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  • 8/18/2019 toag.7.1.034.27040

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    REVIEW

    The Obstetrician& Gynaecologist

    2005;7:34–39

    Keywords

    group Bstreptococcus,

    intrapartumantibiotic

    prophylaxis,neonatal sepsis

    © 2005 Royal College of Obstetricians and Gynaecologists34

    Introduction

    Maternal colonisation

    Group B streptococci (GBS) are facultatively

    anaerobic, Gram-positive bacteria. They colonise

    the rectum or vagina in approximately 28% of the

    pregnant population,1 although their presence in

    the genital tract tends to be transient or 

    intermittent rather than chronic.2 Carriage rates

    vary between different countries and ethnic

    groups,with rates as high as 41% being reported in

    African American populations1,3 but rates as low as

    12% being reported on the Indian subcontinent.4

    For most women,GBS colonises the lower vagina

    or rectum as an asymptomatic commensal

    organism. Occasionally, however,clinical evidence

    of maternal infection with GBS arises in the form

    of urinary tract infection,5 chorioamnionitis6,7 or 

    postpartum endometritis.7 Maternal symptoms

    tend to be mild, although systemic sepsis and

    meningitis have been described.

    Clinical features of perinatalinfection

    When GBS colonisation occurs during

    pregnancy, the fetus may be exposed in utero as

    the bacterium ascends or as the fetus descends

    through the genital tract. This process isfacilitated by the ability of GBS to adhere to

    chorionic membranes,6 although infection is

    more likely following prolonged membrane

    rupture. Congenital pneumonia resulting in fetal

    demise before or during labour is well

    documented.8 More commonly, however,

    clinical evidence of sepsis does not become

    apparent until birth. Early-onset group B

    streptococcal sepsis (EOGBSS) is defined as

    presentation within the first 72 hours of life, the

    majority of babies developing signs of infection

    within a few hours of birth. Most babies with

    EOGBSS present with nonspecific signs of 

    systemic infection including poor feeding,

    lethargy and temperature instability. Pneumonic

    and meningitic presentations are also common,

    while rarer complications such as osteomyelitis

    and septic arthritis are occasionally encountered.

    All babies developing EOGBSS are at risk of 

    death or long-term neurodevelopmental

    impairment and this is especially so for those

    who develop meningitis (Figure 1).

    GBS sepsis has been recognised as an important

    cause of neonatal morbidity for over 30 years andis now known to be the most common serious

    neonatal infection in the developed world. The

    current UK prevalence of EOGBSS confirmed by

    Group B streptococcaldisease: screening and

    treatment in pregnancyBassel Abd El Malek, Nicholas D Embleton,Andrew D Loughney

    Intermittent, asymptomatic colonisation of the vagina and rectum withgroup B streptococci is common in pregnancy. Vertical transmission ofthe bacterium from mother to fetus may lead to neonatal sepsis,characterised by pneumonia, meningitis and death in the most severelyaffected babies. Intrapartum prophylaxis with penicillin reduces the

    burden of disease when given to women with risk factors for thedevelopment of group B streptococcal sepsis such as preterm labour,prolonged rupture of the membranes or maternal pyrexia in labour.Some professionals advocate the universal screening of all pregnantwomen for group B streptococci near term and the administration ofintrapartum antibiotic prophylaxis to all women testing swab-positive.This article summarises the salient features of group B streptococcaldisease and explores the rationale behind the use of intrapartumantibiotics for the prevention of neonatal infection.

    10.1576/toag.7.1.034.27040   www.rcog.org.uk/togonline

    Author details

    Bassel Abd El Malek MRCOG, Specialist 

    Registrar in Obstetrics and 

    Gynaecology , Royal Victoria

    Infirmary, Newcastle upon Tyne, UK.

    Nicholas D Embleton MD MRCPCH,

    Consultant in Neonatal Medicine,

    Royal Victoria Infirmary, Newcastle

    upon Tyne, UK.

    Andrew D Loughney PhD MRCOG,

    Consultant Obstetrician, The Royal

    Victoria Infirmary, University of

    Newcastle upon Tyne, RichardsonRoad, Newcastle upon Tyne NE1

    4LP, UK.

    email: andrew.loughney@nuth.

    northy.nhs.uk

    (corresponding author)

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    bacteriological culture is approximately 0.58 cases

    per 1000 live births,9 although some authors

    believe the true prevalence to be significantly

    higher at around 3.6 per cases 1000 live births.10

    Case fatality rates have improved in recent years,

    with advances in neonatal care, but still stand at

    between 4% and 10%, with higher rates

    recognised for babies born prematurely.8 Seminalstudies in the USA in the mid-1980s were able to

    show that the number of babies developing

    EOGBSS could be reduced dramatically by

    administering intrapartum antibiotic prophylaxis

    to women, thereby decreasing bacterial

    transmission to the fetus rather than treating fetal

    infection itself.There are essentially two strategies

    for the prevention of EOGBSS that have been

    developed around this idea. In the ‘risk-based’

    approach, intrapartum antibiotic prophylaxis is

    given to any woman whose clinical history

    suggests that her baby is at high risk of developingEOGBSS, such as a woman with prolonged

    membrane rupture. In the ‘universal prenatal

    screening’ approach, intrapartum antibiotic

    prophylaxis is given to all women known to be

    colonised with GBS, even in the absence of 

    clinically based risk factors.

    The risk-based strategy

    Risk factors for EOGBSS are well established and

    have been confirmed in case–control studies

    (Table 1).8 In addition, babies born to women

    with a previously affected child are also at an

    increased risk.11 The risk-based strategy requires

    women with any one of these risk factors to be

    given intrapartum antibiotic prophylaxis. The

    strategy also allows for women with a positive

    urine culture and women with a fortuitous finding

    of GBS on any vaginal or cervical swab taken

    during the index pregnancy to be treated. If these

    criteria were strictly applied to the UK

    population, at least 16% of women8,12 would

    receive antibiotics in labour. It is estimated thatapproximately 625 women with one or more of 

    these risk factors would need to be treated to

    prevent one case of EOGBSS, and one neonatal

    death would be prevented for every 5882 women

    treated.13

    Although the number of women requiring

    treatment in this scheme appears high, in 1996

    the US Centers for Disease Control and

    Prevention (CDC) published guidelines

    accepting the risk-based approach as a viable

    alternative for the prevention of EOGBSS.14

    Theprinciple that a calculation of risk should be used

    to inform maternal choice was later endorsed by

    the Public Health Laboratory Service (PHLS)

    GBS Working Group in the UK15 and forms the

    basis of advice given in the present RCOG

    Guideline.12 Subsequent experience in the USA

    confirmed that, when rigorously applied,

    intrapartum antibiotic prophylaxis given to

    women with risk factors for EOGBSS could

    deliver a clear reduction in neonatal morbidity

    and mortality.16,17 Reflecting this, implemen-

    tation of the risk-based treatment strategy

    measurably reduced high-dependency neonatal

    special care cot occupancy in US states

    implementing the strategy. Given the high cost

    35

    Figure 1. Outcome

    following maternal group

    B streptococcal

    colonisation

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    © 2004 Royal College of Obstetricians and Gynaecologists

    of neonatal intensive care and supportive

    treatments such as extracorporeal membrane

    oxygen, a similar experience in the UK might

    effectively make the exercise cost neutral to the

    NHS.

    While this approach has many advocates,

    30–40% of babies with EOGBSS are born towomen with no identifiable risk factors. Even

    rigorous application of the risk-based strategy

    cannot, therefore, reduce the incidence of 

    EOGBS by more than 60–70%. Experience

    from the USA suggests that this is true in

    practice, leading the CDC to publish guidelines

    backing the potentially more effective alternative

    strategy of universal prenatal screening.17

    Universal prenatal screening

    The 2002 CDC guidelines recommended

    bacteriological screening for all pregnant women

    and the use of intrapartum antibiotic prophylaxis

    for all screen-positive women, regardless of the

    presence or absence of other risk factors for

    EOGBSS. To achieve this, low vaginal and

    endoanal swabs must be taken at 35–37 weeks of 

    gestation. This relatively late gestation is

    necessary because the positive and negative

    predictive values of swabs taken more than 5

    weeks before delivery are insufficiently high inmost populations to guide treatment.

    Since the site of colonisation does not influence

    the decision to use intrapartum antibiotic

    prophylaxis, screening can be performed by

    passing a swab into the lower part of the vagina

    then passing the same swab into the anus before

    placing it in culture medium.Separate swabs may

    also be used, but both swabs should then be

    placed into the same culture medium so that a

    single bacteriological report is generated. Studies

    have shown that, with appropriate instruction,most pregnant women can take their own swabs,

    improving the acceptability of the procedure

    without affecting its sensitivity.18 A sample of 

    urine should also be analysed in the third

    trimester, since GBS bacteriuria is associated with

    exposure of the fetus to a high bacterial load.19

    For screening to be effective, a method of 

    culture must be employed that is both sensitive

    and specific. Standard bacteriological swabs

    plated directly on to agar fail to detect GBS inup to 50% of colonised women. In contrast, by

    placing swabs directly into a selective enriched

    broth,20 the assay sensitivity can be increased

    dramatically.

    Some babies exposed to GBS will develop early-

    onset disease even after optimal antibiotic

    prophylaxis, particularly when infection has

    arisen in utero.21 Nevertheless, US states

    employing the screening strategy have reported a

    reduction in rates of EOGBSS of up to 86%, a

    decline that is significantly better than that foundin states following the risk-based strategy.17

    In the UK, implementation of a universal

    prenatal screening policy would impact

    significantly upon the provision of antenatal care.

    The organisational challenge of obtaining and

    processing swabs from a large number of women

    and ensuring that results are available to care

    providers during labour would be considerable.

    The screening system would also have to comply

    with the NICE guidelines on the provision of 

    routine antenatal care.22 Access to written

    information and personal, professional advice

    would be needed before swabs were obtained,

    when results were available and prior to

    instituting antibiotic prophylaxis. While these

    requirements could be met in the course of 

    present antenatal care arrangements for most

    women, some additional time allocation would

    inevitably be required to fulfil the counselling

    obligations attendant to the screening

    programme.

    Although the National Screening Committee in

    the UK is currently considering adoption of theuniversal screening approach,this is unlikely to be

    their favoured option because it would almost

    certainly lead to the treatment of more women

    with intrapartum antibiotic prophylaxis than

    would adoption of the risk-based approach, with

    up to 30% being offered antibiotics in labour.23

    The finding of a positive swab would also impact

    upon the woman’s care in labour in a wider sense,

    influencing the woman’s decision regarding place

    of confinement and possibly colouring clinicians’

    views when choosing management options in

    labour. Furthermore, the cost implications of universal prenatal screening would be significant,

    even though a reduction in usage of high-

    dependency neonatal care might be expected to

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    Table 1. Risk factors for early onset group B streptococcal disease; from

    Oddie and Embleton8

    95% confidenceFactor Odds ratio interval

    Preterm birth 37 weeks 10.4 3.9–27.6Preterm birth 34 weeks 33.6 4.0–283.3

    Rupture of the membranes 25.8 10.2–64.818 hours

    Preterm prolonged rupture 30.3 6.3–144.5

    of the membranesIntrapartum fever 38C 10.0 2.4–40.8Any antenatal maternal 17.7 1.9–163.5

    culture of GBSPreviously affected child Presently

    unquantified

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    offset these costs to some degree. Perhaps, more

    pertinently, the balance may lie between the

    inconvenience to the mother and to the health

    service of implementing a screening programme,

    set against achieving the maximum possible

    reduction in neonatal morbidity and mortality.

    Combining universal prenatalscreening and the risk-basedstrategy

    The Canadian Task Force on Preventative Health

    Care has shown that by adopting a universal

    screening strategy but then only offering

    intrapartum antibiotic prophylaxis to women

    who test swab-positive and who have additional

    risk factors for EOGBSS, the number of women

    treated with penicillin in labour can be reduced

    to as little as 3.4%.24 Although this approach is

    likely to cause less morbidity in labouringwomen by reducing antibiotic usage, it retains

    the financial and organisational obstacles

    inherent in implementing a universal antenatal

    screening programme and has the potential to

    reduce the incidence of EOGBSS by only a little

    over 50%.25 Because of these limitations, the

    approach is rarely encountered in UK or US

    practice.

    Chemoprophylaxis and therapy

    Intrapartum antibiotic prophylaxis

    Several studies have confirmed the efficacy of 

    intrapartum antibiotic prophylaxis for EOGBSS

    prevention, with most concluding that the use

    of antibiotics significantly reduces the rate of 

    neonatal colonisation and sepsis.16,25 To be

    effective, it may be necessary for drug

    administration to commence 4 or more hours

    before delivery, since efficacy increases with

    both the length of time the fetus has been

    exposed to antibiotics in labour and the number 

    of doses administered. This 4-hour rule shouldnot be adhered to dogmatically, since clear 

    evidence defining the minimum necessary time

    exposure to intrapartum antibiotic prophylaxis

    to achieve neonatal benefit is lacking.16,26

    To date, there has been no reported resistance of 

    GBS to either penicillin or ampicillin in vivo and

    virtually no resistance in vitro. Since ampicillin

    has a relatively broad spectrum of antimicrobial

    activity, its widespread use has the potential to

    select for resistant organisms. Because of this,

    penicillin remains the drug of choice for intrapartum antibiotic prophylaxis, given at an

    intravenous dose of 3 g (5 MU) initially then 1.5 g

    (2.5 MU) 4-hourly until delivery.

    As much as 10% of the UK population claims to be

    allergic to penicillin. Although true allergic

    reactions probably occur in less than 1%,

    anaphylaxis has been reported in women receiving

    intrapartum antibiotic prophylaxis for GBS27 and

    might be expected to arise in 1/100 000 women

    treated.28 The RCOG estimates that, if a universal

    screening policy were adopted leading to theadministration of intrapartum antibiotic

    prophylaxis to 30% of parturients, two anaphylaxis-

    related maternal deaths could be expected annually

    in the UK.12 In the search for a suitable alternative

    antibiotic, up to 25% of GBS isolates have been

    found to be resistant to erythromycin, which also

    fails to achieve bactericidal levels in the amniotic

    fluid. Up to 15% are resistant to clindamycin, the

    currently recommended second-line drug in the

    UK.12 First-generation cephalosporins such as

    cefazolin may be more effective and have the

    advantage of achieving high intra-amnioticconcentrations while retaining a relatively narrow

    spectrum of antimicrobial activity.

    In theory, the widespread use of intrapartum

    antibiotic prophylaxis could lead to an increase in

    the incidence of early-onset non-GBS sepsis in

    neonates, negating any beneficial effect.Clinicians

    might also expect to encounter an increase in the

    prevalence of drug-resistant bacteria causing

    disease. In reality, these phenomena have rarely

    been observed and some centres following CDC

    guidelines have actually recorded a fall in the

    incidence of non-GBS sepsis.17 To preserve this

    advantage, however, the use of antibiotics with a

    broad spectrum of activity should be reserved for 

    women with true penicillin allergy and close

    surveillance should be kept of the range of 

    bacteria causing neonatal disease.

    Treating the neonate

    Combining infant antimicrobial prophylaxis (100

    mg/kg intravenous penicillin given daily in two

    divided doses)15 with intrapartum antibiotic

    prophylaxis reduces the rate of EOGBSS in bothterm and preterm infants when compared with a

    strategy of no intervention29 but such routine

    neonatal prophylaxis has not gained wide support

    and its benefits remain uncertain.At present, the

    PHLS, RCOG and CDC recommend that, in

    general, whether concern arises because of the

    presence of maternal risk factors or maternal

    swab results, babies who have received

    intrapartum antibiotic prophylaxis before birth

    require heightened observation alone for 12–48

    hours after delivery, with intravenous penicillin

    reserved for babies developing signs of disease.15,17 As exceptions to this rule, penicillin

    should also be considered for babies who are

    otherwise well but who have a combination of 

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    risk factors such as maternal GBS bacteriuria in

    the presence of prolonged membrane rupture.

    Most paediatricians also treat babies born to

    mothers with unequivocal features of 

    chorioamnionitis, babies with twin siblings

    affected by EOGBSS and babies with siblings

    who have had previously confirmed EOGBSS.

    Obstetric issues

    The risk of fetal infection in women with intact

    membranes who are not in labour is low.

    Because of this, antibiotic cover for GBS need

    not be administered routinely to women

    undergoing an elective caesarean section, even in

    the presence of positive swabs. A dilemma may

    arise when, for example, a woman who is swab

    positive or has EOGBSS risk factors and who is

    due to be delivered by caesarean section presents

    with rupture of the membranes or in labour. Inthese circumstances, GBS cover may be given,

    accepting that delivery is likely to take place

    below the theoretical 4-hour prophylaxis

    threshold. Delaying delivery to achieve this

    threshold would be illogical, since fetal bacterial

    exposure increases with time.

    Standard obstetric practice dictates that some

    women with positive GBS swabs or risk factors for 

    neonatal sepsis will undergo one of a number of 

    common obstetric interventions during the course

    of pregnancy and labour.For example,induction of 

    labour is as likely in this group of women as in the

    general population.There is no present evidence to

    suggest that antenatal vaginal examination,

    membrane sweeping or insertion of prostaglandin

    pessaries for labour induction increase the rate of 

    transmission of GBS from the mother to the fetus.

    In labour,although neonatal infection rates increase

    in association with the frequency of vaginal

    examinations and the placement of fetal scalp

    electrodes, cause and effect have not been proven in

    these circumstances. Furthermore, there are few

    data available specifically relating GBS sepsis to

    these intrapartum procedures. There is, therefore,no clear evidence to suggest that women whose

    babies are at risk of EOGBSS should receive

    anything other than normal obstetric or midwifery

    care in labour in addition to antibiotic prophylaxis.

    Issues relating to infants bornprematurely

    Approximately 6% of women give birth after 

    spontaneous labour before 37 weeks of 

    gestation and, of these, one-third give birth

    before 32 weeks.30 Premature babies are atparticularly high risk of developing EOGBSS

    and they are also more likely to die or develop

    long-term sequelae as a result. The CDC

    recommends administration of intrapartum

    antibiotic prophylaxis to all women who seem

    likely to give birth because of preterm labour,

    regardless of the presence of membrane

    rupture, while the PHLS and the RCOG

    concur that intrapartum antibiotic prophylaxis

    should be considered in this group.12 When

    tocolytics are used in an attempt to arrestlabour, low vaginal and rectal swabs should be

    taken to determine the woman’s colonisation

    status, although reliable results may not be

    available in time to influence the use of 

    antibiotic prophylaxis.After delivery, continued

    treatment with penicillin is essential for babies

    showing signs of infection. In practice, signs of 

    infection are frequently non-specific and it is

    also impossible readily to distinguish

    surfactant-deficient lung disease from

    congenital pneumonia, so it is common for 

    preterm babies to receive antibioticsimmediately after delivery.

    Future perspectives

    Rapid detection of GBS

    Because of the transient or intermittent pattern

    of maternal colonisation normally encountered,

    an intrapartum assay for GBS could hold a

    significant advantage over an earlier screening test

    by more accurately reflecting the colonisation

    status of a woman in labour. For this, an assaywould be required that could provide a result

    rapidly, that was highly sensitive to the presence

    of GBS and that was sufficiently specific to give a

    low false-positive result rate. Such a test would

    also allow the accurate assessment of women

    presenting with threatened preterm labour and

    preterm rupture of the membranes.

    A number of GBS rapid detection kits are

    commercially available but, for many, their 

    sensitivity is too low to allow effective

    intervention based on their results.31,32 A new

    polymerase chain reaction assay has been studied,

    which is sensitive to the presence of GBS in 97%

    of cases and claims 100% specificity.33

    Furthermore, assay results are available within 45

    minutes. The assay is not, however, currently

    commercially available so a true analysis of benefit

    remains to be determined.

    Immunisation

    Maternal immunisation against GBS prior to or 

    during pregnancy has the potential to prevent

    fetal colonisation in utero, thereby eliminatingGBS-mediated stillbirth in addition to

    EOGBSS. It could also impact significantly on

    late-onset disease firstly by reducing vertical

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    transmission of the bacterium and secondly by

    providing the neonate with passive immunity

    against infection acquired ex utero. At least eight

    different GBS serotypes exist, based upon the

    specific structure of the capsular polysaccharide

    and embedded proteins.Although only three or 

    four serotypes are responsible for the majority of 

    disease, a vaccine would nevertheless have to bemultivalent to be effective. Current phase one

    and two clinical tr ials have generally investigated

    the use of monovalent vaccines, with limited

    potential for widespread disease prevention.34

    Conclusions

    In order to meet the challenge of reducing

    morbidity and mortality caused by group B

    streptococcal disease after birth, the RCOG has

    proposed that a woman should be offered

    intrapartum antibiotic prophylaxis based upon

    maternal risk factor assessment.12 This contrasts

    with the current US CDC strategy based upon the

    use of universal prenatal screening. It is likely that

    the former policy will be cheaper to implement,

    easier to administer and less likely to impact

    adversely upon a woman’s care in labour,while the

    latter would possibly deliver greater reductions inneonatal disease. In the future, rapid assays for 

    maternal GBS colonisation may be available for 

    use in labour while vaccination against GBS

    represents the greatest hope of reducing the

    burden of neonatal and maternal disease. While

    GBS remains the most prevalent organism causing

    early-onset infections, it should be remembered

    that more than 50% of early-onset infections are

    caused by non-GBS organisms,35 so the

    eradication of EOGBSS should not be seen as the

    endpoint in combating neonatal sepsis.   ■

    39

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