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Otocerebral anomalies associated with topical tretinoin use
Brain & Development 22 (2000) 218±220
www.elsevier.com/locate/braindev
Original article
Otocerebral anomalies associated with topical tretinoin use Duygu Selcen a,*, Steven Seidman b, Michael A. Nigro a, b a
Children's Hospital of Michigan, Department of Pediatrics, Division of Neurology, Wayne State University, Detroit, MI, USA b Michigan Institute for Neurological Disorders, Farmington Hills, MI, USA Received 24 November 1999; received in revised form 19 January 2000; accepted 19 January 2000
Abstract Topical preparations of tretinoin are used for the treatment of various skin conditions and for rejuvenation of the skin. Published information on pregnancy outcome following maternal exposure to topical tretinoin is limited to three case reports. We report a case of a patient with anomalies involving the ear and central nervous system with exposure to topical tretinoin during the ®rst trimester. Though the potential link between the use of topical tretinoin and the existence of fetal malformations remains to be further documented by animal as well as epidemiological studies, we strongly recommend that the use of topical tretinoin during pregnancy should be discouraged, and effective contraception should be used in patients of childbearing age. q 2000 Published by Elsevier Science B.V. All rights reserved. Keywords: Vitamin A; Tretinoin; Anotia; Ischemia
1. Introduction Retinoic acids are analogues of Vitamin A and known to be teratogenic in laboratory animals and humans. Isotretinoin (13-cis-retinoic acid) is a con®rmed human teratogen and its use is contraindicated during pregnancy due to the serious risk of characteristic patterns of anomalies that could result from ®rst trimester exposure [1]. Topical preparations of tretinoin are used for the treatment of various skin conditions and for rejuvenation of the skin. Published information on pregnancy outcome following maternal exposure to topical tretinoin is limited to three case reports [2±4]. We report a case of a patient with anomalies involving the ear and central nervous system (CNS) with exposure to topical tretinoin during the ®rst trimester. 2. Case report The patient was born at 41 weeks of gestation weighing 4090 g and exhibited absence of the right ear and external auditory canal. Before conception and during the ®rst 2±3 months of pregnancy the mother had used a topical preparation of tretinoin (Retin A 0.025%) for her face and over a large surface of her back. His father was using oral isotre* Corresponding author. Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA. Fax: 11-507-2845831. E-mail address: [email protected] (D. Selcen).
tinoin before conception. The mother used prenatal vitamins during pregnancy. On examination at 16 months of age, he was babbling. Optokinetic response with tape moving to right was diminished and there was no oculovestibular response when rotating towards the right. Muscle strength, tone and bulk were age-appropriate. At 20 months of age he was non-verbal and had poor receptive language compatible with cognitive impairment. CT of the brain showed cerebral calci®cation of the right posterior hemisphere (Fig. 1). MRI of the brain revealed overall reduction in the volume of the right cerebral hemisphere, a remote infarct in the deep basal ganglia, focal atrophy and encephalomalacia of the right parieto-occipital lobe (Fig. 2). MRA of the brain showed marked attenuation of the ambient portion of the posterior cerebral artery with poor delineation of the more distal cortical, temporal and occipital branches (Fig. 3). 2-Deoxy-2 [18F]-¯uoro-d-glucose PET scan showed severe hypometabolism of the right posterior parietal, occipital and temporal lobes as well as right basal ganglia and thalamus and mild hypometabolism of the left cerebellum. 3. Discussion Fetal exposure to isotretinoin results in characteristic pattern of malformations including craniofacial, cardiac, thymic and CNS structures, including microtia/anotia, micrognathia, cleft palate, conotruncal heart defects, aortic arch abnormalities, retinal or optic nerve abnormalities in approximately 25% of fetuses exposed in the ®rst trimester
0387-7604/00/$ - see front matter Copyright q 2000 Published by Elsevier Science B.V. All rights reserved. PII: S03 87-7604(00)0010 4-2
D. Selcen et al. / Brain & Development 22 (2000) 218±220
219
Fig. 1. CT of the head without contrast showing calci®cation of right parietooccipital lobe.
[1]. Contrary to well-established teratogenicity of the oral retinoids, the potential link between the use of topical tretinoin and the existence of fetal malformations are not well de®ned. In the literature there were three other reports of malformations. The ®rst case [2] involved a girl with ear malformation after maternal use of tretinoin cream during the ®rst 11 weeks of pregnancy. The second case [3] involved a girl born with multiple congenital defects of supraumbilical exomphalos, an anterior diaphragmatic hernia, an inferior pericardial defect, dextroposition of the heart, and a right-sided upper limb reduction defect after maternal application of tretinoin cream before conception and for the ®rst 5 weeks of gestation. The third case [4] involved a girl with coarctation of aorta, hypoplastic left hand, hypertelorism and small ear canal with maternal use of topical cream before conception and during the ®rst 2
months of gestation. Various animal [5] and epidemiological studies [6] of the mothers exposed to topical tretinoin provide no evidence of a relation between topical tretinoin use and the congenital abnormalities that are associated with oral isotretinoin. However, in one study it is shown that exposure of the pregnant rats to topical tretinoin results in increased frequencies of skeletal anomalies, primarily tail defects in the dam [7]. In our case, the ear abnormality is a very typical feature of retinoic acid embryopathy and makes it unlikely to represent a coincidental anomaly. The mechanism of teratogenicity is not clear but may be due to isotretinoin's interference with migration and proliferation of the cranial neural crest cells, leading to de®cient mesenchyme in the branchial arches, and/or increased programmed cell death [8]. CNS cells may be susceptible to isotretinoin speci®cally because of the presence of cellu-
Fig. 2. MRI of the brain (T2 weighed image) showing overall reduction of right hemisphere size with encephalomalacic changes of right parietooccipital lobe, and hyperdense lesion of right basal ganglia.
Fig. 3. MRA of the brain showing marked attenuation of the ambient portion of the posterior cerebral artery with poor delineation of the more distal cortical, temporal and occipital branches.
220
D. Selcen et al. / Brain & Development 22 (2000) 218±220
lar retinoic acid binding proteins. [9] The reported CNS defects of retinoic acid embryopathy include Dandy± Walker malformation with associated aqueductal stenosis, hydrocephalus, pontine and medullary olivary dysplasia, cerebellar heterotopias, agenesis of cerebellar vermis, and calci®cations. [1,9] In this case the CNS abnormalities are associated with ischemic changes in the distribution of posterior cerebral artery territory with consequent atrophy and calci®cation. The timing of the malformations is also important. The severe malformations of the auricle seen with retinoic acid toxicity are explained by the early formation of these structures during embryogenesis. The external ear canal forms in the 4th week after conception and by 12 weeks a de®nitive auricle forms. [10] On the other hand, by 5 weeks many of the de®nitive arteries of the brain are present. Hence, an insult in the ®rst 4±5 weeks of gestation may result in the malformations seen in this child. This case had exposure to topical tretinoin during this time and we believe that these malformations are drug-related. It is unlikely that there is any contribution of the father's use of oral isotretinoin with the malformations seen in this patient. In conclusion, though the potential link between the use of topical tretinoin and the existence of fetal malformations remains to be further documented by animal as well as epidemiological studies, we strongly recommend that the use of topical tretinoin during pregnancy should be discouraged, and effective contraception should be used in patients of childbearing age.
References [1] Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, et al. Retinoic acid embryopathy. N Engl J Med 1985;313:837±841. [2] Camera G, Pregliasco P. Ear malformation in baby born to mother using tretinoin cream (letter). Lancet 1992;339:687. [3] Lipson AH, Collins F, Webster WS. Multiple congenital defects associated with maternal use of topical tretinoin. Lancet 1993;341:1352± 1353. [4] Navarre-Belhassen C, Blanchet P, Hillaire-Buys D, Sarda P, Blayac JP. Multiple congenital malformations associated with topical tretinoin. Ann. Pharmacother. 1998;32:505±506. [5] Christian MS, Mitala JJ, Powers Jr WJ, McKenzie BE, Latriano L. A developmental toxicity study of tretinoin emollient cream (Renova) applied topically to New Zealand white rabbits. J Am Acad Dermatol 1997;36:S67±S76. [6] Shapiro L, Pastuszak A, Curto G, Koren G. Safety of ®rst-trimester exposure to topical tretinoin: prospective cohort study. Lancet 1997;350:1143±1144. [7] Seegmiller RE, Carter MW, Ford WH, White RD. Induction of maternal toxicity in the rat by dermal application of retinoic acid and its effect on fetal outcome. Reprod Toxicol 1990;4:277±281. [8] Pratt RM, Goulding EH, Abbott BD. Retinoic acid inhibits migration of cranial neural crest cells in the cultured mouse embryo. J Craniofac Genet Dev Biol 1987;7:205±217. [9] Lammer EJ, Armstrong DL. Malformations of hindbrain structures among humans exposed to isotretinoin (13-cis-retinoic acid) during early embryogenesis. In: Morriss-Kay G, editor. Retinoids in normal development and teratogenesis. New York: Oxford University Press, 1991. pp. 281±295. [10] Jahn AF. Embryological development of human ear. Univ. Toronto Med. J. 1972;50:16±20.
www.elsevier.com/locate/braindev
Original article
Otocerebral anomalies associated with topical tretinoin use Duygu Selcen a,*, Steven Seidman b, Michael A. Nigro a, b a
Children's Hospital of Michigan, Department of Pediatrics, Division of Neurology, Wayne State University, Detroit, MI, USA b Michigan Institute for Neurological Disorders, Farmington Hills, MI, USA Received 24 November 1999; received in revised form 19 January 2000; accepted 19 January 2000
Abstract Topical preparations of tretinoin are used for the treatment of various skin conditions and for rejuvenation of the skin. Published information on pregnancy outcome following maternal exposure to topical tretinoin is limited to three case reports. We report a case of a patient with anomalies involving the ear and central nervous system with exposure to topical tretinoin during the ®rst trimester. Though the potential link between the use of topical tretinoin and the existence of fetal malformations remains to be further documented by animal as well as epidemiological studies, we strongly recommend that the use of topical tretinoin during pregnancy should be discouraged, and effective contraception should be used in patients of childbearing age. q 2000 Published by Elsevier Science B.V. All rights reserved. Keywords: Vitamin A; Tretinoin; Anotia; Ischemia
1. Introduction Retinoic acids are analogues of Vitamin A and known to be teratogenic in laboratory animals and humans. Isotretinoin (13-cis-retinoic acid) is a con®rmed human teratogen and its use is contraindicated during pregnancy due to the serious risk of characteristic patterns of anomalies that could result from ®rst trimester exposure [1]. Topical preparations of tretinoin are used for the treatment of various skin conditions and for rejuvenation of the skin. Published information on pregnancy outcome following maternal exposure to topical tretinoin is limited to three case reports [2±4]. We report a case of a patient with anomalies involving the ear and central nervous system (CNS) with exposure to topical tretinoin during the ®rst trimester. 2. Case report The patient was born at 41 weeks of gestation weighing 4090 g and exhibited absence of the right ear and external auditory canal. Before conception and during the ®rst 2±3 months of pregnancy the mother had used a topical preparation of tretinoin (Retin A 0.025%) for her face and over a large surface of her back. His father was using oral isotre* Corresponding author. Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA. Fax: 11-507-2845831. E-mail address: [email protected] (D. Selcen).
tinoin before conception. The mother used prenatal vitamins during pregnancy. On examination at 16 months of age, he was babbling. Optokinetic response with tape moving to right was diminished and there was no oculovestibular response when rotating towards the right. Muscle strength, tone and bulk were age-appropriate. At 20 months of age he was non-verbal and had poor receptive language compatible with cognitive impairment. CT of the brain showed cerebral calci®cation of the right posterior hemisphere (Fig. 1). MRI of the brain revealed overall reduction in the volume of the right cerebral hemisphere, a remote infarct in the deep basal ganglia, focal atrophy and encephalomalacia of the right parieto-occipital lobe (Fig. 2). MRA of the brain showed marked attenuation of the ambient portion of the posterior cerebral artery with poor delineation of the more distal cortical, temporal and occipital branches (Fig. 3). 2-Deoxy-2 [18F]-¯uoro-d-glucose PET scan showed severe hypometabolism of the right posterior parietal, occipital and temporal lobes as well as right basal ganglia and thalamus and mild hypometabolism of the left cerebellum. 3. Discussion Fetal exposure to isotretinoin results in characteristic pattern of malformations including craniofacial, cardiac, thymic and CNS structures, including microtia/anotia, micrognathia, cleft palate, conotruncal heart defects, aortic arch abnormalities, retinal or optic nerve abnormalities in approximately 25% of fetuses exposed in the ®rst trimester
0387-7604/00/$ - see front matter Copyright q 2000 Published by Elsevier Science B.V. All rights reserved. PII: S03 87-7604(00)0010 4-2
D. Selcen et al. / Brain & Development 22 (2000) 218±220
219
Fig. 1. CT of the head without contrast showing calci®cation of right parietooccipital lobe.
[1]. Contrary to well-established teratogenicity of the oral retinoids, the potential link between the use of topical tretinoin and the existence of fetal malformations are not well de®ned. In the literature there were three other reports of malformations. The ®rst case [2] involved a girl with ear malformation after maternal use of tretinoin cream during the ®rst 11 weeks of pregnancy. The second case [3] involved a girl born with multiple congenital defects of supraumbilical exomphalos, an anterior diaphragmatic hernia, an inferior pericardial defect, dextroposition of the heart, and a right-sided upper limb reduction defect after maternal application of tretinoin cream before conception and for the ®rst 5 weeks of gestation. The third case [4] involved a girl with coarctation of aorta, hypoplastic left hand, hypertelorism and small ear canal with maternal use of topical cream before conception and during the ®rst 2
months of gestation. Various animal [5] and epidemiological studies [6] of the mothers exposed to topical tretinoin provide no evidence of a relation between topical tretinoin use and the congenital abnormalities that are associated with oral isotretinoin. However, in one study it is shown that exposure of the pregnant rats to topical tretinoin results in increased frequencies of skeletal anomalies, primarily tail defects in the dam [7]. In our case, the ear abnormality is a very typical feature of retinoic acid embryopathy and makes it unlikely to represent a coincidental anomaly. The mechanism of teratogenicity is not clear but may be due to isotretinoin's interference with migration and proliferation of the cranial neural crest cells, leading to de®cient mesenchyme in the branchial arches, and/or increased programmed cell death [8]. CNS cells may be susceptible to isotretinoin speci®cally because of the presence of cellu-
Fig. 2. MRI of the brain (T2 weighed image) showing overall reduction of right hemisphere size with encephalomalacic changes of right parietooccipital lobe, and hyperdense lesion of right basal ganglia.
Fig. 3. MRA of the brain showing marked attenuation of the ambient portion of the posterior cerebral artery with poor delineation of the more distal cortical, temporal and occipital branches.
220
D. Selcen et al. / Brain & Development 22 (2000) 218±220
lar retinoic acid binding proteins. [9] The reported CNS defects of retinoic acid embryopathy include Dandy± Walker malformation with associated aqueductal stenosis, hydrocephalus, pontine and medullary olivary dysplasia, cerebellar heterotopias, agenesis of cerebellar vermis, and calci®cations. [1,9] In this case the CNS abnormalities are associated with ischemic changes in the distribution of posterior cerebral artery territory with consequent atrophy and calci®cation. The timing of the malformations is also important. The severe malformations of the auricle seen with retinoic acid toxicity are explained by the early formation of these structures during embryogenesis. The external ear canal forms in the 4th week after conception and by 12 weeks a de®nitive auricle forms. [10] On the other hand, by 5 weeks many of the de®nitive arteries of the brain are present. Hence, an insult in the ®rst 4±5 weeks of gestation may result in the malformations seen in this child. This case had exposure to topical tretinoin during this time and we believe that these malformations are drug-related. It is unlikely that there is any contribution of the father's use of oral isotretinoin with the malformations seen in this patient. In conclusion, though the potential link between the use of topical tretinoin and the existence of fetal malformations remains to be further documented by animal as well as epidemiological studies, we strongly recommend that the use of topical tretinoin during pregnancy should be discouraged, and effective contraception should be used in patients of childbearing age.
References [1] Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, et al. Retinoic acid embryopathy. N Engl J Med 1985;313:837±841. [2] Camera G, Pregliasco P. Ear malformation in baby born to mother using tretinoin cream (letter). Lancet 1992;339:687. [3] Lipson AH, Collins F, Webster WS. Multiple congenital defects associated with maternal use of topical tretinoin. Lancet 1993;341:1352± 1353. [4] Navarre-Belhassen C, Blanchet P, Hillaire-Buys D, Sarda P, Blayac JP. Multiple congenital malformations associated with topical tretinoin. Ann. Pharmacother. 1998;32:505±506. [5] Christian MS, Mitala JJ, Powers Jr WJ, McKenzie BE, Latriano L. A developmental toxicity study of tretinoin emollient cream (Renova) applied topically to New Zealand white rabbits. J Am Acad Dermatol 1997;36:S67±S76. [6] Shapiro L, Pastuszak A, Curto G, Koren G. Safety of ®rst-trimester exposure to topical tretinoin: prospective cohort study. Lancet 1997;350:1143±1144. [7] Seegmiller RE, Carter MW, Ford WH, White RD. Induction of maternal toxicity in the rat by dermal application of retinoic acid and its effect on fetal outcome. Reprod Toxicol 1990;4:277±281. [8] Pratt RM, Goulding EH, Abbott BD. Retinoic acid inhibits migration of cranial neural crest cells in the cultured mouse embryo. J Craniofac Genet Dev Biol 1987;7:205±217. [9] Lammer EJ, Armstrong DL. Malformations of hindbrain structures among humans exposed to isotretinoin (13-cis-retinoic acid) during early embryogenesis. In: Morriss-Kay G, editor. Retinoids in normal development and teratogenesis. New York: Oxford University Press, 1991. pp. 281±295. [10] Jahn AF. Embryological development of human ear. Univ. Toronto Med. J. 1972;50:16±20.