PTB related trials

Question 1

ORACLE 1 AND 2
Authors
published
Year and journal

OCS (ORACLE FU) when was it published, who and where
?

Answer 1

Kenyon et al
lancet 2001

OCS 2008, Lancet, Kenyon et al

Question 2

ORACLE 1 inclusion exclusion criteria

Answer 2

Inclusion
<37 weeks
PPROM
Need to prescribe Abs was uncertain

Exclusion
Abs already prescribed or needed to treat infection
Immediate delivery desirable or unstoppable
Fetus not premature enough to cause concern
Contraindications

Question 3

What were the ORACLE outcomes 1&2

primary and secondary

Answer 3

Primary outcome
Composite of death before hospital discahrage or major adverse outcome before discharge eg chronic lung disease or major cerebral abnormality on US

Secondary outcome 
Delivery <48 hours
Delivery <7 days
Mode of delivery
Number of days in hospital
Maternal Ab prescription
Neonates gestational age at delivery
BW <2,500g, 1,500g
Admission to NICU/SCBU
Number ventiliated
Number requiring >21% O2 at 48 hours, 7 days, 14 day

Question 4

ORACLE 1 &2 intervention

Methods

Answer 4

~1200 each arm for 1
1600 for 2
Randomised to receive 325mg co-amoxiclav alone, 250mg erythromycin alone, co-amoxiclav+erythromycin or placebo taken orally, QID for 10 days or until delivery

Question 5

Results ORACLE 1

Answer 5

ERYTHROMYCIN
Fewer erythromycin alone delivered <32/40 cf placebo
More taking any erythromycin had prolongation of pregnancy >7 days
Fewer babies requiring >21% O2 at 48 hours, 7, 14, 28 days
Less need for exogenous surfactant
Fewer babies whose mothers were assigned erythromycin had the composite primary outcome, but this finding was not significant

CO-AMOXICLAV
Significant prolongation in pregnancy >48 hours, >7 days
Lower rate of maternal Ab prescription post-partum
Fewer babies requiring O2 supplementation
Significantly greater number of babies with suspected or proven NEC received any co-amoxiclav. 4x greater with co-amoxiclav alone, 2.5x greater with any co-amoxiclav

Question 6

Results ORACLE 2

Answer 6

No evidence that any Ab prolonged pregnancy, influenced mode of delivery or hospital stay

No difference in primary outcomes between groups

Non-significant doubling of suspected or proven NEC in those who received any co-amoxiclav

Question 7

Population inclusion for ORACLE 2

Answer 7

<37 weeks
Suspected or definite preterm labour
Substantial uncertainty as to whether Abs should be prescribed

Question 8

OCS 1 + 2 7 year follow up
what was the purpose?

Who was included?

Answer 8

To determine the long-term effects on children of the ORACLE I/ II interventions

Those who successfully completed ORACLE I/ II, living in UK

Excluded:
Death
withdrawn
Outside the UK

Question 9

OCS I/II what was the primary outcome?

Secondary outcome?

Answer 9

Any level of functional impairment in vision, hearing, speech, ambulation, dexterity, emotion, cognition and pain

Presence of >/= 3 of primary outcomes
Degree of impairment of primary outcomes
Number of deaths since trial entry
Frequency of other medical conditions

Question 10

What % of ORACLE 1/ 2 were followed up in 7 years for the OCS ?

Answer 10

4148 completed ORACLE I and eligible for follow-up. 3298 GP and/or parents contacted and outcome known (75%)

4221 eligible for ORACLE II follow-up. 3196 outcome known (71%)

Question 11

Outcomes of OCS 2?

Answer 11

More children whose mothers received any erythromycin or any co-amoxiclav had cerebral palsy compared to those who received no erythromycin or no co-amoxiclav. More children had cerebral pasy when their mother received both Ab compared to only one or neither

Number needed to harm for any erythromycin was 64, for any co-amoxiclav was 79
Increased risk of functional impairment after erythromycin was most evident for singleton pregnancies at earlier gestations

Question 12

PPROMT trial
Where published
Who
When
What

Answer 12

Late PPROM delivery vs expectant
Multicentre RCT 65 centre 11 countries

Morris, Roberts
Lancet
2015

Question 13

PPROMT

Primary and secondary outcomes

Answer 13

The primary outcome was the incidence of neonatal sepsis.

Secondary infant outcomes included a composite neonatal morbidity and mortality indicator (ie, sepsis, mechanical ventilation ≥24 h, stillbirth, or neonatal death); respiratory distress syndrome; any mechanical ventilation; and duration of stay in a neonatal intensive or special care unit.

Secondary maternal outcomes included antepartum or intrapartum haemorrhage, intrapartum fever, postpartum treatment with antibiotics, and mode of delivery

Question 14

PPROMT population inclusion and intervention + numbers

Answer 14

Women aged over 16 years with singleton pregnancies and ruptured membranes before the onset of labour between 34 weeks and 36 weeks and 6 days weeks who had no signs of infection were included

1839 women were recruited and randomly assigned: 924 to the immediate birth group and 915 to the expectant management group.

Question 15

Results PPROMT trial

Answer 15

Same results in neonatal sepsis (primary outcome)
Neonatal composite morbidity and mortality was the same in both groups

Immediate delivery
more RDS + mechanical ventilation
more time in ICU

Expectant management
More APH / intrapartum haemorrhage / post partum antibiotics
Lower caesarean delivery

Question 16

Outcome OCS 1

Answer 16

No difference in any functional impairment amongst those born to mothers who received Abs in any regime versus no Abs

Neither Ab had any effect on overall level of behavioural difficulties experienced, on specific medical conditions or on proprtions achieving at expected level

No Ab associated with change of risk of death or death+functional impairment