Pregnancy Outcomes Following Systemic Prenatal Acyclovir Exposure - - June 1, 1984-June 30, 1993

Herpes infections are common among women of reproductive age (i.e., aged 15-44 years) (1). Acyclovir (Zovirax Registered *), an antiviral drug effective in the treatment of herpes simplex infection, was approved by the Food and Drug Administration (FDA) in 1984. Since its approval, the effects of acyclovir on human pregnancies have not been determined. However, inadvertent pregnancy exposures to acyclovir were expected to occur among women in whom treatment had been indicated for preexisting herpes simplex infections. Some physicians have reported intentional use of acyclovir during pregnancy for treatment of life-threatening herpes simplex infection. ** To assess the outcomes of pregnancies exposed to acyclovir, the Acyclovir in Pregnancy Registry was established on June 1, 1984, by the manufacturer, in collaboration with CDC. This report summarizes data on pregnancies reported to the registry through June 30, 1993.

The registry is managed by the Burroughs Wellcome Co. (Research Triangle Park, North Carolina) -- the manufacturer of the drug -- with oversight from an advisory committee with representation from CDC, a county health agency, and Burroughs Wellcome Co.; committee members have expertise in sexually transmitted diseases, teratology, epidemiology, and pharmacology. Reports to the registry have been received from physicians, other health professionals, and persons using the drug. A prenatal exposure to acyclovir is defined as inadvertent or intentional use of oral or intravenous acyclovir at any time during pregnancy. Information is obtained from mailed questionnaires (primarily to obstetricians) regarding pregnancy dates; maternal risk factors; dose, length, and indication of acyclovir therapy; and pregnancy outcome. Telephone contacts are used to clarify or obtain additional information about pregnancy outcomes.

Birth defects identified up to the first year of life are included in the registry, but for most reports, defects are generally identified during the neonatal period. The registry considers any report of an exposure, whether written or oral, to be a registered case even if the initial report provided insufficient baseline data to allow for adequate follow-up (e.g., an estimated date of delivery or medical chart number).

From June 1, 1984, through June 30, 1993, 811 prospective reports of women with a pregnancy exposure to acyclovir were received from 18 countries ***; 210 (26%) women were lost to follow-up. For 132 (63%) of the 210 reports, attempts to obtain follow-up information did not yield a response from the health-care professional who reported; for 64 (30%), the pregnancy outcome was unknown to the reporter because the patient did not remain under the reporter's care; and for 11 (5%), the reporting health-care professional had left the practice/institution from which the original report was received. The reason for loss to follow-up could not be determined for two (1%) reports, and the patient refused to allow release of medical information at the time of follow-up for one ( less than 1%) report.

Of the 601 (74%) women for whom pregnancy outcome data were obtained (Table_1), 456 (76%) were being treated for herpes simplex virus; 120 (20%), for varicella-zoster virus; and 25 (4%), for other or unspecified conditions. Pregnancy exposures for 425 women occurred during the first trimester. Outcomes of these pregnancies were legal induced abortions (67 {16%}), spontaneous abortions (47 {11%}), and live-born infants without birth defects (298 {70%}). Of the 311 live-born infants exposed to acyclovir during the first trimester, 13 (4%) had a birth defect. The birth defects reported were heterogeneous, and no specific pattern was noted. Reported by: R Eldridge, E Andrews, PhD, H Tilson, MD, Div of Epidemiology, Surveillance, and Pharmacoeconomics, G Davis, PhD, Infectious Diseases, Burroughs Wellcome Co., Research Triangle Park, North Carolina; B Hurn, MD, Clinical and Safety Surveillance Svc, Wellcome Research Laboratories, Beckenham, England. ER Alexander, MD, Seattle-King County Health Dept, Seattle. Div of Sexually Transmitted Diseases and HIV Prevention, National Center for Prevention Svcs; Div of Birth Defects and Developmental Disabilities, National Center for Environmental Health, CDC.

Editorial Note

Editorial Note: Based on comparisons with birth defects surveillance data maintained by CDC, the registry findings summarized in this report indicate no increased risk for birth defects among infants born to women exposed to acyclovir during pregnancy (3). Human teratogens often cause a recognizable pattern of birth defects; in this cohort of exposed pregnancies, no pattern of birth defects was noted. Therefore, the findings in this report should assist in counseling women regarding prenatal exposure to acyclovir while surveillance continues. Potential limitations of this and other registries include differential reporting of outcomes, losses to follow-up, underreporting, and small sample size. Although, the current sample size of the registry is sufficient to detect a teratogenic risk of twofold over the 3% baseline rate of birth defects, it is not yet sufficient to detect smaller increases in risk if they exist.

Acyclovir is available as a prescription medication and is used most commonly in its oral form to treat genital herpes; it is also used to treat primary varicella (chickenpox) and varicella zoster (shingles). Among users of oral acyclovir in the United States, an estimated 30%-50% are women aged 15-44 years. All formulations of acyclovir are assigned FDA pregnancy category C status ****, which indicates that safety in human pregnancies has not been determined; therefore, the drug should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. As with most drugs, no formal testing has been performed in pregnant women.

The registry described in this report is an effective collaboration involving the manufacturer, public health and health-care professionals, and federal agencies to evaluate the potential risk of new drugs for which inadvertent pregnancy exposures are likely to occur. A similar registry has been recently established for antiretroviral drugs used in the treatment of persons infected with human immunodeficiency virus.

This registry continues to register pregnancy exposures to acyclovir; health-care providers are encouraged to report such exposures to the registrar ({800} 722-9292, extension 58465 {from the United States} or {919} 315-8465 {from other countries}). Copies of the updated registry report are available from the same telephone numbers. Written reports and requests should be addressed to Acyclovir in Pregnancy Registry, Burroughs Wellcome Co., 3030 Cornwallis Road, Research Triangle Park, NC 27709.

References

1. Johnson RE, Nahmias AJ, Magder LS, Lee FK, Brooks CA, Snowden CB. A seroepidemiologic survey of the prevalence of herpes simplex virus type 2 infection in the United States. N Engl J Med 1989;321:7-12.

2. CDC. 1993 Sexually transmitted diseases treatment guidelines. MMWR 1993;42(no. RR-14)(in press).

3. CDC. Congenital malformations surveillance report, January 1982- December 1985. Atlanta: US Department of Health and Human Services, Public Health Service, 1988.

* Use of trade names and commercial sources is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services. 

** CDC's 1993 Sexually Transmitted Diseases Treatment Guidelines state that the safety of systemic acyclovir therapy among pregnant women has not been established. In the presence of life-threatening maternal herpes simplex virus infections (e.g. disseminated infection that includes encephalitis, pneumonitis, and/or hepatitis), acyclovir administered intravenously is indicated. Among pregnant women without life-threatening disease, systemic acyclovir treatment should not be used for recurrences nor should it be used as suppressive therapy near term (or other times during pregnancy) to prevent reactivation (2). 

*** Australia, Bermuda, Canada, Czech Republic, Finland, France, Germany, Greece, Ireland, Malaysia, New Zealand, Oman, South Africa, Spain, Sweden, the Netherlands, the United Kingdom, and the United States. *

*** Pregnancy category C indicates that the risk associated with drug exposure to the fetus is unclear because human studies are lacking, and animal studies are either positive for fetal risk or lacking. However, potential benefits may justify the potential risk. FDA's pregnancy categories are based on the degree to which available information has ruled out risk to the fetus. Ratings range from "A," for drugs that have been tested for teratogenicity under controlled conditions without showing evidence of damage to the fetus, to "D" for drugs that are teratogenic but have no safer alternatives. An "X" rating is reserved for drugs that should never be used during pregnancy.
Table_1
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TABLE 1. Acyclovir exposure during pregnancy, by earliest trimester of exposure and
outcome -- June 1, 1984-June 30, 1993
=====================================================================================
                                Earliest trimester of exposure
                                ------------------------------
  Outcome                        First      Second      Third      Total
------------------------------------------------------------------------
  Birth defects                    13          1           2         16

  No birth defects
    Live births                   298         68         104        470
    Spontaneous fetal losses       47          0           1         48
    Legal induced abortions        67          0           0         67

  Total                           425         69         107        601
------------------------------------------------------------------------
=====================================================================================

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