Aciclovir en El Embarazo PDF

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 in The Cochrane Library
2008, 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.
T A B L E O F C O N T E N T S
1 HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3 OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3 METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4 RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7 AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10 CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15 DATA 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
19 WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19 HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19 CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20 DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20 INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
i Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection
(Review)
[Intervention Review]
Third trimester antiviral prophylaxis for preventing maternal
genital herpes simplex virus (HSV) recurrences and neonatal
infection
Lisa M Hollier
1
, George D Wendel
2
1
Department of Obstetrics and Gynecology, LBJ General Hospital, Houston, USA.
2
Department of Obstetrics and Gynecology, UT
Southwestern Medical Center, Dallas, USA
Contact address: Lisa MHollier, Department of Obstetrics and Gynecology, LBJ General Hospital, 5656 Kelley Street, Houston, Texas,
77026, USA. lisa.m.hollier@uth.tmc.edu.
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.
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 eld.
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.
1 Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection
(Review)
Main results
Seven randomized controlled trials (1249 participants) which met our inclusion criteria compared acyclovir to placebo or no treatment
(ve 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 signicantly less likely to have a recurrence of genital herpes at delivery (relative risk
(RR) 0.28, 95% condence interval (CI) 0.18 to 0.43, I
2
= 0%). Women who received antiviral prophylaxis were also signicantly
less likely to have a cesarean delivery for genital herpes (RR 0.30, 95% CI 0.20 to 0.45, I
2
= 27.3%). Women who received antiviral
prophylaxis were signicantly less likely to have HSV detected at delivery (RR 0.14, 95% CI 0.05 to 0.39, I
2
= 0%).
Authors conclusions
Women with recurrent genital herpes simplex virus should be informed that the risk of neonatal herpes is low. There is insufcient
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, benets, and alternatives to antenatal prophylaxis should be discussed with women who
have 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 are-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 are-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 identied
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 most
common viral sexually transmitted infections in the United States
(US), nowaffecting anestimated 45 millionadolescents and adults
(Corey 2000; Fleming 1997). The seroprevalence (the frequency of
individuals in a population that have a particular element (as anti-
bodies toHSV) intheir bloodserum) is higher among womenthan
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 (Shefeld 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).
(Review)
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 classied 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 for ther-
apy and for prophylaxis 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 out only by vi-
ral thymidine kinase (a viral-specic enzyme) (Elion 1993; Larsson
1986). Inthis way, the drugs become active only in cells that are in-
fectedwiththe herpes virus. Inthese cells, the phosphorylateddrug
(nucleoside analog) is incorporated into the replicating viral DNA
and this terminates the growth of the DNA chain. 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; Shefeld 2006;
Stray-Pedersen 1990; Watts 2003). The ndings of these studies
have been controversial: several studies nding evidence of bene-
t and others nding 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 (Shefeld
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 insufcient data to recommend this prophylaxis. (Baker
1999; Brown 2003; Handseld 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
Oral antiviral 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
(Review)
Search methods for identication 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
identied 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 awareness service can be
found in the Search strategies for identication of studies section
within the editorial information about the Cochrane Pregnancy
and Childbirth Group.
Trials identied 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 for each reviewusing 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 MEDLINEfromJanuary 1966 to February 2007 and
EMBASEfrom1974 to February 2007 to generate three subsets of
citations. The rst used the keywords acyclovir and aciclovir,
and all possible sufxes 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 with a third subset generated using keywords Herpes viri-
dae, herpes genitalis, herpes simplex, Herpesviridae, and
all possible sufxes and derivatives. We restricted the nal analysis
to clinical trials.
We handsearched abstracts from the following scientic 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 bibliographies of all relevant articles for further references
and contacted experts in the eld.
We did not apply any language restrictions.
Data collection and analysis
The authors independently reviewed the studies identied 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 followup 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; denitions of initial, primary, rst 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; and
neonatal 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 (see Analysis in the Methods used in Reviews section
of 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 the
sequence is truly random and whether it is secure, i.e. whether
the random allocation is xed 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 usedThe Cochrane Collaborations ReviewManager software (
RevMan 2003) for the data analysis. We analyzed data by intention
to treat. We calculated risk ratios for the outcomes using a xed-
effect model. We evaluated heterogeneity of treatment using the I
2
statistic.
R E S U L T S
Description of studies
(Review)
See: Characteristics of includedstudies; Characteristics of excluded
studies.
We identied 10 potentially eligible randomized controlled trials
(RCTs) from which we excluded three (see Characteristics of ex-
cluded studies table). Two studies were not randomized clinical
trials (Kimberlin1998; Scott 1998) . Inthe thirdexcludedtrial, the
methods of randomizationwere not clear and after correspondence
with the primary author, it was apparent that women were not
randomized to antiviral treatment or 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; Shefeld 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;
Shefeld2006). Gravid womenwere recruited inthe United States
(Andrews 2006; Scott 1996; Scott 2002; Shefeld 2006; Watts
2003), England (Brocklehurst 1998) and France (Braig 2001). In
one study, womenwere includedonly if they hadthe rst 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 reviewin 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 rst clinical episode of
genital herpes during the index pregnancy. Diagnosis was con-
rmed by a positive genital culture for herpes simplex virus (HSV).
Eligible womenwere randomizedtoeither oral acyclovir 400mg 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 signicant 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
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
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
genital herpes. The womans history of infection was conrmed 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 in
cesarean 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
conrmedby documentationof seropositivity for HSV-2antibody
or a previous genital culture positive for HSV-2. Women with a
rst episode were specically 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.
Shefeld 2006
This RCT included 350 gravid women with either initial or re-
current genital herpes. The womans history of infection was con-
rmed by documentation of seropositivity along with genital cul-
(Review)
tures. Eligible women were randomized to either oral valacyclovir
500 mg or an identical placebo twice daily beginning at 36 weeks
gestation. The primary outcome was reduction in cesarean deliv-
ery for HSV recurrence. Other assessed outcomes are listed in the
table. Neonates were evaluated for vertical transmissionusing both
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;
Shefeld 2006; Watts 2003) and was not used in one trial (Braig
2001). The generation of the random allocation sequence was ad-
equate in ve studies (Andrews 2006; Scott 1996; Scott 2002;
Shefeld 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 in four trials (Andrews 2006; Brocklehurst 1998; Scott 1996;
Scott 2002) and rated adequate intwo trials (Shefeld 2006; Watts
2003). The loss to follow up was zero or negligible in ve studies
(Andrews 2006; Braig 2001; Brocklehurst 1998; Shefeld 2006;
Watts 2003). The loss to follow up was 10% in one trial (Scott
1996) and 18% in another (Scott 2002). In both cases the loss was
non-differential and infant outcomes were available in the second
trial.
Effects of interventions
Seven randomized controlled trials (1249 participants) which met
our inclusion criteria compared acyclovir to placebo or no treat-
ment (ve 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 symptomatic
neonatal 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
groups and one in a placebo group. All infants were asymptomatic.
Maternal outcomes
Women who received antiviral prophylaxis were signicantly less
likely to have a recurrence of genital herpes at delivery (relative
risk (RR) 0.28, 95% CI 0.18 to 0.43, I
2
= 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 until
delivery to prevent a recurrence at delivery would be 10.
Women who received antiviral prophylaxis were also signicantly
less likely to have a cesarean delivery for genital herpes (RR 0.30,
95% CI 0.20 to 0.45, I
2
= 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 cesareandelivery for herpes would
be 10.
Detectionof HSVat delivery was assessed inve studies. Results of
PCR and culture were combined for the purposes of this analysis.
Women who received antiviral prophylaxis were signicantly less
likely to have HSV detected at delivery (RR 0.14, 95% CI 0.05
to 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 specically 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 side effects were evaluatedby twostudies. These included
oligohydramnios (Andrews 2006), renal function (Andrews 2006;
Shefeld 2006), serum chemistries (Andrews 2006; Shefeld
2006), and neutropenia (Andrews 2006; Shefeld 2006). The
mean aspartate aminotransferase (a liver enzyme) was signicantly
increased in the placebo-exposed infants in one trial (Shefeld
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; Shefeld 2006). No infants in
either treatment or placebo group had white blood cell counts less
than 4000/mm
3
. There were no signicant differences in other
neonatal outcomes.
D I S C U S S I O N
We found insufcient 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
(Review)
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 signicantly 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 identied. 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 nd evidence that prophylactic
antivirals given to pregnant women reduced the frequency of de-
tectable HSV.
Antiviral prophylaxis was associated with a signicant reduction in
recurrence 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 signicant reduction
in cesarean delivery for genital HSV. These ndings are similar to
a previous meta-analysis, which included only trials involving the
use of acyclovir (Shefeld 2003) and showed signicant 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 HSVto 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 signicantly reducing the detec-
tion of virus at delivery (Shefeld 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 signicant 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 justies 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 insufcient
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, benets, 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 signicantly 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 benets
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 clarication.
As part of the pre-publicationeditorial process, this reviewhas been
commentedonby twopeers (aneditor, anda referee whois external
to the editorial team), one or more members of the Pregnancy
and Childbirth Groups international panel of consumers and the
Groups Statistical Adviser.
(Review)
R E F E R E N C E S
References to studies included in this review
Andrews 2006 {published data only}
Andrews W, Kimberlin D, Whitley R, Cliver S, Deeter R.
Valaciclovir suppressive therapy in pregnant women reduces
recurrent genital herpes (hsv): results of a randomized trial
[abstract]. American Journal of Obstetrics and Gynecology
2002;187(6 Pt 2):S73.
Andrews WW, Kimberlin DF, Whitley R, Cliver S,

Ramsey PS, Deeter R. Valacyclovir therapy to reduce
recurrent genital herpes in pregnant women. American
Journal of Obstetrics and Gynecology 2006;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
recurrent genital herpes and viral shedding. European
Journal of Obstetrics & Gynecology and Reproductive Biology
2001;96:558.
Brocklehurst 1998 {published data only}
Brocklehurst P, Kinghorn G, Carney O, Helsen K,

Ross E, Ellis E, et al.A randomised placebo controlled
trial of suppressive acyclovir in late pregnancy in women
with recurrent genital herpes infection. British Journal of
Obstetrics and Gynaecology 1998;105:27580.
Mindel A. Trial to evaluate efcacy and safety of a
prophylactic course of orally administered acyclovir
vs placebo to prevent viral shedding, herpes lesion
development and subsequent need for Caesarean section in
pregnant women with genital herpes infection. Personal
communication 1991.
Scott 1996 {published data only}
Scott LL, Sanchez PJ, Jackson GL, Zeray F, Wendel GD Jr.
Acyclovir suppression to prevent cesarean delivery after rst-
episode genital herpes. Obstetrics & Gynecology 1996;87(1):
6973.
Scott LL, Hollier LM, Baum A, Jackson G, Sanchez PJ,
Wendel GDJr. Prevention of recurrent genital herpes at
delivery using acyclovir suppression for herpes infection
diagnosed prior to pregnancy - an interim analysis. American
Journal of Obstetrics and Gynecology 1998;178(1 Pt 2):S213.
Scott LL, Hollier LM, McIntire D, Sanchez PJ, Jackson

GL, Wendel GD Jr. Acyclovir suppression to prevent
recurrent genital herpes at delivery. Infectious Diseases in
Obstetrics and Gynecology 2002;10(2):717.
Shefeld 2006 {published data only}
Shefeld JS, Hill J, Laibl V, Hollier LM, Sanchez P, Wendel
GD. Valacyclovir suppression to prevent recurrent herpes at
delivery: a randomized controlled trial [abstract]. Obstetrics
& Gynecology 2005;105(4 Suppl):5S.
Shefeld JS, Hill JB, Hollier LM, Laibl VR, Roberts

SW, Sanchez PJ, et al.Valacyclovir prophylaxis to prevent
recurrent herpes at delivery: a randomized clinical trial.
Obstetrics & Gynecology 2006;108(1):1417.
Watts 2003 {published data only}
Watts DH, Brown ZA, Money D, Selke S, Aura J, Remple
V, et al.A double-blind randomized, placebo-controlled trial
of acyclovir in late pregnancy for reduction of herpes simplex
virus (HSV) shedding and cesarean section [abstract].
Infectious Diseases in Obstetrics & Gynecology 2001;9(3):
1656.
Watts DH, Brown ZA, Money D, Selke S, Huang ML,

Sacks SL, et al.A double-blind, randomized, placebo-
controlled trial of acyclovir in late pregnancy for the
reduction of herpes simplex virus shedding and cesarean
delivery. American Journal of Obstetrics and Gynecology
2003;188:83643.
References to studies excluded from this review
Kimberlin 1998 {published data only}
Kimberlin DF, Weller S, Andrews WW, Hauth JC, Whitley
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 Gynecology 1998;179(4):84651.
Scott LL, Hollier LM, Jackson G, Sanchez PJ, Baum A,
Wendel GD. Acyclovir suppression to prevent cesarean
delivery after rst episode genital simplex infection.
American Journal of Obstetrics and Gynecology 1998;178(1
Pt 2):12.
Stray-Pedersen 1990 {published data only}
Stray-Pedersen B. Acyclovir in late pregnancy to prevent
neonatal herpes simplex [letter]. Lancet 1990;336(8717):
756.
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Corey L, Handseld HH. Genital herpes and public health:
addressing a global problem. JAMA 2000;283(6):7914.
Corey 2004
Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, et
al.Once-daily valacyclovir to reduce the risk of transmission
of genital herpes. New England Journal of Medicine 2004;
350:1120.
(Review)
Cowan 2004
Cowan FM, French RS, Mayaud P, Gopal R, Robinson
NJ, de Oliveira SA, et al.Seroepidemiological study of
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Elion GB. Acyclovir: discovery, mechanism of action, and
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Handseld HH, Stone KM, Wasserheit JN. Prevention
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Embree JE, et al.Neonatal herpes siimplex virus infections
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Larsson 1986
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Mertz 1997
Mertz GJ, Loveless MO, Levin MJ, Kraus SJ, Fowler
SL, Goade D, et al.Oral famciclovir for suppression of
recurrent genital herpes simplex virus infection in women.
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Reitano 1998
Reitano M, Tyring S, Lang W, Thoming C, Worm AM,
Borelli S, et al.Valaciclovir for the suppression of recurrent
genital herpes simplex virus infection: a large-scale dose
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Smith JR, Cowan FM, Munday P. The management of
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Stone KM, Reiff-Eldridge R, White AD, Cordero JF, Brown
Z, Alexander ER, et al.Pregnancy outcomes following
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1999. Birth Defects Research. Part A, Clinical and Molecular
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Tookey P, Peckham CS. Neonatal herpes simplex virus
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Whitley RJ, Corey L, Arvin A, Lakeman FD, Sumaya CV,
Wright PF, et al.Changing presentation of herpes simplex
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neonatal herpes simplex virus infections in a managed-
care population. Sexually Transmitted Diseases 2007;34(9):
7048.
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Wutzler P, Doerr HW, Farber I, Eichhorn U, Helbig B,
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Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK,
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296:96473.
Indicates the major publication for the study

(Review)
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, neonatal
HSV positive, symptomatic neonatal HSV
Notes
Risk of bias
Item Authors judgement Description
Allocation concealment? Yes A - Adequate
Braig 2001
Methods Randomized controlled clinical 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
Allocation concealment? Unclear D - Not used
Brocklehurst 1998
Participants Gravid women with documented recurrent genital herpes infection
Interventions Acyclovir 200 mg po 4 times daily vs placebo from 36 weeks gestation
(Review)
Brocklehurst 1998 (Continued)
Outcomes Clinical recurrence at time of labor, cesarean delivery for HSV, infants with neonatal herpes
Notes
Risk of bias
Scott 1996
Participants Gravid women with rst 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
Scott 2002
Participants Gravid women with recurrent genital HSV-2 infection.
Outcomes Clinical HSV recurrence at delivery, cesarean delivery for HSV, HSV culture at delivery, neonatal HSV
cultures
Notes
Risk of bias
(Review)
Scott 2002 (Continued)
Shefeld 2006
Participants Gravid women with documented recurrent genital HSV-2 infection conrmed 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
Watts 2003
Participants Gravid women with documented recurrent genital HSV-2 infection conrmed with serology or culture
Outcomes HSV outbreak at delivery, HSV culture and PCR at delivery, cesarean delivery for herpes, neonatal herpes
Notes
Risk of bias
BID: dosing twice daily
HSV: herpes simplex virus
PCR: polymerase chain reaction
po: oral dosing
TID: three times a day
vs: versus
(Review)
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
(Review)
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 title
No. 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]
4 Genital herpes simplex virus
detection at delivery
5 887 Risk Ratio (M-H, Fixed, 95% CI) 0.14 [0.05, 0.39]
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 ]
Shefeld 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: Chi
2
= 0.0, df = 0 (P<0.00001); I
2
=0.0%
Test for overall effect: Z = 0.0 (P < 0.00001)
0.01 0.1 1 10 100
Favors treatment Favors control
(Review)
Analysis 1.2. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 2 Genital herpes
simplex virus recurrence at delivery.
Outcome: 2 Genital herpes simplex virus recurrence at delivery
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
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 ]
Heterogeneity: Chi
2
= 4.76, df = 4 (P = 0.31); I
2
=16%
2 Valacyclovir
Andrews 2006 3/57 8/55 9.0 % 0.36 [ 0.10, 1.29 ]
Shefeld 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 ]
Heterogeneity: Chi
2
= 0.01, df = 1 (P = 0.90); I
2
=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 ]
Heterogeneity: Chi
2
= 4.59, df = 6 (P = 0.60); I
2
=0.0%
0.001 0.01 0.1 1 10 100 1000
(Review)
Analysis 1.3. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 3 Cesarean delivery.
Outcome: 3 Cesarean delivery
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 ]
Heterogeneity: Chi
2
= 8.69, df = 4 (P = 0.07); I
2
=54%
2 Valacyclovir
Andrews 2006 3/57 7/55 8.2 % 0.41 [ 0.11, 1.52 ]
Shefeld 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 ]
Heterogeneity: Chi
2
= 0.08, df = 1 (P = 0.77); I
2
=0.0%
Total (95% CI) 651 598 100.0 % 0.30 [ 0.20, 0.45 ]
Heterogeneity: Chi
2
= 8.25, df = 6 (P = 0.22); I
2
=27%
0.001 0.01 0.1 1 10 100 1000
(Review)
Analysis 1.4. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 4 Genital herpes
simplex virus detection at delivery.
Outcome: 4 Genital herpes simplex virus detection at delivery
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 ]
Heterogeneity: Chi
2
= 0.96, df = 3 (P = 0.81); I
2
=0.0%
2 Valacyclovir
Shefeld 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 ]
Heterogeneity: not applicable
Total (95% CI) 457 430 100.0 % 0.14 [ 0.05, 0.39 ]
Heterogeneity: Chi
2
= 1.14, df = 4 (P = 0.89); I
2
=0.0%
0.001 0.01 0.1 1 10 100 1000
(Review)
Analysis 1.5. Comparison 1 Antenatal antiviral prophylaxis versus placebo, Outcome 5 Neonatal viral
detection.
Outcome: 5 Neonatal viral detection
Study or subgroup Treatment Control Risk Ratio Risk Ratio
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 ]
Shefeld 2006 0/170 0/168 0.0 [ 0.0, 0.0 ]
Total (95% CI) 370 367 1.63 [ 0.22, 12.13 ]
Heterogeneity: Chi
2
= 0.28, df = 1 (P = 0.60); I
2
=0.0%
0.01 0.1 1 10 100
W H A T S N E W
Last 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 rst published: Issue 4, 2004
Review rst published: Issue 1, 2008
Date Event Description
15 October 2007 New citation required and conclusions have changed Substantive amendment
(Review)
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 rst 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
(Review)

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Third trimester antiviral prophylaxis for preventing maternal

genital herpes simplex virus (HSV) recurrences and neonatal

Andrews WW, Kimberlin DF, Whitley R, Cliver S,

Brocklehurst P, Kinghorn G, Carney O, Helsen K,

Scott LL, Hollier LM, McIntire D, Sanchez PJ, Jackson

Shefeld JS, Hill JB, Hollier LM, Laibl VR, Roberts

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

Kimberlin DF, Weller S, Whitley RJ, Andrews WW,

Indicates the major publication for the study

therapeutic use]; Herpes Genitalis [drug therapy;

prevention &control]; Pregnancy Complications,

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