Preterm Labour, Antibiotics, and

Cerebral Palsy
Scientific Impact Paper No. 33
February 2013

Preterm Labour, Antibiotics, and Cerebral Palsy

1.

Introduction

The rate of preterm birth (pregnancy under 37+0 weeks of gestation) is 59% of all births in Europe, and
1213% in the United States of America (USA); the rates in both continents increased up to 2008, partly
due to the higher number of multiple births associated with assisted conceptions.1 Recent data from
Scotland shows nearly a quarter of these births are medically induced with the aim of improving
maternal or fetal outcome.2 Most (62%) of the remainder involve premature delivery after spontaneous
preterm labour without premature rupture of membranes and a few (15%) are premature delivery
following premature membrane rupture, although rates may vary between populations. For families
struggling to cope with having a baby in special care, this will be one of the most difficult, emotional
and stressful times of their lives,3 regardless of the longer term outcome. The sequelae of preterm birth
also pose significant challenges. Children born preterm are at increased risk of major disabilities such as
cerebral palsy. The risk of cerebal palsy increases as gestation at birth decreases.4 Many children who
were born preterm without disability develop significant behavioural and educational difficulties.5
This paper will examine the evidence for:

2.

Prescribing antibiotics to symptomatic women and women with no evidence of infection in

preterm labour (with and without ruptured membranes)
The effects in both the short and longer term
Whether there is a plausible link between infection and cerebral palsy
The clinical implications of any findings
Implications for the design of future maternity trials.

Cerebral palsy

Cerebral palsy is a group of disorders that can involve brain and nervous system functions such as
movement, learning, hearing, seeing, and thinking. It is the most common cause of motor disability in
childhood, with a prevalence of 1.53 cases per 1000 births.6 The risk of cerebral palsy is inversely
proportional to gestational age; the prevalence of cerebral palsy is 80 times higher in infants born prior
to 28 weeks of gestation compared to those born at term. Currently, preterm birth is the strongest known
risk factor for cerebral palsy.7
3.

The link between infection and cerebral palsy

Infection/inflammation is commonly associated with preterm birth (particularly when the membranes
have ruptured) especially less than 30 weeks of gestation1 and must therefore be considered to contribute,
either directly or indirectly, to the high mortality and neurological morbidity in this group.1,8 The high
risk of brain injury in preterm infants could be directly related to the intrauterine hostile inflammatory
environment,9,10 in addition to the effects of the complicated period of neonatal intensive care following
preterm birth. Although a number of studies do not report that infection/inflammation is associated with
central nervous system injury and cerebral palsy,11,12 a direct effect of intrauterine infection/inflammation
is supported by studies showing a higher risk of brain injury in infants born preterm with spontaneous
onset of labour (high frequency of infection) compared with physicianinitiated delivery (low frequency
of infection).13,14 Furthermore, funisitis (inflammation of the connective tissue of the umbilical cord)15,16
high cytokines (IL6, IL8, TNF, IL1) in amniotic fluid and fetal blood are associated with white
matter injury and cerebral palsy.1719 A recent systematic review demonstrated that clinical
chorioamnionitis is associated with white matter injury and cerebral palsy (12 studies included, RR 1.9,
95% CI 1.52.5), and histological chorioamnionitis with periventricular leukomalacia (3 studies, RR
1.6, 95% CI 1.02.5).20,21 Infection/inflammation may not exert adverse effects alone but experimental

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and clinical studies suggest that it may sensitise the immature brain to hypoxiaischemia and other
insults demonstrating the complexity of this process.22,23 Furthermore, recent work suggests there may be
a link between fetal infections and other neurological and psychiatric conditions during childhood and
even in adults.24 Although a causal link has been proposed between antibiotics and cerebral palsy, no
direct association has been demonstrated.25
4.

Short term effect of antenatal antibiotics on preterm birth

Subclinical infection is implicated in a large proportion of preterm births, so theoretically, the acute use
of antibiotics could eradicate the infection, prolong the pregnancy and improve neonatal outcome.
Alternatively, antibiotics might suppress the infection, thus prolonging the pregnancy, but leaving the
fetus in a hostile inflammatory environment.

4.1 Asymptomatic women at risk of preterm labour

A recent metaanalysis of antibiotic treatment during the antenatal period for asymptomatic women at
risk of preterm birth showed no reduction in preterm delivery.26 17 trials were included; 12 trials
identified women at risk by abnormal vaginal flora, 3 trials studied women at high risk from a previous
preterm birth and 2 trials recruited women based on positive fetal fibronectin status. There has been the
suggestion that antibiotics may increase preterm birth in these circumstances,27 and routine treatment is
therefore not recommended.
Bacterial vaginosis has been confirmed as a risk factor for preterm birth and maternal infectious
morbidity and a strong risk factor for miscarriage,28 yet clinical trials of antibiotic therapy during the
antenatal period to reduce these complications have yielded conflicting results;29 antibiotic therapy is not
routine practice.
In summary, the current evidence (which excludes long term follow up of the children) does not support
the routine use of antibiotics in the antenatal period for asymptomatic women.

4.2 Symptomatic women in preterm labour

Evidence of the effects of administration of antibiotics in the acute situation, after the diagnosis of
preterm labour (with or without preterm premature rupture of membranes [pPROM]), came from two
Cochrane reviews which were dominated by the Overview of the Role of Antibiotics in the Curtailment
of Labour and Early Delivery (ORACLE) studies. These studies randomised 4826 women with pPROM30
and 6295 women with suspected preterm labour from 15 countries.31
The review of antibiotics for women with preterm rupture of the membranes was updated in 201032 and
included 22 trials, involving 6800 women and babies. The use of antibiotics following pPROM is
associated with statistically significant reductions in chorioamnionitis (RR 0.66, 95% CI 0.460.96) and
a reduction in the numbers of babies born within 48 hours (average RR 0.71, 95% CI 0.580.87) and
7 days of randomisation (RR 0.79, 95% CI 0.710.89). The following markers of neonatal morbidity
were reduced: neonatal infection (RR 0.67, 95% CI 0.520.85), use of surfactant (RR 0.83, 95% CI
0.720.96), oxygen therapy (RR 0.88, 95% CI 0.810.96), and abnormal cerebral ultrasound scan prior
to discharge from hospital (RR 0.81, 95% CI 0.680.98), although no reduction in perinatal mortality
was observed (RR 0.93, 95% CI 0.761.14) Coamoxiclav was associated with an increased risk of
neonatal necrotising enterocolitis (RR 4.72, 95% CI 1.5714.23).32
The second Cochrane review of the routine use of antibiotics for women with spontaneous preterm
labour (with intact membranes) was updated in 2002.33 Metaanalysis of 11 included trials (7428
women enrolled) showed a reduction in maternal infection with the use of prophylactic antibiotics (RR
0.74, 95% CI 0.640.87) but failed to demonstrate benefit or harm for any of the prespecified neonatal
outcomes. Indeed, there was a suggestion of harm with a near significant increase in neonatal mortality
in the antibiotic group (RR 1.52, 95% CI 0.992.34).33

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5.

Longer term effects of antibiotics on childhood outcomes

The most robust evidence on the role of antibiotics (administered in pregnancy) on longer term
childhood outcomes comes from the ORACLE Children Study (OCS) which followedup surviving
children at 7 years of age in the UK using a parentreport postal questionnaire.34 The primary outcome
was defined as the presence of any level of functional impairment using the Multi Attribute Health Status
(MAHS) classification system.35 Secondary outcomes included a range of medical and behavioural
outcomes. Educational attainment of children at 7 years of age was assessed for those residents in
England using results from National Curriculum tests at Key Stage 1.
For children whose mothers had pPROM, the prescription of antibiotics seemed to have little effect on
the health and educational attainment of children at 7 years36 which was surprising since antibiotics
might have been expected to improve clinical outcomes in this group as positive amniotic fluid cultures
are found in 32% of women at presentation,37 and in as many as 75% during subsequent labour.38 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.30 There is also evidence that
antibiotics neither eradicate nor prevent intraamniotic infection.39
For children whose mothers had spontaneous preterm labour 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 from 38% to 42% (OR 1.18, 95% CI 1.021.37). Similarly proportions of
children with cerebral palsy increased from 1.7% to 3.3% (OR 1.93, 95% CI 1.213.09) associated with
erythromycin and from 1.9% to 3.2% (OR 1.69, 95% CI 1.072.67) with coamoxiclav. There was a
suggestion that more children who developed cerebral palsy had been born to mothers who had received
both antibiotics.40
It is not clear why receipt of antibiotics increased the risk of functional impairment and cerebral palsy.
Rates of subclinical infection in this group are found to be relatively low at 1322%, and an absence of
benefit is therefore not unexpected, but evidence of harm is surprising.
A number of pathways have been suggested but none is established. The most obvious 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 1520% giving birth within 7 days.31 An episode
of preterm labour which settles could reflect an infective episode, where maternal defences facilitated
by the antibiotics overcome the insult, thus prolonging the pregnancy, but not necessarily resolving the
associated intrauterine and fetal inflammation. A continuing inflammatory environment could lead to
fetal brain injury and thereby cerebral palsy. Finally, it is also possible that the episode of spontaneous
preterm labour was not associated with infection, but with other pathologies associated with the so
called preterm parturition syndrome.38
A recently published nested study41 investigated the profile of impairment, recorded by parents and
physiotherapists, for children in the OCS, and contrasted outcomes with those in a population cerebal
palsy registry called 4Child (Four countries database of cerebral palsy, vision loss and hearing loss in
Children).42 Cerebral palsy was more prevalent among OCS children compared to 4Child (standardised
morbidity ratios: spontaneous preterm labour group: 3.12, 95%CI 2.473.87); preterm rupture of
membranes (pPROM) group: 1.56 (95% CI 1.241.92). Of the children with cerebral palsy in the
spontaneous preterm labour group, more were born > 32 weeks of gestation (71%), compared to
pPROM (30%); prevalence was higher in this spontaneous preterm labour group than pPROM or
4Child. OCS children with cerebral palsy tended to have similar distributions of neuroimpairment but
with less severe motor impairment or associated vision and hearing problems compared to 4Child. The
pattern of cerebral palsy for both pPROM and spontaneous preterm labour groups 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 spontaneous preterm labour group; this is
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related to an ongoing lowgrade antenatal neurological insult. This is because despite later birth, the
injury is consistent with a more preterm origin.
6.

Opinion

6.1. Clinical implications in practice

The evidence relates to women with subclinical infection and it is important that women with clinical
evidence of infection are treated with antibiotics since clinical chorioamnionitis remains an important
cause of maternal, fetal and neonatal death. The evidence reviewed suggests that women with
spontaneous preterm labour with intact membranes and no evidence of overt infection should not
routinely be prescribed antibiotics because there is evidence that antibiotics given under these
circumstances increase the risk to their offspring of functional impairment and cerebral palsy.
The decision to prescribe antibiotics routinely for women with pPROM and without evidence of overt
infection is not clear cut, although current guidance endorses the routine use of antibiotics for women
with pPROM43 in the acute situation. Benefits in some shortterm outcomes (prolongation of pregnancy,
reductions in infection, need for surfactant, oxygen therapy and fewer babies with abnormal cerebral
ultrasound before discharge from hospital) should be balanced against a lack of evidence of benefit for
others, including perinatal mortality, and longer term outcomes. Given the lack of any longterm
demonstrable benefit, a decision not to prescribe antibiotics to women with pPROM without evidence of
infection would also be reasonable, especially in a high-income setting where support is available. There
may be a stronger argument for routine antibiotic treatment in low income settings, where access to other
interventions (antenatal steroids, surfactant therapy, ventilation and antibiotic therapy) may be low.
Subgroup comparisons undertaken as part of the Cochrane review32 did not indicate a particular antibiotic
to be the more effective. On the other hand, erythromycin has been recommended as an antibiotic of
choice after being tested by the ORACLE.43 Coamoxiclav should be avoided in women at risk of preterm
delivery due to increased risk of neonatal necrotising enterocolitis. Indeed, where organisms are sensitive
to other antibiotics, it would seem sensible to avoid using coamoxiclav in pregnancy. Antibiotics should
not be prescribed unless a definite diagnosis of pPROM has been made. The diagnosis of pPROM is not
always clear cut; a policy to prescribe antibiotics for all women with suspected pPROM will inevitably
lead to some women with spontaneous preterm labour, but with intact membranes, being prescribed
antibiotics in the belief that their membranes have ruptured. Consequently, these women would be given
antibiotics which would then expose their child to an increased risk of cerebal palsy.
Women with spontaneous preterm labour and intact membranes may be considered at increased risk of
Group B Streptococcus infection (GBS). However, the RCOG44 does not recommend routine prophylaxis
in this situation. These women are not dissimilar to the women in the ORACLE study; they are admitted
in spontaneous preterm labour and at the time of assessment, it is unclear whether they will go on to
give birth.

6.2. Implications for the design of further obstetric trials

The ORACLE studies strengthen the argument that shortterm outcomes are not sufficient to assess the
full impact of the interventions given to pregnant women to improve outcome. The need for more
comprehensive, longer and more detailed followup of such interventions needs to be the default
position for both clinicians and funders, with clear justification given for followup not being required.
Given its importance to parents and clinicians, assessment of neurodevelopment of the child, including
rates of cerebral palsy are key outcome measures.

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This Scientific Impact Paper was produced on behalf of the Royal College of Obstetricians and Gynaecologists by:
Dr S Kenyon PhD, Birmingham; Professor H Hagberg, Imperial College Healthcare Trust, London and
Professor JE Norman FRCOG, Edinburgh, Scotland
and peer-reviewed by:
Dr S Bewley FRCOG, London; British Association of Perinatal Medicine (BAPM); Mr DI Fraser FRCOG, Norfolk; Dr RG Hughes
FRCOG, Edinburgh, Scotland; International Federation of Gynaecology and Obstetrics (FIGO); Professor N Marlow, London;
Professor DM Peebles FRCOG, London and Professor GCS Smith FRCOG, Cambridge.
Conflicts of interest: Dr S Kenyon RM PhD led the ORACLE Trial and Children Study and leads the Cochrane review of Antibiotics
for preterm rupture of the membranes.
The Scientific Advisory Committee lead reviewer was: Mr JP Ash MRCOG, Exeter.
The final version is the responsibility of the Scientific Advisory Committee of the RCOG.

The reviewing process will commence in 2016, unless otherwise indicated.

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