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Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial
S Kenyon, K Pike, D R Jones, P Brocklehurst, N Marlow, A Salt, D J Taylor

Summary

Background The ORACLE I trial compared the use of erythromycin and/or amoxicillinclavulanate (co-amoxiclav) with that of placebo for women with preterm rupture of the membranes without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present studythe ORACLE Children Study Iwas to determine the long-term eects on children of these interventions. Methods We assessed children at age 7 years born to the 4148 women who had completed the ORACLE I trial and who were eligible for follow-up with a structured parental questionnaire to assess the childs health status. Functional impairment was dened as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classication system. Educational outcomes were assessed with national curriculum test results for children resident in England. Findings Outcome was determined for 3298 (75%) eligible children. There was no dierence in the proportion of children with any functional impairment after prescription of erythromycin, with or without co-amoxiclav, compared with those born to mothers who received no erythromycin (594 [383%] of 1551 children vs 655 [404%] of 1620; odds ratio 091, 95% CI 079105) or after prescription of co-amoxiclav, with or without erythromycin, compared with those born to mothers who received no co-amoxiclav (645 [406%] of 1587 vs 604 [381%] of 1584; 111, 096128). Neither antibiotic had a signicant eect on the overall level of behavioural diculties experienced, on specic medical conditions, or on the proportions of children achieving each level in reading, writing, or mathematics at key stage one. Interpretation The prescription of antibiotics for women with preterm rupture of the membranes seems to have little eect on the health of children at 7 years of age. Funding UK Medical Research Council.

Published Online September 18, 2008 DOI:10.1016/S01406736(08)61202-7 See Online/Comment DOI:10.1016/S01406736(08)61248-9 See Online/Articles DOI:10.1016/S01406736(08)61203-9 Reproductive Sciences Section, Cancer Studies and Molecular Medicine (S Kenyon MA, K Pike MSc, Prof D J Taylor FRCOG) and Health Sciences Department (Prof D R Jones PhD), University of Leicester, Leicester, UK; National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK (Prof P Brocklehurst FRCOG); Academic Division of Child Health, University of Nottingham, Nottingham, UK (Prof N Marlow FMedSci); Great Ormond Street Hospital for Children and Institute of Child Health, University College London, London, UK (A Salt FRCPCH) Correspondence to: Sara Kenyon, Reproductive Sciences Section, Cancer Studies and Molecular Medicine, University of Leicester, 2228 Princess Road West, Leicester LE1 6TP, UK oracle@leicester.ac.uk

Introduction
The sequelae of preterm birth pose major public-health challenges. Children born preterm are at risk of major disabilitieseg, cerebral palsywith risk increasing as length of gestation at birth decreases;1 many preterm children without disability develop important behavioural and educational diculties.2,3 The prevention of preterm birth and reduction of associated disability are therefore important health priorities. Intrauterine infection and inammation have been associated with an increased risk of preterm birth4 and independently with cerebral palsy and chronic lung disease.5 The antecedent of preterm birth which has been most strongly associated with infection and inammation is preterm rupture of the fetal membranes (PROM). With conventional microbiological techniques, microbial invasion of the amniotic cavity has been identied in about 30% of cases of PROM;6 more sensitive PCR techniques that detect conserved 16s rRNA genes suggest that about 70% of births are found to be colonised after PROM.7 Against this background, there is unbiased evidence from randomised controlled trials for antibiotic treatment

of women with PROM. The ORACLE I trial8 assessed the use of amoxicillinclavulanate (co-amoxiclav) 375 mg, or erythromycin 250 mg, or both, or placebo, four times daily for 10 days or until birth (whichever was sooner) in women presenting with PROM using a factorial randomised controlled trial design. In singleton babies born to women after PROM, erythromycin decreased the risk of the composite primary outcome (death or major cerebral abnormality or chronic neonatal lung disease). The prescription of erythromycin was also associated with prolongation of pregnancy and reductions in neonatal morbidity compared with women who did not receive erythromycin, and is now recommended practice.9 Coamoxiclav was not associated with any change in the primary endpoint. However, although women who received co-amoxiclav had prolonged pregnancy compared with those who did not receive any co-amoxiclav, it was also associated with a signicantly higher incidence of neonatal necrotising enterocolitis. In this paper we report the results of the ORACLE Children Study I (OCS I), which provided a unique opportunity to determine whether the perinatal use of

www.thelancet.com Published online September 18, 2008 DOI:10.1016/S0140-6736(08)61202-7

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4826 women entered to ORACLE I trial

17 women excluded 15 protocol violations 2 lost to follow-up

4809 women completed ORACLE I trial

661 women excluded 246 women excluded due to death of child in ORACLE I trial 376 women randomised outside the UK 39 women withdrew before start of OCS

4148 women eligible for OCS follow-up

4378 children

3298 children (75%) whose outcome is known: 3171 (72%) parents returned a questionnaire 90 (2%) health of child known from GPs and parents 37 (1%) children died

1080 children whose outcome is not known: 55 emigrated, no contact made 135 lost to follow-up, no contact made 83 opted out by parents after initial contact 807 no response to questionnaire or other contact

response (eg, the child was currently in care or was a non-English speaker). Translations of all study materials were available. For those children who were not 7 years of age at the initial invitation, contact was maintained from 2001 onwards with birthday cards, newsletters, and change of address cards, and via a website. When the child was 7 years old we conrmed their current address with ONS and the GP. An information leaet was sent to the parents, and 2 weeks later the study questionnaire was sent. If no response was obtained, contact details were checked with the GP and a reminder letter, including a 5 high street voucher,11 was sent by registered post to the parents or carers of the child during the week of the childs 7th birthday. If no response was forthcoming, 3 weeks later, a nal letter was sent or telephone contact was made. The West Midlands Multi-centre Research and Ethics Committee (MREC) approved the study and the University of Leicester, UK, sponsored the OCS. Oversight was provided by an independent trial steering committee and data monitoring committee, both of which met annually. Those involved in tracing and data entry remained blind to the allocated treatment. All data to assess health and educational outcomes were double entered and subject to validation and logic checks.

Data collection

Figure 1: Flowchart for PROM group through ORACLE I and extended follow-up in OCS I *291 babies died during ORACLE I. However, only 246 women were excluded because a number had a multiple birth. Of the 291 babies, 225 were singletons, 42 were twins where both babies died (21 sets), and 24 were multiple births with live siblings.

08TL3044_1 Ella 22/07/08

Flexishapes and other vectors

Data were collected with a parent-completion postal questionnaire. This comprised the Health Utilities Index (HUI)12 from which the Multi-Attribute Health Status (MAHS) is derived, the Strengths and Diculties Questionnaire,13 and specic questions on respiratory symptoms,14 hospital admissions, convulsions, other erythromycin and/or co-amoxiclav for women with specic medical conditions, and demographic data. PROM in ORACLE I resulted in dierences in funcThe primary outcome was dened as the presence of tional and educational ability in childhood. any level of functional impairment (severe, moderate, or Urgent Measuring bars Graph marks Arrows Font reference and special characters Keys Labels mild) derived from the mark III MAHS classication 13 2 125 Methods system within any of the individual attributes of vision, Key 1 Key 1 Text typed Key 2 Key 2 A B Participants hearing, speech, ambulation, dexterity, emotion, cognition, Key 3 Key 3 Image OCS I redrawn in 2002 and sought 4follow-up information and pain. Each attribute has either ve or six dened levels began Key Key 4 D C Key 5 Key 5 for children at 7 years of age who were born to the of impairment, ranging from normal function to severe Tick Marks NSBC $ Key 6 Key 6 E 4809 women with PROM who completed ORACLEF I.8 dysfunction.15 Thesebarhave been classied further into Error +<> Key 7 Key 7 Axis break Checked by The study protocol has been described in detail elsewhere.10 none, mild, moderate, or severe levels of severity for the H G Briey, in the original trial, women were informed of the individual attributes from the standard algorithms intention to do a subsequent follow-up assessment when available within the HUI coding/procedure manual. The 1 Text they gave written informed consent. Children in the rst box is centred were traced overall level of functional impairment was determined by with the help of the UK Oce of National Statistics (ONS) their worst score in any attribute. Sensitivity analyses were and by contact with their family doctors (general also done based on the HUI3 multi-attribute utility scores practitioners; GPs). Details of deaths and families who of overall health-related quality of life,16 which became moved out of the UK were notied to us by ONS. We did available after the study had begun. not attempt to contact the families of children who had Secondary outcomes were the presence of three or been adopted, were in foster care, or had emigrated. more abnormal attributes derived from the MAHS Contact details of surviving children were obtained classication system and the degree of functional from the National Health Service (NHS) National impairment (severe, moderate, mild, none) within the Strategic Tracing Service (NSTS). If no response was individual domains; the number of deaths between trial obtained to an invitation letter, the childs GP was entry and discharge and age 7 years; overall and subscale contacted to check details and possible reasons for non- scores derived from the parent-completed Strengths and
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Diculties Questionnaire; the frequency of specic medical conditions including CNS problems (cerebral palsy, ts/seizures, hydrocephalus with a shunt), respiratory problems (wheezing, medication for asthma), hospital admission (both in the last year and for chest problems), diabetes, bowel disorders, and developmental problems (attention decit hyperactivity disorder derived from the Strengths and Diculties Questionnaire17 or parent report), and other development problems. With support from the UK Qualications and Curriculum Authority (QCA), we used results from national curriculum tests (key stage one), done at 7 years of age to assess the childrens educational attainment for residents in England. Such tests are not routinely done in other parts of the UK. Changes to the way in which the results of these tests are derived have occurred since 2005, when the assessment became teacher-based rather than test-based, with the results of written tests used by the teacher to inform the level awarded.18 At key stage one, all children are awarded a level for each of reading, writing, and mathematics. These include levels three and four, which are above average, level two (the
Erythromycin and co-amoxiclav At entry to ORACLE I Number of women Maternal age (years) Gestational age (days) Multiple births Maternal antibiotics in the postnatal period Short-term outcomes of ORACLE I Number of babies Birth within 48 h of trial entry Birth within 7 days of trial entry Gestational age (days) Birthweight (g) Sex (male) Admission to neonatal unit Ventilated Respiratory distress syndrome Supplementary oxygen at 28 days Positive blood culture Necrotising enterocolitis (suspected or proven) Abnormal cerebral ultrasonography At entry to OCS I Ethnic origin (white) Smoking in family Damp or mould problems Family history of asthma Childs age at completion of questionnaire (years) Childs age at the start of the academic year they sat key stage one tests (years)
Data are n (%) or median (IQR).

average level awarded to 6070% of pupils, and which is also subdivided into three sublevels), and below level two, which includes children who attained level one, those who were working towards level one, or who were not entered by the teacher. For all eligible OCS I children in England, key stage one level data were provided anonymously by the UK Department for Children, Schools and Families (DCSF), categorised by treatment group.

Statistical analysis
The size of the study was predened by the number of women recruited to the ORACLE I trial. The indicative power calculation in the protocol noted that about 4400 children were expected to be eligible for the followup study. About 31% of the children in the any erythromycin group were expected to have three or more abnormal attributes using the MAHS scale.12 Assuming an 85% response rate, this gave 80% power (with two-tailed =005) to detect a prevalence of three or more abnormal attributes in the no erythromycin group of 5% (a relative dierence between the two groups of 38%).
Erythromycin Co-amoxiclav Placebo

737 288 (242328) 226 (209238) 52 (71%) 180 (244%) 783 270 (345%) 442 (565%) 237 (222249) 2120 (16702585) 413 (527%) 570 (728%) 147 (188%) 154 (197%) 61 (78%) 44 (56%) 22 (28%) 26 (33%) 710 (907%) 351 (448%) 47 (60%) 354 (452%) 697 (691708) 646 (625667)

754 284 (237326) 225 (205237) 56 (74%) 191 (253%) 807 296 (367%) 516 (639%) 236 (221247) 2092 (16112490) 422 (523%) 605 (750%) 169 (209%) 164 (203%) 69 (86%) 39 (48%) 13 (16%) 26 (32%) 743 (921%) 364 (451%) 43 (53%) 368 (456%) 697 (691707) 650 (625675)

808 288 (244326) 225 (2082385) 46 (57%) 211 (261%) 849 279 (329%) 498 (587%) 237 (222248) 2115 (16752560) 454 (535%) 623 (734%) 168 (198%) 159 (187%) 81 (95%) 48 (57%) 23 (27%) 20 (24%) 757 (892%) 387 (456%) 41 (48%) 346 (408%) 694 (691705) 650 (625667)

775 287 (244327) 226 (205238) 49 (6.3%) 209 (27.0%) 822 343 (417%) 539 (656%) 236 (221247) 2075 (16262550) 463 (563%) 630 (766%) 158 (192%) 163 (198%) 74 (90%) 57 (69%) 20 (24%) 27 (33%) 748 (910%) 351 (427%) 51 (62%) 353 (429%) 695 (691706) 650 (625675)

Table 1: Characteristics of the responders in the PROM group

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Any erythromycin No erythromycin (N=1551) (N=1620) No functional impairment Any functional impairment Mild Moderate Severe Three or more abnormal attributes 957 (617%) 594 (383%) 336 (217%) 173 (112%) 85 (55%) 128 (83%) 965 (596%) 655 (404%) 382 (236%) 181 (112%) 92 (57%) 130 (80%)

OR (95% CI) Ref 091 (079105) 089 (075105) 096 (077121) 093 (068127) 103 (080133)

Any co-amoxiclav (N=1587) 942 (594%) 645 (406%) 375 (236%) 175 (110%) 95 (60%) 135 (85%)

No co-amoxiclav (N=1584) 980 (619%) 604 (381%) 343 (217%) 179 (113%) 82 (52%) 123 (78%)

OR (95% CI) Ref 111 (096128) 114 (096135) 102 (081128) 121 (089164) 110 (086142)

Table 2: Overall level of functional impairment at age 7 years from the mark III Multi-Attribute Health Scale in children whose mothers had PROM

Erythromycin and OR (95% CI) co-amoxiclav (N=763) No functional impairment Any functional impairment Mild Moderate Severe Three or more abnormal attributes 462 (606%) 301 (394%) 178 (233%) 80 (105%) 43 (56%) 63 (83%) 098 (080121) 102 (083125) 101 (079129) 098 (070136) 113 (072177) 115 (079166)

Erythromycin only (N=788) 495 (628%) 293 (372%) 158 (201%) 93 (118%) 42 (53%) 65 (82%)

OR (95% CI) 108 (088133) 092 (075113) 084 (065107) 106 (077146) 103 (066161) 114 (079165)

Co-amoxiclav only (N=824) 480 (583%) 344 (417%) 197 (239%) 95 (115%) 52 (63%) 72 (87%)

OR (95% CI) 089 (073109) 112 (092136) 108 (085136) 112 (081153) 131 (085202) 122 (085175)

Double placebo (N=796) 485 (609%) 311 (391%) 185 (232%) 86 (108%) 40 (50%) 58 (73%)

OR (95% CI) Ref Ref Ref Ref Ref Ref

Odds ratios are comparisons with the double placebo group.

Table 3: Inside the table analysis of overall level of functional impairment at age 7 years from the mark III Multi-Attribute Health Scale in children whose mothers had PROM

For more on indices of deprivation see http://www. neighbourhood.statistics.gov.uk

Odds ratios with 95% CI are presented for primary and secondary outcomes in the groups receiving co-amoxiclav (any co-amoxiclav: either with or without erythromycin) and erythromycin (any erythromycin: either with or without co-amoxiclav) separately. Odds ratios approximate relative risks when the risk is low.19 Logistic models with terms indicating allocation to co-amoxiclav and erythromycin and an interaction term, corresponding to the ORACLE I trials factorial design, were also tted.20 Since our ndings were generally not altered when interaction terms were included, for simplicity they have not been included in models presented in the main tables, but they are available on the internet. Multiple births were treated as being independent in the analyses, but sensitivity analyses based on randomly selecting one child were also done.21 Data from the Strengths and Diculties Questionnaire were classied as normal, borderline, or abnormal. Odds ratios and CI for proportions with borderline or abnormal scores are presented. Models with interaction terms were also tted as above. Subgroup analyses were done as specied in the protocol, relating to multiple and singleton pregnancies, and gestational age subgroups used at the time of randomisation (<32 weeks gestation and <28 weeks gestation). Relative risks and 95% CI for key stage one educational data were obtained from Poisson regression models, adjusting for test year. Because of restricted information available from the anonymous summary of these data supplied by the DCSF, sensitivity and subgroup analyses were not possible for these data.

Most of the outcomes presented, including the primary outcome of the follow-up study, can only be assessed in surviving children. Thus the analyses presented are not based on the intention-to-treat principle (ie, by analysis of outcomes in all those entered into the trial). However, the absolute risk of death was low, limiting any potential bias that might be introduced by undertaking the analyses of surviving children only, as pre-specied in the study protocol. There were no clear dierences in the numbers of deaths in each of the study groups at the end of ORACLE I, but we present sensitivity analyses using a composite death or any functional impairment outcome to conrm the limited eect of including deaths in the analyses. Informal allowance for the large number of comparisons undertaken is made in interpreting the results throughout.22 Outcomes for children not assessed may dier from outcomes for those who were assessed.23 To explore this, we investigated dierences between responders and nonresponders for a variety of factors: treatment group, shortterm maternal and neonatal outcomes, ethnicity, indices of deprivation from ONS derived from post code, and for those children in England, educational attainment.

Role of the funding source


The study sponsors had no involvement in the study design; collection, analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication. DJ and KP had full access to all the data. SK had nal responsibility for the decision to submit for publication.

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Results
Of the 4378 UK children eligible for follow-up, outcome was known for 3298 (75%). Full questionnaire data are available for 3171 (72%) children, data were collected from telephone interview or GP for 90 children (2%; included in the analysis of specic medical conditions); 37 (1%) children had died (gure 1). Women were unaware of their treatment allocation with the exception of one woman who requested this information before returning data for OCS I. Only 08% of data within returned questionnaires were missing. Full key stage one educational data were available for 3238 (96%) of the 3377 English children who had been entered into the tests by 2007. The characteristics of the responders, in each factorial group, were broadly similar in terms of maternal, demographic, and neonatal data to that of the main ORACLE I trial results (table 1). Children whose outcome was unknown had younger mothers and experienced less neonatal morbidity (webtable 1), and, at least for those in England, were from more deprived areas than those whose outcome was known (webtable 2). More English children whose outcome was unknown scored below level two in key stage one tests, and were less likely to be white than were those whose outcome was known (webtable 2). There was no dierence in the proportion of children with any functional impairment whose mothers had been prescribed any erythromycin, compared with those who received no erythromycin, or in the proportion of children
Any erythromycin No erythromycin Number of women Number of children Stillbirths Deaths in rst year Deaths after rst year Total deaths Total death or any functional impairment Total death or three or more abnormal attributes 2178 2323 42 (18%) 107 (46%) 7 (03%) 156 (67%) 750 (323%) 284 (122%) 2255 2389 44 (18%) 124 (52%) 4 (02%) 172 (72%) 827 (346%) 302 (126%)

with any functional impairment whose mothers had received co-amoxiclav, compared with those who received no co-amoxiclav (table 2). There was no evidence of an eect of either antibiotic on any functional impairment when tting a logistic model with terms for erythromycin, co-amoxiclav, and an interaction between the antibiotics (webtable 3); this model also showed no evidence for an interaction in eects between the antibiotics (webtable 3). Neither antibiotic had an eect on any functional impairment when missing data were assumed to correspond to a functional impairment (data not shown). Table 3 presents the results for the four treatment groups inside the table of the factorial trial;24 there were no clear dierences between the treatment groups. Sensitivity analyses based on the HUI3 multi-attribute utility function16 showed similar results (webtable 4). The use of erythromycin or of co-amoxiclav was not associated with any change in risk of death or of a composite endpoint of death or any functional impairment (table 4; webtable 5). Neither antibiotic had a signicant eect on the overall level of behavioural diculties experienced or the impact on families (table 5; webtable 6). Neither antibiotic had any eect on the proportions of children failing to achieve each level in reading, writing, or mathematics at key stage one (table 6). Compared with national data, a higher proportion of the children surveyed here attained a score below level two (table 6). There were no signicant dierences with either antibiotic in the proportions of children reported as having
Any co-amoxiclav No co-amoxiclav 2204 2336 2229 2376 41 (17%) 118 (50%) 6 (03%) 165 (69%) 769 (324%) 288 (121%) 112 (073171) 097 (075127) 085 (026278) 101 (080126) 111 (098125) 106 (089126) OR (95% CI)

See Online for webtables 17

OR (95% CI)

098 (064150) 088 (068115) 179 (052612) 093 (074116) 090 (080102) 096 (081114)

45 (19%) 113 (48%) 5 (02%) 163 (70%) 808 (346%) 298 (128%)

Table 4: Deaths in ORACLE I and during OCS I in children whose mothers had PROM

Any erythromycin (N=1551) Emotional symptoms Conduct problems Hyperactivity Peer problems Prosocial behaviour Overall (total diculties) Impact on family 295 (190%) 398 (257%) 372 (240%) 334 (215%) 98 (63%) 310 (200%) 278 (179%)

No erythromycin (N=1620) 284 (175%) 433 (267%) 443 (273%) 343 (212%) 131 (81%) 340 (210%) 307 (190%)

OR (95% CI) 110 (092132) 095 (081111) 084 (071098) 102 (086121) 077 (058101) 094 (079112) 093 (078112)

Any co-amoxiclav (N=1587) 290 (183%) 415 (261%) 398 (251%) 350 (221%) 118 (74%) 329 (207%) 298 (188%)

No co-amoxiclav (N=1584) 289 (182%) 416 (263%) 417 (263%) 327 (206%) 111 (70%) 321 (203%) 287 (181%)

OR (95% CI) 100 (084120) 099 (085116) 094 (080110) 109 (092129) 107 (081140) 103 (087122) 104 (087125)

Data are number of children scoring borderline or abnormal on each scale (%).

Table 5: Behaviour at age 7 years from the Strengths and Diculties Questionnaire in children whose mothers had PROM

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CNS or development problems, diabetes, or total bowel disorders (table 7; webtable 7). There is some evidence of a reduction in respiratory problems in the children whose mothers received any erythromycin compared with those who received no erythromycin (table 7). Although there is no evidence of a signicant increase in the prevalence of total bowel problems with either antibiotic, more children were reported to have other bowel problems (eg, hospital admission for constipation, diarrhoea, or stomach troubles, or under care of doctor for bowel problems) in the any co-amoxiclav group than in the no co-amoxiclav group (table 7). However, both of these results must be interpreted with caution because
Any erythromycin (N=1596) Reading Writing Maths 360 (226%) 418 (262%) 257 (161%) No erythromycin (N=1642) 363 (221%) 426 (259%) 257 (157%) RR (95% CI)* 103 (099107) 101 (097105) 101 (097106)

of the lack of formal adjustment for multiple comparisons. Subgroup analyses for multiple/single births and for gestation above and below 28 and 32 weeks were preplanned; they generally suggest eects consistent with neither antibiotic having an eect on any functional impairment or on the presence of three or more abnormal attributes (gure 2). Adjustment for maternal baseline, social class, and other factors did not substantially alter any of the treatment eects seen here (data not shown). For further analyses, see http://www2. le.ac.uk/Members/drj/supplementary-materials-forpapers.
Any co-amoxiclav (N=1623) 354 (218%) 405 (250%) 250 (154%) No co-amoxiclav (N=1615) 369 (228%) 439 (272%) 264 (163%) RR (95% CI)* 098 (094102) 098 (094101) 099 (095103)

Data are number of children failing to achieve level two or higher (%). Overall relative risks (RR) and 95% CI are from Poisson models for level achieved adjusting for test year, 200207. National norms for 200207 have been standardised by the numbers of children in the OCS I cohort each year, and suggest that we would expect the following percentages of children to fail to achieve level two or above: reading 15%, writing 18%, maths 11%. *No evidence of overdispersion when these Poisson models are tted.

Table 6: Educational attainment in reading, writing, and mathematics at key stage one, for England only, for children whose mothers had PROM

Any erythromycin No erythromycin (N=1590) (N=1671) CNS problems Cerebral palsy Seizures On prescribed medication Hydrocephalus with shunt Developmental problems ADHD from SDQ or parental report Other developmental problems Respiratory problems Wheezing in last year Medication for chest problems in last year Prednisolone Oxygen Relievers Preventers Hospital admission Admission to hospital in last year Admission for chest problems Diabetes Diabetes Bowel disorders All bowel problems Bowel stoma Other bowel problems 61 (38%) 23 (14%) 38 (24%) 57 (34%) 25 (15%) 32 (19%) 3 (02%) 1 (01%) 196 (123%) 27 (17%) 223 (133%) 45 (27%) 305 (192%) 286 (180%) 25 (16%) 15 (09%) 261 (164%) 197 (124%) 320 (192%) 316 (189%) 46 (28%) 26 (16%) 293 (175%) 219 (131%) 109 (69%) 6 (04%) 135 (81%) 11 (07%) 46 (29%) 101 (64%) 12 (08%) 3 (02%) 41 (25%) 107 (64%) 19 (11%) 6 (04%)

OR (95% CI)

Any co-amoxiclav No co-amoxiclav OR (95% CI) (N=1632) (N=1629) 39 (24%) 103 (63%) 15 (09%) 6 (04%) 124 (76%) 9 (06%) 309 (189%) 298 (183%) 42 (26%) 21 (13%) 273 (169%) 211 (129%) 211 (129%) 35 (21%) 4 (02%) 65 (40%) 21 (13%) 44 (27%) 48 (29%) 105 (64%) 16 (10%) 3 (02%) 120 (74%) 8 (05%) 316 (194%) 304 (187%) 29 (18%) 20 (12%) 279 (171%) 205 (126%) 208 (128%) 37 (23%) 0 (00%) 53 (33%) 27 (17%) 26 (16%) 081 (053124) 098 (074129) 094 (046190) 200 (050801) 103 (080134) 112 (043292) 097 (082116) 097 (082116) 146 (090235) 105 (057194) 098 (082118) 103 (084127) 101 (083125) 094 (059150) 123 (085178) 077 (044137) 171 (105279)

118 (077181) 099 (075131) 066 (032137) 052 (013210) 084 (064109) 057 (021155) 100 (084119) 094 (079112) 056 (035092) 060 (032114) 092 (077111) 094 (076115) 091 (074112) 062 (039101) 316 (0333038) 113 (078163) 097 (055171) 125 (078202)

ADHD=attention decit hyperactivity disorder. SDQ=Strengths and Diculties Questionnaire.

Table 7: Medical conditions reported by parents of children at age 7 years whose mothers had PROM

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Erythromycin
Any functional impairment

Co-amoxiclav

Overall Multiple births Singleton births Gestation <28 weeks Gestation >28 weeks Gestation <32 weeks Gestation >32 weeks
05 1 15 2 25 05 1 15 2 25

Three or more abnormal attributes

Overall Multiple births Singleton births Gestation <28 weeks Gestation >28 weeks Gestation <32 weeks Gestation >32 weeks 05 1 15 2 25 05 1 15 2 25

Figure 2: Subgroup analyses for overall functional impairment for children whose mothers had PROM

Discussion
In this long-term follow-up of children whose mothers were entered into the ORACLE I trial of antibiotics prescribed for women with PROM and no overt signs of infection, there is no evidence of any substantial longterm eect in children at age 7 years associated with the prescription of either erythromycin or co-amoxiclav. Although there were some apparent dierences in a small number of secondary outcomeseg, improvement in respiratory function with erythromycin and increased bowel disorders with co-amoxiclavand despite the fact that these changes are biologically plausible and consistent with the short-term outcomes from the ORACLE I trial, they should be viewed with caution because of the large number of comparisons made. The size of the ORACLE population made direct face-toface assessment of outcome impracticable and thus we elected to obtain proxy information about the children from parents. This was possible using well validated and standardised parent report tools, namely the Health Utilities Index and the Strengths and Diculties Questionnaire, to assess health-related quality-of-life and behaviour, respectively. Although these are validated ways of collecting outcome data, using a questionnaire may mean more subtle dierences between the treatment groups were missed. Health conditions could only be assessed through parental report, which also leads to the potential for under reporting and some inaccuracy in ascertainment; in general, this might reduce the power to detect any associations present, since almost all the women in the study remained blind to their allocated treatment. To achieve high follow-up rates using postal questionnaires is dicult. We used evidence-based

strategies to optimise the response25 and developed our own randomised evidence during the conduct of the study to maximise response.11 We maintained regular contact with the women originally entered into the trial, allowing us to achieve a high follow-up rate of 75%. Nonetheless, disadvantaged groups are over-represented in the non-responders but there was no evidence of dierential non-response between the randomised groups. Although this response rate is lower than that assumed in the initial power calculation, the increased prevalence of functional impairment resulted in power being increased overall. Cognitive impairment is the most common disability associated with preterm birth.26,27 School performance is aected by a range of disabilities, of which general cognitive function is the most important, although additional decits of executive function28 and attention may be contributory in the preterm child.2 Although we were unable to achieve direct cognitive assessment, we were able to use anonymised results from national curriculum tests, which allowed us to examine the scholastic attainment for virtually the whole population of surviving children in England, which we have used as a proxy for cognitive outcome. While the results showed no treatment dierences in the level of performance reached with either antibiotic, this group of children as a whole have educational attainment below national norms, in keeping with the excess of preterm children with poor academic attainment.2 Level scores are arguably rather weak measures of attainment; the power of these comparisons would have been increased by use of the raw scores for individual tests, but these are not available centrally.
Labels Measuring bars 13 2 5 Graph marks Arrows

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In women with PROM, positive amniotic uid cultures are found in 32% of cases at the time of presentation29 and in as many as 75% during subsequent labour.30 Antibiotics might therefore be expected to improve clinical outcomes in this situation. There is also increasing evidence that, in addition to preterm birth, intrauterine infection is an independent antecedent of other disability, particularly cerebral palsy31 and chronic lung disease.32 Prescription of antibiotics for PROM could prevent neurological and respiratory disability by prolonging pregnancy or by reducing inammation. It is thus disappointing that the ndings of decreased neonatal morbidity after receipt of erythromycin in ORACLE I have not translated into long-term benet detectable within the measures we used. The reasons for this are not clear but might be linked to the length of antibiotic exposure, which in this group of women was fairly short, since about 60% gave birth within a week.8 There is also some evidence that antibiotic administration to women with PROM may neither eradicate nor prevent intra-amniotic infection. In a recent study of 18 women with intra-amniotic infection following PROM, only three showed no evidence of infection or inammation after combination antibiotic treatment for 714 days and nine of 28 women with no evidence of intra-amniotic inammation at admission developed inammatory changes despite therapy; ve of these nine women developed positive amniotic uid cultures.33 This evidence suggests that other strategies are necessary to prevent the progress of infection and inammatory changes in utero in the presence of ruptured membranes. In the accompanying paper reporting the results of the ORACLE Children Study II34 in the presence of spontaneous preterm labour with intact membranes, we have observed an increase in the risk of any functional impairment with the use of erythromycin (with or without co-amoxiclav) and, particularly, increases in the numbers of children with cerebral palsy associated with the use of both erythromycin and co-amoxiclav. These results would suggest further caution should be used when considering the routine treatment of women with antibiotics where there is uncertainty about the diagnosis of PROM. It is clear that we need to better understand the role of infection in women with PROM and the role and wider eects of antibiotics in the perinatal period. However, it is important to clarify that the women in ORACLE I with PROM were entered into the trial when there was clinical uncertainty about the need to prescribe antibioticsie, they showed no overt clinical signs of maternal or fetal infection. It is critical that women with evidence of clinical infection are treated with antibiotics, since clinical chorioamnionitis remains an important cause of maternal, fetal, and neonatal death. The results of this study should not lead to fewer women with overt signs of maternal or fetal infection receiving treatment.
8

Contributors All authors contributed to the study design, developed the protocol, and contributed to drafting the paper. SK led the study and together with DJT and PB contributed knowledge of maternity practice. KP and DRJ provided statistical knowledge; NM and AS contributed knowledge on childhood outcomes. OCS I Study Team OCS Oce: Ann Blackburn, Kate Taylor, and the oce sta. Department of Health Sciences, University of Leicester: Mary Dixon Woods, Carolyn Tarrant, Clare Jackson, Janet Willars. Trial steering committee: Richard Lilford, Richard Cooke, Gill Gyte, Chris Whetton, Philippa Russell, Julie Cahill. Data monitoring committee: Diana Elbourne, Helena McNally, Martin Whittle. Conict of interest statement We declare that we have no conict of interest. Acknowledgments This study was funded by the UK Medical Research Council and sponsored by University Hospitals of Leicester and approved by their research and development directorate. We thank all the women and children who took part in the study and the obstetricians and midwives who recruited them to the original ORACLE trials. We thank the Oce of National Statistics, the NHS National Strategic Tracing Service, and the Data Services Group within the Department of Children, Schools and Families. We also thank the key stage one group (Maggie McLean, John Crookes, Peter Tymms, and Tony Cline) for helpful comments on educational aspects. We thank Steve Gould, Barbara Farrell, Phil Edwards, and Martin Rosser for advice on questionnaire design. We convened a group of experts from within the eld to help us understand and interpret these nding before publication. This group consisted of Martin Whittle, Alison Bedford Russell, Phil Bennett, Kate Costeloe, Francis Cowan, Olaf Dammann, Diana Elbourne, Catherine Elliott, Mike Millar, Jane Norman, Micheal OShea, Max Parmar, Roberto Romero, and Dieter Wolke. References 1 Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005; 352: 919. 2 Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ. Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 2002; 288: 72837. 3 Johnson S. Cognitive and behavioural outcomes following very preterm birth. Semin Fetal Neonatal Med 2007; 12: 36373. 4 Gotsch F, Romero R, Kusanovic JP, et al. The fetal inammatory response syndrome. Clin Obstet Gynaecol 2007; 50: 65283. 5 Dammann O, Leviton A, Gappa M, Dammann CEL. Lung and brain damage in preterm newborns and their association with gestational age, prematurity subgroup, infection/in ammation and long term outcome. Br J Obstet Gynaecol 2005; 112: 49. 6 Gomez R, Romero R, Mazor M, Ghezzi F, David C, Yoon BH. The role of infection in preterm labour and delivery. In: Elder MG, Romero R, Lamont RF, eds. Preterm labour. Edinburgh: Churchill and Livingstone, 1997: 85126. 7 Miralles R, Hodge R, McParland PC, et al. Relationship between antenatal inammation and antenatal infection identied by detection of microbial genes by polymerase chain reaction. Pediatr Res 2005; 57: 57077. 8 Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for preterm, prelabour rupture of the fetal membranes: the ORACLE I randomised trial. Lancet 2001; 357: 98190. 9 Royal College of Obstetricians and Gynaecologists. Preterm prelabour rupture of the membranes. Green Top Guideline No 44. London: Royal College of Obstetricians and Gynaecologists, 2006. 10 Kenyon S, Brocklehurst P, Jones D, Marlow N, Salt A, Taylor D. MRC ORACLE Children Study. Long term outcomes following prescription of antibiotics to pregnant women with either spontaneous preterm labour or preterm rupture of the membranes. BMC Pregnancy Childbirth 2008; 8: 14.

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11 12

13 14 15 16 17 18 19 20 21 22

Kenyon S, Pike K, Jones D, et al. The eect of a nancial incentive on return of a postal health and development questionnaire: a randomised trial. BMC Health Serv Res 2005; 5: 55. Saigal S, Rosenbaum P, Stoskupf B, et al. Comprehensive assessment of the health status of extremely low birthweight children at eight years of age: comparisons with a reference group. J Pediatr 1994; 125: 41117. Goodman R. The strengths and diculties questionnaire: a research note. J Child Psychol Psychiatry 1997; 38: 58186. Asher MI, Keil U, Anderson HR, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995; 8: 48391. Anon. Multi-attribute health status classication system: health utilities index mark 3 (HUI3). http://www.healthutilities. com/hui3.htm (accessed Aug 8, 2008). Feeny D, Furlong W, Saigal S, Sun J. Comparing directly measured standard gamble scores to HUI2 and HUI3 utility scores: group- and individual-level comparisons. Soc Sci Med 2004; 58: 799809. Cue SP, Moore CG, McKeown RE. Prevalence and correlates of ADHD symptoms in the National Health Survey. J Atten Disorder 2005; 9: 392401. Qualications and Curriculum Authority. Key stage 1 assessments and reporting arrangements. London: Qualications and Curriculum Authority, 2007. Altman DG. Practical statistics for medical research. London: Chapman and Hall, 2006. Montgomery AA, Peters TJ, Little P. Design, analysis and presentation of factorial randomised controlled trials. BMC Med Res Methodol 2003; 3: 26. Gates S, Brocklehurst P. How should randomised trials including multiple pregnancies be analysed? BJOG 2004; 111: 21319. Bland JM, Altman DG. Multiple signicance tests: the Bonferroni method. BMJ 1995; 310: 170.

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Tin W, Fritz S, Wariyer U, Hey E. Outcome of very preterm birth: children reviewed with ease at 2 years dier from those followed up with diculty. Arch Dis Child Neonatal Ed 1998; 79: F8387. McAlister FA, Straus SE, Sackett DL, Altman DG. Analysis and reporting of factorial trials: a systematic review. JAMA 2003; 289: 254553. Edwards P, Roberts I, Clarke M, et al. Increasing response rates to postal questionnaire: systemic review. BMJ 2002; 324: 118385. Marlow N. Neurocognitive outcome after very preterm birth. Arch Dis Child Neonatal Ed 2004; 89: F22428. Salt AT, Redshaw M. Neurodevelopment follow-up after preterm birth: follow up after two years. Early Hum Dev 2006; 82: 18597. Marlow N, Hennessy EM, Bracewell MA, Wolke D. Motor and executive function at 6 years of age after extremely preterm birth. Pediatrics 2007; 120: 793804. Goncalves LK, Chaiworapongsa T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res 2002; 8: 313. Romero R, Quintero R, Oyarzun E, et al. Intraamniotic infection and the onset of labour in preterm premature rupture of the membranes. Am J Obstet Gynecol 1988; 159: 66166. Dammann O, Leviton A. Perinatal brain damage causation. Dev Neurosci 2007; 29: 28088. Jobe AH. Glucocorticoids, inammation and the perinatal lung. Semin Neonatol 2001; 6: 33142. Gomez R, Romero R, Nien JK, et al Antibiotic administration to patients with preterm premature rupture of membranes does not eradicate intra-amniotic infection. J Matern Fetal Neonatal Med 2007; 20: 16773. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 2008; published online Sept 18. DOI:10.1016/S0140-6736(08)61203-9.

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Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial
S Kenyon, K Pike, D R Jones, P Brocklehurst, N Marlow, A Salt, D J Taylor

Summary

Background The ORACLE II trial compared the use of erythromycin and/or amoxicillinclavulanate (co-amoxiclav) with that of placebo for women in spontaneous preterm labour and intact membranes, without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present studythe ORACLE Children Study IIwas to determine the long-term eects on children after exposure to antibiotics in this clinical situation. Methods We assessed children at age 7 years born to the 4221 women who had completed the ORACLE II study and who were eligible for follow-up with a structured parental questionnaire to assess the childs health status. Functional impairment was dened as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classication system. Educational outcomes were assessed with national curriculum test results for children resident in England. Findings Outcome was determined for 3196 (71%) eligible children. Overall, a greater proportion of children whose mothers had been prescribed erythromycin, with or without co-amoxiclav, had any functional impairment than did those whose mothers had received no erythromycin (658 [423%] of 1554 children vs 574 [383%] of 1498; odds ratio 118, 95% CI 102137). Co-amoxiclav (with or without erythromycin) had no eect on the proportion of children with any functional impairment, compared with receipt of no co-amoxiclav (624 [407%] of 1523 vs 608 [400%] of 1520; 103, 089119). No eects were seen with either antibiotic on the number of deaths, other medical conditions, behavioural patterns, or educational attainment. However, more children whose mothers had received erythromycin or co-amoxiclav developed cerebral palsy than did those born to mothers who received no erythromycin or no co-amoxiclav, respectively (erythromycin: 53 [33%] of 1611 vs 27 [17%] of 1562, 193, 121309; co-amoxiclav: 50 [32%] of 1587 vs 30 [19%] of 1586, 169, 107267). The number needed to harm with erythromycin was 64 (95% CI 37209) and with co-amoxiclav 79 (42591). Interpretation The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at 7 years of age. The risk of cerebral palsy was increased by either antibiotic, although the overall risk of this condition was low. Funding UK Medical Research Council.

Published Online September 18, 2008 DOI:10.1016/S01406736(08)61203-9 See Online/Comment DOI:10.1016/S01406736(08)61248-9 See Online/Articles DOI:10.1016/S01406736(08)61202-7 Reproductive Sciences Section, Cancer Studies and Molecular Medicine (S Kenyon MA, K Pike MSc, Prof D J Taylor FRCOG) and Health Sciences Department (Prof D R Jones PhD), University of Leicester, Leicester, UK; National Perinatal Epidemiology Unit, University of Oxford, Oxford, UK (Prof P Brocklehurst FRCOG); Academic Division of Child Health, University of Nottingham, Nottingham, UK (Prof N Marlow FMedSci); Great Ormond Street Hospital for Children and Institute of Child Health, University College London, London, UK (A Salt FRCPCH) Correspondence to: Sara Kenyon, Reproductive Sciences Section, Cancer Studies and Molecular Medicine, University of Leicester, 2228 Princess Road West, Leicester LE1 6TP, UK oracle@leicester.ac.uk

Introduction
Preterm birth is associated with later disabilities among surviving children that pose major challenges for public health and education; these problems increase in frequency as gestational age at birth decreases,1 such that around 25% of babies born before 26 weeks of gestation have serious disability2 and many children without serious disability have learning or behavioural diculties.3,4 Observational evidence suggests that perinatal intrauterine infection or inammation might have a role in the causation of 1322% of cases of spontaneous preterm labour (SPL)5,6 and infection or inammation have been implicated in the genesis of neonatal lung disease7 and brain injury.8 Despite a number of randomised trials of the use of antibiotics for women with SPL and intact membranes, no clear evidence of benet has been found and there is some evidence to

suggest that such treatment might be associated with increased neonatal mortality.9 ORACLE II10 enrolled women who presented with SPL and intact membranes and assessed the use of amoxicillinclavulanate (co-amoxiclav) 375 mg, or erythromycin 250 mg, or both, or placebo, four times a day for 10 days or until birth (whichever was soonest), by use of a factorial randomised design. Neither antibiotic was associated with any improvement in neonatal mortality or morbidity. In view of the poor predictive validity of neonatal morbidity after preterm birth for childhood outcome, it is important to determine whether there are long-term sequelae associated with the use, or not, of these antibiotic treatments in women presenting with SPL. We report the results of the ORACLE Children Study II (OCS II), which was designed to assess the long-term outcomes for children born in the UK to women enrolled in the original ORACLE II trial.

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Methods

Participants
OCS II began in 2002 and sought follow-up information for children at 7 years of age who were born to the 6241 women who completed the ORACLE II trial.10 Tracing and contact of participants in the follow-up study are described in detail in the accompanying paper.11 The West Midlands Multi-centre Research and Ethics Committee (MREC) approved the study and the University of Leicester, UK, sponsored the OCS. Oversight was provided by an independent trial steering committee and data monitoring committee, both of which met annually. Those involved in tracing and data entry remained blind to the allocated treatment. All data to assess health and educational outcomes were double entered and subject to validation and logic checks.

Data collection
Data were collected with a parent-completion postal questionnaire, which consisted of the the Health Utilities Index (HUI),12 from which the Multi-Attribute Health Status (MAHS) is derived, the Strengths and Diculties Questionnaire,13 and specic questions on respiratory symptoms,14 hospital admissions, convulsions, other specic medical conditions, and demographic data.
6295 women entered into ORACLE II trial

54 women excluded 14 protocol violations 40 lost to follow-up

6241 women completed ORACLE II trial

2020 women excluded 98 women excluded due to death of child in ORACLE II trial 1877 women randomised outside the UK 45 women withdrew before start of OCS

4221 women eligible for OCS follow-up

4473 children

3196 children (71%) whose outcome is known: 3052 (68%) parents returned a questionnaire 121 (3%) health of child known from GPs and parents 23 (1%) children died

1277 children whose outcome is not known: 65 emigrated, no contact made 149 lost to follow-up, no contact made 80 opted out by parents after initial contact 983 no response to questionnaire or other contact

The primary outcome was dened as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III MAHS classication system12 within any of the individual attributes of vision, hearing, speech, ambulation, dexterity, emotion, cognition, or pain. Each attribute has either ve or six dened levels of impairment, ranging from normal function to severe dysfunction.15 These have been classied further into none, mild, moderate, or severe levels of severity for the individual attributes from the standard algorithms available within the HUI coding/ procedure manual. The overall level of functional impairment was determined by their worst score on any attribute. Sensitivity analyses were also done based on the HUI3 multi-attribute utility scores of overall healthrelated quality of life,16 which became available after this study had begun. Secondary outcomes were the presence of three or more abnormal attributes derived from the MAHS classication system and the degree of functional impairment (severe, moderate, mild, none) within the individual domains; the number of deaths between trial entry and discharge and age 7 years; overall and subscale scores derived from the parent-completed Strengths and Diculties Questionnaire; the frequency of specic medical conditions including CNS problems (cerebral palsy, ts/seizures, hydrocephalus with a shunt), respiratory problems (wheezing, medication for asthma), hospital admission (both in the last year and for chest problems), diabetes, bowel disorders, and developmental problems (attention decit hyperactivity disorder derived from the Strengths and Diculties Questionnaire17 or parent report), and other development problems. We used results from national curriculum tests (key stage one), done at 7 years of age to assess the childrens educational attainment for residents in England.18 Such tests are not routinely done in other parts of the UK. At key stage one, all children are awarded a level for each of reading, writing, and mathematics. These include levels three and four, which are above average, level two (the average level awarded to 6070% of pupils, and which is also subdivided into three sublevels), and below level two, which includes children who attained level one, those who were working towards level one, or who were not entered by the teacher. For all eligible children in England, key stage one level data were provided anonymously by the UK Department for Children, Schools and Families (DCSF), categorised by treatment group.

Statistical analysis
The size of the study was predened by the number of women recruited to the ORACLE II trial. The indicative power calculation in the protocol noted that about 4500 children were expected to be eligible for the followup study. About 31% of the children in the any erythromycin group were expected to have three or

Figure 1: Flowchart for SPL group through ORACLE II and extended follow-up in OCS II *133 babies died during ORACLE II. However, only 98 women were excluded because a number had a multiple birth. Of the 133 babies, 86 were singletons, 26 multiple births where all babies died (10 sets of twins and two sets of triplets), and 21 were multiple births with live siblings.

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Erythromycin and co-amoxiclav At entry to ORACLE II Number of women Maternal age (years) Gestational age at trial entry (days) Multiple births Maternal antibiotics in the postnatal period Short-term outcomes of ORACLE II Number of babies Birth within 48 h of trial entry Birth within 7 days of trial entry Gestational age (days) Birthweight (g) Sex (male) Admission to neonatal unit Ventilated Respiratory distress syndrome Supplementary oxygen at 28 days Positive blood culture Necrotising enterocolitis (suspected or proven) Abnormal cerebral ultrasonography At entry to OCS II Ethnic origin (white) Smoking in family Damp or mould problems Family history of asthma Childs age at completion of questionnaire (years) Childs age at the start of the academic year they sat key stage one tests (years)
Data are n (%) or median (IQR).

Erythromycin only

Co-amoxiclav only

Placebo

755 269 (229311) 220 (201233) 44 (58%) 76 (101%) 795 87 (109%) 120 (151%) 267 (247278) 2980 (23003460) 416 (523%) 232 (292%) 78 (98%) 91 (115%) 39 (49%) 24 (30%) 13 (16%) 15 (19%) 718 (903%) 375 (472%) 72 (91%) 414 (521%) 697 (691706) 642 (625675)

764 272 (230317) 219 (202233) 45 (68%) 89 (117%) 816 93 (114%) 141 (173%) 266 (245278) 2940 (22693395) 460 (564%) 242 (297%) 66 (81%) 75 (92%) 33 (40%) 12 (15%) 8 (10%) 10 (12%) 737 (903%) 372 (456%) 51 (63%) 418 (512%) 697 (691707) 642 (617667)

744 265 (228309) 217 (200232) 49 (66%) 86 (116%) 792 83 (105%) 130 (164%) 266 (245278) 2970 (22873460) 400 (505%) 233 (294%) 73 (92%) 79 (100%) 34 (43%) 16 (20%) 14 (18%) 8 (10%) 716 (904%) 358 (452%) 43 (54%) 415 (524%) 698 (691708) 650 (625667)

728 272 (237314) 219 (201233) 47 (65%) 111 (153%) 770 96 (125%) 127 (165%) 266 (245277) 2920 (22903420) 436 (566%) 234 (304%) 71 (92%) 80 (104%) 38 (49%) 16 (21%) 5 (07%) 12 (16%) 682 (886%) 332 (431%) 37 (48%) 382 (496%) 697 (691706) 642 (617667)

Table 1: Characteristics of the responders in the SPL group

more abnormal attributes using the MAHS scale.12 Assuming an 85% response rate, this gave 80% power (with two-tailed =005) to detect a prevalence of three or more abnormal attributes in the no erythromycin group of 5% (a relative dierence between the two groups of 38%). Odds ratios with 95% CI are presented for primary and secondary outcomes in the groups receiving co-amoxiclav (any co-amoxiclav: either with or without erythromycin) and erythromycin (any erythromycin: either with or
Any erythromycin No erythromycin (N=1554) (N=1498) None Any functional impairment Mild Moderate Severe Three or more abnormal attributes 896 (577%) 658 (423%) 372 (239%) 185 (119%) 101 (65%) 131 (84%) 924 (617%) 574 (383%) 319 (213%) 162 (108%) 93 (62%) 149 (99%)

without co-amoxiclav) separately. Odds ratios approximate relative risks when the risk is low.19 Logistic models with terms indicating allocation to co-amoxiclav and erythromycin and an interaction term, corresponding to the ORACLE II trials factorial design, were also tted.20 Since our ndings were generally not altered when interaction terms were included, for simplicity they have not been included in models presented in the main tables, but they are available on the internet. Multiple births were treated as being independent in the analyses,
Any co-amoxiclav (N=1532) 908 (593%) 624 (407%) 349 (228%) 176 (115%) 99 (65%) 147 (96%) No co-amoxiclav (N=1520) 912 (600%) 608 (400%) 342 (225%) 171 (113%) 95 (63%) 133 (88%) OR (95% CI) Ref 103 (089119) 102 (086122) 103 (082130) 105 (078141) 111 (087142)

OR (95% CI) Ref 118 (102137) 120 (101143) 118 (094148) 112 (083151) 083 (065107)

Table 2: Overall level of functional impairment at age 7 years from the mark III Multi-Attribute Health Scale in children whose mothers had SPL

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Any erythromycin Number of women Number of children Stillbirths Deaths in rst year Deaths after rst year Total deaths Total death or any functional impairment Total death or three or more abnormal attributes Total death or cerebral palsy 2219 2375 20 (08%) 61 (26%) 5 (02%) 86 (36%) 744 (313%) 217 (91%) 139 (59%)

No erythromycin 2145 2279 24 (11%) 41 (18%) 5 (02%) 70 (31%) 644 (283%) 219 (96%) 97 (43%)

OR (95% CI)

Any co-amoxiclav 2158 2304

No co-amoxiclav 2206 2350 24 (10%) 53 (23%) 4 (02%) 81 (34%) 689 (293%) 214 (91%) 111 (47%)

OR (95% CI)

080 (044145) 144 (096214) 097 (028334) 119 (086163) 116 (102131) 095 (078115) 140 (107182)

20 (09%) 49 (21%) 6 (03%) 75 (33%) 699 (303%) 222 (96%) 125 (54%)

085 (047154) 094 (063139) 153 (043542) 094 (068130) 105 (093119) 106 (087130) 116 (089150)

Table 3: Deaths in ORACLE II and during OCS II in children whose mothers had SPL

Erythromycin and OR (95% CI)* co-amoxiclav (N=769) None Any functional impairment Mild Moderate Severe Three or more abnormal attributes 444 (577%) 325 (423%) 181 (235%) 91 (118%) 53 (69%) 72 (94%) 082 (066100) 122 (100151) 124 (096160) 122 (088170) 117 (077177) 092 (066130)

Erythromycin OR (95% CI)* only (N=785) 452 (576%) 333 (424%) 191 (243%) 94 (120%) 48 (61%) 59 (75%) 081 (066100) 123 (100151) 129 (100165) 124 (089172) 104 (068159) 073 (051104)

Co-amoxiclav only (N=763) 464 (608%) 299 (392%) 168 (220%) 85 (111%) 46 (60%) 75 (98%)

OR (95% CI)* 093 (075114) 108 (088133) 110 (085142) 109 (078153) 097 (063149) 097 (069137)

Double placebo (N=735) 460 (626%) 275 (374%) 151 (205%) 77 (105%) 47 (64%) 74 (101%)

OR (95% CI)* Ref Ref Ref Ref Ref Ref

Odds ratios are comparisons with the double placebo group.

Table 4: Inside the table analysis of overall level of functional impairment at age 7 years from the mark III Multi-Attribute Health Scale in children whose mothers had SPL

For more on indices of deprivation see http://www. neighbourhood.statistics.gov.uk

but sensitivity analyses based on randomly selecting one child were also done.21 Data from the Strengths and Diculties Questionnaire were classied as normal, borderline, or abnormal. Odds ratios and CI for proportions with borderline or abnormal scores are presented. Models with interaction terms are also tted as above. Subgroup analyses were done as specied in the protocol, relating to multiple and singleton pregnancies, and gestational age subgroups used at the time of randomisation (<32 weeks gestation and <28 weeks gestation). Relative risks and 95% CI for key stage one educational data were obtained from Poisson regression models, adjusting for test year. Because of restricted information available from the anonymous summary of these data supplied by the DCSF, sensitivity and subgroup analyses were not possible for these data. Most of the outcomes presented, including the primary outcome of the follow-up study, can only be assessed in surviving children. Thus the analyses presented are not based on the intention-to-treat principle (ie, by analysis of outcomes in all those entered into the trial). However, the absolute risk of death was low, limiting any potential bias that might be introduced by undertaking the analyses of surviving children only, as pre-specied in the study protocol. There were no clear dierences in the numbers of deaths in each of the study groups at the end of the ORACLE II trial, but we present sensitivity analyses using a composite death or any functional impairment

outcome to conrm the limited eect of including deaths in the analyses. Informal allowance for the large number of comparisons undertaken is made in interpreting the results throughout.22 Outcomes for children not assessed may dier from outcomes for those who were assessed.23 To explore this, we investigated dierences between responders and nonresponders for a variety of factors: treatment group, short-term maternal and neonatal outcomes, ethnicity, indices of deprivation from ONS derived from post code, and for those children in England, educational attainment.

Role of the funding source


The study sponsors had no involvement in the study design; collection, analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication. DJ and KP had full access to all the data. SK had nal responsibility for the decision to submit for publication.

Results
Of the 4473 UK children eligible for follow-up, outcome was known for 3196 (71%): 3052 (68%) parents returned a questionnaire, data were collected from telephone interview or the family doctor for 121 (3%) children (included in the analysis of specic medical conditions), and 23 (1%) died (gure 1). Women were unaware of their treatment allocation, with the exception of three people

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who requested this information before returning data for this study. Only 06% of data within returned questionnaires were missing. Full key stage one level data were available for 3239 (95%) of the 3394 children in England who had been entered for the tests by 2007. The characteristics of the responders to the questionnaires were broadly similar to the total population enrolled in the ORACLE II trial (table 1), but mothers in the double placebo group were less likely to be white, and received more postnatal antibiotics than those in the other groups (table 1). Children whose outcome was unknown had younger mothers and had less neonatal morbidity (webtable 1), and at least for those in England, were from more deprived areas than those whose outcome was known (webtable 2). More English children whose outcome was unknown scored below level two in key stage one tests and were less likely to be white than were those whose outcome was known (webtable 2). More children whose mothers had received any erythromycin had any functional impairment than did those whose mothers received no erythromycin (table 2). The proportion of children categorised as having moderate or severe functional impairment, or with three or more abnormal attributes, did not vary markedly between treatment groups, but the proportion of children with mild functional impairment was higher in the any erythromycin group than in the no erythromycin group (table 2). Findings were similar for the composite outcome of death or any functional impairment (table 3). Sensitivity analyses based on the HUI3 multi-attribute utility function16 lead to broadly similar results (webtable 3).
Any erythromycin (N=1554) Emotional symptoms Conduct problems Hyperactivity Peer problems Prosocial behaviour Overall (total diculties) Impact on families 327 (210%) 480 (309%) 424 (273%) 405 (261%) 122 (79%) 384 (247%) 334 (215%) No erythromycin (N=1498) 330 (220%) 420 (280%) 415 (277%) 391 (261%) 99 (66%) 363 (242%) 292 (195%)

By contrast, there was no dierence between children whose mothers had received any co-amoxiclav and those whose mothers had received no co-amoxiclav in terms of the proportion of children with any functional impairment; in the categories of mild, moderate, severe, or three or more abnormal attributes; or when functional impairment was combined with death (table 2 and table 3). These ndings were supported when tting a logistic model with terms for erythromycin, co-amoxiclav, and an interaction between the two drugs (webtable 4); there was no evidence of an interaction in eects between the drugs (webtable 4). Results were consistent when missing data were assumed to correspond to a functional impairment (data not shown). Table 4 presents the results of the four treatment groups inside the table of the factorial trial;24 again, increases in functional impairment were seen with the prescription of erythromycin. The number of deaths (table 3; webtable 5), behaviour (table 5; webtable 6), educational attainment (table 6), and non-neurological conditions (table 7; webtable 7) did not dier between children whose mothers had received any erythromycin, compared with those whose mothers had received no erythromycin, except for more children presenting with bowel disorders if their mother had received any erythromycin. Receipt of co-amoxiclav seemed to have no eect on any of these outcomes, compared with receipt of no co-amoxiclav (tables 3, 57). However, more children whose mothers had received any erythromycin or whose mothers had received any co-amoxiclav had cerebral palsy than did those whose mothers had received no erythromycin or no
Any co-amoxiclav (N=1532) 341 (223%) 454 (296%) 418 (273%) 396 (258%) 112 (73%) 385 (251%) 312 (204%) No co-amoxiclav (N=1520) 316 (208%) 446 (293%) 421 (277%) 400 (263%) 109 (72%) 362 (238%) 314 (207%) OR (95% CI) 109 (092130) 101 (087118) 098 (084115) 098 (083115) 102 (078134) 107 (091127) 098 (082117)

See Online for webtables 17

OR (95% CI) 094 (079112) 115 (098134) 098 (084115) 100 (085117) 120 (091159) 103 (087121) 113 (095135)

Data are number of children scoring borderline or abnormal on each scale (%).

Table 5: Behaviour at age 7 years from the Strengths and Diculties Questionnaire in children whose mothers had SPL

Any erythromycin (N=1641) Reading Writing Maths 377 (230%) 413 (252%) 239 (146%)

No erythromycin (N=1598) 367 (230%) 413 (258%) 225 (141%)

RR (95% CI) * 100 (096104) 100 (097104) 099 (096103)

Any co-amoxiclav (N=1608) 366 (228%) 395 (246%) 230 (143%)

No co-amoxiclav (N=1631) 378 (232%) 431 (264%) 234 (143%)

RR (95% CI)* 099 (095103) 099 (095102) 099 (095103)

Data are number of children failing to achieve level 2 or higher (%). Overall relative risks (RR) and 95% CI are from Poisson models for level achieved adjusting for test year, 200207. National norms for 200207 have been standardised by the numbers of children in the OCS II cohort each year, and suggest that we would expect the following percentages of children to fail to achieve level 2 or above: reading 15%, writing 18%, maths 12%. *No evidence of overdispersion when these Poisson models are tted.

Table 6: Educational attainment in reading, writing and mathematics, for England only, for children whose mothers had SPL

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Any erythromycin No erythromycin OR (95% CI) (N=1611) (N=1562) CNS problems Cerebral palsy Seizures On prescribed medication Hydrocephalus with shunt Developmental problems ADHD from SDQ or parental report 120 (74%) Other developmental problems Respiratory problems Wheezing in last year Medication for chest problems in last year Prednisolone Oxygen Relievers Preventers Hospital admission Admission to hospital in last year Admission for chest problems Diabetes Diabetes Bowel disorders All bowel problems Bowel stoma Other bowel problems 64 (40%) 24 (15%) 40 (25%) 38 (24%) 13 (08%) 25 (16%) 166 (110249) 180 (091355) 157 (095259) 0 (00%) 2 (01%) .. 243 (151%) 32 (20%) 202 (129%) 38 (24%) 120 (098146) 081 (051131) 295 (183%) 262 (163%) 29 (18%) 22 (14%) 235 (146%) 182 (113%) 295 (189%) 280 (179%) 33 (21%) 22 (14%) 259 (166%) 199 (127%) 096 (081115) 089 (074107) 085 (051, 141) 097 (053176) 086 (071104) 087 (070108) 10 (06%) 116 (74%) 15 (10%) 100 (077131) 064 (029144) 53 (33%) 149 (92%) 27 (17%) 2 (01%) 27 (17%) 116 (74%) 17 (11%) 3 (02%) 193 (121309) 127 (099164) 155 (084285) 065 (011387)

Any co-amoxiclav No co-amoxiclav OR (95 % CI) (N=1587) (N=1586) 50 (32%) 144 (91%) 22 (14%) 4 (03%) 128 (81%) 8 (05%) 291 (183%) 257 (162%) 28 (18%) 17 (11%) 244 (154%) 186 (117%) 220 (139%) 33 (21%) 2 (01%) 54 (34%) 21 (13%) 33 (21%) 30 (19%) 121 (76%) 22 (14%) 1 (01%) 108 (68%) 17 (11%) 299 (189%) 285 (180%) 34 (21%) 28 (18%) 250 (158%) 195 (123%) 225 (142%) 37 (23%) 0 (00%) 48 (30%) 16 (10%) 32 (20%) 169 (107267) 121 (094156) 100 (055181) 401 (0453587) 120 (092157) 047 (020109) 097 (081116) 088 (073106) 082 (049, 136) 060 (033111) 097 (080118) 095 (076117) 097 (080119) 089 (055143) .. 113 (076168) 132 (068253) 103 (063169)

ADHD=attention decit hyperactivity disorder. SDQ=Strength and Diculties Questionnaire.

Table 7: Medical conditions reported by parents of children at age 7 years in those whose mothers had SPL

co-amoxiclav, respectively (table 7). A logistic model with erythromycin, co-amoxiclav, and treatment interaction terms suggested that there was no evidence of an interaction between the two antibiotics (webtable 7). However, the study is underpowered to test the interaction term and thus further examination of results inside the table was done.24 These analyses suggest
Erythromycin and co-amoxiclav (N=35) None Any functional impairment Mild Moderate Severe Ambulation Dexterity Cognition Pain 1 (29%) 33 (943%) 4 (114%) 10 (286%) 19 (543%) 18 (514%) 6 (171%) 5 (143%) 5 (143%) Erythromycin only (N=18) 1 (56%) 16 (889%) 2 (111%) 3 (167%) 11 (611%) 9 (500%) 6 (333%) 0 (00%) 3 (167%) Co-amoxiclav only (N=15) 1 (67%) 12 (800%) 0 (00%) 1 (67%) 11 (733%) 7 (467%) 8 (533%) 4 (267%) 3 (200%) Double placebo (N=12) 0 (00%) 12 (1000%) 1 (83%) 3 (250%) 8 (667%) 5 (417%) 3 (250%) 4 (333%) 4 (333%)

Children scoring severe functional impairment do so in the following domains

Functional impairment outcomes are not available for four children for whom a questionnaire was not returned (one in both antibiotics group, one in erythromycin only group, and two in the co-amoxiclav only group).

Table 8: Functional impairment outcomes of the children with cerebral palsy whose mothers had SPL

that more children who developed cerebral palsy had been born to mothers who had received both antibiotics (35 children) than to mothers who received erythromycin only (18 children), co-amoxiclav only (15 children), or double placebo (12 children). Although there is evidence of an excess risk in the both antibiotics group compared with double placebo (OR 291, 150565), there is insucient power to exclude an excess risk in those exposed to either drug alone (erythromycin alone: OR 142, 95% CI 068298; co-amoxiclav alone: 122, 057262). In this study the number needed to harm in the any erythromycin group was 64 (95% CI 37209) and in the any co-amoxiclav group was 79 (42591). In view of the unexpected excess of cerebral palsy associated with antibiotic prescription, further exploratory analyses of the characteristics of the children with cerebral palsy, and of risk factors for this condition, were done. The excess of cases of cerebral palsy was not oset by a lower number of deaths in the any erythromycin group: death and cerebral palsy were both increased in the any erythromycin group (table 3). There is no evidence that the children reported with cerebral palsy in the combined antibiotic group were more severely aected than were those in the other treatment groups (table 8). Analysis of

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Erythromycin
Any functional impairment

Co-amoxiclav

Overall Multiple births Singleton births Gestation <28 weeks Gestation >28 weeks Gestation <32 weeks Gestation >32 weeks 05 1 15 2 25 05
10 Overall Multiple births Singleton births Gestation <28 weeks Gestation >28 weeks Gestation <32 weeks Gestation >32 weeks

15

25

Three or more abnormal attributes

05

15

25

05

15

25

Figure 2: Subgroup analyses for overall functional impairment in children whose mothers had SPL

individual HUI attributes did not show any treatment eects; the attributes for which children with cerebral palsy were most commonly categorised as having severe functional impairment were ambulation, dexterity, cognition, and pain (table 8). Children with cerebral palsy were more likely to be have been born to women recruited at earlier gestations, and to be born sooner after the enrolment of the mother than were children without cerebral palsy (webtable 8). Maternal antibiotic prescription for postnatal infection was more likely for children with cerebral palsy than for those without; the duration of time from trial entry to birth was more likely to be less than 1 day or between 1 and 10 days for children with cerebral palsy than for those without (webtable 8). Babies with cerebral palsy were more likely to be male and to be admitted to a neonatal intensive care unit than were those without, and, as anticipated, were at increased risk of associated neonatal morbidity (webtable 8). By contrast with the cerebral palsy group as a whole, more detailed inside the table comparisons show more children with cerebral palsy whose mothers had received both antibiotics were entered into the trial between 28 and 32 weeks of gestation than were those whose mothers received one or other of the antibiotics, or who had received placebo (webtable 8). Further examination of this group (24 children) showed an excess in the both antibiotic group of those that had cervical dilation 0 to 1 cm at recruitment, who received the randomised treatment for 10 days, and who were born after 32 weeks (webtable 9). Subgroup analyses for multiple versus singleton births and for gestation above and below 28 and 32 weeks at

randomisation were pre-planned (gure 2). The increased risk of functional impairment observed after receipt of any erythromycin is most clearly apparent in singleton births and those children who were born at low gestational age, with sampling variation being larger in the small multiple birth and other gestational age subgroups. Adjustment for maternal baseline, social class, and other factors did not substantially alter the treatment eects noted (data not shown). For further analyses, see http:// www2.le.ac.uk/Members/drj/supplementary-materialsfor-papers.

See Online for webtable 8

Discussion
In this long-term follow-up of children whose mothers took part in the ORACLE II trial of antibiotics for preterm labour in the presence of intact membranes, we found an unexpected increase in the number of children with any functional impairment who were exposed to erythromycin. Furthermore, we found an increased prevalence of cerebral palsy (as reported by parents) associated with treatment with either antibiotic; there is some evidence to suggest that there is an additive eect in the children of mothers who received both antibiotics. Although formal evidence of an interaction between the two antibiotics is lacking, and the power of the study to detect such interactions is low, the excess of children with cerebral palsy born to mothers who received both antibiotics is clear enough to suggest that this should not be dismissed as a chance result of multiple testing. While a Bonferroni correction24 (based on a family size of ten main comparisons per treatment, as in table 7) might suggest that chance cannot be ruled out as an explanation, there are a number of features that suggest it would be
Measuring bars 13 2 5 Graph marks Arrows

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08TL3044_2 Urgent www.thelancet.com Published online September 18, 2008 DOI:10.1016/S0140-6736(08)61203-9 Labels Keys RB Text typed Key 1 Key 1

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unwise to dismiss the excess of cerebral palsy as a chance nding. These include a potential dose-response relationship (if the subgroup receiving both antibiotics is regarded as having received a higher dose of antibiotic), biological plausibility, and possibly specicity to cerebral palsy. There is also evidence to suggest that the treatment eect seen here is not simply a result of a spuriously low rate of cerebral palsy in the placebo groupstratied data from a register of children with cerebral palsy in four counties in the UK suggest that 75 cases would have been expected, compared with the 12 cases observed.25 These results provide strong evidence for the importance of childhood follow-up of perinatal and neonatal trials and interventions. We chose to obtain proxy information about the children from parents because the size of the study population made individualised assessment both impractical and prohibitively expensive. Where possible we used well validated and standardised instruments,12,13 but use of a questionnaire could mean it was not possible to detect more subtle dierences between treatment groups, nor has it been possible to conrm the ndings. In spite of not having face-to-face contact, we achieved an acceptable follow-up rate of 71% by maintaining regular contact with the women originally entered into the trial. Although we attempted to minimise non-response, disadvantaged groups are over-represented in the nonresponders. There is evidence to suggest that outcomes for children assessed with diculty might dier from those assessed with ease.23 However, there was no evidence of dierential response bias and most women remained unaware of their treatment allocation. Despite the response rate being lower than that assumed in the initial power calculation, the increased prevalence of functional impairment resulted in power being increased overall. The results of this study must be viewed within the clinical context of this group of women. First, the accurate diagnosis of SPL was and remains imperfect, as many women who present with painful preterm uterine contractions do not give birth preterm. This was the case in this study, where almost 64% of women who were entered into the ORACLE II trial gave birth after 37 weeks of gestation. Second, the proportion of women who had subclinical intrauterine infection at the time of randomisation is not known; however, it will probably have been low (1322%5,6). Why receipt of antibiotics increased the risk of functional impairment and cerebral palsy in a population at low risk of intrauterine infection is unclear. We suggest a number of pathways, although others will no doubt emerge. Length of exposure to antibiotics for this group of women was fairly long, with 1520% giving birth within 7 days.10 An episode of preterm labour which settles could genuinely reect an infective episode, where maternal defencesfacilitated by antibioticsovercome the insult, thus prolonging pregnancy, but not necessarily
8

resolving the associated intrauterine and fetal inammation. A continuing inammatory environment could have led to fetal brain injury and thereby cerebral palsy. Alternatively, cerebral palsy could have resulted from a direct eect of the antibiotics themselves; erythromycin, for example, has signicant eects on the cardiovascular systemeg, arrythmiaswhich could have led to cerebral ischaemic events and thereby cerebral palsy.26 It is also possible that the episode of SPL was not associated with infection, but rather with other pathologies within the so-called preterm parturition syndrome,6 which might have been exacerbated by the antibiotics by as yet undetermined mechanisms. The results of this study add weight to the argument that we should be vigilant about interfering with systems we poorly understand in the absence of benet. For example, there is little known about the eect of antibiotics on early patterns of microbial colonisation of newborn children, which might have important, longlasting consequences for early human development.27 Whatever the causal pathway, the ndings in our study, together with concerns about the potential increase in neonatal mortality,9 support the opinion that antibiotics are not advisable in SPL without clinical signs of infection. Indeed, in the UK, women are not routinely prescribed antibiotics if they have intact membranes, although there are no national guidelines; likewise, in the USA, antibiotics are not recommended in preterm labour.28 Nonetheless, it is critical that women with evidence of clinical infection are treated with antibiotics, since clinical chorioamnionitis remains an important cause of maternal, fetal, and neonatal death. The results of this study should not lead to fewer women with overt signs of maternal or fetal infection receiving treatment.
Contributors All authors contributed to the study design, developed the protocol, and contributed to drafting the paper. SK led the study and together with DJT and PB contributed knowledge of maternity practice. KP and DRJ provided statistical knowledge; NM and AS contributed knowledge on childhood outcomes. OCS II Study Team OCS Oce: Ann Blackburn, Kate Taylor, and the oce sta. Department of Health Sciences, University of Leicester: Mary Dixon Woods, Carolyn Tarrant, Clare Jackson, Janet Willars. Trial steering committee: Richard Lilford, Richard Cooke, Gill Gyte, Chris Whetton, Philippa Russell, Julie Cahill. Data monitoring committee: Diana Elbourne, Helena McNally, Martin Whittle. Conict of interest statement We declare that we have no conict of interest. Acknowledgments This study was funded by the UK Medical Research Council and sponsored by University Hospitals of Leicester and approved by their research and development directorate. We thank all the women and children who took part in the study and the obstetricians and midwives who recruited them to the original ORACLE trials. We thank the Oce of National Statistics, the NHS National Strategic Tracing Service, and the Data Services Group within the Department of Children, Schools and Families. We also thank the key stage one group (Maggie McLean, John Crookes, Peter Tymms, and Tony Cline) for helpful comments on educational aspects. We thank Steve Gould, Barbara Farrell,

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Phil Edwards, and Martin Rosser for advice on questionnaire design. We convened a group of experts from within the eld to help us understand and interpret these nding before publication. This group consisted of Martin Whittle, Alison Bedford Russell, Phil Bennett, Kate Costeloe, Francis Cowan, Olaf Dammann, Diana Elbourne, Catherine Elliott, Mike Millar, Jane Norman, Micheal OShea, Max Parmar, Roberto Romero, and Dieter Wolke. References 1 Salt AT, Redshaw M. Neurodevelopment follow-up after preterm birth: follow up after two years. Early Hum Dev 2006; 82: 18597. 2 Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005; 352: 919. 3 Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ. Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 2002; 288: 72837. 4 Johnson S. Cognitive and behavioural outcomes following very preterm birth. Semin Fetal Neonatal Med 2007; 12: 36373. 5 Goncalves LK, Chaiworapongsa T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res 2002; 8: 313. 6 Romero R, Espinoza J, Kusanovic JP, et al. The preterm parturition syndrome. BJOG 2006; 113 (suppl 3): 11835. 7 Jobe AH. Glucocorticoids, inammation and the perinatal lung. Semin Neonatol 2001; 6: 33142. 8 Dammann O, Leviton A. Inammation, brain damage and visual dysfunction in preterm infants. Semin Fetal Neonatal Med 2006; 11: 36368. 9 King J, Flenady V. Prophylactic antibiotics for inhibiting preterm labour with intact membranes. Cochrane Database Syst Rev 2002; 4: CD000246. 10 Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. Lancet 2001; 357: 99196. 11 Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial. Lancet 2008; published online Sept 18. DOI:10.1016/S0140-6736(08)61202-7. 12 Saigal S, Rosenbaum P, Stoskupf B, et al. Comprehensive assessment of the health status of extremely low birthweight children at eight years of age: comparisons with a reference group. J Pediatr 1994; 125: 411. 13 Goodman R. The strengths and diculties questionnaire: a research note. J Child Psychol Psychiatry 1997; 38: 58186.

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17 18 19 20 21 22 23 24 25

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Asher MI, Keil U, Anderson HR, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995; 8: 48391. Anon. Multi-attribute health status classication system: health utilities index mark 3 (HUI3). http://www.healthutilities. com/hui3.htm (accessed Aug 8, 2008). Feeny D, Furlong W, Saigal S, Sun J. Comparing directly measured standard gamble scores to HUI2 and HUI3 utility scores: group- and individual-level comparisons. Soc Sci Med 2004; 58: 799809. Cue SP, Moore CG, McKeown RE. Prevalence and correlates of ADHD symptoms in the National Health Survey. J Atten Disorder 2005; 9: 39240. Qualications and Curriculum Authority. Key stage 1 assessments and reporting arrangements. London: Qualiciations and Curriculum Authority, 2007. Altman DG. Practical statistics for medical research. London: Chapman and Hall, 2006. Montgomery AA, Peters TJ, Little P. Design, analysis and presentation of factorial randomised controlled trials. BMC Med Res Methodol 2003; 3: 26. Gates S. Brocklehurst P. How should randomised trials including multiple pregnancies be analysed? BJOG 2004; 111: 21319. Bland JM, Altman DG. Multiple signicance tests: the Bonferroni method. BMJ 1995; 310: 170. Tin W, Fritz S, Wariyer U, Hey E. Outcome of very preterm birth: children reviewed with ease at 2 years dier from those followed up with diculty. Arch Dis Child Neonatal Ed 1998; 79: F8387. McAlister FA, Straus SE, Sackett DL, Altman DG. Analysis and reporting of factorial trials: a systematic review. JAMA 2003; 289: 254553. 4Child. Four counties database of cerebral palsy, vision loss and hearing loss in children. Annual report, 2007. http://www.npeu. ox.ac.uk/downloads/4child/annual-report/4Child-annual-report2007.pdf (accessed Aug 11, 2008). Kallen BA, Otterblad Olausson P, Danielsson BR. Is erythromycin therapy teratogenic in humans? Reprod Toxicol 2005; 20: 20914. Bedford Russell AR, Murch SH. Could peripartum antibiotics have delayed health consequences for the infant? BJOG 2006; 113: 75865. American College of Obstetricians and Gynecologists. Management of preterm labor. ACOG Practice Bulletin No 43. Obstet Gynecol 2003; 101: 103947.

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Antibiotics in preterm labourthe ORACLE speaks


In recent decades, several major trials of perinatal care have substantially changed practice. Important examples include the use of antenatal steroids to mature the fetal lungs,1 mode of delivery at term for breech presentation,2 and the use of antibiotics in preterm labour3 and preterm prelabour rupture of the membranes4 (PROM)the ORACLE studies. Steroids signicantly reduce the incidence of neonatal respiratory distress syndrome and neonatal mortality; elective caesarean section is safer for the breech fetus than vaginal delivery; and erythromycin given for up to 10 days to women with PROM led to a modest but statistically signicant reduction in adverse short-term neonatal outcomes in singletons (from 144% to 112%, p=002). However, there seems to be an inexorable tendency for these interventions to be overused. For example, concern has been recently expressed about the potential harmful eects of repeated doses of antenatal steroids, particularly in women who eventually prove not to have been in preterm labour.5 The widespread adoption of caesarean section for term breech presentations has been credited with accelerating the rise of caesarean-section rate for other less clear-cut indications, to levels suggested by some to be unacceptable.6 So, is the current widespread use of erythromycin in PROM really justied? In ORACLE II, the administration of antibiotics to women in spontaneous preterm labour produced no benet, and indeed the diculty of diagnosing preterm labour accurately was shown by the fact that 635% of women delivered after 37 weeks gestation.3 The positive nding of a small benet from erythromycin in PROM in singletons may have been due to chance.7 The intention-to-treat analysis including multiple pregnancies did not show a statistically signicant benet from erythromycin (127% had the composite adverse outcome vs 152% with placebo, p=008). The singleton subgroup analysis was not prespecied, and an interaction between treatment group and type of pregnancy was not tested for.8 The clinical signicance of the short-term benets (less oxygen dependence at 28 days, fewer major cerebral abnormalities on cerebral ultrasound, and fewer positive blood cultures) was also debatable.9 Co-amoxiclav produced no such benet, and was associated with an increase in necrotising enterocolitis. In todays Lancet, the ORACLE investigators present the 7-year outcomes. Reassuringly, the short-term gains from giving erythromycin in PROM have not been counterbalanced by any long-term disadvantage.10,11 However, neither has there been any persisting advantage. Meanwhile, there has been a substantial increase in prescriptions for peripartum erythromycin,9 unfortunately with no specic microbiological surveillance of the consequences. Worryingly, nationally collected data show a large rise in the number of isolates of erythromycin-resistant group-B streptococcus, from 64% in 2002 to 112% in 2006.12,13 Although it is well established that antibiotic resistance is driven by antibiotic pressure, this increase in the number of isolates of erythromycin-resistant group-B streptococcus cannot be linked specically to increased peripartum erythromycin use, as these data have not been collected. Even more worryingly, in the follow-up, the administration of either co-amoxiclav or erythromycin to women in threatened preterm labour increased the risk
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of cerebral palsy signicantly (erythromycin: 53 [33%] of 1611 vs 27 [17%] of 1562, odds ratio 193, 95% CI 121309; co-amoxiclav: 50 [32%] of 1587 vs 30 [19%] of 1586, 169, 107267); the number needed to harm with erythromycin was 64 (95% CI 37209) and with co-amoxiclav 79 (42591). Also, the number of children with cerebral palsy was greater when both antibiotics were given together (35 of 769, 455%) compared with erythromycin alone (18 of 785, 229%), co-amoxiclav alone (15 of 763, 197%) or placebo alone (12 of 735, 163%). The mechanism of this eect is unclear but, when subclinical infection is provoking labour, treatment with low doses of oral antibiotic (250 mg erythromycin and 325 mg co-amoxiclav, both four times a day) might only suppress rather than eradicate infection from the amniotic uid and uterine cavity. Suppression without eradication might prolong the pregnancy, thus allowing continued fetal exposure to a damaging environment. The association between denite perinatal infection and neurological damage is well described,14,15 but ORACLE did not recruit mothers who required antibiotic treatment for clinical indications such as chorioamnionitis. Such mothers would have received antibiotics in substantially higher doses, given intravenously to achieve bactericidal concentrations in amniotic uid. The doses of antibiotic used in ORACLE were too small and the route inappropriate for proper treatment of in-utero infection. Antibiotics can aect gut ora, and the development of the naive immune system depends crucially on the gut ora of the newborn baby. Use of perinatal antibiotic can thus alter immune tolerance, which could have contributed to the substantial increase in the incidence of allergic and autoimmune disease in young children over the past three decades in resourcerich countries.16 The lessons to be learned seem clear: contrary to popular opinion (might as well give them, they dont do any harm), antibiotics are not risk free. There are good reasons not to give them in association with threatened preterm labour unless there is clear evidence of infection. It is vital that practice is not extended by stealth beyond that which is justied by the evidence, and interventions in pregnancy should always be evaluated with proper long-term follow-up. Many drugs have dierent pharmacodynamics during pregnancy,
2

and their eects can vary between mother and fetus. Research in perinatal medicine is poorly funded compared with conditions aecting the end of life. Drug companies are reluctant to research in pregnancy because of the litigation risk. The data from these ORACLE follow-ups emphasise the case for increased governmental funding for such important long-term outcome studies. A R Bedford Russell, *P J Steer
Warwick Medical School, Warwick, UK (ARBR); Neonatal Unit, Heart of England NHS Trust, Birmingham, UK (ARBR); Division of Surgery, Anaesthetics, Oncology, and Reproductive Medicine, Faculty of Medicine, Imperial College London, London, UK (PJS); and Chelsea and Westminster NHS Foundation Trust, London SW10 9NH, UK (PJS) p.steer@imperial.ac.uk
ARBR was a member of the expert group invited by the ORACLE team to discuss the ndings before publication and is acknowledged in the papers. PJS co-holds, with others, a grant with Sara Kenyon and Peter Brocklehurst (ORACLE investigators) to study intrapartum care. 1 2 Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972; 50: 51525. Hannah ME, Hannah WJ, Hewson SA, Hodnett ED, Saigal S, Willan AR, for the Term Breech Trial Collaborative Group. Planned caesarean section versus planned vaginal birth for breech presentation at term: a randomised multicentre trial. Lancet 2000; 356: 137583. Kenyon SL, Taylor DJ, Tarnow-Mordi W, for the ORACLE Collaborative Group. Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. Lancet 2001; 357: 98994. Kenyon SL, Taylor DJ, Tarnow-Mordi W, for the ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. Lancet 2001; 357: 97988. Steer PJ. Giving steroids before elective caesarean section. BMJ 2005; 331: 645-46. Agnew G,.Turner M. Can a 29% cesarean delivery rate possibly be justied? Obstet Gynecol 2006; 108: 452. Hannah M. Antibiotics for preterm prelabour rupture of membranes and preterm labour? Lancet 2001; 357: 97374. Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 2000; 355: 106469. Tan S, Holliman R, Bedford Russell AR. Hazards of widespread use of erythromycin for preterm prelabour rupture of membranes. Lancet 2003; 361: 437. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial. Lancet 2008; published online Sept 18. DOI:10.1016/S0140-6736(08)61202-7. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 2008; published online Sept 18. DOI:10.1016/S0140-6736(08)61203-9. Pearson A. Pyogenic and non-pyogenic streptococcal bacteraemias, England, Wales, and Northern Ireland: 2004. CDR Weekly 2004; 15: 4. Health Protection Agency. Health protection report. Nov 16, 2007; 1: 9. http://www.hpa.org.uk/hpr/archives/2007/hpr4607.pdf (accessed Sept 10, 2008). Jacobsson B, Hagberg G. Antenatal risk factors for cerebral palsy. Best Pract Res Clin Obstet Gynaecol 2004; 18: 42536. Inder TE, Volpe JJ. Mechanisms of perinatal brain injury. Semin Neonatol 2000; 5: 316. Bedford Russell AR, Murch SH. Could peripartum antibiotics have delayed health consequences for the infant? BJOG 2006; 113: 75865.

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www.thelancet.com Published online September 18, 2008 DOI:10.1016/S0140-6736(08)61248-9