M O D E R A T O R
P R O F . M . M A T A H
S P E A K E R
Scientific impact paper no.33
RCOG Feb 2013
Rate of preterm birth 5-9% in Europe, 12-
13% in USA.
1/4th- medically induced
62% -preterm without prom
15%-preterm with prom
increased risk of major disabilities like
risk of cerebral palsy increases as gestation
at birth decreases.
Significant behavioural and educational
Prescribing antibiotics to symptomatic
women and women with no evidence of
infection in preterm labour.
effects in both short and longer term.
Whether there is a plausible link between
infection and cerebral palsy.
clinical implications of any findings.
Implications for the design of future
most common cause of motor disability in
prevalence - 1.5-3 cases per 1000 births.
risk inversely proportional to GA;
80 times higher in infants born prior to 28wks
campared to term.
Currently, preterm birth - strongest known risk
Direct effect-high risk of brain injury
funisitis, high cytokines( IL-6, IL-8,
TNF-@,IL-1B)in amniotic and fetal blood - ass.
with white matter injury and cerebral palsy
Recent systematic review:
clinical chorioamnionitis - ass with white
matter injury and cerebral palsy(12 studies
histological chorioamnionitis - periventricular
Infection may not exert adverse effects alone
but it may sensitise the immature brain to
Causal link between antibiotics and cerebral
palsy proposed,no direct association
Subclinical infection implicated in a large
proportion of preterm birth
acute use of antibiotics
eradicate the infection,
prolong the pregnancy
improve neonatal outcome.
antibiotics suppress infection, thus
but leaving fetus in a hostile inflammatory
recent meta-analysis of antibiotic treatment
during the antenatal period for aymptomatic
women at risk of preterm birth showed no
reduction in preterm delivery.
17 trials included;
12 trials identified women at risk by abnormal
3 trials studied women at high risk from
previous preterm birth
2 trials recruited women based on positive fetal
suggestion - antibiotics may increase
preterm birth in these circumstances, routine
treatment is not recommended
Bacterial vaginosis- risk factor for preterm
Yet clinical trials of antibiotic therapy yielded
Current evidence (which
excludes long term follow up )
does not support routine use
of antibiotics in antenatal
period for asymptomatic
Evidence of effects of antibiotics in acute
situation,after diagnosing preterm
labour(with or without PPROM) came from 2
Dominated by ORACLE(Overview of the Role
of Antibiotics in the Curtailment of labour
and Early Delivery)studies
Randomised 4826 women with PPROM &
6295 with suspected preterm labour from 15
Review of antibiotics for women with PROM,
updated in 2010 included 22 trials,involving
6800 women & babies.
Use of antibiotics following PPROM ass with
statistically sinificant reduction in
1) Chorioamnionitis(RR 0.66)
2) No. of babies born within 48hrs(0.71)
Markers of neonatal morbidity reduced
I. Neonatal infection(RR 0.67)
II. Use of surfactant(RR 0.83)
III. Oxygen therapy(RR 0.88)
IV. Abnormal USG prior to discharge from
Although no reduction in perinatal mortality
was observed(RR 0.93)
Co-amoxiclav - increased risk of neonatal
Second Cochrane review updated in 2002.
Meta-analysis of 11 included trials (7428
a. Reduction in maternal infection (RR 0.74)
b. Failed to demonstrate benefit or harm for
any of pre-specified neonatal outcomes.
c. Suggestion of harm with significant increase
in neonatal mortality(RR 1.52).
ORACLE Children Study(OCS) which followed
up surviving children at 7 yrs of age in the UK
using a parent-report postal questionnaire.
primary outcome : presence of any level of
functional impairment using the MAHS
secondary outcomes : range of medical and
children whose mothers had PPROM,
prescription of antibiotics seemed to have
little effect on the health and educational
attainment of children at 7yrs.
reason for this not clear but might be linked
to length of antibiotic exposure ( fairly short)
Evidence that antibiotics neither eradicate
nor prevent intra-amniotic infection.
children whose mothers had spontaneous
preterm labour the prescription of
erythromycin associated with
increase in proportions of children with any
level of functional impairment from 38 to42%.
Increased proportions of children with
cerebral palsy from 1.9 to 3.2% asso with
erythromycin and from 1.9 to 3.2% with co-
The most obvious reason for this is a direct effect
of the antibiotics, but this seems unlikely as it
was not seen in the PPROM group. Length of
exposure to antibiotics to this group was fairly
long, with only 15-20% giving birth within 7
An episode of preterm labour which settles could
reflect an infective episode, where maternal
defences-facilitated by antibiotics-overcome the
insult, thus prolonging the pregnancy, but not
necessarily resolving the ass. intrauterine and
continuing inflammatory environment could
lead to fetal brain injury and thereby cerebral
it is also possible that episode of
spontaneous preterm labour was not ass with
infection, but with other pathologies ass with
“preterm parturition syndrome”.
Recent published nested study investigated
the profile of impairment,recorded by parents
& physiotherapists, for children in OCS and
contrasted outcomes with those in population
cerebral palsy registry called 4Child.
CP more prevalent among OCS children
compared to 4Child
Standardised morbidity ratios:
1. Spontaneous preterm labour group: 3.12
2. PPROM group: 1.56
Children with CP in 1. were born
>32wks,compared to PPROM
Prevalence was higher in 1. than PPROM or
OCS children with CP have similar
distributions of neuroimpr but with less
severe motor impairm or ass vision &
hearing problems compaired to 4 Child
The pattern of cerebral palsy for both PPROM
and spontaneous preterm labour group was
similar and milder than in the general
population, but with increased risk
independent of gestation.
These results have led to further speculation
that ,for the antibiotic treated spont preterm
labour grp; this is related to an ongoing low-
grade antenatal neurological insult
This is because despite later birth , injury is
consistent with more preterm injury.
Clinical implications in practice
women with spontaneous preterm labour with
intact membranes and no evidence of overt
infection should not routinely be prescribed
because there is evidence that antibiotics
given under these circumstances increase
risk to their offspring of functional
impairment and cerebral palsy.
Decision to prescribe antibiotics routinely
with PPROM & without evidence of overt
infection is not clear cut.
Current guidance endorses the routine use of
antibiotics with PPROM in acute situation
Benefits in some short term outcomes
A. Prolongation of pregnancy
B. Reductions in infecions
C. Need for surfactant
D. Oxygen therapy
E. Babies with abnormal cerebral USG before
discharge from hsptl
Should be balanced against a lack of evidence
of benefit for others, including
A. Perinatal mortality
B. Longer term outcomes
Given the lack of any long term benefit , decision
not to prescribe antibiotics with PPROM without
evidence of infection would be reasonable,esp in
high income setting.
There may be stronger argument for routine
antibiotic in low income setting where access to
A. Antenatal steroids
may be low
Comparisons undertaken as part of Cochrane
review did not indicate a particular antibiotic
Erythromycin has been recommended by
Co-amoxiclav avoided(increased risk of NEC)
Antibiotics not prescribed unless definite
diagnosis of PPROM has been made
Spont preterm labour and intact membranes
considered at risk of GBS.
RCOG does not recommend routine
prophylaxis in this situation
ORACLE strengthen the argument that short
term outcomes are not sufficient to assess
the full impact of interventions.
The need for more comprehensive, longer &
more detailed follow-up
Assessment of neurodevelopment of the
child, including rates of CP are key outcpme