Premature rupture of the membranes: effect of penicillin prophylaxis and long-term outcome of the children. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of the membranes. A randomized controlled trial. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Use of ampicillin and corticosteroids in premature rupture of membranes: a randomized study. Erythromycin therapy in preterm premature rupture of the membranes: a prospective, randomized trial of 220 patients. Antibiotic therapy for preterm premature rupture of membranes - results of a multicenter study. Double-blind; placebo-controlled trial of piperacillin prophylaxis in preterm membrane rupture. Antibiotic therapy in preterm premature rupture of membranes: a randomized, prospective, double-blind trial. Randomized trial of prophylactic antibiotic therapy after preterm amnion rupture. Ampicillin prophylaxis in preterm premature rupture of the membranes: a prospective randomized study. Antimicrobial therapy in preterm premature rupture of membranes: results of a prospective, double-blind, placebo-controlled trial of erythromycin. Group B Streptococcus and preterm premature rupture of membranes: a randomized, double-blind clinical trial of antepartum ampicillin. A prospective, randomized, placebo-controlled trial of penicillin in preterm premature rupture of membranes. Duration of antibiotic therapy after preterm premature rupture of fetal membranes. Expectant management of preterm ruptured membranes: effects of antimicrobial therapy. Antibiotic therapy in preterm premature rupture of membranes: Are seven days necessary? A preliminary, randomized clinical trial. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. ORACLE Collaborative Group.
To assess the value of prophylaxis with penicillin in women with premature rupture of membranes (PROM) and the long-term outcome of children born after prolonged PROM, we studied 221 women with this condition. Penicillin (5 mu twice, 6 hours apart) was given intravenously to 50 women and placebo to 51 women, whereas 76 comparable patients were treated without penicillin or placebo. The time interval between PROM and delivery ranged from 14 hours to 56 days. Chorioamnionitis occurred more frequently (p less than 0.05) among patients with placebo (14%) than among those treated with penicillin (2%). One puerperal endometritis appeared in the placebo group compared with none in the penicillin group. One newborn (1.7%) born to a mother with placebo prophylaxis developed septicemia, compared with none in the penicillin group. The outcomes of pregnancies complicated with PROM treated without penicillin or placebo were comparable with those in the placebo group. In addition, we compared somatic and psychomotor development of 159 children born to mothers with prolonged PROM (more than 12 hours; mean, 5.6 days; range, 14 to 1344 hours) with those of 43 children born at similar gestational age within 5 hours after PROM. No pulmonary sequelae could be linked to the long time period between PROM and delivery, but infants born soon after PROM more often (p less than 0.05) had cerebral palsy (8 of 43, 18.6%) than did infants born after prolonged PROM (7 of 159; 4.4%). We conclude that, in cases with PROM, penicillin prophylaxis decreases maternal and neonatal infectious morbidity and that the long interval between PROM and delivery does not impair the long-term outcome for these children. Intrauterine infection is thought to be one cause of preterm premature rupture of the membranes (PPROM). Antibiotic therapy has been shown to prolong pregnancy, but the effect on infant morbidity has been inconsistent.
                To determine if antibiotic treatment during expectant management of PPROM will reduce infant morbidity.
                Randomized, double-blind, placebo-controlled trial.
                University hospitals of the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
                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.
                Intravenous ampicillin (2-g dose every 6 hours) and erythromycin (250-mg dose every 6 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.
                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.
                In the total study population, the primary outcome (44.1 % vs 52.9%; 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).
                We recommend that women with expectantly managed PPROM remote from term receive antibiotics to reduce infant morbidity. A randomized study was conducted to investigate the effects of antenatal corticosteroids and ampicillin in the management of preterm pregnancies under 34 weeks complicated by premature rupture of membranes. Patients with documented lecithin/sphingomyelin (L/S) ratios of less than 2.0 and a singleton gestation were eligible to participate in the study. One hundred sixty-five patients qualified and were randomized, using sealed envelopes, to four study groups. All patients were followed expectantly. Group I (41 patients) received neither ampicillin nor corticosteroids. Group II (43 patients) received 24 mg of antenatal betamethasone. Group III (37 patients) received 2 g of intravenous ampicillin every 6 hours, with discontinuation of antibiotic therapy if cultures were negative for pathogenic bacteria. Group IV (44 patients) received both corticosteroids and ampicillin as described for groups II and III, respectively. Compared with patients not receiving corticosteroids, those administered antenatal corticosteroids experienced a reduction in the incidences of respiratory distress syndrome (53 versus 26%), bronchopulmonary dysplasia (23 versus 9%), severe grades of intracranial hemorrhage (15 versus 3%), and patent ductus arteriosus (18 versus 6%), with no difference in the incidence of maternal or neonatal infection. Compared with patients not receiving antenatal antibiotics, the group of patients treated with ampicillin on admission had a lower incidence of clinical chorioamnionitis (4 versus 26%) and neonatal sepsis (5 versus 10%). This reduction in infectious morbidity by antenatal ampicillin was restricted to those patients (28.4% of the study population) colonized with group B streptococci.(ABSTRACT TRUNCATED AT 250 WORDS) The use of prophylactic antibiotics in the management of preterm premature rupture of the membranes has not been adequately studied. The purpose of this study was to evaluate the efficacy of oral erythromycin therapy in the prolongation of latency and reduction of infectious morbidity after preterm premature rupture of membranes.
                In this randomized, prospective, double-blind, placebo-controlled study, 220 women at 20 to 35 weeks' gestation were evaluated. Subjects received oral erythromycin 333 mg (n = 106) or indistinguishable placebo (n = 114) every 8 hours from randomization to delivery.
                Prolongation of latency was identified with erythromycin therapy (p = 0.02), particularly for those destined to have chorioamnionitis (p = 0.003) and those with oligohydramnios (p = 0.01). No decrease in the incidence of maternal or neonatal infectious morbidity was seen.
                Oral erythromycin delays, but does not prevent, the onset of clinical infection when administered to women with preterm premature rupture of membranes. This regimen does not decrease neonatal morbidity and mortality. To evaluate whether primary application of mezlozillin in preterm premature rupture of membranes (pPROM) prolongs pregnancy and lowers neonatal morbidity.
                In this prospective, randomized, double blind, placebo-controlled multicenter study a total of 105 pregnant women with pPROM between 24 + 0 and 32 + 6 weeks of gestation were examined receiving i.v. injections of corticoids and tocolytics as well as mezlocillin (3 x 2 g/d) or placebo. Assessed factors were prolongation of pregnancy and neonatal morbidity such as neonatal infection, respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC).
                Prolongation of pregnancy by more than 7 days was achieved in 63.8% of the mezlocillin group versus 44.8% of the placebo group (P < 0.05). The babies of mothers treated with anibiotics had fewer neonatal infections, RDS, IVH and NEC. Total morbidity was significantly lowered in the verum group (P = 0.02).
                Antibiotic administration following preterm premature rupture of membranes is associated with a prolongation of pregnancy and a reduction of neonatal infectious morbidity. We attempted to test whether antibiotic therapy prolongs pregnancy in preterm premature rupture of membranes, because preterm premature rupture of membranes is frequently associated with chorionic-decidual infection.
                Women with preterm premature rupture of membranes and a singleton gestation at 24 to 34 completed weeks were randomized to receive either piperacillin 3 gm or placebo intravenously every 6 hours for 72 hours and were managed conservatively until spontaneous delivery, chorioamnionitis, or fetal distress.
                Between January 1987 and January 1992, a total of 75 patients were randomized to receive piperacillin (n = 38) or placebo (n = 37). There were no differences between the piperacillin group and the placebo group in mean gestational age at randomization (30.2 +/- 3 vs 30.3 +/- 2.9 weeks). However, a greater number of patients had pregnancy prolonged beyond 7 days (42.1% vs 10.8% p = 0.005) and the mean latency period was significantly prolonged (11.4 +/- 18.8 vs 6.1 +/- 13.6 days, p = 0.001) in the piperacillin group compared with the control groups.
                Use of intravenous piperacillin for 72 hours in preterm premature rupture of membranes significantly prolongs the latency period between membrane rupture and delivery. The use of antibiotics in the management of preterm, premature rupture of membranes remains controversial. By use of a prospective randomized double-blind design we investigated the maternal-fetal benefits associated with antibiotic therapy in 85 women with premature rupture of membranes at 34 weeks' estimated gestational age. In the treatment group 40 patients received intravenous mezlocillin for 48 hours followed by oral ampicillin until delivery. In the control group 45 patients received intravenous and oral placebo. Patients who received antibiotics had chorioamnionitis and endometritis less frequently than the control group (p less than 0.01 and p less than 0.05). Pathologic examination of the placentas showed a lower incidence of chorioamnionitis in the treatment group (p less than 0.05). The period from premature rupture of membranes to delivery (latency) was prolonged with antibiotics (p less than 0.05) and resulted in significant weight gain in the infants in the antibiotic group (p less than 0.0001). These infants also had higher 1- and 5-minute Apgar scores. Clinically suspected sepsis, respiratory distress syndrome, intraventricular hemorrhage, perinatal death rate, and prolonged hospitalization (greater than 30 days) were also increased in the control group. Our purpose was to determine whether maternal administration of prophylactic ampicillin or erythromycin after preterm amnion rupture is associated with maternal or neonatal benefits.
                Women with singleton pregnancies between 24 and 33 weeks 6 days of gestation were eligible if they had no immediate indication for delivery. After giving informed consent, patients were randomized either to receive ampicillin (erythromycin if penicillin allergic) until delivery or to enter a control group. Women whose cervical cultures were positive for either group B streptococci or Neisseria gonorrhoeae received treatment. Tocolytics and corticosteroids were not used.
                From January 1990 to February 1992 117 patients (antibiotics 59, control 58) were recruited and analyzed. Prophylactic antibiotics were associated with a longer latent phase (mean 12 vs 7.0 days, p = 0.004) and fewer maternal infectious complications (29% vs 60%, p = 0.001). A higher incidence of neonatal necrotizing enterocolitis was observed in the treatment group (14% vs 3.5%, p = 0.05). Other neonatal complications, including death, were lower in the treatment group, but none attained statistical significance (p = 0.09 to 0.33).
                The use of prophylactic antibiotics in selected patients after preterm amnion rupture appears to have a demonstrable maternal benefit. Large, multicenter trials may demonstrate a significant neonatal benefit or confirm any adverse outcomes. It is hypothesized that ampicillin may treat subclinical deciduitis and prolong the "effective" latent period in patients with preterm premature rupture of the membranes. We studied 82 patients with preterm rupture of membranes who were managed expectantly and were randomly assigned either to receive ampicillin prophylaxis (n = 43) or not to receive ampicillin prophylaxis (n = 39). Patients were excluded from study entry on admission if they had suspected or frank chorioamnionitis, active preterm labor, a history of penicillin allergy, multiple gestation, or cervical cerclage. There were no significant differences between the groups in duration of membrane rupture prior to admission, gestational age at membrane rupture, use of steroids and tocolysis, and demographic factors. Life-table analysis showed that the risk of delivery was significantly lower for the group of patients receiving prophylactic ampicillin. The incidence of neonatal infection was significantly lower in the ampicillin group, 1 (2%) versus 6 (17%), p less than 0.04. This study was conducted to evaluate the effectiveness of oral erythromycin treatment in safely prolonging pregnancy among women experiencing preterm premature rupture of membranes. Sixty-five women were randomly assigned to receive double-blind treatment with either erythromycin base or an identical-appearing placebo three times daily for 7 days. Only women between 23 and 34 completed weeks' gestation who did not have an indication for delivery were enrolled in the study. Pretreatment microbiologic tests were obtained and women were followed expectantly. Fifty-five women and their newborns completed the protocol and were fully evaluated. Overall, time from rupture of membranes to onset of labor and to delivery was longer, although not significantly, for erythromycin-treated women. Similarly, there was a trend for reduced neonatal intensive care (level II, p = 0.07). When gestational age at enrollment was controlled, erythromycin treatment of women between 28 to 32 weeks' gestation was associated with a prolonged interval from enrollment to delivery [erythromycin: 292 hours (5 to 679); placebo: 54 (12 to 323); p less than 0.044]. Fifty percent of erythromycin-treated women between 28 to 32 weeks' gestation continued their pregnancies at least 13 days after premature rupture of membranes, whereas 50% of placebo-treated women were delivered of infants within 4 days (p = 0.02). Erythromycin treatment among women less than 28 and between 33 to 34 weeks' gestation was not associated with prolonged latency or other changes. There were no differences between erythromycin- and placebo-treated women in the occurrence of clinically recognized chorioamnionitis, postpartum endometritis, or neonatal infectious morbidity. In this double-blind, placebo-controlled trial, erythromycin treatment was well tolerated, safe, and associated with prolongation of pregnancy and reduced intensive neonatal care requirements for selected mother-newborn pairs with preterm premature rupture of membranes. Our purpose was to determine whether ampicillin prolongs the latency period after preterm premature rupture of membranes in patients colonized with group B Streptococcus.
                Sixty patients presenting at < or = 35 weeks' gestation with preterm premature rupture of membranes were included in the study. Cervical, vaginal, and perianal cultures for group B premature rupture were obtained. The participants then were randomized to receive either ampicillin or placebo intravenously for 24 hours and then orally until hospital discharge or delivery. All patients were treated without the use of tocolytic drugs. The chi(2) test, Fisher exact test, Student t test, and Wilcoxon signed-rank test were used for statistical analysis when appropriate.
                Fifteen patients had cultures positive for group B Streptococcus. Patients with cultures positive for group B Streptococcus who received ampicillin (n = 8) were more likely not to have been delivered of their infants 48 hours after preterm premature rupture of membranes than patients who received placebo (n = 7), a statistically significant difference (100% vs 43%; p = 0.01; relative risk 2.3; 95% confidence interval 1.2 to 4.5). Seven days after preterm premature rupture of membranes, however, there was no significant difference in percentage of patients with cultures positive for group B Streptococcus who remained undelivered (63% vs 29%; p = 0.19; relative risk, 2.2; 95% confidence interval 0.7 to 7.1). Among patients with cultures negative for group B Streptococcus, there was a trend for patients who received ampicillin to remain undelivered 48 hours after preterm premature rupture of membranes compared with those who received placebo, but the difference was not statistically significant (87% vs 64%; p = 0.07; relative risk, 1.4; 95% confidence interval 1.0 to 1.9). There also was no difference in percentage of patients with cultures negative for group B Streptococcus who remained undelivered 7 days after preterm premature rupture of membranes 39% vs 27%; p = 0.40; relative risk, 1.4; 95% confidence interval 0.61 to 3.3). There were no differences between the treatment and placebo arms of the group B Streptococcus positive and negative cohorts in incidence of cesarean section, chorioamnionitis, postpartum endometritis, or neonatal infectious morbidity.
                Use of antibiotics increases the percentage of patients with cultures positive for group B Streptococcus who remain undelivered 48 hours after preterm premature rupture of membranes. Antibiotic therapy may provide a window of opportunity for maternal treatment with corticosteroids to decrease the risk for neonatal morbidity among these preterm gestations. Preterm premature rupture of the fetal membranes is common and frequently results in infectious complications. A prospective, randomized, controlled trial of penicillin versus placebo in preterm premature rupture of membranes is reported. The aim of the study was to determine if prophylactic antibiotics after preterm premature rupture of membranes would reduce infectious complications in the mother or neonate.
                Patients with preterm premature rupture of membranes between 21 and 37 weeks' gestation were randomized into a penicillin group that received 1 million units of benzylpenicillin intravenously every 4 hours followed by 250 mg of potassium phenoxymethyl penicillin (Pen-Vee K, Wyeth-Ayerst) orally twice daily or a placebo group before delivery. Latency period, infectious complications, and neonatal outcomes were studied.
                Patients with preterm premature rupture of membranes who received prophylactic penicillin had fewer infectious complications, including intraamniotic infection and postpartum endometritis (4 vs 11, p < 0.03), without adverse effects on the mother or fetus.
                Prophylactic penicillin in patients with preterm premature rupture of membranes reduces maternal infectious complications without adversely affecting the mother or newborn. This study was undertaken to compare the efficacy of 3 days versus 7 days of ampicillin in prolonging gestation for at least 7 days in women with preterm premature rupture of membranes (PPROM).
                We performed a randomized clinical trial comparing 3 days of ampicillin with 7 days ampicillin in patients with PPROM. Our primary outcome was the prolongation of pregnancy for at least 7 days. Secondary outcomes included rates of chorioamnionitis, postpartum endometritis, and neonatal morbidity and mortality.
                Forty-eight patients were randomly selected. There was no statistically significant difference in the ability to achieve a 7-day latency (relative risk 0.83, 95% CI 0.51-1.38). In addition, there was no statistically significant difference in the rates of chorioamnionitis, endometritis, and our composite neonatal morbidity.
                In patients with PPROM, length of antibiotic therapy does not change the rate of a 7-day latency or affect the rate of chorioamnionitis, postpartum endometritis, or neonatal morbidity. To determine whether the addition of broad-spectrum antimicrobial therapy to traditional expectant management improves pregnancy outcome in patients with premature rupture of membranes (PROM) remote from term.
                Patients with preterm PROM before 34 weeks' gestation who were not in labor and had no signs of infection or fetal distress were randomized to one of two study groups: 1) expectant management alone and 2) expectant management plus antimicrobial therapy. Women in the latter group received intravenous ampicillin, gentamicin, and clindamycin for 24 hours, followed by amoxicillin plus clavulanic acid orally for 7 days. Other than antibiotic use, management of the two groups was identical.
                Significantly more women (P < .01) treated with antibiotics (20 of 48, 42%) remained undelivered 7 days after admission compared with those managed expectantly without antibiotics (seven of 46, 15%). In addition, more neonates in the group managed with antibiotics were admitted to the routine nursery (nine of 48 versus two of 45; P = .03). However, there was no difference between the groups in the frequency of serious maternal or neonatal morbidity.
                The addition of broad-spectrum antimicrobial therapy to traditional expectant management of pregnancy complicated by preterm PROM may increase the number of gestations undelivered 7 days after admission. It may also decrease the proportion of infants admitted to special care nurseries. Whether these effects result in significant short- or long-term maternal or neonatal benefit remains to be determined. The purpose of this study was to determine whether 3 days of broad-spectrum antibiotic therapy, which is intended to prolong latency in patients with preterm premature rupture of membranes, is comparable to 7 days of therapy.
                Patients with preterm premature rupture of membranes at three separate study sites were asked to participate in this intent-to-treat, prospective, randomized trial. They were assigned randomly to either 3 or 7 days of ampicillin-sulbactam (3 g intravenously every 6 hours). The primary outcome of interest was the latency period from membrane rupture to delivery.
                Forty-two individuals were enrolled in each group. No difference was noted in the latency interval between the two groups (3 days, 214 +/- 225 hours, vs 7 days, 229 +/- 218 hours). A significantly higher number of patients in the 3-day group completed therapy (80.1% vs 47.6%, P =.003). No other parameters were significantly different between the two groups. No adverse events or trends were noted in either group.
                There appears to be no difference in the latency period between 3 and 7 days of ampicillin-sulbactam antibiotic therapy. More patients are needed to exclude a type II error. Preterm, prelabour rupture of the fetal membranes (pPROM) is the commonest antecedent of preterm birth, and can lead to death, neonatal disease, and long-term disability. Previous small trials of antibiotics for pPROM suggested some health benefits for the neonate, but the results were inconclusive. We did a randomised multicentre trial to try to resolve this issue.
                4826 women with pPROM were randomly assigned 250 mg erythromycin (n=1197), 325 mg co-amoxiclav (250 mg amoxicillin plus 125 mg clavulanic acid; n=1212), both (n=1192), or placebo (n=1225) four times daily for 10 days or until delivery. The primary outcome measure was a composite of neonatal death, chronic lung disease, or major cerebral abnormality on ultrasonography before discharge from hospital. Analysis was by intention to treat.
                Two women were lost to follow-up, and there were 15 protocol violations. Among all 2415 infants born to women allocated erythromycin only or placebo, fewer had the primary composite outcome in the erythromycin group (151 of 1190 [12.7%] vs 186 of 1225 [15.2%], p=0.08) than in the placebo group. Among the 2260 singletons in this comparison, significantly fewer had the composite primary outcome in the erythromycin group (125 of 1111 [11.2%] vs 166 of 1149 [14.4%], p=0.02). Co-amoxiclav only and co-amoxiclav plus erythromycin had no benefit over placebo with regard to this outcome in all infants or in singletons only. Use of erythromycin was also associated with prolongation of pregnancy, reductions in neonatal treatment with surfactant, decreases in oxygen dependence at 28 days of age and older, fewer major cerebral abnormalities on ultrasonography before discharge, and fewer positive blood cultures. Although co-amoxiclav only and co-amoxiclav plus erythromycin were associated with prolongation of pregnancy, they were also associated with a significantly higher rate of neonatal necrotising enterocolitis.
                Erythromycin for women with pPROM is associated with a range of health benefits for the neonate, and thus a probable reduction in childhood disability. However, co-amoxiclav cannot be routinely recommended for pPROM because of its association with neonatal necrotising enterocolitis. A follow-up study of childhood development and disability after pPROM is planned.
The decision to prescribe antibiotics for women with PROM is not clearcut. Benefits in some short-term outcomes (prolongation of pregnancy, infection, less abnormal cerebral ultrasound before discharge from hospital) should be balanced against a lack of evidence of benefit for others, including perinatal mortality, and longer term outcomes. If antibiotics are prescribed it is unclear which would be the antibiotic of choice.
Co-amoxiclav should be avoided in women at risk of preterm delivery due to increased risk of neonatal necrotising enterocolitis.