acyclovir and Abnormalities--Drug-Induced

Topics: Abnormalities, Drug-Induced; Acyclovir; Animals; Animals, Newborn; Antiviral Agents; Cell Transformation, Neoplastic; Eye; Female; Growth; Guanine; Immunity; Lethal Dose 50; Male; Mutagenicity Tests; Mutation; Neoplasms; Pregnancy; Reproduction; Skin; Wound Healing

Herpes simplex and herpes zoster infections are common and often treated with antiviral drugs including acyclovir, valacyclovir, and famciclovir. Safety of these antivirals when used in the first trimester of pregnancy is insufficiently documented.. To investigate associations between exposure to acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and risk of major birth defects.. Population-based historical cohort study of 837,795 live-born infants in Denmark from January 1, 1996, to September 30, 2008. Participants had no diagnoses of chromosomal aberrations, genetic syndromes, birth defect syndromes with known causes, or congenital viral infections. Nationwide registries were used to ascertain individual-level information on dispensed antiviral drugs, birth defect diagnoses (categorized according to a standardized classification scheme), and potential confounders.. Prevalence odds ratios (PORs) of any major birth defect diagnosed within the first year of life by exposure to antiviral drugs.. Among 1804 pregnancies exposed to acyclovir, valacyclovir, or famciclovir in the first trimester, 40 infants (2.2%) were diagnosed with a major birth defect compared with 19,920 (2.4%) among the unexposed (adjusted POR, 0.89; 95% confidence interval [CI], 0.65-1.22). For individual antivirals, a major birth defect was diagnosed in 32 of 1561 infants (2.0%) with first-trimester exposure to acyclovir (adjusted POR, 0.82; 95% CI, 0.57-1.17) and in 7 of 229 infants (3.1%) with first-trimester exposure to valacyclovir (adjusted POR, 1.21; 95% CI, 0.56-2.62). Famciclovir exposure was uncommon (n = 26), with 1 infant (3.8%) diagnosed with a birth defect. Exploratory analyses revealed no associations between antiviral drug exposure and 13 different subgroups of birth defects, but the number of exposed cases in each subgroup was small.. In this large nationwide cohort, exposure to acyclovir or valacyclovir in the first trimester of pregnancy was not associated with an increased risk of major birth defects.

Topics: 2-Aminopurine; Abnormalities, Drug-Induced; Acyclovir; Adolescent; Adult; Antiviral Agents; Cohort Studies; Denmark; Famciclovir; Female; Herpes Simplex; Herpes Zoster; Humans; Middle Aged; Pregnancy; Pregnancy Trimester, First; Retrospective Studies; Risk; Valacyclovir; Valine; Young Adult

Topics: Abnormalities, Drug-Induced; Acyclovir; Antiviral Agents; Cohort Studies; Data Collection; Denmark; Female; Herpes Simplex; Humans; Pregnancy; Pregnancy Trimester, First; Registries; Sample Size; United States

Topics: 2-Aminopurine; Abnormalities, Drug-Induced; Acyclovir; Cohort Studies; Data Interpretation, Statistical; Denmark; Famciclovir; Female; Humans; Pregnancy; Pregnancy Trimester, First; Prescriptions; Risk; Valacyclovir; Valine

Oral acyclovir is commonly used for genital herpes and other herpesvirus infections. Data on potential fetal risk are extremely limited. From 1984 to 1998, the Acyclovir in Pregnancy Registry monitored birth outcomes of women exposed to oral or intravenous acyclovir during pregnancy. This report describes the final results.. The registry was publicized to health care providers most likely to diagnose pregnancy; providers called the registry telephone number, then mailed in a brief questionnaire. Pregnancy outcomes were categorized either as outcomes with birth defects or outcomes without birth defects, subcategorized as live births, spontaneous pregnancy losses (including stillbirths), and induced abortions. Birth defects were defined using a modification of the CDC definition for birth defects surveillance systems. Observed rates were compared to the rate (3.2%) of birth defects expected in the general population.. Between June 1, 1984 and June 30, 1998, 1695 pregnancies exposed to oral or IV acyclovir were registered; 461 (27%) were lost to follow-up. A total of 1234 pregnancies in 24 countries were followed, with a total of 1246 outcomes. Among 1246 pregnancy outcomes, 756 involved acyclovir exposure in the first trimester, 197 in the second trimester, and 291 in the third trimester. Among live births with first trimester acyclovir exposure, risk of birth defects was 19 of 596 (3.2%; 95% CI, 2.0-5.0%). No unusual defects or pattern of defects were apparent.. The observed rates and types of birth defects for pregnancies exposed to acyclovir did not differ significantly from those in the general population. Birth Defects Research (Part A), 2004. Published 2004 Wiley-Liss, Inc.

Topics: Abnormalities, Drug-Induced; Acyclovir; Antiviral Agents; Female; Humans; Maternal-Fetal Exchange; Pregnancy; Pregnancy Outcome

This study aimed to examine the risk of adverse pregnancy outcomes in children born to mothers who redeemed a prescription for systemic or topical acyclovir during pregnancy. Data on prescriptions of acyclovir were obtained from the Danish North Jutland Prescription Database and data on pregnancy outcomes from the Danish Medical Birth Registry and the County Hospital Discharge Registry. The risk of malformations, low birth weight, preterm birth and stillbirth in users of acyclovir were compared with non-exposed women using a follow-up design, while the risk of spontaneous abortion was examined using a case-control design. 90 pregnant women had redeemed a prescription for systemic acyclovir, and 995 women for topical acyclovir, during 30 d before conception, or during their pregnancies from 1 January 1990 to 31 December 2001. The odds ratios (95% confidence intervals) of the exposed relative to the non-exposed for the systemic and topical acyclovir were: malformations, 0.69 (0.17-2.82) and 0.84 (0.51, 1.39); low birth weight, 2.03 (0.50-8.35) and 0.48 (0.21-1.07); preterm birth, 1.04 (0.38-2.85) and 0.95 (0.70-1.28); stillbirth (for topical acyclovir), 1.70 (0.80-3.60); and spontaneous abortion, 2.16 (0.60-7.80) and 1.29 (0.80-3.60). There is increasing evidence that the use of systemic acyclovir is not associated with an increased prevalence of malformations at birth and preterm delivery. The data for low birth weight and spontaneous abortion are still inconclusive, although the risk of spontaneous abortion is increased in women exposed to acyclovir during the first month of pregnancy. The use of topical acyclovir does not seem to be associated with any adverse pregnancy outcome, although data on stillbirth are inconclusive.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Acyclovir; Administration, Oral; Administration, Topical; Adult; Case-Control Studies; Confidence Intervals; Female; Fetal Death; Follow-Up Studies; Gestational Age; Herpes Simplex; Humans; Infant, Newborn; Infant, Premature; Logistic Models; Obstetric Labor, Premature; Odds Ratio; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Registries; Risk Assessment; Thailand

Glaxo Wellcome becomes aware of prenatal exposures to its medications as early as the clinical trial phase of development. An international process for monitoring prenatal exposure to all Glaxo Wellcome medicines has been developed. For specific products there are prospective pregnancy registries.. The registries are observational, case-registration, and follow-up studies designed to detect evidence of teratogenicity associated with specific medications. After prenatal exposure to the registry medication, pregnancies are registered prospectively, through voluntary reports by health care providers. An advisory committee of independent scientists for each registry reviews data and advises in dissemination of information. Risk of birth defects, as defined by the Centers for Disease Control and Prevention, is compared with published risks both in women in the general population and in women with the underlying condition being treated, if available.. The following data show results from the prospective first-trimester exposures registered since establishment of each registry. The published risk of birth defects in the general population range is 3% to 5%, and the risk in women with epilepsy is 6% to 9%. The proportions of outcomes with birth defects are as follows: in the Acyclovir (antiviral medication) Pregnancy Registry (1984-1998) (19/581), 3.3% (95% confidence interval, 2.0%-5.2%); in the Lamotrigine (monotherapy and polytherapy antiepileptic medication) Pregnancy Registry (1992-September 1998) (8/123), 6.5% (95% confidence interval, 3.1%-12.8%); in the Sumatriptan (migraine medication) Pregnancy Registry (1996-October 1998) (7/183), 3.8% (95% confidence interval, 1.7%-8.0%). The Valacyclovir, Bupropion, and Naratriptan registries have insufficient data for analysis.. None of the registries has provided a risk estimate exceeding that expected in the disorder treated, and no pattern of defects has been observed. Whereas information from the larger registries is reassuring regarding risk, these studies cannot rule out possible small excess risks from use of these drugs in pregnancy. Data obtained through these registries are shared with the medical community as a supplement to animal toxicology studies to assist in weighing potential risks and benefits of treatment for individual patients. The success of the registries depends on the continued willingness of the obstetrics and gynecology community to notify the registries of prenatal exposures.

Topics: Abnormalities, Drug-Induced; Acyclovir; Anticonvulsants; Antiviral Agents; Drug Industry; Epilepsy; Female; Humans; Lamotrigine; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, First; Prospective Studies; Registries; Risk Factors; Sumatriptan; Triazines; Vasoconstrictor Agents

Topics: 2-Aminopurine; Abnormalities, Drug-Induced; Acyclovir; Amantadine; Antiviral Agents; Cidofovir; Contraindications; Cytosine; Drug Resistance, Microbial; Eye Infections, Viral; Famciclovir; Foscarnet; Ganciclovir; Guanine; Humans; Interferon-alpha; Kidney Diseases; Lamivudine; Organophosphonates; Organophosphorus Compounds; Prodrugs; Ribavirin; Rimantadine; Trifluridine; Valacyclovir; Valine; Virus Diseases

Five pregnant rats were treated during organogenesis with sc injections of acyclovir (50 mg/kg body weight) on days 9, 10 and 11 of pregnancy. The fetuses (N=62) were evaluated on day 20 of gestation and presented decreased body weight as well as delayed differentiation of fetal rat palate epithelium, with increased nuclear volume, decreased cytoplasmic and cellular volumes, decreased epithelial and keratin thicknesses, and increased cellular numerical density.

Topics: Abnormalities, Drug-Induced; Acyclovir; Animals; Antiviral Agents; Body Weight; Embryonic and Fetal Development; Epithelium; Female; Mouth Mucosa; Palate; Palate, Soft; Pregnancy; Rats; Rats, Wistar; Statistics, Nonparametric; Teratogens

Topics: Abnormalities, Drug-Induced; Acyclovir; Female; Fetal Diseases; Humans; Pregnancy; Registries; Risk Factors

Herpes infections are common among women of reproductive age (i.e., aged 15-44 years). Acyclovir (Zovirax), 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.

Topics: Abnormalities, Drug-Induced; Abortion, Legal; Abortion, Spontaneous; Acyclovir; Female; Humans; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Registries

The effect of aciclovir (ACV) on embryonic development was investigated using the chick embryo in ovo and treatment during organogenesis. ACV 30-1000 micrograms was applied as single doses prior to or after 24 h of incubation into the yolk sac, and ACV 3-100 micrograms after 2, 3 or 4 days of incubation (DI) directly to the embryo. Data were evaluated after a total of 8 days of incubation. (1) A dose-related increase in the rate of abnormal development was found in the surviving embryos. Depending on the route of drug administration a dose of 300, respectively, 5 micrograms ACV/egg had to be applied to induce 50% abnormal development. (2) Gross structural abnormalities of the surviving embryos mainly concerned the beak and the extremities. With the experimental set-up used a different pattern of abnormalities in the survivors after treatment at various stages could not be observed. The results are compared with data obtained with ACV in rodents in our laboratory. It is suggested that chick embryos are also capable of converting ACV into its triphosphate to interfere with DNA metabolism, probably through a chain break mechanism.

Topics: Abnormalities, Drug-Induced; Acyclovir; Animals; Chick Embryo; Cytarabine; DNA; Dose-Response Relationship, Drug; Embryonic and Fetal Development

Several virustatic agents are known to be teratogenic in laboratory animals. Since routinely performed in vivo studies do not always offer the best conditions to detect the teratogenic potential of a drug, we used a combined in vivo/in vitro approach for comparative studies on the prenatal toxicity of five nucleoside analogues. Rat embryos were exposed for 48 h to various concentrations of vidarabine-phosphate (VAP), ganciclovir (GCV), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxycytidine (ddC) and zidovudine (= azidothymidine, AZT) in a whole-embryo culture system. The steepness of the concentration-response curves as well as the induced abnormality pattern (head, neural tube, shape) were similar for these compounds. However, a wide range in embryotoxic potency was observed: VAP was the most potent compound (100% abnormal embryos at 25 microM) in this in vitro system, while AZT showed the lowest potency to interfere with normal embryonic development (40% abnormal embryos at 3000 microM). In addition to these experiments we treated rats on day 10 of gestation with three s.c. injections (8 a.m.; 12 a.m.; 4 p.m.) of 200 mg of each drug/kg body wt. The embryos were evaluated on day 11.5 of gestation, i.e. at a time of development corresponding to the developmental stage at the end of the whole-embryo culture. The same criteria were used as during the in vitro studies for the evaluation of these in vivo exposed embryos. With VAP and GCV we obtained similar results with both exposure routes (in vitro and in vivo), while no abnormalities were detectable with the other compounds after exposure in utero.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abnormalities, Drug-Induced; Acyclovir; Animals; Antiviral Agents; Embryo, Mammalian; Female; Head; Male; Nucleosides; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains

Following three s.c. injections of acyclovir (100 mg acyclovir/kg) into rats on day 10 of pregnancy 19 litters were evaluated on day 21 of gestation and the effects were compared to the results obtained from controls (nine litters) which received the vehicle (0.1 N NaOH) only. The following results were obtained (treated group versus control group): 1) Implantations/litter: 11.2 +/- 1.3 versus 10.2 +/- 1.1; 2) resorptions/implantations: 27.7% versus 2.2%; 3) number of viable fetuses evaluated: 154 versus 90; 4) fetuses with anomalies of the skull: 78% versus 12%; 5) fetuses with anomalies of the vertebral column: 38% versus 13%; 6) gross-structural anomalies predominantly affected the skull and tail. The most frequently registered defects were: os tympanicum (smaller): 23%, os tympanicum (missing): 23%; missing tail: 7%; protruding tongue (15%); none of these defects were seen in the control fetuses. Postnatally we observed a high mortality rate among the offspring. From a total of 85 newborn (nine litters) we obtained 73 viable offspring (9.1 +/- 3.4); 81% of them had tail alterations. In the control group of eight litters (9.4 +/- 2.3) no tail alterations occurred. On day 21 postnatally 40 viable offspring were alive (mortality rate: 38.8%). Nearly all of these animals had visible alterations at multiple sites of their bodies; most frequently observed were: tail impairment, closed eyes, dragging hind-limbs, and urogenital alterations (e.g. testicular atrophy). These studies how for the first time that prenatal treatment with acyclovir induces gross-structural defects which persist postnatally.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abnormalities, Drug-Induced; Acyclovir; Animals; Body Weight; Female; Litter Size; Maternal-Fetal Exchange; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred Strains; Teratogens

Observational epidemiologic methods are being used to evaluate the safety of acyclovir in pregnancy. An essential component of this research is the establishment of a baseline expectation of pregnancy outcomes among women with herpes not receiving acyclovir. Continuing studies will be described in this report. To supplement these structured studies, an international case registration study was established. Through the Acyclovir in Pregnancy Registry, all cases of reported prenatal exposures to acyclovir are tracked to ascertain maternal exposure, risk factor, and pregnancy outcome information. The reports originate in all countries where oral acyclovir is marketed; data consolidation and analysis are coordinated at Burroughs Wellcome Co. with the assistance of a government/industry advisory panel. This presentation summarizes provisional data from the prospective reports, including trimester of exposure and reported outcomes of pregnancy. The total number of monitored pregnancies remains too small to support conclusions about the safety of acyclovir during pregnancy at this point. The potential for the registry and other epidemiologic studies to address the safety-in-pregnancy question will be discussed.

Topics: Abnormalities, Drug-Induced; Acyclovir; Evaluation Studies as Topic; Female; Herpes Simplex; Humans; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Product Surveillance, Postmarketing; Prospective Studies; Registries; United Kingdom; United States

Examples of a combined approach using in vivo as well as in vitro methods for the assessment of prenatal toxicity are presented. The topics discussed include the analysis of the possible embryotoxic potential of valproic acid (VPA), female sex hormones, bis(tri-n-butyltin) oxide (TBTO), and acyclovir and the problem of supplementing in vitro systems with drug-metabolizing activity.

Topics: Abnormalities, Drug-Induced; Acyclovir; Animals; Disinfectants; Embryo, Mammalian; Estrogens; Mice; Mice, Inbred C57BL; Organ Culture Techniques; Progesterone; Rats; Teratogens; Trialkyltin Compounds; Valproic Acid

A short review on available toxicological data of acyclovir is given. In principle, a substance which interferes with the nucleic acid metabolism should be judged with special care for carcinogenic and mutagenic properties. Although the substance is mainly incorporated into the viral genome, very high doses have also shown genotoxic effects in mammalian cell systems. However, since such effects are found only in doses where also naturally occurring nucleosides show the same effect, this manifestation does not appear to represent a potential hazard. In general, acyclovir seems to have a low toxic potential. Data from available investigations do not give support for a mutagen, teratogen or carcinogen hazard in patients receiving recommended clinical doses. An awareness of a potential risk for the fetus, especially with infusion treatment should nonetheless be kept in mind. The possibility of kidney damage with accumulation of the drug should also be taken into account. Such damage seems to have less importance with p.o. administration, and has little or no importance with the proposed use of eye ointment.

Topics: Abnormalities, Drug-Induced; Acyclovir; Animals; Dogs; Female; Humans; Lethal Dose 50; Mice; Mutagenicity Tests; Neoplasms; Pregnancy; Rabbits; Rats

Acyclovir [9-(2-hydroxyethoxymethyl)guanine] interfered with embryonic development in vitro when assessed with the "whole-embryo" culture technique. The "no-observed-effect level" was at 10 microM acyclovir; Minor impairment of embryonic development (retarded development of ear anlagen) was observed in vitro at 25 microM acyclovir in the culture medium. At high concentrations (100 or 200 microM) development of the ear anlagen was largely inhibited. At concentrations of 50 microM acyclovir or higher, additional disturbances of embryonic differentiation in vitro became obvious, resulting in gross structural abnormalities, especially of the brain (telencephalon); Histological examinations confirmed and extended these observations: at 100 microM acyclovir alterations of the neuroepithelium of the ventricles were pronounced, the telencephalon had developed poorly or was almost completely absent, and necroses were seen in the ear anlagen, the maxillary branch and within the somites; In a limb bud culture (mouse embryos, starting with day 11 of gestation) acyclovir interfered with the differentiation of cartilaginous bone anlagen at concentrations of 200 microM and more in the culture medium. A concentration of 100 microM induced no significant effect. Thus, this organ culture system is less sensitive to the action of acyclovir when compared with whole-embryo culture; Contrary to the results achieved with acyclovir, physiological nucleosides (2'-deoxyguanosine and 2'-deoxyadenosine) did not interfere with embryonic development in vitro even at the highest concentration tested (500 microM).

Topics: Abnormalities, Drug-Induced; Acyclovir; Animals; Central Nervous System; Culture Techniques; Deoxyadenosines; Deoxyguanosine; Dose-Response Relationship, Drug; Ear; Embryo, Mammalian; Extremities; Female; Organ Culture Techniques; Rats; Rats, Inbred Strains