fetal or neonatal benefit in the preterm group.

Additionally, tetracyclines are no longer used in obstetric practice due to potential adverse fetal effects. A placebo controlled study of Brelje et al’6 was excluded because local therapy with nitrofurazone vaginal suppositories (6 mg every 6 h) was studied in term and preterm pregnancies. No systemic treatment was given. In 1976, Huff" conducted a prospective evaluation of penicillin and kanamycin therapy after PROM. This nonrandomised study allowed enrolment of labouring patients and used retrospective controls. Two studies published by Fortunato et al‘S°’9 also used retrospective controls. A study of 47 women by Norri et ap4 identified no maternal or fetal benefit with antimicrobial therapy (750 mg kefuroxin intramuscular plus 400 mg metronidazole taken orally three times daily for 3 days) compared with controls. However, the published abstract provided insufficient data for analysis of the evaluated variables and further information could be obtained. In 1992, McCaul et a 121 published a prospective placebo controlled study of intravenous and oral ampicillin therapy for 7

no

Figure 2: Impact

on

chorioamnionitis of antimicrobial therapy after pPROM

with pPROM were evaluated after 26 excluded for positive cultures, steroid or tocolytic use, and 12 were excluded for not taking all of their medications. This study was excluded because of excessive post-randomisation exclusion (38/122, 31-2%). Matsuda et aPI,22 published two papers describing unblinded ampicillin therapy. The second publication seems to be an expansion of the original study rather than a separate trial. The trial is confounded by the use of tocolytic therapy only in the ampicillin treatment group. Additionally, labouring women were included in the trial. In a study by Spitzer et al,23 continuous and intermittent antimicrobial therapies were compared. This study was of routine administration of excluded because to the control and the use of antimicrobial agents group non-concurrent controls. Most recently, Ernest and Givner24 evaluated penicillin therapy in a placebocontrolled fashion. This study was removed from further

days.

84

women

women were

Figure

3:

Impact

on

analysis because labouring patients were included. In addition, post-randomisation exclusion was done for many indications including delivery before initiation of study medication," antimicrobial therapy of the placebo group (four), discharge before delivery (three), and fetal death after enrolment but before initiation of

treatment

(eight). Evaluated trials 13 prospective randomised clinical trials of antimicrobial therapy in non-labouring women with pPROM were further evaluated.’3°25-36 1594 women participated in these 13 trials. These trials demonstrate heterogeneity in study

design including antimicrobial agent(s) studied, route(s) of therapy, duration of therapy, intrapartum therapy, of group B streptococcus, use of corticosteroids induction of pulmonary maturity, and use of prophylactic or therapeutic tocolysis for preterm labour treatment

for

postpartum infection of antimicrobial therapy after pPROM 1273

Total placebocontrolled trials**

387/419

(92-4)

402/433

(92.8) (

Breslow

Day: 6.8, p=0’24 4: Figure Impact on survival of antimicrobial therapy after pPROM subsequent to enrolment (table). However, within individual trials, no systemic differences in treatment

could be identified between

study groups.

Study design by Gordon and Weingold,2; study group achieved by means of medical record was assignment number characteristics, allowing predetermination of study groups before enrolment. Nine other studies explicitly stated that prerandomisation blinding was maintained by pharmacy personnel or through the use of sealed envelopes. 13.28,3o36 Three studies used a factorial design. Morales et a 121 concurrently evaluated the impact of corticosteroid administration, while Dunlop et aP" studied the efficacy of tocolytic therapy. In the study by Debodinance et al,29 digital vaginal examinations were In the trial

restricted at one centre of a multicentre trial. However, an equal number of treatment and control patients were recruited at this centre (52 and 50, respectively). A matching placebo was used in six trials. 13,30-32,34,35 The other studies used unblinded concurrent controls.25-29.33,36 Post-

Figure 1274

5:

Impact

on

confirmed infant

randomisation exclusion was documented in the trials of Morales (mature L/S ratio, L/S ratio not done, neonatal assessment of gestation >3 weeks different from obstetric estimate),2s and McGregor et al (inadequate diagnosis of

PROM, dating errors, pre-eclampsia, pulmonary hypoplasia, pharmacy error).3’ In addition to Morales’ study, which assigned corticosteroid usage to study groups, four other studies either required or permitted corticosteroid administration.26,27,32,3; Similarly, tocolytic therapy was allowed or required in five studies in addition to the trial of Dunlop et al. 26-28,32,3.13; Antimicrobial therapy The agents used in the clinical trials provide a broad of antimicrobial and have spectrum coverage demonstrated the ability to penetrate pelvic tissues, the amniotic cavity, and/or the fetal circulation (table). Agents used included: penicillins, extended spectrum penicillins, cephalosporins, erythromycin, as well as multiagent therapy with ampicillin, gentamicin, and clindamycin."" The use of concurrent antimicrobial therapy might alter

sepsis of antimicrobial therapy after pPROM

Figure 6: Impact on pneumonia of antimicrobial therapy after pPROM the observed antimicrobial effect within the various trials. This is particularly the case with prophylaxis against group B streptococcus carriage and postnatal prophylaxis against neonatal sepsis. However, the impact of this therapy would likely be to decrease the observed benefit of antimicrobial therapy because the control group would receive antimicrobial treatment. While treatment of group B streptococcus carriers was not restricted to one study group in any of the trials, the lack of physician blinding could allow for bias in neonatal therapy in seven trials.2;-29,33,36

Study populations The reviewed studies include women from the USA, UK, and Europe. It is not possible to describe the range of socioeconomic status among participants. A wide range of gestational ages were studied in the clinical trials (20-36 weeks). The overall weighted mean gestational ages of treatment and control populations were 30-2 and 30-3 weeks, respectively (table). The inclusion of women presenting before fetal viability could reduce the impact of antimicrobial treatment on neonatal morbidity and mortality as a short prolongation of pregnancy with antibiotics will not lead to the birth of a potentially viable infant.27.30,32,33 Additionally, the inclusion of women with PROM near term further reduces the potential for improvement in infant outcome because survival is usual and morbidity is uncommon after 34 weeks’ gestation.42-44 Obstetric outcomes In the evaluated studies, latency was variably described as time from: membrane rupture to delivery, admission to delivery, or randomisation to delivery. Seven studies

Figure 7: Impact on positive infant blood

cultures of antimicrobial

evaluated mean latency.27,28,30,33-36 The weighted mean latencies for the 359 antimicrobial treatment and 360 control subjects were 8-9 and 5-7 days, respectively. Seven trials provided information regarding the number of women delivering within 1 week (figure 1). Antimicrobial treatment offered significant benefit (68’5 vs 75-9% delivered; odds ratio 0-51, 95% CI 0-41-0-68). Fewer women delivered by 24 h with antimicrobial therapy (29/217 vs 47/225, 13.4 vs 20’8%)27,30-32 and at 48 h (64/215 vs 102/217, 29°8 vs 47.0%).27,31,32,35 The proportion of the study population not delivering as a direct result of antimicrobial therapy (attributable benefit) after 24 h, 48 h, 7 days, and 14 days was 7-5%, 17-2%, 14-4%, and 5-3%, respectively. 13,27,30-33,35 Antimicrobial therapy seemed to reduce maternal chorioamnionitis and febrile morbidity after delivery (figures 2 and 3). However, the incidence of caesarean delivery was not decreased with antibiotics (28-9 vs 25-7%; 1-17,

0-92—1-51 13,27,28,30,32-36 Fetal/infant morbidity

and mortality Mean birthweights in the antimicrobial treatment and control groups were 1757 and 1722 g, respectively. Stillbirth complicated 1-0% of deliveries in the treatment population versus 2-2% in the control population (6/592 vs 13/599; 0-46, 0.18-1.20).13,26,27,30-36 Similarly, the incidence of infant death after birth was not affected by

antimicrobial

therapy (35/588 vs 31/591; 1-14, 0.70-1.88),13,26,27,30-36 Additionally, fetal or infant death, adjusted for lethal malformations, was not decreased by antimicrobial therapy (47/525 vs 49/527; 0-94, 0.62-1.44).25-28,31-36 Fetal/infant survival subsequent to randomisation is evaluated in figure 4.

therapy after pPROM 1275

--

0.1

Figure 8: Impact

on

necrotising enterocolitis of antimicrobial therapy after pPROM

Antimicrobial treatment seems to offer a significant reduction in infectious outcomes in infants. Diagnosis of sepsis was confirmed variably in the different studies by positive blood or cerebrospinal fluid cultures, with or without diagnostic radiography, or presence of necrotising enterocolitis. Despite this variability in diagnostic criteria, infants in the treatment group demonstrated a significant reduction in confirmed sepsis, as is shown in figure 5. This reduction was associated with a similar reduction in the diagnosis of pneumonia (1-1vs 3-3%, figure 6). Strikingly, none of the 337 infants receiving antibiotics was diagnosed with neonatal group B streptococcal sepsis, compared with 1-5% (5/340) of controls. A similar but statistically insignificant trend towards reduction of positive infant blood cultures was seen in the overall study population (2-8 vs 50%; n=797; OR 0-50, 95% CI 0-23-1-07) (figure 7). Despite the reduction in infectious morbidity, a significant reduction in necrotising enterocolitis did not occur with antimicrobial therapy (5-5 vs 5-7% figure 8). Additionally, infant mortality due to sepsis was not significantly decreased with antimicrobial therapy (1-0 vs 25%; 4/402 vs 10/400; 0-39, 0.13-1.21).26,27,31-36 However, the powers of these findings were low (0-04 and 0-37, respectively).

Figure 9: Impact 1276

on

Respiratory distress was variably described in the as respiratory distress syndrome (RDS), RDS plus respiratory insufficiency of the premature infant, or respiratory distress requiring ventilation. Despite being the most common complication of prematurity in the study populations, no reduction in respiratory distress was seen with antimicrobial therapy (figure 9). The incidence of intraventricular haemorrahge was significantly reduced from 13-8 to 9-4% with antimicrobial therapy (OR 0-65, figure 10). studies

Placebo-controlled trials The six placebo-controlled trials were evaluated separately in an attempt to reduce potential investigator bias.13,30-32,34,35; Results of these analyses are presented in each figure. Reduction of evaluable patients from 1594 to 842 did not prevent the identification of significant findings. The incidence of delivery within 1 week was decreased (OR 0-56, 95% CI 0-47-0-76), as were chorioamnionitis (0-61, 0-39-0-95) and neonatal sepsis (0-53, 0-30-0-93). In this subanalysis, the incidence of caesarean section was higher after antimicrobial (1-39, 1-01-1-92). therapy not Additionally, although significantly different compared with the placebo group, antimicrobial therapy

respiratory distress of antimicrobial therapy after pPROM

Breslow Day: 7.2, p=0-12

0.01

Figure 10: Impact on intraventricular haemorrhage of antimicrobial therapy after pPROM associated with similar ORs for endometritis (0-65, 0-36-1-16), stillbirth (0-57, 0-19-1-69), intraventricular haemorrhage (0-78, 0-49-1-25), positive blood cultures (0-28, 0-06-1-26), and infant death from sepsis (0-51, 0-96-2-75).

was

Discussion

analysis, we have reviewed the currently available prospective clinical trials that evaluate the impact of systemic antimicrobial therapy on expectant management of pregnancies complicated by PROM before 37 weeks’ gestation. We have identified a significant improvement in pregnancy prolongation, as well as a reduction in the diagnosis of chorioamnionitis and postpartum febrile morbidity. Despite differences in treatment regimens and evaluation bias that might reduce the apparent benefit of antimicrobial therapy, a similar decrease is seen in infectious infant morbidity including sepsis and pneumonia. Antimicrobial therapy is also associated with a parallel, but statistically insignificant, reduction in the incidence of positive infant blood cultures. This finding In this

may reflect

reduction in neonatal infection or may simply represent an inability to culture bacteria that have been exposed to antimicrobial agents before delivery. Unfortunately, further information regarding the severity of illness is not generally available in the trials. The reduction of detected intraventricular haemorrhage may provide some insight. This neonatal complication is known to be associated with neonatal sepsis and also with respiratory distress, which was not reduced in this evaluation.45,46 Perhaps the lower incidence of intraventricular haemorrhage is due to a reduction in severity of these other two moribidities. Further study regarding the severity of infant morbidities would be helpful in delineating such an objective effect of antimicrobial therapy. Nonetheless, the apparent reduction in maternal and infant infectious morbidity is consistent with a direct protective effect of antimicrobial agents against ascending infection, vertical transmission from mother to fetus, and/or immediate neonatal protection via transplacental passage of antibiotics. It is not surprising that respiratory distress and overall infant mortality were not reduced in the reviewed studies. This finding may be due to two factors. First, a broad range of gestational ages have been evaluated. Because a

infant mortality is particularly low with delivery after 32 weeks’ gestation," a significant number of those studied could not realistically have been expected to benefit, in terms of mortality, from pregnancy prolongation. Specifically, given the 92% survival in the control population, the potential for additional antimicrobial benefit is low. Second, although antimicrobial therapy is associated with a 60% increase in the number of women undelivered after 1 week (38-5 vs 24-1%), a small percentage of patients actually accrue the benefit of significant pregnancy prolongation. Combining the available data regarding latency, the attributable benefit of antimicrobial treatment is just 7-5%, 17-2%, 14-3%, and 5-3% of enrolled women at 24 h, 48 h, 7 days, and 14 days, respectively. 13,27,30-33,35 Given the low risk of infant morbidity and mortality and the small impact of expectant management on latency, we have previously studied and found it beneficial to deliver women with pPROM at 32-36 weeks’ if fetal pulmonary maturity is present. 43 Unfortunately, the current clinical trials of antimicrobial therapy do not provide adequate information regarding the impact of treatment for women presenting before 32 weeks’ gestation. We wondered whether aggressive antimicrobial therapy might be associated with additional benefit over less aggressive treatments (oral therapy alone, brief therapy). To evaluate this possibility, the eight studies in which antimicrobial agents were given intravenously for at least 24 h and therapy was given for at least 1 week if delivery did not occur were analysed separately.13,25,27,29,30,33,35,36 No additional improvement in latency or in gestational age dependent or infectious morbidity was identified with more

aggressive treatment.

We used the Mantel-Haenszel statistic to assist our literature review. Such a meta-analysis has inherent risks that may impact on the conclusions. First, exclusion of "negative" trials might lead to publication bias and a falsely significant result. We were able to obtain data from a large multicentre clinical trial that has not yet been completely published." Although that trial did not demonstrate significant benefit from antimicrobial treatment despite aggressive parenteral therapy, its inclusion in this analysis did not prevent the identification of impressive benefits of such treatment. The inability to demonstrate a significant benefit with treatment in the 1277

trial might be due to the prolonged latency placebo group (median 11days) or to the women up to 36 weeks’ gestation where the for potential pregnancy prolongation is reduced and infant morbidity uncommon. Second, in performing a meta-analysis we assume

unpublished in the inclusion of seen

similar treatments among the various evaluated trials. Excessive heterogeneity in study design might prevent meta-analysis from identifying significant benefit of a therapy. The studies in this analysis used a variety of different combinations of antimicrobial agents and treatment regimens. However, they were unified by a goal of expectant management for pregnancy prolongation and reduction of infant morbidity. Overall, the studied antimicrobial agents provide coverage against a broad spectrum of genital and gastrointestinal flora associated with intrauterine infection and neonatal sepsis. The inclusion of trials evaluating less aggressive oral therapy could have the effect of masking any impact of more aggressive trials, but this effect did not seem to occur in our analysis. The variation in treatment protocols, and small sample size in some studies, might explain some of the variability identified in study outcomes. in particular demonstrated significant between in odds ratios studies. heterogeneity Chorioamnionitis occurred in 0-26% of treated patients and 10-47% of control patients (OR 0-11-1-7). However, intrapartum infection was seen less commonly with treatment in ten of 12 studies. Neonatal sepsis also showed a wide range of incidence in the different studies (0-21% and 0-24% in the treatment and control groups, respectively). Again, sepsis was seen less commonly with treatment in eight of ten studies; these eight studies account for 89% of the participating women. Whilst the Breslow-Day X2 test identifies chorioamnionitis and confirmed sepsis as having excess heterogeneity of odds ratios, inclusion of only those outcomes in which no variability is identified could also lead to undue exclusionary analytic bias in which the only parameters reported would be those where all studies agree. We have chosen to report the findings but warn the reader of this Two

outcomes

potentially confounding heterogeneity. Meta-analytic comparison of studies requires that similar outcome criteria are used. Unfortunately the outcomes in the clincial trials were not always delineated explicitly. The relevant outcomes, including chorioamnionitis, postpartum infection, neonatal sepsis, respiratory distress, and pneumonia, are often difficult to diagnose. Nevertheless, no systematic bias in diagnostic criteria was identified within the individual studies. Finally, neonatal head ultrasounds

are not done all newborn infants after Most pPROM. routinely perinatal centres have policies of scanning all newborn babies under a certain weight (eg, 1500 g), and performing head ultrasounds on larger infants only if they are symptomatic. Therefore, we expect that the actual incidence of grade I-II intraventricular haemorrhage is underestimated in the studied clinical trials. The impact of this underestimate would be to reduce our ability to detect a difference in intraventricular haemorrhage, or to suggest that antibiotics reduce overall intraventricular haemorrhage, whereas such therapy actually reduces the incidence of severe intraventricular haemorrhage (grades III-IV), which is more closely linked to long-term infant morbidity. Again, we identified no systematic bias in the reviewed studies.

Although many meta-analyses include both blinded and unblinded control groups, there remains some concern that such evaluations will be biased due to unintentional alterations in treatment of the study groups. The initial and obvious impact of such an analysis is to reduce the number of evaluable patients to 842 from 1594 and thus potentially reduce the power of the analyses, particularly where the evaluated outcomes are uncommon. Nevertheless, this more specific analysis did not prevent us from identifying significant improvements in latency and reductions in chorioamnionitis and neonatal sepsis. A finding that warrants further evaluation is the trend towards increased caesarean section (OR 1-39), which was not seen in the overall study population (OR 1-17). It is difficult to understand why antimicrobial therapy would lead to increased caesarean section unless the improved latency caused more fetuses to reach viability and thus resulted in more intervention on behalf of the fetus. It is encouraging to note that those morbidities that were not significantly improved with antimicrobial therapy in the sub analysis carried similar ORs to the total population analysis. This finding suggests the possibility of inadequate sample size given the rarity of the outcomes studied. We believe that the currently available clinical trials evaluating antimicrobial therapy in the expectant management of pPROM suggest a beneficial effect regarding pregnancy prolongation as well as a reduction in maternal infectious morbidity. Additionally, neonatal infectious morbidity seems to be ameliorated by anatenatal antimicrobial therapy after PROM. The available literature does not suggest an improvement in the incidence of infant mortality and gestational agedependent morbidity such as respiratory distress. Unfortunately, the benefit of antimicrobial therapy seems to be accrued by a small proportion of the populations studied. This analysis raises the potential for future studies in a number of areas. &bul et; Will aggressive antimicrobial therapy prove beneficial when applied to a population at high risk for infant morbidity and mortality (eg, before 32 weeks’

gestation)? <

&bul et;

&bul et;

on

1278

*

Does antimicrobial therapy reduce the severity of objectively defined complications among those infants

developing perinatal morbidity? What is the optimal route and duration for antimicrobial therapy in the management of women presenting with pPROM? Can we identify sub-populations of women with pPROM who are more likely to benefit from antimicrobial therapy after pPROM? Can antimicrobial therapy be used to prolong pregnancy and enhance corticosteroid induction of

&bul et;

pulmonary maturity? Can tocolytic therapy be used to prolong pregnancy initially and allow time for the antimicrobial effect within the uterus? Such aggressive treatment might increase the number of undelivered women who could then benefit from pregnancy prolongation with aggressive antimicrobial treatment.

We believe antimicrobial treatment to be a promising adjuvant therapy for the expectant management of pPROM. Further study in this area should be directed towards enhancement of objectively defined benefits so that clinical practice can be more appropriately applied.

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