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ADC-FNN Online First, published on August 11, 2016 as 10.1136/archdischild-2015-310144

Original article

The ORACLE Children Study: educational outcomes

at 11 years of age following antenatal prescription
of erythromycin or co-amoxiclav
Neil Marlow,1 Hannah Bower,2 David Jones,2 Peter Brocklehurst,1 Sara Kenyon,3
Katie Pike,4 David Taylor,5 Alison Salt6
Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
archdischild-2015-310144).
1

Institute for Womens Health,

University College London,
London, UK
2
Health Sciences Department,
University of Leicester,
Leicester, UK
3
Institute of Applied Health
Research, University of
Birmingham, Edgbaston, UK
4
Clinical Trials and Evaluation
Unit, School of Clinical
Sciences, University of Bristol,
Bristol, UK
5
Maternal and Newborn Health
Initiative, International
Federation of Gynaecology and
Obstetrics, London, UK
6
Great Ormond Street Hospital
for Children and Institute of
Child Health, University College
London, London, UK
Correspondence to
Professor Neil Marlow, Institute
for Womens Health, University
College London, 74 Huntley
Street, London WC1E 6AU,
UK;
[email protected]
Received 12 November 2015
Revised 21 June 2016
Accepted 26 June 2016

ABSTRACT
Background Antibiotics used for women in
spontaneous preterm labour without overt infection, in
contrast to those with preterm rupture of membranes,
are associated with altered functional outcomes in their
children.
Methods From the National Pupil Database, we used
Key Stage 2 scores, national test scores in school year 6
at 11 years of age, to explore the hypothesis that
erythromycin and co-amoxiclav were associated with
poorer educational outcomes within the ORACLE
Children Study.
Results Anonymised scores for 97% of surviving
children born to mothers recruited to ORACLE and
resident in England were analysed against treatment
group adjusting for key available socio-demographic
potential confounders. No association with crude or with
adjusted scores for English, mathematics or science was
observed by maternal antibiotic group in either women
with preterm rupture of membranes or spontaneous
preterm labour with intact membranes. While the
proportion receiving special educational needs was
similar in each group (range 31.634.4%), it was higher
than the national rate of 19%.
Conclusions Despite evidence that antibiotics are
associated with increased functional impairment at
7 years, educational test scores and special needs at
11 years of age show no differences between trial
groups.
Trial registration number ISCRT Number 52995660
(original ORACLE trial number).

What is already known on this topic?

Antibiotics given to women with preterm
rupture of membranes and no overt infection
have neonatal benet and appear safe in terms
of childhood outcomes at 7 years of age.
In contrast, when administered to women with
spontaneous preterm labour with intact
membranes there is no neonatal benet and
evidence of poorer outcomes in terms of
neurodevelopmental impairment and cerebral
palsy at 7 years of age.
Previous studies are open to ascertainment bias
in outcomes in middle childhood.

What this study adds?

Using independently collected and scored
national attainment tests of English,
mathematics and science, we demonstrate no
differences in long-term educational outcomes
at 11 years, or in special needs, following
antenatal prescription of antibiotics.
While attainment test results are within
national norms, special needs requirements
among these children are higher.
The use of anonymised educational national
data provides good coverage of the population
and a robust middle childhood outcome.

INTRODUCTION

To cite: Marlow N,
Bower H, Jones D, et al.
Arch Dis Child Fetal
Neonatal Ed Published
Online First: [ please include
Day Month Year]
doi:10.1136/archdischild2015-310144

The ORACLE Children Study evaluated the

outcome of children born to women who were
entered into the ORACLE study and were randomly assigned
to
receive
erythromycin,
co-amoxiclav or placebo in two factorial trials relating to women in spontaneous labour with intact
membranes (SPL)1 or with prelabour preterm
rupture of membranes (PROM).2 Children whose
mothers received antibiotics during SPL had an
excess of impairments at 7 years, in contrast to
those whose mothers were entered into the PROM
arm of the trial. These data, however, are based on
follow-up of 71% (SPL) and 75% (PROM),
respectively, of the children born to mothers who
took part.
Reports of long-term outcomes following perinatal trials aim for as complete ascertainment as is
possible. One potential solution to this is to use

nationally collected educational data. We have

recently reported outcomes for 7-year-old children
using Key Stage 1 (KS1) results.3 The disadvantage
of these tests is that they represent the performance
of the child based on teacher assessment and do
not include pupils in all schools. In contrast, Key
Stage 2 tests (KS2) are universal, standardised,
scored independently and reported unmodied;
they thus provide an opportunity to review an
independently collected and scored measure of
childrens educational attainment outcomes in relation to trial groups.
This paper examines the hypothesis that, within
the ORACLE trial, treatment of women in SPL or
with PROM leads to changes in brain development
that are manifested as altered educational attainment at KS2 in their children.

Marlow N, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1F5. doi:10.1136/archdischild-2015-310144

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Original article
METHODS
The ORACLE study
The original trial recruited 4221 and 4148 women, respectively,
to the SPL and PROM trials. Questionnaire-based follow-up
information was obtained for 3196 (71%)1 and 3298 of 4358
children (75%) for SPL and PROM arms of the study,2 respectively. Mean gestational age at birth was 38 and 34 weeks,
respectively, for SPL and PROM arms of the study. Overall,
6295 of 8369 (75%) children were resident in England at the
completion of the ORACLE Children Study and formed the
population for this study.

Data
The Department for Education (DfE) supplied full KS2 data at
11 years of age anonymously for ORACLE children categorised
by treatment group. Linkage was performed by the DfE, and
based on information we held on individual children. Matching
was carried out probabilistically based on forename, surname,
date of birth and postcode. No further information on those
not matched is available because of data anonymity requirements. The KS2 data supplied comprised continuous scores for
English, mathematics and science and a DfE measure of educational progress entitled contextual value added (CVA). CVA
measures the progress made by pupils from the end of KS1 to
the end of KS2, adjusting for external factors, such as the childs
sex, changing school and levels of deprivation, that impact

pupil results at school. For further information on the derivation of this measure, see http://www.education.gov.uk/schools/
performance/archive/schools_10/cvacalc.pdf (accessed 30 March
2016). In addition, the data set included the following data: age
at the beginning of the KS2 assessment year, ethnicity of the
child, English as rst language (yes/no), free school meal eligibility (yes/no), childs sex, Income Deprivation Affecting Children
Index (IDACI) score,4 school type (community, voluntary/faith,
foundation, other) and academic year of KS2 assessment, in
addition to ORACLE group allocation information.
The DfE Research Unit was sent a computer le of study
members records in four groups (according to their treatment
allocation), and data were returned with identiers removed (ie,
anonymised) separately for each of the four treatment groups.
Identiers comprised either the name, date of birth and postcode for each child or the Unique Pupil Identier (UPI) for
linking to KS2 outcomes; individual identiers were then
removed (leaving only the trial allocation) on the le when
returned to the authors. As this was an anonymised analysis, no
research ethics committee permission was required. Permission
was obtained from the DfE Research Unit to use these data.

Statistical analysis
KS2 data were dichotomised into level 4 or above (considered
to be appropriate progress at school) and below level 4, and
MantelHaenszel ORs were calculated comparing erythromycin

Table 1 Summary statistics for contextual value added score and raw scores for English, maths and science by ORACLE treatment groups
Erythromycin

No erythromycin

Co-amoxiclav

No co-amoxiclav

1512

1528

1523

1517

1275
57 (45 to 67)
1265
64 (47 to 78)
798
59 (49 to 67)
1090
100.1 (98.6 to 101.5)
1356
467 (34.4%)

1304
58 (46 to 68)
1314
64 (47 to 79)
814
59 (50 to 67)
1113
100.1 (98.7 to 101.7)
1387
438 (31.6%)

1303
58 (46 to 68)
1300
64 (47 to 78)
812
60 (50 to 67)
1105
100.1 (98.6 to 101.5)
1379
463 (33.6%)

1276
57 (45 to 67)
1279
64 (47 to 79)
800
58 (49 to 67)
1098
100.2 (98.7 to 101.6)
442/1364
(32.4%)

Total with data

1550

1497

1498

1549

English (n)
Median (IQR)
Mathematics (n)
Median (IQR)
Science (n)
Median (IQR)
Contextual VA (n)*
Median (IQR)
Special needs (n)
n (%)

1328
56 (45 to 66)
1334
62 (46 to 77)
813
59 (48 to 66)
1138
100.0 (98.5 to 101.6)
1421
475 (33.4%)

1285
56 (45 to 67)
1287
62 (47 to 77)
787
58 (48 to 66)
1066
100.0 (98.5 to 101.5)
1345
426 (31.7%)

1275
57 (45 to 68)
1281
63 (47 to 78)
776
59 (48 to 67)
1065
101.1 (98.7 to 101.6)
1353
427 (31.6%)

1338
56 (44 to 66)
1340
61 (46 to 77)
824
58 (48 to 66)
1139
100.0 (98.3 to 101.5)
1413
474 (33.5%)

Preterm rupture of membranes

English (n)
Median (IQR)
Mathematics (n)
Median (IQR)
Science (n)
Median (IQR)
Contextual VA (n)*
Median (IQR)
Special needs (n)
n (%)
Spontaneous preterm labour

Scores are the number of marks achieved.

*Contextual value added (VA) scores are expressed as a per cent improvement compared with previous assessments; for further definitions, see
http://www.education.gov.uk/schools/performance/archive/schools_10/s3.shtml; accessed 30 March 2016.
Special need categories: school action, school action plus (for 20042006 also includes educational statements and statutory assessment); for definitions, see,
https://http://www.gov.uk/children-with-special-educational-needs/support-before-september-2014; accessed 30 March 2016.

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Original article
Table 2

Educational attainment lower than level 4* in English, mathematics and science at Key Stage 2 by ORACLE treatment groups
Erythromycin

No erythromycin

Co-amoxiclav

No co-amoxiclav

1512

1528

1523

1517

350 (25.6)
1.05 (0.89 to 1.26)

342 (24.6)

326 (23.5)
0.85 (0.71 to 1.01)

366 (26.7)

377 (27.7)
1.08 (0.91 to 1.29)

364 (26.1)

366 (26.4)
0.95 (0.80 to 1.13)

375 (27.4)

126 (15.1)
0.98 (0.75 to 1.30)

129 (15.3)

119 (14.1)
0.84 (0.64 to 1.11)

136 (16.3)

1550

1497

1498

352 (24.8)
1.00 (0.84 to 1.19)

335 (24.8)

321 (23.8)
0.90 (0.75 to 1.07)

366 (25.8)

394 (27.7)
1.06 (0.89 to 1.25)

360 (26.6)

354 (26.1)
0.90 (0.76 to 1.07)

400 (28.2)

130 (15.4)
1.07 (0.81 to 1.42)

117 (14.5)

105 (13.2)
0.76 (0.57 to 1.01)

142 (16.7)

Preterm rupture of membranes

English (n)
<Level 4 (%)
OR (95% CI)
Mathematics (n)
<Level 4 (%)
OR (95% CI)
Science (n)
<Level 4 (%)
OR (95% CI)
Spontaneous preterm labour

English (n)
<Level 4 (%)
OR (95% CI)
Mathematics (n)
<Level 4 (%)
OR (95% CI)
Science (n)
<Level 4 (%)
OR (95% CI)

1549

*Level 4 is the minimum standard which children are expected to achieve.

OR, MantelHaenszel ORs (95% CIs).

and co-amoxiclav separately for effects on the odds of achieving

less than a level 4 at KS2.
Log-linear models including covariates for erythromycin and
co-amoxiclav were tted for the aggregate KS2 levels (<2, 2, 3,
4, 5 and 6) for English, mathematics and science. Linear regression models were tted for the raw scores for each of the three
KS2 subjects. All models are adjusted for a selection of covariates. Covariates considered for inclusion within log-linear and
linear regression models in addition to the antibiotic indicators
were: age at the beginning of the KS2 assessment year, ethnicity,
English as rst language, free school meal eligibility, sex, IDACI
score, school type and KS2 assessment year.
Univariate analyses were performed rst to determine which
covariates should be considered for inclusion within the multivariate models. All models included erythromycin and
co-amoxiclav terms. Covariates (including interaction terms
between the two antibiotic indicators as in the original analyses1) were selected through the use of likelihood ratio tests.
All statistical modelling including model selection was performed for the PROM and SPL cohorts separately. Due to large
numbers of missing values for some variables (see online supplementary table S2), complete case analyses and analyses which
considered only variables with <10% missing data were performed (see online supplementary tables S3 and S4).

in the SPL and PROM groups appear similar across all variables
(see online supplementary table S1).
Analysis of continuous scores and antibiotic effects was
carried out separately for women in PROM and SPL groups
and reported in their four factorial groups (table 1).
Attainment scores in English, maths and science were similar
for those who received erythromycin or not, and for those
who received co-amoxiclav or not; scores between the four
groups did not vary, with similar IQRs for each. The CVA
score showed evidence of a small positive improvement in performance across KS1 to KS2, which did not vary by antibiotic
group for either PROM or SPL. Special needs were identied
in similar proportions in each group/condition ranging from
31.6% to 34.4%.
Attainment of KS2 level 4 is considered appropriate progress
within this assessment paradigm; we dichotomised KS2 results
and present them for PROM and SPL populations (table 2).
ORs for each subject did not vary signicantly by antibiotic
group in either population. We then derived a log-linear model
for aggregated KS2 levels adjusted for baseline data, including
only variables with <10% missing data, shown in table 3. Again
no effect of antibiotic or maternal trial population was
observed. Finally, we performed a linear regression using the
crude KS2 scores, adjusting as before, and found no signicant
variation of effect size by antibiotic or trial group (table 4).

RESULTS
Within the ORACLE Study, for children who were born to
women resident in England at the conclusion of the follow-up
study (2007), anonymised KS2 data were available for up to
6087 of 6295 children recruited to the original trial (97%). The
DfE-supplied baseline characteristics of children born to women

DISCUSSION
Educational attainment is a good marker for cognitive outcome
within perinatal cohorts, and the prevalence of special needs is
closely related to gestational age at birth.5 We have used the
results of a national, independently administered and scored

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Original article
Table 3 Erythromycin and co-amoxiclav HRs (95% CI) from the adjusted log-linear models for aggregate KS2 levels*
PROM

English
CC
<10%
Mathematics
CC
<10%
Science
CC
<10%

SPL

Erythromycin

Co-amoxiclav

Erythromycin

Co-amoxiclav

1.00 (0.96 to 1.05)

1.00 (0.96 to 1.03)

1.03 (0.99 to 1.08)

1.02 (0.98 to 1.06)

0.97 (0.92 to 1.03)

0.98 (0.95 to 1.02)

1.01 (0.95 to 1.06)

1.01 (0.98 to 1.05)

0.98 (0.94 to 1.03)

0.98 (0.95 to 1.02)

1.02 (0.97 to 1.07)

1.00 (0.96 to 1.04)

0.99 (0.95 to 1.03)

0.99 (0.95 to 1.02)

1.00 (0.96 to 1.05)

1.01 (0.97 to 1.05)

1.00 (0.95 to 1.05)

1.00 (0.95 to 1.04)

1.02 (0.97 to 1.07)

1.01 (0.97 to 1.06)

0.98 (0.93 to 1.04)

0.99 (0.94 to 1.04)

1.01 (0.96 to 1.07)

1.02 (0.97 to 1.07)

*See supplemental table 2 for details of covariates used (with <10% missing data).
<10%, <10% missing data; CC, complete case analysis; KS2, Key Stage 2; PROM, preterm rupture of membranes; SPL, spontaneous labour with intact membranes.

Table 4 Erythromycin and co-amoxiclav estimates (95% CI) from the adjusted linear regression models for raw KS2 scores*
PROM

English
CC
<10%
Mathematics
CC
<10%
Science
CC
<10%

SPL

Erythromycin

Co-amoxiclav

Erythromycin

Co-amoxiclav

0.54 (2.05 to 0.97)

1.05 (2.29 to 0.19)

1.03 (0.48 to 2.54)

0.71 (0.54 to 1.95)

0.18 (1.46 to 1.82)

0.42 (1.61 to 0.77)

0.79 (0.86 to 2.43)

1.02 (0.18 to 2.21)

1.10 (3.18 to 0.97)

0.74 (2.40 to 0.92)

0.82 (1.26 to 2.89)

0.09 (1.57 to 1.74)

0.18 (2.07 to 2.42)

0.07 (1.67 to 1.54)

1.46 (0.80 to 3.71)

1.55 (0.05 to 3.15)

0.17 (1.34 to 1.67)

0.07 (1.34 to 1.19)

1.64 (0.14 to 3.15)

0.94 (0.33 to 2.20)

1.47 (0.40 to 3.34)

0.37 (0.91 to 1.65)

1.31 (0.57 to 3.18)

0.96 (0.32 to 2.24)

*See supplemental table 3 for details of covariates used (with <10% missing data).
<10%, <10% missing data; CC, complete case analysis; KS2, Key Stage 2; PROM, preterm rupture of membranes; SPL, spontaneous labour with intact membranes.

educational test battery to evaluate outcome for children of

women recruited to the ORACLE studies.6 7 No effect of trial
intervention has been demonstrated on continuous outcome
scores, a measure of education progress (CVA measure), or on
criterion-referenced attainment or on identied special needs.
Adjusted models yield very similar results to the unadjusted analyses here, although it should be noted that adjustment for
factors postrandomisation in principle runs the risk of over
adjustment. The data show similarities to national datain
2010, 80% of children in England at KS2 achieved level 4 or
better (the national oor for test results) in English and 79%
in mathematics (DfE School performance tables (see http://www.
education.gov.uk; accessed 31 July 2014)). In ORACLE, respective gures were 75% and 74%. Nationally, 19% of 11-year-old
pupils have special needs, compared with 3134% across all
study groups. It should be remembered that a high proportion
of the ORACLE trial participants gave birth prematurely (36%
in SPL and 85% in PROM groups, respectively) and one would
expect lower attainment and higher rates of special needs in
ex-preterm children.5
The strength of using national data lies in their independent
ascertainment, coverage and low dropout rate (4% of children).
The tests may vary slightly from year to year, but they are continually restandardised between years to produce consistent
outcome data. The advantage of near complete coverage from
this source, as against 7175% from parent-based follow-up in
the original ORACLE Children Study,1 2 is in the avoidance of
ascertainment bias.
F4

Within a trial of antenatal interventions aimed at improving

neonatal and childhood condition, national educational data
provide a sensitive and robust measure of outcome. However, the
limitation of using anonymised data lies in our inability to associate data from education with our research database without individual parental permission; hence, the effect of linkage
information and missing data (which for some results means we
only have information on half of the cohort, eg, in Science), and
thus the degree of bias contributed thereby, cannot be ascertained, more granular evaluation of the effects of the two antibiotics in the two trial groups is not possible, and the inuence on
educational attainment of other perinatal events or disability
ratings from the main study cannot be determined. Furthermore,
current data protection strategies on the part of the DfE and the
researchers may make a study such as this difcult in the future
by insisting on individual participant permissions.
Within the original ORACLE Children Study reports, we
raised concern about a small but signicant increase in the risk
of cerebral palsy, following antibiotic prescription in spontaneous preterm labour. Subsequently, the use of macrolide antibiotics in term pregnancy has been associated with the occurrence
of cerebral palsy using the Health Improvement Network
(adjusted HR: 1.78, 95% CI 1.18 to 2.69),8 which appears to
conrm our concerns. Cerebral palsy is a rare outcome in the
population, and within the ORACLE studies, it comprises <3%
of the population.9 Cerebral palsy may be associated with learning problems but for children in this study the functional motor
decit associated with cerebral palsy on the ORACLE Children

Marlow N, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1F5. doi:10.1136/archdischild-2015-310144

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Original article
Study tended to be less severe,9 and anticipated effects on academic attainment would also be less severe. Furthermore, the
later the age at follow-up will allow the effect of social and
environmental inuences to dilute the important neonatal inuences. For example, despite the success of neonatal caffeine in
improving neonatal and outcomes in the second year, including
cerebral palsy rates, re-evaluation of the population at 5 years
failed to demonstrate continuing benet.10 Such ndings
provide reassurance of longer term safety but do not diminish
identied short-term inuences.11 Thus, any effect on educational scores from this excess would be overwhelmed by the
results of the remainder of the population without cerebral
palsy, but it is reassuring to see no evidence of poorer educational attainment overall.
The ORACLE study has demonstrated short-term neonatal
benet from the use of antibiotics for women with preterm
rupture of the membranes and suggested longer term harm
from giving women antibiotics in the presence of SPL.
The follow-up of those children at 7 years of age whose
mothers had SPL suggested that the prescription of erythromycin (with or without co-amoxiclav) was associated with an
increase in the proportions of children with any level of functional impairment and cerebral palsy. This paper provides
reassurance from the use of standardised national attainment
tests and special needs for 6087 children resident in England
that no benet or harm was demonstrated on overall educational attainment for these children at 11 years.
Acknowledgements Both the ORACLE Trial and the Children Study were funded
by the UK Medical Research Council (MRC) ISCRT Number 52995660, sponsored by
University Hospitals of Leicester and approved by their research and development
directorate. The authors 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. NM receives part funding from the Department of Healths NIHR
Biomedical Research Centres funding scheme at UCLH/UCL. SK is supported by the
NIHR CLAHRC West Midlands initiative. This paper presents independent research,
and the views expressed are those of the authors and not necessarily those of the
NHS, the NIHR or the Department of Health. The authors are most grateful to the
National Pupil Database and Data Sharing Team of the Department for Education,
who performed the data linkage.
Contributors NM, AS and SK conceived the idea, HB carried out the analysis
under the supervision of DJ and NM wrote the initial draft of the paper. All authors

contributed to the design of the study, interpretation of the results and revisions of
the draft.
Funding Medical Research Council (ISCRT Number 52995660).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data are available after discussion with the Oracle Study
Investigators in accordance with our data-sharing policy.
Open Access This is an Open Access article distributed in accordance with the
terms of the Creative Commons Attribution (CC BY 4.0) license, which permits
others to distribute, remix, adapt and build upon this work, for commercial use,
provided the original work is properly cited. See: http://creativecommons.org/licenses/
by/4.0/

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The ORACLE Children Study: educational

outcomes at 11 years of age following
antenatal prescription of erythromycin or
co-amoxiclav
Neil Marlow, Hannah Bower, David Jones, Peter Brocklehurst, Sara
Kenyon, Katie Pike, David Taylor and Alison Salt
Arch Dis Child Fetal Neonatal Ed published online August 11, 2016

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