Pharmacology and toxicology
Aciclovir (acyclovir) is an acyclic nucleoside analog, highly specific for HSV-infected cells. It inhibits viral ribonucleotide production in Herpes 1 and 2 and in varicella zoster infections. Valaciclovir is the prodrug of aciclovir, with the benefit of a greater bioavailability and a longer half-life (less frequent dosing). Aciclovir can cross the placenta, and fetal aciclovir levels arc comparable to maternal levels once a steady state is reached. It is concentrated in the amniotic fluid, approximately four-fold, but does not concentrate in the fetus (Frenkel 1991). There is substantial experience with systemic use of aciclovir during pregnancy. The manufacturer initiated the Acyclovir Pregnancy Registry (June 1984-April 1999). In total, the outcomes of 1234 prospectively registered pregnancies were obtained; 756 infants were exposed during the first trimester and 291 in the third trimester. There was no evidence of an increased risk of congenital defects or adverse fetal or neonatal outcomes in this study (Stone 2004). The same applies to other publications. In total, more than 1800 infants are reported to have been prenatally exposed without any apparent drug-related adverse outcome (Scott 1999). Many studies have been conducted to evaluate the safety and efficacy of systemic aciclovir for the treatment of genital herpes in pregnancy, with the objective of preventing transmission of the virus and subsequent serious neonatal herpes. Of neonatal herpes, 85% results from viral transmission near delivery. To date, the conclusions and recommendations made are not definitive, but as maternal primary and nonprimary first-episode genital herpes seem to have the greatest risk for prolonged shedding and transmitting the virus, treatment of these conditions is generally viewed as justified. Treatment of recurrent episodes of genital herpes, when there is no or minimal risk of transmission, is not routinely recommended, but can be considered when maternal infection is severe (Brown 2005, Hill 2005, Scott 1999, RCOG 1998). To reduce the need for cesarean delivery in women with symptomatic genital herpes, antiviral suppressive therapy initiated at 36 weeks to all asymptomatic HSV-2 seropositive pregnant women is presently a focus of discussion (Brown 2005, Whitley 2004, Watts 2003). Intravenous administration is required in patients with life-threatening conditions like disseminated herpes infection or varicella pneumonia.
After topical use of aciclovir, ihere will be only minimal resorption through the skin.
Valaciclovir, the prodrug of aciclovir, has an increased bioavailabil ity to the mother (and possibly to the fetus). Pregnancy outcomes were obtained from 111 prospectively registered pregnancies in the Valaciclovir Pregnancy Registry (same manufacturer), including 29 infants exposed in the first trimester and 50 in the third trimester. Although no apparent adverse outcomes were reported, these data, together with those from some other small studies, provide insufficient information for a risk evaluation.
There are a few case reports describing normal pregnancy outcome after first-trimester treatment with ganciclovir (Pescovitz 1999). However, these data are inadequate to evaluate the safety of ganciclovir in pregnancy. The same applies to the prodrug valgan-cicliovir, and penciclovir or its prodrug famciclovir. In animal studies, embryotoxicity of ganciclovir was reported.
Recommendation. Topical use of aciclovir is, regarding the minimal systemic absorption, probably safe. Oral treatment should be considered when first-episode genital herpes is diagnosed in a pregnant woman, to prevent neonatal infection by vertical transmission of the virus. Intravenous administration is indicated for treatment of life-threatening maternal infections like varicella pneumonia or disseminated herpes simplex infection. It should not be routinely administered in case of uncomplicated herpes zoster. The use of famciclovir, ganciclovir, pencidovir or valacidovir is not recommended during pregnancy because of insufficient data. Inadvertent use does not require termination of pregnancy or invasive diagnostic procedures.
2.6.45 Antiviral drugs for influenza
Amantadine, oseltamivir, and zanamivir are the available drugs for prophylaxis or treatment of influenza-virus infection. Amantadine (against influenza A) has been on the market for a long time now. It is a drug with dopaminergic activity, and is therefore also used in Parkinsonian-like disorders. In one animal study the drug was found to be teratogenic (no specific anomalies were mentioned), but no other reports of teratogenicity have been locatcd. A few case reports describe malformations in the offspring, but none of these reports provide sufficient information for any conclusion about developmental toxicity. In a letter to the editor (Rosa 1994), 64 pregnancies were reported where first-trimester exposure to amantadine had occurred. There were five congenital defects (three statistically expected), one of which was a cardiovascular defect. The author concluded that no definite conclusion could be drawn from these numbers, but that if there is any risk with amantadine it is not high, based on the available data.
Experience during pregnancy with oseltamivir or zanamivir (against influenza A and B, the latter especially in HIV-infected patients) is insufficient for a risk assessment. Reports from animal studies have not clearly indicated the teratogenic potentials of these drugs.
Recommendation. Amantadine, oseltamivir, and zanamivir are not recommended during pregnancy, and should be reserved for vital indications. Inadvertent use does not require termination of pregnancy or invasive diagnostic procedures. However, a detailed fetal ultrasound may be considered after first-trimester exposure.
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