isotretinoin and Abnormalities--Drug-Induced

Acne vulgaris is the most common skin disease treated by dermatologists. It can be severe and result in permanent scars. Isotretinoin is the most effective treatment for acne and has the potential for long-term clearance. Prescribing and monitoring protocols can vary widely among prescribers. Recent studies, reports, and consensus statements help shed light on optimizing the use of isotretinoin for acne. A recent literature review is summarized in this article to help the practitioner optimize isotretinoin use for acne. The article outlines the advantages and disadvantages of standard, high-dose, and low-dose isotretinoin regimens; discusses the current status of controversies surrounding isotretinoin (including depression/suicide, pregnancy, and inflammatory bowel disease); reviews monitoring recommendations and treatment for hypertriglyceridemia and elevated transaminase levels; and discusses common adverse effects seen with isotretinoin, along with their treatment and prevention.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Anxiety; Contraception; Depression; Dose-Response Relationship, Drug; Drug Monitoring; Drug Prescriptions; Female; Humans; Inflammatory Bowel Diseases; Isotretinoin; Patient Compliance; Patient Education as Topic; Practice Guidelines as Topic; Pregnancy; Suicide; Teratogens; Wound Healing

Although most teenagers experience acne, for sexual and gender minority teenagers, acne could be more challenging and require specific psychosocial considerations. Acne may be more strongly associated with mental health issues in sexual and gender minority adolescents. Acne development during puberty may trigger gender dysphoria in transgender patients. Transgender and gender nonbinary patients receiving testosterone therapy may experience new or worsening acne. Comprehensive care for moderate to severe acne in sexual and gender minority adolescents should include culturally competent discussions about sexual behaviors, contraception, and/or gender-affirmation treatment plans.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Androgen Antagonists; Androgens; Contraception; Culturally Competent Care; Depression; Dermatologic Agents; Estrogens; Female; Gonadotropin-Releasing Hormone; Humans; Isotretinoin; Male; Mental Health; Sex Reassignment Procedures; Sexual and Gender Minorities; Sexual Health; Spironolactone; Suicidal Ideation; Testosterone; Transgender Persons

Isotretinoin has revolutionized the treatment of severe acne vulgaris, a condition which if left untreated may result in significant socio-psychological implications for those affected. Timely access to isotretinoin therapy is important to avoid the risks of potential physical and emotional scarring. However, due to its high risks of teratogenicity, isotretinoin must be used with care in females of childbearing potential. Since isotretinoin's introduction, numerous risk management programs have been implemented across the world in an attempt to prevent isotretinoin use in pregnancy. This paper aims to provide an evidence-based review of the risk management programs for isotretinoin in Australia, Europe, Singapore, New Zealand, and the United States of America. The effectiveness of these programs and the factors leading to isotretinoin exposure in pregnancy are critically analyzed in an effort to inform the future direction with respect to designing the ideal regulatory program. Stringent risk management programs, such as the iPLEDGE in the US and Pregnancy Prevention Program (PPP) in Europe, may not be effective in reducing the risks of fetal exposure to isotretinoin when used alone. There is evidence that such strenuous regulation results in increased fear of teratogenic risks but does not translate into a reduced rate of pregnancies exposed to isotretinoin. A successful program must prioritize education about effective contraception, while minimizing any extraneous requirements, to ensure that women are not inadvertently undertreated for acne.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Australia; Dermatologic Agents; Europe; Female; Humans; Isotretinoin; New Zealand; Pregnancy; Risk Management; Singapore; Teratogens; United States

Although genetic defects are the leading cause of central nervous system malformations including in the posterior fossa, specific malformative patterns should alert the clinician to consider rather a teratogenic etiology. We discuss the imaging features of 2 mid-hindbrain malformations consecutive to the intake of isotretinoin (Roaccuatane®; case 1) and misoprostol (Cytotec®; case 2) during pregnancy and review the pertinent literature. We correlate the morphological appearance of the mid-hindbrain malformation, as seen on high-resolution magnetic resonance imaging to possible drug-induced pathogenetical mechanisms. The recognition of characteristic imaging patterns enables diagnosis of and/or confirmation of suspected drug-induced hindbrain malformations. This has important medicolegal implications and also clinical significance to avoid unsuccessful and misleading genetic testing.

Topics: Abnormalities, Drug-Induced; Dermatologic Agents; Female; Humans; Imaging, Three-Dimensional; Infant; Isotretinoin; Magnetic Resonance Imaging; Male; Misoprostol; Oxytocics; Pregnancy; Prenatal Exposure Delayed Effects; Rhombencephalon

Topics: Abnormalities, Drug-Induced; Abortion, Therapeutic; Acne Vulgaris; Adult; Female; Humans; Isotretinoin; Patient Education as Topic; Pregnancy; Pregnancy, High-Risk; Risk Assessment; Teratogens

Most of the publications on isotretinoin, pregnancy and compliance with the pregnancy prevention programme (PPP) originate from North America. Information specific for the European situation is very limited. The aim of this study was to identify publications describing the use of isotretinoin in humans and the compliance with the PPP in Europe, a systematic search in Medline and Embase was conducted using the terms 'isotretinoin, pregnancy (and Europe)'. Furthermore, a manual search in publications was performed. A total of 17 publications were identified. Publications consisted of case reports of exposed pregnancies, surveys among dermatologists or pharmacists and database studies evaluating compliance with the PPP. The studies and surveys dealt with groups of patients exposed to isotretinoin before or during pregnancy and/or compliance with the isotretinoin PPP. Where the information was provided, in 6-26% of cases isotretinoin was prescribed in full accordance with the PPP. Pregnancy incidence was seen in 0·2-1·0 per 1000 women of childbearing age using isotretinoin. Between 65% and 87% of these pregnancies were terminated. This review of studies in Europe performed to date shows failures in the implementation of the PPP. Therefore, the isotretinoin PPP must be scrutinized to identify whether new measures should be taken or whether the failures in the implementation need to be corrected. New measures should take into account the definition of the ultimate goal of a PPP and the acceptable burden. In the meantime, stakeholders could make a start with adjustments in the implementation of the PPP by taking responsibility and enhancing the performance by explicit instructions, monitoring the performance and adjusting, if necessary.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Child; Dermatologic Agents; Europe; Female; Guideline Adherence; Health Surveys; Humans; Isotretinoin; Middle Aged; Pregnancy; Teratogens; Young Adult

This review of the central nervous system (CNS) and behavioral teratology of the retinoids over the last 50 years is a commemorative retrospective organized by decade to show the prominent research focus within each period and the most salient findings. In the 1960s, research focused on the gross CNS malformations associated with exposure and the delineation of dose-response and stage-specific responses in rodent models. Relevant scientific events before and during the 1960s are also discussed to provide the zeitgeist in which the field of neurobehavioral teratology emerged in the 1970s. During this period, studies demonstrated that adverse effects on postnatal behavior could be produced in animals exposed to doses of vitamin A lower than those that were teratogenic or impacted growth. Work during the 1980s showed an overrepresentation of behavioral studies focused on the reliability of screening methods, while the marked effects of human exposure were illustrated in children born to women treated with isotretinoin during pregnancy. The human catastrophe invigorated research during the 1990s, a period when technological advances allowed more elegant examinations of the developing CNS, of biochemical, cellular, and molecular developmental events and regulatory actions, and of the effects of direct genetic manipulations. Likewise, research in the 1990s reflected a reinvigoration of research in neurobehavioral teratology evinced in studies that used animal models to try to better understand human vulnerability. These foci continued in the 2000-2010 period while examinations of the role of retinoids in brain development and lifelong functioning became increasingly sophisticated and broader in scope. This review of the work on retinoids also provides a lens on the more general ontogeny of the field of neurobehavioral teratology. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Topics: Abnormalities, Drug-Induced; Animals; Brain; Central Nervous System; Female; History, 20th Century; History, 21st Century; Humans; Hypervitaminosis A; Isotretinoin; Male; Pregnancy; Retinoids; Teratogens; Teratology; Tretinoin

Acne benefits from a series of treatments. The introduction of isotretinoin was a therapeutic breakthrough which considerably improved both the evolution and the prognosis of the disease. Indications of this retinoid kept changing over the past twenty years. New clinical conditions emerged including the management of disease recurrences. The daily dosages must be selected according to the type of acne, the gender of the patient and the pharmaco-economical implications. Teratogenicity must never be neglected as it represents the dreadful adverse event of the drug. A European Directive currently marks out the way to use this retinoid.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Dermatologic Agents; Humans; Isotretinoin

Topics: Abnormalities, Drug-Induced; Anti-Asthmatic Agents; Anticonvulsants; Asthma; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Humans; Isotretinoin; Patient Care Planning; Preconception Care; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Care; Risk; Teratogens

Isotretinoin is an effective treatment for severe acne, a condition which can be physically, emotionally, and socially disabling. Because the drug is teratogenic, causing severe birth defects, women taking the drug are directed to avoid pregnancy. In the United States, a series of risk reduction programs have been implemented that aim to prevent pregnant women from taking the drug and to prevent women taking it from getting pregnant. The most recent, and most stringent, is an Internet-based, performance-linked system called iPLEDGE, which tries to ensure that the drug is dispensed only when there is documentary proof that the patient is not pregnant and is using two forms of birth control. Is iPLEDGE the best way to reduce isotretinoin birth defects, or is it an unproven and overly burdensome system?

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Contraindications; Female; Humans; Isotretinoin; Pregnancy; Risk Management

Isotretinoin is a very effective medication for the treatment of severe recalcitrant acne. However, its use is associated with many side effects, some of which can be very serious. The most important issue is its teratogenicity, which has resulted in new pregnancy prevention policies and programmes implemented by the manufacturer. Recently, the association of isotretinoin with depression has been recognised and new guidelines have been adopted for this possible side effect. The most common adverse events, observed during treatment, are mucocutaneous and ophthalmological. In addition, laboratory abnormalities and effects in the nervous, musculoskeletal, gastrointestinal, pulmonary and other systems have been described.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Cheilitis; Depression; Humans; Isotretinoin; Practice Guidelines as Topic

Topics: Abnormalities, Drug-Induced; Alcoholism; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Anticonvulsants; Dermatologic Agents; Developmental Disabilities; Female; Fetal Alcohol Spectrum Disorders; Humans; Infant, Newborn; Isotretinoin; Lithium; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Smoking

Acne is a chronic disease which evolves under periodic eruptions. Resolution occurs around the late teens. Conventional treatment clears the lesions, but treatment by isotretinoin alone can achieve long remissions indeed definitive clearing. Indications are nodulo-cystic acne and resistant acne to a conventional treatment of at least 3 months duration. This drug is prescribed in cures, a cure is the period during which the patient receives a continuous treatment. The daily dose is computed according to the patient's weight and varies between 0.5 and 1 mg/kg. To prevent relapses, it is recommended to cumulate a dose between 100 and 150 mg/kg. No other topical or systemic treatment is needed. Side effects exist, among which teratogenicity is the most severe. Very strict contraception is necessary for women of child-bearing age. The most important mucocutaneous side effect is dryness and has to be counteracted by emollients. It is recommended that the drug be prescribed by doctors having a fair experience of oral retinoids and a perfect understanding of the teratogenic risk of the drug.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Administration, Oral; Contraception; Drug Administration Schedule; Humans; Isotretinoin; Recurrence; Risk Factors; Treatment Outcome

After studying the information in this article, the reader should be able to: 1. Describe the purpose of the pregnancy prevention program. 2. Discuss the five most common reasons for unintended pregnancy. 3. List the components of the expanded pregnancy prevention program. Preventing unintended pregnancy is currently an unsolved problem in the United States, especially among teens. However, successful programs to minimize unintended pregnancy do exist and can serve as a model for other efforts. One such program is the Pregnancy Prevention Program, for use when prescribing isotretinoin to women with childbearing potential. Isotretinoin is a known teratogen and is prescribed disproportionately to teens, who are at higher risk of unintended pregnancy. The program has shown impressive effectiveness despite these handicaps, but since exposure to isotretinoin is so harmful to the fetus and some women still become pregnant while taking the drug, the program has been revised to reduce the failure rate further.

Topics: Abnormalities, Drug-Induced; Contraception; Contraceptive Agents; Female; Fetus; Humans; Isotretinoin; Maternal Exposure; Patient Education as Topic; Pregnancy; Program Evaluation; Teratogens

Isotretinoin (Accutane, Roche Laboratories Inc, Nutley, NJ) is an important drug, not only for the treatment of severe acne, but also for other diagnoses and in chemoprevention settings. Because the use of isotretinoin is increasing, it is important for physicians to be aware of the adverse events, toxicities, and management issues related to its use. The most important issue is that of congenital defects, which has resulted in new pregnancy prevention policies and programs implemented by the manufacturer. A relatively new concern is that of depression associated with isotretinoin use, also resulting in new policies placed by the manufacturer and the FDA. The most common adverse effects observed during treatment are mucocutaneous and ocular in nature, but laboratory abnormalities and effects in the nervous, musculoskeletal, gastrointestinal, pulmonary, hematologic, and other systems are also described. Additionally, potential drug interactions, follow-up, and toxicity prevention measures are discussed.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Cheilitis; Dermatologic Agents; Drug Interactions; Eye Diseases; Humans; Isotretinoin; Liver Function Tests; Mental Disorders; Mouth Mucosa; Musculoskeletal Diseases

This paper reviews the teratogenicity of isotretinoin in regard to aspects of species variation, toxicokinetics, and metabolism. Particular emphasis is given to the hypothesis that most effects of isotretinoin (13-cis-retinoic acid) are mediated by isomerization to the all-trans-retinoic acid. This mechanism of action would provide a basis for the understanding of species differences and the extrapolation of experimental results to the human situation and thus improve drug development. The insensitive species (rat, mouse) eliminate the drug rapidly through detoxification to the beta-glucuronide; also, placental transfer is limited in these species. On the other hand, in sensitive species (primates), the drug is predominantly metabolized to the active 13-cis-4-oxo-retinoic acid; placental transfer is more extensive here. The beta-glucuronides showed limited placental transfer in all species examined; these metabolites exhibited very low, if any, measurable concentrations in the human. The 13-cis-retinoic acid is not appreciably bound to cellular retinoid-binding proteins or nuclear receptors and exhibits low tissue distribution and placental transfer. Its access to the nucleus may be extensive. Because of the long half life of 13-cis-retinoic acid, continuous isomerization results in significant area under the concentration-time curve levels of all-trans-retinoic acid in the mouse, monkey and the human; the all-trans-retinoic acid formed is extensively distributed across the placenta and may be an important factor that contributes to the teratogenic potency of 13-cis-retinoic acid. Isomerization cannot explain the teratogenic effects of 13-cis-retinoic acid in the rat and rabbit. It is concluded that the high teratogenic activity of isotretinoin in sensitive species (human, monkey) is related to slow elimination of the 13-cis-isomer, to metabolism to the 4-oxo-derivative, to increased placental transfer, to continuous isomerization and significant exposure of the target tissue to all-trans-retinoic acid; and to lack of binding to cytoplasmic retinoid binding proteins that could possibly result in ready access to the nucleus.

Topics: Abnormalities, Drug-Induced; Animals; Dermatologic Agents; Female; Half-Life; Humans; Isomerism; Isotretinoin; Keratolytic Agents; Maternal-Fetal Exchange; Mice; Pregnancy; Primates; Rabbits; Rats; Teratogens; Tretinoin

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Female; Fetus; Humans; Infant, Newborn; Isotretinoin; Neural Crest; Pregnancy; Prenatal Exposure Delayed Effects; Tretinoin

Topics: Abnormalities, Drug-Induced; Animals; Counseling; Dicyclomine; Doxylamine; Drug Combinations; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Epidemiologic Studies; Female; Fetus; Humans; Infant, Newborn; Information Services; Isotretinoin; Pharmaceutical Preparations; Pregnancy; Pregnancy Complications; Pyridoxine; Risk; Teratogens; Thalidomide

Important determinants or principles in developmental toxicology are: (1) genotype; (2) developmental stage when an insult is hitting; (3) mechanisms of action; (4) pharmacokinetics of the drug in the mother, conceptus and the neonate; (5) the manifestations of embryo/foeto- and neonatal toxicity such as death, malformations, growth inhibition and functional disturbances; and (6) dose-effect and dose-response relationships. The present paper will give a broad review of some important developmental events and sensitivity periods, such as the preimplantation period, the period of gastrulation, organogenesis and placental formation, the foetal and neonatal period during which xenobiotics can cause perturbation in the normal development. Mostly pharmaceuticals are used as examples due to their often well documented effects and sometimes known sensitivity periods. For the postnatal period, some neurotoxic pesticides and environmental pollutants, known to affect adult behaviour in experimental animals after perinatal exposure, are given as examples.

Topics: Abnormalities, Drug-Induced; Animals; Anticonvulsants; Blastocyst; Diethylstilbestrol; Dose-Response Relationship, Drug; Ethanol; Genotype; Gestational Age; Humans; Isotretinoin; Mice; Rats; Thalidomide

A still unresolved public health concern is that excessive vitamin A intake, like vitamin A deficiency, possibly causes birth defects not only in animals but also in man. Due to the low incidence of possibly vitamin A-related malformations in man, available data cannot convincingly define the upper safe limit of periconceptional vitamin A intake. Direct human intervention studies are not feasible for ethical reasons. Therefore, a novel approach in addressing this issue was chosen by combining teratogenicity data from a validated animal model with data on systemic exposure to vitamin A and its major metabolites in female volunteers. In a study in pregnant women endogenous plasma concentrations of vitamin A metabolites during early pregnancy ranged from 0.26 to 7.72 ng/ml. Since they did not cause any foetal malformations, retinoid plasma levels in this range can be considered non-teratogenic. Results of a trial in non-pregnant women document that daily oral vitamin A supplements of 4000, 10,000 and 30,000 IU given for 3 weeks were in the range or slightly above the range of endogenous plasma levels seen in early pregnancy. Even after a 3-week treatment with 30,000 IU/day, peak plasma levels of retinoic acid and isotretinoin were within or just slightly above the range of their physiological levels. In cynomolgus monkeys (average weight: 3-4 kg), a NOAEL (no observed adverse effect level) of 7500 IU per kg body weight and a LOAEL (lowest observed adverse effect level) for developmental toxicity of 20,000 IU/kg was found. Considering these results in the cynomolgus monkey, a dose of 30,000 IU/day should also be considered as non-teratogenic in man.

Topics: Abnormalities, Drug-Induced; Animals; Clinical Trials as Topic; Dietary Supplements; Female; Humans; Isotretinoin; Liver; Macaca fascicularis; Pregnancy; Tretinoin; Vitamin A

Tretinoin has been thoroughly evaluated for its potential as an embryofetal developmental toxicant. Oral tretinoin produces developmental anomalies in animal models; the minimal teratogenic dose is consistently 2.5 to 10 mg/kg. In contrast, topical application does not induce developmental malformations in laboratory animals. A structurally related compound, isotretinoin, is a potent toxicant in humans and animals; the lowest systemic dose that induces fetal anomalies varies more than 100-fold depending on the model. Oral isotretinoin is a more potent developmental toxicant than oral tretinoin in monkeys. Between-drug differences in the metabolism and transplacental transfer of the two retinoids account for the differences in toxicant potency. Pharmacokinetic studies reveal that absorption of tretinoin from the skin is poor and yields maternal plasma concentrations below the developmentally toxic threshold established after oral administration. Analysis of outcomes of developmental toxicology and pharmacokinetic studies suggests that the human risk of fetal anomalies is negligible after therapeutic application of topical tretinoin.

Topics: Abnormalities, Drug-Induced; Animals; Humans; Isotretinoin; Keratolytic Agents; Tretinoin

Vitamin A (retinol) is a fat-soluble vitamin that is necessary for cell growth and differentiation. Excess vitamin A has been associated with teratogenic effects in animals and humans. Because vitamin A deficiency is very uncommon in the industrialized world, the current recommendation is that routine vitamin A supplementation is not necessary. If vitamin A supplements are used, they should be limited to less than 5,000 IU per day. Systemic administration of the naturally occurring retinoid tretinoin has been associated with birth defects, fetal resorption, and stillbirths in animals; however, topical use is not associated with increased birth defects and is classified as a category B drug during pregnancy. The synthetic retinoids isotretinoin, etretinate, and etretin are strictly contraindicated during pregnancy (category X) as they have been associated with teratogenic syndromes in humans. In addition, owing to the prolonged elimination half-life of aromatic retinoids, effective contraception should be used for at least 2 years following discontinuation of treatment with these drugs.

Topics: Abnormalities, Drug-Induced; Acitretin; Etretinate; Female; Humans; Isotretinoin; Pregnancy; Retinoids; Tretinoin; Vitamin A

Retinoids, the synthetic derivates of vitamin A, have a key role on cellular differentiation and developmental tissue specificity. Their effects are mediated by nuclear receptors which transactivate homeobox genes. They are teratogenic to animals and they all induce similar malformations dependent on the dose and the duration of exposure. This is a review of the teratogenic effects of vitamin A and its synthetic derivates--isotretinoin, acitretine and topical retinoids--in humans. High dose vitamin A have a potent teratogenic effect and are therefore contra-indicated during pregnancy. Isotretinoin is responsible for a syndrome including malformations of the central nervous system, heart and thymus, together with craniofacial defects. The incidence rate is high and comparable to thalidomide (ie, 25%). This high teratogenic potency justifies a strict limitation of such a prescription in women susceptible to become pregnant. Acitretine, which replaces etretinate because of its long half life of 120 days, might also be teratogenic in humans. In addition, it may be back transformed into etretinate, thus contraindicating pregnancy for 2 years after withdrawal. Finally, despite a low percutaneous resorption, available data on the use of retinoids as topicals are limited and their use during pregnancy is therefore not recommended. Although they are efficient in skin diseases, the use of retinoids in women of the child bearing age is very limited because of their potent teratogenic effect.

Topics: Abnormalities, Drug-Induced; Acitretin; Animals; Female; Humans; Isotretinoin; Keratolytic Agents; Pregnancy; Retinoids; Teratogens; Vitamin A

The oral retinoids isotretinoin and etretinate are uniquely effective in the treatment of severe cystic acne and keratinisation disorders. Because of their known teratogenicity, there are strict prescription guidelines, but exposure during pregnancy still occurs. A dedicated effort by women and their clinicians is required, involving patient selection, education and informed consent, detailed contraceptive counselling, and careful monitoring and management, including pregnancy testing before commencement of therapy.

Topics: Abnormalities, Drug-Induced; Acitretin; Administration, Oral; Etretinate; Female; Humans; Isotretinoin; Keratolytic Agents; Pregnancy

Topics: Abnormalities, Drug-Induced; Animals; Behavior, Animal; Child, Preschool; Female; Humans; Isotretinoin; Nervous System Diseases; Pregnancy; Teratogens

The retinoids, a group of compounds consisting of vitamin A and its derivatives, have been the subject of intense investigation over the past 30 years. These molecules have shown beneficial effects in the areas of acne, psoriasis, neoplastic processes and, most recently, reversal of extrinsically aged skin. Additional retinoids are currently under development. Adverse reactions to these drugs include mucocutaneous irritation, hyperlipidemia, and profound teratogenicity. Appropriate patient selection is imperative before beginning therapy with these medications. An overview of retinoid metabolism and the currently available compounds is presented. The newest class of retinoids, the arotinoids, is also discussed.

Topics: Abnormalities, Drug-Induced; Etretinate; Female; Humans; Isotretinoin; Pregnancy; Retinoids; Skin Diseases; Tretinoin

Isotretinoin (13-cis-retinoic acid) remains the drug of choice for treatment of severe, recalcitrant nodulocystic acne that is unresponsive to conventional therapy, including oral antibiotics. The drug has been shown to produce dramatic clearing of lesions and prolonged remissions. The length of remission may be dependent on both the dosage used and the duration of therapy. Since fetal malformations have been observed in infants born of mothers taking isotretinoin during pregnancy, it is mandatory to prevent women who are pregnant or may become pregnant during treatment from taking isotretinoin. Because the half-life of isotretinoin is ten to twenty hours, and because it is eliminated from the body rapidly enough, women may become pregnant one month after discontinuation of therapy without an increased risk of birth defects. Common side effects of the drug include mucocutaneous reactions, serum lipid alterations, eye irritation, and myalgias. Less commonly observed are hyperostoses and exuberant granulation tissue, and rarely, pseudotumor cerebri. Recommendations for substantially reducing or eliminating these effects are made.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isotretinoin; Male; Pregnancy; Sebaceous Glands; Sebum; Triglycerides

Topics: Abnormalities, Drug-Induced; Humans; Isotretinoin; Italy

Between October 1982 and June 1985 the Adverse Drug Reaction Reporting System received reports of 104 suspected adverse reactions occurring in 93 patients who took isotretinoin. Adverse reactions involving the skin and mucous membranes (29 reports), central nervous system (23), musculoskeletal system (12), pregnancy (11), and eyes (8) were most commonly reported. Severe headache was the most frequently reported adverse reaction (15 reports). In four cases headaches were attributed to pseudotumor cerebri. Some of the reported reactions, for example, a disulfiram (Antabuse)-like reaction and oculogyric crisis, have not been described previously in the literature. Other reports, such as congenital malformations, serve to emphasize some of the serious reactions that are known to occur. These spontaneous reports of adverse reactions associated with isotretinoin use, together with the literature we review, may help alert physicians to the diverse spectrum of adverse reactions that may develop in patients taking isotretinoin.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Central Nervous System; Eye; Female; Humans; Isotretinoin; Male; Musculoskeletal System; Pregnancy; Skin; Teratogens; Tretinoin

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Animals; Female; Humans; Infant, Newborn; Isotretinoin; Kinetics; Precancerous Conditions; Pregnancy; Skin Neoplasms; Tretinoin

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Female; Humans; Infant, Newborn; Isotretinoin; Pregnancy; Teratogens; Tretinoin

Approximately 120,000 women of childbearing age used isotretinoin in the first 16 months after its release for the treatment of cystic acne. In September, 1983, the American Academy of Dermatology requested its members to relate the outcome of pregnancies of women inadvertently exposed to isotretinoin ( Accutane ) during pregnancy to its Adverse Drug Reaction Reporting System ( ADRRS ). Of nine pregnancies reported, seven ended in spontaneous abortion or the birth of an infant with birth defects. Of thirty-five pregnancies with isotretinoin exposure reported to the ADRRS or the U.S. Food and Drug Administration, twenty-nine (83%) resulted in spontaneous abortion or infants with birth defects. The most frequently reported severe birth defects involved the central nervous system (microcephaly or hydrocephalus) and the cardiovascular system (anomalies of the great vessels). Microtia or absence of external ears were also noted in a majority of cases. These findings illustrate the usefulness of specialty-based reporting of adverse drug effects and emphasize the teratogenic risk of isotretinoin in humans. Physicians need to fully and carefully inform women of childbearing age of these risks.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Acne Vulgaris; Female; Heart Defects, Congenital; Humans; Hydrocephalus; Infant, Newborn; Isotretinoin; Microcephaly; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Tretinoin

In the one year since isotretinoin has been available in the United States for the treatment of severe, recalcitrant, nodulocystic acne, there has been extensive clinical verification of the reports of its dramatic efficacy in the treatment of this troublesome disease. Proper selection of patients, as well as treatment with adequate doses of drug for 3 to 5 months, will most often result in significant clinical improvement or total clearing. Although dosages of less than 1 mg/kg/day may produce a nearly equivalent degree of improvement with somewhat fewer or less severe side effects, the recommended daily dose remains 1 mg/kg/day because lower dosages are associated with more frequent relapses. In severe cases, the daily dosage may be increased to 2 mg/kg/day. Teratogenicity, elevation of serum triglycerides, liver function abnormalities, pancreatitis, and pseudotumor cerebri may all be associated with isotretinoin therapy and require close monitoring of the patient.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Animals; Central Nervous System; Chemical and Drug Induced Liver Injury; Folliculitis; Humans; Isotretinoin; Middle Aged; Mucous Membrane; Musculoskeletal System; Rats; Skin Diseases; Sweat Gland Diseases; Tretinoin

Topics: Abnormalities, Drug-Induced; Australia; Clinical Trials as Topic; Etretinate; Female; Humans; Isotretinoin; Neoplasms; Pregnancy; Skin Diseases; Tretinoin; Vitamin A

In 2018, following an EU-wide safety review, a revised pregnancy prevention programme (PPP) was introduced for isotretinoin (Roaccutane®). This study aimed to examine awareness, knowledge, and experience implementing the revised isotretinoin PPP in clinical practice across three healthcare professional (HCP) groups in Ireland.. A cross-sectional study using anonymous online surveys among general practitioners (GPs), community pharmacists, and specialist consultants was undertaken. Descriptive analyses are presented.. Across all HCP groups there was high (≥87%) awareness that oral isotretinoin is contraindicated in women of childbearing potential (WCBP) unless the conditions of the PPP are fulfilled, but varying awareness among GPs (54.9%) and community pharmacists (45.9%) that exposure during pregnancy can cause both severe fetal malformations and spontaneous abortions. Implementation of the PPP in clinical practice varied across HCP groups. When initiating isotretinoin in WCBP, 66.7% of specialists and 40.8% of GPs indicated they had considered alternative treatment options, and 71.4% of specialists and 31.6% of GPs reported they first requested a pregnancy test. There was limited provision of the patient reminder card to WCBP, where 26.1% of community pharmacists provide this at each dispensing, while 47.6% of specialists and 11.8% of GPs ensured WCBP had a copy of the card when initiating treatment. Across all HCP groups, there was high (≥81.6%) awareness of the need for urgent consultation and immediate cessation of isotretinoin in the event of an unplanned or suspected pregnancy.. Reinforcement of the provision and utilisation of the isotretinoin patient reminder card may be required, and further targeted education on specific elements of the PPP should be considered for GPs and community pharmacists.

Topics: Abnormalities, Drug-Induced; Cross-Sectional Studies; Delivery of Health Care; Female; General Practitioners; Humans; Ireland; Isotretinoin; Pregnancy

Teratogens are responsible for 5% of all known causes of congenital anomalies. Isotretinoin, a retinoic acid-derived agent, leads to congenital anomalies in 21-52% of cases when exposure occurs during pregnancy according to studies conducted before 2006. However, rates of congenital anomalies were much lower in later studies. The purpose of this study was to investigate the rates of congenital anomalies in isotretinoin exposure during pregnancy, isotretinoin exposure before pregnancy, and a control group unexposed to any teratogenic agents.. In this cohort study, we divided pregnant women admitted to our center between 2009 and 2020 into two groups: isotretinoin exposure before and during the pregnancy (n = 77) and isotretinoin exposure before the pregnancy (n = 75). We selected the control group from among the non-teratogen exposed pregnant women with a simple random sampling method. Obstetricians calculated the ages of all pregnancies via ultrasound (USG) (crown-rump diameter for the first trimester; biparietal diameter and femur length for the second trimester). After birth, a pediatric genetics specialist examined all babies. Whole-exome sequencing (WES) was conducted on the babies who displayed complex phenotypes.. Among the isotretinoin exposure before and during the pregnancy, isotretinoin exposure before the pregnancy, and the control groups, there were statistically significant differences in live births (respectively, 64.3 %, 88 %, 93.3 %), congenital anomalies (respectively, 28.6 %, 6.1 %, 1.4 %), miscarriages (respectively, 13 %, 2.7 %, 4 %), terminations (respectively, 32.5 %, 9.3 %, 2.7 %), and premature births (11.9 %, 16.7 %, 2.9 %) (respectively, p < 0.001, p < 0.001, p = 0.014, p < 0.001). We detected novel phenotypical features in five patients.. Our study demonstrated that study design, long-term follow-up, teratological counseling, and implementation of advanced molecular analysis in complex phenotypes with novel phenotypical features are beneficial for understanding the association of congenital anomalies with isotretinoin exposure. While evaluating congenital anomalies, we detected statistically significant differences between isotretinoin exposure before and during the pregnancy vs control, but we did not detect any statistically significant differences between isotretinoin exposure before the pregnancy and controls. Another finding of the study is that WES might be an efficient way to evaluate complex phenotypes in isotretinoin-exposed babies; however, further research is required.

Topics: Abnormalities, Drug-Induced; Child; Cohort Studies; Female; Humans; Isotretinoin; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, First; Teratogens

Case Scenerio: A 26-year-old patient presents to the dermatology clinic with severe nodulocystic scarring acne. The patient identifies as a transgender male and notes that he has been receiving hormone replacement therapy for the past 4 years with weekly intramuscular testosterone injections.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adult; Dermatologic Agents; Dermatology; Drug Prescriptions; Female; Gender Identity; Humans; Isotretinoin; Male; Practice Guidelines as Topic; Sex Reassignment Procedures; Testosterone; Transgender Persons

Since its approval in 1982, oral isotretinoin has revolutionized acne therapy. However, oral isotretinoin use has long been associated with challenges of variable bioavailability and food dependence. It is recommended to ingest oral isotretinoin with a high-fat meal in order to maximize absorption, but many patients fail to adhere to this recommendation. This may lead to inadequate isotretinoin absorption levels. Patients who fail to achieve isotretinoin target cumulative dose are more likely to experience symptom relapse. To address the challenge of traditional isotretinoin variable bioavailability, subsequent isotretinoin formulations have attempted to improve its absorption abilities. In 2014, an isotretinoin formulation utilizing Lidose technology, known as Absorica, showed significant improvements in absorption levels compared to traditional oral isotretinoin in the fasted state. In 2019, isotretinoin absorption levels were further advanced in a new formulation approved by the FDA known as Absorica LD. Utilizing advanced micronization technology that physically reduces the size of the drug molecule, Absorica LD exhibits twice the absorption levels of Absorica under fasting conditions. In the fed state, Absorica LD achieves similar plasma levels to Absorica with a 20 percent lower dose. Absorica LD also produces consistent serum isotretinoin levels irrespective of gastrointestinal contents. By eliminating the “food effect” seen in traditional oral isotretinoin, Absorica LD has the potential to improve patient adherence and long-term patient outcomes. J Drugs Dermatol. 20:5(Suppl):s5-11.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Administration, Oral; Adolescent; Adult; Area Under Curve; Biological Availability; Clinical Trials as Topic; Dermatologic Agents; Diet, High-Fat; Drug Compounding; Female; Food-Drug Interactions; Gastrointestinal Absorption; Humans; Isotretinoin; Male; Medication Adherence; Particle Size; Young Adult

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Contraception; Dermatologic Agents; Drug Prescriptions; Humans; Isotretinoin; Office Visits; Patient Safety; Patient-Centered Care; Risk Evaluation and Mitigation; Teratogens

For persons of childbearing potential prescribed isotretinoin, the iPLEDGE program requires use of 2 simultaneous methods of contraception or commitment to abstinence.. To model the relative effectiveness of a variety of contraception strategies for patients taking isotretinoin, including those that are acceptable according to iPLEDGE.. We performed a decision analysis modeling the estimated rate of pregnancy with various contraception strategies during a typical 6-month course of isotretinoin.. Tier 1 contraception options (eg, subdermal hormonal implant, intrauterine devices) each had effectiveness of >99.5% alone. When combined with a secondary form of contraception, tier 2 contraception options (eg, depot medroxyprogesterone injections, combined oral contraceptives) each had effectiveness >99%.. Sensitivity analyses were conducted to evaluate the impact of uncertain parameters on the results.. There may be opportunities to simplify iPLEDGE by recognizing the high effectiveness of tier 1 contraception options and increasing use of secondary forms of contraception among those using tier 2 contraception options as their primary form of contraception. Future studies are needed to understand the most effective strategies in clinical practice to prevent unintended pregnancy for patients taking isotretinoin to improve outcomes and provide patient-centered care.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adult; Condoms; Contraception; Contraceptive Agents, Female; Contraceptive Devices, Female; Contraceptive Effectiveness; Decision Support Techniques; Dermatologic Agents; Female; Humans; Isotretinoin; Pregnancy; Sexual Abstinence

Topics: Abnormalities, Drug-Induced; COVID-19; Dermatologic Agents; Female; Humans; Isotretinoin; Policy Making; Pregnancy; Pregnancy Tests; Risk Assessment; Risk Factors; Risk Management; Telemedicine; Teratogens; Urinalysis

Topics: Abnormalities, Drug-Induced; Color; Culture; Drug Labeling; Female; Gender Dysphoria; Gender Identity; Humans; Infertility, Female; Isotretinoin; Male; Patient Education as Topic; Symbolism; Transgender Persons

The purpose of the study is to develop an algorithm to identify pregnancies in administrative databases and apply it to assess pregnancy rates and outcomes in women prescribed isotretinoin or tretinoin.. Using the 2011 to 2015 Truven Health MarketScan Database, we identified pregnancies, including losses and terminations. In a cohort design, nonpregnant women filling a prescription for isotretinoin or tretinoin were matched to five women without either prescription. Women were followed for 365 days or until conception, medication discontinuation, or enrollment discontinuation ("prescription episode"). Rates of pregnancy, risks of pregnancy losses, and prevalence of infant malformations at birth were assessed by exposure.. We identified 2 179 192 livebirths, 8434 stillbirths, 2521 mixed births, 415 110 spontaneous abortions, 124 556 elective terminations, and 8974 unspecified abortions. There were 86 834 isotretinoin and 973 587 tretinoin episodes, matched to 5 302 105 unexposed women. Pregnancy rates were 3 (isotretinoin), 19 (tretinoin), and 34 (unexposed) per 1000 person-years. Risk of spontaneous pregnancy losses were similar; however, terminations were more common in the isotretinoin-exposed (28% [95% CI: 21%-36%]) than the tretinoin-exposed (10% [95% CI: 9%-11%]) or unexposed pregnancies (6%). Malformations occurred in 4.5% (95% CI: 3.5%-5.6%) of the tretinoin-exposed pregnancies and 4.2% of the unexposed pregnancies (adjusted odds ratio: 1.16 [95% CI: 0.85-1.58]); isotretinoin-exposed births were too few to assess malformations.. Administrative databases can complement risk evaluation and mitigation strategies (REMS) for known teratogens and contribute to safety surveillance for other medications. Here, isotretinoin-exposed pregnancy rates were low, but existent, and many pregnancies were terminated. Tretinoin exposure was not associated with a meaningfully elevated risk of losses or malformations as compared with unexposed pregnancies.

Topics: Abnormalities, Drug-Induced; Administrative Claims, Healthcare; Adolescent; Adult; Databases, Factual; Drug Prescriptions; Female; Humans; Infant, Newborn; Isotretinoin; Maternal Exposure; Middle Aged; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Prevalence; Product Surveillance, Postmarketing; Tretinoin; United States; Young Adult

Topics: Abnormalities, Drug-Induced; Dermatologic Agents; Female; Humans; Isotretinoin; Pregnancy; Teratogens

Isotretinoin is the most effective drug in the treatment of severe recalcitrant nodulocystic acne. However, treatment with this drug is associated with adverse effects, the most severe being teratogenesis. It has been estimated that 40% of pregnancies exposed to isotretinoin present spontaneous abortion and 35% develop embryopathy. We present the case of a newborn with a history of prenatal exposure to isotretinoin, a clinical entity that can be avoided, with severe congenital defects in the central nervous system and important facial dysmorphisms, with unfavorable clinical course.. La isotretinoína es el medicamento más efectivo en el tratamiento del acné noduloquístico recalcitrante grave. Sin embargo, el tratamiento con este fármaco se encuentra asociado con efectos adversos, y el más grave es la teratogénesis. Se ha estimado que 40% de los embarazos expuestos a isotretinoína presenta un aborto espontáneo y 35% desarrolla embriopatía. Se presenta el caso de un recién nacido con antecedente de exposición prenatal a isotretinoína, una entidad clínica que puede evitarse, con graves defectos congénitos en el sistema nervioso central e importantes dismorfias faciales, con evolución clínica desfavorable.

Topics: Abnormalities, Drug-Induced; Fatal Outcome; Humans; Infant, Newborn; Isotretinoin; Male

To evaluate awareness of and compliance in Belgium by French-speaking health care professionals and patients with the isotretinoin safety recommendations regarding its teratogenic risk.. Survey using online questionnaires, delivered from December 2014 to March 2015 for patients, pharmacists, dermatologists, and GPs and delivered again from September 2015 to October 2015 for GPs.. Questionnaires were completed by 24 dermatologists, 24 GPs, 58 pharmacists, and 33 female patients. The pregnancy prevention programme was poorly known by health care professionals (23.6%) and patients (15.2%). Health care professionals informed women of childbearing age in depth about the teratogenic risk (98.3% of pharmacists and 100.0% of GPs and dermatologists) and the importance of an effective contraceptive method (87.9% and 100.0%, respectively). Patients were less informed about the pregnancy test (25.9% and 14.6%) and the need to use a second contraceptive method (29.3% and 27.1%). The low compliance with the last 2 recommendations was due to a lack of adoption by health care professionals regarding the need for these recommendations if female patients have an effective contraceptive method and the pregnancy risk is discussed in detail with them.. The effectiveness of the pregnancy prevention programme recommendations should be reconsidered by an expert committee. Justifications should be added to effective recommendations to increase their adoption by health care professionals and patients.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Belgium; Contraception; Dermatologic Agents; Dermatologists; Female; Guideline Adherence; Health Knowledge, Attitudes, Practice; Humans; Isotretinoin; Middle Aged; Patient Compliance; Pharmacists; Pregnancy; Pregnancy Complications; Surveys and Questionnaires; Teratogens; Young Adult

Isotretinoin, a synthetic derivative of vitamin A, is one of the most potent human teratogens, and is mainly utilized for the treatment of severe recalcitrant nodular acne. Retinoic acid embryopathy is well defined in the literature.. The mother was referred for a fetal posterior fossa abnormality, first detected at 20 weeks of gestation. The mother used isotretinoin until 18 weeks gestation. Ultrasound examination revealed hypertelorism, cerebellar hypoplasia, vermian agenesis, truncus arteriosus, anotia, thymic aplasia, corpus callosum hypoplasia. An intrauterine diagnosis of fetal retinoid syndrome was confirmed by fetopsy after termination of pregnancy.. The typical findings of fetal retinoid syndrome can be visualized with ultrasound in early second trimester.

Topics: Abnormalities, Drug-Induced; Adult; Dermatologic Agents; Female; Humans; Isotretinoin; Magnetic Resonance Imaging; Male; Pregnancy; Prenatal Diagnosis; Prenatal Exposure Delayed Effects; Ultrasonography, Prenatal

The impact of in-utero isotretinoin exposure has been widely reported, with many affected pregnancies failing to reach term.

Topics: Abnormalities, Drug-Induced; Cleft Lip; Cleft Palate; Diagnosis, Differential; Female; Fingers; Humans; Infant; Isotretinoin; Magnetic Resonance Imaging; Pregnancy; Prenatal Exposure Delayed Effects; Syndactyly; Teratogens; Toes

Isotretinoin, a teratogen, is widely used to treat cystic acne. Although the risks of pregnancy during isotretinoin therapy are well recognized, there are doubts about the level of adherence with the pregnancy prevention program in Canada. Our objective was to evaluate the effectiveness of the Canadian pregnancy prevention program in 4 provinces: British Columbia, Saskatchewan, Manitoba and Ontario.. Using administrative data, we identified 4 historical cohorts of female users of isotretinoin (aged 12-48 yr) for the period 1996 to 2011. We defined pregnancy using International Statistical Classification of Diseases and billing codes. One definition included only cases with documented pregnancy outcomes (high-specificity definition); the other definition also included individuals recorded as receiving prenatal care (high-sensitivity definition). We studied new courses of isotretinoin and detected pregnancies in 2 time windows: during isotretinoin treatment only and up to 42 weeks after treatment. Live births were followed for 1 year to identify congenital malformations.. A total of 59 271 female patients received 102 308 courses of isotretinoin. Between 24.3% and 32.9% of participants received prescriptions for oral contraceptives while they were taking isotretinoin, compared with 28.3% to 35.9% in the 12 months before isotretinoin was started. According to the high-specificity definition of pregnancy, there were 186 pregnancies during isotretinoin treatment (3.1/1000 isotretinoin users), compared with 367 (6.2/1000 users) according to the high-sensitivity definition. By 42 weeks after treatment, there were 1473 pregnancies (24.9/1000 users), according to the high-specificity definition. Of these, 1331 (90.4%) terminated spontaneously or were terminated by medical intervention. Among the 118 live births were 11 (9.3%) cases of congenital malformation. Pregnancy rates during isotretinoin treatment remained constant between 1996 and 2011.. Adherence to the isotretinoin pregnancy prevention program in Canada was poor during the 15-year period of this study.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Canada; Child; Contraception; Dermatologic Agents; Female; Humans; Isotretinoin; Live Birth; Middle Aged; Pregnancy; Pregnancy Outcome; Retrospective Studies; Young Adult

Topics: Abnormalities, Drug-Induced; Humans; Isotretinoin; Teratogens; Teratology

Topics: Abnormalities, Drug-Induced; Anti-Retroviral Agents; Azathioprine; Female; Humans; Infant, Newborn; Isotretinoin; Methotrexate; Pregnancy; Sumatriptan

Isotretinoin, a known teratogen, is strictly regulated through the iPLEDGE program. However, isotretinoin-exposed pregnancies continue to occur.. To evaluate an information sheet's effect on women's contraceptive knowledge.. Women aged 18 to 45 years visiting a dermatology practice completed anonymous surveys assessing their knowledge of the typical effectiveness of 8 contraceptive methods before and after reviewing an educational information sheet. Participants categorized each contraceptive as "most effective, >99% effective," "medium effective, 92%-97% effective," or "least effective, <89% effective" or indicated that they had "never heard of" it. All participants were recruited from a single dermatology clinic between April and May 2014. A total of 118 women were approached by consecutive sampling, and surveys were completed by 100 women.. Preintervention contraceptive effectiveness knowledge and change in contraceptive effectiveness knowledge after viewing the educational tool.. Prior to viewing the contraceptive information sheet, more than half of women overestimated the typical effectiveness of condoms (75%), contraceptive injections (57%), and oral contraceptives (51%). Thirty-four percent had never heard of contraceptive implants, whereas 16% had never heard of an intrauterine contraceptive device (IUD). Participants correctly identified the typical effectiveness of only a mean (SD) of 3.8 (1.9) of the 8 contraceptives that they were asked about. Only 3% of participating women were able to correctly identify the typical effectiveness of all available contraceptives. On average, women spent less than 1 minute reviewing the contraceptive information sheet (mean [SD], 31 [27] seconds). After viewing the educational handout, the proportions of participants able to correctly identify the typical effectiveness of contraceptives increased for almost all methods (subdermal implant, 45% to 78% [P < .001]; IUD, 61% to 83% [P < .001]; injection, 28% to 44% [P = .02]; ring, 60% to 69% [P = .18]; patch, 50% to 71% [P = .002]; pills, 41% to 65% [P < .001]; condoms, 25% to 45% [P = .003]; withdrawal, 74% to 90% [P = .003]).. A contraceptive information sheet can significantly improve patients' contraceptive knowledge and may be a useful addition to efforts to prevent isotretinoin-induced birth defects.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Contraception; Data Collection; Dermatologic Agents; Female; Health Knowledge, Attitudes, Practice; Humans; Isotretinoin; Patient Education as Topic; Young Adult

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Contraception; Dermatologic Agents; Female; Humans; Isotretinoin; Patient Compliance; Patient Education as Topic; Pregnancy; Teratogens

Topics: Abnormalities, Drug-Induced; Congenital Microtia; Female; Humans; Infant, Newborn; Isotretinoin; Pregnancy

Topics: Abnormalities, Drug-Induced; Congenital Microtia; Female; Humans; Infant, Newborn; Isotretinoin; Pregnancy

We describe a neonate with isotretinoin embryopathy and an incidental finding of congenital neuroblastoma. Diffuse liver metastases led to the decision to provide oncologic therapy followed by tumor resection. Despite the possible need for chronic care related to the comorbidities of the isotretinoin embryopathy and oncologic management, the patient remains disease-free. Because of the uncertain etiology of neuroblastoma, it remains unclear whether exposure to isotretinoin during embryogenesis and fetal development had an oncogenic effect on this patient.

Topics: Abnormalities, Drug-Induced; Adrenal Gland Neoplasms; Humans; Infant, Newborn; Isotretinoin; Neuroblastoma

Approximately 150 women annually become pregnant while taking isotretinoin despite participation in the iPLEDGE program. Noncompliance with the requirement to be abstinent or use 2 contraceptive methods may be a contributing factor.. We sought to determine the degree of adherence to contraception or abstinence among women taking isotretinoin.. We conducted an anonymous survey of women of childbearing potential taking isotretinoin for at least 2 months.. Among 75 participants, 21 (28%) chose abstinence as their primary means of pregnancy prevention, of whom 4 (19%) were sexually active during treatment. The most commonly chosen contraceptive methods among the 39 women who were sexually active were condoms (35, 90%) and oral contraceptive pills (18, 46%). Twelve women (31%) admitted to having intercourse at least once using 1 or fewer forms of contraception; 10 failed to use condoms, and 1 reported completely unprotected intercourse. Among sexually active oral contraceptive pill users, 7 (39%) reported missing 1 or more pills in the previous month.. Data were self-reported, thus participants may have inaccurately reported contraception use.. Encouraging the use of highly effective, patient-independent contraception and limiting abstinence to women who have never been sexually active may further reduce the rate of isotretinoin-exposed pregnancies.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adult; Condoms; Contraception; Contraception Behavior; Contraceptives, Oral; Female; Humans; Isotretinoin; Medication Adherence; Pregnancy; Sexual Abstinence; United States; Young Adult

Topics: Abnormalities, Drug-Induced; Contraception; Counseling; Dermatologic Agents; Female; Health Knowledge, Attitudes, Practice; Humans; Isotretinoin; Pregnancy

Isotretinoin, an effective anti-acne therapy, is a known teratogen that is strictly regulated through the iPLEDGE program. However, since this program has not significantly reduced rates of pregnancies exposed to isotretinoin, new strategies for reducing rates of isotretinoin-exposed pregnancies are needed.. To explore women's experiences with counseling about isotretinoin risk reduction.. Structured interviews were conducted between January and September 2012. Two independent coders performed content analysis using a grounded theory approach. The study participants were 16 women who had used isotretinoin to treat severe skin disease and who were recruited from a single urban community via flyers displayed on college campuses, at dermatology clinics, and at student health facilities.. Perceptions of isotretinoin-associated risks and understanding of ways teratogenic risks can be avoided.. Participants clearly understood that isotretinoin is teratogenic but had less understanding of contraceptive methods that effectively prevent pregnancy. Most described the counseling they received as anxiety provoking. Few were counseled about highly effective reversible contraceptives such as the subdermal implant or intrauterine contraception; most counseling focused on oral contraceptives. Women cited multiple influences on their contraceptive choices, including friends, family, physicians, the internet, and other media; however, some expressed concerns about the accuracy of these sources of information. For many, iPLEDGE was their first introduction to contraception. When presented with evidence-based information on the relative effectiveness of available contraceptives, participants expressed surprise that this was not part of the iPLEDGE materials.. Since few clinicians provide women information on highly effective (ie, intrauterine or subdermal) contraceptives, the iPLEDGE program increases anxiety about isotretinoin more than it helps women feel protected from the teratogenic risks of isotretinoin.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Contraception; Contraceptive Agents; Contraceptives, Oral; Counseling; Dermatologic Agents; Drug Implants; Female; Health Knowledge, Attitudes, Practice; Humans; Interviews as Topic; Intrauterine Devices; Isotretinoin; Practice Patterns, Physicians'; Pregnancy; Risk Reduction Behavior; Young Adult

The increase in online purchasing of medications raises safety concerns regarding teratogenic drugs. The use of the teratogenic drug 'isotretinoin' for women of childbearing age requires strict adherence to the Pregnancy Prevention Programme (PPP), a risk minimisation measure imposed on prescribers and users. We sought to determine how readily consumers can purchase isotretinoin online and the associated safety procedures and information.. A descriptive cross-sectional survey was conducted of 50 e-pharmacies identified from commonly used search engines. E-pharmacy characteristics and isotretinoin PPP specific criteria were evaluated. Purchases of isotretinoin from seven e-pharmacies not bearing authentication logos and not requiring a prescription were assessed for PPP policy adherence, purchasing procedures and compound quality.. Forty-three (86%) of the e-pharmacies did not have an authentication seal/logo. Isotretinoin could be purchased from 42 sites without a valid prescription. Information on isotretinoin causing birth defects was lacking in 25 of the 50 sites, on not taking isotretinoin in pregnancy in 24 sites and not taking isotretinoin if planning or at risk of a pregnancy in 33 sites. Of the eight attempted purchases, seven arrived, all without any patient information leaflet. All were verified as isotretinoin.. The Internet provides a loophole for purchasing of medications known to cause congenital abnormalities, which needs to be addressed by medicines regulatory agencies worldwide. The current PPP for isotretinoin may be failing to protect mothers and babies from preventable harm-clinicians need to be aware of this, and the public needs to be educated about the potential risks.

Topics: Abnormalities, Drug-Induced; Commerce; Cross-Sectional Studies; Dermatologic Agents; Drug Prescriptions; Female; Guideline Adherence; Health Care Surveys; Humans; Internet; Isotretinoin; Patient Education as Topic; Pharmaceutical Services, Online; Practice Guidelines as Topic; Practice Patterns, Physicians'; Pregnancy; Teratogens

Topics: Abnormalities, Drug-Induced; Contraceptive Agents; Dermatologic Agents; Drug Utilization; Female; Humans; Isotretinoin

Topics: Abnormalities, Drug-Induced; Contraceptive Agents; Dermatologic Agents; Drug Utilization; Female; Humans; Isotretinoin

To estimate isotretinoin exposure in Dutch pregnant women despite the implemented pregnancy prevention programme (PPP) and second, to analyse the occurrence of adverse fetal or neonatal outcomes in these isotretinoin exposed pregnancies.. Population-based study.. The Netherlands.. A cohort of 203,962 pregnancies with onset between 1 January 1999 and 1 September 2007 consisting of 208,161 fetuses or neonates.. Isotretinoin exposure in the 30 days before or during pregnancy. Proportions of adverse fetal or neonatal outcomes, defined as intrauterine deaths ≥16 week of gestation and neonates with major congenital anomalies. ORs with 95% CIs adjusted for maternal age were calculated to estimate the risk of adverse fetal or neonatal outcome after maternal isotretinoin exposure.. 51 pregnancies, 2.5 (95% CI 1.9 to 3.3) per 10,000 pregnancies, were exposed to isotretinoin despite the pregnancy prevention programme. Forty-five of these pregnancies, 2.2 (95% CI 1.6 to 2.9) per 10,000 pregnancies, were exposed to isotretinoin during pregnancy and six additional women became pregnant within 30 days after isotretinoin discontinuation. In 60% of isotretinoin exposed pregnancies, women started isotretinoin while already pregnant. In five out of the 51 isotretinoin exposed pregnancies (53 fetuses), 9.4% (95% CI 1.3% to 17.6%), had an adverse fetal or neonatal outcome. The OR for adverse fetal or neonatal outcomes after isotretinoin exposure in 30 days before or during pregnancy was 2.3 (95% CI 0.9 to 5.7) after adjustment for maternal age.. Although a PPP was already implemented in 1988, we showed that isotretinoin exposed pregnancies and adverse fetal and neonatal events potentially related to the exposure still occur. These findings from the Netherlands add to the evidence that there is no full compliance to the isotretinoin PPP in many Western countries. Given the limited success of iPLEDGE, the question is which further measures are able to improve compliance.

Topics: Abnormalities, Drug-Induced; Adult; Dermatologic Agents; Female; Fetal Death; Humans; Infant, Newborn; Isotretinoin; Netherlands; Pregnancy; Young Adult

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Female; Humans; Isotretinoin; Pregnancy; Pregnancy, High-Risk; Teratogens

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Female; Humans; Isotretinoin; Pregnancy; Pregnancy, High-Risk; Teratogens

The major concern associated with isotretinoin treatment is its high teratogenic potential. Therefore, ensuring use of contraception while on therapy is an important strategy for at-risk patients and has been emphasized in all risk management programs. iPledge, the latest and most rigorous isotretinoin program, requires, among other stipulations, monthly assessments of contraceptive use for patients undergoing isotretinoin treatment. The purpose of this study is to evaluate isotretinoin usage patterns and assess concomitant use of isotretinoin and contraceptives before and after iPledge.. Female patients aged 13-45 years with a new prescription for isotretinoin products during 2004-2008 were identified in the IMS Health longitudinal prescription claims database. Monthly concomitant use of isotretinoin and contraceptives was estimated. Segmented regression analysis of interrupted time series data was used to assess changes in monthly proportion of concomitant use in the 24 months preceding versus following iPledge implementation.. The number of isotretinoin prescriptions decreased after iPledge implementation. A small but significant increase in monthly proportion of patients concomitantly using isotretinoin and contraceptive therapies was observed immediately after iPledge implementation (1.3%, p-value = 0.02), particularly among younger patients (2.5%, p-value < 0.01). No changes in the proportion of concomitancy over time (i.e. slope) between the periods before and after iPledge implementation were observed.. The findings of this pharmacy prescription claims-based study suggest a small increase in concomitant use of isotretinoin and contraceptives coincident with the time of implementation of iPledge, particularly among younger women. Published 2013. This article is a U. S. Government work and is in the public domain in the USA.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Contraceptive Agents; Dermatologic Agents; Drug Prescriptions; Drug Utilization; Female; Government Programs; Humans; Isotretinoin; Least-Squares Analysis; Middle Aged; Risk Management; United States; Young Adult

Acne is a common problem that is increasingly being effectively treated with isotretinoin, a highly teratogenic agent. According to the pregnancy prevention program, contraception should be used until at least one month after discontinuing the medication.. A 29-year-old woman became pregnant shortly after discontinuing isotretinoin. She was referred to the gynaecologist for an abortion. However, since she wished to continue the pregnancy, she received personal advice on the risk of bearing a child with congenital abnormalities. After an uneventful pregnancy she gave birth to a healthy son.. Given the teratogenicity of isotretinoin, every woman in the fertile phase of life should use contraception while taking the medication. If she becomes pregnant, however, the individual risk of having a child with congenital abnormalities can be carefully and reliably estimated by determining the precise date of conception through ultrasound and the date that isotretinoin was stopped.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adult; Contraception; Female; Humans; Isotretinoin; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Teratogens

Topics: Abnormalities, Drug-Induced; Contraceptive Agents; Dermatologic Agents; Drug Utilization; Female; Humans; Isotretinoin

Many doctors still tell some patients that a (subsequent) pregnancy is contraindicated. Aside from the fact that the desire to have a (or another) child is often extremely strong, which often results in ignoring the message, this type of advice may have serious negative consequences. Women at high risk of cardiovascular complications may decide to delay in making their first appointment to avoid an angry doctor who might push them towards an abortion. Women may postpone a subsequent pregnancy out of fear of preeclampsia, while this in fact increases the recurrence risk. Doctors often scare patients with stories about drugs causing fetal anomalies, while only a small minority of drugs, and then only during a limited time in pregnancy, are truly teratogenic. Prepregnancy counselling should involve a well-informed, balanced discussion on risks, while acknowledging a woman's desire for childbearing and ensuring that she will receive all possible support when she does become pregnant.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Female; Humans; Isotretinoin; Pregnancy

Three online surveys explored compliance with the PPP by pharmacists and dermatologists, in the Netherlands. In 2007 and 2011, two pharmacist surveys were conducted to assess improvement over time.. In 2007, survey was sent to members of the Utrecht Pharmacy Panel for Education & Research (UPPER) network (n = 1000) and in 2011, to the research group of the Dutch Association of Pharmacists (KNMP) (n = 556). In 2010, a survey was sent to 564 dermatologists of the Dutch Association of Dermatology and Venereology (NVDV).. Both pharmacists' questionnaires had response rates of 20% and the dermatologist questionnaire of 28%. Pharmacists' checks on 30-day dispensing remained 82%, but a check whether the prescription is out-of-date decreased (61 to 53%). Pharmacists asked the patient for a negative pregnancy test in 15%, but use of contraception was checked by 44 - 49%. One hundred and five dermatologists (64%) always prescribe contraception; 35 (22%) occasionally. Ninety-three percent of the dermatologists were of the opinion that they performed the PPP. Analysis of different elements of the PPP showed that 41 (25%) were compliant.. The observed non-adherence to the isotretinoin PPP calls for careful evaluation of risk minimisation plans and participation of all stakeholders in the development of these plans.

Topics: Abnormalities, Drug-Induced; Attitude of Health Personnel; Awareness; Community Pharmacy Services; Contraception; Contraindications; Dermatologic Agents; Dermatology; Drug Prescriptions; Female; Guideline Adherence; Health Care Surveys; Health Knowledge, Attitudes, Practice; Health Plan Implementation; Humans; Isotretinoin; Netherlands; Patient Education as Topic; Practice Guidelines as Topic; Practice Patterns, Physicians'; Pregnancy; Pregnancy Tests; Program Evaluation; Risk Assessment; Risk Factors; Surveys and Questionnaires

Topics: Abnormalities, Drug-Induced; Dermatologic Agents; Female; Guideline Adherence; Humans; Isotretinoin; Pregnancy; Teratogens

There is little information on the status of the implementation of the isotretinoin Pregnancy Prevention Programme (PPP) in the EU, and on compliance with this programme by the regulatory agencies.. The aim of the study was to obtain information on implementation of the harmonized PPP of isotretinoin in the EU member states plus Norway and Iceland.. In January 2009, a questionnaire (request for non-urgent information [NUI]) was sent to all 25 EU member states, plus Norway and Iceland, to collect information on the implementation status of the PPP and its effectiveness.. The response rate was 82% (22 of the 27 countries). In 21 of the 27 member states, isotretinoin is marketed and the PPP is in force, and in 18 of the 22 responding countries, the total required elements (seven) following a formal EU review are incorporated in the PPP. Seven member states had additional measures in place. In spite of implementation of the PPP and additional measures, a total of 143 isotretinoin-exposed pregnancies have been reported in 16 of the 22 responding member states since implementation of the harmonized PPP.. Despite implementation of the isotretinoin PPP in most member states, isotretinoin-exposed pregnancies were reported. This has led some member states to implement additional measures to the PPP, resulting in inconsistency with the approach agreed in 2003 following the European-wide review. It has been further suggested that common elements should be developed for PPPs for all medicines that are known to carry a high teratogenic risk.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Contraception; Dermatologic Agents; European Union; Female; Government Agencies; Guideline Adherence; Health Plan Implementation; Health Surveys; Humans; Iceland; Isotretinoin; Norway; Pregnancy; Pregnancy Complications; Surveys and Questionnaires; Teratogens; Young Adult

To assess the compliance with the isotretinoin Pregnancy Prevention Programme (PPP) by evaluating the use of prescribed contraceptives among isotretinoin users. The PPP contains a requirement for the use of contraceptive methods for women of childbearing potential.. A drug utilisation study was performed using data from a drug prescription database (containing Dutch community pharmacy data) covering a population of 500 000 patients. Contraceptive use in female isotretinoin users and in a reference group of female non-isotretinoin users (aged 15-49 years) was compared using data from 1999 until 2006 in 2-year periods. Descriptive statistics were used.. Of the female isotretinoin users (n = 651), 52%-54% filled prescriptions on contraceptives in strict accordance to the PPP, used before, during, and after discontinuation of isotretinoin, compared with 39%-46% in the reference group. A more liberal approach of a minimum of one prescription for a contraceptive method showed 61%-64% use of contraceptives among isotretinoin users. Similar patterns were seen when data were broken down in age groups. Furthermore, a higher proportion of female patients using isotretinoin prescribed by general practitioners used prescribed contraceptives compared with those receiving isotretinoin by specialists.. Compliance with the contraceptive use according to a PPP for a teratogenic drug such as isotretinoin is 52%-64%, which is lower than anticipated. Reasons for the low compliance will need to be clarified before further measures can be taken.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Age Distribution; Contraceptive Agents; Contraindications; Dermatologic Agents; Female; Humans; Isotretinoin; Male; Middle Aged; Netherlands; Prescriptions

We aimed to study the pregnancy outcomes of women exposed to isotretinoin and to identify the factors influencing their decision to request an abortion.. The study prospectively identified 79 women who had been treated for acne with isotretinoin during the periconceptional period, and who were followed up until completion of their pregnancy. Characteristics of exposure and doses were self-reported by participants.. Of the 56 participants who decided to continue their pregnancy, there were 11 spontaneous abortions and 44 women who delivered healthy full-term babies of which 19 had been exposed to isotretinoin <1 month before conception or during pregnancy. In a nominal logistic regression analysis including 68 patients who provided adequate information for analysis, exposure to isotretinoin >2 weeks post-conception and pregnancy termination recommended by the first-contact physician were found to be significantly associated with patients' decision to undergo elective abortion: adjusted OR = 9.87 (95% CI 1.18-82.34) and 12.51 (95% CI 2.36-66.29), respectively.. Our study reports an elevated rate of babies born without evidence of gross malformation or neurofunctional abnormality even tough exposure occurred during the teratogenic risk period. However, caution is recommended since a substantial risk of congenital malformations has been reported with low doses of isotretinoin and at exposures limited to early pregnancy. We also found that primary-care physicians may influence patients' decision to request pregnancy termination independently of their timing of exposure to isotretinoin.

Topics: Abnormalities, Drug-Induced; Abortion, Eugenic; Acne Vulgaris; Adult; Dermatologic Agents; Female; Humans; Infant, Newborn; Isotretinoin; Live Birth; Pregnancy; Prospective Studies; Republic of Korea; Teratogens

Topics: Abnormalities, Drug-Induced; Adverse Drug Reaction Reporting Systems; Dermatologic Agents; Female; Humans; Isotretinoin; Pregnancy; Pregnancy Complications; Program Development; Program Evaluation; United States; United States Food and Drug Administration

Oral isotretinoin is a highly-effective treatment for severe acne. It is also highly teratogenic. Recently, funded access was widened (from vocationally registered dermatologists only) to include vocationally trained general practitioners and nurse practitioners acting within their scope of practice. This decision has caused some debate. While it is hoped that it will increase access to those living in more deprived areas, there are concerns that there will be an increase in the number of affected pregnancies. This study aims to report on terminations of pregnancy occurring while using isotretinoin in New Zealand.. Using NHI numbers, termination of pregnancy admissions were matched to recent isotretinoin prescriptions.. This study has revealed that there appears to have been more unintended pregnancies related to isotretinoin use than previously thought. A total of 39 terminations of pregnancy related to isotretinoin use were identified in the year ending June 2008. This gave a crude termination of pregnancy rate of 73 per 10,000 females aged 10-44 years.. While there are some limitations to this study, the results are consistent with recent international research suggesting previous pregnancy rates on isotretinoin have been underestimates. Widening funding of isotretinoin will likely increase the absolute numbers of pregnancies but also has the potential to increase relative numbers. As such, it will be vital that primary care is alert to the risks of isotretinoin use and gain experience in its day-to-day usage. Although access has been widened, all requests for funding will now be recorded on a national database (Special Authority database) to enable closer monitoring of isotretinoin usage.

Topics: Abnormalities, Drug-Induced; Abortion, Induced; Acne Vulgaris; Adolescent; Adult; Child; Dermatologic Agents; Female; Humans; Isotretinoin; New Zealand; Pregnancy

Apart from thalidomide, retinoids like isotretinoin are the strongest teratogens in humans known today. The overall risk of birth defects is estimated as up to 30% after exposure during embryogenesis. In spite of well established pregnancy prevention programs, pregnancies still occur during isotretinoin therapy in many countries including Germany. A detailed investigation of the incidence and outcome of these pregnancies would fill an important gap.. The Berlin Institute for Clinical Teratology documents prospectively the course of drug-exposed pregnancies when contacted for individual drug risk assessment. Datasets of isotretinoin exposed pregnancies recorded between 1993 and 2008 were evaluated as to the outcome of pregnancy.. A total of 108 pregnancies exposed to systemic isotretinoin (median dosage 20 mg/day) during the contraindicated period were registered. 76% (69/91) of the pregnancies with known outcome were electively terminated-mainly for fear of medication risk. No terminations due to abnormal prenatal ultrasound findings were reported. Spontaneous abortions occurred in five pregnancies. Of 18 live births including 1 pair of twins 1 major birth defect (small ventricular septal defect) was observed. None of the infants showed symptoms of retinoid embryopathy. 70% (48/69) of the patients with data on contraception did not use any method, in 30% contraception failed. There was no evidence that poor maternal education was a major cause for the omission of contraception documented in 48 women.. Inadvertent isotretinoin exposure during the first 2 weeks post conception does not necessarily require discussion of termination of pregnancy, as the risk of major birth defects appears to be much lower than it becomes beyond this period. Nevertheless, additional efforts are required to improve the effectiveness of contraception while on isotretinoin treatment considering psycho-social aspects such as improved self-confidence, unexpected new partnership and sexual activity and incorrect perception of infertility.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Cohort Studies; Dermatologic Agents; Female; Germany; Humans; Incidence; Infant, Newborn; Isotretinoin; Middle Aged; Pregnancy; Prospective Studies; Teratogens; Young Adult

Isotretinoin is very effective in the treatment of severe acne. However, because of the teratogenic properties of this agent an isotretinoin Pregnancy Prevention Programme (PPP) was implemented in the Netherlands to guarantee that treatment is contraindicated in women of reproductive age unless at least one effective method of contraception is used. Furthermore, the PPP stipulates that isotretinoin treatment should be managed by physicians or specialists experienced in treatment with this drug and that only monthly prescriptions are issued.. To assess compliance with the Dutch isotretinoin PPP in women of reproductive age during the study period of 1 January 2005 to 31 December 2008.. Detailed information on dispensed medication and co-medication was available from the Dutch Foundation of Pharmaceutical Statistics. Four types of outcome were studied: concomitant dispensing of hormonal contraceptive with isotretinoin; the proportion of specialist prescribing of isotretinoin; prescribing of conventional acne therapy prior to isotretinoin initiation; and isotretinoin dispensing exceeding the maximum amount. The use of contraceptives in women aged between 15 and 45 years was defined as concomitant if the period of systemic contraceptive use overlapped the period of isotretinoin dispensing for at least 10 days, or if any dispensing of an intrauterine or intravaginal contraceptive was recorded since the year 2000. Dispensings were separated into those prescribed by either specialists or general practitioners (GPs). The use of antibacterials, antiandrogens or topical agents against acne was checked 4 months prior to an isotretinoin dispensing, and a possible excess of the maximum amount of isotretinoin was defined as prescriptions of more than 100 defined daily doses.. During the study period, data were available for 442 Dutch pharmacies encompassing 4881 women of reproductive age using isotretinoin at least once during study period. Among women of reproductive age, the use of isotretinoin increased during the study period. The proportion of isotretinoin initiation with concomitant oral hormonal or intrauterine contraceptives was low (59.3% [95% CI 57.6, 61.0]). Initiation of isotretinoin by a specialist increased the chance for concomitant contraception by 26% (95% CI 6.0, 49.0); in 78.2% (95% CI 76.8, 79.6) of women, isotretinoin was initiated by a specialist. Conventional acne therapy up to 16 months prior to isotretinoin initiation was found in 70% of the women (70.3% [95% CI 66.0, 74.6]). In 1.4% (95% CI 1.0, 1.8) of cases of treatment initiation, the amount of isotretinoin dispensed on one prescription seemed too high.. Attention should be paid to improving the implementation of the isotretinoin PPP. Despite clear guidelines and warnings in the product information, our study strongly suggests that concomitant use of isotretinoin and contraceptives is too low. Even though we will have missed non-pharmacological forms of contraception, these results raise doubts about the safe use of isotretinoin in women of reproductive age in the Netherlands. Furthermore, isotretinoin does not seem to be used in cases of severe acne only. Reserving isotretinoin prescribing to specialists may improve adherence to the PPP.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Cohort Studies; Contraceptive Agents; Contraindications; Drug Prescriptions; Female; Guideline Adherence; Humans; Isotretinoin; Middle Aged; Netherlands; Pharmaceutical Services; Retrospective Studies; Teratogens

In three previous studies, we have shown that pregnant women were still being exposed to isotretinoin and that compliance with recommendations was incomplete. The relaxation of these recommendations (summary of product characteristics 2004), combined with the release of generic brands, encouraged us to carry out a fourth study.. To assess isotretinoin exposure during pregnancy following the application of less stringent recommendations and the marketing of generic isotretinoin brands.. All cases of isotretinoin exposure during pregnancy, between 1 January 2003 and 31 December 2006, spontaneously reported to pharmacovigilance centres, the Teratogenic Agent Information Centre, and pharmaceutical companies in France were assessed. Cases were classified for analysis into the following groups: 'conception <1 month after isotretinoin discontinuation', 'conception during isotretinoin treatment' and 'patient already pregnant when isotretinoin was started'. The rate of spontaneously reported isotretinoin exposure during pregnancy was estimated by dividing the number of isotretinoin-exposed pregnancies by the number of women of childbearing age treated with isotretinoin.. Over 4 years, 147 cases of isotretinoin exposure during the teratogenic risk period were spontaneously reported, i.e. 'conception <1 month after isotretinoin discontinuation' (23%), 'conception during isotretinoin treatment' (61%), and 'patient already pregnant when isotretinoin was started' (16%). Nineteen percent of the patients did not use any form of contraception. In 23% of the patients, the method of contraception used did not comply with recommendations, while in 86% of the cases, isotretinoin was prescribed by a dermatologist. Among the 44 pregnancies with available data on fetuses or neonates, there were two (4.5%) malformations compatible with the time of exposure and with isotretinoin embryopathy. The rate of spontaneously reported isotretinoin exposure during pregnancy has increased by approximately 30%, from 0.32 (95% CI 0.26, 0.38) to 0.41 (95% CI 0.34, 0.49) per 1000 women of childbearing age treated since 1999-2002.. We suggest that recommendations be tightened, with specific information regarding the most effective contraceptive method combined with compulsory monthly pregnancy testing during treatment. The French Drug Agency has informed the European Medicines Agency of the need for measures aimed at improving compliance.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Contraception; Female; France; Health Planning Guidelines; Humans; Infant, Newborn; Isotretinoin; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Young Adult

To describe the clinical and radiologic findings in a case of isotretinoin embryopathy-like syndrome and discuss management of hearing loss, congenital external auditory canal (EAC) stenosis, and EAC cholesteatoma.. Review of medical, audiological, and radiological records.. An 8 year old female presented with bilateral moderate conductive hearing loss, bilateral microtia, left EAC stenosis, and right EAC atresia, secondary to prenatal isotretinoin exposure. Comorbidities included developmental delay, ventricular septal defect, hypotonia, and retinal maldevelopment. The left EAC was sharply upsloping with a 2mm-diameter meatus. Computed tomography (CT) scan of the temporal bone demonstrated normal middle and inner ears bilaterally; serial CT scans over 6 years demonstrated progressive development of left canal cholesteatoma. Implantation of a right BAHA system was performed, followed by left canalplasty and excision of cholesteatoma with facial nerve monitoring. An endaural incision was utilized to avoid compromising future microtia repair. Postoperative left-sided hearing improved to mild low-frequency conductive hearing loss rising to normal at 2000 Hz and above.. Despite extensive precautions for its use, isotretinoin remains a cause of major birth defects, including sensorineural, conductive or mixed hearing loss. Congenital EAC stenosis is much less common than congenital atresia or acquired stenosis; optimal surgical approaches vary depending on hearing status and facial nerve anatomy. Close monitoring for development of canal cholesteatoma is necessary.

Topics: Abnormalities, Drug-Induced; Child; Cholesteatoma; Ear; Ear Canal; Ear Diseases; Female; Hearing Loss, Conductive; Humans; Isotretinoin; Pregnancy; Prenatal Exposure Delayed Effects; Radiography; Teratogens

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Dermatologic Agents; Female; Humans; Isotretinoin; Male; Mood Disorders; Practice Guidelines as Topic; Pregnancy; United Kingdom

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Contraception; Dermatologic Agents; Female; Humans; Isotretinoin; Male; Private Practice; Prospective Studies; Young Adult

Isotretinoin is a known human teratogen that can cause multiple malformations. At present, women who conceive one cycle after discontinuing isotretinoin are told that their teratogenic risk is not higher than baseline. We present a case of both-ear malformation in a newborn whose mother had taken isotretinoin for 2 years until one month prior to the time when she became pregnant. We suggest that further studies of pharmacokinetics and malformation of isotretinoin are needed.

Topics: Abnormalities, Drug-Induced; Adult; Female; Humans; Infant, Newborn; Isotretinoin; Male; Pregnancy; Prenatal Exposure Delayed Effects

Retinoic acid is a widely used drug in the treatment of cystic acne. It has teratogenic effects that depend on the gestational period in which it is used. We report a seven months old female whose mother was exposed to retinoic acid in both pre-gestational and gestational periods. She had a retardation of psychomotor development and a brain MRI showed frontal atrophy and a malformation of the posterior fossa. We discuss the mechanisms of the teratogenic effects of retinoic acid.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Acne Vulgaris; Atrophy; Cranial Fossa, Posterior; Craniofacial Abnormalities; Female; Frontal Lobe; Humans; Infant; Isotretinoin; Keratolytic Agents; Maternal Exposure; Pregnancy; Prenatal Exposure Delayed Effects; Psychomotor Disorders; Teratogens; Tretinoin

Isotretinoin is a known teratogen. Pregnancy prevention programs aimed at minimizing isotretinoin exposure in pregnancy have been implemented in North America with limited success.. To compare the management of fetal risk of isotretinoin in three countries, including information given to women, implementation of contraceptive methods, and pregnancy outcomes.. Pregnant women exposed to isotretinoin who called teratogen information services (TIS) in Israel, Italy and Canada between July 1998 and October 2006 were interviewed at the time of initial consultation and after the expected day of delivery.. Fifty-three pregnant women exposed to isotretinoin contacted the TIS. Only 41% reported using a birth control method. Just one patient reported using two different forms. Forty-five percent of exposed pregnancies were terminated before delivery and 22% delivered healthy babies. Two babies were born with malformations.. Since isotretinoin-exposed pregnancies still occur, there is a need for more effective strategies, which should take into account the cultural differences.

Topics: Abnormalities, Drug-Induced; Abortion, Therapeutic; Adult; Canada; Contraception; Dermatologic Agents; Drug Information Services; Female; Fetus; Follow-Up Studies; Global Health; Guideline Adherence; Health Knowledge, Attitudes, Practice; Humans; Infant, Newborn; Isotretinoin; Israel; Italy; Live Birth; Patient Education as Topic; Practice Guidelines as Topic; Pregnancy; Pregnancy Trimester, First; Surveys and Questionnaires; Teratogens

To estimate the population-based incidence rates of pregnancy, spontaneous and elective abortions, and birth defects associated with isotretinoin use, and to determine predictors of pregnancy while on isotretinoin.. Using the RAMQ (medical and pharmaceutical data), MED-ECHO (hospitalizations) and ISQ (births and deaths) databases for the period 1984-2002, a cohort of 8609 women between 13 and 45 years of age and with a first prescription for isotretinoin (date of entry in the cohort) was identified. Women were eligible if they were insured by RAMQ for their medications at least 12 months before entry in the cohort and until 1 month after the end of their isotretinoin treatment. Pregnancies, spontaneous and elective abortions, and birth defects were identified using procedure codes and medical diagnoses.. Of the 8609 women included, 90 became pregnant, an annual incident pregnancy rate during isotretinoin treatment of 32.7 per 1000 person-years of treatment (95% confidence interval 26.6, 40.1). Of the 90 women who became pregnant while on the drug, 76 terminated the pregnancy (84%), three had a spontaneous abortion (3%), two had trauma during delivery resulting in neonatal deaths (2%) and nine had a live birth (10%). Among the live births, only one had a congenital anomaly of the face and neck (11%). Adjusting for potential confounders, predictors of becoming pregnant while on isotretinoin were lower socio-economic level, one or more visits to the doctor or to the emergency department, or one or more hospitalization while on isotretinoin; concomitant isotretinoin and oral contraceptive use had a preventive effect.. This first non-interventional population-based study generated incidence rates of pregnancy while on isotretinoin four times greater than what has been reported in the literature thus far; elective abortion rates were also much higher in our study. This shows the importance of using population-based data for public health purposes.

Topics: Abnormalities, Drug-Induced; Abortion, Induced; Abortion, Spontaneous; Acne Vulgaris; Adolescent; Adult; Dermatologic Agents; Female; Humans; Isotretinoin; Middle Aged; Pregnancy

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adverse Drug Reaction Reporting Systems; Contraindications; Cost-Benefit Analysis; Drug and Narcotic Control; Drug Approval; Female; Fetus; Guidelines as Topic; History, 20th Century; History, 21st Century; Humans; Isotretinoin; Legislation, Pharmacy; Male; Maternal-Fetal Exchange; Pharmaceutical Services; Pregnancy; Reproductive Behavior; Risk Management; Skin Diseases; Social Control Policies; United States; United States Food and Drug Administration

Topics: Abnormalities, Drug-Induced; Female; Fetus; Humans; Infant, Newborn; Isotretinoin; Pregnancy

The aim of the article is to describe the communication development of a child with Fetal Retinoid syndrome (FRS) from six months to seven years of age. Little is known about this rare acquired syndrome and its long-term implications, especially on a child's communication development. A descriptive, ex post facto research design was used to study the participant's communication development from 1996 when the family enrolled in an early communication intervention programme. Annual serial assessments of the participant and her family were conducted and the data were stored in a research database after each assessment. The results are described according to a 4-level assessment framework and indicated consistent, but moderate to minor delays in the participant's communication development with a mild hearing loss in the right ear, associated with ear anomalies. Although prenatal exposure to isotretinoin may have serious effects on the unborn fetus and even cause death, the participant did not display all the symptoms of FRS described in the literature. The favorable family circumstances, early commencement of intervention, and supporting early educational environments were protecting factors that could have contributed positively to the participant's communication development. The importance of knowledge accumulation about rare syndromes such as FRS in Communication Pathology and Audiology is discussed and guidelines for early identification, assessment and treatment applicable to the case are proposed as an intervention option.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Child; Child Development; Child, Preschool; Communication; Communication Aids for Disabled; Female; Fetal Diseases; Follow-Up Studies; Humans; Infant; Isotretinoin; Language Development Disorders; Pregnancy; Prenatal Exposure Delayed Effects; Teratogens

Topics: Abnormalities, Drug-Induced; Canada; Dermatologic Agents; Female; Health Policy; Humans; Isotretinoin; Pregnancy; Registries; United States

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Contract Services; Dermatologic Agents; Dermatology; Drug Prescriptions; Female; Humans; Isotretinoin; Legislation, Pharmacy; Male; Pregnancy; Registries; Software; United States; United States Food and Drug Administration

Topics: Abnormalities, Drug-Induced; Canada; Dermatologic Agents; Drug Approval; Drugs, Generic; Female; Humans; Isotretinoin; Pregnancy

A case of teratogenesis in a 16-year-old pregnant patient is described. She had been using 60 mg Ro-Accutane daily till the 16th week of gestation. Sonography showed no cephalic skull up to the frontal bone of the fetus. A central lagostroma was also detected.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Dermatologic Agents; Esophageal Atresia; Female; Heart Septal Defects; Humans; Isotretinoin; Pregnancy; Skull

To review adherence to selected procedures outlined in the System to Manage Accutane-Related Teratogenicity (SMART) program during the first year of implementation vs the procedures in effect in the year prior to initiation of the SMART program.. Observational.. A novel pharmacy compliance survey and an ongoing, voluntary survey.. Female recipients of isotretinoin.. In April 2002, Hoffmann-La Roche Inc, Nutley, NJ, manufacturer of Accutane brand isotretinoin and at that time the sole source of isotretinoin, revised earlier guidelines and instituted the SMART risk management program, which included the use of qualification stickers to affix to all prescriptions for Accutane to indicate, among other things, a negative pregnancy test just before the prescription was written. The goal of the SMART program was to decrease or eliminate isotretinoin-exposed pregnancies.. Use and completion of prescription qualification stickers; changes in pretherapy pregnancy testing and birth control use.. The results of the pharmacy compliance survey indicated high (>90%) use of prescription qualification stickers. Results of the patient survey suggested that 9% of prescription qualification stickers within the observed user cohort were issued without a pregnancy test. Furthermore, the pregnancy rate for patients participating in the survey was similar to that reported for cohorts recruited before the SMART program.. The usefulness of the results derived from 2 surveys designed to evaluate the SMART program is limited by the lack of reliability and validity of the survey instruments and by questionable generalizability to all female recipients of isotretinoin. The presence of a qualification sticker may not have an impact on pregnancy testing or compliance with effective birth control behavior as outlined in the SMART program.

Topics: Abnormalities, Drug-Induced; Contraception; Contraindications; Drug Labeling; Female; Guideline Adherence; Humans; Isotretinoin; Patient Compliance; Pharmacies; Pregnancy; Pregnancy Tests; Retrospective Studies; Risk Management; Surveys and Questionnaires; Teratogens; United States; United States Food and Drug Administration

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Dermatology; Humans; Isotretinoin

The aim of this survey is to ascertain if the incidence of isotretinoin exposed pregnancies was reduced by the late recommendations of prescription and issue (AMM modification on 06/08/2001 and 25/09/2001).. All isotretinoin exposed pregnancies registered by the French Regional Drug Monitoring Centres, the Information Centre for Teratogenic Agents and Roche (Roaccutane), Pierre Fabre (Curacné Gé) and Expanscience (Procuta Gé) laboratories, from January 1st, 1999 to December 31st, 2002, were analysed. Enforcement of the strengthening of isotretinoin prescription recommendations was analysed on a sample of 68 prescriptions from 45 pharmacies throughout France.. In 4 years, 103 isotretinoin exposed pregnancies (Roaccutane 97 p. 100, Curacné(R) Gé 3 p. 100) during teratogenic risk period, were registered. Pregnancy started less than one month after isotretinoin stopping (37 p. 100), during the treatment (43 p. 100), or was in progress when the treatment was initiated (20 p. 100). The reason of the 22 lacking contraception was known 12 times, i.e. an absence of prescription (6 times), a refusal to take a prescribed contraception (3 times) and a self-medication (3 times). Among the 71 pregnancies whose contraceptive status is known, 48 p. 100 could had been avoided if recommendations had been followed (pregnancies due to a premature stopping or an absence of contraception). The issue of pregnancies is a voluntary termination in 60 cases (87 p. 100). Malformations frequency is 25 p. 100. Incidence of isotretinoin exposed pregnancies remained stable, 0.26/1000 treated women (vs 0.34 after 2001's AMM modifications). Of 68 prescriptions studied, 23 (24 p. 100) carried all the legal warnings, which is close to the previous survey's results. Contraception was in accordance with the recommendations in 78 p. 100 of cases and women learned and applied information given in 38 p. 100 of cases. At last, only 6 patients (9 p. 100) have both a correctly written prescription, a contraception and a time between the pregnancy test date and prescription and issue dates, in accordance with the licence and have had a correct information and understood it. Regarding the previous survey, pregnancy test before treatment was more often prescribed (96 p. 100 vs 88 p. 100). On the other hand, less women knew the necessity to keep on taking contraception one month after isotretinoin stopping (82 p. 100 vs 93 p. 100).. Despite 3 successive isotretinoin prescription and issue recommendations strengthening in childbearing women, pregnancies can't be totally avoided. Bad compliance concerns the prescription and/or an incomplete or not understood information by the patient who does not scrupulously apply the care and contraception agreement. However, this study does not allow to assess the proportion of issued prescriptions despite their non-accordance with the licence criteria. The National Commission of Pharmacovigilance did not like to limit isotretinoin prescription to dermatologists only. It estimates that the administrative authority must intensify information by dermatologists, general practitioners and pharmacists, about measures to take to avoid an exposure to isotretinoin during pregnancy.

Topics: Abnormalities, Drug-Induced; Adult; Contraceptive Agents; Contraindications; Female; France; Guideline Adherence; Health Surveys; Humans; Isotretinoin; Pregnancy; Registries; Retrospective Studies

Isotretinoin is an effective acne medication. The evidence for it causing depression and suicide, although widely publicised, remains uncertain.. Twenty-six semi-structured interviews with patients with acne were coded and subjected to thematic analysis.. Isotretinoin was perceived to be effective but dangerous. The most well known adverse effects were depression and suicide.. The overemphasis of serious psychological adverse events in patients might discourage the use of isotretinoin by those who might benefit from it.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Depression; Female; Health Care Surveys; Health Knowledge, Attitudes, Practice; Humans; Isotretinoin; Male; Middle Aged; Qualitative Research; Risk Assessment; Suicide

Isotretinoin is a known human teratogen, causing birth defects and/or subnormal cognitive performance in prenatally-exposed children.. A survey was conducted among women who called teratology information services throughout North America. Using a structured questionnaire, women with an isotretinoin-exposed pregnancy were prospectively interviewed before the outcome of the pregnancy was known.. Almost 1/4 of the women surveyed (24%; 8/34) did not recall having contraception counseling before starting their medications. Once therapy was initiated, 62% (21/34) recalled using a birth control method, but only 29% (6/21) recalled using 2 forms of birth control, as specified by the voluntary pregnancy prevention programs. Monthly pregnancy tests were not always conducted during treatment, as recalled by the surveyed women (56%; 19/34). As many as 24% (8/34) of the women surveyed recalled that they were not screened using 2 pregnancy tests before receiving a prescription, another recommendation of the programs. Only a small number of the women (30%; 6/20) in the United States recalled being enrolled in any manufacturers' voluntary pregnancy prevention survey.. Results demonstrate that essential components of voluntary pregnancy prevention programs were not consistently followed, which resulted in fetal exposures.

Topics: Abnormalities, Drug-Induced; Adult; Contraception; Dermatologic Agents; Female; Humans; Isotretinoin; Pregnancy; Pregnancy Tests; Surveys and Questionnaires; Teratogens

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Dermatologic Agents; Female; Humans; Isotretinoin; Pregnancy; Quality of Life; Quality-Adjusted Life Years

Topics: Abnormalities, Drug-Induced; Adverse Drug Reaction Reporting Systems; Contraindications; Depression; Drug Monitoring; Humans; Isotretinoin; Keratolytic Agents; Mandatory Programs; Patient Selection; Risk Management; Teratogens; United States; United States Food and Drug Administration

Topics: Abnormalities, Drug-Induced; Dermatologic Agents; Female; Health Promotion; Humans; Isotretinoin; Pregnancy; Prenatal Exposure Delayed Effects; Risk; Teratogens

The prescription of known teratogenic medications requires a careful balance between allowing women access to medications that they might need and avoiding unnecessary exposure to these medications during pregnancy because of their devastating fetal effects. Isotretinoin, a potent human teratogen, is of particular concern because of its widespread use among reproductive-aged women and the dramatic increase in use from 1992 through 2000. A revised risk management system was implemented in 2002 because of concerns about the continued occurrence of isotretinoin-exposed pregnancies. However, the recent approval of three generic versions of isotretinoin in the US has further complicated risk management and raises concerns that use might increase further if the lower cost of generics serves to increase accessibility. There are now four separate isotretinoin risk management systems in the US, each with its own distinct packaging, though the requirements for and substance of each are identical. Some additional concrete steps could be taken to minimise any unnecessary use of isotretinoin and help allow an adequate assessment of the current risk management systems. In addition to being familiar with and following all aspects of the current risk management system, physicians could choose to limit the use of isotretinoin to those who meet the labelled indications in order to reduce the number of exposed pregnancies. All four companies currently marketing isotretinoin in the US could jointly and voluntarily establish a consolidated, mandatory registration and follow-up of all women of reproductive potential who receive an isotretinoin prescription. Mandatory registration has many challenges, but it could allow a clear accounting of the total number of women for whom follow-up information is and is not available. Although the companies cannot be legally compelled to use a consolidated approach, the use of a single registry for the originator's product and all generic brands would allow identification of duplicates and also avoid the confusion that is introduced by providing materials that not only look different, but also have different addresses, contact information and names for participation in follow-up surveys. This is particularly important because women might take more than one version of isotretinoin during a single course of therapy or might receive a different programme's materials from their doctor than from the pharmacy. Though the introduction of generic v

Topics: Abnormalities, Drug-Induced; Dermatologic Agents; Drugs, Generic; Female; Health Services Accessibility; Humans; Isotretinoin; Pregnancy; Risk Management; Safety; Teratogens; United States

A pharmacy claims database was assessed retrospectively to analyze which antiacne medications patients had used in the six months before receiving oral isotretinoin. Before being given a prescription for oral isotretinoin, at least 47% of patients in the database, and possibly as many as 72%, had not received conventional therapy (at minimum, a topical retinoid and an oral antibiotic), as advised in the product labeling. A prior authorization policy restricting oral isotretinoin to patients who were unresponsive to a topical retinoid, at least two other topical medications, and two oral antibiotics reduced oral isotretinoin utilization by 47% and the per member per month spend by 35%.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Administration, Oral; Administration, Topical; Adolescent; Adult; Arizona; Clinical Pharmacy Information Systems; Drug Labeling; Drug Utilization Review; Female; Health Maintenance Organizations; Health Services Research; Humans; Isotretinoin; Male; Patient Compliance; Pregnancy; Retrospective Studies

We have previously reported that exposure of monkey embryos to 13-cis-retinoic acid (cRA) results in thymic defects. In this study, we analyzed lymphocyte and antigen-presenting cell populations at gestational days (GDs) 80-100 in the thymus, spleen, mesenteric lymph nodes, and gut-associated lymphoid tissue following a teratogenic dosing regimen of cRA (2.5 and 5 mg/kg) at GD14-27. Tissue sections were immunostained for T-cells (anti-CD3), B-cells (anti-CD20), dendritic cells (p55), and major histocompatibility class II (anti-HLA-DR). Digital images of spleen sections were analyzed to obtain the relative area occupied by the cell subsets within the white pulp (WP). Compared with controls, the T-cell dependent compartment of the spleen WP in specimens with perturbed thymic development (aplasia and severe hypoplasia) showed a reduction in size and proportion of CD3(+) T cells. Our findings indicate that cRA-induced thymic defects result in disrupted development of the splenic T-cell dependent compartment.

Topics: Abnormalities, Drug-Induced; Animals; CD3 Complex; Embryonic and Fetal Development; Female; Immunohistochemistry; Isotretinoin; Macaca fascicularis; Pregnancy; T-Lymphocytes; Thymus Gland

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Craniofacial Abnormalities; Humans; Infant; Isotretinoin; Lacrimal Apparatus Diseases; Male; Ophthalmoplegia

Topics: Abnormalities, Drug-Induced; Female; Humans; Isotretinoin; Pregnancy; Safety Management; United States

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Depression; Humans; Isotretinoin; Psychoses, Substance-Induced; Therapeutic Equivalency

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Clinical Trials as Topic; Female; Humans; Isotretinoin; Pregnancy

Topics: Abnormalities, Drug-Induced; Contraception; Female; Health Knowledge, Attitudes, Practice; Humans; Isotretinoin; Patient Education as Topic; Pregnancy; Product Labeling

Accutane a teratogenic prescription drug licensed to treat severe, recalcitrant nodular acne. First-trimester pregnancy exposure can cause major birth defects. The manufacturer began a Pregnancy Prevention Program (PPP) in 1988; however, exposed pregnancies continue to occur. In 1996, the manufacturer began a direct-to-consumer advertising campaign, raising concerns of more exposed pregnancies.. We examined trends in Accutane use by reproductive-aged women. We also interviewed a series of 14 women in California who had recent Accutane-exposed pregnancies to identify opportunities for prevention.. The estimated number of Accutane prescriptions for reproductive-aged women has more than doubled in the past 10 years; it is the most widely used teratogenic drug in the United States, with approximately 2.5 per 1,000 reproductive-aged women exposed to Accutane in 1999. One-half of the women interviewed reported seeing an advertisement for prescription acne treatment before taking Accutane. Eight of the 14 women used no contraception at the time of the exposed pregnancy; 13 of the 14 women did not use two forms of contraception. Four of the 14 women did not have pregnancy tests before starting Accutane. None reported seeing all PPP components, and four saw only the information on the pill packet. These 14 pregnancies resulted in four live infants who had no apparent birth defects, one live-born infant with multiple defects, four spontaneous abortions, and five induced abortions.. The increase in Accutane use observed among females may be exacerbated by advertising. Physicians and patients must use more caution with teratogenic prescription drugs. Published 2001 Wiley-Liss, Inc.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Acne Vulgaris; Adolescent; Adult; Contraception; Contraception Behavior; Contraindications; Female; Humans; Incidence; Isotretinoin; Keratolytic Agents; Patient Education as Topic; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, First; Time Factors

Accutane (Roche Laboratories, Nutley, New Jersey), known by the generic name "isotretinoin," is a prescription oral medication approved by the Food and Drug Administration (FDA) to treat severe, recalcitrant nodular acne. It is also a known human teratogen that can cause multiple major malformations. Embryopathy associated with the mother's exposure to isotretinoin during the first trimester of pregnancy includes craniofacial, cardiac, thymic, and central nervous system malformations . In response to FDA recommendations, the manufacturer began a pregnancy-prevention program (PPP) in 1988 that included educational materials for physicians and patients and offered women reimbursement for contraceptive counseling by a physician. The PPP coordinators asked reproductive-aged women being treated with isotretinoin to enroll voluntarily in the Boston University Accutane Survey (BUAS). The total number of reproductive-aged women taking isotretinoin in the United States is unknown; however, 454,273 women enrolled in the BUAS from 1989 to October 1999. BUAS has estimated that 38%-40% of reproductive-aged women taking isotretinoin chose to enroll in the survey (BUAS, unpublished data, 1999). Although isotretinoin is contraindicated in pregnancy and has a package label warning users to avoid pregnancy while taking it, exposed pregnancies occur. Approximately 900 pregnancies occurred among BUAS enrollees during 1989-1998 (BUAS, unpublished data, 1999). Roche Laboratories began direct-to-consumer print advertisements in 1996, added television and radio advertisements to selected cities in 1997, and expanded the campaign to the entire United States in 1998.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Contraception; Contraindications; Female; Humans; Isotretinoin; Keratolytic Agents; Patient Education as Topic; Pregnancy

Psoriasis treatment requires consideration of patient-specific concerns in addition to the severity of skin involvement. There may be sex-specific differences in the treatment of severe psoriasis.. The purpose of this study was to determine whether there are sex-specific differences in the treatment of severe psoriasis.. We analyzed the medications prescribed to patients with a primary and only diagnosis of psoriasis recorded in the 1990-1994 National Ambulatory Medical Care Survey.. There were 8.5 million visits to physicians for the treatment of psoriasis in the years 1990-1994. These visits were made by approximately 4.3 million women and 4.1 million men. Only 39% of patients receiving systemic treatments were women. Women received less methotrexate (23% women) and etretinate (35% women) than men, but more psoralen photochemotherapy (PUVA) (63% women) and isotretinoin (100% women) than men. In contrast, there was no notable difference by sex in the potency of topical corticosteroid agents prescribed.. For mild disease treated with topical agents alone, there is no notable difference in the treatment of men and women. Men are more likely than women to receive intensive treatments for severe psoriasis, at least in part because of the teratogenic potential of these treatments. There is a need for development of new treatments for severe psoriasis that are safe for women of childbearing potential.

Topics: Abnormalities, Drug-Induced; Administration, Topical; Anti-Inflammatory Agents; Dermatologic Agents; Drug Utilization; Etretinate; Female; Glucocorticoids; Humans; Isotretinoin; Male; Methotrexate; Middle Aged; Psoriasis; PUVA Therapy; Sex Factors

Ro 23-9223 is a highly lipophilic aromatic retinoid with antiproliferative and sebum supressive effects in preclinical disease models of acne. To investigate the relation between Ro 23-9223 developmental toxicity, drug distribution, and transplacental transfer, groups of pregnant hamsters were given oral doses of 50-500 mg/kg Ro 23-9223 on days 8 and 9 of gestation. The teratogenic phenotype induced at doses greater than 125 mg/kg per day was similar to that found after exposure to doses of 13-cis-retinoic acid (isotretinoin, Accutane) greater than 37.5 mg/kg per day. Oral bioavailability of Ro 23-9223 was very low compared to 13-cis-retinoic acid. The highest concentrations of Ro 23-9223 were found in maternal liver, lung, adipose tissue, cardiac muscle, and placenta, whereas only little of the compound crossed the blood-brain barrier. Based on embryo AUC, Ro 23-9223 had a 30- to 50-fold greater embryo:maternal concentration ratio than 13-cis-retinoic acid plus its bioactive metabolites following similar doses of the two retinoids. In preclinical pharmacology studies, oral doses of Ro 23-9223 (5 mg/kg per day) and 13-cis-retinoic acid (10 mg/kg per day) produced comparable gland size reductions in the hamster ear sebaceous gland reduction assay. Under these conditions, Ro 23-9223 plasma AUC was 40 times smaller than that of 13-cis-retinoic acid plus its bioactive metabolites. Assuming that the near linear dose-exposure relationship of Ro 23-9223 extends beyond the dose range of this study, embryo AUCs of Ro 23-9223 and 13-cis-retinoic acid (plus metabolites) would be near identical following pharmacologically equivalent doses. A comparison of embryo retinoid AUCs suggests a 4-fold lower teratogenic potency of Ro 23-9223 compared to with 13-cis-retinoic acid. Despite high embryo levels in hamsters, the data suggest an improved therapeutic index for Ro 23-9223 compared with 13-cis-retinoic acid in a preclinical acne disease model.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Area Under Curve; Cricetinae; Dose-Response Relationship, Drug; Embryo, Mammalian; Female; Isotretinoin; Maternal-Fetal Exchange; Pregnancy; Retinoids; Teratogens; Tissue Distribution

Topics: Abnormalities, Drug-Induced; Contraception Behavior; Drug and Narcotic Control; Drug Prescriptions; Female; France; Humans; Infant, Newborn; Isotretinoin; Pregnancy

The recommendations for prescription and dispensing of Roaccutane (isotretinoid) were strengthened in 1997 in order to reduce the number of pregnancies exposed to Roaccutane. The aim of this study was to evaluate the incidence of exposed pregnancies since this time and the compliance with the new recommendations.. All pregnancies exposed to Roaccutane reported to French Regional Drug Monitoring Centers, to Laboratoire Roche or to the Information Center for Teratogenic Agents since the publication of these recommendations for prescription were studied (March 1997-December 1998). In addition, compliance with the new recommendations was evaluated by sampling 169 drug prescriptions dispensed at 105 pharmacies in France.. Thirty-seven pregnancies were exposed to Roaccutane during the risk period because of failure of contraceptive methods (28 p. 100), contraception incorrectly followed (52 p. 100) or not prescribed (20 p. 100). The incidence of pregnancies exposed to Roaccutane during the risk period evaluated at 0.6/1,000 women of child-bearing age [0.4-0.8] is very close to the incidence reported in the earlier study which prompted the new recommendations. Thirty-three percent of the 169 prescriptions studied did not carry all the legal warnings. Roaccutane was correctly prescribed for only 18 p. 100 of women, i.e. with a contraceptive method as recommended by the French Drugs Monitoring Agency and with full, correct information. Although the most important recommendations had been followed, 12 p. 100 of women were treated with Roaccutane without contraception and 16 p. 100 received a contraceptive method not recommended by the French Drugs Monitoring Agency (in particular Diane).. The provision of information must be further improved by enforcing the modalities of prescription and dispensing of Roaccutane. However, it appears that there is no way of completely avoiding patient-related failure.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Contraception Behavior; Drug and Narcotic Control; Drug Information Services; Drug Prescriptions; Female; France; Humans; Infant, Newborn; Isotretinoin; Middle Aged; Pregnancy

One of my adolescent patients was prescribed isotretinoin for severe acne by a dermatologist. I was shocked to discover she does not use any means of contraception. The dermatologist insists he told her about the need for contraception. How can we do better?. Clearly this dermatologist, like many of his colleagues, does not comply with the Pregnancy Prevention Program. Until physicians become more aware of this program, babies will continue to be born with embryopathy due to isotretinoin.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Contraception; Counseling; Dermatology; Female; Humans; Isotretinoin; Keratolytic Agents; Patient Education as Topic; Pregnancy; Pregnancy in Adolescence; Referral and Consultation

Topics: Abnormalities, Drug-Induced; Contraception; Dermatology; Family Practice; Female; Guideline Adherence; Humans; Isotretinoin; Keratolytic Agents; Practice Guidelines as Topic; Pregnancy

Topics: Abnormalities, Drug-Induced; Drug Utilization Review; Female; Humans; Isotretinoin; Pregnancy; Sweden; Teratogens

Vitamin A and its derivatives are known teratogens. To our knowledge, this is the second temporal bone histopathologic report on anomalies related to these substances. A white boy (aged 4 years 5 months at death) was born with a complex central nervous system dysgenesis related to his mother's use of isotretinoin (Accutane) early in pregnancy. Histopathologic examination revealed multiple anomalies in the temporal bones: a narrow external auditory canal, protrusion of bone marrow into the middle ear cavity, anomalies of the ossicles, hypoplasia of the facial nerve, absence of the chorda tympani nerve and the stapedius muscle, anomalies of the membranous labyrinth in the vestibule, a hypoplastic lateral semicircular canal, and a large vestibular aqueduct and endolymphatic sac.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Child, Preschool; Female; Humans; Isotretinoin; Male; Maternal-Fetal Exchange; Pregnancy; Temporal Bone; Teratogens

Isotretinoin (ITR), a teratogen in many species, is associated with increased oxidative stress. Metallothionein (MT) is an important tissue antioxidant whose concentrations are induced by zinc. To study the role of supplemental Zn as an inducer of embryonic MT, we injected pregnant CD-1 mice subcutaneously with saline vehicle, or 20 or 40 mg/kg Zn on gestational day (GD) 6.5. After 48 h, embryonic MT concentrations increased in a dose-related manner (r = 0.64, P < 0.05) with Zn treatment. The possible protective role of Zn pretreatment against ITR teratogenicity was investigated in vivo and in vitro. CD-1 mice were pretreated with saline or Zn (20 and 40 mg/kg) on GD 8.5 and 9.5. ITR was administered to both groups of mice via three intragastric intubations of 100 mg ITR/kg at 4 h intervals on GD 10.5. On GD 18.5, Zn pre-treated mice demonstrated decreased ITR-mediated growth retardation, cleft palates and postpartum mortality. A reduction in embryonic MT concentrations was observed in mice exposed to ITR. Mouse embryos cultured on GD 8.5 with an addition of 15 micromol/L Zn for 48 h had a sixfold greater MT concentration (688 microg/g protein) than controls. The Zn pretreatment of cultured embryos prevented malformations and lessened growth retardation caused by 24 h exposure to 17 micromol/L ITR. These results suggest that Zn-mediated induction of MT in mouse embryos could protect against ITR teratogenicity.

Topics: Abnormalities, Drug-Induced; Animals; Culture Techniques; Embryo, Mammalian; Female; Fetus; Gestational Age; Isotretinoin; Metallothionein; Mice; Pregnancy; Yolk Sac; Zinc

Topics: Abnormalities, Drug-Induced; Female; Humans; Infant; Infant, Newborn; Isotretinoin; Keratolytic Agents; Male; Microcephaly; Pregnancy; Prenatal Exposure Delayed Effects; Teratogens

Isotretinoin is the most potent human teratogen on the market. Women for whom contraception fails may conceive during or soon after discontinuing isotretinoin therapy, making its elimination kinetics a crucial determinant of fetal safety. The steady-state pharmacokinetics of isotretinoin and its major 4-oxo metabolite were studied in 16 adult patients treated for acne who were receiving doses that ranged from 0.47 to 1.7 mg/kg daily. This is the first study of the pharmacokinetics of isotretinoin in women of childbearing age (n = 11). The clinical efficacy and tolerability of isotretinoin was investigated, and the correlation between these data and steady-state serum concentrations of isotretinoin was tested. The concentration-time data best fitted a two-compartment open model with linear elimination. There was no correlation between efficacy and tolerability of isotretinoin and steady-state serum concentrations. There was no correlation between dose of isotretinoin and steady-state concentration, due to the large variability in apparent clearance. Values for elimination half-life (t1/2) of isotretinoin and its metabolite were 29+/-40 hours and 22+/-10 hours, respectively. These data suggest a longer elimination t1/2 of the parent drug than previously reported. This is probably due to the longer sampling time used in this study (as long as 28 days). This study suggests that a greater variability exists in the safe time after discontinuation of the drug for onset of conception.

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Area Under Curve; Chromatography, High Pressure Liquid; Female; Half-Life; Humans; Isotretinoin; Keratolytic Agents; Male; Pregnancy; Teratogens; Tretinoin

Topics: Abnormalities, Drug-Induced; Contraception; Drug Labeling; Female; Humans; Isotretinoin; Managed Care Programs; Teratogens; United States; United States Food and Drug Administration

Although topically applied all-trans-retinoic acid (tretinoin) undergoes minimal absorption and adds negligibly to normal endogenous levels, its safety in humans is occasionally questioned because oral ingestion of retinoids at therapeutic levels is known to entail teratogenic risks.. To assess the actual potential for developmental toxicity from treatment with topical tretinoin.. Risk assessments were conducted on four known human developmental toxicants (valproic acid, methotrexate, thalidomide, and isotretinoin) and a potential developmental toxicant (acetylsalicylic acid). The margin of safety for each chemical was calculated from the ratio of animal no-observed adverse effect levels to human lowest-observed adverse effect levels or estimated exposure doses.. The derived safety margin of more than 100 for topical tretinoin (with 2% absorption) contrasted sharply with the near unity values for valproic acid, methotrexate, thalidomide, and isotretinoin and was larger than that for acetylsalicylic acid.. These data support other epidemiologic and animal data that topical tretinoin is not a potential human developmental toxicant.

Topics: Abnormalities, Drug-Induced; Administration, Topical; Animals; Female; Humans; Isotretinoin; Keratolytic Agents; Methotrexate; Pregnancy; Risk Assessment; Teratogens; Thalidomide; Tretinoin; Valproic Acid

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Acne Vulgaris; Fatal Outcome; Humans; Isotretinoin

All-trans-retinoic acid (all-trans-RA) is required in normal embryogenesis and both deficiency and excess are teratogenic. Isotretinoin (13-cis-RA) is teratogenic in all species examined; based on administered dose, humans appear most sensitive, followed by (in order or decreasing sensitivity) monkey, rabbit, hamster, mouse, and rat. Identification of the teratogenic threshold in these species is difficult because RAs are normal physiologic constituents. The rabbit no-observed-adverse-effect-level (NOAEL) and lowest-observed-adverse-effect-level (LOAEL) administered doses (3 and 15 mg/kg/day, respectively, on gestation Days 8-11) are less than the corresponding values in hamster (7.5 and 37.5 mg/kg/day, respectively, on gestation Days 7 and 8), but drawing conclusions from administered dose alone ignores differences in absorbed, metabolized, and embryonic delivered dose. Therefore, distribution and metabolism studies of 13-cis-RA at the NOAEL and LOAEL in pregnant hamsters were performed and plasma and tissue concentrations of parent compound and metabolites were compared to those found in rabbits. Metabolites of 13-cis-RA common to all species include three RAs (all-trans-RA, all-trans-4-oxoRA, 13-cis-4-oxoRA) and the glucuronide conjugate of 13-cis-RA (13-cis-RAG). As in rabbits, we found 13-cis-4-oxoRA also to be the major metabolite of 13-cis-RA in hamster plasma, peripheral tissues, and embryo. Of maternal tissues, peak 13-cis-RA concentrations were highest in liver. Total concentration of RA (13-cis-RA + 13-cis-4-oxoRA + all-trans-RA + all-trans-4-oxoRA) per gram of wet tissue was greatest in maternal liver, followed by that in lung, adipose tissue, muscle, kidney, and brain. At the NOAEL, total RA plasma Cmax in hamster was 6 times that in rabbit; at the LOAEL, hamster plasma total RA Cmax was 4 times that in rabbit. Hamster absorbed and metabolized dose (as AUC of plasma total RA) at the NOAEL and LOAEL was 2.6 and 2.4 times that in rabbit, respectively. In the embryo, hamster total RA Cmax was 2.7 times (at NOAEL) and 2.6 times (at LOAEL) that in rabbit. However, embryonic delivered dose (total RA AUC in hamster and rabbit embryo, respectively) at the NOAEL (2.08 and 2.14 microg . hr.g-1) and LOAEL (5.34 and 5.54 microg . hr . g-1) was virtually identical. Embryonic AUCs in hamster and rabbit for all-trans-RA and all-trans-4-oxoRA, metabolites which transactivate directly the nuclear RA receptors (RARs), were also very similar at the NOAEL (0.66

Topics: Abnormalities, Drug-Induced; Animals; Cricetinae; Dose-Response Relationship, Drug; Embryo, Mammalian; Female; Isotretinoin; Pregnancy; Rabbits; Receptors, Retinoic Acid; Species Specificity; Teratogens

Despite prominent warnings, pregnancies continue to be reported in women exposed to isotretinoin.. We report results of the analysis of 318 questions asked to pharacovigilance structures in France from 1987 to 1995 because of an exposition to isotretinoin during the risk period and of a prospective inquiry concerning isotretinoin prescription in women conducted among pharmacists.. These 318 pregnancies began during the month after Roaccutane withdrawal (n = 104, 33 p. 100), during Roaccutane treatment (n = 163, 51 p. 100) or before Roaccutane treatment (n = 51, 16 p. 100). Of the 267 women with pregnancies conceived during treatment with isotretinoin (n = 104) or during the month after its discontinuation (n = 163), contraception was not prescribed in 28 (15 p. 100) or prescribed but with poor compliance in 109 (60 p. 100). Pregnancy was terminated voluntarily in 199 women (81 p. 100). In the 173 women who were interviewed in pharmacies, 49 (28 p. 100) did not use contraception and among them contraception was prescribed in only 59 p. 100. Only 14 p. 100 had received full information about isotretinoin and pregnancy. The teratogenic effects of isotretinoin were known by 98 p. 100 of the women and the need of contraception during treatment and for one month after discontinuation by 70 p. 100.. Insufficient compliance with warnings is the main reason for pregnancies in women receiving isotretinoin therapy. A pregnancy prevention program is needed before prescription to ensure comprehension and to obtain informed consent of patients.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Contraindications; Drug Prescriptions; Female; Health Surveys; Humans; Isotretinoin; Keratolytic Agents; Patient Compliance; Patient Education as Topic; Practice Guidelines as Topic; Pregnancy; Risk Factors; Teratogens

Topics: Abnormalities, Drug-Induced; Abortion, Induced; Acne Vulgaris; Adult; Australia; Drug Packaging; Female; Humans; Isotretinoin; Patient Education as Topic; Pregnancy; United States

Topics: Abnormalities, Drug-Induced; Female; Humans; Isotretinoin; Patient Education as Topic; Pregnancy; Teratology; Thalidomide

9-cis retinoic acid (RA) is a naturally occurring isomer of all-trans RA. While both isomers can bind with high affinity and activate RA receptors, only 9-cis RA is the specific ligand for the retinoid X receptors. 9-cis RA has also been shown to be much more potent than all-trans RA in inducing digit duplication in the chick embryo wing bud. To gain further insight into its mechanisms, here we investigated the teratogenic activity in pregnant mice of 9-cis RA and compared it with those of all-trans RA and 13-cis RA. Using frequency and severity of limb reduction defects as well as palatal clefts in the resultant fetuses as indicators, we found that orally administered 9-cis RA was one-half as potent a teratogen as all-trans RA. That 9-cis RA was intrinsically less active than all-trans RA was deduced by comparing the inhibitory activities of the two retinoids in the limb bud mesenchymal cell micromass cultures using chondrogenesis as an end-point. Since placental transfer of cis isomers of RA is generally poor, we monitored the identities and amounts of retinoids in the embryo after administration of 9-cis RA to the mother. We found that 9-cis RA undergoes extensive metabolism and isomerization during absorption resulting in a number of metabolites in the maternal circulation within 30 min after administration. Although some of these metabolites remain to be identified, the most abundant RA isomers in the plasma coeluted with 13-cis RA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abnormalities, Drug-Induced; Animals; Cell Differentiation; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Embryo, Mammalian; Female; In Vitro Techniques; Isotretinoin; Limb Buds; Maternal-Fetal Exchange; Mice; Mice, Inbred ICR; Placenta; Pregnancy; Pregnancy Outcome; Stereoisomerism; Teratogens; Tretinoin

The major antiepileptic drugs used for the control of seizures can induce developmental toxicity when administered during pregnancy. Vitamin A and retinoids are thought to control many processes of embryonic development including growth, differentiation and morphogenesis. We have therefore studied if the teratogenic action of antiepileptic agents could be mediated via alteration of the endogenous vitamin A--retinoid metabolism. Retinol and its oxidative metabolites all-trans-, 13-cis- and 13-cis-4-oxo-retinoic acid were measured in the plasma of 75 infants and children treated with various antiepileptic drugs for the control of seizures, and in 29 untreated controls of comparable age. Retinol levels increased with age, while the concentrations of retinoic acid compounds did not exhibit age-dependency. Valproic acid monotherapy increased retinol levels in the young age group and a trend toward increased retinol concentrations was also observed in all other patient groups. The plasma levels of the oxidative metabolites 13-cis- and 13-cis-4-oxo-retinoic acids were strongly decreased in all patient groups treated with phenytoin, phenobarbital, carbamazepine and ethosuximide, in combination with valproic acid, to levels which were below 1/3rd and 1/10th of corresponding control values, respectively. Little changes were observed with all-trans-retinoic acid except in one patient group treated with valproic acid/ethosuximide cotherapy where increased levels of this retinoid were found. Our study indicates that therapy with antiepileptic agents can have a profound effect on the endogenous retinoid metabolism. Because of the importance of retinoids for the signaling of crucial biological events during embryonic development, such altered retinoid metabolism may be highly significant in regard to antiepileptic drug teratogenesis.

Topics: Abnormalities, Drug-Induced; Anticonvulsants; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Isotretinoin; Male; Oxidation-Reduction; Retinoids; Seizures; Tretinoin; Vitamin A

"Will it work?" is the question usually asked first and most frequently about any contraceptive method. This question is especially salient for women using teratogenic drugs and their clinicians, particularly dermatologists. As discussed in other articles in this issue of the ARCHIVES, dermatologists prescribe two of the most potent teratogenic drugs, isotretinoin (Accutane, Roche Laboratories, Nutley, NJ) and thalidomide. Because this question cannot be answered with certainty for any particular couple, most clinicians and counselors try to help patients understand factors influencing contraceptive efficacy.

Topics: Abnormalities, Drug-Induced; Contraception; Female; Humans; Isotretinoin; Pregnancy; Teratogens; Thalidomide

Isotretinoin is effective in treating severe acne, but it is also teratogenic. To minimize pregnancies among exposed women, the manufacturer, together with the U.S. Food and Drug Administration, implemented a multicomponent Pregnancy Prevention Program in 1988. We report the results of an ongoing survey designed to assess compliance with this program.. Treated women enrolled in the survey through their physician, by filling out a form in the medication package, or by calling a toll-free telephone number. They were randomly assigned to be followed by telephone or by mail. Telephone interviews were conducted at the start of therapy, in the middle of it, and 6 months after it ended; mailed questionnaires were completed 6 months after therapy ended (median duration of therapy, 20 weeks).. Between 1989 and 1993, 177,216 eligible women enrolled in the survey. Interviews with 24,503 women within one month of enrollment revealed that 99 percent had been told to avoid pregnancy. At that time, approximately 54 percent were not sexually active (of whom 37 percent used contraception) and 42 percent were sexually active (of whom 99 percent used contraception); 4 percent were infertile. Among 124,216 women with completed telephone or mail follow-up results, there were 402 pregnancies during therapy (3.4 per 1000 courses of isotretinoin); 72 percent of the pregnant women had elective abortions, 16 percent spontaneous abortions, 3 percent ectopic pregnancies, and 8 percent live births.. The pregnancy rate among women receiving isotretinoin therapy was substantially lower than that in the general population and was compatible with the characteristics and behavior of the enrolled women.. Isotretinoin is effective in treating severe acne, but it is also teratogenic. To minimize pregnancies among exposed women, the manufacturer, together with the US Food and Drug Administration, implemented a multicomponent Pregnancy Prevention Program in 1988. The results of an ongoing survey designed to assess compliance with this program are reported. Treated women enrolled in the survey through their physician, by filling out a form in the medication package, or by calling a toll-free telephone number. They were randomly assigned to be followed by telephone or by mail. Telephone interviews were conducted at the start of therapy, in the middle of it, and 6 months after it ended; mailed questionnaires were completed 6 months after therapy ended (median duration of therapy, 20 weeks). Between January 1, 1989, and December 31, 1993, 177,216 eligible women enrolled in the survey. First telephone interviews were completed with 24,503 women within 1 month of enrollment. The median age of these women was 26 years, the median number of years of education was 14, and the median duration of acne was 8 years. 99% had been told to avoid pregnancy; 85% were told of the importance of using effective contraception for 1 month before starting isotretinoin. At that time, approximately 54% were not sexually active (of whom 37% used contraception); 42% were sexually active (of whom 99% used contraception); and 4% were infertile. As of June 30, 1994, 124,216 women had completed telephone or mail follow-up. There were 402 pregnancies during therapy (0.3% or 3.4 per 1000 20-week courses of isotretinoin); 46 were pregnant when therapy began, and 356 became pregnant during therapy. 290 (72%) of the 402 pregnant women had elective abortions, 63 (16%) had spontaneous abortions, 13 (3%) had ectopic pregnancies, and 32 (8%) had live births. Of the 32 liveborn infants, the survey teratologist examined 13, of whom 5 were judged to have defects compatible with the isotretinoin embryopathy. The pregnancy rate among women receiving isotretinoin therapy was substantially lower than that in the general population and was compatible with the characteristics and behavior of the enrolled women.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Child; Contraception; Contraception Behavior; Data Collection; Female; Health Knowledge, Attitudes, Practice; Humans; Infant, Newborn; Isotretinoin; Middle Aged; Patient Compliance; Physicians; Pregnancy; Surveys and Questionnaires; Telephone

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Child; Contraception Behavior; Female; Health Knowledge, Attitudes, Practice; Humans; Isotretinoin; Middle Aged; Patient Compliance; Pregnancy

The analysis of 4 craniofacial teratological models in the mouse (13-cis-retinoic acid and methyl triazene administration, irradiation, 'far' strain) permits to study the similarities, but also the differences between these models and malformative syndromes in the human. Retinoic acid administration provides a phenocopy of mandibulofacial dysostosis, and irradiation gives rise to a centrofacial dysplasia evoking several holoprosencephalia and Crouzon syndrome. However, triazene administration does not reproduce the hemicraniofacial microsomia.

Topics: Abnormalities, Drug-Induced; Abnormalities, Radiation-Induced; Animals; Craniofacial Dysostosis; Ear, External; Embryo, Mammalian; Humans; Isotretinoin; Maxillofacial Development; Mice; Mice, Inbred C57BL; Teratogens; Triazenes

No embryotoxic or teratogenic effects, considered to be treatment related, were observed in rabbits after daily oral doses of 3 mg/kg of 13-cis-retinoic acid (13-cis-RA) from Day 8 to Day 11 of gestation. In contrast, treatment with 15 mg/kg/day significantly increased the rate of fetal resorptions (22%) and 13 out of 68 surviving fetuses (16%) were malformed. Pharmacokinetic studies with both dosing regimens of 13-cis-RA in pregnant rabbits showed that on Day 11 of gestation, high concentrations of parent compound, 13-cis-RA, and its major metabolite, 13-cis-4-oxoRA, existed in maternal plasma. Much lower concentrations were found for all-trans-4-oxoRA and all-trans-RA. The area under the concentration-time curve (AUC) of all-trans-RA following the 15 mg/kg/day dosing regimen of 13-cis-RA was only 1.2% that of parent compound 13-cis-RA. At this dose, embryo levels of 13-cis-RA, 13-cis-4-oxoRA, and all-trans-4-oxoRA were 2.5-, 4.7-, and 3.6-fold higher by AUC comparison (24-hr period of Day 11) compared with the dose of 3 mg/kg. However, embryo levels of all-trans-RA were virtually identical at both doses and were, in fact, somewhat lower than endogenous concentrations measured in untreated rabbit embryos. In contrast to mice, where isomerization from 13-cis- to all-trans-RA was suggested to be crucial for the teratogenic action of 13-cis-RA, we found that the teratogenic action of 13-cis-RA (15 mg/kg/day) in rabbits is characterized by increased whole embryo concentrations of 13-cis-RA, 13-cis-4-oxoRA, and all-trans-4-oxoRA, but not of all-trans-RA.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Embryo, Mammalian; Female; Fetus; Gestational Age; Isotretinoin; Maternal-Fetal Exchange; Placenta; Pregnancy; Rabbits; Stereoisomerism; Tretinoin

The teratogenicity of 13-cis-retinoic acid (RA) either administered alone or following pretreatment with phenobarbital sodium (PB), was assessed. Groups of gravid CF-1 mice were administered dosages of either 10, 100, 200, or 400 mg/kg of RA orally on either days 11, 12 or 13 of gestation, in order to determine structural alterations. In addition, separate groups of mice were orally pretreated with 80 mg/kg/day of PB on days 7 through 10 of gestation prior to the administration of RA. Skeletal alterations attributed to maternal administration of either 100, 200 or 400 mg/kg of RA on days 11-13 included delayed ossification of the limbs and supraoccipital bone, the presence of extra ribs, and various sternebral defects. Soft tissue alterations included cleft palate and dilation of the renal pelves which occurred following maternal exposure on days 11 and 12-13, respectively. Significant decreases in the incidence of cleft palate and delayed ossification of the limbs were observed in those dams administered RA on days 11 or 12, respectively, following prior treatment with PB. These data suggest that administration of PB, a prototypical hepatic microsomal enzyme inducer, may partially antagonize the teratogenicity of RA.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Animals, Newborn; Body Weight; Bone and Bones; Cleft Palate; Female; Isotretinoin; Male; Mice; Organ Size; Osteogenesis; Phenobarbital

The teratogenic potential of 13-cis retinoic acid (13-cis RA) was further assessed in cynomolgus macaques (Macaca fascicularis) following exposure to two different regimens during the preorganogenic period to determine the influence of time of treatment on the 13-cis RA malformation syndrome established previously (Hummler et al., Teratology, 42:263-272, 1990). In experiment (Exp) 1, 13-cis RA was orally administered once daily (2.5 mg/kg) on gestational day (GD) 16-25 and twice daily (2 x 2.5 mg/kg) on GD 26-27. In Exp 2, the same oral dose was administered once daily on GD 10-20 and twice daily on GD 21-24. Although the ear was affected at about the same incidence (6/9, 67%) in Exp 1 as previously reported, the defects were less severe. Except for hypoplastic vermis of the cerebellum (2/9, 22%), no other defects were seen. In Exp 2, the teratogenic effects of 13-cis RA on the craniofacial skeleton (1/9, 11%), external ear (5/9, 56%), and heart (2/9, 22%) were similar to that reported by Hummler et al.; however, no thymus or cerebellar malformations were observed. Analysis of the three different treatments (GD 16-27 in Exp 1, GD 10-24 in Exp 2, and GD 10-27 in Hummler et al.) suggests that the sensitive periods in the macaque are 1) craniofacial skeleton and heart GD 10-24, 2) thymus and cerebellum > GD 24, and 3) external ear GD 16-24, although the defects are less severe following the shorter exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abnormalities, Drug-Induced; Animals; Dose-Response Relationship, Drug; Ear, External; Female; Gestational Age; Humans; Isotretinoin; Macaca fascicularis; Maternal-Fetal Exchange; Pregnancy; Species Specificity; Syndrome

Among the findings associated with the human Retinoic Acid Embryopathy are hindbrain defects including the Arnold-Chiari malformation. The human Arnold-Chiari malformation (ACM) is a malformation complex where the cardinal feature is herniation of the caudal hindbrain into the vertebral column; it is frequently accompanied by lumbosacral myelorachischisis and hydrocephalus. Mice exposed to all-trans-retinoic acid or etretinate on day 8.25 of pregnancy, produce offspring with hindbrain herniation and caudal lumbosacral myelorachischisis in addition to a variety of other craniofacial and caudal malformations. Several experimental animals were observed to lack the caudal myelorachischisis proving that this lesion is not required to generate hindbrain herniation. We provide evidence that the cranial malformations, including hindbrain herniation, result from primary damage to the neural crest and the rhombencephalon. The vulnerability of these sites appears to be correlated with the presence of normal physiological cell death. While these experimental animals differ in many respects from the typical human Arnold-Chiari malformation, they may provide some insight into the pathogenesis of the latter.

Topics: Abnormalities, Drug-Induced; Animals; Disease Models, Animal; Ear; Exophthalmos; Female; Humans; Isotretinoin; Male; Mandible; Mice; Mice, Inbred C57BL; Neural Crest; Pregnancy; Rhombencephalon; Tretinoin

Oral administration of 13-cis retinoic acid (RA) to pregnant mice on the 9th gestation day provokes important malformations of the middle ear ossicles, associated with a general kind of craniofacial dysmorphogenesis evoking the human mandibulofacial dysostosis. The malleus, incus and stapes are affected. The malleus exhibits a handle separated from its head and keeping a persistant relationship with the tubotympanic recess. The stapes makes no contact with the otic capsule. The malformation pattern is visible early as shown by the appearance of an abnormally curved Meckel's cartilage at day 12, followed by the development of atypically shaped ossicular anlagen. The mouse "far" (first arch malformation) mutation is responsible for minor ossicular abnormalities which disrupts the normal relationships between the stapes, Reichert's cartilage and stapedial muscle. The administration of RA to pregnant mice and the comparison with a genetically induced malformation (the mutation far) provides some interesting information about the postulated mechanisms of human middle ear dysmorphogenesis, as well as precious data about the features of normal ossicular primordia formation. The comparison of these features with human middle ear abnormalities as revealed by medical imaging sheds light on human malformation patterns and provides a better understanding of normal and abnormal radiologic ossicular aspects.

Topics: Abnormalities, Drug-Induced; Animals; Disease Models, Animal; Ear Ossicles; Humans; Isotretinoin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains

Inner ear malformations induced in anotic hamster fetuses following maternal treatment with 50 mg/kg isotretinoin (13-cis-retinoic acid) on gestational day 8 are described. Computer-assisted three dimensional reconstruction was used. Two general types of defective vestibulocochlear development were seen. Defects were bilateral and correlated with extent of middle ear deficiency and severity of mandibular defects. In the more severely affected fetuses the inner ear was limited to an epithelial sac with occasional small projections, no apparent innervation and a correspondingly reduced otic capsule. In most of the fetuses examined the inner ear was less severely affected and was characterized by a reduction in the number of semicircular ducts and alterations in the size and shape of the cochlear duct. These defects are similar to those seen in a child with the isotretinoin embryopathy. Pathogenesis may result from a direct effect on otic epithelium or from faulty inductive interactions with the rhombencephalon or with periotic neural crest cells.

Topics: Abnormalities, Drug-Induced; Animals; Cell Death; Cricetinae; Ear, Inner; Isotretinoin; Mesocricetus; Neural Crest

Topics: Abnormalities, Drug-Induced; Administration, Topical; Adrenal Cortex Hormones; Anti-Bacterial Agents; Antifungal Agents; Antiviral Agents; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isotretinoin; Pharmaceutical Preparations; Podophyllin; Pregnancy; Risk

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Contraindications; Etretinate; Female; Humans; Isotretinoin; Pregnancy; Psoriasis

The primary objectives of this study were to determine how dermatologists currently prescribe isotretinoin and to determine if the potential for adverse effects, especially those affecting the fetus, has influenced dermatologists' prescribing patterns.. A survey was mailed to 1618 dermatologists practicing in the US. The survey comprised 22 multiple-choice and fill-in-the-blank questions about the use of isotretinoin. Eight weeks were allowed for completion and return of the survey.. The setting of the study included dermatologists in private practice, those with academic appointments, those in administration, and a few dermatologists in other pursuits.. The membership roster of the American Academy of Dermatology served as the sampling frame from which survey recipients were drawn. After arranging the list by zip code, a sample of dermatologists was taken by systematically choosing every fifth name on the list, giving the researchers the total sample of 1618 physicians.. Questions were organized into the following sections: (1) practice status of respondent, (2) prescriber demographics, (3) influence of adverse effects on prescribing, (4) prescribing practices, (5) discontinuation of therapy, and (6) restriction of isotretinoin to dermatologists. The survey concluded by providing participants the opportunity to make further observations or comments.. Of the 1618 surveys mailed, 670 usable responses were received (41.4 percent). Most respondents were in private practice. Data show that dermatologists were prescribing isotretinoin for indications other than those contained in the official labeling. Most physicians reported that they do perform a pregnancy test before prescribing the drug, and many require written informed consent before prescribing. Physicians report that, in general, their patients tolerate isotretinoin well. When therapy is discontinued, it is most often secondary to hypertriglyceridemia. Dermatologists believe that they should have sole authority for prescribing isotretinoin.. Our results show that there is still a need for emphasizing the limited indications for isotretinoin and a need for effective patient education for women of childbearing potential who may be prescribed this drug.

Topics: Abnormalities, Drug-Induced; Adult; Dermatology; Drug Prescriptions; Drug Utilization; Female; Humans; Isotretinoin; Menarche; Practice Patterns, Physicians'; Pregnancy; Surveys and Questionnaires; United States

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Etretinate; Female; Humans; Isotretinoin; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Retinoids; Skin Diseases

Exposure to isotretinoin during pregnancy is associated with a high risk of major fetal malformations.. Our purpose was to determine the reasons for and outcomes of in utero isotretinoin exposure.. On the basis of 433 spontaneous reports, we describe the likely reasons these exposures occurred and the outcomes of these pregnancies. In our analysis of the outcomes of pregnancy, we separately consider the pregnancies known to us before their outcomes were determined as prospective cases.. Timing of conception in relation to initiation of therapy with isotretinoin was known for 396 women. Of these, 130 patients (33%) were already pregnant when they started isotretinoin. An additional 65 patients (16%) became pregnant in the first 3 weeks of isotretinoin use. Pregnancy outcomes were known on 409 pregnancies. Among these, 222 (54%) ended in elective abortion and 29 (7%) in spontaneous or missed abortion. Of 151 births, 72 (48%) were normal, 71 (47%) had congenital malformations, and 8 (5%) had abnormalities other than malformations. Of 94 prospectively ascertained pregnancies that ended in births, 28% had congenital malformations (95% confidence interval 19% to 37%). Exposure to isotretinoin during any time and for as little as one capsule within the first trimester have been associated with congenital malformations.. The high proportion of exposures in already or recently pregnant women illustrates the importance of obtaining a negative pregnancy test before the initiation of isotretinoin therapy and of delaying the commencement of isotretinoin therapy until the onset of the next menstrual period. Furthermore, the importance of reliable contraceptive methods should be emphasized to patients when isotretinoin is prescribed. Young women seem to be at an especially high risk of pregnancy exposure to isotretinoin. There is a substantial risk of congenital malformation at all therapeutic doses of isotretinoin, even when the duration of exposure is brief.

Topics: Abnormalities, Drug-Induced; Abortion, Induced; Abortion, Spontaneous; Adolescent; Adult; Contraception Behavior; Female; Humans; Isotretinoin; Pregnancy; Pregnancy Outcome; Prospective Studies; Retrospective Studies

Retinoic acid has long been used to induce limb reductions defects in experimental animal studies. No limb malformations, however, have been reported among malformed retinoic acid-exposed human fetuses from case reports or epidemiologic studies. We report a child and a fetus with limb reduction malformations following maternal use of isotretinoin (13-cis-retinoic acid) during the first trimester of pregnancy. The child had a unilaterally absent clavicle and nearly absent scapula, with a short humerus and short, synostotic forearm bones. He also had ventriculomegaly and developmental delay, minor dysmorphic facial features, and a short sternum with a sterno-umbilical raphe. The fetus had a unilaterally absent thumb with normal proximal bony structures. Other findings included hydrocephalus, craniofacial anomalies, thymic agenesis, supracristal ventricular septal defect, single umbilical artery, anal and vaginal atresia, and urethral agenesis with dysplastic, multicystic kidneys. Although the limb malformations were quite dissimilar, a number of anomalies that are frequently found among isotretinoin-exposed fetuses/infants were present in both cases. This increases the probability that retinoic acid caused these limb defects, but a causal association cannot be conclusively drawn on the basis of these two retrospective case reports.

Topics: Abnormalities, Drug-Induced; Arm; Clavicle; Female; Fetus; Humans; Hydrocephalus; Infant, Newborn; Isotretinoin; Kidney; Limb Deformities, Congenital; Male; Maternal-Fetal Exchange; Pregnancy; Thumb; Ultrasonography, Prenatal

Isotretinoin (13-cis-RA) is known to be teratogenic in humans and laboratory animals. The relatively low potency of 13-cis-RA in NRMI mice in comparison to the all-trans isomer has been proposed to be due to minimal transfer across the placenta (Creech-Kraft et al., '87). To further delineate the teratogenic potential of 13-cis-RA, a dose-response, temporal study was conducted in vivo and in vitro using submerged limb culture and image analysis evaluation of development. Dose-dependent embryotoxicity was produced by treatment on GD 7, while later treatments produced inconsistent effects on resorption rate and fetal weight. Treatment on either GD 7 or GD 8 produced a number of malformations in dose-dependent manner. Most common were tail and cleft palate defects, which were produced by 13-cis-RA on each of the days tested (GD 7-GD 11), with peak malformations occurring on GD 9 and GD 10 for tail and cleft palate, respectively. Most limb defects were produced after GD 10 and GD 11 exposure. The observed frequency of defects confirmed that in ICR mice 13-cis-RA is about 10-fold less potent than all-trans-RA as a limb teratogen (Kwasigroch and Kochhar, '80; Kochhar and Penner, '87). Effects observed via image analysis following maintenance of limbs in serum-free culture medium were dose dependent. Low dose treatment produced occasional polydactyly. The intermediate dose caused somewhat variable region-dependent increases in cartilaginous bone anlagen area. The high dose of 13-cis-RA produced irregular limb outlines, a reduction in bone anlagen area, and an inhibition of alcian blue staining of cartilage without affecting morphogenesis of bone anlagen. These results confirm that, when the effects of the administered doses are evaluated, 13-cis-RA is a much less potent teratogen in comparison to the all-trans isomer. More importantly, the results show that retinoids can enhance (at low and intermediate doses), depress (at high doses), or eliminate (high dose) chondrogenenic expression during limb morphogenesis in vitro. This indicates that retinoids such as 13-cis-RA can manipulate events in development in a variety of ways (i.e., produce malformations, interfere with chondrogenic expression without affecting morphogenesis, and stimulate growth) in a dose- and time-dependent manner. Although the ability of RA to act as a true morphogen has recently been questioned (Wanek et al., '91; Noji et al., '91), the results presented here support the position that RA can

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Cleft Palate; Culture Techniques; Dose-Response Relationship, Drug; Extremities; Female; Fetal Resorption; Fetal Viability; Gestational Age; Isotretinoin; Limb Deformities, Congenital; Maternal-Fetal Exchange; Mice; Mice, Inbred ICR; Pregnancy; Radiography; Tail

The developmental toxicity of five compounds was evaluated with the Frog Embryo Teratogenesis Assay: Xenopus (FETAX) and the results were compared to mammalian literature. Small cell Xenopus laevis blastulae were exposed to ascorbic acid, sodium selenate, coumarin, serotonin and 13-cis retinoic acid for 96 hr. Three separate static-renewal assays were conducted for each compound. Teratogenic potential of the test materials was determined based on Teratogenic Index values [TI = LC50/EC50 (malformation)], types and severity of induced malformations and embryo growth. Ascorbic acid had little or no teratogenic potential. Sodium selenate and coumarin tested as having moderately positive teratogenic potential. Serotonin scored as having moderately strong teratogenic potential and 13-cis retinoic acid scored as having strong teratogenic potential. Results were consistent with mammalian data and support the use of FETAX for the screening of developmental toxicants.

Topics: Abnormalities, Drug-Induced; Animals; Ascorbic Acid; Coumarins; Dose-Response Relationship, Drug; Isotretinoin; Lethal Dose 50; Selenic Acid; Selenium; Selenium Compounds; Serotonin; Xenopus laevis

Topics: Abnormalities, Drug-Induced; Animals; Contraindications; Female; Humans; Isotretinoin; Risk Factors

At the in vitro threshold serum concentration of 500 ng/ml, isotretinoin induces defects of visceral arch development in 9.5-day rat embryos grown in culture for 48 h. Experiments were performed to determine the minimum period of exposure necessary to induce these arch defects and whether an increase in concentration of isotretinoin could compensate for reduced exposure time. The results showed that a minimum 6-h exposure to 500 ng/ml immediately prior to cranial neural crest migration was necessary to induce severe defects of the second visceral arch in a majority of embryos. Maximal increase in isotretinoin concentration to 16,000 ng/ml did not compensate for shorter exposure periods. These results suggest that to cause malformations of the visceral arches, the embryo must be exposed to isotretinoin for a minimum period of time regardless of the concentration of isotretinoin above the threshold.

Topics: Abnormalities, Drug-Induced; Animals; Embryo, Mammalian; Embryonic and Fetal Development; Female; Isotretinoin; Organ Culture Techniques; Rats; Rats, Inbred Strains; Teratogens

Isotretinoin (Accutane), a widely used dermatologic drug, produces severe congenital malformations when used during pregnancy. The isotretinoin teratogen syndrome consists of multiple cardiovascular and craniofacial anomalies, most commonly involving the external ear. This study examined the pathogenesis of isotretinoin teratogenicity in a mouse model, using microdissection and histologic examination of fetal mouse ears after treatment with the drug at various stages of embryonic development. In this study, earlier treatment times frequently produced microtia similar to that seen in affected infants, as well as recognizable patterns of temporal bone and ossicular abnormalities; exposure at a later developmental stage resulted in facial tags with less severely affected ears. Possible teratogenic mechanisms of isotretinoin are discussed. Suitability of the mouse model for studying human congenital craniofacial malformations, such as Goldenhar's and Treacher Collins Syndrome, is also explored.

Topics: Abnormalities, Drug-Induced; Animals; Ear, External; Ear, Inner; Ear, Middle; Embryo, Mammalian; Isotretinoin; Mice; Mice, Inbred Strains

Topics: Abnormalities, Drug-Induced; Abortion, Incomplete; Acne Vulgaris; Female; Humans; Isotretinoin; Patient Education as Topic; Pregnancy; Pregnancy Complications

The extent of clustering of 2 or more defects in the same infant can be expressed as the ratio of the observed number of infants with the defects (O) over the expected number of such infants (E). The expected is usually derived from the product of population rates of individual defects. Because large O/E ratios are obtained for many defect combinations, it has been suggested that clustering of defects is generalized and nonspecific. To control for the tendency of nonspecific clustering of defects, an alternative method is to perform the same calculations among multimalformed infants only. A main limitation of this method is that it adjusts for the clustering tendency of all defects rather than the ones of interest, often resulting in spuriously low O/E ratios. We present a new method to adjust for the tendency for nonspecific clustering between defects that overcomes this limitation. With this method, adjusted O/E ratios are inversely related to the proportion of infants who are multimalformed and have one or more of the defects being examined. Using data from the Metropolitan Atlanta Congenital Defects Program, we apply this method to the previously described associations among VACTERL defects and midline or "schisis" defects. We show that adjusted O/E ratios obtained are greater than those obtained by using multimalformed infants. For midline defects, many of the adjusted ratios were close to one, indicating nonspecific clustering of these defects. Finally, using the example of isotretinoin embryopathy, we show that O/E ratios depend highly on the frequency of exposure in the population, and thus, they should be interpreted with caution.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Cluster Analysis; Congenital Abnormalities; Humans; Infant, Newborn; Isotretinoin; Mathematics

The embryotoxic and teratogenic potential of 13-cis retinoic acid was assessed in the cynomolgus macaque (Macaca fascicularis). A total of 41 animals was orally administered 13-cis retinoic acid in four sequential experiments. In Exp. 1 three dose levels, 2, 10, and 25 mg/kg, were administered on gestational day (GD) 18-28; 5 mg/kg was administered as an equally divided dose twice daily in Exp. 2 and 3 on GD 21-24 and on GD 25-27, respectively; in Exp. 4 the drug was administered at 2.5 mg/kg once daily from GD 10 to 25 and twice daily (2 x 2.5 mg/kg) on GD 26 and 27. Maternal death and toxicity, manifested as reduction in maternal weight and food consumption, and diarrhea, was observed in Exp. 1 in all three dose groups. No significant maternal toxicity was observed in the treatment groups in Exp. 2, 3, and 4 or in the control group. The primary manifestation of developmental toxicity was embryolethality in Exp. 1 and 2. The incidence of embryonic deaths in Exp. 3 was comparable to the historical controls. No malformations in GD 100 fetuses were observed in Exp. 1, 2, and 3. In Exp. 4, five of seven fetuses (71%) had malformations of both external ears, four of seven fetuses (57%) exhibited hypo- or aplasia of the thymus, and two of seven (29%) had malformations (transposition of the great vessels, ventricular septal defect) of the heart. The teratogenic dose for the cynomolgus monkey in the present study was lower than that reported for all other experimental species. Although central nervous system and craniofacial defects were not observed, the incidence of ear and thymus defects was similar to that reported for the human. The cardiovascular defects resembled those reported clinically, but the incidence was lower in the cynomolgus monkey. The similarity in teratogenic sensitivity to humans supports the use of the monkey as a model for developmental toxicity studies of vitamin A-related compounds.

Topics: Abnormalities, Drug-Induced; Animals; Dose-Response Relationship, Drug; Ear; Female; Fetus; Isotretinoin; Macaca fascicularis; Organ Specificity; Pregnancy; Teratogens; Tretinoin

High doses of vitamin A cause birth defects in animals. Concern over vitamin A teratogenicity in humans has been prompted by reports of teratogenic effects of the vitamin A analogue, isotretinoin. The pattern of defects observed among isotretinoin- and vitamin A-exposed infants and animals suggests a possible mechanism involving cranial neural crest cell activity. Data from a case-control study were used to assess maternal use of vitamin A supplements alone and vitamin A-containing multivitamin supplements in relation to the occurrence of certain birth defects involving structures derived, at least in part, from cranial neural crest cells. Cases were 2,658 infants with such defects (primarily craniofacial and cardiac malformations). Controls were 2,609 infants with other malformations. Vitamin A supplementation was defined as daily use for at least 7 days of retinol alone or with vitamin D, or of fish oils. Information on vitamin A dose and nutrition was not available. The mothers of six controls used vitamin A supplements in each of the first three lunar months of pregnancy in comparison to the mothers of 15, 14, and 10 cases in lunar months 1, 2, and 3, respectively. Relative risk estimates and 95% confidence intervals were 2.5(1.0-6.2) for lunar month 1, 2.3(0.9-5.8) for lunar month 2, and 1.6(0.6-4.5) for lunar month 3. These findings should be considered tentative because no dose information was available, small numbers of cases and controls were exposed to vitamin A supplements, and relative risk estimates were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abnormalities, Drug-Induced; Canada; Cranial Nerves; Female; Humans; Infant; Isotretinoin; Neural Crest; Pregnancy; Risk Factors; United States; Vitamin A

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Acne Vulgaris; Drug Labeling; Drug Prescriptions; Female; Humans; Isotretinoin; Pregnancy

First trimester exposure to isotretinoin is associated with an estimated 20% risk of major fetal malformations. Product labeling in force up to August 1988 included a statement that the drug is contraindicated in pregnancy and suggested procedures for prescribing physicians to follow to prevent inadvertent first trimester exposure to the product. This limited educational intervention did not prevent the continued occurrence of isotretinoin-related birth defects. The effectiveness of recent changes in the package labeling in preventing such birth defects remains to be demonstrated. Two infants with major birth defects associated with first trimester exposure to isotretinoin (Accutane, Roche Laboratories) were reported to the New Jersey Birth Defects Registry within 6 months. Stimulated by these reports, we sought additional cases in New Jersey and found three. We here describe these five cases of isotretinoin embryopathy, including available information on the circumstances which led to maternal use of isotretinoin during the first trimester of pregnancy. In response to a preliminary report of these cases and to investigations by epidemiologists at the U.S. Food and Drug Administration (FDA), the manufacturer altered the package labeling. The revised product information includes a more prominent "contraindication and warning" section and a new "patient information/consent" section. The effectiveness of this educational intervention should be evaluated.

Topics: Abnormalities, Drug-Induced; Adult; Female; Humans; Infant, Newborn; Isotretinoin; Male; Pregnancy; Pregnancy Trimester, First

Topics: Abnormalities, Drug-Induced; Drug Industry; Female; Humans; Isotretinoin; Pregnancy

Topics: Abnormalities, Drug-Induced; Drug Labeling; Female; Humans; Isotretinoin; Legislation, Drug; Physician's Role; Pregnancy; United States; United States Food and Drug Administration

Isotretinoin (13-cis-retinoic acid, Accutane) increases the risk of major congenital malformations in infants exposed to isotretinoin during pregnancy. However, there have been no epidemiologic reports to date on the effect of a subsequent pregnancy after discontinuation of isotretinoin. This article describes our analysis of pregnancy case reports from patients in whom conception occurred after isotretinoin treatment had been discontinued. Based on the 88 prospectively ascertained cases, the incidence rate of both spontaneous and missed abortions from all pregnancies was 9.1% (eight patients), and the incidence rate of congenital malformation among the live births was 5.0% (four patients). The incidence rates for both these outcomes were not significantly different from the rates reported for women of reproductive age in the general population. In addition, the malformations reported were not characteristic of retinoic acid-induced congenital anomalies.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Adult; Female; Humans; Isotretinoin; Pregnancy; Pregnancy Outcome; Prospective Studies; Time Factors

Topics: Abnormalities, Drug-Induced; Female; France; Humans; Infant, Newborn; Isotretinoin; Pregnancy; Tretinoin

Topics: Abnormalities, Drug-Induced; Female; Humans; Infant, Newborn; Isotretinoin; Pregnancy; Prospective Studies; Retrospective Studies; Teratogens; Tretinoin

Topics: Abnormalities, Drug-Induced; Etretinate; Female; Humans; Infant, Newborn; Isotretinoin; Pregnancy

Topics: Abnormalities, Drug-Induced; Female; Humans; Infant, Newborn; Isotretinoin; Pregnancy

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Female; Humans; Isotretinoin; Legislation, Drug; Pregnancy; Tretinoin; United States; United States Food and Drug Administration

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Female; Humans; Isotretinoin; Pregnancy; Pregnancy Complications; Tretinoin; United States; United States Food and Drug Administration

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Female; Humans; Isotretinoin; Pregnancy; Pregnancy Complications; Tretinoin

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Female; Humans; Infant, Newborn; Isotretinoin; Male; New Jersey; Teratogens; Tretinoin; United States; United States Food and Drug Administration

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Female; Humans; Infant, Newborn; Isotretinoin; Male; New Jersey; Teratogens; Tretinoin; United States; United States Food and Drug Administration

Topics: Abnormalities, Drug-Induced; Female; Humans; Isotretinoin; Pregnancy; Teratogens; Tretinoin

Topics: Abnormalities, Drug-Induced; Contraception; Female; Humans; Isotretinoin; Teratogens

Topics: Abnormalities, Drug-Induced; Embryonic and Fetal Development; Female; Humans; Infant, Newborn; Isotretinoin; Longitudinal Studies; Pregnancy

Topics: Abnormalities, Drug-Induced; Female; Humans; Isotretinoin; Pregnancy; Tretinoin

Vitamin A and vitamin A derivatives have been described as etiologic factors for a number of congenital malformations. Two infants are presented with major auricular malformations including anotia and severe microtia. The infants were products of a pregnancy complicated by Accutane ingestion during the first trimester. Both infants had associated central nervous system malformations. With the increasing use of Accutane for the treatment of cystic acne in young women of child-bearing age, the dangers of teratogenesis in the head and neck area are greatly increased. This presentation will review two such cases as well as give an overview of the embryogenesis and teratogenesis of the auricle.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Acne Vulgaris; Adult; Ear, External; Female; Humans; Infant, Newborn; Isotretinoin; Male; Teratogens; Tretinoin

Recent concerns have been raised about the ability of birth defects monitoring programs to detect increases in the incidence of birth defects following the introduction of new teratogens. The authors illustrate how most monitoring programs in the United States and Europe are limited in their ability to detect new teratogens because of a combination of parameters: the small population size, the low population frequency of exposure to the new teratogen, the weakness of many suspected teratogens (measured in terms of relative risk R), the low background rate, and the etiologic heterogeneity in the measured defects. In a system that monitors 25,000 births per year, it can be shown that although a new teratogen such as thalidomide (R = 175) can lead to a significant increase in the number of observed cases in 1-2 weeks of monitoring, even strong teratogens such as valproic acid and isotretinoin (R = 20-25) require more than 20 years of monitoring to show a significant increase in the number of cases because of low exposure frequency. Also, most mild to moderate teratogens (R = 2-5) can be totally missed. To improve the ability of birth defects monitoring programs to detect new teratogens, it is suggested that surveillance systems ought to examine subsegments of the population with maximal exposure potential, classify birth defects into more etiologically homogeneous groups, and expand the sample size of the monitored population.

Topics: Abnormalities, Drug-Induced; Epidemiologic Methods; Humans; Infant, Newborn; Isotretinoin; Risk; Teratogens; Thalidomide; Tretinoin; Valproic Acid

Topics: Abnormalities, Drug-Induced; Family Planning Services; Female; Humans; Isotretinoin; Pregnancy; Tretinoin

13-cis-Retinoic acid (isotretinoin) is teratogenic in man at therapeutic doses (0.5-1.5 mg/kg body wt), but only marginally teratogenic in the mouse at exceedingly high doses (greater than 100 mg/kg). On the other hand, the isomer all-trans-retinoic acid (tretinoin) is teratogenic in the mouse at dose levels which are 10 times lower than those for the 13-cis isomer. We have therefore studied whether the greatly different teratogenic potencies of these two compounds in the mouse are the result of differences in their transplacental kinetics. Following a single oral dose of 100 mg all-trans- or 13-cis-retinoic acid per kg body wt, concentrations of the parent drugs, of the C-13 isomerization products, as well as of their 4-oxo metabolites were determined in maternal plasma and embryo at two sensitive stages of organogenesis, i.e., Days 9 or 11 of gestation. All-trans-retinoic acid and its 4-oxo metabolite were transferred to the embryo to a much greater extent (embryo/maternal plasma concentration ratios, approximately 0.4) than the 13-cis-retinoic acid and its 4-oxo metabolite (embryo/maternal plasma concentration ratios, approximately 0.02). Embryo concentrations of all-trans-retinoic acid on Day 9 of gestation exceeded those on Day 11, whereas the embryo levels of 13-cis-retinoic acid were minimal at both gestational stages. The concentration of the 4-oxo metabolite of all-trans-retinoic acid was generally lower than that of the parent drug, whereas the level of the 4-oxo metabolite of the 13-cis-retinoic acid was comparable with or even higher than that of the parent compound. Concentrations of the C-13 isomerization products in maternal plasma were less than 20% of corresponding parent drug levels. However, due to the different extent of transfer of the two isomers, the concentration of all-trans-retinoic acid in the embryo exceeded that of the cis isomer even after administration of 13-cis-retinoic acid. Our results indicate that the low teratogenicity of 13-cis-retinoic acid in the mouse is the result of minimal placental transfer of this compound and of its 4-oxo metabolite, which contrast sharply with extensive placental transfer and high teratogenicity of the corresponding isomers with the all-trans configuration.

Topics: Abnormalities, Drug-Induced; Animals; Female; Isotretinoin; Maternal-Fetal Exchange; Mice; Mice, Inbred Strains; Placenta; Pregnancy; Structure-Activity Relationship; Teratogens; Tretinoin

The teratogenicity of vitamin A has been repeatedly reported in the literature and confirmed on the basis of several cases of adverse pregnancy outcome associated with maternal isotretinoin exposure. We report a case which shows a striking similarity with this syndrome, but the child was born to a mother who took a normal supplementation of vitamin A during pregnancy. The differential diagnosis is discussed.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adult; Diagnosis, Differential; Female; Humans; Infant, Newborn; Isotretinoin; Phenotype; Pregnancy; Tretinoin; Vitamin A; Vitamins

Topics: Abnormalities, Drug-Induced; Aorta, Thoracic; Diagnosis, Differential; Ear, External; Humans; Infant, Newborn; Isotretinoin; Male; Tretinoin

Previous observations have indicated that isotretinoin (IT), a drug in common use for therapy of cystic acne, is teratogenic in humans but possesses low embryotoxicity in pregnant mice, probably because of its shorter half-life and limited placental transfer in rodents. In human volunteers and patients, one major blood metabolite of IT is 4-oxo-isotretinoin (4-oxo-IT) which undergoes slower elimination than IT and may itself be a participant in teratogenesis. To investigate the problem of species differences displayed by IT and the role of its metabolism, embryotoxic effects of 4-oxo-IT were examined after its single or repeated intubations into pregnant ICR mice and compared with the effects of a similar regimen of IT. The two compounds were also tested for their relative ability to suppress chrondrogenesis in the in vitro cell and organ culture assays. We found that a single dose of 4-oxo-IT, 100 mg/kg, given on day 11 of gestation (plug day = day 0 of gestation) produced a moderate incidence of limb reduction defects and cleft palate (39% and 27% of surviving fetuses, respectively), while a dose of 150 mg/kg affected virtually every fetus. IT, on the other hand, produced no defects in fetuses exposed to similar dose levels. Repeated intubations with IT, however, resulted in increasing the frequencies of limb reduction defects and cleft palate to levels obtained after 4-oxo-IT administration. We found that a 3-hour interval between IT intubations was more effective in this regard than an 8-hour interval. Repeated IT intubations also uncovered sharper stage-dependency of limb and palatal defects than obtained otherwise.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Abnormalities, Drug-Induced; Animals; Cartilage; Cleft Palate; Female; In Vitro Techniques; Isotretinoin; Limb Deformities, Congenital; Male; Mice; Mice, Inbred ICR; Pregnancy; Teratogens; Tretinoin

A newborn had isotretinoin embryopathy, including thymic hypoplasia. Evaluation of her immune functions demonstrated progressive attrition of T cells over the nine weeks until her death due to pneumonia. These studies strongly suggest an insult by isotretinoin to the immune system. Immune abnormalities may predispose infants with isotretinoin embryopathy to infection and contribute to their high mortality.

Topics: Abnormalities, Drug-Induced; Adult; Facial Bones; Female; Humans; Infant, Newborn; Isotretinoin; Leukocyte Count; Maternal-Fetal Exchange; Pregnancy; Skull; T-Lymphocytes; Thymus Gland; Tretinoin

Topics: Abnormalities, Drug-Induced; Abortion, Induced; Acne Vulgaris; Ethics, Medical; Female; Humans; Isotretinoin; Pregnancy; Tretinoin

Topics: Abnormalities, Drug-Induced; Female; Humans; Infant, Newborn; Isotretinoin; Pregnancy; Statistics as Topic; Tretinoin

Topics: Abnormalities, Drug-Induced; Humans; Isotretinoin; Tretinoin

Birth defects caused by human teratogens are an important and potentially preventable cause of perinatal morbidity and mortality. Case reports provide an initial suggestion that a specific agent may be a human teratogen and provide the basis for further study. This review discusses the importance of case reports in human teratology and provides guidance in evaluating new case reports.

Topics: Abnormalities, Drug-Induced; Animals; Antiemetics; Dicyclomine; Doxylamine; Drug Combinations; Erythromycin; Female; Humans; Infant, Newborn; Isotretinoin; Medical Records; Pregnancy; Publishing; Pyridoxine; Teratogens; Thalidomide; Tretinoin; Warfarin

Topics: Abnormalities, Drug-Induced; Etretinate; Female; Humans; Infant, Newborn; Isotretinoin; Pregnancy; Retinoids; Skin Diseases; Teratogens; Tretinoin

Recent clinical observations strongly suggest that isotretinoin [13-cis-retinoic acid (cis RA)] is a human teratogen causing primarily heart and craniofacial malformations including ear and palatal defects. The purpose of the present study was to determine if cis RA could induce similar craniofacial malformations in mouse embryo culture. Day 8 CD-1 mouse embryos were cultured for 48 hours in rat serum in the presence or absence of various concentrations of cis RA dissolved in DMSO. DMSO by itself had no effect on embryonic development; however, cis RA at 2 X 10(-5) M (6 micrograms/ml) was clearly toxic. At 2 X 10(-6) M cis RA, growth retardation was minimal, and approximately one-third of the embryos exhibited very specific defects including a dramatic reduction in the size of the first and second visceral arches, which eventually give rise to the maxilla, mandible, and ear. Similar observations were also made with 4-oxo-13-cis RA, which is a major metabolite of cis RA in the mouse and human. These malformations would be expected to result in defects similar to those observed in the human, and preliminary observations suggest these defects are due to cis RA-induced inhibition of cranial neural crest cell migration. Using day-10 mouse embryos cultured for 48 hours in Waymouth's medium containing 50% fetal calf serum, we observed that cis RA at 2 X 10(-5) M produced a high percentage of embryos with limb defects and median cleft lip. Our results demonstrate that labeled cis RA enters the tissues of the embryo both in vivo and in vitro. Cis RA inhibited proliferation of the frontonasal mesenchyme cells in primary culture with 31% inhibition occurring at 2 X 10(-5) M cis RA.

Topics: Abnormalities, Drug-Induced; Animals; Cleft Lip; Culture Techniques; DNA; Embryo, Mammalian; Female; Isotretinoin; Limb Deformities, Congenital; Mice; Microscopy, Electron, Scanning; Pregnancy; Proteins; Time Factors; Tretinoin

Topics: Abnormalities, Drug-Induced; Brain; Embryo, Mammalian; Female; Humans; Isotretinoin; Pregnancy; Tretinoin

Despite animal vitamin A congener teratogenicity in animal studies since 1954, striking human findings only arose in 1983 following isotretinoin (ITR) marketing for oral treatment of severe acne. By November 1985, 44 outcomes with central nervous system (CNS), cardioaortic (CV), microtia, facial palsy, micrognathia, cleft palate, and/or thymic aplasia defects, and 33 spontaneous abortions have been reported. The critical period for exposure appears to be two to five weeks postconception, although this is clinically inexact. ITR half life is less than a day, although a teratogenic metabolite, 4-oxo-isoretinoin, has a half life of several days. Seven defect outcomes and one stillbirth have been reported with another congener, etretinate (ETR), used for psoriasis. Three of these had meningomyeloceles. Half life of several months makes levels cumulative. Only one additional defect, which may have occurred by chance, is reported with use stopped before conception (4 months). Other discontinuations 1 to 6 months before conception had 11 normal outcomes and two spontaneous abortions. ITR and ETR dose ranged from 0.5 to 1.5 mg/kg. Normal outcomes are reported both with ITR and ETR, but some of these appear not to have been exposed during the critical period. Less striking defects, abortions, and normal outcomes are less well reported. Because vitamin A analogs are therapeutically important and unplanned outcome not always avoidable, further animal research is needed for better risk/benefits. Megadose vitamin A (retinol) use is widespread, but experience poorly observed. Eighteen suspicious birth defect outcomes have been reported from pregnancies with high dose exposure. Twelve had findings similar to those seen in animals and in human retinoid syndromes, e.g., CNS, CV, microtia, and clefts. Epidemiological controls are lacking to establish human teratogenicity, but based on animal studies and experience with ITR and ETR, avoiding long term megadose Vitamin A use in fertile women is warranted.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Animals; Etretinate; Female; Gestational Age; Humans; Infant, Newborn; Isotretinoin; Maternal-Fetal Exchange; Pregnancy; Species Specificity; Teratogens; Tretinoin; Vitamin A

Severe congenital malformations have been associated with the inadvertant use in early pregnancy of a new dermatological drug, isotretinoin. We present proposals for the pathogenesis of this embryopathy based on the study of animal models. The characteristic malformations of the face, thymus, and great vessels were induced in mice by prenatal exposure to the drug during the early somite stages of development. From histological examination of mouse embryos it was shown that the drug directly interferes with the development of cranial neural crest cells. Subsequent deficiency of crest cell-derived mesenchyme adequately explains most of the observed malformations. Rat embryo culture studies showed that, when used at concentrations of 500 ng/ml, both isotretinoin and its main metabolite in the human, 4-oxo-isotretinoin, induce malformations similar to those seen in vivo. Since during normal repetitive dosing in the human the mean trough blood concentration of isotretinoin ranges from 132 to 196 ng/ml, while 4-oxo-isotretinoin ranges from 610 to 791 ng/ml, it is likely that the metabolite plays a major role in the induction of the isotretinoin embryopathy.

Topics: Abnormalities, Drug-Induced; Animals; Embryo, Mammalian; Embryonic and Fetal Development; Female; Fetal Resorption; Humans; Infant, Newborn; Isotretinoin; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Neural Crest; Organ Culture Techniques; Pregnancy; Rats; Rats, Inbred Strains; Teratogens; Tretinoin

Oral administration of 40-80 mg/d of isotretinoin (13-cis-retinoic acid, Ro 4-3780, Accutane) during the first month of human pregnancy can induce severe congenital malformation. The human Accutane dysmorphic syndrome includes rudimentary external ears, absent or imperforate auditory canals, a triangular microcephalic skull, cleft palate, depressed midface, and anomalies of the brain, jaw, and heart. Children who suffer from this syndrome have large occiputs with narrowing of the frontal bone. Microphthalmia is reported in two cases; notations are made about the orbits in three cases; and the fact that infants could not follow with their eyes is noted in three cases. A decrease in muscle tone is noted in six, cleft palate is present in four, and limb reduction defects are described in two. The cardiac malformations usually include overriding aorta, interrupted or hypoplastic aortic arch, and septation defects of atria and ventricles. There are at least two cases of abnormal origin of the subclavian arteries. Oral isotretinoin in the pregnant hamster also induces similar congenital malformations. A human case of isotretinoin-induced dysmorphia is presented and compared with other affected infants and affected hamsters. The metabolic fate and pharmacokinetic parameters of isotretinoin in humans and rodents are discussed in relation to the teratogenic response. The results suggest that humans are approximately 16 times more sensitive to the teratogenic effects of oral isotretinoin than are hamsters.

Topics: Abnormalities, Drug-Induced; Animals; Cricetinae; Facial Bones; Female; Humans; Infant, Newborn; Isotretinoin; Mesocricetus; Microscopy, Electron, Scanning; Pregnancy; Skull; Species Specificity; Tretinoin

Topics: Abnormalities, Drug-Induced; Child; Female; Humans; Isotretinoin; Limb Deformities, Congenital; Male; Pregnancy; Pregnancy Trimester, First; Tretinoin

Topics: Abnormalities, Drug-Induced; Female; Humans; Infant, Newborn; Isotretinoin; Limb Deformities, Congenital; Pregnancy; Tretinoin

Topics: Abnormalities, Drug-Induced; Animals; Female; Humans; Infant, Newborn; Isotretinoin; Pregnancy; Rats; Teratogens; Tretinoin

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Animals; Exostoses; Female; Humans; Isotretinoin; Lipids; Pregnancy; Tretinoin

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adult; Brain; Female; Heart Defects, Congenital; Humans; Hydrocephalus; Isomerism; Isotretinoin; Pregnancy; Teratogens; Tretinoin

Isotretinoin, a drug used for the treatment of acne, has been shown to have teratogenic effects. We report an additional case of isotretinoin teratogenicity in which the patient had agenesis of the cerebellar vermis, multiple leptomeningeal neuroglial heterotopias, hydrocephalus, and abnormalities of the corticospinal tracts. These findings are related to those reported previously.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Acne Vulgaris; Adult; Brain; Female; Humans; Infant, Newborn; Isotretinoin; Teratogens; Tretinoin

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Female; Humans; Isotretinoin; Pregnancy; Risk; Tretinoin

Retinoic acid, an analogue of vitamin A, is known to be teratogenic in laboratory animals and has recently been implicated in a few clinical case reports. To study the human teratogenicity of this agent, we investigated 154 human pregnancies with fetal exposure to isotretinoin, a retinoid prescribed for severe recalcitrant cystic acne. The outcomes were 95 elective abortions, 26 infants without major malformations, 12 spontaneous abortions, and 21 malformed infants. A subset of 36 of the 154 pregnancies was observed prospectively. The outcomes in this cohort were 8 spontaneous abortions, 23 normal infants, and 5 malformed infants. Exposure to isotretinoin was associated with an unusually high relative risk for a group of selected major malformations (relative risk = 25.6; 95 per cent confidence interval, 11.4 to 57.5). Among the 21 malformed infants we found a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and central nervous system structures. The malformations included microtia/anotia (15 infants), micrognathia (6), cleft palate (3), conotruncal heart defects and aortic-arch abnormalities (8), thymic defects (7), retinal or optic-nerve abnormalities (4), and central nervous system malformations (18). The pattern of malformation closely resembled that produced in animal studies of retinoid teratogenesis. It is possible that a major mechanism of isotretinoin teratogenesis is a deleterious effect on cephalic neural-crest cell activity that results in the observed craniofacial, cardiac, and thymic malformations.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Acne Vulgaris; Adolescent; Adult; Female; Fetal Death; Heart Defects, Congenital; Humans; Infant, Newborn; Isotretinoin; Male; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Retrospective Studies; Risk; Tretinoin

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Adolescent; Cerebellum; Ear, External; Face; Female; Humans; Infant, Newborn; Isotretinoin; Male; Pregnancy; Tretinoin

Topics: Abnormalities, Drug-Induced; Brain; Ear; Heart Defects, Congenital; Humans; Isotretinoin; Syndrome; Teratogens; Tretinoin

Topics: Abnormalities, Drug-Induced; Female; Humans; Isotretinoin; Pregnancy; Teratogens; Tretinoin

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Female; Humans; Infant, Newborn; Isotretinoin; Maternal-Fetal Exchange; Pregnancy; Tretinoin

Topics: Abnormalities, Drug-Induced; Adult; Female; Humans; Infant, Newborn; Isotretinoin; Male; Pregnancy; Tretinoin

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Cost-Benefit Analysis; Female; Humans; Infant, Newborn; Isotretinoin; Pregnancy; Tretinoin

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Face; Female; Fetus; Humans; Infant, Newborn; Isotretinoin; Male; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Skull; Tretinoin

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Ear, External; Female; Fetus; Humans; Hydrocephalus; Infant, Newborn; Isotretinoin; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Tretinoin

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Adolescent; Adult; Central Nervous System; Female; Humans; Infant, Newborn; Isotretinoin; Male; Pregnancy; Tretinoin; Triglycerides

Topics: Abnormalities, Drug-Induced; Abortion, Induced; Acne Vulgaris; Germany, West; Humans; Isotretinoin; Risk; Tretinoin

Topics: Abnormalities, Drug-Induced; Female; Fetus; Humans; Isotretinoin; Pregnancy; Prospective Studies; Tretinoin

Topics: Abnormalities, Drug-Induced; Chemical and Drug Induced Liver Injury; Female; Heart Defects, Congenital; Humans; Hydrocephalus; Infant, Newborn; Infant, Premature, Diseases; Isotretinoin; Liver Diseases; Tretinoin

Topics: Abnormalities, Drug-Induced; Blood Donors; Drug Labeling; Female; Gestational Age; Humans; Isotretinoin; Pregnancy; Tretinoin

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Female; Humans; Infant, Newborn; Isotretinoin; Maternal-Fetal Exchange; Pregnancy; Tretinoin

Topics: Abnormalities, Drug-Induced; Acne Vulgaris; Drug Administration Schedule; Drug Eruptions; Female; Humans; Isotretinoin; Mucous Membrane; Pregnancy; Tretinoin

Topics: Abnormalities, Drug-Induced; Corneal Opacity; Humans; Ileitis; Isotretinoin; Pseudotumor Cerebri; Tretinoin; Uric Acid

Four retinoids - retinol (vitamin A), tretinoin (retinoic acid), etretinate (the ethyl ester of trimethoxymethylphenyl retinoic acid), and isotretinoin (13-cis-retinoic acid, Accutane) - have been administered orally in humans for therapeutic purposes. A review of the available information on the clinical toxic effects of these substances indicated that, while they express similar spectra of toxicity, they also differ in the extent to which they affect various body systems. This suggests that differential efficacy of the retinoids may be related, in part, to the cutaneous sites of maximum activity.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Adolescent; Adult; Child; Etretinate; Female; Humans; Infant; Isomerism; Isotretinoin; Male; Tretinoin; Vitamin A