PRETERM LABOUR, ANTIBIOTICS AND CEREBRAL PALSY

M O D E RAT O RP R O F. M . M ATA H

S P E A K E RJIGYASA

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 cerebral

palsy. risk of cerebral palsy increases as gestation at

birth decreases. Significant behavioural and educational

difficulties

INTRODUCTION

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

maternity trials

This paper will examine the evidence for

most common cause of motor disability in childhood,

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 factor

CEREBRAL PALSY

. 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 palsyRecent systematic review: clinical chorioamnionitis - ass with white

matter injury and cerebral palsy(12 studies ;rr1.9)

histological chorioamnionitis - periventricular leukomalacia(3 studies;rr1.6)

THE LINK BETWEEN INFECTION AND CEREBRAL PALSY

Infection may not exert adverse effects alone but it may sensitise the immature brain to hypoxia-ischemia.

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.

SHORT TERM EFFECT OF ANTENATAL ANTIBIOTICS ON PRETERM BIRTH

antibiotics suppress infection, thus prolonging pregnancy

but leaving fetus in a hostile inflammatory environment.

Alternatively

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

vaginal flora 3 trials studied women at high risk from

previous preterm birth 2 trials recruited women based on positive fetal

fibronectin status. .

Asymptomatic women at risk of preterm labour

suggestion - antibiotics may increase preterm birth in these circumstances, routine treatment is not recommended

Bacterial vaginosis- risk factor for preterm birth,maternal infectious morbidity,miscarriage

Yet clinical trials of antibiotic therapy yielded conflicting results

Current evidence (which excludes long term follow up ) does not support routine use of antibiotics in antenatal period for asymptomatic women

summary

Evidence of effects of antibiotics in acute situation,after diagnosing preterm labour(with or without PPROM) came from 2 Cochrane reviews

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 countries.

Symptomatic women in preterm labour

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 reducedI. 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

hsptl(RR 0.81)

Although no reduction in perinatal mortality was observed(RR 0.93)

Co-amoxiclav - increased risk of neonatal NEC(RR 4.72)

Second Cochrane review updated in 2002.Meta-analysis of 11 included trials (7428

women)showed: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 classification system.

secondary outcomes : range of medical and behavioural outcomes.

Longer term effects of antibiotics on childhood outcomes

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.

Cont....

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-amoxiclav.

Cont...

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 days.

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 fetal inflammation.

continuing inflammatory environment could lead to fetal brain injury and thereby cerebral palsy.

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: 3.122. PPROM group: 1.56 Children with CP in 1. were born

>32wks,compared to PPROM Prevalence was higher in 1. than PPROM or

4Child

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 antibiotics

because there is evidence that antibiotics given under these circumstances increase risk to their offspring of functional impairment and cerebral palsy.

OPINION

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 outcomesA. Prolongation of pregnancyB. Reductions in infecionsC. Need for surfactantD. Oxygen therapyE. Babies with abnormal cerebral USG before

discharge from hsptl Should be balanced against a lack of evidence

of benefit for others, includingA. Perinatal mortalityB. 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 other interventions

A. Antenatal steroidsB. Surfactant C. Ventilation D. Antibiotic may be low

Comparisons undertaken as part of Cochrane review did not indicate a particular antibiotic

Erythromycin has been recommended by ORACLE

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 measures.

Implication for the design of further obstetric trials

THANK YOU