Antibiotic Therapy for Reduction of Infant Morbidity After Preterm Premature Rupture of the Membranes A Randomized Controlled Trial Brian M. Mercer, MD; Menachem Miodovnik, MD; Gary R. Thurnau, MD; Robert L. Goldenberg, MD; Anita F. Das, MS; Risa D. Ramsey, BSN; Yolanda A. Rabello, MSEd; Paul J. Meis, MD; Atef H. Moawad, MD; Jay D. lams, MD; J. Peter Van Dorsten, MD; Richard H. Paul, MD; Sidney F. Bottoms, MD\s=d\; Gerald Merenstein, MD; Elizabeth A. Thom, PhD; James M. Roberts, MD; Donald McNellis, MD; for the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network infection is thought to be one cause of preterm premature of the membranes rupture (PPROM). Antibiotic therapy has been shown to prolong on but the effect infant morbidity has been inconsistent. pregnancy, Objective.\p=m-\To determine if antibiotic treatment during expectant management of PPROM will reduce infant morbidity. Design.\p=m-\Randomized, double-blind, placebo-controlled trial. Set ing.\p=m-\University hospitals of the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Patients.\p=m-\A total of 614 of 804 eligible gravidas with PPROM between 24 weeks' and 0 days' and 32 weeks' and 0 days' gestation who were considered candidates for pregnancy prolongation and had not received corticosteroids for fetal maturation or antibiotic treatment within 1 week of randomization. Interv ntion.\p=m-\Interavenous ampicillin (2-g dose every 6 hours) and erythro6 dose mycin (250-mg every hours) for 48 hours followed by oral amoxicillin (250-mg dose every 8 hours) and erythromycin base (333-mg dose every 8 hours) for 5 days vs a matching placebo regimen. Group B streptococcus (GBS) carriers were identified and treated. Tocolysis and corticosteroids were prohibited after randomization. Main Outcome Measures.\p=m-\The composite primary outcome included pregnancies complicated by at least one of the following: fetal or infant death, respiratory distress, severe intraventricular hemorrhage, stage 2 or 3 necrotizing enterocolitis, or sepsis within 72 hours of birth. These perinatal morbidities were also evaluated individually and pregnancy prolongation was assessed. the total study population, the primary outcome (44.1% vs 52.9%; Results.\p=m-\In P=.04), respiratory distress (40.5% vs 48.7%; P=.04), and necrotizing enterocolitis (2.3% vs 5.8%; P=.03) were less frequent with antibiotics. In the GBS-negative cohort, the antibiotic group had less frequent primary outcome (44.5% vs 54.5%; P=.03), respiratory distress (40.8% vs 50.6%; P=.03), overall sepsis (8.4% vs 15.6%; P=.01), pneumonia (2.9% vs 7.0%; P=.04), and other morbidities. Among GBS-negative women, significant pregnancy prolongation was seen with antibiotics (P<.001). Conclusions.\p=m-\We recommend that women with expectantly managed PPROM remote from term receive antibiotics to reduce infant morbidity. Context.\p=m-\Intrauterine JAMA. 1997;278:989-995 MORE THAN 400000 preterm births occur in the United States each year. Preterm premature rupture of the mem¬ branes (PPROM) accounts for approxi¬ mately one third of all preterm births.1 The etiology of PPROM is thought to include intrauterine infection in many cases.2"5 This relationship is particularly strong in the late second and early third trimesters of pregnancy. The clinical course after PPROM is one of short duration, with 70% to 80% of women delivering within 1 week of membrane rupture. Clinical trials of expectantly managed patients have demonstrated significant pregnancy prolongation with antibiotic therapy,611 but the effect on From the University of Tennessee, Memphis (Dr Merand Ms Ramsey); University of Cincinnati, Cincin- cer nati, Ohio (Dr Miodovnik); University of Oklahoma, Oklahoma City (Dr Thurnau); University of Alabama, Birmingham (Dr Goldenberg); George Washington University, Washington, DC (Ms Das and Dr Thom); University of Southern California, Los Angeles (Ms Rabello-$ and Dr Paul); Bowman Gray School of Medicine, Winston-Salem, NC (Dr Meis); University of Chicago, Chicago, III (Dr Moawad); Ohio State University, Columbus (Dr lams); Medical University of South Carolina, Charleston (Dr Van Dorsten); Wayne State University, Detroit, Mich (Dr Bottoms); University of Colorado, Denver (Dr Merenstein); University of Pittsburgh, Pittsburgh, Pa (Dr Roberts); and the National Institute of Child Health and Human Development, Bethesda, Md (Dr McNellis). \s=d\Deceased. Reprints: Brian M. Mercer, MD, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Tennessee, Memphis, 853 Jefferson Ave, Suite E102, Memphis, TN 38103 (e-mail: [email protected]). Downloaded from jama.ama-assn.org at University of Kansas on April 1, 2012 infant morbidity has been inconsistent.7,8,12 In part, this may be because of the inclusion of grávidas with PPROM near term when the infant is less likely to benefit from expectant management. We report a randomized, placebo-con¬ trolled, double-blind trial to evaluate the impact of antibiotic therapy as adjunctive therapy to the expectant manage¬ ment of patients with PPROM remote from term (<32 weeks, 0 days). Our purpose was to determine if antibiotic therapy would lead to a reduction in peri¬ natal morbidity and mortality. METHODS This study was developed and ap¬ proved by the Steering Committee ofthe National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. The protocol was reviewed and approved by the hu¬ man research committees of all partici¬ pating institutions. Study Design and Subjects At 11 clinical centers, women present¬ rup¬ ture of the membranes at 24 weeks' and 0 days' to 32 weeks' and 0 days' gestation were identified. Women were eligible for entry ifmembrane rupture had occurred within 36 hours of randomization, cervi¬ cal dilatation was 3 cm or less on visual examination, and if women had 4 or fewer contractions in the 60-minute monitoring period before randomiza¬ tion. Women with nonreassuring fetal testing, vaginal bleeding, maternal or fe¬ tal indication for delivery, or cervical cerclage in place and those who had re¬ ceived antibiotic therapy within 5 days or corticosteroid therapy within 7 days were ineligible. Recent antibiotic use and corticosteroid administration were used as exclusion criteria because both interventions could potentially have a confounding effect on the study treat¬ ments and outcomes. Women with al¬ ing with spontaneous premature lergy to penicillins or erythromycin, bacteriuria, febrile illness requiring antibiotics, or significant medical com¬ plications (class 2-4 cardiac disease, class D or F diabetes, endocrinopathy requir¬ ing medication, hematological disorders other than anemia, hypertensive disor¬ ders, acute and chronic liver disease, pul¬ monary hypertension, or acute or chronic renal failure) were also excluded. Women requiring tocolytic therapy were considered candidates for partici¬ pation if tocolysis was successfully dis¬ continued and the patient continued to meet all other eligibility requirements. Ultrasound was performed to evaluate fetal presentation, growth, placental lo¬ cation, and amniotic fluid volume and to exclude fetal malformations. Women with placenta previa, fetuses estimated to be below the 10th percentile of weight for gestational age, or fetuses with mal¬ formations were excluded. Eligible women were offered partici¬ pation, and written informed consent was obtained. The American College of Obstetricians and Gynecologists and American Academy of Pediatrics have suggested intrapartum prophylaxis of women delivering preterm in the ab¬ sence of a recent negative group strep¬ tococcus (GBS) culture.1314 The Centers for Disease Control and Prevention have recently suggested intrapartum prophy¬ laxis of all grávidas deliveringpreterm.15 Before initiation of this trial, we decided to perform distal vaginal sampling for GBS culture on all participants and treat GBS carriers before and during labor. All microbiology laboratories used se¬ lective culture techniques for the isola¬ tion of GBS. Because the primary intent ofthis trial was to determine the impact ofantibiotic treatment during expectant management on those who would not otherwise receive prophylactic antibi¬ otic therapy before labor, the primary outcome was evaluated in those grávi¬ das who were not confirmed to be GBS carriers (GBS-negative cohort). The primary outcome for this study was the occurrence of an infant with any ofthe following: fetal or postnatal death, respiratory distress syndrome, docu¬ mented sepsis within 72 hours of de¬ livery, grade 3 or 4 intraventricular hemorrhage, or stage 2 or 3 necrotizing enterocolitis. For twin pregnancies, an adverse outcome was considered to have occurred if at least 1 infant suffered the evaluated morbidities or mortality. The sample size was based on an an¬ ticipated 35% incidence of primary out¬ come in the placebo group of the GBSnegative cohort, a one-third reduction with antibiotic treatment, a noncompliof .05, and ance rate of 10%, a 2-tailed ß of .20. It was determined that 300 wom¬ en would be required in each arm of the GBS-negative cohort. Randomization and Treatment Study participants were assigned to receive either treatment with intrave¬ nous and oral antibiotics or a visually in¬ distinguishable intravenous and oral pla¬ cebo regimen, using an urn randomiza¬ tion scheme stratified by clinical center. The urn randomization scheme adjusts the likelihood of the next study subject being allocated to either study arm based on the distribution of study sub¬ jects previously randomized and im¬ proves the chance of the 2 study arms being similar in number throughout the study.16 An independent data coordinat¬ ing center generated the randomization scheme and provided it to the research pharmacy at each clinical center. Study group assignment was performed by the research pharmacy subsequent to docu¬ mentation of eligibility and patient con¬ sent to participate in the trial. All study participants and their caregivers were masked as to their study regimen throughout the study. The antibiotic regimen consisted of ampicillin (2-g in¬ travenous dose every 6 hours) and eryth¬ romycin (250-mg intravenous dose ev¬ ery 6 hours) for 48 hours, followed by amoxicillin (250-mg oral dose every 8 hours) and erythromycin base (333-mg oral dose every 8 hours) for 5 days. Oral amoxicillin was provided by Warner Chilcott (Morris Plains, NJ). Oral eryth¬ romycin base and matching placebo were provided by Boots Laboratories (Lincolnshire, 111). Study medications were to be taken for 7 days unless deliv¬ ery occurred sooner. Patients with posi¬ tive urine cultures or Neisseria gonorrhoeae cultures received appropriate an¬ tibiotic treatment in addition to their study medications. Women with positive GBS cultures received a 7-day course of oral ampicillin (500-mg oral dose every 6 hours) and intrapartum intravenous am¬ picillin prophylaxis (2-g intravenous dose every 6 hours) in addition to their assigned study medications. Patient Management Participating women were expect¬ antly managed in the hospital unless fluid leakage stopped and amniotic fluid volume returned to normal. Women un¬ derwent assessment for evidence of in¬ trauterine infection, including daily clinical assessment and examination, while receiving study medications. Fe¬ tal well-being was evaluated with daily nonstress testing, and biophysical pro¬ file scoring as needed, during the first week. Subsequent fetal evaluation was performed at least twice weekly until de¬ livery, unless leakage subsided and fluid volume returned to normal. Corticoste¬ roid and tocolytic therapy were not per¬ mitted after enrollment. Elective deliv¬ ery was prohibited prior to 34 weeks' and 0 days' gestation and discouraged subsequently. Specific neonatal treatments were not standardized between centers. How¬ ever, pediatrie caregivers were masked as to the study arm. Each center agreed not to alter neonatal management be¬ cause of the possibility of prenatal anti¬ biotic exposure. Neonatal head sonograms were per¬ formed routinely on infants with a birth weight less than 1750 g and on largerweight infants when clinically indicated. Neonatal management otherwise was left to the discretion ofthe neonatal care- Downloaded from jama.ama-assn.org at University of Kansas on April 1, 2012 Infants were followed up until death or discharge to home or a chronic giver. care facility. Data Collection and Statistical Analysis Data were collected concurrently and transmitted weekly to the data coordi¬ nating center. Charts of all infants suf¬ fering any component of the primary outcome, a 10% sampling of other in¬ fants, and a 10% sampling of mothers were reviewed by a blinded chart re¬ view committee for accuracy of docu¬ mentation. Standardized definitions for outcome variables were used (Table 1). A Lan DeMets group sequential-analy¬ sis plan, using a generalization of the O'Brien and Flemingboundary, was cho¬ sen before the study started.17,18 An ex¬ ternal data monitoring committee re¬ viewed interim analyses for safety and efficacy. Statistical analyses included the Pear¬ 2 test, the Fisher exact test, the Wilcoxon rank sum test, and the WeiLachin test. The log-rank test was used to compare the survival distributions of the study groups. Stratified analyses (Mantel-Haenzel and Wei-Lachin) were used for the combined culture cohort af¬ ter performing the Breslow-Day test for heterogeneity. In addition, the Cox pro¬ portional hazards model was used to test the difference in latency between treat¬ ment groups, controlling for culture co¬ hort. All patients were analyzed within their original study group, regardless of compliance with therapy or confounding treatments (eg, open-label antibiotic ad¬ ministration). Postrandomization exclu¬ sion was not performed. The critical value for the final analysis of the pri¬ mary outcome was .048 (2-tailed). Table 1.—Study Definitions Amnionitis Any 2 of antepartum temperature >38°C (100.4°F), uterine tenderness, foul smelling vaginal discharge or amniotlc fluid, maternai tachycardia (>100 beats/mln), fetal tachycardia (>160 beats/mln), or white blood cell count >20x109/L Endometrltis Persistent postpartum fever >38°C (100.4°F) with abnormal uterine tenderness and no other Identifiable cause of Infection Documented sepsis An Infant with clinical findings suggesting infection and a positive result on a blood or cerebrospinal fluid culture. Infants with clinical symptoms suspicious for infection who also demonstrated evidence of cardiovascular collapse requiring volume expansion or pressor agents were also considered to have had confirmed sepsis, even in the absence of positive blood cultures Respiratory distress syndrome Compatible symptoms with radiographlcally confirmed hyaline membrane disease or with respiratory insufficiency of prematurity requiring ventilatory support for at least 24 h Pneumonia Compatible symptoms with diagnostic radiograph findings and positive results on blood cultures, persistent leukopenla (white blood cell count <4.0x109/L) or a band cell count >15% Stage 2 or 3 necrotizing enterocolitis Compatible symptoms with radiograph findings of pneumatosis intestinalls, portal air, or pneumoperitoneum Grade 3 or 4 intraventrlcular hemorrhage Intraventrlcular hemorrhage with parenchymal spread or concurrent ventrlculomegaly Composite morbidity A pregnancy complicated by stillbirth, Infant death before discharge, respiratory distress syndrome, documented neonatal sepsis within 72 h of birth, or grade 3 or 4 intraventrlcular hemorrhage or stage 2 or 3 necrotizing enterocolitis before discharge Bronchopulmonary dysplasla Persistent oxygen requirement >28 d after delivery son RESULTS Between February 1992 and January 1995, 1867 women with PPROM be¬ tween 24 weeks' and 0 days' and 32 weeks' and 0 days' gestation were screened (Figure 1). Of these, 804 wom¬ en (43%) met eligibility criteria. A total of 807 women were excluded for obstet¬ ric or medical reasons; 256 were ex¬ cluded because they had received anti¬ biotics or corticosteroids. Six hundred fourteen women, 76% of eligible women, agreed to participate (300 were assigned to the antibiotic regimen and 314 to pla¬ cebo). There were 29 twin gestations. The incidence ofGBS carriage was 19.2% (118 patients), leaving 496 women in the GBS-negative cohort (83% of the antici¬ pated recruitment goal). Three interim analyses were per¬ formed. The data monitoring committee recommended discontinuation of re¬ cruitment because of reduced enroll- Eligible Patients (N=804) X (n=190) (Refused Consent) Not Randomized Total Stratum Group Group Twins (n=314) Streptococcus Negative (n=257) Streptococcus Positive (n=57) (n=19) (n=300) Total Stratum Group Streptococcus Negative (n=239) Group Streptococcus Positive (n=61) Twins (n=10) I Received Placebo as Allocated Did Not Receive Placebo as Allocated Delivered Before Placebo Given Other (n=306) (n=8) (n=4) (n=4) Received Antibiotics as Allocated Did Not Receive Antibiotics as Allocated Delivered Before Antibiotics Given Other (n=2) Withdrawn Unavailable for (n=312) (n=331) Followed up To Maternal Delivery To Infant Discharge (n=295) (n=5) (n=3) (n=2) I Withdrawn Unavailable for Follow-up I Followed up To Maternal Delivery To Infant Discharge - Completed Thai Mothers Neonates Follow-up T. (n=1) (n=299) (n=309) I (n=312) (n=331) Figure 1.—Trial profile. ment related to changes to clinical prac¬ tice regarding GBS prophylaxis and the recommendations ofthe recent National Institute of Child Health and Human De- Completed Trial Mothers Neonates (n=299) (n=309) consensus conference that corticosteroids be administered to pa¬ tients with premature rupture of mem¬ branes.19 Additionally, because a higher velopment Downloaded from jama.ama-assn.org at University of Kansas on April 1, 2012 Table 2.—Demographic and Antibiotics Patient Characteristics (n=300) 25.2 (5.9) Mean maternal age (SD), y African American, % Hispanic, (n=314) (6.2) 24.9 56.1 31.3 33.8 73.3 10.1 Married, % Receiving government assistance, % % Prior SPTD, %t Twins, % Mean gestational age Placebo 61.0 % Multiparity, ated with a significant reduction in the incidences of both documented late neo¬ natal sepsis (>72 hours after delivery) and overall neonatal sepsis. Maternal an¬ tibiotic therapy was associated with re¬ ductions in the incidence of pneumonia diagnosed within 72 hours of delivery and of pneumonia diagnosed prior to death or discharge. Antibiotic treatment was associated with less frequent noninfectious outcomes, including patent duc- Baseline Clinical Characteristics at Randomization (SD), wk Median cervical dilatation, cm Mean white blood cell count (SD), x109/L Mean amniotlc fluid Index, Mean maximum vertical amniotic fluid pocket, cm§ 78.0 76.3* 41.5 3.3 28.6 (2.2) 28.5 10.6(3.2) 10.7(3.1) 5.0 68.5* 6.1 Group 20.3 5.1 2.3 18.2 Neisseria 7.5 13.8 15.4 3.7 3.8 streptococcus, % gonorrhoeae, % Chlamydia trachomatis, % Asymptomatic bacterlurla, % arteriosus, bronchopulmonary dysplasia, or hyperbilirubinemia requiring phototherapy or exchange transfusion. Analysis of the total population re¬ vealed significant reductions in broncho¬ pulmonary dysplasia and patent ductus arteriosus in those assigned to antibiot¬ ics. In the GBS-positive cohort, how¬ ever, no improvement in other infant tus (2.4) *P=.03. tSPTD indicates spontaneous preterm delivery due to preterm labor or preterm rupture of the membranes. This includes only multíparas. ^Measurement of mean amniotlc fluid index included 238 women receiving antibiotics and 247 women receiving placebo. §Measurement of mean maximum vertical amniotic fluid pocket Included 168 women receiving antibiotics and 157 women receiving placebo. incidence of primary outcome was seen in the placebo group than anticipated, the study had achieved adequate power to evaluate the primary outcome. During the study, 3 women were un¬ available for follow-up. Thus, the results include the 299 women receiving antibi¬ otics and the 312 women assigned to pla¬ cebo. Table 2 highlights selected demo¬ graphic and baseline characteristics of the study groups. Within the GBS-nega¬ tive cohort, women assigned to the an¬ tibiotic and placebo groups had similar demographic characteristics and clinical findings at randomization. Those in the antibiotic group were more likely to be multiparous; however, the incidence of prior spontaneous preterm delivery among multíparas in the 2 groups was similar. Primary Outcome mary outcome 312 (132/299 [44.1%] vs 165/ [52.9%]; RR, 0.84; P=.04), respira¬ tory distress (121/299 [40.5%] vs 152/312 [48.7%]; RR, 0.83; P=.04) and stage 2 to 3 necrotizing enterocolitis (7/299 [2.3%] vs 18/312 [5.8%]; RR, 0.40; P=.03) in the antibiotic group. The RRs of grade 3 to 4 intraventrlcular hemorrhage (0.82) and early onset sepsis (0.83) after maternal antibiotic treatment were similar to those seen for primary outcome and res¬ piratory distress syndrome. As anticipated, the incidence of pri¬ mary outcome in both the antibiotic and placebo groups of the GBS-positive co¬ hort was similar to that in the antibiotic group of the GBS-negative cohort. No significant improvement in the primary outcome could be identified with addi¬ tional maternal antibiotic treatment in this cohort (26/61 [42.6%] vs 25/55 [45.5%]). The incidence of primary outcome in the GBS-negative cohort was signifi¬ cantly lower in women assigned to anti¬ biotic treatment (106/238 [44.5%] vs 140/ 257 [54.5%]; relative risk [RR], 0.82; =.03; Table 3). Individually, respira¬ tory distress syndrome was less fre¬ quently diagnosed among infants of mothers receiving antibiotic therapy (97/238 [40.8%] vs 130/257 [50.6%]; RR, 0.80; P= .03). Infants ofmothers assigned to receive antibiotics had a 0.66 RR of having more than 1 component ofthe pri¬ mary outcome when compared with those of the placebo group (95% confi¬ dence interval, 0.43-1.04; P=.07). Secondary analysis of outcomes of all 611 women's pregnancies (combined cul¬ ture cohorts) demonstrated significant reductions in the incidences of the pri- Other Infant Morbidities Analysis of the total population re¬ vealed that 95.1% (294/309) and 94.3% (312/331) of infants in the antibiotic and placebo study groups received antibiot¬ ics within the first day of life (P=.62), while 42.1% and 48.0%, respectively, re¬ ceived at least 7 total days of treatment (P=.13). In the GBS-positive cohort, 98.4% of antibiotic-group and 94.6% of placebo-group infants received antibiot¬ ics starting on the first day of life (P= .33). Individual infant morbidities in the GBS-negative cohort are further evaluated in Table 4. Blood cultures posi¬ tive for GBS were obtained from 12.2% and 17.8% ofinfants in the antibiotic and groups, respectively (P=.08). Maternal antibiotic therapy was associ- placebo morbidities was identified with addi¬ tional study antibiotic treatment. Pregnancy Outcomes Survival analysis in the GBS-negative cohort revealed a significant prolonga¬ tion in the interval from randomization to delivery for those assigned to receive antibiotics (P<.001; Figure 2). This group had a prolonged median time to delivery (6.1 vs 2.9 days, P<.001). A sig¬ nificantly increased number of women assigned to antibiotics compared with placebo remained pregnant at each day between 2 days and 3 weeks after ran¬ domization: 27.3% vs 36.6% delivered within 48 hours (P=.03), 55.5% vs 73.5% delivered within 7 days (P=.001), 75.6% vs 87.9% delivered within 14 days (P=.001), and 85.7% vs 93.0% delivered within 21 days (P=.008). A significantly higher infant birth weight (1549 g±497 g vs 1457 g±508 g; =.03) was seen with mothers receiving antibiotics. For the overall population, significant improve¬ ment in latency (P< .001 ) was seen in the group assigned to antibiotics. In the GBS-positive cohort, no improvement in latency or birth weight was seen with additional antibiotics. Maternal Outcomes The antibiotic group had a lower inci¬ dence of clinical amnionitis in the GBSnegative cohort (23.4% vs 33.9%; P=.01) and in the total population (23.0% vs 32.5%; P= .01). The incidence of postpar¬ tum endometritis was similar regardless of antibiotic treatment in the GBS-nega¬ tive cohort (11.8% vs 11.3%; P=.87), the GBS-positive cohort (8.2% vs 12.7%; P=.41), and the total population (11.0% vs 11.5%; P=.85). The rate of cesarean delivery was not significantly affected by study group in the GBS-negative co¬ hort (31.1% vs 29.6%; P=.71) or the total population (30.0% vs 31.2%; P=.65). Downloaded from jama.ama-assn.org at University of Kansas on April 1, 2012 3.—Primary Outcome and Individual Component Morbidities According to Study Group Assignment and the Presence or Absence of Positive Vaginal Group Streptococcus (GBS) Cultures* Table GBS-Negative Cohort, GBS-Positive Cohort, % % Total Receiving Receiving Antibiotics Placebo (n=238) (n=257) Placebo (n=61) (n=55) .03 39.3 40.0 .88 (95% CI) 0.97(0.62-1.51) 40.8 50.6 82 32 0.72(0.38-1.38) 8~2 5~5 .72 1.48 hemorrhage, grade 3 or 4 Sepsis s72 h_4J5_7.0 2.1 5.4 Necrotizing 53 .26 0.66(0.32-1.36) 0.39(0.14-1.06) 8.2_3.6 .45 2.21 .05 7.3 .42 (0.45-10.94) 0.44(0.08-2.32) 9.8_5.5 Respiratory RR distress syndrome Intraventrlcular 3.3 Antibiotics Placebo (n=299) (n=312) 40.5 48.7 .04 RR (95% CI) 0.83(0.69-0.99) 6~4 7/7 S\ 0.82(0.46-1.48) 5.4_6.4 .56 .03 0.83(0.42-1.57) 0.40(0.17-0.95) (0.47-6.87)_6^4_5.8 RR enterocolitis, stage 2 or 3 Death_5J>_5.8 % Receiving Receiving Receiving Receiving Antibiotics (95% CI) 0.80(0.66-0.98) Infant Morbidities Population, -1 -1 1.80 (1.37-5.89) 2.3 5.8 Composite morbidity 44.5 54.5 .86 .03 0.94(0.46-1.93) 0.82(0.69-0.98) 42.6 45.5 .50 .76 0.94(0.62-1.41) 44.1 52.9 .78 .04 1.10(0.58-2.05) 0.84(0.71-0.99) >1 Outcome 11.3 17.1 .07 0.66(0.43-1.04) 16.4 11.1 .41 1.48(0.57-3.79) 12.4 16.0 .19 0.77(0.51-1.15) *RR indicates relative risk; and CI, confidence interval. Table 4.—Other Infant Morbidities According to Study Group Assignment and the Presence or Absence of Positive Vaginal Group Streptococcus (GBS) Cultures* GBS-Negative Cohort, % GBS-Positive Cohort, % Total Population! I Receiving Receiving Infant Morbidities Antibiotics Placebo (n=238) (n=257) Sepsis (95% CI) >72h 3.8 9.7 Overall Pneumonia s72h >72h 8.4 15.6 0.4 4.7 2.5 2.9 18.9 2.3 7.0 23.7 .04 .19 0.09(0.01-0.68) 1.08 (0.35-3.29) 0.42(0.18-0.98) 0.80(0.57-1.88) 4.0 7.8 .09 8.0 7.8 14.3 Overall Overall intraventrlcular hemorrhage Posthemorrhagic hydrocephalus Overall necrotizing .009 Hyperbilirubinemia Patent ductus 0.39(0.19-0.81) 0.54(0.32-0.89) Antibiotics Placebo (n=61) (n=55) 1.1 .37 12.7 .17 1.59(0.57-4.46) 1.77(0.77-4.06) 6.3 0.0 .12 N/A 1.6 8.2 19.7 3.6 3.6 12.7 0.54(0.26-1.1 6.6 5.5 1.00 .93 1.03(0.56-1.1 8.2 12.7 .40 0.63(0.21-1.88) 21.0 .05 0.68 (0.46-1.00) 8.2 18.2 .10 0.44(0.16-1.21) 17.7 20.6 .39 0.85 (0.59-1.23) 13.1 14.5 .79 66.8 11.8 75.1 21.0 .04 0.89 (0.80-0.99) 0.56(0.37-0.85) 60.7 61.8 16.4 .80 .003 .90 .005 11.5 *RR indicates relative risk; CI, confidence interval, and N/A, not applicable. tElllpses indicate the Breslow-Day test for heterogeneity results were P<.05; Adverse Effects and Compliance Antibiotic therapy was more fre¬ quently associated with nausea (27.7% vs 3.9%; P<.001), vomiting (11.9% vs 3.3%; P<.001), and abdominal pain (5.1% vs 1.0%; =.003). Overall compliance with intravenous therapy was accept¬ able in both study groups but was sig¬ nificantly lower in the antibiotic group vs (95% CI) 14.8 arteriosus (83.7% RR 23.0 .01 enterocolitis Bronchopulmonary dysplasia Retinopathy of prematurity Receiving Receiving Receiving Receiving RR 89.2%, P=.046). Grávidas unwilling or unable to complete the in¬ travenous regimen, but remaining un¬ delivered, received oral therapy until completion of the prescribed 7 days of treatment. Oral therapy was associated with infrequent adverse effects, excel¬ lent compliance, and no reductionin com¬ pliance in the antibiotic group (93.1% vs 94.2% in the placebo group; P=.66). no stratified RR or (n=312) 6.0 9.6 11.4 15.1 RR (95% CI) 1.7 3.8 2.6 4.0 19.1 6.4 21.8 .85 .17 .42 0.61(0.29-1.29) 0.88(0.63-1.20) 4.7 7.4 .16 0.63(0.33-1.22) 8.7 .75 0.92 (0.54-1.55) 13.0 20.5 .01 0.64 (0.45-0.92) 0.89(0.36-2.20) 16.7 19.6 .37 0.86(0.61-1.20) 0.96(0.72-1.28) 0.69(0.28-1.72) 65.6 72.8 20.2 .06 0.90(0.81-1.00) .004 0.58 (0.40-0.85) 1.18(0.28-5.04) value was 11.7 0.91 (0.33-2.52) calculated. There were no cases of pseudomem¬ branous enterocolitis, maternal sepsis, or maternal deaths. One maternal yeast infection was identified in the antibiotic group. There were 8 cases of neonatal candidai sepsis: 5 in the placebo group (1.6%) and 3 in the antibiotic group (0.7%; P=.45). COMMENT The purpose of this trial was to evalu¬ ate the ability of antibiotic treatment to reduce infant morbidity and mortality subsequent to expectant management of PPROM remote from term. Meta-analy¬ sis of similar trials has demonstrated a lack of effect on respiratory distress, the most Placebo (n=299) 2.3 .60 0.44(0.04-4.75) .45 2.21 (0.45-10.94) .33 1.52(0.21-1.88) .42 Antibiotics frequent gestational age-depen¬ dent morbidity in this population.20 Pre¬ vious trials have allowed inclusion of many pregnancies with membrane rup¬ ture near term. These infants were at low risk for perinatal morbidity and could not have benefited from the study intervention. Thus, we elected to include pregnancies with membrane rupture re¬ mote from term (between 24 weeks' and 0 days' gestation and 32 weeks' and 0 days' gestation), where pregnancy pro¬ longation could reasonably be expected to reduce gestational age-dependent morbidity. Recognizing that antibiotics might improve neonatal outcome through either a reduction in gestational age-dependent or infectious morbidity, we elected to use a composite primary outcome encompassing a number of se¬ rious acute morbidities that are associ¬ ated with long-term adverse sequelae. The use of a composite morbidity makes Downloaded from jama.ama-assn.org at University of Kansas on April 1, 2012 intrauterine infection that could shorten latency. The efficacy and safety of corticoste¬ 50- 9 10 11 Latency, 12 13 14 15 16 17 18 19 20 21 d Figure 2.—Interval from randomization to delivery after expectant management of preterm premature rup¬ ture of the membranes at 24 weeks' and 0 days' gestation to 32 weeks' and 0 days' gestation according to antibiotic-group or placebo-group assignment. The values reflect analysis of percentage of women whose neonates remained undelivered. For the survival it more difficult to demonstrate a benefit of treatment since failure to prevent all serious complications in an infant origi¬ nally destined to suffer 2 or more com¬ plications would be considered a treat¬ ment failure. Despite this, we have been able to demonstrate reductions in com¬ posite morbidity as well as individual gestational age-dependent and infec¬ tious morbidities with antibiotic treat¬ ment during expectant management of PPROM remote from term. Current practice guidelines recom¬ mend antibiotic prophylaxis during la¬ bor for grávidas with positive GBS cul¬ tures and for those delivering preterm when culture results are not available. Our purpose was to evaluate antibiotic treatment during expectant manage¬ ment rather than treatment during la¬ bor. We recognized the potential confu¬ sion with confounding intrapartum GBS prophylaxis and elected to culture for GBS and exclude carriers from the pri¬ mary analysis. In this way, we were able to evaluate the specific value of antibi¬ otic administration prior to the onset of labor. Antibiotic therapy during the ex¬ pectant management of PPROM remote from term reduced the incidence of com¬ posite fetal-infant morbidity, as well as gestational age-dependent morbidity (respiratory distress syndrome, oxygen therapy, bronchopulmonary dysplasia, and hyperbilirubinemia) and infectious morbidity (documented sepsis before discharge and pneumonia) among wom¬ en not colonized with GBS. Antibiotic analysis, P<.001. therapy was associated with a reduced incidence of clinically diagnosed intra¬ uterine infection (amnionitis) without causing evident maternal or neonatal superinfection or fungal infection. We found no significant benefit from additional antibiotic therapy among GBS carriers, but our study had inadequate power to state confidently that such ad¬ ditional treatment does not help infants of maternal GBS carriers. As the current guidelines ofthe American College of Ob¬ stetricians and Gynecologists and the Centers for Disease Control and Preven¬ tion do not support routine early prenatal screening, the carrier status of most women presenting with PPROM remote from term will not be known.13,15 Our sec¬ ondary analysis of the total population suggests that women presenting with PPROM and unknown culture status can be counseled that antenatal maternal an¬ tibiotic therapy will significantly prolong pregnancy, reduce the incidence of com¬ posite fetal-infant morbidity, and reduce the incidence of respiratory distress syn¬ drome as well as stage 2 to 3 necrotizing enterocolitis. Previous trials of antibiotic therapy after PPROM have documented in¬ creased latency.610 Our data confirm that antibiotic treatment enhances latency. This benefit is long lasting, with twice as many women remaining undelivered 2 and 3 weeks after randomization (P<.001 and P=.008, respectively), and suggests that antibiotic treatment sup¬ presses or prevents clinically significant roid administration for fetal maturation in the setting of PPROM has been ques¬ tioned because of the brief latency and concern regarding the potential for in¬ creased neonatal infection. When this study was initiated, the majority of phy¬ sicians in the United States and in the participating clinical centers did not give corticosteroids to women with PPROM.19 By prohibiting corticosteroid treatment within this protocol, we have been able to demonstrate a direct correlation between antibiotic therapy and less frequent res¬ piratory distress syndrome. This effect is likely caused by the significant prolonga¬ tion of pregnancy with antibiotic treat¬ ment. Alternatively, had corticosteroid administration been permitted within this trial, it would have been unclear whether the reduction in respiratory dis¬ tress was due to antibiotics or corticoste¬ roids. The National Institute of Child Health and Human Development consen¬ sus conference on the use of corticoste¬ roids recommended corticosteroid ad¬ ministration to reduce intraventricular hemorrhage after PPROM at less than 30 to 32 weeks' gestation.19 We do not antici¬ pate that such a change in clinical practice should alter our recommendations re¬ garding antibiotic therapy in this setting. Antibiotic administration leads to shortterm pregnancy prolongation and in¬ creases the number of grávidas remain¬ ing pregnant long enough to accrue corticosteroid benefit. A broad spectrum of aerobic and an¬ aerobic bacteria and mycoplasmas have been implicated as causative agents for intrauterine infection at the time of pre¬ term delivery and PPROM.6·2129 A num¬ ber of antimicrobial regimens have pre¬ viously been studied, including initial parenteral therapy followed by pro¬ longed oral therapy, only oral therapy, or only parenteral therapy.612,29"36 A va¬ riety of penicillins, cephalosporins, eryth¬ romycin, and multiagent regimens have been studied. A recent trial suggested en¬ hanced spectrum ampicillin therapy to be superior to ampicillin therapy alone.37 Published trials of ampicillin and eryth¬ romycin have demonstrated efficacy pro¬ longing pregnancy after PPROM.6·7,9,29 Additionally, antibiotic therapy has been shown to reduce the incidence of clinical amnionitis.8,12,30,31,36 Oral therapy with erythromycin, however, has not consis¬ tently reduced maternal or infant infec¬ tious morbidity.6,9 Similarly, a 72-hour regimen with piperacillin did not reduce neonatal infectious complications. We chose a regimen of ampicillin-amoxicillin and erythromycin because of its broad antimicrobial spectrum (including Urea- Downloaded from jama.ama-assn.org at University of Kansas on April 1, 2012 plasma urealyticum). Initial intrave¬ nous therapy was given to provide rapid and adequate maternal tissue levels. This was followed by prolonged maintenance oral therapy. The antibiotic regimen was discontinued after 7 days to reduce the potential for selection of resistant organ¬ isms. It is possible that other regimens will be effective in this clinical setting. In summary, antibiotic treatment of expectantly managed women with PPROM at 24 weeks' and 0 days' to 32 weeks' and 0 days' gestation will reduce infectious and gestational age-depen¬ dent infant morbidity. Treatment leads to less frequent clinical amnionitis and significantly enhanced pregnancy pro¬ longation. The patient presenting with PPROM and unknown GBS culture sta- tus can be counseled that her fetus could benefit from such intervention. All wom¬ en undergoing expectant management of PPROM remote from term should re¬ ceive antibiotics prior to the onset of la¬ bor, regardless of GBS carrier status. Protocol Subcommittee: B. Mercer, MD (chair); M. Miodovnik, MD; G. Thurnau, MD; R. Goldenberg, MD; A. Das, MS; R. Ramsey, BSN; Y. Rabello, MSEd; E. Thorn, PhD; D. McNeills, MD. In addition to the authors, participating members of the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Net¬ work were as follows: J. Hauth, R. Copper, D. Davis, University of Alabama, Birmingham; E. MuellerHeubach, M. Swain, G. Phillips, Bowman Gray School of Medicine, Winston-Salem, NC; M. Lindheimer, P. Jones, M. Brown, University of Chicago, Chicago, 111; T. Siddiqi, N. Elder, University of Cin¬ cinnati, Cincinnati, Ohio; R. Bain, J. Evans, E. Row¬ land, George Washington University Biostatistics Center, Washington, DC; S. Yaffe, C. Catz, M. Klebanoff, National Institute of Child Health and Hu¬ man Development, Bethesda, Md; M. Landon, F. Johnson, S. Meadows, Ohio State University, Colum¬ bus; J. Carey, A. Meier, V. Minton, University of Oklahoma, Oklahoma City ; R. Newman, B. Collins, S. Stramm, Medical University of South Carolina, Charleston; S. Caritis, J. Harger, P. Cotroneo, Uni¬ versity of Pittsburgh, Pittsburgh, Pa; B. Sibai, L. Manners, University of Tennessee, Memphis; M. Dombrowski, G. Norman, D. Wilson-Lacey, Wayne State University, Detroit, Mich; C. Kovacs, D. McCart, University of Southern California, Los An¬ geles County Hospital; and M. Dinsmoor, S. McCoy, Medical College of Virginia, Richmond. This study was funded by grants U10-HD-21434, U10-HD-27917, U10-HD-27915, U10-HD-27869, U10HD-27905, U10-HD-27861, U10-HD-27860, U10-HD27889, U10-HD-27883, U10-HD-21414, and U10-HD- 19897 from the National Institute of Child Health and Human Development, Bethesda, Md. The authors are indebted to R. Depp, MD, R. Romero, MD, and S. Korones, MD, for their contri¬ butions during the development of this trial. References PJ, Ernest JM, Moore ML. Causes of low birth weight births in public and private patients. Am J Obstet Gynecol. 1987;156:1165-1168. 2. Alger LS, Lovchik JC, Hebel JR, Blackmon LR, Crenshaw MC. 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