The ORACLE Children StudySara Kenyon University of Leicester

Peter Brocklehurst University of Oxford

Neil Marlow University College London

David Taylor University of Leicester

Rationale for ORACLE

• 1 in 8 babies in the UK are born prematurely.

• Being born prematurely is the leading cause of death in the first month of life.

• The consequences of prematurity are a major public health challenge with increased risk of disability and those without disability having behavioural and educational difficulties.

ORACLE Trial 1994 - 2000

• Previous research: • Spontaneous premature labour with intact membranes

(SPL) or premature rupture of the membranes-broken waters- (PROM) possibly due to underlying infection.

• Evidence suggested antibiotics may prevent or delay labour and improve neonatal outcome.

• The women in the study had no obvious infection.

• Trial evaluated the antibiotics erythromycin and co-amoxiclav.

• Women randomly allocated to one of four arms using a factorial design:• Erythromycin• Co-amoxiclav• Erythromycin and co-amoxiclav• Placebo pills

ORACLE Trial - results

• In women whose waters broke early:• Erythromycin was beneficial for babies in the short-term:

• Prolonged pregnancy• Babies had less infection, respiratory difficulties, and

abnormal brain scans• Co-amoxiclav, while prolonging pregnancy, also increased

the risks of necrotising enterocolitis (NEC).

• No short-term effects were seen for babies born to women showing signs of going into premature labour without broken waters.

ORACLE Children Study

• UK follow up began in 2002.

• Original ORACLE trial participants asked to fill in questionnaire about their child’s health and how they were doing at school at age 7.

• 4148 children born to mothers with early broken waters were eligible; 3171 (75%) returned a questionnaire.

• 4221 children were born to mothers without early broken waters were eligible; 3196 (71%) returned a questionnaire.

ORACLE Children Study – Results for women without broken waters

• As expected in a group of children like this, 40% of the children born to mothers who showed signs of premature labour have some kind of functioning problem.

• In the group who received erythromycin (either with or without co-amoxiclav) there were slightly more children with a ‘functioning’ problem compared to those who did not receive erythromycin.

• Functioning problems included very mild difficulties and most of the functioning problems reported by parents were classified as minor (e.g. wearing glasses, some difficulty walking or struggling with day to day problem solving).

ORACLE Children Study – Results for women without broken waters

Functioning problems in children

42% 38%

0%

20%

40%

60%

80%

100%

Erythromycin No erythromycin

ORACLE Children Study – Results for women without broken waters

• Unexpected increase in numbers of children with cerebral palsy in those who were given either antibiotic.

• Cerebral palsy is the description of a physical impairment disorder that affects movement. The movement problems vary from mild to extremely severe. Cerebral palsy is most commonly the result of failure of a part of the brain to develop, either before birth or in early childhood.

ORACLE Children Study – Results for women without broken waters

Cerebral palsy in children

3.30% 1.70%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Erythromycin No erythromycin

Cerebral palsy in children

3.20% 1.90%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Co-amoxiclav No co-amoxyclav

The risk was clearest for mothers given both antibiotics: 35 (4.4%) of children had cerebral palsy compared with 12 (1.6%) for mothers receiving double placebo.

ORACLE Children Study – Results for women without broken waters

• For mothers who had signs of premature labour without broken waters, having antibiotics did not make any difference to their child’s behaviour, most medical conditions, or Key Stage 1 results.

• Being in the co-amoxiclav group did not make any difference to children’s functioning.

ORACLE Children Study - Results for women with broken waters.

• For mothers whose waters broke early, neither erythromycin or co-amoxiclav made any clear differences to child’s functioning, behaviour, most medical conditions, or Key Stage 1 results.

Impact of ORACLE

• Erythromycin may have some short-term, but not long-term, benefits for children whose mothers have early broken waters.

• Antibiotics should not be given to women who are showing signs of going into premature labour but do not have broken waters and do not have an obvious infection.

• These findings do not mean that antibiotics are unsafe for use in pregnancy. Where there is obvious infection, antibiotics can be life-saving for both mother and baby.

• These findings will make a difference to future generations.

References

• Kenyon, S, Pike, K, Jones DR, Brocklehurst, P, Marlow, N, Salt, A, Taylor, DJ. (2008) Childhood outcomes following prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the Oracle I trial. Advance online publication, Lancet.

• Kenyon, S, Pike, K, Jones DR, Brocklehurst, P, Marlow, N, Salt, A, Taylor, DJ. (2008) Childhood outcomes following prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the Oracle II trial. Advance online publication, Lancet.

• Original Oracle Trial papers Lancet 2001; 357: 979-88 and 989-94.