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    Third trimester antiviral prophylaxis for preventing maternal

    genital herpes simplex virus (HSV) recurrences and neonatal

    infection (Review)

    Hollier LM, Wendel GD

    This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published inThe Cochrane Library2008, Issue 2

    http://www.thecochranelibrary.com

    Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

    (Review)

    Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

    http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/
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    T A B L E O F C O N T E N T S

    1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    6DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    7AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    7ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    8REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    10CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    15DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    Analysis 1.1. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 1 Neonatal herpes. . . . . . 15

    Analysis 1.2. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 2 Genital herpes simplex virus

    recurrence at delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

    Analysis 1.3. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 3 Cesarean delivery. . . . . 17

    Analysis 1.4. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 4 Genital herpes simplex virus

    detection at delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

    Analysis 1.5. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 5 Neonatal viral detection. . . 19

    19WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    19HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    19CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    20DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    20INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

    iThird trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

    (Review)

    Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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    [Intervention Review]

    Third trimester antiviral prophylaxis for preventing maternalgenital herpes simplex virus (HSV) recurrences and neonatalinfection

    Lisa M Hollier1, George D Wendel2

    1Department of Obstetrics and Gynecology, LBJ General Hospital, Houston, USA. 2 Department of Obstetrics and Gynecology, UT

    Southwestern Medical Center, Dallas, USA

    Contact address: Lisa M Hollier, Department of Obstetrics and Gynecology, LBJ General Hospital, 5656 Kelley Street, Houston, Texas,77026, [email protected].

    Editorial group:Cochrane Pregnancy and Childbirth Group.

    Publication status and date: Edited (no change to conclusions), published in Issue 2, 2008.

    Review content assessed as up-to-date: 14 October 2007.

    Citation: Hollier LM, Wendel GD. Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus

    (HSV) recurrences and neonatal infection. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD004946. DOI:10.1002/14651858.CD004946.pub2.

    Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

    A B S T R A C T

    Background

    Genital herpes simplex virus (HSV) infection is one of the most common viral sexually transmitted infections. The majority of women

    with genital herpes will have a recurrence during pregnancy. Transmission of the virus from mother to fetus typically occurs by direct

    contact with virus in the genital tract during birth.

    Objectives

    To assess the effectiveness of antenatal antiviral prophylaxis for recurrent genital herpes on neonatal herpes and maternal recurrences at

    delivery.

    Search methods

    We searched the Cochrane Pregnancy and Childbirth Groups Trials Register (January 2007), the Cochrane Central Register of

    Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 4), MEDLINE (January 1966 to February 2007) and EMBASE(January 1974 to February 2007; handsearched conference proceedings; reviewed bibliographies of all relevant articles for further

    references; and contacted experts in the field.

    Selection criteria

    Randomized controlled trials which assessed the effectiveness of antivirals compared to placebo or no therapy, on neonatal herpes and

    maternal disease endpoints among pregnant women with genital herpes.

    Data collection and analysis

    Two authors independently applied study selection criteria and extracted data.

    1Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

    (Review)

    Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

    mailto:[email protected]:[email protected]
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    Main results

    Seven randomized controlled trials (1249 participants) which met our inclusion criteria compared acyclovir to placebo or no treatment

    (five trials) and valacyclovir to placebo (two trials). The effect of antepartum antiviral prophylaxis on neonatal herpes could not be

    estimated. There were no cases of symptomatic neonatal herpes in the included studies in either the treatment or placebo groups.

    Women who received antiviral prophylaxis were significantly less l ikely to have a recurrence of genital herpes at delivery (relative risk

    (RR) 0.28, 95% confidence interval (CI) 0.18 to 0.43, I2 = 0%). Women who received antiviral prophylaxis were also significantly

    less likely to have a cesarean delivery for genital herpes (RR 0.30, 95% CI 0.20 to 0.45, I2 = 27.3%). Women who received antiviral

    prophylaxis were significantly less likely to have HSV detected at delivery (RR 0.14, 95% CI 0.05 to 0.39, I2 = 0%).

    Authors conclusions

    Women with recurrent genital herpes simplex virus should be informed that the risk of neonatal herpes is low. There is insufficient

    evidence to determine if antiviral prophylaxis reduces the incidence of neonatal herpes. Antenatal antiviral prophylaxis reduces viral

    shedding and recurrences at delivery and reduces the need for cesarean delivery for genital herpes. Limited information exists regarding

    the neonatal safety of prophylaxis. The risks, benefits, and alternatives to antenatal prophylaxis should be discussed with women whohave a history and prophylaxis initiated for women who desire intervention.

    P L A I N L A N G U A G E S U M M A R Y

    Use of antiviral drugs in late pregnancy for reducing the recurrence of genital herpes at labor and birth and reducing the risk

    of newborn HSV infection

    The incidence of herpes, a sexually transmitted disease, varies across the world. Among pregnant women with herpes, nearly 75% can

    expect at least one flare-up during their pregnancy. Transmission of the virus from mother to baby typically occurs by direct contact

    with the virus during birth. It is often recommended that a cesarean should be offered to women with active lesions to reduce the risk

    of transmission to the baby. In addition, several antiviral agents are available for use both for therapy and for preventing a flare-up.These antiviral drugs include acyclovir, penciclovir, valacyclovir, and famciclovir. The review assessed whether antiviral drugs given to

    pregnant women with herpes before a recurrence might be effective in reducing transmission to the baby. Seven studies were identified

    involving 1249 women. Giving antiviral drugs reduces viral shedding and recurrences at labor and birth. They also reduced the use of

    cesarean, but there is no evidence of reduction in neonatal herpes. Women should also be informed that the risk of the baby getting

    herpes during birth is low.

    B A C K G R O U N D

    Genital herpes simplex virus (HSV) infection is one of the mostcommon viral sexually transmitted infections in the United States

    (US), nowaffectingan estimated 45 million adolescents and adults

    (Corey 2000; Fleming 1997). The seroprevalence(the frequency of

    individuals in a population that have a particular element (as anti-

    bodiestoHSV)intheirbloodserum)ishigheramongwomenthan

    among men across various populations (Cowan 2004;Wutzler

    2000). A very large serologic (the science dealing with the im-

    munological properties and actions of serum) study in the US

    found that approximately 23% of women had serologic evidence

    of HSV-2 infection (Xu 2006). The seroprevalence of HSV-2 in

    western and southern Europe appears to be lower than in northern

    Europe and North America (Smith 2002).

    Among women with recurrent genital HSV, nearly 75% can ex-

    pect at least one recurrence during pregnancy, and about 14%of women will have prodromal symptoms (early symptoms in-

    dicating the onset of an attack) or clinical recurrence at deliv-

    ery (Sheffield 2006;Watts 2003). Transmission of the virus from

    mother to fetus typically occurs by direct contact with the virus in

    the genital tract during delivery. The risk of vertical transmission

    is related to the gestational age at delivery, the presence of ma-

    ternal antibodies to HSV and the route of delivery (Baker 1999;

    Brown 2003). To reduce neonatal transmission, it is currently rec-

    ommended that a cesarean delivery be offered to all women with

    active genital lesions or prodromal symptoms at delivery (Baker

    1999;NGC 2002).

    2Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

    (Review)

    Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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    The estimated incidence of neonatal herpes infection is broad,

    ranging from 5 to 80 per 100,000 live births ( Kropp 2006;Mahnert 2007;Whitley 2007). Infection can be classified as dis-

    seminated disease (25%), central nervous systemdisease (30%), or

    disease limited to the skin, eyes, or mouth (45%) (Whitley 1988).

    About 30% of infants with disseminated disease and 4% of in-

    fants with CNS disease will die from their infection. Long-term

    neurologic sequelae occur in about 20% of survivors (Kimberlin

    2001).

    There are several antiviral agents that have been used both forther-

    apyand forprophylaxis in the management of women with genital

    herpes virus infections. Acyclovir and penciclovir are nucleoside

    analogs. These drugs become active only after initial phosphoryla-

    tion (additionof a phosphorus group) that is carried outonly by vi-ral thymidine kinase (a viral-specificenzyme) (Elion 1993; Larsson

    1986). Inthis way, thedrugsbecome active only in cells that are in-

    fectedwiththe herpes virus. Inthesecells,the phosphorylated drug

    (nucleoside analog) is incorporated into the replicating viral DNA

    and this terminates the growth of the DNAchain. Valacyclovir is a

    prodrug (inactive form) of acyclovir that is rapidly metabolized to

    acyclovir (Weller 1993). Famciclovir is converted to penciclovir.

    Among non-pregnant women, daily oral acyclovir, valacyclovir,

    and famciclovir have been shown to reduce the frequency of re-

    current genital herpes (Mertz 1988;Mertz 1997;Reitano 1998).

    Additionally, oral valacyclovir has been shown to reduce the risk

    of symptomatic transmission of genital herpes (Corey 2004).

    Oral antiviral agents are used in pregnancy to treat genital herpes

    infections. Acyclovir in pregnancy is well tolerated, with minimal

    fetal drug accumulation (Haddad 1993). The Acyclovir in Preg-

    nancy Registry included data from more than 1200 women ex-

    posed to acyclovir. No increase in drug-related fetal abnormalities

    was ascribed to acyclovir, although long-term developmental out-

    comes were not evaluated (Stone 2004).

    In an effort to reduce neonatal transmission of HSV and to re-

    duce the number of cesarean deliveries performed for genital her-

    pes infections, a number of studies have investigated whether an-

    tiviral therapy in the last month of pregnancy would decrease

    HSV recurrence at delivery among women with genital her-pes diagnosed before or during pregnancy (Andrews 2006;Braig

    2001; Brocklehurst 1998; Scott 1996; Scott 2002; Sheffield 2006;

    Stray-Pedersen 1990;Watts 2003). The findings of these studies

    have been controversial: several studies finding evidence of bene-

    fit and others finding no reduction in recurrent HSV or cesarean

    delivery. A previous meta-analysis found reduction in recurrences

    and cesarean delivery, but did not address adverse effects (Sheffield

    2003). Although the American College of Obstetricians and Gy-

    necologists states that the use of acyclovir to suppress recurrent

    HSV infection in pregnancy is acceptable, some reports note that

    there are insufficient data to recommend this prophylaxis. (Baker

    1999;Brown 2003;Handsfield 1999;IHMF 2003;Smith 1998).

    O B J E C T I V E S

    To estimate the effect of prophylactic antiviral medication pro-

    vided to pregnant women near term on:

    1. the rate of neonatal HSV transmission;

    2. the rate of recurrent genital herpes at delivery;

    3. the number of cesarean deliveries performed for clinical

    herpes simplex virus (HSV) recurrences or prodromal symptoms;

    4. the prevalence of HSV detection at delivery.

    M E T H O D S

    Criteria for considering studies for this review

    Types of studies

    Randomized clinical trials that used antiviral agents (acyclovir,

    valacyclovir, and famciclovir) in the third trimester of pregnancy

    as prophylaxis for recurrent genital herpes at delivery. We did not

    include quasi-randomized trials.

    Types of participants

    Pregnant women in third trimester who have been diagnosed with

    genital herpes infection before or during pregnancy.

    Types of interventions

    Oralantiviral medication for prophylaxis for recurrent genital her-

    pes at delivery compared to placebo or no intervention.

    Types of outcome measures

    Primary outcomes

    Neonatal herpes

    Secondary outcomes

    Proportion of women with recurrent herpes simplex virus (HSV)

    (diagnosed clinically) at the time of presentation

    Proportion of women undergoing cesarean delivery with HSV as

    the primary indication

    Prevalence of HSV at the time of delivery (diagnosed by culture

    or polymerase chain reaction)

    Side effects

    3Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

    (Review)

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    Search methods for identification of studies

    Electronic searches

    We searched the Cochrane Pregnancy and Childbirth Groups Tri-

    als Register by contacting the Trials Search Co-ordinator (January

    2007).

    The Cochrane Pregnancy and Childbirth Groups Trials Register

    is maintained by the Trials Search Co-ordinator and contains trials

    identified from:

    1. quarterly searches of the Cochrane Central Register of

    Controlled Trials (CENTRAL);

    2. monthly searches of MEDLINE;

    3. handsearches of 30 journals and the proceedings of major

    conferences;4. weekly current awareness search of a further 36 journals

    plus monthly BioMed Central email alerts.

    Details of the search strategies for CENTRAL and MEDLINE,

    the list of handsearched journals and conference proceedings, and

    the list of journals reviewed via the current awarenessservice canbe

    found in the Search strategies for identification of studies section

    within the editorial information about the Cochrane Pregnancy

    and Childbirth Group.

    Trials identified through the searching activities described above

    are given a code (or codes) depending on the topic. The codes are

    linked to review topics. The Trials Search Co-ordinator searches

    the register foreach review using these codes rather than keywords.

    In addition, we searched the Cochrane Central Register of Con-

    trolled Trials (CENTRAL) (The Cochrane Library 2006,Issue 4).We searched MEDLINEfrom January 1966 to February 2007 and

    EMBASEfrom 1974 to February 2007 to generate three subsets of

    citations. The first used the keywords acyclovir and aciclovir,

    and all possible suffixes and derivatives of each. A second subset

    used pregnancy as the keyword or pregnant, pregnancy, or

    delivery as title words. We combined these two subsets using

    AND witha thirdsubset generated using keywords Herpes viri-

    dae, herpes genitalis, herpes simplex, Herpesviridae, and

    all possible suffixes and derivatives. We restricted the final analysis

    to clinical trials.

    We handsearched abstracts from the following scientific forums:

    Society for Maternal-Fetal Medicine (1990 to 2007), Infectious

    Disease Society for Obstetrics and Gynecology (1990 to 2006),

    and the Society for Gynecologic Investigation (1990 to 2006). We

    reviewed bibliographiesof all relevant articles for furtherreferences

    and contacted experts in the field.

    We did not apply any language restrictions.

    Data collection and analysis

    The authors independently reviewed the studies identified by

    means of the criteria described above. The following data were

    abstracted onto standardized forms.

    Methodologic issues

    Publication year; years of study; presentation as article or abstract;allocation concealment; blinding of participants; blinding of care-

    givers; blinding of outcome assessment; completeness of data col-

    lection (including loss to follow up and non-compliance); analysis

    by intent to treat.

    Clinical issues

    Medication type; dosage and interval; gestational age at initiation

    of medication; clinical or laboratory diagnosis of herpes infection,

    or both; definitions of initial, primary, first episode non-primary,

    and recurrent herpes simplex virus (HSV) infection; HSV detec-

    tion at delivery via polymerase chain reaction, culture, and clini-

    cal examination; cesarean delivery incidence and indications; andneonatal outcomes. Clinical and virologic recurrences on the day

    of delivery were used for analysis. Side effects included maternal

    and neonatal toxicities, maternal acceptability of the prophylactic

    regimen, and maternal anxiety related to the regimen.

    The trial quality was assessed and reported according to

    the Cochrane Reviewers Handbook (Higgins 2005) and the

    Cochrane Pregnancy and Childbirth Groups Methodological

    Guidelines (seeAnalysis in the Methods used in Reviews sectionof the editorial information about the Group (PCG 2004).

    1. Allocation concealment: scored as adequate, unclear or

    inadequate.

    2. Generation of random allocation sequence: adequate,

    unclear or inadequate. (This should include both whether thesequence is truly random and whether it is secure, i.e. whether

    the random allocation is fixed once it has been obtained, or can

    be changed. For example, tossing a coin gives a random

    allocation sequence but is not secure because it can be repeated

    until the desired result is obtained).

    3. Binding of participants (yes/no/unclear).

    4. Blinding of caregivers (yes/no/unclear).

    5. Blinding of outcome assessment (yes/no/unclear).

    6. Completeness of data collection, including differential

    withdrawal of participants or loss to follow up from different

    groups (less than 5%, 5% to 10%, 10 to 20%, greater than 20%).

    7. Analysis of randomized participants in randomized groups.

    We used The Cochrane CollaborationsReview Managersoftware (RevMan 2003) forthe data analysis. We analyzed data by intention

    to treat. We calculated risk ratios for the outcomes using a fixed-

    effect model. We evaluated heterogeneity of treatment using the I2 statistic.

    R E S U L T S

    Description of studies

    4Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

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    See: Characteristics of included studies; Characteristics of excluded

    studies.We identified 10 potentially eligible randomized controlled trials

    (RCTs) from which we excluded three (seeCharacteristics of ex-cluded studies table). Two studies were not randomized clinical

    trials(Kimberlin1998; Scott1998).Inthethirdexcludedtrial,the

    methods of randomizationwere not clearand aftercorrespondence

    with the primary author, it was apparent that women were not

    randomized to antiviral treatmentor no treatment (Stray-Pedersen

    1990). The remaining seven studies with 1249 participants met

    our inclusion criteria (Andrews 2006;Braig 2001;Brocklehurst

    1998;Scott 1996;Scott 2002;Sheffield 2006;Watts 2003).

    The included RCTs compared acyclovir to a placebo or no

    treatment (Braig 2001; Brocklehurst 1998; Scott 1996; Scott

    2002;Watts 2003) and valacyclovir to placebo (Andrews 2006;Sheffield2006). Gravid women were recruitedin the United States

    (Andrews 2006;Scott 1996;Scott 2002;Sheffield 2006;Watts

    2003), England (Brocklehurst 1998) and France (Braig 2001). In

    onestudy, women were included only ifthey hadthe first episode of

    genital herpes infection during the index pregnancy (Scott 1996).

    The remaining studies included women with a history of genital

    herpes that antedated pregnancy.

    We have described the seven RCTs included in this review in detail

    in the table of Characteristics of included studies, and summa-

    rized their main features below.

    Scott 1996

    This RCT included gravid women with a first clinical episode ofgenital herpes during the index pregnancy. Diagnosis was con-

    firmed by a positive genital culture forherpes simplex virus(HSV).

    Eligiblewomenwererandomizedto eitheroral acyclovir400 mg or

    an identical placebo thrice daily beginning at 36 weeks gestation.

    The primary outcome was reduction in HSV recurrence at deliv-

    ery. Other assessed outcomes are listed in the table. Neonates were

    evaluated for vertical transmission using surface cultures, in addi-

    tion to being followed for development of symptomatic neonatal

    herpes. The trial was terminated after a planned interim analysis

    demonstrated a significant difference in the primary outcome.

    Brocklehurst 1998

    This RCT included 63 gravid women with a history of recurrent

    genital herpes. Infection was not documented. At one of the cen-ters enrolling just over half the participants, women were required

    to have experienced at least one symptomatic recurrence during

    pregnancy. Eligible women were randomized to either oral acy-

    clovir 200 mg or an identical placebo four times daily beginning

    at 36 weeks gestation. The primary outcome was reduction in the

    frequency of caesarean delivery for genital herpes. Other outcomes

    are described in the table. Neonates were observed for evidence of

    symptomatic genital herpes infection and followed for one year.

    The trial was terminated early due to slow enrollment.

    Braig 2001

    This RCT included 288 gravid women with a history of recurrent

    genital herpes. Infection was not documented. Women were re-

    quired to have at least one symptomatic recurrence during preg-nancy. Eligible women were randomized to either oral acyclovir

    200 mg four times daily beginning at 36 weeks gestation or no

    treatment. The primary outcome was reduction in viral shedding

    at delivery. Other outcomes are described in the table. Neonates

    were observed for evidence of symptomatic genital herpes infec-

    tion.

    Scott 2002

    This RCT included 234 gravid women with a history of recurrent

    genital herpes. Infection was not documented. Eligible women

    were randomized to either oral acyclovir 400 mg or an identical

    placebo thrice daily beginning at 36 weeks gestation. The primary

    outcome was reduction in HSV recurrence at delivery. Other as-sessed outcomes are listed in the table. Neonates were followed for

    development of symptomatic neonatal herpes and surface cultures

    were obtained. The trial was terminated early due to slow enroll-

    ment.

    Watts 2003

    This RCT included 170 gravid women with a history of recurrent

    genital herpes. The womans history of infection was confirmed by

    documentation of seropositivity or genital culture. Women were

    required to have had a symptomatic recurrence within one year

    of the pregnancy. Eligible women were randomized to either oral

    acyclovir 400 mg or an identical placebo thrice daily beginning

    at 36 weeks gestation. The primary outcome was reduction incesarean delivery for HSV recurrence. Other assessed outcomes

    are listed in the table. Neonates were followed for development of

    symptomatic neonatal herpes. The trial was terminated early due

    to slow enrollment.

    Andrews 2006

    This RCT included gravid women with a history of recurrent

    HSV-2 genital infection. The womans history of infection was

    confirmed by documentation of seropositivity for HSV-2 antibody

    or a previous genital culture positive for HSV-2. Women with a

    first episode were specifically excluded. Eligible women were ran-

    domized to either oral valacyclovir 500 mg or an identical placebo

    twice daily beginning between 36 and 36 6/7 weeks gestation.The primary outcome was reduction in HSV recurrence at deliv-

    ery. Other assessed outcomes are listed in the table. Neonates were

    evaluated for vertical transmission using both surface cultures and

    polymerase chain reaction (PCR), in addition to being followed

    for development of symptomatic neonatal herpes. Neonatal blood

    samples were obtained for assessment of toxicity.

    Sheffield 2006

    This RCT included 350 gravid women with either initial or re-

    current genital herpes. The womans history of infection was con-

    firmed by documentation of seropositivity along with genital cul-

    5Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

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    tures. Eligible women were randomized to either oral valacyclovir

    500 mg or an identical placebo twice daily beginning at 36 weeksgestation. The primary outcome was reduction in cesarean deliv-

    ery for HSV recurrence. Other assessed outcomes are listed in the

    table.Neonateswere evaluated for vertical transmission usingboth

    surface cultures and PCR, in addition to being followed for devel-

    opment of symptomatic neonatal herpes. Neonatal blood samples

    were obtained in a subset of infants for assessment of toxicity.

    Risk of bias in included studies

    Allocation concealment was scored as adequate in six trials

    (Andrews 2006; Brocklehurst 1998; Scott 1996; Scott 2002;

    Sheffield 2006;Watts 2003) and was not used in one trial (Braig2001). The generation of the random allocation sequence was ad-

    equate in five studies (Andrews 2006; Scott 1996; Scott 2002;

    Sheffield 2006; Watts 2003) and unclear in two (Braig 2001;

    Brocklehurst 1998). With the exception of one trial that was com-

    pletely unblinded (Braig 2001), all other trials blinded partici-

    pants and providers. The blinding of outcome assessors was un-

    clear infourtrials (Andrews 2006; Brocklehurst 1998; Scott 1996;

    Scott2002)andratedadequateintwotrials( Sheffield 2006;Watts

    2003). The loss to follow up was zero or negligible in five studies

    (Andrews 2006;Braig 2001;Brocklehurst 1998;Sheffield 2006;

    Watts 2003). The loss to follow up was 10% in one trial ( Scott

    1996) and 18% in another (Scott 2002). In both cases theloss was

    non-differential and infant outcomes were available in the secondtrial.

    Effects of interventions

    Seven randomized controlled trials (1249 participants) which met

    our inclusion criteria compared acyclovir to placebo or no treat-

    ment (five trials) and valacyclovir to placebo (two trials).

    Neonatal herpes

    The effect of antepartum antiviral prophylaxis on neonatal her-

    pes could not be estimated. There were no cases of symptomaticneonatal herpes in the included studies in either the treatment or

    placebo groups. Four of the studies reported the results of neona-

    tal surface cultures or polymerase chain reaction (PCR), or both.

    Three infants had virus detected after delivery, two in treatment

    groupsand one in a placebo group. Allinfants were asymptomatic.

    Maternal outcomes

    Women who received antiviral prophylaxis were significantly less

    likely to have a recurrence of genital herpes at delivery (relative

    risk (RR) 0.28, 95% CI 0.18 to 0.43, I2 = 0%). Expressed as an

    absolute risk reduction, antiviral prophylaxis reduced the risk of

    recurrence by 10.7%. The corresponding number of women who

    would need to receive antiviral prophylaxis from 36 weeks untildelivery to prevent a recurrence at delivery would be 10.

    Women who received antiviral prophylaxis were also significantly

    less likely to have a cesarean delivery for genital herpes (RR 0.30,

    95% CI 0.20 to 0.45, I2 = 27.3%). Expressed as an absolute risk

    reduction, antiviral prophylaxis reduced the risk of cesarean de-

    livery for genital HSV by 10.1%. The corresponding number of

    women who would need to receive antiviral prophylaxis from 36

    weeks until delivery to prevent a cesarean delivery for herpes would

    be 10.

    Detectionof HSV at delivery wasassessedin fivestudies.Results of

    PCR and culture were combined for the purposes of this analysis.

    Women who received antiviral prophylaxis were significantly less

    likely to have HSV detected at delivery (RR 0.14, 95% CI 0.05to 0.39, I = 0%). Expressed as an absolute risk reduction, antiviral

    prophylaxis reduced the risk of viral detection at delivery by 5.8%.

    The corresponding number of women who would need to receive

    antiviral prophylaxis from 36 weeks until delivery to prevent viral

    detection at delivery would be 17.

    Two of the studies specifically reported maternal side effects asso-

    ciated with the antiviral prophylaxis. Maternal renal function was

    evaluated in one trial and no differences were reported (Andrews

    2006). Another study reported no evidence of haematological or

    biochemical toxicity (Brocklehurst 1998). Symptoms attributed

    to the study drug included nausea, vomiting, diarrhea, headache,

    bitter taste, and skin rash. There were two reports of symptoms

    in the treatment group and 13 reports in the placebo group(Brocklehurst 1998). No studies assessed maternal acceptability of

    the intervention or maternal anxiety.

    Neonatal sideeffects wereevaluatedby two studies. These included

    oligohydramnios (Andrews 2006), renal function (Andrews 2006;

    Sheffield 2006), serum chemistries (Andrews 2006; Sheffield

    2006), and neutropenia (Andrews 2006; Sheffield 2006). The

    mean aspartate aminotransferase (a liver enzyme) was significantly

    increased in the placebo-exposed infants in one trial (Sheffield

    2006), but no differences in the number of infants with transam-

    inases (liver enzymes) greater than two standard deviations above

    the mean were reported in the other trial (Andrews 2006). Data

    from complete blood counts were available for 238 infants (123

    were exposed to valacyclovir and 115 were exposed to placebo)from two trials (Andrews 2006;Sheffield 2006). No infants in

    either treatment or placebo group had white blood cell counts less

    than 4000/mm3 . There were no significant differences in other

    neonatal outcomes.

    D I S C U S S I O N

    We found insufficient evidence to evaluate the effect of antiviral

    prophylaxis given to pregnant women with a history of recurrent

    genital herpes on the incidence of neonatal herpes. There were

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    no cases of neonatal herpes in the seven included trials, which

    included over 1200 infants. The estimated incidence of neona-tal herpes in North America ranges from 5 to 80 per 100,000

    live births (Brown 2003;Kropp 2006;Mahnert 2007;Whitley

    2007). Corresponding to the lower prevalence of herpes simplex

    virus (HSV) in women outside the United States, the incidence

    of neonatal herpes is significantly lower in the United Kingdom

    - estimated at 1.6/100,000 (Tookey 1996). Approximately 70%

    to 80% of infected infants are born to mothers with no reported

    history of HSV infection (Tookey 1996;Whitley 1988). Because

    the outcome of neonatal herpes is expected to be infrequent in

    this population, the total sample size included in the meta-analysis

    is inadequate to detect even large relative reductions in neonatal

    infection. Neutropenia is a recognized, transient complication of

    acyclovir treatment of neonatal HSV infection (Kimberlin 2001).Data were available on a limited number of infants, but no adverse

    fetal/neonatal effects were identified. Continued assessment of the

    neonatal safety of maternal prophylaxis is important.

    Surrogate outcomes are often measured in situations where an

    important outcome is rare. Samples from mucosal surfaces of

    neonates in several trials were taken and tested for the presence

    of HSV both by culture and by polymerase chain reaction. Three

    infants, two treatment-exposed and one placebo-exposed, had de-

    tectable virus. Thus, we did not find evidence that prophylactic

    antivirals given to pregnant women reduced the frequency of de-

    tectable HSV.

    Antiviral prophylaxis was associated with a significant reduction inrecurrence at the time of delivery. Because the practice of perform-

    ing a cesarean delivery when women present with active genital

    herpes is relatively common, there was also a significant reduction

    in cesarean delivery for genital HSV. These findings are similar to

    a previous meta-analysis, which included only trials involving the

    useof acyclovir(Sheffield 2003) and showed significant reductions

    in recurrence at delivery, cesarean delivery for HSV and in total

    cesarean deliveries. The effectiveness in reducing recurrences was

    consistent for acyclovir and for valacyclovir.

    Cesarean delivery has been shown to reduce the risk of transmis-

    sion of HSV to the neonate (Brown 2003). One potential concern

    of using prophylactic antivirals would be that suppression of vi-ral activity would be incomplete and women might have asymp-

    tomatic shedding rather than an active lesion, and hence would

    not have a cesarean delivery. In our analysis and in a previous anal-

    ysis, prophylaxis was effective in significantly reducing the detec-

    tion of virus at delivery (Sheffield 2003).

    Limitations of the analysis

    The major weakness of our review relates to the inherent short-

    comings of the original research. Half the trials were stopped be-fore the planned sample sizes were reached. Additionally, the rate

    of study withdrawal in two large studies was greater than 15%.

    The withdrawal did appear to be non-differential and neonatal

    outcomes were available in a significant proportion of women

    (Scott 2002). In this meta-analysis, we combined two different

    drugs used for prophylaxis and different treatment regimens of

    one drug (acyclovir). We believe that the similarity in the drugs

    and the similarity of the treatment effects justifies the evaluation

    of summary measures.

    A U T H O R S C O N C L U S I O N S

    Implications for practice

    Women with recurrent genital herpes simplex virus should be in-

    formed that the risk of neonatal herpes is low. There is insufficient

    evidence to determine if antiviral prophylaxis for women with a

    history of genital herpes reduces the incidence of neonatal herpes.

    Antenatal antiviral prophylaxis reduces viral shedding and recur-

    rences at delivery and reduces the need for cesarean delivery for

    genital herpes. Limited information exists regarding the neonatal

    safety of prophylaxis. The risks, benefits, and alternatives to an-

    tenatal prophylaxis should be discussed with women who have a

    history and prophylaxis initiated in women who desire interven-tion.

    Implications for research

    Because neonatal HSV is an infrequent complication in this pop-

    ulation, other interventions will be needed to significantly reduce

    the overall incidence of neonatal herpes. Continued assessment

    of the safety of antepartum antiviral prophylaxis is important to

    inform the womans decision made based on the risks and benefits

    of the intervention.

    A C K N O W L E D G E M E N T S

    We would like to thank the authors of the studies who responded

    to our requests for additional information and clarification.

    As part of the pre-publication editorial process, this review has been

    commentedonbytwopeers(aneditor,andarefereewhoisexternal

    to the editorial team), one or more members of the Pregnancy

    and Childbirth Groups international panel of consumers and the

    Groups Statistical Adviser.

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    R E F E R E N C E S

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    Valaciclovir suppressive therapy in pregnant women reduces

    recurrent genital herpes (hsv): results of a randomized trial

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    Ramsey PS, Deeter R. Valacyclovir therapy to reduce

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    Journal of Obstetrics and Gynecology2006;194(3):77481.

    Braig 2001 {published data only}

    Braig S, Luton D, Sibony O, Edlinger C, Boissinot C, Blot

    P, et al.Acyclovir prophylaxis in late pregnancy prevents

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    Ross E, Ellis E, et al.A randomised placebo controlled

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    Mindel A. Trial to evaluate efficacy and safety of a

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    Scott 1996 {published data only}

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    Scott LL, Hollier LM, Baum A, Jackson G, Sanchez PJ,

    Wendel GDJr. Prevention of recurrent genital herpes at

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    diagnosed prior to pregnancy - an interim analysis.American

    Journal of Obstetrics and Gynecology1998;178(1 Pt 2):S213. Scott LL, Hollier LM, McIntire D, Sanchez PJ, Jackson

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    Sheffield 2006 {published data only}

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    & Gynecology2005;105(4 Suppl):5S. Sheffield JS, Hill JB, Hollier LM, Laibl VR, Roberts

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    Infectious Diseases in Obstetrics & Gynecology2001;9(3):

    1656. Watts DH, Brown ZA, Money D, Selke S, Huang ML,

    Sacks SL, et al.A double-blind, randomized, placebo-

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    2003;188:83643.

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    Kimberlin 1998 {published data only}

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    RJ, Lakeman F, et al.Valaciclovir pharmacokinetics in late

    pregnancy. American Journal of Obstetrics and Gynecology

    1998;178(1 Pt 2):S12. Kimberlin DF, Weller S, Whitley RJ, Andrews WW,

    Hauth JC, Lakeman F, et al.Pharmacokinetics of oral

    valacyclovir and acyclovir in late pregnancy. American

    Journal of Obstetrics and Gynecology1998;179(4):84651.

    Scott 1998 {published data only}

    Scott LL, Hollier LM, Jackson G, Sanchez PJ, Baum A,

    Wendel GD. Acyclovir suppression to prevent cesareandelivery after first episode genital simplex infection.

    American Journal of Obstetrics and Gynecology1998;178(1

    Pt 2):12.

    Stray-Pedersen 1990 {published data only}

    Stray-Pedersen B. Acyclovir in late pregnancy to prevent

    neonatal herpes simplex [letter]. Lancet1990;336(8717):

    756.

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    transmission rates of herpes simplex virus from mother to

    infant. JAMA2003;289:2039.

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    addressing a global problem. JAMA2000;283(6):7914.

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    Mertz GJ, Loveless MO, Levin MJ, Kraus SJ, Fowler

    SL, Goade D, et al.Oral famciclovir for suppression of

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    Reitano M, Tyring S, Lang W, Thoming C, Worm AM,

    Borelli S, et al.Valaciclovir for the suppression of recurrent

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    recurrence at delivery: a systematic review. Obstetrics &

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    Smith 1998

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    herpes simplex virus infection in pregnancy. British Journal

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    with herpes simplex virus types 2 and 1: a global review.

    Journal of Infectious Diseases2002;186(Suppl 1):S3S28.

    Stone 2004

    Stone KM, Reiff-Eldridge R, White AD, Cordero JF, Brown

    Z, Alexander ER, et al.Pregnancy outcomes following

    systemic prenatal acyclovir exposure: Conclusions from

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    Tookey P, Peckham CS. Neonatal herpes simplex virus

    infection in the British Isles. Paediatric and Perinatal

    Epidemiology1996;10:43242.

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    Weller S, Blum MR, Doucette M. Pharmacokinetics of the

    acyclovir pro-drug valaciclovir after escalating single- and

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    multiple-dose administration to normal volunteers. Clinical

    Pharmacology and Therapeutics1993;54:595605.Whitley 1988

    Whitley RJ, Corey L, Arvin A, Lakeman FD, Sumaya CV,

    Wright PF, et al.Changing presentation of herpes simplex

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    Wutzler P, Doerr HW, Farber I, Eichhorn U, Helbig B,Sauerbrei A, et al.Seroprevalence of herpes simplex virus

    type 1 and type 2 in selected Gernam populations: relevance

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    Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK,

    Nahmias AJ, et al.Trends in Herpes Simplex Virus type 1

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    296:96473. Indicates the major publication for the study

    10Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

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    C H A R A C T E R I S T I C S O F S T U D I E S

    Characteristics of included studies [ordered by study ID]

    Andrews 2006

    Methods Randomized double-masked, placebo-controlled clinical trial.

    Participants Gravid women with documented recurrent genital HSV-2 infection

    Interventions Valacyclovir 500 mg po BID vs placebo beginning at 36 weeks gestation

    Outcomes HSV shedding within 7 days of delivery, active HSV lesions at delivery, cesarean for active HSV, neonatalHSV positive, symptomatic neonatal HSV

    Notes

    Risk of bias

    Item Authors judgement Description

    Allocation concealment? Yes A - Adequate

    Braig 2001

    Methods Randomized controlled cl inical trial.

    Participants Gravid women with documented recurrent genital herpes infection

    Interventions Acyclovir 200 mg po 4 times daily or no treatment.

    Outcomes Cesarean delivery for genital herpes, asymptomatic viral shedding

    Notes

    Risk of bias

    Item Authors judgement Description

    Allocation concealment? Unclear D - Not used

    Brocklehurst 1998

    Methods Randomized double-masked, placebo-controlled clinical trial.

    Participants Gravid women with documented recurrent genital herpes infection

    Interventions Acyclovir 200 mg po 4 times daily vs placebo from 36 weeks gestation

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    Brocklehurst 1998 (Continued)

    Outcomes Clinical recurrence at time of labor, cesarean delivery for HSV, infants with neonatal herpes

    Notes

    Risk of bias

    Item Authors judgement Description

    Allocation concealment? Yes A - Adequate

    Scott 1996

    Methods Randomized double-masked, placebo-controlled clinical trial.

    Participants Gravid women with first episode genital herpes infection during index pregnancy

    Interventions Acyclovir 400 mg po TID vs placebo from 36 weeks gestation.

    Outcomes HSV outbreak at delivery, HSV culture at delivery, cesarean delivery for genital HSV, positive neonatal

    HSV cultures

    Notes

    Risk of bias

    Item Authors judgement Description

    Allocation concealment? Yes A - Adequate

    Scott 2002

    Methods Randomized double-masked, placebo-controlled clinical trial.

    Participants Gravid women with recurrent genital HSV-2 infection.

    Interventions Acyclovir 400 mg po TID vs placebo from 36 weeks gestation.

    Outcomes Clinical HSV recurrence at delivery, cesarean delivery for HSV, HSV culture at delivery, neonatal HSV

    cultures

    Notes

    Risk of bias

    Item Authors judgement Description

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    Scott 2002 (Continued)

    Allocation concealment? Yes A - Adequate

    Sheffield 2006

    Methods Randomized double-masked, placebo-controlled clinical trial.

    Participants Gravid women with documented recurrent genital HSV-2 infection confirmed with serology

    Interventions Valacyclovir 500 mg po BID vs placebo beginning at 36 weeks gestation

    Outcomes HSV outbreak at delivery, HSV culture and PCR at delivery, cesarean delivery for genital HSV, positive

    neonatal HSV cultures

    Notes

    Risk of bias

    Item Authors judgement Description

    Allocation concealment? Yes A - Adequate

    Watts 2003

    Methods Randomized double-masked, placebo-controlled clinical trial.

    Participants Gravid women with documented recurrent genital HSV-2 infection confirmed with serology or culture

    Interventions Acyclovir 400 mg po TID vs placebo from 36 weeks gestation.

    Outcomes HSV outbreak at delivery, HSV culture and PCR at delivery, cesarean delivery for herpes, neonatal herpes

    Notes

    Risk of bias

    Item Authors judgement Description

    Allocation concealment? Yes A - Adequate

    BID: dosing twice daily

    HSV: herpes simplex virus

    PCR: polymerase chain reaction

    po: oral dosing

    TID: three times a day

    vs: versus

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    Characteristics of excluded studies [ordered by study ID]

    Study Reason for exclusion

    Kimberlin 1998 Not a randomized trial comparing antiviral to placebo for prophylaxis of recurrent genital herpes

    Scott 1998 Not a randomized trial comparing antiviral to placebo for prophylaxis of recurrent genital herpes

    Stray-Pedersen 1990 After corresponding with the author, it was determined that this study was not a randomized clinical trial

    14Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

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    D A T A A N D A N A L Y S E S

    Comparison 1. Antenatal antiviral prophylaxis versus placebo

    Outcome or subgroup titleNo. of

    studies

    No. of

    participants Statistical method Effect size

    1 Neonatal herpes 7 1240 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

    2 Genital herpes simplex virus

    recurrence at delivery

    7 1249 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.18, 0.43]

    2.1 Acyclovir 5 799 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.15, 0.43]

    2.2 Valacyclovir 2 450 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.17, 0.68]

    3 Cesarean delivery 7 1249 Risk Ratio (M-H, Fixed, 95% CI) 0.30 [0.20, 0.45]

    3.1 Acyclovir 5 799 Risk Ratio (M-H, Fixed, 95% CI) 0.27 [0.16, 0.46]

    3.2 Valacyclovir 2 450 Risk Ratio (M-H, Fixed, 95% CI) 0.35 [0.17, 0.70]

    4 Genital herpes simplex virus

    detection at delivery

    5 887 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.05, 0.39]

    4.1 Acyclovir 4 632 Risk Ratio (M-H, Fixed, 95% CI) 0.11 [0.03, 0.45]

    4.2 Valacyclovir 1 255 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.04, 0.85]

    5 Neonatal viral detection 4 737 Risk Ratio (M-H, Fixed, 95% CI) 1.63 [0.22, 12.13]

    Analysis 1.1. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 1 Neonatal herpes.

    Review: Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

    Comparison: 1 Antenatal antiviral prophylaxis versus placebo

    Outcome: 1 Neonatal herpes

    Study or subgroup Treatment Control Risk Ratio Risk Ratio

    n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

    Andrews 2006 0/57 0/55 0.0 [ 0.0, 0.0 ]

    Braig 2001 0/167 0/121 0.0 [ 0.0, 0.0 ]

    Brocklehurst 1998 0/31 0/32 0.0 [ 0.0, 0.0 ]

    Scott 1996 0/21 0/25 0.0 [ 0.0, 0.0 ]

    Scott 2002 0/116 0/115 0.0 [ 0.0, 0.0 ]

    Sheffield 2006 0/170 0/168 0.0 [ 0.0, 0.0 ]

    Watts 2003 0/84 0/78 0.0 [ 0.0, 0.0 ]

    Total (95% CI) 646 594 0.0 [ 0.0, 0.0 ]

    Total events: 0 (Treatment), 0 (Control)

    Heterogeneity: Chi2 = 0.0, df = 0 (P

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    Analysis 1.2. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 2 Genital herpes

    simplex virus recurrence at delivery.

    Review: Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

    Comparison: 1 Antenatal antiviral prophylaxis versus placebo

    Outcome: 2 Genital herpes simplex virus recurrence at delivery

    Study or subgroup Treatment Control Risk Ratio Weight Risk Ration/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

    1 Acyclovir

    Braig 2001 0/167 15/121 19.9 % 0.02 [ 0.00, 0.39 ]

    Brocklehurst 1998 2/31 6/32 6.6 % 0.34 [ 0.08, 1.58 ]

    Scott 1996 2/26 10/29 10.5 % 0.22 [ 0.05, 0.93 ]

    Scott 2002 7/116 16/115 17.8 % 0.43 [ 0.19, 1.01 ]

    Watts 2003 4/84 11/78 12.7 % 0.34 [ 0.11, 1.02 ]

    Subtotal (95% CI) 424 375 67.5 % 0.25 [ 0.15, 0.43 ]

    Total events: 15 (Treatment), 58 (Control)

    Heterogeneity: Chi2 = 4.76, df = 4 (P = 0.31); I2 =16%

    Test for overall effect: Z = 5.09 (P < 0.00001)

    2 Valacyclovir

    Andrews 2006 3/57 8/55 9.0 % 0.36 [ 0.10, 1.29 ]

    Sheffield 2006 7/170 21/168 23.5 % 0.33 [ 0.14, 0.75 ]

    Subtotal (95% CI) 227 223 32.5 % 0.34 [ 0.17, 0.68 ]

    Total events: 10 (Treatment), 29 (Control)

    Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.90); I2 =0.0%

    Test for overall effect: Z = 3.06 (P = 0.0022)

    Total (95% CI) 651 598 100.0 % 0.28 [ 0.18, 0.43 ]

    Total events: 25 (Treatment), 87 (Control)

    Heterogeneity: Chi2 = 4.59, df = 6 (P = 0.60); I2 =0.0%

    Test for overall effect: Z = 5.93 (P < 0.00001)

    0.001 0.01 0.1 1 10 100 1000

    Favors treatment Favors control

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    Analysis 1.3. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 3 Cesarean delivery.

    Review: Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

    Comparison: 1 Antenatal antiviral prophylaxis versus placebo

    Outcome: 3 Cesarean delivery

    Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

    n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

    1 Acyclovir

    Braig 2001 0/167 15/121 20.8 % 0.02 [ 0.00, 0.39 ]

    Brocklehurst 1998 4/31 8/32 9.1 % 0.52 [ 0.17, 1.54 ]

    Scott 1996 0/26 10/29 11.5 % 0.05 [ 0.00, 0.86 ]

    Scott 2002 8/116 14/115 16.3 % 0.57 [ 0.25, 1.30 ]

    Watts 2003 3/84 8/78 9.6 % 0.35 [ 0.10, 1.27 ]

    Subtotal (95% CI) 424 375 67.3 % 0.27 [ 0.16, 0.46 ]

    Total events: 15 (Treatment), 55 (Control)

    Heterogeneity: Chi2 = 8.69, df = 4 (P = 0.07); I2 =54%

    Test for overall effect: Z = 4.84 (P < 0.00001)

    2 Valacyclovir

    Andrews 2006 3/57 7/55 8.2 % 0.41 [ 0.11, 1.52 ]

    Sheffield 2006 7/170 21/168 24.5 % 0.33 [ 0.14, 0.75 ]

    Subtotal (95% CI) 227 223 32.7 % 0.35 [ 0.17, 0.70 ]

    Total events: 10 (Treatment), 28 (Control)

    Heterogeneity: Chi2 = 0.08, df = 1 (P = 0.77); I2 =0.0%

    Test for overall effect: Z = 2.94 (P = 0.0033)

    Total (95% CI) 651 598 100.0 % 0.30 [ 0.20, 0.45 ]

    Total events: 25 (Treatment), 83 (Control)

    Heterogeneity: Chi2 = 8.25, df = 6 (P = 0.22); I2 =27%

    Test for overall effect: Z = 5.65 (P < 0.00001)

    0.001 0.01 0.1 1 10 100 1000

    Favors treatment Favors control

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    Analysis 1.4. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 4 Genital herpes

    simplex virus detection at delivery.

    Review: Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

    Comparison: 1 Antenatal antiviral prophylaxis versus placebo

    Outcome: 4 Genital herpes simplex virus detection at delivery

    Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

    n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

    1 Acyclovir

    Braig 2001 0/167 6/121 25.9 % 0.06 [ 0.00, 0.98 ]

    Scott 1996 0/23 1/25 4.9 % 0.36 [ 0.02, 8.45 ]

    Scott 2002 0/102 6/102 22.3 % 0.08 [ 0.00, 1.35 ]

    Watts 2003 0/47 2/45 8.8 % 0.19 [ 0.01, 3.89 ]

    Subtotal (95% CI) 339 293 61.9 % 0.11 [ 0.03, 0.45 ]

    Total events: 0 (Treatment), 15 (Control)

    Heterogeneity: Chi2 = 0.96, df = 3 (P = 0.81); I2 =0.0%

    Test for overall effect: Z = 3.06 (P = 0.0022)

    2 Valacyclovir

    Sheffield 2006 2/118 12/137 38.1 % 0.19 [ 0.04, 0.85 ]

    Subtotal (95% CI) 118 137 38.1 % 0.19 [ 0.04, 0.85 ]

    Total events: 2 (Treatment), 12 (Control)

    Heterogeneity: not applicable

    Test for overall effect: Z = 2.18 (P = 0.029)

    Total (95% CI) 457 430 100.0 % 0.14 [ 0.05, 0.39 ]

    Total events: 2 (Treatment), 27 (Control)

    Heterogeneity: Chi2 = 1.14, df = 4 (P = 0.89); I2 =0.0%

    Test for overall effect: Z = 3.78 (P = 0.00016)

    0.001 0.01 0.1 1 10 100 1000

    Favors treatment Favors control

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    Analysis 1.5. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 5 Neonatal viral

    detection.Review: Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

    Comparison: 1 Antenatal antiviral prophylaxis versus placebo

    Outcome: 5 Neonatal viral detection

    Study or subgroup Treatment Control Risk Ratio Risk Ratio

    n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

    Andrews 2006 1/57 1/55 0.96 [ 0.06, 15.05 ]

    Scott 1996 0/27 0/29 0.0 [ 0.0, 0.0 ]

    Scott 2002 1/116 0/115 2.97 [ 0.12, 72.26 ]

    Sheffield 2006 0/170 0/168 0.0 [ 0.0, 0.0 ]

    Total (95% CI) 370 367 1.63 [ 0.22, 12.13 ]

    Total events: 2 (Treatment), 1 (Control)

    Heterogeneity: Chi2 = 0.28, df = 1 (P = 0.60); I2 =0.0%

    Test for overall effect: Z = 0.48 (P = 0.63)

    0.01 0.1 1 10 100

    Favors treatment Favors control

    W H A T S N E WLast assessed as up-to-date: 14 October 2007.

    Date Event Description

    4 February 2008 Amended Converted to new review format.

    H I S T O R Y

    Protocol first published: Issue 4, 2004

    Review first published: Issue 1, 2008

    Date Event Description

    15 October 2007 New citation required and conclusions have changed Substantive amendment

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    C O N T R I B U T I O N S O F A U T H O R S

    LM Hollier and GD Wendel reviewed all potential trials and assessed all included trials. LM Hollier wrote the first draft of the review

    and GD Wendel reviewed it.

    D E C L A R A T I O N S O F I N T E R E S T

    Dr Wendel has received research funding from Glaxo from 1994 to 2004. Dr Wendel was on the GlaxoSmithKline speakers bureau

    for six months in 2006. In 1997, Dr Hollier received honoraria for several local talks sponsored by the makers of Valacyclovir and

    Famciclovir.

    I N D E X T E R M S

    Medical Subject Headings (MeSH)Acyclovir [analogs & derivatives; therapeutic use]; Antiviral Agents [therapeutic use]; Herpes Genitalis [drug therapy; prevention &

    control; transmission]; Infant, Newborn; Infectious Disease Transmission, Vertical [prevention & control]; Pregnancy Complications,

    Infectious [prevention & control]; Pregnancy Trimester, Third; Randomized Controlled Trials as Topic; Recurrence [prevention &

    control]; Valine [analogs & derivatives; therapeutic use]

    MeSH check words

    Female; Humans; Pregnancy

    20Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection

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    Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.