Acyclovir

 Risk Factor: BM
 Class: ANTI-INFECTIVES / Antivirals

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Acyclovir is a synthetic acyclic purine nucleoside analogue used as an antiviral agent against the herpes viruses. Three studies observed no teratogenic effects in animals at nontoxic doses (1,2 and 3). One study, however, observed abnormal thymus development and functional deficits of the immune system in rats exposed in utero to acyclovir (4). Chromosome breaks were observed in some tests with cultured human lymphocytes, but only with prolonged exposure and at doses much higher than those obtainable in clinical use (5). A 1997 publication, however, cited studies that gave SC doses of 100 mg/kg once, twice, or three times to pregnant rats on day 10 of gestation (6). Altered development was observed in fetuses examined on day 11.5 (reduced crown-rump length, number of somites, and protein content) or on day 21 (skull, eye, and tail defects). The SC doses caused slight and reversible maternal nephropathia, but this was not thought to have induced the fetal anomalies (6).

Reproduction studies in mice, rats, and rabbits, as reported by the manufacturer, did not observe teratogenic effects (7). The doses used in the three species were 450 mg/kg/day orally (plasma levels the same as human levels), 50 mg/kg/day SC (plasma levels one to two times human levels), and 50 mg/kg/day SC and IV (plasma levels four and nine times human levels), respectively.

Although there are no approved indications for acyclovir in pregnancy, the principal clinical use of acyclovir during this period is for the treatment of primary genital herpes simplex virus (HSV) type 2 infection and for the prophylaxis against recurrent genital HSV infection. The Acyclovir in Pregnancy Registry found that, of the American women reported to the Registry as exposed during pregnancy, 62% and 70% of their prospective and retrospective samples, respectively, had been treated for genital herpes (8,9). They estimated that as many as 7,500 live-births per year in the United States may be exposed to acyclovir (8).

The treatment of genital herpes is intended to prevent the adverse outcomes on the fetus and newborn that the primary infection may cause, such as prematurity, intrauterine growth retardation (IUGR), and neonatal HSV infection, and to reduce the incidence of cesarean section with recurrent disease. Reviews evaluating the various indications for acyclovir in pregnancy concluded that life-threatening maternal HSV infection and varicella pneumonia were the most justifiable indications (10,11). Some evidence was cited that the benefits of treatment of primary genital herpes, under certain conditions, might outweigh the risks, but the lack of controlled studies prevented any conclusion (10,11). Similarly, the treatment of uncomplicated varicella infections and the prophylaxis against recurrent genital HSV were unproven indications because of the absence of supporting data (10,11). Some authors have proposed the use of acyclovir for the prophylaxis of genital HSV during pregnancy, although all qualify their proposals with statements that controlled studies are needed to assess efficacy and safety (12,13 and 14).

A 1998 randomized, placebo controlled study was conducted to determine if oral acyclovir (800 mg/day) could reduce the rate of cesarean section in women with recurrent genital herpes infection at <36 weeks' gestation (15). A total of 63 women were enrolled (acyclovir N=31, placebo N=32) in the study. Except for a significant reduction in clinical recurrences (odds ratio [OR] 0.10, 95% confidence interval [CI] 0.000.86), the other outcome measures showed no significant difference from placebo: cesarean section (OR 0.44, 95% CI 0.091.59), and clinical recurrence or asymptomatic shedding (OR 0.32, 95% CI 0.051.56). None of the newborns were infected with herpes simplex virus and no abnormal findings were detected in the 19 exposed infants examined 1 year later. The investigators concluded that acyclovir should not be used for recurrent genital herpes infection during pregnancy outside of randomized controlled trials (15).

The Centers for Disease Control and Prevention (CDC) 1998 Sexually Transmitted Diseases Treatment Guidelines states, in part: The first clinical episode of genital herpes during pregnancy may be treated with oral acyclovir. In the presence of life-threatening maternal HSV infection (e.g., disseminated infection, encephalitis, pneumonitis, or hepatitis), acyclovir-administered IV is indicated. Investigations of acyclovir use among pregnant women suggest that acyclovir treatment near term might reduce the rate of abdominal deliveries among women who have frequently recurring or newly acquired genital herpes by decreasing the incidence of active lesions. However, routine administration of acyclovir to pregnant women who have a history of recurrent genital herpes is not recommended at this time (16).

The drug readily crosses the placenta to the fetus (17,18,19,20,21,22,23 and 24). After intravenous dosing, acyclovir levels in cord blood were higher than those in maternal serum with ratios of 1.4 and 1.25 reported (17,18). A 1992 study concluded that the placental transfer of acyclovir was most consistent with a carrier-dependent, nucleobase-type uptake of the drug, but that the overall net transfer was passive and dependent on solubility characteristics (17).

The pharmacokinetics of oral acyclovir in term pregnant women were reported in 1991 (22). Fifteen women with a history of active recurrent genital HSV type 2 infection antedating and during pregnancy, but without currently active disease, were given either 200 mg (N=7) or 400 mg (N=8) orally every 8 hours from 38 weeks' gestation until delivery. The mean steady-state plasma peak and trough levels in the 200-mg group were 1.9 and 0.7 mol/L, respectively; those in the 400-mg group were 3.3 and 0.8 mol/L, respectively. Acyclovir was concentrated in the amniotic fluid with concentrations ranging from 1.87 to 6.06 mol/L in the low-dose group compared with 4.20 to 15.5 mol/L in the high-dose group. The maternal:cord plasma ratio was similar in both groups with a mean of 1.3, a value comparable to that observed after intravenous dosing.

Acyclovir has been administered orally and intravenously during all stages of pregnancy (8,10,15,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35, 36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55, 56,57,58,59,60,61 and 62). Topical acyclovir, which may produce low levels of the drug in maternal serum, urine, and vaginal excretions, has been used in pregnancy, and the manufacturer is aware of two women treated topically during the 3rd trimester who were delivered of normal infants (A. Clark, personal communication, Burroughs-Wellcome, 1985). However, no published reports of these cases have been located.

Favorable maternal and fetal outcomes were observed in two cases of isolated HSV encephalitis treated with IV and oral acyclovir (37,38). Treatment in the two mothers began at 29 and 26 weeks' gestation, respectively, and continued until term. In the only other reported cases occurring during pregnancy, none of whom were treated with acyclovir, four mothers and three fetuses died (38). The onset of the encephalitis in the mother of the surviving fetus was at term. A 1996 case report described the successful treatment with IV acyclovir of a woman with herpes simplex hepatitis at 24 weeks' gestation (39). A viable 1,013-g male infant was delivered at 28 weeks' because of severe preeclampsia. Both the mother and her infant were doing well at the time of the report.

A 1991 case report and review cited data indicating that varicella pneumonia occurring during pregnancy resulted in a maternal mortality up to 44% (48). In 15 cases treated with IV acyclovir, however, only two (13%) mothers died, one fetus was stillborn, and one infant expired (48). Another 1991 Reference added 5 new cases plus a review of 16 cases from the literature to total 21 women treated during pregnancy with acyclovir for varicella pneumonia (49). Twelve women were treated during the 2nd trimester and nine during the 3rd trimester. The mean duration of acyclovir treatment was 7 days. Maternal mortality occurred in four cases, but two of the deaths occurred after delivery. One mother died of multi-organ failure 11 days after delivery, and one mother died after surgery for intestinal obstruction 1 month after delivery. The three maternal deaths directly attributable to varicella pneumonia were in the 3rd trimester at the onset of disease. Two fetal or infant deaths occurred, one from prematurity after birth at 26 weeks' gestation, and one stillborn at 34 weeks' (both cases also described in Reference 48). No adverse effects were observed in the surviving infants. None of the infants had features of congenital varicella infection, nor did any develop active perinatal varicella infection. A 1993 abstract briefly described data collected retrospectively (19881992) on 14 pregnant women with varicella pneumonia, 11 of whom were treated with acyclovir (59). No specific information was given on the outcome of the 11 treated pregnancies. A 1998 case report described a woman at 32 weeks' gestation who was treated with IV acyclovir for varicella pneumonia (60). A healthy female infant was delivered approximately 3 days later because of fetal distress secondary to cord compression and prolapse into the right uterine segment. The infant was given varicella immunoglobulin and a 5-day course of IV acyclovir and was discharged home at 20 days of age without ever showing signs of varicella.

Data gathered for 6 years covering the period of June 1, 1984 through June 30, 1990, by the Acyclovir in Pregnancy Registry, a group sponsored by the manufacturer and the CDC, were published in 1992 (8). (See required statement for use of these data.) These data, reviewed below, have now been updated to include reported pregnancy exposures through April 30, 1999 (9). Excluding patients with exposure to topical acyclovir only, a total of 1,246 (1,234 pregnancies, 12 sets of twins) known outcomes were followed prospectively, in which the initial exposure occurred during the 1st, 2nd, and 3rd trimesters, of 756 (7 sets of twins), 197 (2 sets of twins), and 291 (3 sets of twins) fetuses, respectively. The timing of initial exposure was unknown in two outcomes. There were 79 spontaneous losses (75 abortions/2 stillbirths after initial exposure in the 1st trimester and 2 stillbirths initial exposure in the 3rd trimester) and 85 induced abortions (83 after initial exposure in the 1st trimester, 1 after initial exposure in the 2nd trimester, and 1 after initial exposure in an unknown trimester) in which no congenital malformations were reported (but cannot be ruled out) (9). Among the remaining 1,082 outcomes there were 1,054 live births without birth defects (including all 12 sets of twins) and 28 cases with anomalies (2 induced abortions, 26 live births). The timing of initial exposure among the cases with defects in the 1st, 2nd, and 3rd trimesters was 19, 2, and 7, respectively. There was no uniqueness or pattern among the malformations that suggested a common cause (9). For exposures during the 1st trimester with known outcomes (excluding losses and abortions), the rate of birth defects was 3.2% (19 of 596), an incidence no different from the general population (9). Combining the data from all trimesters, the rate of anomalies was 2.6% (28 of 1,082), again no different from that expected in a nonexposed population (9). The specific defects observed were as follows: Initial Exposure During 1st Trimester - number of cases Hemangiomas 1 Diaphragmatic hernia 1 Neural tube defect (induced abortion) 1 Defects attributed to fragile X chromosome 1 Pyloric stenosis (mild IUGR in 1) 3 Hip dysplasia 1 Ascites, cardiomegaly, cardiomyopathy, hydrocephalus, calcified foci in CNS; at 1 month, respiratory impairment and heart failure 1 Cleft palate and micrognathia 1 Lower limb deformities probably because of amniotic bands 1 Unilateral intermittent ureteral pelvic junction obstruction plus left postural/lateral wall bladder-based diverticulum (most likely representing a hutch diverticulum) 1 Congenital blindness; cessation in development of iris and retina 1 Nondescended testes, spontaneous resolution at 2 months 1 Plagiocephaly (diagnosed at 9 months), IUGR 1 Cleft lip 1 Defect of distal joint of 4 fingers on left hand (hypoplasia congenital ossis), hydronephrosis of right kidney 1 Down's syndrome (trisomy 21) (induced abortion) 1 Congenital absence of right fibula and 3 toes 1 Initial Exposure During 2nd Trimester - number of cases Pulmonary valve stenosis (mild) 1 Talipes (positional) 1 Initial Exposure During 3rd Trimester - number of cases Transposition of great vessels and ventricular septal defect 1 Hip dysplasia 1 Talipes (positional) 1 Down's Syndrome 1 Craniosynostosis 1 Congenital lobar emphysema, respiratory distress 1 Digits of right hand fused 1 As for pregnancies reported retrospectively (i.e., in which the outcome was known before reporting), there were 616 outcomes (3 sets of twins) in which initial exposure occurred in 259 (1 set of twins) during the 1st, 76 during the 2nd, and 280 (2 sets of twins) during the 3rd trimester, and 1 during an unknown gestational time (9). These data exclude those pregnancies exposed to topical acyclovir only. There were 45 spontaneous losses (37 abortions/4 stillbirths after initial exposure during the 1st trimester, 2 abortions after initial exposure during the 2nd trimester, and 2 stillbirths after initial exposure in 3rd trimester) and 22 induced abortions (20 and 2 after initial exposure in the 1st and 2nd trimesters, respectively). Congenital defects were observed in 47 outcomes in which the initial exposure had occurred in 34, 8, and 5 during the 1st, 2nd, and 3rd trimesters, respectively.

In a surveillance study of Michigan Medicaid recipients conducted between 1985 and 1992 involving 229,101 completed pregnancies, 478 newborns had been exposed to acyclovir during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 18 (3.8%) major birth defects were observed (20 expected). Specific data were available for six defect categories, including (observed/expected) 5/5 cardiovascular defects, 0/1 oral clefts, 0/0 spina bifida, 1/1 polydactyly, 1/1 limb reduction defects, and 2/1 hypospadia. These data do not support an association between the drug and the defects.

A 1998 non-interventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (61). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Acyclovir was taken during the 1st trimester in 24 pregnancies. The outcomes of these pregnancies included 1 spontaneous abortion, 5 elective abortions, and 18 normal term babies (61).

In summary, no adverse effects in the fetus or newborn attributable to the use of acyclovir during pregnancy have been reported. Congenital malformations have been reported in infants exposed during pregnancy, but these do not appear to be related to the drug. Systemic IV treatment is indicated for life-threatening disseminated HSV infections to reduce the maternal, fetal, and infant mortality of these infections. Oral acyclovir treatment of primary genital HSV infections also appears to be indicated to prevent adverse fetal outcomes, such as prematurity, IUGR, and neonatal HSV infection. In contrast, the benefit of therapy to prevent recurrent genital HSV infection and to reduce the need for cesarean section has not been established. At least one study has failed to find such a benefit, but additional controlled studies with larger subject populations are needed. Because there is more human pregnancy experience with acyclovir than with similar antiviral agents (e.g., valacyclovir or famciclovir) and this experience does not demonstrate a major risk, some authors consider acyclovir to be the drug of choice when indicated (63,64). However, long-term studies of children exposed in utero to acyclovir are needed.

Required statement: The registry findings do not show an increase in the number of birth defects identified among the prospective reports when compared with those expected in the general population. In addition, there is no pattern of defects among prospective and retrospective reports. These findings should provide some assurance in counseling women following prenatal exposure. While the registry data are sufficient to exclude a 7-fold increase in risk of overall birth defects, these data cannot address the risk of rare or specific defects or long-term follow-up for defects that may be detected after the postnatal period, consistent with this type of registry design. In addition, underreporting, differential reporting, and losses to follow-up were potential limitations of the registry. Despite these limitations, the registry was intended to supplement animal toxicology studies and assist clinicians in weighing the risks and benefits of treatment for individual patients and circumstances.

Breast Feeding Summary

Acyclovir is concentrated in human milk with levels usually exceeding those found in maternal serum (65,66,67,68 and 69). In an in vitro experiment, the transfer of acyclovir from the plasma to breast milk was determined to be due to passive diffusion (65).

A woman, breast feeding a 4-month-old infant, was treated with acyclovir 200 mg orally every 3 hours (five times daily) for presumed oral herpes (66). She had taken 15 doses of the drug before the study dose. Approximately 9 hours after her 15th dose, she was given another 200-mg dose and paired maternal plasma and breast milk samples were drawn at 0, 0.5, 1.5, 2.0, and 3.0 hours. Breast feeding was discontinued during the study interval. Milk:plasma ratios ranged from 0.6 to 4.1. Milk concentrations were greater than those in maternal serum at all times except at 1.5 hours, the time of peak plasma concentration (4.23 mol/L). (Note: 1 mol/L = 0.225 g/mL [10]). The initial level in the milk was 3.3 mol/L, reflecting the doses taken prior to the study period. The highest level measured in milk was 5.8 mol/L at 3.2 hours, but this was not the peak concentration because it was still rising at the time of sampling. Acyclovir was demonstrated in the infant's urine. Based on the poor lipid solubility of the drug, the pKa's, and other known pharmacokinetic parameters, the authors calculated a theoretical milk:plasma ratio of 0.15 (66). Because the actual measured ratio was much greater than this value, the authors concluded that acyclovir entered the milk by an active or facilitated process that would make it unique from any other medicinal agent (66). The maximum ingested dose, based on 750 mL of milk/day, was calculated to be 1500 g/day, approximately 0.2 mg/kg/day in the infant, or about 1.6% of the adult dose. This was thought not to represent an immediate risk to the infant, and, in fact, no adverse effects of the exposure were observed in the infant.

In a second case, a woman 1 year postpartum was treated with oral acyclovir, 200 mg five times a day, for presumed herpes zoster (67). The mean concentrations in the milk and serum were 1.06 g/mL and 0.33 g/mL, respectively, a milk:plasma ratio of 3.24. Detectable amounts were present in both serum and milk 48 hours after the last dose with an estimated half-life in the milk of 2.8 hours (67). The estimated amount of acyclovir ingested by the infant consuming 1,000 mL/day of milk was about 1 mg.

Two recent studies measured the excretion of acyclovir in milk (68,69). In one, a woman 6 weeks postpartum suffering from eczema herpeticum received acyclovir IV 300 mg three times daily for 5 days (68). Breast feeding was interrupted during the treatment. Serum and milk samples were collected after the last dose at 6-hour intervals for 4 days. Acyclovir levels in the milk exceeded those in the serum at every analysis, and within the first 72 hours the milk concentration was 2.25 times higher than that in the serum. During the 88 hours that acyclovir was detectable in breast milk, a total of 4.448 mg was excreted (3.515 mg [79%] was recovered during the first 24 hours).

In the other study, a woman was taking 800 mg 5 times daily for herpes zoster (69). She continued to breast-feed her 7-month-old infant. Three random milk samples were obtained (0.259.42 hours after a dose) with acyclovir levels ranging from 18.5 mol/L (4.16 g/mL) to 25.8 mol/L (5.81 g/mL). The highest level occurred 9.42 hours after a dose. No adverse effects were observed in the infant who had ingested from the milk, what was thought to be, a clinically insignificant amount of acyclovir (0.73 mg/kg/day or about 1% of the maternal dose in mg/kg/day) (69).

Because acyclovir has been used to treat herpes virus infections in the neonate, and because of the lack of adverse effects in the above cases, mothers undergoing treatment with acyclovir can probably breast-feed safely. The American Academy of Pediatrics considers acyclovir to be compatible with breast feeding (70).

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