Ampicillin prophylaxis in preterm premature rupture of the membranes: A prospective randomized study

American Journal of Obstetrics

and Gynecology Founded in 1920

volume 159

number 3

SEPTEMBER

1988

TRANSACTIONS OF THE EIGHTH ANNUAL MEETING OF THE SOCIETY OF PERINATAL OBSTETRICIANS Ampicillin prophylaxis in preterm premature rupture of the membranes: A prospective randomized study Erol Amon, MD," Samuel V. Lewis, MD," BahaM. Sibai, MD," Marco A. Villar, MD,b and Kristopher L. Arheart, MS< St. Louis, Missouri, and Memphis, Tennessee 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 < 0.04. (AM J OesTET GYNECOL 1988;159:539-43.)

Key words: Preterm labor or delivery; premature rupture of membranes; ampicillin and pregnancy Premature rupture of the membranes (PROM) in the preterm gestation remains one of the leading causes of preterm delivery and perinatal morbidity and mortality. Maternal and neonatal infection associated with PROM are important complicating factors. The incidence of chorioamnionitis ranges from 8% to 28% of patients with prolonged PROM and the incidence of neonatal infection ranges from 2% to 19%.' In randomized study patients managed expectantly from 28 to 34 weeks' gestation, about 50% will be delivered From the Departments of Obstetrics and Gynecology, Washington University School of Medicine," and the Departments of Obstetrics and Gynecology' and Biostatistics,' University of Tennessee College of Medicine, Memphis. Presented at the Eighth Annual Meeting of the Society of Perinatal Obstetricians, Las Vegas, Nevada, February 4-6, 1988. Reprint requests: Erol Amon, MD, 4911 Barnes Hospital Plaza, St. Louis, MO 63110.

within 48 hours of rupture of the membranes and about 80% to 90% will be delivered within a week of membrane rupture! Furthermore, in randomized study patients managed expectantly at 25 to 30 weeks' gestation about 25% will be delivered within 48 hours and 67% within 1 week of membrane rupture.' The use of antibiotics to prevent maternal and neonatal infections in the presence of ruptured membranes is not new but reports are limited. In a randomized prospective study from the early 1960s, Lebherz et al.< found that prophylactic demethyl chlortetracycline provided no benefit in the prevention of amnionitis and neonatal infection. However, they did find a reduction in the incidence of postpartum morbidity, primarily endometritis and parametritis. From 1971 to 1972, Gordon and Weingold5 performed a randomized study to determine the effectiveness of ampicillin prophylaxis in preterm (<37 weeks) PROM and found a reduction 539

540 Amon et al.

September 1988 Am J Obstet Gynecol

Table I. Clinical characteristics: Part I Gestational age at PROM Mean Median 20-25 wk 26-30 wk 31-34 wk Oligohydramnios(%) PROM to admission < 12 hr 12-24 hr 25-48 hr > 48 hr

Treatment

Control

30.1 ::t 3.2 30 4 (9%) 19 (44%) 20 (47%) 52

29.5 ::t 3.9 30

32 5 3 3

31

6 (15%)

15 (39%) 18 (46%) 65 6

2

0

p == ns. in postpartum maternal morbidity but not in perinatal mortality. In a nonrandomized, retrospective study of patients with preterm PROM (26 to 34 weeks), Miller et aJ.6 found that prophylactic ampicillin combined with antenatal steroids was associated with a significant reduction in the incidence of maternal and neonatal infectious complications. It is accepted that patients with PROM who develop significant intrauterine infections either begin to labor spontaneously or undergo active intervention with expeditious delivery as the goal. It has been suggested that the phospholipase A 2 -induced prostaglandin cascade can lead to preterm labor. 7 Subclinical deciduitis may lead to preterm labor. Therefore the early use of ampicillin may prolong the latent period. The purpose of this study was to determine if prophylactic ampicillin offered any protection from infectious complications or had any effect on prolonging the latent period.

Material and methods Rupture of the membranes was confirmed by a sterile speculum examination visualizing the pooling of amniotic fluid, by alkaline pH Nitrazine testing, and by the presence of ferning by microscopic examination. Gestational age was determined by menstrual history, prenatal records, and immediate ultrasound measurements. Endocervical cultures for gonococci and group B 13-hemolytic streptococci were performed. Rectal cultures for these organisms were not performed. Complete blood count and urine culture were also performed. On admission to the hospital patients were monitored in labor and delivery with continuous external fetal heart rate monitoring and tocodynamometry. Patients were excluded from entry on admission if they were not between 20 and 34 weeks' gestation or if they had suspected or obvious chorioamnionitis, active premature labor, multiple gestation, cervical cerclage, or a history of penicillin allergy.

After providing informed consent, 82 patients were then randomized into two study groups. The group of patients that received ampicillin prophylaxis was classified as the treatment group. The group of patients that was randomized not to receive ampicillin prophylaxis was classified as the control group. Patients in the treatment group (n = 43) received ampicillin 1 gm intravenously every 6 hours for the first 24 hours. They were then maintained on a regimen of 500 mg orally every 6 hours until they returned for delivery. At that time they were restarted on a regimen of I gm intravenously every 6 hours until delivery. After entry into the study patients in both groups who were experiencing preterm labor underwent tocolysis if there were no clinical contraindications. The presence of uterine activity per se did not constitute a contraindication to tocolysis. Antenatal steroids were used at the discretion of the attending physician. Fetal assessment included maternal perception of fetal activity, auscultation of the fetal heart rate, and weekly nonstress testing. The pregnancy was allowed to continue until a diagnosis of active labor, clinical chorioamnionitis, fetal distress, or significant vaginal bleeding was made. Vaginal bleeding was considered significant if in the opinion of the managing physician the bleeding was excessive or if a clinical diagnosis of abruptio placentae was made. Significant bleeding requiring delivery occurred in four patients. None of the patients had placenta previa. Delivery was attended by a neonatal intensive care unit physician. Clinical chorioamnionitis was defined, in the absence of other causes of fever, by a temperature ~38° C with either uterine tenderness or contractions, leukocytosis, maternal or fetal tachycardia, or foul-smelling amniotic fluid or a foul-smelling infant at delivery. Chorioamnionitis was suspected in patients who were clinically thought to have intraamniotic infection but did not meet the preceding criteria for clinical chroioamnionitis. Postpartum endometritis was defined as a temperature of ~38° C after the first 24 hours post partum, with the presence of uterine tenderness. Systemic neonatal infection was defined as a clinically ill infant with a diagnosis by the neonatologist within the first week of postnatal life and documented positive cultures. The two groups were analyzed with the independent t test for normally distributed interval level data, the Mann-Whitney U test for non parametrically distributed data, and the x" test (with Fisher's exact test when appropriate) for nominal data. Life-table analysis including Kaplan-Meier estimates and the modified Wilcoxon statistic was used to analyze the risk of delivery and the risk of developing clinical chorioamnionitis. Statistical significance was set at p < 0.05. This study was not blinded.

Ampicillin prophylaxis in PROM

Volume 159 Number 3

0

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00

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ff 8

0 0

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00 0 0

0 0 0

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541

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GROUP D Treatment

o Control

0 o~~~l~07 0~~~2o~o~~~3~oo~~~4~oo~J_~soo

HOURS FROM RANDOMIZATION TO DELIVERY

Fig. 1. Ampicillin prophylaxis and the cumulative risk of delivery over time.

Results Forty-three patients were randomly assigned to the treatment group and 39 were randomly assigned to the control group. There were no significant differences in maternal characteristics between both groups. Twenty-eight percent of patients were primigravid. Table I compares the prerandomization pregnancy characteristics. Comparisons of maternal demographics, gestational age at rupture of the membranes, incidence of oligohydramnios, and duration of membrane rupture prior to admission indicate that the process of randomization provided well-matched groups. Factors relating to clinical management after randomization are compared in Table II. These data indicate no significant differences in patient management between the two groups. Note that the incidences of chorioamnionitis and endometritis were actually slightly higher in the treatment group but not statistically different from those of the control group. Three of four patients harboring endocervical group B ~-hemolytic streptococci in the control group developed clinical chorioamnionitis and all were delivered within 40 hours of randomization. One of two such colonized patients in the treatment group developed clinical chorioamnionitis and was delivered of her infant 13 days after randomization. The other patient was delivered within 24 hours of randomization. The "effective" latent (randomization-to-delivery) interval was significantly prolonged in the group receiving ampicillin prophylaxis. Severity percent of the patients in the treatment group remained undelivered for at least 3 days after randomization compared with 44% of the control group. This difference was statistically significant (p < 0.02). Of perhaps greater clinical importance was the percent of pregnancies prolonged be-

Table II. Clinical characteristics: Part II Treatment

Tocolysis only Steroids only Both Neither Leaking stopped Chorioamnionitis Fetal distress Induction of labor Cesarean section Vertex presentation Endometritis

Control

n

%

n

%

7/43 4/43 6/43 26/43 5 7 7 6 10 35 5

16 9 14 61 12 16 16 14 23 81 12

4/39 5/39 4/39 26/39 5

10 13 10 67 13 10 26 13 23 82 8

4

10 5 9 32 3

p = ns. yond 1 week (47% versus 26%, p = 0.05). It was noted that patients with rupture of the membranes prior to 26 weeks had significantly longer latent intervals than those with rupture at greater gestational ages. With life-table analysis, the risk of delivery was significantly lower in the group receiving ampicillin prophylaxis. The cumulative probability of delivery over time for both groups is shown in Fig. 1. For presentation purposes cases with effective latent intervals >500 hours (two in each group) have been eliminated from the figure but not from the analysis. Patients with labor induced for noninfectious reasons (three in the treatment group and four in the control group) were considered "censored." The modified Wilcoxon statistic indicated that the two groups had significantly different probability curves (p < 0.04). Table III shows cumulative probabilities of delivery at different clinical times of interest. The risk of developing clinical chorioamnionitis was

542 Amon et al.

September 1988 Am .J Obstet Gynecol

Table III. Cumulative probability of delivery Time after randomization

24 hr 48 hr 72 hr I wk

2 wk

Treatment group

Control group

0.14 0.23 0.33 0.53 0.87

0.21 0.42 0.50 0.71 0.94

Table IV. Neonatal characteristics Treatment

Gestational age at delivery (wk) Mean:±: I SD Median Birth weight (gm) Mean:±: I SD Median Stillbirth Female infant Apgar score < 4 at I min Apgar score < 7 at 5 min Intraventricular hemorrhage Necrotizing enterocolitis Pulmonary complications Neonatal death Hospital stay >30 days Neonatal infection

31.5 ± 3.3 32

Control

30.7 :±: 3.2 31

1670 :±: 580 1750 1143 (2%) 17/43 (40%) 14/24 (33%) 5/42 (12%) 4/42 (10%)

1743 :±: 846 1750 3/39 (8%) 14/39 (36%) 9/36 (25%) 6/36 (17%) 6/36(17%)

5/42 (12%) 18/42 (43%) 1142 (2%) 14/42 (33%)

4/36 (1 I%) 15/36 (42%) 3/36 (8%) 11/36(31%)

l/42 (2%)

6/36 (I 7%)

For neonatal infection p < 0.04. For all other parameters

p = ns.

not significantly different between the two groups. By life-table analysis, the modified Wilcoxon statistic showed that the two probability curves were not statistically different (p = 0.5). However, five of seven patients in the treatment group developed chorioamnionitis after 200 hours, while all four patients in the control group developed chorioamnionitis within 72 hours. Evaluation of fetal and neonatal outcomes is shown in Table IV. Two of the three stillbirths in the control group occurred in infants who weighed 380 and 490 gm. In the first instance the pregnancy was prolonged for 220 hours, and in the second instance the pregnancy was prolonged for 78 hours. The third stillborn infant weighed 2360 gm. In this case stillbirth was due to the inappropriate perception of fetal well-being. Postdelivery review of the initial fetal monitor tracing revealed undiagnosed chronic fetal distress. Analysis of the stillbirth in the treatment group revealed that this infant died on day 6 after normal results of fetal testing and that the infant was growth retarded (weighing 990 gm at 31 weeks). Although the control group had a statistically higher incidence of neonatal infectious complications, there was no statistically significant difference in other parameters of neonatal outcome. There was a higher incidence of neonatal death in the control group

but this did not meet statistical significance. Two neonatal deaths in the control group occurred in infants with infectious neonatal complications. The neonatal death in the treatment group occurred on postnatal day 5 from complications of severe necrotizing enterocolitis.

Comment Preterm PROM remains an important complication in modern obstetrics. The management of this complication is controversial. Management varies widely, from rapid delivery, to the use of various tocolytic agents or glucocorticoids, to simple, unmedicated, expectant management. The purpose of this study was to determine the value of ampicillin prophylaxis in the prevention of infectious complications as well as to test its effectiveness in prolonging the latency interval. Ampicillin was chosen for study because it is safe for use during pregnancy, it provides coverage for many organisms of perinatal concern, it is inexpensive, and it transfers well into the fetal compartment. One of the major findings of this study is that the risk of delivery, in a select population of patients with preterm PROM, can be lowered significantly by ampicillin prophylaxis. At 72 hours after randomization, the risk of delivery was only 33% in the treatment group whereas it was 50% in the control group. Of greater clinical importance is that at 1 week the risk of delivery was only 53% in the treatment group but 71% in the control group. This study was unable to demonstrate a reduction in maternal infectious morbidity, but it did show a tendency, in the treatment group, to prolong the latent interval in patients who eventually developed clinical chorioamnionitis. Although not statistically significant, a trend favoring decreased neonatal and perinatal mortality in the treatment group is evident from the data. We consider this difference of 6% to be of potential clinical importance. If neonatal and perinatal death rates remained unchanged and if a power of 80% and an alpha level of 0.05 are assumed, then an increase to 221 patients per group would be required to show a statistically significant lower death rate in the treatment group. An analysis of other factors related to pregnancy prolongation and infectious complications is pertinent. Two different centers have reported that oligohydramnios is a significant risk factor for the development of maternal infection. 8 · 9 Gonik eta!." found no difference in the incidence of neonatal sepsis whereas Vintzileos et al. 9 found an increased incidence of neonatal infection in the group with oligohydramnios. Since oligohydramnios appears to be an important risk factor for the development of infection, it is important to note that its incidence was not significantly different between our study groups. Another variable associated with the duration of the latent period is the gestational age at

Ampicillin prophylaxis in PROM

Volume 159 Number 3

the time of PROM. Taylor and Garite 10 reported that more than 50% of selected patients with PROM at <26 weeks may have latent periods >72 hours and that almost 40% will have a latent period > 1 week. They found an inverse relationship between gestational age at membrane rupture and latent period. In contrast to the findings of Taylor and Garite, Beydoun and Yasin" did not find a strong inverse relationship between gestational age at membrane rupture and the latent period. Both studies suggest a longer latent period for uncomplicated midtrimester PROM compared with thirdtrimester PROM. This study confirms the longer latent period for patients <26 weeks' gestation. The results of our randomized study demonstrate an equal stratification between groups regarding the duration of membrane rupture prior to admission and the gestational age at membrane rupture. Another important variable that may have influenced the outcome was the use of tocolysis and steroids. A prospective randomized trial of ritodrine tocolysis in patients with preterm PROM revealed no clinical advantage to its use' whereas another trial' 2 found that ritodrine tocolysis was useful in prolonging pregnancy only 24 to 48 hours. Whether steroids predispose to the development of infection is a matter of debate and beyond the scope of this article. Such debate even exists among subspecialists within the same academic department. In this study the frequency of use of both steroids and tocolysis was not significantly different between groups. It is likely that the process of randomization also equally distributes unknown risk factors for pregnancy prolongation and maternal-neonatal infectious complications. Therefore it appears that ampicillin can independently prolong the "effective" latent interval. Our results also suggest that ampicillin prophylaxis, given to selected patients with preterm PROM, may decrease the incidence of neonatal infections. However, it does not appear to affect the incidence of maternal infectious complications. A caveat with regard to neonatal infection is that occasionally cultures are negative because the respective mothers are treated with antibiotics, yet the infants may still be clinically infected. Although we did not encounter any obvious problems with bacterial resistance or superinfection, the development of resistant strains of bacteria caused by widespread use of specific antibiotic agents is a real possibility. A potential concern regarding the use of ampicillin prophylaxis is the development of superinfection in both the mother and the infant. Unfortunately, our study was not designed to evaluate the development of resistant strains or superinfection. On further analysis we feel that two of our perinatal deaths may have been preventable. The fetal loss encountered in the treatment group might have been prevented with the use of daily fetal assessment in the form of the nonstress test" or the biophysical profile.'• The

543

nuances regarding the use of the fetal biophysical profile have been reviewed by Vintzileos et a!." Whether these daily approaches to fetal surveillance are more cost effective than other intensified surveillance methods remains to be determined. In summary, it appears that the use of ampicillin in selected patients can prolong gestation, can decrease the incidence of neonatal infection, and may potentially decrease neonatal mortality. Before we can recommend the clinical widespread use of ampicillin prophylaxis in selected patients with PROM, more studies are urgently needed to confirm these results and to address the issues of resistance and superinfection. REFERENCES I. Kitzmiller JL. Preterm premature rupture of the mem-

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