Prevention of perinatal herpes: prophylactic antiviral therapy?

Abstract

So what is the take-home message from these studies? The first question, about fetal and neonatal safety, appears to be answered positively. With more than 1,812 infants reported to have been exposed to varying amounts and duration of maternal acyclovir suppression, there has not been any apparent, short-term adverse fetal or neonatal effect. Use of acyclovir in infants, even in those that are premature, is very well tolerated, with a wide margin of safety. In addition, the pharmacokinetics studies by Frenkel et al and Kimberlin et al, as well as the animal studies, suggest that maternal use of acyclovir may actually provide a prophylactic and therapeutic benefit to an infant who is exposed to HSV. The second question, as to whether acyclovir suppression would simply change symptomatic outbreaks into asymptomatic ones, also appears to have some answers. The information provided by Wald et al indicated that acyclovir suppression actually decreases asymptomatic shedding, along with decreasing clinical recurrences. Because asymptomatic shedding seems to be similar in pregnant and nonpregnant patients, it would be reasonable to assume that asymptomatic shedding also would be decreased at delivery in pregnant women with HSV infection. This supposition is supported by the data from the randomized trials and cohort studies that demonstrated a lower than expected asymptomatic shedding rate. As yet, however, there has been no randomized trial in pregnant women that has had an adequate sample size to confirm this on a statistically significant basis. The third question, whether acyclovir suppression would lower the frequency of symptomatic recurrences at parturition, reducing the need for cesarean in these patients, has answers as well, although they may not be as clear cut as one would like. Women who experience their first genital herpes outbreak while they are pregnant seem to benefit from acyclovir suppression, with both a decrease in the risk of clinical recurrences at delivery and a decreased need for cesarean delivery. This is well documented by a randomized trial and other cohort studies. Acyclovir's efficacy in patients who have a history of genital herpes infections antedating their pregnancy is less clear. The data appear to indicate a clinically important decrease in the likelihood of symptomatic reactivations at the time of delivery, although the sample sizes in the randomized studies have been too small to draw a statistically significant conclusion one way or the other. Unfortunately, a definitive trial for this group of women may never be done. Assuming a 13% recurrence risk at the time of delivery and a 50% decrease in recurrences with the use of acyclovir, 652 women would have to complete the study to achieve a power of 80%. Conducting the study at the largest, single institution, prenatal center in the United States, Scott et al were only able to enroll 222 women during a period of 6 years. Likewise, Brocklehurst et al terminated their trial early because of recruitment difficulties. They enrolled only 63 women during a period of 4 years using two different sites in the United Kingdom. Unless a multicenter trial is conducted or a meta-analysis performed on the available data, we will probably have to be content with the data as it now stands. With valacyclovir and famciclovir now available, it is unlikely that any further work will be done with acyclovir. Information from the valacyclovir trials, however, may reach statistical significance because of changes in the study design that will allow smaller sample sizes to reach adequate power. Famciclovir treatment holds promise because of its longer intracellular half-life, but until concerns about potential mutagenicity are resolved and more information on its efficacy for suppressive therapy becomes available, it should not be considered for maternal suppressive therapy. Acyclovir appears to be effective, at least in some cohorts, and is probably safe for the fetus. (AB