- Email: [email protected]
Genital herpes and pregnancy — preventive measures
.““o*..”
European Journal of Obstetrics & Gynecology and Reproductive Biology 53 (1994) 33-38
Genital
herpes and pregnancy
Henri Blanchier”,
-
preventive
Jean-Marie Huraux* b, Christiane Annick Sainte-Croix le Baleurc
,S”
I
.
.
OBSTETR & .Ie.De. ..DGYNEC “.,.~_“=.,“.
measures
Huraux-Rendu”,
UService de Gyntkologie-ObstPtrique, Centre Hospital& Intercommunal de CrPteil, 40 avenue de Verdun, 94010 CrPreil Cedex. France hI_aboratoire de Virologie du CERVI, H6pital PitiP-Salphtrikre, 83 boulevard de I’Hpiral, 75651 Paris Cedex 13. France ‘DPparrement de Pharmacovigilance. Laboratoires Wellcome-France, 20 rue Rouget de Lisle. 92442 Issy-Les-Moulineaux Cedex, France (Accepted
8 October
1993)
Abstract Genital herpes is particularly dangerous during pregnancy because of the risk of neonatal infection. This is discussed in four situations of genital herpes associated with pregnancy. Choosing the most appropriate method of delivery, i.e. carrying the least risk of transmission from mother to baby, is based on our knowledge of the natural history of genital herpes infection, the risk to the newborn (estimated from epidemiological studies), and, lastly, the possible preventive measures available. Key words: Genital
herpes; Pregnancy;
Caesarean
section;
Acyclovir
1. Introduction Genital herpes is most problematic during pregnancy, as it carries a risk of neonatal infection. Neonatal herpes can be devastating, and is almost always symptomatic. The manifestations are rarely limited to the skin and buccal or ocular mucosa. The disease takes on two major forms: (i) generalized herpes, with cutaneous, hepatic, encephalic, adrenal, pulmonary and vascular involvement (DIVC); and (ii) localized central nervous The system disease presenting as encephalitis. predominance of these two forms accounts for the high mortality rate associated with neonatal herpes (> 50%) and the fact that more than half the survivors have serious neuropsychological sequelae. The lesions most suggestive of neonatal herpes - skin vesicles - are not always present, and can progress unpredictably to disseminate infection or localized central nervous system disease.
* Corresponding
author.
0028-2243/94/$07,00 SSDI 0028-2243(93)0
0 1994 Elsevier Science Ireland I7 12-3
Neonatal herpes is fortunately rare (between 1 and 5 cases/l0 000 pregnancies). This is somewhat surprising given that it is almost always due to maternal genital herpes, a benign condition affecting around 10% of women of child-bearing age in societies in which sexual activity begins at an early age and involves multiple partners. The strongest argument supporting the maternal origin of neonatal herpes is that the ratio of HSV-1 to HSV-2 is the same as that for genital herpes in similar environments (approximately 1:4). HSV-2 is therefore predominant, and it is difficult to imagine how neonates could acquire the infection other than during passage through the birth canal. There are two main problems in the prevention of neonatal herpes. First, it is difficult to identify those women with the highest risk of transmitting the infection to their infants and, second, preventive measures currently available carry a number of drawbacks. With regards to the risk of perinatal transmission there is something of a paradox: the most dangerous situation for the infant is when the mother acquires the primary
Ltd. All rights reserved
H. Blanchier et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 33-38
34
infection at the end of pregnancy, but this is rarely the case; in contrast, in two-thirds of cases in which the neonate acquires the infection from its mother, the maternal genital herpes was unidentified. In other words, neonatal herpes reveals the maternal genital infection in two out of three cases. Preventive measures include sex education, disinfection of the birth canal prior to delivery, caesarean delivery and treatment with acyclovir (ACV). All these measures come up against various problems, and recommendations for prevention have changed with time [l]. The influence of sex education on the spread of sexually transmitted diseases has been disappointing, regardless of the context. The fear of AIDS and the campaigns promoting condom use, however, have a positive impact. Caesarean section is used to avoid contamination during passage through the birth canal but, like all operations, carries a certain degree of maternal morbidity and failure. Antiviral therapy, even with a poorly toxic product such as ACV [2], could in no way be prescribed to 10% of pregnant women (and their unborn infants), for the reason given in Table 1 [3]. Routine culture for HSV-2 from the 32nd week of pregnancy in women with a history of genital herpes was recommended by Nahmias et al. [4] to identify those likely to benefit from caesarean section. However, it emerged that the results of such tests were not predictive of the presence of HSV-2 in the birth canal on the day of delivery, regardless of when they were performed [5], and Nahmias et al. recommended that virological monitoring should be concentrated around the immediate prepartum period [4]. In France, a multidisciplinary working party set up the Groupe d’Etudes et de Recherthe sur l’Herp&s (GERH). In 1987 recommendations were forwaded which distinguished between four different situations, from primary genital infection prior to delivery, to the situation in which the woman and her partner have no known history of genital herpes [6].
Table 1 Objections
to the use of ACV during
pregnancy
f
Theoretical short-term risk of fetal toxicity to concentration in the amniotic fluid
+
Theoretical long-term risk of mutagenesis, despite negative results in most tests? Reduced immune response to the virus? Risk of viral shedding on withdrawal of treatment
+ ++ +++
(rebound effect) Lack of comparative caesarean section
efficacy
(renal) due
data on oral ACV versus
The only clear (mandatory) indication for intravenous ACV at all stages of pregnancy is a severe primary infection carrying a risk of dissemination or hepatitis in the mother
Since that time, the situation has developed with, in particular, indications on the significance of anti-HSV antibodies for the protection of the infants, and the possibility of detecting HSV shedding in the birth canal, not only by viral culture but also by means of polymerase chain reaction (PCR)-based methods. The aim of this paper is to provide an update on neonatal herpes and to indicate the measures that should be taken by the practitioner confronted with a pregnant woman with genital herpes. 2. Recommendations
of the GERH
The recommendationns of the GERH to pregnant women with genital herpes are based on an analysis of the literature by a group of obstetricians, pediatricians, virologists and pharmacotoxicologists, as well as discussions with American colleagues concerned with the prevention of neonatal herpes, particularly Andre Nahmias, Anne Yeager, and Richard Whitley. The GERH measures:
recommends
the
following
basic
Virological confirmation of herpes-like genital lesions during at least one outbreak in all women planning to become pregnant, as well as in their partners, preferably by means of viral cultures which is still the reference technique; serological tests should not be used for diagnostic purposes (Table. 2). (ii) A search for a past history of genital herpes in all pregnant women and their partners. (iii) As recommended by the American College of Obstetricians and Gynecologists [7], weekly viral culture should no longer be used to detect asymptomatic viral shedding towards the end of pregnancy in women with a history of genital herpes, as the result available at the time of delivery is no longer valid. (iv) A thorough clinical examination of the birth canal and the perineal-vulvar region should be carried out at the beginning of labor to detect likely herpetic lesions of which the patient is unaware.
6)
These recommendations distinguish between four highly different situations with regard to likely risk of neonatal herpes and call for four different sets of preventive measures; fortunately, the most dangerous situations are also the least common (Table 3). 2.1. Situation I The situation carrying the highest risk is that in which the woman contracts genital herpes in the prepartum period (which, for maximum safety, can be extended to the month before delivery, given the persistant viral
35
H. Blanchier et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 33-38
Table 2 Laboratory Indicated
diagnosis
of HSV infection
for all serious
forms of herpes and
for genital herpes
++ Best to detect the virus . ++ Viral culture: the gold standard Fragile virus, but effective transport media Rapid cytopathogenic effect (CPE) in various cultures, I-4 days Only test suitable for asymptomatic shedding . Rapid diagnosis: cytodiagnosis by immunofluorescence, ELISA Only valid for new lesions l HSV-UHSV-2 typing by immunofluorescence (molecular epidemiology .
by restriction
mapping)
PCR: under evaluation
‘Serodiagnosis’ of little, if any, use l Primary infection: two sera at 2-3 weeks interval . Recurrences do not cause seroconversion . Encephalitis: intrathecal antibody synthesis is late and inconsistent . Limited value for differential diagnosis of primary and non-primary retrospective diagnosis of neonatal herpes
shedding in this setting). It is now known that the neonate risk varies according to whether the genital infection is genuinely primary, or rather initial but not primary [8]. By definition, primary infection results from the first encounter, during sexual intercourse, with HEX-1 or HSV-2, in a person having escaped the primary oral HSV-1 infection generally acquired during childhood. Initial, non-primary, genital herpes is less symptomatic and less dangerous for the infant. It results from a primary sexual contact with HSV-2 in a woman having
Table 3 Manifestations
of maternal
genital
herpes and their relationship
initial genital
infection
and for
previously acquired oral HSV-1 infection who is thus partially protected 191. The distinction between the two forms of initial genital herpes is often unclear, since oral herpes is asymptomatic in nine cases out of ten; in addition, the obstetricians may not have access to the results of serological tests which can, when anti-HSV antibodies are present during the acute phase, show that the patient has an initial, non-primary, genital infection. In practice, caesarean section is mandatory in both types of initial herpes virus infection in the prepartum period. If possible, it should be carried out before the
with neonatal
herpes: four situations
and proposed
measures
Frequency among mothers of infected neonates
Risk of neonatal herpes
Recommendations
I Primary infection prepartum (month preceeding delivery)
Rare
++++ approx.
Caesarean Acyclovir?
section
II Recurrence prepartum preceding delivery)
+
++ 2-s%
Caesarean
section
++
f l/l000
HSV culture at term Vaginal delivery after Betadine@
+++ 2/3 of cases of neonatal herpes
f l/IO 000
No action other than prevention of STD
Maternal
situation
III Only history of genital (mother or partner) IV No manifestations genital herpes
of
(days
herpes
15%
A small proportion (0.1-l%) of pregnant women with no known risk factors have detectable asymptomatic genital HSV shedding. Two-thirds of cases of neonatal herpes escape all foms of protection. Very occasionally, infants can be contaminated by a maternal herpetic gingivostomatitis, labial herpes in a family member, or during outbreaks in nursery.
H. Blanchier et al. /Eur. J. Obstet. Gynecol. Reprod.
36
rupture of the membranes. Failures in this setting, estimated at about IO%, have more serious consequences, particularly when there are clinical signs of primary initial infection, e.g. severe lesions, swollen lymph nodes and fever. Although it is difficult to make firm recommendations in the latter situation, it is often decided to administer ACV to the mother prior to delivery, as well as to the newborn infant. The fact that this situation is rare makes it difficult to evaluate the efficacy of such dual treatment in controlled trials. At all times, intravenous administration of ACV is essential for infants delivered of mothers who acquire primary genital herpes in the prepartum period and when caesarean section is not possible or is carried out too late (i.e. 4-6 h after the rupture of the membranes, although this time is somewhat arbitrary). Another situation in which it is difficult to make firm recommendations is the acquisition of initial genital herpes at the beginning of the third trimester and premature breaking of the membranes, given the risk of prematurity on one hand and that of neonatal herpes on the other hand. Finally, intravenous administration of ACV is mandatory when the clinical manifestations of initial genital herpes appear to be life-threatening for the mother because of HSV hepatitis [3,8].
Table 5 Sampling
of suspect lesions for isolation
Biol. 53 (1994) 33-38
of HSV
Fresh lesions before application of topical agents Forceful swabbing (causing slight pain) of the ‘active’ zone, i.e. the edges of the floor of the vesicles or ulceration Vigorous shaking of the swab in transport medium Immediate transfer to laboratory, at 0°C if possible; otherwise, can be kept for less than 1 day at +4”C without freezing (prolonged storage possible at -8O’C)
herpes during the immediate prepartum period, given the lack of large-scale comparative trials in this setting. Nevertheless, such trials are badly needed since most of the potential risks of ACV in pregnant women do not apply to treatments started in the last few days of pregnancy and are probably well balanced by the inherent risk of surgery. In the study by Prober et al., none of the 34 children delivered vaginally of mothers with an outbreak of genital herpes developed neonatal herpes, even though chemotherapy was not used [lo].
2.2. Situation II A more frequent situation is that in which recurrent genital herpes occurs during the week preceding delivery. The risk of neonatal herpes is reduced by the less serious nature of the lesions, lesser viral shedding and the pre-existing immune response in the future mother. The risk is between 2% and < 5%, a figure sufficiently high to warrant caesarean delivery, but not treatment with ACV. Even when delivery is inadvertently vaginal, clinical and virological surveillance of the infant is generally adequate, particularly if the birth canal has been disinfected with Betadine@, as recommended in such cases. Additive risk factors (Table 4) can warrant ACV treatment of the infant, as in Situation I. It would be unreasonable to substitute ACV for caesarean delivery in women with a recurrence of genital
2.3. Situation ZZI The situation most frequently faced by obstetricians is that in which the mother or her partner has a history of recurrent genital herpes. It is highly recommended in such cases to obtain virological confirmation by culture during an outbreak (Table 5). In the absence of visible lesions or predictive signs of an outbreak at the time of delivery, the risk of neonatal herpes is about l/1000 and in no way warrants caesarean section or treatment with ACV. The only measures recommended in this situation are tests for HSV in the genital secretions by means of viral cultures (Table 6) and disinfection of the birth canal with Betadine. The use of fetal scalp electrodes should be avoided as far as possible, as this can create a portal of entry to the virus. It is recommended to start local ocular antiviral treatment in the infant (using an ACV-based ointment, for example), to apply foaming Betadine (which should immediately be rinsed off) and to carry out viral cultures of conjunctival and oropharyngeal swabs between 24 and 36 h after delivery.
Table 4 Additional
Table 6 Sampling secretions
risk factors
Prematurity Prolonged breaking
for neonatal
of amniotic
herpes
Use of scalp electrodes Major cervico-vaginal herpetic lesions Cervico-vaginal sampling: massive effect (1 day) Low maternal
titer of anti-HSV
Internal Cervix:
membranes
and
antibodies.
rapid
cytopathogenic
for asymptomatic HSV shedding - swabbing at two sites and external
surfaces
in the maternal
of the labia minor
genital
and the cervix
first eliminate cervical mucus using a swab introduce a second swab I cm into the cervical canal, rotate and shake vigorously in transport medium with a third swab, sample the surface of the cervix and shake vigorously in same tube of transport medium
37
H. Blanchier et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 33-38
2.4. Situation IV The risk of neonatal herpes is lower (l/10 000) when neither the woman nor her partner has any history of genital herpes. None the less, this situation accounts for two-thirds of cases of neonatal herpes. In the absence of direct data, it is impossible to tell whether such cases are due to asymptomatic primary infection or to asymptomatic recurrences in the prepartum period but, according to serological surveys of the prevalence of anti-HSV-2 antibodies, about two-thirds of primary genital infections do not produce clinical manifestations [ 111. The only measures recommended for these women are common-sense precautions aimed at avoiding sexuallytransmitted diseases towards the end of pregnancy. This not only means ruling out sex with other partners (for both the woman and the man), but also the use of condoms during the last 2 months of pregnancy, even by stable couples. Indeed, a recent seroprevalence study of HSV-2 showed the existence of couples in which only one partner had encountered the virus, even after a mean of 7 years of sexual intercourse; in 9.5% of the 190 couples studied, the woman was seronegative and the man seropositive [ 121. 3. Future perspectives Other possibilities have been opened up by the advent of new techniques. Viral culture techniques can only provide results after l-5 days, but more rapid tests capable of detecting asymptomatic genital HSV shedding at the beginning of labor would enable the obstetrician to choose the type of delivery and whether or not to treat the infant. In theory, this is now possible by the use of enzyme-linked immunosorbent assays (ELISA) for soluble viral antigens, and PCR for viral DNA. 3.1. Detection of asymptomatic HSV shedding On the basis of published epidemiological data, Libmann et al. calculated the gains, in term of avoidance of neonatal herpes and unnecessary caesarean sections, likely to be achieved by several strategies combining various measures, including the detection of HSV in the genital secretions at the time of labor by means of a rapid ELISA test [ 131. The most cost-effective strategy was apparently that in which HSV-2-seronegative women with asymptomatic primary infections are identified by tests for HSV antigen, with a view to caesarean section. Unfortunately, this is a difficult approach in practice because the ELISA test, which has a sensitivity and specificity close to that of viral culture for the confirmation of herpetic lesion, has not been validated for the detection of asymptomatic HSV shedding which, in principle, is associated with a lower viral density [14]. The second most cost-effective strategy is the classical approach
based on clinical examination during labor, and the use of caesarean section if suspect lesions are detected. 3.2. Specijk serological tests for anti-HSV-2 gpG antibodies Kulhanjian et al. [ 121 recommended identifying highrisk women unaware of their status, i.e. those with a primary infection or a recurrence, by means of serological tests. They suggested that all pregnant women and their partners should undergo an ELISA test for antibodies directed against HSV-2 glycoprotein G (gpG), particularly to detect HSV-Zseronegative women with seropositive partners. Again, the feasibility of this approach is questionable, as the test was home-made, and required confirmation by Western blot; the authors pointed out the inability of commercial tests to differentiate adequately between anti-HSV- 1 and anti-HSV-2 antibodies. 3.3. HSV PCR One promising approach is the detection of HSV in genital secretions in late pregnancy, or even during labor, by means of PCR amplification of a genomic region common to HSV-1 and HSV-2. In a preliminary study, Hardy et al. [I 51 found that PCR had a sensitivity similar to that of viral culture, both for suspect lesions (12 cases) and for the detection of asymptomatic shedding in the genital secretions (12 cases). Unfortunately, routine application of this approach is still some way off, for several reasons:
(9 (ii) (iii)
(iv)
(v)
PCR requires a high degree of technical expertise given its complexity and the risk of contamination; automation of PCR is not likely to be successful in the foreseeable future; in the above study, the genital secretions were first concentrated by means of microdialysis prior to the detection of asymptomatic virus shedding; similarly, frequent confirmation of the specificity of the PCR product by means of molecular hybridization was necessary; and to be of real use in obstetric decision-taking, the test would have to be available 24 h/day.
4. Conclusions In routine practice, the management of the risk of neonatal HSV infection is still based on a good knowledge of both partners’ medical history, and thorough clinical examination of the birth canal prior to delivery. New tests available in some centers will no doubt contribute to our understanding of the natural history of maternofetal transmission, particularly in women with no identified risk factors, but well-designed controlled trials will be necessary. Information is lacking in a number of essential areas:
H. Blanchier et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 33-38
38
The influence of ACV on the rate of viral replication in the birth canal during asymptomatic recurrences and asymptomatic primary infections. (ii) The local immune response in the genital mucosa and its influence on the transmission of the virus from the mother to her infant, both spontaneously and during treatment with ACV. (iii) The fetoprotective efficacy of the various classes of HSV-specific circulating immunoglobulins. (iv) Widespread use of ACV for the prevention of maternofetal contamination appears to be unwarranted at the present time. In contrast, the administration of inactivated vaccines or antibody preparations might be beneficial, but this requires a knowledge of the immunoprotective components. (i)
Finally, to return to routine practice, Gibbs [16] pointed out that the proportion (32%) of pregnant women seropositive for HSV-2 in the study by Kulhanjian et al. [12] illustrated the almost total failure of health education in this area, and called for urgent measures. 5. Acknowledgements
3 4
5
6
I
8
9
IO
II
I2
We are grateful to MS Marie-Christine Papuchon and Sylvie Past01 for preparing the manuscript and to MS Francoise Seltene for conducting literature searches.
I3
I4
6. References Prober CG, Corey L, Brown ZA nancies complicated by genital virus. Clin Infect Dis 1992; 15: Andrews EB, Yankaskas BC,
et al. The management of prcginfections with herpes simplex 1031-1038. Corder0 JF et al., and the
Acyclovir in Pregnancy Registry Advisory Committee. Acyclovir in pregnancy registry: six years’ experience. Obstet Gynecol 1992; 79: 7-13.
15
I6
Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990; 33: 276-289. Nahmias AJ, Keyserling HL, Whitley R. Changing patterns of neonatal herpes - as affected by antiviral therapy and other factors. In: Kono R, ed. Herpes viruses and virus chemotherapy. Elsevier, 1985; 145-147. Arvin AM, Hensleigh PA, Prober CG et al. Failure of anteparturn maternal cultures to predict the infant’s risk of exposure to herpes simplex at delivery. N Engl J Med 1986; 315: 796-800. Blanchier H, Sainte Croix le Baleur A, Huraux-Rendu C et al. L’herpts chez la femme enceinte et le nouveau-&. J Gynecol Obstet Biol Reprod 1987; I6 (Suppl I): l-28. American College of Obstetricians and Gynecologists (ACOG) Technical Bulletin. Perinatal herpes simplex virus infections. November 1988; No. 122. Brown ZA, Vontver LA, Benedetti J et al. Effects on infants of a first episode of genital herpes during pregnancy. N Engl J Med 1987; 317: 1246-1251. Boucher FD, Yasukawa LL, Bronzan RN et al. A prospective evaluation of primary genital herpes simplex virus type 2 infections acquired during pregnancy. Pediatr Infect Dis J 1990; 9: 499-504. Prober CG, Sullender WM, Yakusawa LL et al. Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of vaginal delivery to mothers with recurrent genital herpes simplex virus infections. N Engl J Med 1987; 316: 240-244. Frenkel LM, Garatty EM, Shen JP et al. Clinical reactivation of herpes simplex virus type 2 infection in seropositive pregnant women with no history of genital herpes. Ann Intern Med 1993; 118: 414-418. Kulhanjian JA, Soroush V, Au DS et al. Identification of women at unsuspected risk of primary infection with herpes simplex virus type 2 during pregnancy. N Engl J Med 1992; 326: 916-920. Libmann MD, Dascal A, Kramer MS et al. Strategies for the prevention of neonatal infection with herpes simplex virus: a decision analysis. Rev Infect Dis 1991; 13: 1093-I 104. Dascal A, Chan-Thim J, Morahan M et al. Diagnosis of herpes simplex virus infection in a clinical setting by a direct antigen detection enzyme immunoassay kit. J Clin Microbial 1989; 27: 700-704. Hardy DA, Arvin AM, Yakusawa LL et al. Use of polymerase chain reaction for successful1 identification of asymptomatic genital infection with herpes simplex virus in pregnant women at delivery. J Infect Dis 1900; 162: 1031-1035. Gibbs RS, Mead PB. Prevention of neonatal herpes - current strategies. N Engl J Med 1992; 326: 946-947.
European Journal of Obstetrics & Gynecology and Reproductive Biology 53 (1994) 33-38
Genital
herpes and pregnancy
Henri Blanchier”,
-
preventive
Jean-Marie Huraux* b, Christiane Annick Sainte-Croix le Baleurc
,S”
I
.
.
OBSTETR & .Ie.De. ..DGYNEC “.,.~_“=.,“.
measures
Huraux-Rendu”,
UService de Gyntkologie-ObstPtrique, Centre Hospital& Intercommunal de CrPteil, 40 avenue de Verdun, 94010 CrPreil Cedex. France hI_aboratoire de Virologie du CERVI, H6pital PitiP-Salphtrikre, 83 boulevard de I’Hpiral, 75651 Paris Cedex 13. France ‘DPparrement de Pharmacovigilance. Laboratoires Wellcome-France, 20 rue Rouget de Lisle. 92442 Issy-Les-Moulineaux Cedex, France (Accepted
8 October
1993)
Abstract Genital herpes is particularly dangerous during pregnancy because of the risk of neonatal infection. This is discussed in four situations of genital herpes associated with pregnancy. Choosing the most appropriate method of delivery, i.e. carrying the least risk of transmission from mother to baby, is based on our knowledge of the natural history of genital herpes infection, the risk to the newborn (estimated from epidemiological studies), and, lastly, the possible preventive measures available. Key words: Genital
herpes; Pregnancy;
Caesarean
section;
Acyclovir
1. Introduction Genital herpes is most problematic during pregnancy, as it carries a risk of neonatal infection. Neonatal herpes can be devastating, and is almost always symptomatic. The manifestations are rarely limited to the skin and buccal or ocular mucosa. The disease takes on two major forms: (i) generalized herpes, with cutaneous, hepatic, encephalic, adrenal, pulmonary and vascular involvement (DIVC); and (ii) localized central nervous The system disease presenting as encephalitis. predominance of these two forms accounts for the high mortality rate associated with neonatal herpes (> 50%) and the fact that more than half the survivors have serious neuropsychological sequelae. The lesions most suggestive of neonatal herpes - skin vesicles - are not always present, and can progress unpredictably to disseminate infection or localized central nervous system disease.
* Corresponding
author.
0028-2243/94/$07,00 SSDI 0028-2243(93)0
0 1994 Elsevier Science Ireland I7 12-3
Neonatal herpes is fortunately rare (between 1 and 5 cases/l0 000 pregnancies). This is somewhat surprising given that it is almost always due to maternal genital herpes, a benign condition affecting around 10% of women of child-bearing age in societies in which sexual activity begins at an early age and involves multiple partners. The strongest argument supporting the maternal origin of neonatal herpes is that the ratio of HSV-1 to HSV-2 is the same as that for genital herpes in similar environments (approximately 1:4). HSV-2 is therefore predominant, and it is difficult to imagine how neonates could acquire the infection other than during passage through the birth canal. There are two main problems in the prevention of neonatal herpes. First, it is difficult to identify those women with the highest risk of transmitting the infection to their infants and, second, preventive measures currently available carry a number of drawbacks. With regards to the risk of perinatal transmission there is something of a paradox: the most dangerous situation for the infant is when the mother acquires the primary
Ltd. All rights reserved
H. Blanchier et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 33-38
34
infection at the end of pregnancy, but this is rarely the case; in contrast, in two-thirds of cases in which the neonate acquires the infection from its mother, the maternal genital herpes was unidentified. In other words, neonatal herpes reveals the maternal genital infection in two out of three cases. Preventive measures include sex education, disinfection of the birth canal prior to delivery, caesarean delivery and treatment with acyclovir (ACV). All these measures come up against various problems, and recommendations for prevention have changed with time [l]. The influence of sex education on the spread of sexually transmitted diseases has been disappointing, regardless of the context. The fear of AIDS and the campaigns promoting condom use, however, have a positive impact. Caesarean section is used to avoid contamination during passage through the birth canal but, like all operations, carries a certain degree of maternal morbidity and failure. Antiviral therapy, even with a poorly toxic product such as ACV [2], could in no way be prescribed to 10% of pregnant women (and their unborn infants), for the reason given in Table 1 [3]. Routine culture for HSV-2 from the 32nd week of pregnancy in women with a history of genital herpes was recommended by Nahmias et al. [4] to identify those likely to benefit from caesarean section. However, it emerged that the results of such tests were not predictive of the presence of HSV-2 in the birth canal on the day of delivery, regardless of when they were performed [5], and Nahmias et al. recommended that virological monitoring should be concentrated around the immediate prepartum period [4]. In France, a multidisciplinary working party set up the Groupe d’Etudes et de Recherthe sur l’Herp&s (GERH). In 1987 recommendations were forwaded which distinguished between four different situations, from primary genital infection prior to delivery, to the situation in which the woman and her partner have no known history of genital herpes [6].
Table 1 Objections
to the use of ACV during
pregnancy
f
Theoretical short-term risk of fetal toxicity to concentration in the amniotic fluid
+
Theoretical long-term risk of mutagenesis, despite negative results in most tests? Reduced immune response to the virus? Risk of viral shedding on withdrawal of treatment
+ ++ +++
(rebound effect) Lack of comparative caesarean section
efficacy
(renal) due
data on oral ACV versus
The only clear (mandatory) indication for intravenous ACV at all stages of pregnancy is a severe primary infection carrying a risk of dissemination or hepatitis in the mother
Since that time, the situation has developed with, in particular, indications on the significance of anti-HSV antibodies for the protection of the infants, and the possibility of detecting HSV shedding in the birth canal, not only by viral culture but also by means of polymerase chain reaction (PCR)-based methods. The aim of this paper is to provide an update on neonatal herpes and to indicate the measures that should be taken by the practitioner confronted with a pregnant woman with genital herpes. 2. Recommendations
of the GERH
The recommendationns of the GERH to pregnant women with genital herpes are based on an analysis of the literature by a group of obstetricians, pediatricians, virologists and pharmacotoxicologists, as well as discussions with American colleagues concerned with the prevention of neonatal herpes, particularly Andre Nahmias, Anne Yeager, and Richard Whitley. The GERH measures:
recommends
the
following
basic
Virological confirmation of herpes-like genital lesions during at least one outbreak in all women planning to become pregnant, as well as in their partners, preferably by means of viral cultures which is still the reference technique; serological tests should not be used for diagnostic purposes (Table. 2). (ii) A search for a past history of genital herpes in all pregnant women and their partners. (iii) As recommended by the American College of Obstetricians and Gynecologists [7], weekly viral culture should no longer be used to detect asymptomatic viral shedding towards the end of pregnancy in women with a history of genital herpes, as the result available at the time of delivery is no longer valid. (iv) A thorough clinical examination of the birth canal and the perineal-vulvar region should be carried out at the beginning of labor to detect likely herpetic lesions of which the patient is unaware.
6)
These recommendations distinguish between four highly different situations with regard to likely risk of neonatal herpes and call for four different sets of preventive measures; fortunately, the most dangerous situations are also the least common (Table 3). 2.1. Situation I The situation carrying the highest risk is that in which the woman contracts genital herpes in the prepartum period (which, for maximum safety, can be extended to the month before delivery, given the persistant viral
35
H. Blanchier et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 33-38
Table 2 Laboratory Indicated
diagnosis
of HSV infection
for all serious
forms of herpes and
for genital herpes
++ Best to detect the virus . ++ Viral culture: the gold standard Fragile virus, but effective transport media Rapid cytopathogenic effect (CPE) in various cultures, I-4 days Only test suitable for asymptomatic shedding . Rapid diagnosis: cytodiagnosis by immunofluorescence, ELISA Only valid for new lesions l HSV-UHSV-2 typing by immunofluorescence (molecular epidemiology .
by restriction
mapping)
PCR: under evaluation
‘Serodiagnosis’ of little, if any, use l Primary infection: two sera at 2-3 weeks interval . Recurrences do not cause seroconversion . Encephalitis: intrathecal antibody synthesis is late and inconsistent . Limited value for differential diagnosis of primary and non-primary retrospective diagnosis of neonatal herpes
shedding in this setting). It is now known that the neonate risk varies according to whether the genital infection is genuinely primary, or rather initial but not primary [8]. By definition, primary infection results from the first encounter, during sexual intercourse, with HEX-1 or HSV-2, in a person having escaped the primary oral HSV-1 infection generally acquired during childhood. Initial, non-primary, genital herpes is less symptomatic and less dangerous for the infant. It results from a primary sexual contact with HSV-2 in a woman having
Table 3 Manifestations
of maternal
genital
herpes and their relationship
initial genital
infection
and for
previously acquired oral HSV-1 infection who is thus partially protected 191. The distinction between the two forms of initial genital herpes is often unclear, since oral herpes is asymptomatic in nine cases out of ten; in addition, the obstetricians may not have access to the results of serological tests which can, when anti-HSV antibodies are present during the acute phase, show that the patient has an initial, non-primary, genital infection. In practice, caesarean section is mandatory in both types of initial herpes virus infection in the prepartum period. If possible, it should be carried out before the
with neonatal
herpes: four situations
and proposed
measures
Frequency among mothers of infected neonates
Risk of neonatal herpes
Recommendations
I Primary infection prepartum (month preceeding delivery)
Rare
++++ approx.
Caesarean Acyclovir?
section
II Recurrence prepartum preceding delivery)
+
++ 2-s%
Caesarean
section
++
f l/l000
HSV culture at term Vaginal delivery after Betadine@
+++ 2/3 of cases of neonatal herpes
f l/IO 000
No action other than prevention of STD
Maternal
situation
III Only history of genital (mother or partner) IV No manifestations genital herpes
of
(days
herpes
15%
A small proportion (0.1-l%) of pregnant women with no known risk factors have detectable asymptomatic genital HSV shedding. Two-thirds of cases of neonatal herpes escape all foms of protection. Very occasionally, infants can be contaminated by a maternal herpetic gingivostomatitis, labial herpes in a family member, or during outbreaks in nursery.
H. Blanchier et al. /Eur. J. Obstet. Gynecol. Reprod.
36
rupture of the membranes. Failures in this setting, estimated at about IO%, have more serious consequences, particularly when there are clinical signs of primary initial infection, e.g. severe lesions, swollen lymph nodes and fever. Although it is difficult to make firm recommendations in the latter situation, it is often decided to administer ACV to the mother prior to delivery, as well as to the newborn infant. The fact that this situation is rare makes it difficult to evaluate the efficacy of such dual treatment in controlled trials. At all times, intravenous administration of ACV is essential for infants delivered of mothers who acquire primary genital herpes in the prepartum period and when caesarean section is not possible or is carried out too late (i.e. 4-6 h after the rupture of the membranes, although this time is somewhat arbitrary). Another situation in which it is difficult to make firm recommendations is the acquisition of initial genital herpes at the beginning of the third trimester and premature breaking of the membranes, given the risk of prematurity on one hand and that of neonatal herpes on the other hand. Finally, intravenous administration of ACV is mandatory when the clinical manifestations of initial genital herpes appear to be life-threatening for the mother because of HSV hepatitis [3,8].
Table 5 Sampling
of suspect lesions for isolation
Biol. 53 (1994) 33-38
of HSV
Fresh lesions before application of topical agents Forceful swabbing (causing slight pain) of the ‘active’ zone, i.e. the edges of the floor of the vesicles or ulceration Vigorous shaking of the swab in transport medium Immediate transfer to laboratory, at 0°C if possible; otherwise, can be kept for less than 1 day at +4”C without freezing (prolonged storage possible at -8O’C)
herpes during the immediate prepartum period, given the lack of large-scale comparative trials in this setting. Nevertheless, such trials are badly needed since most of the potential risks of ACV in pregnant women do not apply to treatments started in the last few days of pregnancy and are probably well balanced by the inherent risk of surgery. In the study by Prober et al., none of the 34 children delivered vaginally of mothers with an outbreak of genital herpes developed neonatal herpes, even though chemotherapy was not used [lo].
2.2. Situation II A more frequent situation is that in which recurrent genital herpes occurs during the week preceding delivery. The risk of neonatal herpes is reduced by the less serious nature of the lesions, lesser viral shedding and the pre-existing immune response in the future mother. The risk is between 2% and < 5%, a figure sufficiently high to warrant caesarean delivery, but not treatment with ACV. Even when delivery is inadvertently vaginal, clinical and virological surveillance of the infant is generally adequate, particularly if the birth canal has been disinfected with Betadine@, as recommended in such cases. Additive risk factors (Table 4) can warrant ACV treatment of the infant, as in Situation I. It would be unreasonable to substitute ACV for caesarean delivery in women with a recurrence of genital
2.3. Situation ZZI The situation most frequently faced by obstetricians is that in which the mother or her partner has a history of recurrent genital herpes. It is highly recommended in such cases to obtain virological confirmation by culture during an outbreak (Table 5). In the absence of visible lesions or predictive signs of an outbreak at the time of delivery, the risk of neonatal herpes is about l/1000 and in no way warrants caesarean section or treatment with ACV. The only measures recommended in this situation are tests for HSV in the genital secretions by means of viral cultures (Table 6) and disinfection of the birth canal with Betadine. The use of fetal scalp electrodes should be avoided as far as possible, as this can create a portal of entry to the virus. It is recommended to start local ocular antiviral treatment in the infant (using an ACV-based ointment, for example), to apply foaming Betadine (which should immediately be rinsed off) and to carry out viral cultures of conjunctival and oropharyngeal swabs between 24 and 36 h after delivery.
Table 4 Additional
Table 6 Sampling secretions
risk factors
Prematurity Prolonged breaking
for neonatal
of amniotic
herpes
Use of scalp electrodes Major cervico-vaginal herpetic lesions Cervico-vaginal sampling: massive effect (1 day) Low maternal
titer of anti-HSV
Internal Cervix:
membranes
and
antibodies.
rapid
cytopathogenic
for asymptomatic HSV shedding - swabbing at two sites and external
surfaces
in the maternal
of the labia minor
genital
and the cervix
first eliminate cervical mucus using a swab introduce a second swab I cm into the cervical canal, rotate and shake vigorously in transport medium with a third swab, sample the surface of the cervix and shake vigorously in same tube of transport medium
37
H. Blanchier et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 33-38
2.4. Situation IV The risk of neonatal herpes is lower (l/10 000) when neither the woman nor her partner has any history of genital herpes. None the less, this situation accounts for two-thirds of cases of neonatal herpes. In the absence of direct data, it is impossible to tell whether such cases are due to asymptomatic primary infection or to asymptomatic recurrences in the prepartum period but, according to serological surveys of the prevalence of anti-HSV-2 antibodies, about two-thirds of primary genital infections do not produce clinical manifestations [ 111. The only measures recommended for these women are common-sense precautions aimed at avoiding sexuallytransmitted diseases towards the end of pregnancy. This not only means ruling out sex with other partners (for both the woman and the man), but also the use of condoms during the last 2 months of pregnancy, even by stable couples. Indeed, a recent seroprevalence study of HSV-2 showed the existence of couples in which only one partner had encountered the virus, even after a mean of 7 years of sexual intercourse; in 9.5% of the 190 couples studied, the woman was seronegative and the man seropositive [ 121. 3. Future perspectives Other possibilities have been opened up by the advent of new techniques. Viral culture techniques can only provide results after l-5 days, but more rapid tests capable of detecting asymptomatic genital HSV shedding at the beginning of labor would enable the obstetrician to choose the type of delivery and whether or not to treat the infant. In theory, this is now possible by the use of enzyme-linked immunosorbent assays (ELISA) for soluble viral antigens, and PCR for viral DNA. 3.1. Detection of asymptomatic HSV shedding On the basis of published epidemiological data, Libmann et al. calculated the gains, in term of avoidance of neonatal herpes and unnecessary caesarean sections, likely to be achieved by several strategies combining various measures, including the detection of HSV in the genital secretions at the time of labor by means of a rapid ELISA test [ 131. The most cost-effective strategy was apparently that in which HSV-2-seronegative women with asymptomatic primary infections are identified by tests for HSV antigen, with a view to caesarean section. Unfortunately, this is a difficult approach in practice because the ELISA test, which has a sensitivity and specificity close to that of viral culture for the confirmation of herpetic lesion, has not been validated for the detection of asymptomatic HSV shedding which, in principle, is associated with a lower viral density [14]. The second most cost-effective strategy is the classical approach
based on clinical examination during labor, and the use of caesarean section if suspect lesions are detected. 3.2. Specijk serological tests for anti-HSV-2 gpG antibodies Kulhanjian et al. [ 121 recommended identifying highrisk women unaware of their status, i.e. those with a primary infection or a recurrence, by means of serological tests. They suggested that all pregnant women and their partners should undergo an ELISA test for antibodies directed against HSV-2 glycoprotein G (gpG), particularly to detect HSV-Zseronegative women with seropositive partners. Again, the feasibility of this approach is questionable, as the test was home-made, and required confirmation by Western blot; the authors pointed out the inability of commercial tests to differentiate adequately between anti-HSV- 1 and anti-HSV-2 antibodies. 3.3. HSV PCR One promising approach is the detection of HSV in genital secretions in late pregnancy, or even during labor, by means of PCR amplification of a genomic region common to HSV-1 and HSV-2. In a preliminary study, Hardy et al. [I 51 found that PCR had a sensitivity similar to that of viral culture, both for suspect lesions (12 cases) and for the detection of asymptomatic shedding in the genital secretions (12 cases). Unfortunately, routine application of this approach is still some way off, for several reasons:
(9 (ii) (iii)
(iv)
(v)
PCR requires a high degree of technical expertise given its complexity and the risk of contamination; automation of PCR is not likely to be successful in the foreseeable future; in the above study, the genital secretions were first concentrated by means of microdialysis prior to the detection of asymptomatic virus shedding; similarly, frequent confirmation of the specificity of the PCR product by means of molecular hybridization was necessary; and to be of real use in obstetric decision-taking, the test would have to be available 24 h/day.
4. Conclusions In routine practice, the management of the risk of neonatal HSV infection is still based on a good knowledge of both partners’ medical history, and thorough clinical examination of the birth canal prior to delivery. New tests available in some centers will no doubt contribute to our understanding of the natural history of maternofetal transmission, particularly in women with no identified risk factors, but well-designed controlled trials will be necessary. Information is lacking in a number of essential areas:
H. Blanchier et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 33-38
38
The influence of ACV on the rate of viral replication in the birth canal during asymptomatic recurrences and asymptomatic primary infections. (ii) The local immune response in the genital mucosa and its influence on the transmission of the virus from the mother to her infant, both spontaneously and during treatment with ACV. (iii) The fetoprotective efficacy of the various classes of HSV-specific circulating immunoglobulins. (iv) Widespread use of ACV for the prevention of maternofetal contamination appears to be unwarranted at the present time. In contrast, the administration of inactivated vaccines or antibody preparations might be beneficial, but this requires a knowledge of the immunoprotective components. (i)
Finally, to return to routine practice, Gibbs [16] pointed out that the proportion (32%) of pregnant women seropositive for HSV-2 in the study by Kulhanjian et al. [12] illustrated the almost total failure of health education in this area, and called for urgent measures. 5. Acknowledgements
3 4
5
6
I
8
9
IO
II
I2
We are grateful to MS Marie-Christine Papuchon and Sylvie Past01 for preparing the manuscript and to MS Francoise Seltene for conducting literature searches.
I3
I4
6. References Prober CG, Corey L, Brown ZA nancies complicated by genital virus. Clin Infect Dis 1992; 15: Andrews EB, Yankaskas BC,
et al. The management of prcginfections with herpes simplex 1031-1038. Corder0 JF et al., and the
Acyclovir in Pregnancy Registry Advisory Committee. Acyclovir in pregnancy registry: six years’ experience. Obstet Gynecol 1992; 79: 7-13.
15
I6
Brown ZA, Watts DH. Antiviral therapy in pregnancy. Clin Obstet Gynecol 1990; 33: 276-289. Nahmias AJ, Keyserling HL, Whitley R. Changing patterns of neonatal herpes - as affected by antiviral therapy and other factors. In: Kono R, ed. Herpes viruses and virus chemotherapy. Elsevier, 1985; 145-147. Arvin AM, Hensleigh PA, Prober CG et al. Failure of anteparturn maternal cultures to predict the infant’s risk of exposure to herpes simplex at delivery. N Engl J Med 1986; 315: 796-800. Blanchier H, Sainte Croix le Baleur A, Huraux-Rendu C et al. L’herpts chez la femme enceinte et le nouveau-&. J Gynecol Obstet Biol Reprod 1987; I6 (Suppl I): l-28. American College of Obstetricians and Gynecologists (ACOG) Technical Bulletin. Perinatal herpes simplex virus infections. November 1988; No. 122. Brown ZA, Vontver LA, Benedetti J et al. Effects on infants of a first episode of genital herpes during pregnancy. N Engl J Med 1987; 317: 1246-1251. Boucher FD, Yasukawa LL, Bronzan RN et al. A prospective evaluation of primary genital herpes simplex virus type 2 infections acquired during pregnancy. Pediatr Infect Dis J 1990; 9: 499-504. Prober CG, Sullender WM, Yakusawa LL et al. Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of vaginal delivery to mothers with recurrent genital herpes simplex virus infections. N Engl J Med 1987; 316: 240-244. Frenkel LM, Garatty EM, Shen JP et al. Clinical reactivation of herpes simplex virus type 2 infection in seropositive pregnant women with no history of genital herpes. Ann Intern Med 1993; 118: 414-418. Kulhanjian JA, Soroush V, Au DS et al. Identification of women at unsuspected risk of primary infection with herpes simplex virus type 2 during pregnancy. N Engl J Med 1992; 326: 916-920. Libmann MD, Dascal A, Kramer MS et al. Strategies for the prevention of neonatal infection with herpes simplex virus: a decision analysis. Rev Infect Dis 1991; 13: 1093-I 104. Dascal A, Chan-Thim J, Morahan M et al. Diagnosis of herpes simplex virus infection in a clinical setting by a direct antigen detection enzyme immunoassay kit. J Clin Microbial 1989; 27: 700-704. Hardy DA, Arvin AM, Yakusawa LL et al. Use of polymerase chain reaction for successful1 identification of asymptomatic genital infection with herpes simplex virus in pregnant women at delivery. J Infect Dis 1900; 162: 1031-1035. Gibbs RS, Mead PB. Prevention of neonatal herpes - current strategies. N Engl J Med 1992; 326: 946-947.