Therapy Morbidity Rupture for Reduction

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. The association of Chlamydia trachomatis, Neisseria gonorrhoeae, and group B
streptococci with preterm rupture of the membranes and pregnancy outcome. Am J Obstet Gynecol. 1988;159:397-404.
3. Gibbs RS, Romero R, Hillier SL, Eschenbach
DA, Sweet RL. A review of premature birth and
subclinical infection. Am J Obstet Gynecol. 1992;166:
1515-1528.
4. McGregor JA. Prevention of preterm birth: new
initiatives based on microbial-host interactions. Obstet Gynecol Surv. 1988;43:1-13.
5. Hillier SL, Witkin SS, Krohn MA, Watts DH,
Kiviat NB, Eschenbach DA. The relationship of amniotic fluid cytokines in preterm delivery, amniotic
fluid infection, histologic horioamnionitis, and chorioamnion infection. Obstet Gynecol. 1993;81:941\x=req-\
948.
6. Mercer B, Moretti M, Rogers R, Sibai B. Antibiotic prophylaxis in preterm premature rupture of
the membranes: prospective randomized doubleblind trial of 220 patients. Am J Obstet Gynecol.
1. Meis
1992;166:794-802.
E, Lewis SV, Sibai BM, Villar MA, ArAmpicillin prophylaxis in preterm premature rupture of the membranes: a prospective
randomized study. Am J Obstet Gynecol. 1988;159:
7. Amon
heart KL.
539-543.
8. Johnston
Todd
term
MM, Sanchez-Ramos L, Vaughn AJ,
MW, Benrubi GI. Antibiotic therapy in pre-
premature rupture of the membranes: a randomized prospective double-blind trial. Am J Obstet
Gynecol. 1990;163:743-747.
McGregor JA, French JI, Seo K. Antimicrobial
therapy in preterm premature rupture of membranes: results of a prospective, double-blind, placebo-controlled trial of erythromycin. Am J Obstet
Gynecol. 1991;165:632-640.
10. Christmas JT, Cox SM, Andrews W, Dax J, Leveno KJ, Gilstrap LC. Expectant management of preterm ruptured membranes: effects of antimicrobial
therapy. Obstet Gynecol. 1992;80:759-762.
11. Lockwood CJ, Costigan K, Ghidini A, et al.
Double-blind placebo-controlled trial of Piperacillin
prophylaxis in preterm membrane rupture. Am J
Obstet Gynecol. 1993;169:970-976.
12. Morales WJ, Angel JL, O'Brien WF, Knuppel
9.
RA. Use of ampicillin and corticosteroids in premature rupture ofthe membranes: a randomized study.
Obstet Gynecol. 1989;73:721-726.
13. Prevention of early-onset group B streptococcal disease in newborns. In: Committee Opinion:
ACOG Committee on Obstetric Practice. Washington, DC: American College of Obstetricians and Gynecologists; June 1996:1-8.
14. Committee on Infectious Diseases and Committee on Fetus and Newborn of the American Acad-
prevention of
group B streptococcal (GBS) infection by chemoproemy of Pediatrics. Guidelines for
phylaxis. Pediatrics. 1992;90:775-778.
15. Schuchat A. Prevention of perinatal group B
streptococcal disease: a public health perspective.
MMWR Morb Mortal Wkly Rep. 1996;45:1-24.
16. Wei LJ, Lachin JM. Properties of urn random-
ization in clinical trials. Control Clin Trials. 1988;9:
345-364.
17. Lan KKG, DeMets DL. Discrete sequential
boundaries for clinical trials. Biometrika. 1983;70:
659-663.
18. O'Brien PC, Fleming TR. A multiple testing
procedure for clinical trials. Biometrics. 1979;35:549\x=req-\
556.
19. National Institutes of Health Consensus Development Conference Statement: effects of corticosteroids for fetal maturation on perinatal outcomes,
February 28-March 2,1994. Am J Obstet Gynecol.
1995;173:246-252.
20. Mercer B, Arheart K. Antimicrobial therapy in
expectant management of preterm premature rupture of the membranes. Lancet. 1995;346:1271-1279.
21. Garite TJ, Freeman RK. Chorioamnionitis in the
preterm gestation. Obstet Gynecol. 1982;59:539-545.
22. Romero R, Ghidini A, Mazor M, Behnke E. Microbial invasion of the amniotic cavity in premature
rupture of membranes. Clin Obstet Gynecol. 1991;
34:769-778.
23. Cotton DB, Hill LM, Strassner HT, Platt LD,
Ledger WJ. The use of amniocentesis in preterm
gestation with ruptured membranes. Obstet Gynecol. 1984;63:38-48.
24. Vintzileos AL, Campbell WA, Nochimson DJ,
Weinbaum PJ, Escoto DT, Mirochnick MH. Qualitative amniotic fluid volume versus amniocentesis
in predicting infection in preterm premature rupture of the membranes. Obstet Gynecol. 1986;67:579\x=req-\
583.
25. Romero R, Quintero R, Oyarzune K, et al. Intraamniotic infection in the onset of labor in preterm
premature rupture of the membranes. Am J Obstet
Gynecol. 1988;159:661-666.
Gochay DW, Meyer WJ, Bieniarz A. Biophysical
profile as a predictor of amniotic fluid culture results. Obstet Gynecol. 1992;80:102-105.
26.
27. Broekhuizen FF, Gilman M, Hamilton PR. Amniocentesis for gram stain and culture in preterm
premature rupture ofthe membranes. Obstet Gyne-
col. 1985;66:316-321.
28. Romero R, Emamian M, Quintero R, et al. The
value and limitations of the gram stain examination
in the diagnosis of intra-amniotic infection. Am J
Obstet Gynecol. 1988;159:114-119.
29. Mc Caul JF, Perry KG, Moore JL, Martin RW, Bucovaz ED, Morrison JC. Adjunctive antibiotic treatment of women with preterm rupture of membranes
or preterm labor. Int J Gynecol Obstet. 1992;38:19-24.
30. Kurki T, Hallman M, Zilliacus R, Teramo K, Ylikorkala O. Premature rupture of the membranes:
effect of penicillin prophylaxis and long-term outcome of the children. Am J Perinatol. 1992;9:11-16.
31. Blanco J, Iams J, Artal R, et al. Multicenter
double-blind prospective random trial of ceftizoxime vs. placebo in women with preterm premature
ruptured membranes (pPROM). Am J Obstet Gynecol. 1993;168:378. Abstract.
32. Owen J, Groome LJ, Hauth JC. Randomized
trial of prophylactic antibiotic therapy after preterm amnion rupture. Am J Obstet Gynecol. 1993;
169:976-981.
33. Ernest JM, Givner LB. A prospective randomized placebo-control trial of penicillin in preterm premature rupture of membranes. Am J Obstet Gynecol. 1994;170:516-521.
34. Dunlop PDM, Crowley PA, Lamont RF, Hawkins DF. Preterm ruptured membranes, no contractions. J Obstet Gynecol. 1986;7:92-96.
35. Gordon M, Weingold AB. Treatment of patients
with rupture of the fetal membranes: (a) prior to 32
weeks; (b) after 32 weeks. Controvers Obstet Gynecol. 1974;2:42-44.
36. Debodinance P, Parmentier D, Devulder G,
Closset P, Querleu D, Crepin GIV. Peut-on reduire
le risque infectieux neonatal dans les ruptures prematurees des membranes. J Gynecol Obstet Biol
Reprod (Paris). 1990;19:533-536.
37. Lewis DF, Fontenot MT, Brooks GG, Wise R,
Perkins MB, Heymann AR. Latency period after
preterm premature rupture of the membranes:
comparison
tam. Obstet
a
of ampicillin with and without sulbac-
Gynecol. 1995;86:392-395.
Downloaded from jama.ama-assn.org at University of Kansas on April 1, 2012