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Broad-spectrum antibiotics for preterm, prelabour rupture of fetal


membranes: the ORACLE I randomised trial

S L Kenyon, D J Taylor, W Tarnow-Mordi, for the ORACLE Collaborative Group*

Summary Introduction
Preterm, prelabour rupture of the fetal membranes
Background Preterm, prelabour rupture of the fetal (pPROM) occurs in 2035% of pregnancies and is the
membranes (pPROM) is the commonest antecedent of commonest antecedent of preterm birth, being present in
preterm birth, and can lead to death, neonatal disease, and 3040% of cases.1 Although the latency period between
long-term disability. Previous small trials of antibiotics for fetal-membrane rupture and birth varies with gestation,
pPROM suggested some health benefits for the neonate, but spontaneous labour and birth is a consequence and can
the results were inconclusive. We did a randomised result in the complications of prematurityie, death;
multicentre trial to try to resolve this issue. short-term neonatal disease and long-term disability
(including cerebral palsy, blindness, and deafness); the
Methods 4826 women with pPROM were randomly assigned complications of infection including chorioamnioitis,
250 mg erythromycin (n=1197), 325 mg co-amoxiclav (250 maternal wound infection, and neonatal sepsis; and the
mg amoxicillin plus 125 mg clavulanic acid; n=1212), both complications of prolonged oligohydramnios including
(n=1192), or placebo (n=1225) four times daily for 10 days pulmonary hypoplasia, pneumothorax, and skeletal
or until delivery. The primary outcome measure was a deformities.1
composite of neonatal death, chronic lung disease, or major Usually, fetal-membrane rupture is preceded by
cerebral abnormality on ultrasonography before discharge structural weakness associated with extracellular-matrix
from hospital. Analysis was by intention to treat. degradation and cellular apoptosis,2,3 but a substantial
proportion of cases are associated with subclinical
Findings Two women were lost to follow-up, and there were chorioamnionitis.4 Micro-organisms are believed to
15 protocol violations. Among all 2415 infants born to degrade the fetal membranes either directly through
women allocated erythromycin only or placebo, fewer had the proteases or phospholipases, or indirectly by the activation
primary composite outcome in the erythromycin group (151 of collagenasesmembers of the matrix metalloproteinase
of 1190 [127%] vs 186 of 1225 [152%], p=008) than in family.5 Evidence for the role of subclinical
the placebo group. Among the 2260 singletons in this chorioamnionitis in pPROM comes from case-control and
comparison, significantly fewer had the composite primary cohort studies that have shown that women with
outcome in the erythromycin group (125 of 1111 [112%] vs pPROM have a higher rate of abnormal microbial
166 of 1149 [144%], p=002). Co-amoxiclav only and co- colonisation of the lower genital tracts than women who
amoxiclav plus erythromycin had no benefit over placebo with have normal births, and from microbiological studies of
regard to this outcome in all infants or in singletons only. Use amniotic fluid taken by amniocentesis from women with
of erythromycin was also associated with prolongation of pPROM. From published studies, the overall prevalence
pregnancy, reductions in neonatal treatment with surfactant, of positive amniotic-fluid cultures in such women is
decreases in oxygen dependence at 28 days of age and 3235%.4
older, fewer major cerebral abnormalities on ultrasonography Administration of antibiotics to the mother could
before discharge, and fewer positive blood cultures. Although therefore improve neonatal health and long-term child
co-amoxiclav only and co-amoxiclav plus erythromycin were health by preventing infectious morbidity in the fetus, or
associated with prolongation of pregnancy, they were also by delaying the progression to preterm birth. The most
associated with a significantly higher rate of neonatal recent Cochrane review of trials of antibiotics in pPROM6
necrotising enterocolitis. reported that antibiotics seem to be of benefit in the
reduction of the rate of maternal infection, delay of
Interpretation Erythromycin for women with pPROM is delivery, reduction of the rate of neonatal infection, and
associated with a range of health benefits for the neonate, reduction of the numbers of babies requiring neonatal
and thus a probable reduction in childhood disability. intensive care and ventilation for more than 28 days.
However, co-amoxiclav cannot be routinely recommended for However, the review did not show evidence of benefit for
pPROM because of its association with neonatal necrotising necrotising enterocolitis, major cerebral abnormality,
enterocolitis. A follow-up study of childhood development and respiratory distress syndrome, or death (either stillbirth or
disability after pPROM is planned. neonatal death).
We aimed to resolve the issue of whether the effects of
Lancet 2001; 357: 979-88 antibiotics on neonatal outcomes are variable or whether
See Commentary page ??? they are the consequence of biases associated with small
trials. Additionally, we aimed to test whether the
*Members listed at end of paper beneficial effects reported are related to the antibiotic type
Correspondence to: Sara Kenyon, Department of Obstetrics and used.7 Observational evidence has implicated a wide range
Gynaecology, Robert Kilpatrick Building, Leicester Royal Infirmary, of organisms in the genesis of pPROM. When deciding
PO Box 65, Leicester LE2 7LX, UK which antibiotics to test, we considered amoxicillin, co-
(e-mail: oracle@le.ac.uk) amoxiclav (amoxicillin/clavulanic acid), clindamycin,

THE LANCET Vol 357 March 31, 2001 979

Copyright 2001 All Rights Reserved


For personal use only. Reproduce with permission from The Lancet Publishing Group.
ARTICLES

erythromycin, metronidazole, and tetracycline. Tetra- contacted. A serious adverse event was defined as being
cycline would have been the antibiotic of choice, but it is fatal or life-threatening, disabling or incapacitating,
contraindicated in pregnancy because of damage to fetal requiring a lengthy hospital stay, resulting in congenital
bones and teeth.8 Co-amoxiclav and erythromycin have abnormality or cancer, or irreversible.
the broadest spectrum, the best complementary range of Three single-sided forms were completed at entry, at
activities, and provided the opportunity to test a -lactam discharge of the mother after delivery, and at death or
and a macrolide antibiotic. discharge of the baby if he or she was admitted to a
neonatal intensive-care unit or a special-care baby unit.
Participants and methods Incomplete and inconsistent data were checked at source
Participants and corrected. Data were managed according to UK
Pregnant women were eligible if their fetuses were at less Medical Research Council guidelines for good clinical
than 37 weeks of gestation, if pPROM was present, and if practice in trials.10 The trial was registered under the Data
the need to prescribe antibiotics was uncertain. These Protection Act at The University of Leicester. The UK
pragmatic entry criteria were designed to reflect normal data set was 100% complete and overall the data set was
clinical practice. Women were excluded if antibiotics were 999% complete. All data were entered and verified by
already being prescribed, or if they were thought to be two people on two separate occasions. A random sample
needed for infection. Exclusions also included the usual of paediatric data (10%) were checked against source
reasons for which a clinician would not give documentation. The data were accurate to within
antibioticsie, immediate delivery desirable or unstop- acceptable ranges (ie, 020% error). These checks were
pable; fetus not premature enough to cause concern; and done independently of the person completing the forms
contraindications such as allergy, jaundice, and use of and the person entering the data.
theophylline, carbamazepine, digoxin, disopyramide, Further information, including necropsy reports when
terfenadine, or astemizole (all of which are contra- appropriate, was collected on the babies who died. Death
indicated with erythromycin). was classified by use of an amended Wigglesworth
The trial was approved by the local research ethics classification.11 All deaths were classified independently by
committees of all 161 participating centres. Women gave the trial director and the trial paediatrician, who were
written informed consent. both unaware of treatment allocation. An internal audit
was done by the trial coordinator, and a randomly
Methods selected sample of 10% was verified by S Gould
Women were randomly assigned to one of four possible (Chairman of the UK Confidential Enquiry into Stillbirth
treatments: 325 mg co-amoxiclav (250 mg amoxicillin and Death in Infancy Death Classification Committee).
and 125 mg clavulanic acid) plus 250 mg erythromycin; The infant deaths will be the subject of another
co-amoxiclav plus erythromycin placebo; erythromycin publication.
plus co-amoxiclav placebo; or co-amoxiclav placebo plus Some characteristics of the women enrolled were
erythromycin placebo. Trial medicines were to be taken collected: maternal age, gestational age at randomisation,
orally, four times daily, for 10 days or until delivery. cervical dilatation, and drugs prescribed (-agonists,
Each woman was assigned a sequentially numbered corticosteroids, indomethacin, nifedipine, others). No
study-drug pack. The packs contained entry forms, data about past obstetric history and other fetal or
outcome forms, and the study drugs, which were identical maternal disease were collected.
in appearance and weight. An independent clinical- We used a composite primary outcome measure of
supplies company (DHP, Abergavenny, UK) did quality- death before discharge from hospital; or major adverse
control checks throughout the packing process, and 284 outcome in the baby before dischargeie, chronic lung
(2%) packs were randomly selected and analysed disease (defined as receiving daily supplementary oxygen
externally (Nova Laboratories) and confirmed to contain at age 36 weeks post conception); or major cerebral
the allocated medicines. Allocation to the four possible abnormality on ultrasonography before discharge.
treatments was by computer, with randomly selected The secondary outcome measures were: delivery within
blocks of four. Sequential use of the study-drug packs was 48 h and delivery within 7 days; mode of delivery; number
monitored by quarterly checks of pack use in each of days in hospital; maternal antibiotic prescription after
collaborating centre. Over the duration of this trial and a delivery and before discharge (total and within 14 days of
concurrent trial (see page 991),9 14 272 packs were randomisation); neonates gestational age at delivery
produced. There were 461 (32%) missing or void packs. (days); birthweight less than 2500 g or less than 1500 g;
Void packs were those opened by clinicians to randomise, admission to neonatal intensive-care unit or special-care
and the women did not give consent. baby unit; total number of babies ventilated; total number
After randomisation, data were collected on all women, of babies in more than 21% oxygen at 48 h, 7 days,
irrespective of whether trial medicines were actually 14 days, and 28 days of age; respiratory distress syndrome
dispensed or taken. For the purposes of analysis, women confirmed by chest radiograph; treatment with exogenous
remained in the treatment group to which they were surfactant; oxygen dependence at more than 28 days of
allocated (ie, intention-to-treat analyses are reported). age; positive blood culture indicative of clinical infection
The unmasking codes were held at the Pharmacy (total and within 14 days of randomisation); and
Department, Leicester Royal Infirmary, UK. Study necrotising enterocolitis suspected or proven (by
treatment was not revealed, even after delivery, unless radiograph or surgery).
there was a clear medical reason for doing so. The trial The endpoint for data collection was discharge from
medicines were revealed in 11 cases during treatment (in hospital. If more than one outcome was found in a
nine cases the clinicians were made aware, and in two the multiple pregnancy, the worst outcome was used in the
women alone were informed); in all cases the trial staff analysis.
remained unaware of treatment assignment. The data on
these women have been included in the analysis. Statistical analysis
If a serious adverse event that could have been related Differences in categorical outcomes between eryth-
to the study medicines was suspected, the trial office was romycin only and placebo only, co-amoxiclav only and

980 THE LANCET Vol 357 March 31, 2001

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For personal use only. Reproduce with permission from The Lancet Publishing Group.
ARTICLES

placebo only, any erythromycin and no erythromycin, and 4826 randomised


any co-amoxiclav and no co-amoxiclav were tested for
significance by use of the Z test; two-sided p-values are
cited throughout. Differences in outcome between
erythromycin plus co-amoxiclav and placebo, and
between any antibiotic (erythomycin alone, co-amoxiclav
alone, or both erythromycin and co-amoxiclav) and
1197 1212 1192 1225
placebo (3/1 ratio) were also tested for significance.
assigned assigned assigned assigned
Differences between outcomes measured as continuous erythromycin co-amoxiclav erythromycin placebo
variables were tested for significance by use of an unpaired and
t test if normally distributed, and the Mann-Whitney test co-amoxiclav
otherwise. The protocol specified that subsidiary analyses
would be done on women randomised at less than 32
weeks of gestation and at greater than 32 weeks of
1 1
gestation. lost to lost to
The independent data-monitoring committee looked at 3
follow-up follow-up
the results of interim analyses done by the trial statistician protocol
6 6
on four occasions. The committee was to report to the violations
protocol protocol
trial director and steering committee if the randomised violations violations
comparisons in the study had provided proof beyond
reasonable doubt of a difference in a major endpoint
between the study and the control groups, and evidence
that would be expected to alter substantially the choice of 1190 1205 1189 1225
treatment for patients whose doctors are uncertain about completed completed completed completed
whether to recommend antibiotics. Exact criteria for trial trial trial trial
proof beyond reasonable doubt were not specified, but
members of the committee agreed that it should involve a
Trial profile
difference of at least 3 SD in a major outcome. By this
criterion, the exact number of interim analyses were not
prespecified. The steering committee, collaborators, and was no significant difference in number of low birthweight
administrators (except those who produced the babies (<2500 g), very low birthweight babies (<1500 g),
confidential analysis) remained ignorant of the interim or admissions to neonatal intensive or special care
results. (table 3). In the erythromycin groups, there were fewer
babies in more than 21% oxygen at 48 h, 7 days, 14 days,
Results and 28 days of age. In the erythromycin only group
Participants compared with the placebo group, this difference was
Enrolment was from July 1, 1994, until May 31, 2000. significant in babies requiring supplementary oxygen at
4826 women with pPROM were randomised4447 any time and at 48 h of age. There were no significant
within the UK and 379 from the international differences in respiratory-distress syndrome, oxygen
collaborating centres. Two women were lost to follow-up dependency at more than 28 days of age, babies requiring
and there were 15 protocol violations: four women were oxygen at 36 weeks post conception, and positive blood
enrolled in error or were over 37 weeks gestation, and 11 culture. The need for treatment with exogenous
were taking contraindicated drugs. 4809 women surfactant was lower with erythromycin only than with
completed the trial and were analysed (figure). 12 adverse placebo (table 3).
events were reported to the trial director and trial No significant differences between the groups were
coordinator, and were discussed by the data monitoring detected in the number of babies with suspected or proven
committee. None was found to be serious.
Baseline characteristics between the treatment groups Erythromycin Co-amoxiclav Erythromycin Placebo
were similar (table 1). Median gestation at entry was about only (n=1190) only (n=1205) and co-amoxi- only
223 days (32 weeks). On recruitment, cervical dilatation clav (n=1189) (n=1225)
was unknown in 46% of women. This situation is typical of Mean (SD) age 275 (61) 280 (60) 278 (61) 279 (61)
clinical practice, in which there is a reluctance to undertake years
digital vaginal examination because of the known risk of Gestational age at entry
introducing infection. Most women (765%) received Median (range) 223 (109258) 223 (136258) 224 (119258) 222 (128258)
corticosteroids to mature the fetal lungs. However, use of gestation (days)
-agonists to arrest labour was not as common (84%). <26 weeks
2628 weeks
121 (102%)
186 (156%)
127 (105%)
173 (144%)
139 (117%)
162 (136%)
136 (111%)
195 (159%)
2931 weeks 303 (255%) 317 (263%) 290 (244%) 302 (247%)
Erythromycin 3236 weeks 580 (487%) 588 (488%) 598 (503%) 592 (483%)
Significantly fewer women on erythromycin alone Cervical dilatation (cm)
delivered within 48 h than did those on placebo, and more Unknown 527 (442%) 557 (462%) 540 (454%) 574 (469%)
women on any erythromycin had prolongation of 01 565 (475%) 544 (451%) 561 (472%) 536 (438%)
>12 79 (66%) 65 (54%) 55 (46%) 75 (61%)
pregnancy for 7 days than women on no erythromycin. >2 19 (16%) 39 (32%) 33 (28%) 40 (33%)
There was no evidence of effect on the mode of delivery,
Drugs prescribed
or on the number of days spent in hospital. There was a  agonists 114 (96%) 86 (71%) 103 (87%) 101 (82%)
non-significant lower rate of total antibiotic prescription Steroids 908 (763%) 916 (760%) 920 (774%) 936 (764%)
and antibiotic prescription within 14 days of Indomethacin 19 (16%) 21 (17%) 18 (15%) 27 (22%)
randomisation to women assigned erythromycin (table 2). Nifedipine 17 (14%) 30 (25%) 22 (18%) 34 (28%)
Others 70 (59%) 72 (60%) 70 (59%) 67 (55%)
The median birthweight was about the same for women
who were or were not assigned erythromycin, and there Table 1: Baseline characteristics

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ARTICLES

Erythromycin only Placebo only p Any erythromycin No erythromycin p


(n=1190) (n=1225) (n=2379) (n=2430)
Delivery within 48 h 414 (348%) 498 (407%) 0004 786 (330%) 865 (356%) 0062
Delivery within 7 days 725 (609%) 775 (633%) 023 1372 (577%) 1470 (605%) 005
Gestational age at delivery
Median (range) gestation (days) 236 (150300) 236 (142293) .. 237 (129300) 236 (142300) ..
<37 weeks 1006 (845%) 1041 (850%) 076 2024 (851%) 2066 (850%) 095
<26 weeks 48 (40%) 59 (48%) .. 101 (42%) 107 (44%) ..
26286 weeks 92 (77%) 113 (92%) .. 189 (79%) 220 (91%) ..
29316 weeks 220 (185%) 231 (189%) .. 425 (179%) 446 (184%) ..
32366 weeks 646 (543%) 638 (521%) 039 1309 (550%) 1293 (532%) 044
Mode of delivery
Spontaneous vaginal 733 (616%) 746 (609%) .. 1485 (624%) 1501 (618%) ..
Forceps/Ventouse 71 (60%) 72 (59%) .. 143 (60%) 127 (52%) ..
Vaginal breech 51 (43%) 50 (41%) .. 109 (46%) 113 (47%) ..
Caesarean section 335 (282%) 357 (291%) 096 642 (270%) 689 (284%) 053
Median (range) days in hospital 4 (038) 4 (061) 080 4 (044) 4 (0183) 068
Maternal antibiotic prescription 293 (246%) 330 (269%) 019 586 (246%) 640 (263%) 017
Maternal antibiotic prescription within 14 days 241 (203%) 262 (214%) 049 447 (188%) 501 (206%) 011
6
Number of days.

Table 2: Maternal outcomes of women with pPROM randomly assigned erythromycin

necrotising enterocolitis, in the number of babies with an care, ventilation, receipt of oxygen, and respiratory
abnormal cerebral ultrasound scan before discharge from distress syndrome. There were significant differences
hospital, or in the numbers of deaths. Fewer babies whose between the erythromycin only group and the placebo
mothers were assigned erythromycin had the composite group with regard to treatment with exogenous surfactant
primary outcome (death, chronic lung disease, or major (142 [128%] vs 187 [163%], p=002), oxygen
abnormality on cerebral ultrasonography) than those dependence at 28 days of age or older (77 [69%] vs 102
whose mothers were assigned placebo, but this finding [89%], p=003), positive blood culture (59 [53%] vs 85
was not significant (table 3). [74%], p=004), abnormal cerebral ultrasonography (33
The number of women with a multiple pregnancy [30%] vs 53 [46%], p=004), and the composite primary
assigned to each group were as follows: erythromycin only outcome (125 [112%] vs 166 [144%], p=002).
79, placebo only 76, any erythromyin 156, and no Similarly, there were significant differences between the
erythromycin 142. No significant differences were group whose mothers were assigned any erythromycin and
detected for any outcome. When the singleton those whose mothers were assigned no erythromycin with
pregnancies were analysed separately, similar differences respect to treatment with exogenous surfactant (284
to those detected in the main analysis were seen in respect [128%] vs 346 [151%], p=002), oxygen dependence at
of birthweight, admission to neonatal intensive or special 28 days of age or older (156 [70%] vs 197 [86%],

Erythromycin only Placebo only p Any erythromycin No erythromycin p


(n=1190) (n=1225) (n=2397) (n=2430)
Birthweight (g)
Mean (SD) 2102 (766) 2072 (769) 032 2112 (768) 2078 (762) 012
Median (range) 2070 (4404420) 2055 (2404366) .. 2090 (1804710) 2055 (2304488) ..
<2500 863 (725%) 880 (718%) 070 1704 (716%) 1757 (723%) 060
<1500 255 (214%) 284 (232%) 030 505 (212%) 555 (228%) 018
Admission to NICU/SCBU 836 (703%) 880 (718%) 039 1654 (695%) 1728 (711%) 023
Total babies ventilated 251 (211%) 283 (231%) 023 495 (208%) 537 (221%) 028
Total babies in >21% O2 370 (311%) 436 (356%) 002 742 (312%) 819 (337%) 006
At 48 h 302 (254%) 358 (292%) 003 607 (255%) 674 (277%) 008
At 7 days 153 (129%) 181 (148%) 017 311 (131%) 349 (144%) 019
At 14 days 119 (100%) 140 (114%) 026 233 (98%) 275 (113%) 009
At 28 days 95 (80%) 116 (95%) 020 192 (81%) 228 (94%) 011
RDS confirmed by radiography 236 (198%) 266 (217%) 025 478 (201%) 507 (209%) 051
Treatment with exogenous surfactant 176 (148%) 217 (177%) 005 344 (144%) 399 (164%) 006
O2 dependence >28 days 94 (79%) 114 (93%) 022 188 (79%) 225 (93%) 009
O2 at 36 weeks post conception 66 (55%) 76 (62%) 049 133 (56%) 145 (60%) 058
Positive blood culture
Overall 68 (57%) 100 (82%) 002 151 (63%) 182 (75%) 012
If born within 14 days 61 (51%) 85 (69%) 006 119 (50%) 148 (61%) 010
Necrotising enterocolitis
Suspected or proven 25 (21%) 33 (27%) 034 67 (28%) 83 (34%) 023
Proven 11 (09%) 6 (05%) 020 31 (13%) 30 (12%) 083
Abnormal cerebral ultrasonography 50 (42%) 61 (50%) 036 96 (40%) 107 (44%) 053
Deaths 70 (59%) 82 (67%) 041 147 (62%) 161 (66%) 053
Composite primary outcome 151 (127%) 186 (152%) 008 318 (134%) 349 (144%) 032
NICU=neonatal invensive-care unit; SCBU=special-care baby unit; RDS=respiratory distress syndrome.
Table 3: Neonatal outcomes of babies born to women with pPROM randomly assigned erythromycin

982 THE LANCET Vol 357 March 31, 2001

Copyright 2001 All Rights Reserved


For personal use only. Reproduce with permission from The Lancet Publishing Group.
ARTICLES

Co-amoxiclav only Placebo only p Any co-amoxiclav No co-amoxiclav p


(n=1205) (n=1225) (n=2394) (n=2415)
Delivery within 48 h 367 (305%) 498 (407%) <00001 739 (309%) 912 (378%) <00001
Delivery within 7 days 695 (577%) 775 (633%) 0005 1342 (561%) 1500 (621%) <00001
Gestational age at delivery
Median (range) gestation (days) 236 (149307) 236 (142293) .. 237 (129307) 236 (142300) ..
<37 weeks 1025 (851%) 1041 (850%) 095 2043 (853%) 2047 (848%) 058
<26 weeks 48 (40%) 59 (48%) .. 101 (42%) 107 (44%) ..
26286 weeks 107 (89%) 113 (92%) .. 204 (85%) 205 (85%) ..
29316 weeks 215 (178%) 231 (189%) .. 420 (175%) 451 (187%) ..
32366 weeks 655 (544%) 638 (521%) 058 1318 (551%) 1284 (532%) 063
Mode of delivery
Spontaneous vaginal 755 (627%) 746 (609%) .. 1507 (629%) 1479 (612%) ..
Forceps/Ventouse 55 (46%) 72 (59%) .. 127 (53%) 143 (59%) ..
Vaginal breech 63 (52%) 50 (41%) .. 121 (51%) 101 (42%) ..
Caesarean section 332 (276%) 357 (291%) 021 639 (267%) 692 (287%) 017
Median (range) days in hospital 4 (0183) 4 (061) 022 3 (0183) 4 (061) 008
Maternal antibiobic prescription 310 (257%) 330 (269%) 05 602 (251%) 623 (258%) 063
Maternal antibiotic prescription within 14 days 239 (198%) 262 (214%) 034 445 (186%) 503 (208%) 005
6
Number of days.

Table 4: Maternal outcomes of women with pPROM randomly assigned co-amoxiclav

p=005), and positive blood culture (124 [56%] vs 162 special care, or the total number of babies ventilated,
[71%], p=004). compared with use of no co-amoxiclav (table 5). There
were significantly fewer babies on more than 21% oxygen
Co-amoxiclav in the co-amoxiclav only group than in the placebo group,
Significantly fewer women assigned any co-amoxiclav than and fewer at 48 h and 7 days (non-significant). There
assigned no co-amoxiclav delivered within 48 h and within were no significant differences between the groups with
7 days. There were no detected differences in mode of regard to the number of babies with respiratory distress
delivery or number of days in hospital (table 4). With any syndrome confirmed by chest radiography or the number
co-amoxiclav, compared with no co-amoxiclav, there was a of babies receiving exogenous surfactant. No significant
significantly lower rate of maternal antibiotic prescription if differences could be detected in the markers of chronic
delivery occurred within 14 days. This effect was dominated lung disease (oxygen dependence at 28 days and above or
by a significantly lower rate of uterine infection (76 [63%] receipt of oxygen at 36 weeks post conception), or in
vs 103 [84%], p=005) with co-amoxiclav only, and (136 positive blood culture (table 5).
[57%] vs 190 [79%], p=0003) with any co-amoxiclav. There was a significantly greater number of babies with
The use of any co-amoxiclav was not associated with suspected or proven necrotising enterocolitis in the any
differences in birthweight, admissions to intensive or co-amoxiclav group than in the no co-amoxiclav group.

Co-amoxiclav only Placebo only p Any co-amoxiclav No co-amoxiclav p


(n=1205) (n=1225) (n=2394) (n=2415)
Birthweight (g)
Mean (SD) 2083 (755) 2072 (769) 069 2103 (763) 2087 (769) 047
Median (range) 2060 (1804710) 2055 (2404366) .. 2080 (1804710) 2060 (2404420) ..
<2500 877 (728%) 880 (718%) 060 1718 (718%) 1743 (722%) 075
<1500 271 (225%) 284 (232%) 068 521 (218%) 539 (223%) 064
Admission to NICU/SCBU 848 (704%) 880 (718%) 042 1666 (696%) 1716 (711%) 027
Total babies ventilated 254 (211%) 283 (231%) 023 498 (208%) 534 (221%) 027
Total babies in >21% O2 383 (301%) 436 (356%) 005 755 (315%) 806 (334%) 017
At 48 h 316 (262%) 358 (292%) 01 621 (259%) 660 (273%) 027
At 7 days 168 (139%) 181 (148%) 056 326 (136%) 334 (138%) 083
At 14 days 135 (112%) 140 (114%) 080 249 (104%) 259 (107%) 071
At 28 days 112 (93%) 116 (95%) 088 209 (87%) 211 (87%) 099
RDS confirmed by radiography 241 (200%) 266 (217%) 03 483 (202%) 502 (208%) 060
Treatment with exogenous surfactant 182 (151%) 217 (177%) 008 350 (146%) 393 (163%) 011
O2 dependence >28 days 111 (92%) 114 (93%) 094 205 (86%) 208 (86%) 095
O2 at 36 weeks post conception 69 (57%) 76 (62%) 062 136 (57%) 142 (59%) 076
Positive blood culture
Overall 82 (68%) 100 (82%) 020 165 (69%) 168 (70%) 093
If born within 14 days 63 (52%) 85 (69%) 008 121 (51%) 146 (60%) 013
Necrotising enterocolitis
Suspected or proven 50 (41%) 33 (27%) 008 92 (38%) 58 (24%) 0004
Proven 24 (19%) 6 (05%) 0001 44 (18%) 17 (07%) 00005
Abnormal cerebral ultrasonography 46 (38%) 61 (50%) 016 92 (38%) 111 (46%) 019
Deaths 79 (66%) 82 (67%) 089 156 (65%) 152 (63%) 076
Composite primary outcome 163 (135%) 186 (152%) 025 330 (138%) 337 (140%) 087
NICU=neonatal invensive-care unit; SCBU=special-care baby unit; RDS=respiratory distress syndrome.
Table 5: Neonatal outcomes of babies born to women with pPROM randomly assigned co-amoxiclav

THE LANCET Vol 357 March 31, 2001 983

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For personal use only. Reproduce with permission from The Lancet Publishing Group.
ARTICLES

Erythromycin and p Placebo only p Any antibiotic*


co-amoxiclav (n=1189) (n=1225) (n=3584)
Delivery within 48 h 372 (313%) <00001 498 (407%) <00001 1153 (321%)
Delivery within 7 days 647 (544%) <00001 775 (633%) 00006 2067 (577%)
Gestational age at delivery
Median (range) gestation (days) 237 (129296) .. 236 (142293) .. 236 (129307)
<37 weeks 1018 (856%) 066 1041 (850%) 094 3049 (851%)
<26 weeks 53 (45%) .. 59 (48%) .. 149 (42%)
26286 weeks 97 (82%) .. 113 (92%) .. 296 (83%)
29316 weeks 205 (172%) .. 231 (189%) .. 640 (179%)
32366 weeks 663 (558%) 035 638 (521%) 030 1964 (548%)
Mode of delivery
Spontaneous vaginal 752 (632%) .. 746 (609%) .. 2240 (625%)
Forceps/Ventouse 72 (61%) .. 72 (59%) .. 198 (55%)
Vaginal breech 58 (49%) .. 50 (41%) .. 172 (48%)
Caesarean section 307 (258%) 028 357 (291%) 041 974 (272%)
Median (range) days in hospital 3 (044) 012 4 (061) 021 4 (0183)
Maternal antibiotic prescription 293 (246%) 020 330 (269%) 018 896 (250%)
Maternal antibiotic presctiption within 14 days 206 (173%) 001 262 (214%) 009 686 (191%)
*Erythromycin alone, co-amoxiclav alone, or erythromycin and co-amoxiclav. 6Number of days.
Table 6: Maternal outcomes of women with pPROM randomly assigned co-amoxiclav and erythromycin, or any antibiotic

Proven necrotising enterocolitis was four times higher antibiotics and the group assigned any (table 7). For the
with co-amoxiclav alone than with placebo, and 25 times babies whose mothers were assigned both antibiotics or
higher with any co-amoxiclav than with no co-amoxiclav. any antibiotics, significantly fewer received oxygen overall
There were no significant differences in the number of and at 48 h, compared with the babies whose mothers
babies with abnormal cerebral ultrasound scans before were assigned placebo. Significantly fewer received
discharge, or in death. Analysis of the effect of co- exogenous surfactant with any antibiotic compared with
amoxiclav prescription on the composite primary outcome placebo, but no significant differences were found in the
showed no benefit (table 5). number of babies with markers of chronic lung disease
The number of women with a multiple pregnancy (table 7). Significantly fewer babies in the both antibiotics
randomised to each group were as follows: co-amoxiclav and any antibiotics groups had positive blood cultures
only 66, placebo only 76, any co-amoxiclav 143, and no indicative of clinical infection, particularly if the baby was
co-amoxiclav 155. No significant differences were born within 14 days of randomisation, than in the placebo
detected in any outcome. In an analysis of singleton group.
births, no significant differences in neonatal outcome were There was a significantly higher proportion of babies
detected between the co-amoxiclav only and placebo with proven necrotising enterocolitis with the use of both
groups except for admission to intensive or special care antibiotics or any antibiotic than with placebo (table 7).
(869 [763%] vs 915 [796%], p=0005), and the total However, there were no significant differences in the
number of babies receiving supplementary oxygen (341 proportion of babies with abnormal cerebral
[299%] vs 389 [339%], p=005). The only significant ultrasonography before discharge from hospital or in the
differences between the groups assigned any co-amoxiclav proportion who died. Analysis of the effect of both or any
and no co-amoxiclav were for admission to intensive or antibiotic prescription on the composite primary outcome
special care (1715 [762%] vs 1787 [791%], p=002). showed no benefit over placebo for women with pPROM
There was a significantly higher rate of suspected or (table 7).
proven necrotising enterocolitis (42 [37%] vs 26 [23%], The number of women with a multiple pregnancy
p=004) and proven necrotising enterocolitis (18 [16%] randomised to each group were as follows: erythromycin
vs 3 [03%], p=0001) with co-amoxiclav only compared and co-amoxiclav 77, placebo only 76, and any antibiotic
with placebo, and also of suspected or proven necrotising 222. No significant differences in any outcome were
entercolitis (74 [33%] vs 46 [20%], p=0009) and detected. In singleton pregnancies, use of both antibiotics
proven necrotising entercolitis (33 [15%] vs 11 [05%], compared with use of placebo was associated with
p=00007) with any co-amoxiclav compared with no co- significantly fewer admissions to intensive or special care
amoxiclav. (846 [761%] vs 915 [796%], p=004), less need for any
supplementary oxygen (330 [297%] vs 389 [339%],
Erythromycin and co-amoxiclav p=003), less need for supplementary oxygen at 48 h of
In the co-amoxiclav and erythromycin group, and in the age (265 [238%] vs 319 [278%], p=003), less treatment
group assigned any antibiotic, significantly fewer women with exogenous surfactant (142 [128%] vs 187 [163%],
delivered within 48 h than did those on placebo. Results p=002), fewer positive blood cultures (57 [51%] vs 85
were similar for delivery within 7 days (table 6). The [74%], p=003), but a greater proportion of proven
number of women receiving antibiotics after delivery and necrotising enterocolitis (15 [13%] vs three [03%],
before discharge was significantly lower with the use of p=0004). Also for singleton pregnancies, use of any
both antibiotics than with placebo if delivery occurred antibiotic compared with use of placebo was associated
within 14 days of randomisation. Use of both antibiotics with significantly less need for any supplementary oxygen
(60 [50%] vs 103 [84%], p=0001) and any antibiotic (988 [294%] vs 389 [339%], p=0005), less need for
(223 [62%] vs 103 [84%], p=0008) was associated with supplementary oxygen at 48 h (803 [239%] vs 319
significantly less uterine infection than use of placebo. [278%], p=0008), less treatment with exogenous
There were no significant differences in median surfactant (443 [132%] vs 187 [163%], p=0009), fewer
birthweight, or in the number of babies admitted to positive blood cultures (180 [54%] vs 85 [74%],
intensive or special care between the group assigned both p=001), fewer cases of abnormal cerebral ultra-

984 THE LANCET Vol 357 March 31, 2001

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ARTICLES

Erythromycin and p Placebo only p Any antibiotic*


co-amoxiclav (n=1189) (n=1225) (n=3584)
Birthweight (g)
Mean (SD) 2123 (770) 011 2072 (769) 022 2103 (764)
Median (range) 2100 (1804710) .. 2055 (2404366) .. 2080 (1804710)
<2500 841 (707%) 055 880 (718%) 090 2581 (720%)
<1500 250 (210%) 020 284 (232%) 027 776 (217%)
Admission to NICU/SCBU 818 (688%) 010 880 (718%) 018 2502 (698%)
Total babies ventilated 244 (205%) 013 283 (231%) 011 749 (209%)
Total babies in >21% O2 372 (313%) 003 436 (356%) 0007 1125 (314%)
At 48 h 305 (257%) 005 358 (292%) 002 923 (258%)
At 7 days 158 (133%) 029 181 (148%) 022 479 (134%)
At 14 days 114 (96%) 014 140 (114%) 025 368 (103%)
At 28 days 97 (82%) 025 116 (95%) 029 304 (85%)
RDS confirmed by radiography 242 (204%) 041 266 (217%) 022 719 (201%)
Treatment with exogenous surfactant 168 (141%) 002 217 (177%) 001 526 (147%)
O2 dependence >28 days 94 (79%) 022 114 (93%) 03 299 (83%)
O2 at 36 weeks post conception 67 (56%) 056 76 (62%) 045 202 (56%)
Positive blood culture
Overall 83 (70%) 027 100 (82%) 005 233 (65%)
If born within 14 days 58 (49%) 003 85 (69%) 001 182 (51%)
Necrotising enterocolitis
Suspected or proven 42 (35%) 023 33 (27%) 032 117 (33%)
Proven 20 (17%) 0005 6 (05%) 0005 55 (15%)
Abnormal cerebral ultrasonography 46 (39%) 018 61 (50%) 013 142 (40%)
Deaths 77 (65%) 083 82 (67%) 063 226 (63%)
Composite primary outcome 167 (140%) 043 186 (152%) 012 481 (134%)
NICU=neonatal intensive-care unit; SCBU=special-care baby unit; RDS=respiratory distress syndrome. *Erythromycin alone, co-amoxiclav alone, or erythromycin and co-amoxiclav.
Table 7: Neonatal outcomes of women with pPROM randomly assigned co-amoxiclav and erythromycin, or any antibiotic

sonography (110 [33%] vs 53 [46%], p=004), and cases of neonatal necrotising enterocolitis in the co-
fewer instances of the composite primary outcome (406 amoxiclav group, and no cases in the placebo group. This
[121%] vs 166 [144%], p=004). However, there was a effect is plausible, since co-amoxiclav is known to select
significantly greater number of cases of necrotising for Clostridium difficile (a cause of pseudomembranous
enterocolitis (41 [12%] vs three [03%], p=0004). colitis) in adults. One suggested mechanisms of
A subgroup analysis was done on women who were pathogenesis of neonatal necrotising enterocolitis is
randomised at less than 32 weeks gestation. The same abnormal microbial colonisation of the intestinal tract by
pattern of results was found as in the main analysis. one or a few species unhindered by competitors.13 Co-
Analyses were also done on women enrolled in UK amoxiclav, because of its range of activity and
maternity units and on those enrolled at international effectiveness, can facilitate such colonisation.
maternity units for prolongation of pregnancy and the Furthermore, the immature gut is able to absorb any
composite primary outcome; no significant differences exotoxins produced intact, resulting in mucosal damage
were detected between the two groups. and the initiation of necrotising enterocolitis. We
therefore do not recommend routine prescription of co-
Discussion amoxiclav for any preterm delivery, whether it be a
The results of this trial indicate a range of health benefits, preterm prelabour rupture of the membranes,
particularly for singleton pregnancies, with the spontaneous preterm labour, or caesarean section for
prescription of erythromycin, including reduction in preterm delivery. Additionally, its use in the neonatal
delivery at 7 days after randomisation, reduction in period should be examined.
neonatal treatment with surfactant, reduction in the rate The results also show that indicators of short-term
of positive neonatal blood cultures, reduction in chronic neonatal respiratory distress syndrome and chronic lung
lung disease (neonatal ventilation or oxygen at >28 days disease are reduced by erythromycin. These beneficial
of age), reduction in the rate of major cerebral effects might merely be a result of prolonging pregnancy,
abnormality by ultrasonography, and reduction in the but they might have a more direct basis. There is evidence
composite primary outcome of death, chronic lung that lung inflammation or infection can be essential in the
disease, and major cerebral abnormality. Although pathogenesis of neonatal respiratory distress syndrome
erythromycin was less effective than co-amoxiclav at and chronic lung disease. Studies of the constituents of
prolonging pregnancy and reducing maternal infection, bronchoalveolar lavage fluid from infants who develop
there was better evidence of its beneficial effect on neonatal respiratory distress syndrome and recover,
neonatal disease, and there was no evidence of harm. compared with those who progress to chronic lung
In contrast, co-amoxiclav was associated with a disease, have shown that infants who develop chronic lung
significant increase in the occurrence of neonatal disease have higher concentrations of neutrophils,14
necrotising enterocolitis. This finding was also seen, proinflammatory cytokines (including interleukin 1,
although to a lesser extent, in the concurrent trial of co- interleukin 6, interleukin 8),15,16 and proxy markers of
amoxiclav in spontaneous preterm labour.9 On scrutiny of neutrophil recruitment such as soluble L-selectin and
the Cochrane review,6 only one previous trial (which was soluble intercellular adhesion molecule 1 in the broncho-
published only as an abstract) assessed the use of co- alveolar lavage fluid at 710 days of age, than those who
amoxiclav. In this trial of 62 participants,12 there were five recover from respiratory distress syndrome.15,17 Moreover,

THE LANCET Vol 357 March 31, 2001 985

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ARTICLES

there is evidence that intrauterine lung inflammation is Sara Kenyon and the trial team took responsibility for the day-to-day
implicated in the genesis of chronic lung disease, since contact with the centres, the organisation of the drug supplies, and the
management of the data. The statistical analysis was done by
high concentrations of the potent profibrotic agent Ann Blackburn, supported by Richard Peto.
transforming growth factor  have been described in the
first bronchoalveolar lavage fluid after birth of infants who Oracle Collaborative Group
go on to develop chronic lung disease.18,19 Further Steering GroupRichard Lilford (Birmingham, UK), Senga Bond
(Newcastle Upon Tyne, UK), Diana Elbourne (London, UK),
evidence that intrauterine infection or inflammation of the Barbara Farrell (Oxford, UK), Henry Halliday (Belfast, UK),
lung is related to the pathogenesis of neonatal respiratory Sara Kenyon, Naren Patel (Dundee, UK), Richard Peto (Oxford, UK),
distress syndrome and chronic lung disease comes from Steve Walkinshaw (Liverpool, UK), William Tarnow-Mordi, David Taylor.
these disorders associations with the presence of Data Monitoring CommitteeAdrian Grant (Aberdeen, UK),
Forrester Cockburn (Glasgow, UK), Richard Gray (Birmingham, UK),
Ureaplasma urealyticum.20 The health benefits of Charles Rodeck (London, UK).
erythromycin in pPROM are therefore not likely to be due Trial teamFran Vickers, Carol Wallace-Pugh, Ann Blackburn,
merely to prolongation of pregnancy, but to a reduction of Ben Ravillious, Ian Scotland, Jayne Mattlock, Nadine Gilbert, Kate Taylor,
the effects of fetal and neonatal lung infection or Rebecca Smyth, Amanda Rhodes, Sarah Cooper, Amanda Wilson, Sarah
Robinson, Sue Dove, Agnes Byres, Mandy Forrester.
inflammation. We are currently planning a long-term ArgentinaR Lede, G Abriata, C Lede (IAMBE); D Karolinski (Durand
follow-up study to find out whether childhood respiratory Hospital [62]); JL Castaldi (Hospital Jose Penna [467]); M Casares,
disease is reduced by erythromycin for pPROM. L Navarro (Hospital Materno Infantil de Salta [160]); Di Marco (Hospital
The decrease in the occurrence of major neonatal cerebral Materno Infantil Sarda [122]); G Abbriata (Hospital Materno-Infantil de
San Isidro [12]); R Casale, L Parga (Hospital Posadas [367]); D Aleman
abnormality could also be due to prolongation of pregnancy (Hospital San Jose de Cachi [12]); J Arduz (Hospital San Vicente de Paul
alone, or to the effect of erythromycins reduction of [7]); F Althabe, J Ceriani (Maternidad Italiana [8]); V Liliana (Sanatorio
intrauterine infection or inflammation on the fetal and Franchin [9]).
neonatal brain. Again, there is evidence to implicate AustraliaC Georgeson, G Oude Vrielink, J Smoleniec (Liverpool Hospital
[67]); V Flenady, J King (Mater Misericordiae Mothers Hospital [24]);
intrauterine infection or inflammation in fetal and neonatal S Fraser, P Wein (Mercy Hospital for Women [46]); RG Bury,
cerebral damage. Histological chorioamnionitis,2123 and R Murray-Arthur (Royal Hobart Hospital [3]).
funisitis with raised concentrations of interleukin 6 and BelgiumK De Ketelaere, M Temmerman (UZ Gent Vrouwenkliniek
interleukin 8 in amniotic fluid24 have been associated with [33]).
BrazilAM Bertini, W Taborda (Amparo Maternal [8]).
cerebral palsy. Additionly, raised concentrations of Czech RepublicM Veleminsky (Hospital Ceske Budejovice [5]).
umbilical-cord interleukin 6 have been found in neonates GuernseyAH Hunter-Adam, B Lean, R Nelson (Princess Elizabeth
with ultrasonographic evidence of periventricular Hospital [2]).
leucomalacia.25 The preliminary results of a study of more HungaryS Gardo (County Hospital [96]); T Major (University Medical
School Debrecen [14]).
than 40 infants with very low birthweights showed a strong LithuaniaR Valikonyte (Republic Panevezys Hospital [264]).
association between indicators of chorioamnionitis and MalaysiaN Adeeb, N Ismail (Universiti Kebangsaan Malaysia [53]).
damage to cerebral white matter.26 Additionally, NetherlandsRH Stigter (Academisch Ziekenhuis Utrecht [19]).
concentrations of proinflammatory cytokines and CD40- PortugalF Laranjeira (Centro Hospitalar de Gaia [16]); M Meirinho,
R Rodrigues, A Torrado (Hospital Garcia de Orta [125]); M Ceu Almeida,
RO-positive T cells (a marker of exposure to antigen) were V Souto (Maternidade Bissaya Barreto [70]); A Justica, R Magarinho,
higher in cord blood from infants with damage to white C Soares (Maternidade Julio Diniz [14]).
matter than in infants without such damage. South AfricaS Fawcus, E R Foster (Mowbray Maternity Hospital [39]);
The importance of potential effects of pPROM on brain KD Gunston (Somerset Hospital [60]).
Sri LankaRJ Fernando, IMR Goonewardene (University of Ruhuna
development in children is illustrated by the results of two [41]).
clinical studies. In the first, Murphy and colleagues22 did a United Arab EmiratesIS John, Q Khan, M McBeth, M Thomas
case-control study of 59 children with cerebral palsy who (Al Corniche Hospital [75]).
were singleton and less than 32 weeks of gestation at birth. UKP Danielian, L Johnstone, G Lang, D Lloyd, P Winters, J Milne
(Aberdeen Maternity Hospital [20]); C Cadden, M Doherty, M Fisher,
They found that the three most important antenatal risk B McCord, MJR Parker (Altnagelvin Area Hospital [95]); J Jenkins,
factors were prolonged (>24 h) rupture of the membranes M McNeill, M Paul, WAH Ritchie (Antrim Hospital [53]); A Bell,
(odds ratio 23 [95% CI 1242]), chorioamnionitis (42 P Fogarty, C Leonard, S McCloskey (Ards & Ulster Hospitals [40]);
[14120]), and maternal infection (23 [1245]). B Davies, K Elloy, D Manning, CM Thompson, IA Williams (Arrowe Park
Hospital [122]); V Gomes-Harris, D Heller, DW Hyatt, S Jones (Ashford
Results of the second report27 showed a five-fold increase Hospital [5]); B Corbett, P Franks, S Hogg, U Wariya (Ashington Hospital
in the likelihood of severe neurological handicap in infants [18]); HG Dobbie, CS Dochert, S Kinmond, D MacDonald, C Pickavance
born after pPROM at between 24 and 34 weeks gestation, (Ayrshire Central Hospital [66]); EAY Gouta, S M Henella, S Hinchcliffe,
compared with infants who had been born after M Smith, K Wilson (Barnsley District General Hospital [53]); L Cook,
P Croot, M Daly, ARK Haloob, R Ramanan (Basildon Hospital [41]);
spontaneous preterm labour, and that the risk of handicap PG Cooray, F Hughes, M Moore, EJ Neal (Bedford General Hospital
was related to the duration of membrane rupture. [27]); P McFaul, L McGivern, B Morgan, R Tubman (Belfast City
Since erythromycin for pPROM seems to have some Hospital [11]); B Anthon, RS Bhadoria, RH Martin, A Masterton, J Paul
beneficial effect on the rate of ultrasound-identified (Billinge Hospital [62]); F Baillie, S Holmes, J Lyons, B McKenzie,
M Watkinson (Birmingham Heartlands Hospital [76]); V Hunter,
cerebral abnormality, which is known to greatly IE Lowles, A Margerison, C Scott (Borders General Hospital [29]);
underestimate cerebral damage,28 we plan to determine S Chatfield, J Gerard, G Simpson, DJ Tuffnell, A Wardlaw (Bradford
what effect erythromycin given for pPROM has on Royal Infirmary [163]); L Brown, I Claxton, B Ginz, PS Pore, F Wood
childhood neuromotor and cognitive function, and (Burton Hospital [66]); S Quinn, W Reid, T Slaughter, J Storr (Carlisle
City Maternity Hospital [24]); G Bird, B Herbert, M Keble, E Kilmartin,
whether disability is decreased. A J Minchin, B Yuksel (Chase Farm Hospital [20]); D Acolet, Y Choo,
Our results show that a cheap and widely available MR Johnson, S Tomlins (Chelsea & Westminster Hospital [21]); C Currie,
antibiotic, erythromycin, when given to women with J Daubeney, A Day, DM Holmes, S Williams (Cheltenham Hospital [43]);
pPROM, has effects on the occurrence of major neonatal J Baldwin, E Bingham, J Creswell, H Durward, J Heaton (Chesterfield &
North Derbyshire Royal Hospital [65]); JG Bissenden, R Condie,
disease, and might therefore have a substantial health I Gooden, H Hicks, N Hughes (City Hospital, Birmingham [104]);
benefit on the long-term respiratory and neurological T Chapman, A Ferris, S Mukerji, E Sout, C Thomson, IAL Treharne
function of many children. (Colchester General Hospital [69]); A Alaily, V Howard, P Reid,
G Whincup (Conquest Hospital [6]); I Clarkson, A Cunningham,
Contributors P deSilva, T Hinkstridge, J Williams (Countess of Chester Hospital [96]);
Sara Kenyon (Leicester, UK), David Taylor (Leicester), Richard Peto J Boyce, M Hogan, M Hynes, DS Lowry, L Thornbury (Craigavon Area
(Oxford, UK), and William Tarnow-Mordi (Sydney, Australia) designed Hospital [61]); S Calkin, P Jackson, I Lewis, A Shirt (Crawley Hospital
the study protocol. David Taylor and Sara Kenyon supervised the study. [5]); RMK Grieve, L Hamilton, R Mudgal, M Pratt (Cresswell Maternity

986 THE LANCET Vol 357 March 31, 2001

Copyright 2001 All Rights Reserved


For personal use only. Reproduce with permission from The Lancet Publishing Group.
ARTICLES

Hospital [16]); L Brown, D Hutchon, DE Stead, IM Thakur (Darlington U Mannu, S Thornton (Rosie Maternity Hospital [61]); H Allen,
Memorial Hospital [19]); S Appleby, A Butterfield, M Cust, L Galpin, CJ Harrison, S Matthewman, J McVeigh, SF Spooner, R Whiting
P Herod, G Mensah, N Ruggins (Derby City General Hospital [64]); (Rotherham District General Hospital [77]); JA Gemmell, D Hamilton,
H Baumer, S Couch-Hockedy, JM Frappell, J Wier, P Beach (Derriford A McGee, C White (Royal Alexandra Hospital, Strathclyde [53]);
Hospital [56]); M Healey, P Mackay, N McDonald, J Thomlinson, J Bracken, C Bullaugh, L Gaskell, P Gibson, RE Hopkins, P Powell (Royal
P Longbottom (Dewsbury & District Hospital [51]); SJ Ahmad, Bolton Hospital [91]); S Budgen, S Corcoran, P Dale, K Gribble,
M Armstrong, M Bathgate, GP Chandler, V Knight (Doncaster Royal KR Jones, RF Munyard (Royal Cornwall Hospital [169]); N Colley,
Infirmary [80]); S Humphris, L Leonard, M Long, P Thompson (East K Caldwell, J Daly, T McHale, M Quinn (Royal Devon & Exeter Hospital
Surrey Hospital [21]); J Barcock, J Chadwick, MTM Malak, [59]); T Dilger, W Reid, V Van Someren, S Tomlin (Royal Free Hospital
E Wearmouth (Eastbourne District General Hospital [17]); AA Calder, [4]); B Davies, T Hawkins, C Hayes, F Mansell, A Roberts, J Wiener,
B Booth, C Campbell, S Gormley, B Irving, K McLean, B Stenson, A Wilson (Royal Gwent Hospital [92]); J Latona, M Parker, M Placzek,
ML Stewart (Edinburgh Royal Infirmary [147]); H Gill, A Harold, R Shepherd (Royal Lancaster Infirmary [11]); EM Bannon, H Halliday,
A Mulholland, S Shannon, G Shaw, B Yoxall (Fazakerley District General M A Harper, M Hill, M McFarland, J Toner (Royal Maternity Hospital
Hospital [70]); L Gove, L Kirk, J McWalter, L Naismith, CR Steer, [95]); D Anastassopulos, D Brears, V Brooks, N Dunkerley, S Ghanim
DR Urquhart (Forth Park Maternity Hospital [91]); N Hebblethwaite, (Royal Oldham Hospital [43]); SJ Breslin, J Latham, S Morgan, S Oates,
S Hughes, J James, D Styan (Friarage Hospital [27]); JD Bell, P Moody, RJ Welch (Royal Shrewsbury Hospital [69]); F Jones, H Jones,
G Woodall (Furness General Hospital [17]); J Grant, S Ibhanesebhor, PM McKeown, RJ Porter, P Rudd (Royal United Hospital [58]); R Cooke,
M MacKenzie, S Mackenzie, M McGinley (Glasgow Royal Maternity C Hall, M Kelly, S MacPhail, K Robison (Royal Victoria Infirmary [146]);
Hospital [27]); J Beckwith, A Downey, G McCrea, P Morgan, MD Read, S Bjornsson, P Galea, C McGowan, S Wilson (Rutherglen Maternity
M Webb (Gloucestershire Royal Hospital [89]); J Altalabani-Meran, Hospital [40]); L Bates, R Jayatunga, J Kabukoba, F Sneddon (Sandwell
T Carruthers, D Churchill, G Lees, L Cattell (Goodhope Hospital [80]); General Hospital [15]); C Darby, J Devlin, J Hollingworth, LJ Roberts
E Earl, J Grant, R Thomson, S Vogt (Grantham & Kesteven General (Scunthorpe General Hospital [52]); S Butcher, SJ Emery, H Jago,
Hospital [12]); S Claxton, MA DeBono, Y Oade, J Yorke (Halifax General J Matthes, J Paye, M Roberts (Singleton Hospital [63]); S Bosworth,
Hospital [24]); T Moore, RS Prasad, U Rao, K Sian (Harold Wood K Cheevers, R Mupanemunda, R Settatree, A Stoakley (Solihull Hospital
Hospital [35]); V Dawes, JC Jani, C Lakey, AR Robertson (Hartlepool [41]); S Bailey, J Holerin, S Howells, J Pagan, S Sinha, F Toller
General Hospital [37]); AM Butterfill, M Cohn, K Hart (Hereford County (South Cleveland Hospital [174]); M Doherty, M Massam, S Orife,
Hospital [22]); K Costeloe, KJ Erskine, S Fazal-Trayling, N Kennelly, O Tweddle (South Tyneside District Hospital [43]); J Dennick, V Morris,
B Miller, L Read (Homerton Hospital [66]); A Railton, M Robinson, K Olah (South Warwickshire General Hospital [10]); A Angus, M Mann,
C Shuttleworth, M Stapleton, C Tan (Hope Hospital [47]); J Bellerby, V Nerminathan, D Ryan, A Stein, JK Ward (Southend-On-Sea Maternity
J M Campbell, N Roebuck, A Short (Huddersfield Royal Infirmary [17]); Hospital [6]); P Macdonald, A McKenzie, C Milne, IN Ramsay, F Walker
J Atkinson, T Bateman, E Dakkak, M Lewin, SW Lindow, P Robson, (Southern General Hospital [80]); K Ashley, J Campbell, P Dear,
A Ward (Hull Maternity Hospital [119]); G Anthony, J Coyle, A Geddes, L Riley (St James University Hospital [60]); M Kadiri,
C Cuthbertson (Inverclyde Royal Hospital [7]); B Cooke, S Greenaway, R Malik, K Murphy, GS Parker (St Marys Hospital, London [24]);
K ONeill, T Omara-Boto, SM Patient, L Simmonds (Ipswich Hospital MM Brennan, AJB Emmerson, C Lambert, MJA Maresh, R Maxwell,
[87]); R Coombs, F Fairlie, K Fryer, P Mayne, C Nye, M Reid, L Milburn (St Marys Hospital, Manchester [105]); M Ashton, D Davies,
G Walmsley, A Culley (Jessop Hospital for Women [156]); M Brock, J Dillow, A Going, Z Graham, S Hackett, T Hewitt, V McLean,
J Burgess, P Farrington, A Laister, S Sellars, B Truelove, AR Wilkinson G Metcalfe, G Stephens, T Ward, V Wright (St Marys Hospital,
(John Radcliffe Hospital [165]); T Biswas, M Payne, P Roper, C Ward, Portsmouth [123]); P Crawshaw, S Cooke, M Mather-Price, S Newbold,
DJ Wilkin (Kettering & District General Hospital [99]); J Baites, L Sadler, G Slevin, D Skidmore, D Purcell (St Peters Hospital, Chertsey
A Lester, E Osei, D Robinson, M Wren (King George Hospital [64]); [63]); G Carrasco, J Dixon, C Melville, I Timmis (Stafford District
K Crouch, A Dunderdale, CA Gie, R Harris, T Parkin, J Savage (Kings General Hospital [10]); C Mackie, K Stewart, MA Van der Snoek,
Mill Hospital [88]); D Crichton, AB Gill, R Hutton, GC Mason, L Waugh (Stirling Royal Infirmary [29]); R Brown, D Clairmonte,
H Miller, A Geddes (Leeds General Infirmary NHS Trust [138]); J Taylor, M Usherwood (Stoke Mandeville Hospital [10]); E Bryan,
AC Elias-Jones, R Issa, S Khalid, L Moss, I Scudamore, L Wood (Leicester S Elsan , R Johanson, E Perkins, D Sexton-Bradsh, I Surawy (Stoke on
General Hospital [83]); P Bates, D Brookes, P Jones, J Lott, G Matharu, Trent Maternity Hospital [186]); HM Cameron, A Griffen, L Hornby,
L Spicer, D Field (Leicester Royal Infirmary [206]); A Hewitt, P Hill, S Richmond, S Stelling (Sunderland Royal Hospital [163]); A Haggerty,
J Reiser, R Sattin (Lister Hospital [17]); S Bailey, P Coffey, A Fogarty, AI Kiwanuka, AA Massarano, A Sivner (Tameside General Hospital [35]);
E Reynolds, J Riley, S Ryan, SA Walkinshaw, C Yoxall, R Smyth M Glynn, S Imong, D Milmore, P Stannard (Torbay Hospital [10]);
(Liverpool Womens Hospital [300]); M Alfaham, B Hauxwell, M Mitchell, N Davies, M Davis, M Drayton, A Hatcher, A Morgans (University
A Rees, A Vicary (Llandough Hospital [46]); J Berkolds, S Charles, J Deex, Hospital of Wales [146]); S Close, J Kerrone, N MacPherson, M Steel,
MO Lobb, S Moffat, A Morgan (Luton & Dunstable Hospital [69]); R Stevens, D Wells (Victoria Hospital, Blackpool [42]); T Ahmad,
VA Lether, N Rogerson, I Spillman, A Williams (Macclesfield District RG Cross, B Donoghue, L Farrall (Walsgrave Hospital [110]); P Bailey,
General Hospital [28]); G Colley, T Ducker, D Johnston, D M Moore, D Beaver, F Davidson, D Matthews, NA Mir, GH Ramsden (Warrington
G Rogers (Medway Maritime Hospital [40]); A Badger, AJ Dawson, District General Hospital [65]); SA Bober, P Carter, S Goldsworthy,
AD Griffiths, G White (Nevill Hall Hospital [30]); L Allport, FL Spencer (West Cumberland Hospital [35]); P Hanid, J Martindale,
B Kumararatne, S Griggs, A Pratley, S Richardson, RI Simon (New Cross E Owen, S West (West Middlesex University Hospital [20]); G Briars,
Hospital [52]); Y Akinola, J Beal, R Bhat, R Chenoy, M Craddock, G George, S Gull, D Holland (West Suffolk Hospital [8]); P Hartley,
M Mandirahwe (Newham General Hospital [47]); MP Hogg, M Livie, J Langton, L Lowe, J Stokoe, C Whewell, C Woodhall (Whiston Hospital
G Mires, J Richards, W Tarnow-Mordi (Ninewells Hospital [121]); [59]); FC Leyland, M Lodge, E Paniagua, A Rodgers, A Skipworth
DI Fraser, BC Herring, C Sayer, L Skipper, C Upton, RC Warren, (Wordsley Hospital [127]); J Crayford, G Lane, C Ruoss, J Williams
S Wright (Norfolk & Norwich Hospital [181]); WP Bradford, J Drury, (Worthing Hospital [19]); E Boxwell, B Harrington, PG Toon, J Williams
F Goodhind, SA Richardson (North Devon District Hospital [9]); (Wrexham Maelor Hospital [24]); DW Beverley, M Jackson, C Jakenman,
M Deary, J H Macaulay, J Mackie, JS Mason, I Verber (North Tees JE Potter, DW Pring, C Tong (York District Hospital [67]).
General Hospital [105]); D Evans, WT Houlsby, S Simpson, M Wilson
(North Tyneside General Hospital [44]); D Dudman, A Duncan, Acknowledgments
A Fairbrother, L Panter, L Ryan, F Thompson (Northampton General We thank all the women who joined this study, Barbara Farrell,
Hospital [30]); RC Coombs, S Fearnehough, DJ Fothergill, P Preston, Richard Peto, Peter Brocklehurst, David Field, Steve Gould,
K Ryalls, A Vickers (Northern General Hospital [92]); L Abolins, H Crow, Peter Howie, David Isaacs, Roberto Lede, Paul Lewis, Rona McCandlish,
TN Fay, V McGuigan, S Pacey, L Pyke, M Smith, SL Watkin Jim Neilson, Gabriella Phillips, and the UK National Childbirth Trust (Gill
(Nottingham City Hospital [63]); G Boocock, J Cox, PM Hendy-Ibbs, Gyte and Sandy Oliver). Co-amoxiclav (Augmentin) and co-amoxiclav
C Johnson, J Williams (Ormskirk District General Hospital [55]); placebo were supplied free of charge by SmithKline Beecham, and
RE Allen, FW Fowlie, E King, A Symon, R Wilkie (Perth Royal Hospital erythromycin (Erymax) and erythromycin placebo were supplied by Parke
[19]); M Curry, A Patrick, T Rees-Harper, S Steel, K Stone, S Tuck Davis for the duration of the trial. The study was supported by a strategic
(Peterborough District Hospital Maternity Unit [102]); D Burton, project grant from the UK Medical Research Council (ISCRT number
J Clements, T Hillard, C Nugent, D Shortland, C Tickell (Poole Hospital 52995660).
[80]); C Baker, J Colam, S Cheshire, M Elliott, T Gubbins, S Heiliger,
R Ironton, PJ White (Princess Anne Hospital, Southampton [108]);
S Hatton, S Holmes, I Magani, S Zengeya (Princess Margaret Hospital,
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