IT CAN BE VERTICALLY TRANSMITTED TO INFANTS BEORE, DURING OR AFTER DELIVERY. CESAREAN DELIVERY IS PROTECTIVE AGAINST NEONATAL INFECTION.
MEDICAL CARE :
Acyclovir :
Acyclovir, a nucleoside analogue, was the first antiviral therapy approved for the treatment and prevention of HSV infection. Acyclovir selectively inhibits viral DNA replication of HSV, while having little effect on normal cells. Acyclovir is selective for HSV-infected cells because it requires phosphorylation by a viral enzyme (thymidine kinase) to acyclovir monophosphate. Phosphorylation does not occur in uninfected cells, where it remains virtually undetectable. After its conversion to acyclovir monophosphate in infected cells, other cellular enzymes convert it to acyclovir triphosphate, which acts to inhibit HSV-specific DNA polymerase, resulting in termination of the DNA transcript.
With primary HSV infection in nonpregnant women, acyclovir reduces the duration of local pain, dysuria, and viral shedding, and it shortens the time to crusting and healing of lesions. With daily usage, acyclovir also reduces symptomatic recurrences and subclinical viral shedding.
During pregnancy, acyclovir crosses the placenta and concentrates in the amniotic fluid. Postpartum, acyclovir concentrates in breast milk. Fetal serum concentrations are equivalent to maternal serum concentrations. A potential drawback of acyclovir therapy is delayed and decreased antibody response to a primary HSV infection. Whether this is due to a decreased viral load or to immune suppression is unknown. Acyclovir has been labeled a category B drug (no teratogenic effects were found in animal studies, but no or limited human studies are available).
Valacyclovir and famciclovir :
Since the introduction of acyclovir, newer second-generation antivirals have been introduced (eg, valacyclovir, famciclovir). Valacyclovir is identical to acyclovir except for the addition of an ester side chain that increases bioavailability. Once absorbed, it is converted to acyclovir in vivo. This allows for higher serum levels with a less-frequent dosing schedule. Famciclovir is a nucleotide analogue that has a longer intracellular half-life.
As with acyclovir, these second-generation agents have been used for treatment of symptomatic primary and recurrent lesions as well as for daily suppression. Both valacyclovir and famciclovir have been labeled category B drugs.
The recommended dosages of the 3 antiviral agents are as follows:
Indication Acyclovir Valacyclovir Famciclovir
First episode 400 mg tid (for 7-14 d) 1000 mg bid (for 7-14 d) 250 mg tid (for 7-14 d)
Recurrent 400 mg tid (for 5 d) 500 mg bid (for 5 d) 125 mg bid (for 5 d)
Daily suppression 400 mg bid 500 mg qd or 1000 mg qd
(if >9 recurrences/y) 250 mg bid
ANTIVIRAL SAFETY : No increase in the number of malformations occurred with acyclovir, and no pattern of birth defects emerged. Too few cases of valacyclovir-exposed pregnancies precluded the drawing of any meaningful conclusions. Thus, acyclovir appears to be relatively safe to use during pregnancy and should be prescribed as medically indicated.
PREVENTION OF VERTICAL HSV TRANSMISSION :
Current strategies to prevent vertical transmission with antiviral therapy have focused on 3 approaches.
Antiviral suppression for gravidas with first-episode infections during pregnancy
Routine antiviral suppression for gravidas with a history of genital HSV
Identification of seronegative gravidas at risk for primary and nonprimary first-episode genital HSV infections
Antiviral suppression for gravidas with first-episode infections during pregnancy
Recognizing that recurrent infections occur more frequently within the first year after a primary infection, Scott et al (1996) randomized 46 gravidas with first genital outbreak during pregnancy to either acyclovir (400 mg tid) or placebo beginning at 36 weeks' gestation. Patients receiving acyclovir experienced a significant reduction in the percentage of HSV recurrences at delivery (36% vs 0%) and cesarean deliveries for HSV (36% vs 0%). However, the reduction in the total number of cesarean deliveries in enrolled women was not statistically significant (40% vs 19%).
No patients in this study had asymptomatic shedding at the time of delivery, and no infant developed neonatal HSV infection or had complications from acyclovir. No attempt was made to distinguish between primary infections, nonprimary first-episode infections, or first-recognized recurrent infections. This study was, however, the first to demonstrate the utility of antiviral suppression in reducing the number of recurrences at the time of delivery.
Routine antiviral suppression for gravidas with a history of genital HSV
In 1998, Brocklehurst and colleagues performed a double-blind placebo-controlled trial that involved 63 women with a history of recurrent HSV infection. These women were randomized to either acyclovir (200 mg qid) or placebo, both beginning at 36 weeks' gestation. Nonsignificant reductions were found in recurrent HSV outbreaks at delivery, cesarean deliveries for HSV, and total cesareans in the acyclovir group. No infant in either group developed neonatal HSV, and no gravida experienced toxicity from acyclovir. The authors concluded that the sample size was too small to demonstrate a significant benefit from acyclovir and recommended that acyclovir be used only in clinical trials.
Since that time, additional randomized clinical studies have been performed, each demonstrating nonsignificant reductions in cesarean deliveries for recurrent HSV outbreaks and no differences in neonatal outcomes.
In 1996, Randolph and colleagues performed a cost-effectiveness decision analysis of 4 strategies designed to reduce neonatal HSV infections in women with a history of genital HSV. The 4 strategies were as follows:
Cesarean delivery if an HSV lesion was present at the time of labor
Acyclovir prophylaxis beginning at 36 weeks' gestation, with cesarean delivery if a lesion was present
Acyclovir prophylaxis beginning at 36 weeks' gestation, with vaginal delivery if a lesion was present
No intervention (no acyclovir, no cesarean delivery for HSV lesions)
The results suggested that acyclovir prophylaxis with vaginal delivery in the event of a recurrent HSV outbreak was the most cost-effective approach, with the greatest number of cesareans avoided and near-highest number of neonatal HSV infections averted. However, the authors cautioned that acyclovir may not have a large impact on neonatal outcome because most infants who developed neonatal HSV infection are born to asymptomatic women who have no history of HSV infection and, hence, would have no protective antibodies.
Identification of seronegative gravidas at risk for primary and nonprimary first-episode genital HSV infections :
This approach is the most ambitious of all strategies to prevent vertical transmission. Its logic is based on the observation that most neonatal HSV transmission occurs not in gravidas with a history of genital HSV, but rather in women who have primary or nonprimary first-episode genital infections at the time of labor. If routine serologic screening revealed a woman at risk for primary HSV (no antibodies) or nonprimary first-episode infection (either HSV-1 or HSV-2 only), she could be counseled to avoid genital-genital or oral-genital contact in order to prevent new genital infections during the third trimester of pregnancy and, hence, reduce neonatal HSV infections.
An alternative strategy would be to check the serologic status of the sexual partner, as well, and to recommend sexual abstinence only if the woman was at risk and the couple was serologically discordant, which occurs in 15-25% of couples. For example, if a woman was seronegative for HSV-2, and her partner was seropositive for HSV-2, the woman's risk of acquiring HSV-2 during pregnancy would be as high as 20%. Such a couple would, thus, be advised to abstain from sexual activity during pregnancy.
CONCLUSION :
In 1999, the American College of Obstetricians and Gynecologists (ACOG) published a practice bulletin regarding HSV in pregnancy. Their conclusions were as follows:
Level B recommendations (based on limited or inconsistent scientific evidence) :
- Women with primary HSV infection during pregnancy should be treated with antiviral therapy.
- Cesarean delivery should be performed on women with first-episode HSV infection who have active genital lesions at delivery.
- For women at or beyond 36 weeks of gestation with a first episode of HSV infection occurring during the current pregnancy, antiviral therapy should be considered.
Level C recommendations (based on consensus or expert opinion) :
- Cesarean delivery should be performed on women with recurrent HSV infection who have active genital lesions or prodromal symptoms at delivery.
- Expectant management of patients with preterm labor or premature rupture of membranes and active HSV infection may be warranted.
- For women at or beyond 36 weeks of gestation who are at risk for recurrent HSV infection, antiviral therapy may be considered, although such therapy may not reduce the likelihood of cesarean delivery.
- In women with no active lesions or prodromal symptoms during labor, cesarean delivery should not be performed on the basis of a history of recurrent disease.
Currently, recurrent HSV infections account for only a small proportion of neonatal HSV infections. However, routine HSV suppression with antiviral agents, especially in pregnant women with a history of frequent recurrences, may suppress clinical recurrences during labor and may reduce the need for cesarean deliveries in these women.
In order to truly reduce the incidence of neonatal HSV infection, physicians and researchers must focus on the prevention and recognition of asymptomatic primary genital HSV infections. In the future, this might require a combination of PCR analysis for faster diagnosis, as well as type-specific serology to identify pregnancies at risk for primary HSV infections.
PATIENT MONITORING
o Acute episode - followup if complications
o Latent infection - annual pap smear; check pregnant women at prenatal visits and onset of labor
o Reassess chronic suppression therapy yearly
PREVENTION/AVOIDANCE
o Condoms in sexual activity reduces transmission by >60%
o Avoid multiple sexual partners
o Avoid stress when possible
o Avoid sex if lesions or prodromal symptoms present and for 2 days after resolved
o Pregnant women without evidence of HSV antibody should avoid unprotected sex in late pregnancy
o Screening for asymptomatic HSV infection is not recommended by USPSTF, but may be cost-effective in
pregnant women
o HSV-2 glycoprotein subunit vaccine in development, 75% effective (only in women), and only if HSV-1
seronegative
POSSIBLE COMPLICATIONS
o Vaginal discharge
o Secondary bacterial infection
o Urinary retention
o Aseptic meningitis
o Transmission to neonate; spontaneous abortion, preterm birth, low birthweight infants
o Increased risk for HIV infection (2-3 times)
o Emotional impact - lowered self esteem, guilt, anger, depression, fear of rejection, fear of transmission to
partner
EXPECTED COURSE/PROGNOSIS
o Resolution of signs/symptoms: Primary in 14-21 days; first episode - non-primary 14-17 days; recurrent 7-10
days
o Latent infection - recurrences in 80% of patients within 1 year of initial HSV-2 infection; immunocompetent
average 3-4/year
o Treatment with anti-viral agents does not eliminate virus from body
o HSV infection in immunocompromised (AIDS) patient - more severe, difficult to treat
o Monthly recurrence rates - HSV-1 = 0.02-0.08, HSV-2 = 0.33 - 0.35
o Within 1 year of HSV-2 diagnosis, 90% of individuals have 1 recurrence, 38% have >6 recurrences, 20%
have >10 recurrences
AGE-RELATED FACTORS
Pediatric:
o Genital lesions in prepubertal child suggests sexual abuse
o Neonatal infection occurs in 10-20/100,000 live births. Most result from maternal asymptomatic viral shedding.
o Neonatal herpes - generally occurs at 2-3 weeks of age, skin vesicles, fever, irritability, seizures, hepatitis,
pneumonitis, DIC
o Neonatal infection survival rates-localized - > 95%; CNS - 85%; systemic - 30%
o High risk infant: acyclovir 30 mg/kg/day IV q8h for 10-14 days
o Low risk infant: asymptomatic, culture eyes, nasopharynx, mouth at 24-36 hrs old and observe
PREGNANCY
o Primary/1st episode - spontaneous abortion (45%); preterm labor (35%)
o Greatest risk for neonatal infection occurs with primary (50% transmission rate) or non-primary fi rst episode
(30% transmission rate) infected mother at delivery; enhanced by prolonged rupture of membranes, use of
fetal scalp electrode, presence of lesions on cervix, and prematurity
o Low risk - recurrent asymptomatic HSV shedding in mother (3%); mothers with high titer of neutralizing
antibodies
o Cesarean section is indicated if herpetic genital lesions are present during labor
o Culture suspicious lesions during pregnancy
o ACOG Clinical Management Guidelines:
? Women with primary HSV during pregnancy, or active genital herpes infection near term or at delivery,
should receive antiviral therapy
? Women with 1st episode non-primary genital herpes or at risk for recurrent genital herpes at or beyond 36
weeks gestation should be considered for anti-viral therapy; can reduce C-section rate, clinical HSV and HSV shedding at delivery, should continue until delivery, acyclovir 400mg tid or valacyclovir 500mg bid