TERIS Agent Number: 1041 Bibliographic Search Date: 10/2022
Agent Name: ISOTRETINOIN    


Isotretinoin (13-cis-retinoic acid) is a vitamin A congener that is given orally in the treatment of cystic acne and other dermatologic diseases. Isotretinoin cream is used topically to treat photodamaged and wrinkled skin. Very little systemic absorption occurs after topical application.

Magnitude of Teratogenic Risk to Child Born After Exposure During Gestation:

Quality and Quantity of Data on Which Risk Estimate is Based:



Summary of Teratology Studies:



A characteristic pattern of congenital anomalies has been observed in children whose mothers were treated orally with therapeutic doses of isotretinoin during early pregnancy (Anonymous, 1983, 1984; Lammer et al., 1985; Rosa et al., 1986; Coberly et al., 1996). Typical features of this isotretinoin embryopathy include central nervous system malformations, microtia/anotia, micrognathia, cleft palate, cardiac and great vessel defects, thymic abnormalities, and eye anomalies. Limb reduction defects and facial asymmetry with midfacial hypoplasia may also occur (Rizzo et al., 1991; Sarici et al., 2013). Typical malformations have occurred in children born to women who took various dosages of isotretinoin within the usual therapeutic range and in women who were treated for less than one week in the first trimester of pregnancy (Chen et al., 1990; Dai et al., 1992).


In a seminal case series, a high risk of selected major malformations was identified among infants of women using isotretinoin during pregnancy (relative risk=25.6, 95% confidence interval 11.4-57.5) (Lammer et al., 1985). At least one major congenital anomaly was reported in 26 (28%) of 94 liveborn infants of women treated with isotretinoin, most during the first trimester, in a separate study using cases voluntarily reported to the manufacturer (Dai et al., 1992). The rate of major malformations was 9.3% (11/118) among infants born to women who received a prescription for isotretinoin during pregnancy in a Canadian retrospective cohort study (Henry et al., 2016). In multiple clinical series, the typical features of embryopathy were observed in a total of seven (17%) of 42 infants and fetuses of women treated with isotretinoin early in pregnancy (Bensouda-Grimaldi et al., 2005; Robertson et al., 2005; Garcia-Bournissen et al., 2008). When maternal treatment continues beyond the fifteenth day after conception, isotretinoin has an estimated 35% risk of producing congenital anomalies in prenatally-exposed infants (Jones et al., 2022). Major congenital anomalies were reported in 59 (15%, 95% confidence interval 9.0-23.0) of 380 infants of women exposed to isotretinoin during the peri-conception period or pregnancy in a meta-analysis that included controlled and uncontrolled cohort and population-based studies (Choi et al., 2021).


The frequency of congenital anomalies does not appear to be increased among the children of women who discontinue isotretinoin therapy prior to conception in several studies (Dai et al., 1989; Kallen, 1999; Schaefer et al., 2010; Zomerdijk et al., 2014; Altintas Aykan & Ergun, 2020). This finding is consistent with the 10- to 12-hour average serum half-life of isotretinoin in humans (Wiegand & Chou, 1998). However, two case reports have described malformations consistent with isotretinoin embryopathy in infants of women who self-reported discontinuation of treatment before conception (Lee et al., 2009; Shirazi et al., 2012). Ultrasound exams performed at 20 weeks gestation found major congenital anomalies in two (8.7%) of 23 fetuses of women who used isotretinoin around the time of conception, but this frequency did not differ from that seen among untreated women in a Korean prospective cohort study (Cha et al., 2022).




The risk of spontaneous abortion was approximately two times higher in women treated with isotretinoin during pregnancy when compared to unexposed women in a prospective cohort study (17.7% vs 8.7%, respectively, p=0.035) (Cha et al., 2022). In two case series, the rate of spontaneous abortion was 21.4% in 79 pregnant women who used isotretinoin within a month before conception or during pregnancy (Yook et al., 2012) and 18% in 115 isotretinoin-exposed pregnancies that were voluntarily reported to the manufacturer (Dai et al., 1992).




In a follow-up study of 31 five-year-old children born to women who had been treated with isotretinoin during the first 60 days after conception, 47% performed in the subnormal range on standard intelligence tests (Adams, 1990; Adams et al., 1991; Adams & Lammer, 1991, 1993; Adams, 2010). Of 12 children who had major malformations, six (including four with major central nervous system anomalies) had IQ <70, four (including one with major central nervous system anomalies) had IQ 70-85, and two had IQ >85. Six of 19 children with no major malformations had IQ 70-85; the others had IQ >85.




Treatment of laboratory animals with isotretinoin during embryogenesis produces a spectrum of malformations in the offspring similar to that seen in humans. Humans are more sensitive to these teratogenic effects than other species that have been tested (Nau, 2001), but similar malformations have been observed among the offspring of pregnant monkeys, rabbits, hamsters, mice, or rats given isotretinoin in doses several to many times greater than the human therapeutic dose (Hendrickx et al., 2000; Nau, 2001; Makori et al., 2002). A typical dose-response relationship has been demonstrated in hamsters, rabbits, and mice, and characteristic dependence on stage of embryogenesis has been shown in mice.

Selected References:
(Each paper is classified as a review [R], human case report [C], human epidemiological study [E], human clinical series [S], animal study [A], or other [O].)

Adams J: High incidence of intellectual deficits in 5 year old children exposed to isotretinoin "in utero." Teratology 41(5):614, 1990. [S]


Adams J: The neurobehavioral teratology of retinoids: a 50-year history. Birth Defects Res A Clin Mol Teratol 88(10):895-905, 2010. [R]


Adams J, Lammer EJ: Neurobehavioral teratology of isotretinoin. Reprod Toxicol 7(2):175-177, 1993. [E]


Adams J, Lammer EJ: Relationship between dysmorphology and neuro-psychological function in children exposed to isotretinoin "in utero." In: Fujii T, Boer GJ (eds). Functional Neuroteratology of Short-Term Exposure to Drugs. Tokyo: Teikyo University Press, 1991, pp 159-170. [S]


Adams J, Lammer EJ, Holmes LB: A syndrome of cognitive dysfunctions following human embryonic exposure to isotretinoin. Teratology 43(5):497, 1991. [E]


Altintas Aykan D, Ergun Y: Isotretinoin: Still the cause of anxiety for teratogenicity. Dermatol Ther 33(1):e13192, 2020. [S]


Anonymous: Isotretinoin--a newly recognized human teratogen. MMWR 33(13):171-173, 1984. [R]


Anonymous: Update on isotretinoin (Accutane) for acne. Med Lett Drugs Ther 25(649):105-106, 1983. [R]


Bensouda-Grimaldi L, Jonville-Bera A-P, Mouret E, Elefant E, Dhellot H, Delmas C, Gouin T, Coste P, Autret-Leca E; les Centres Regionaux de Pharmacovigilance: [Isotretinoin: compliance with recommendations in childbearing women.] Ann Dermatol Venereol 132(5):415-423, 2005. [S]


Cha E-H, Kim N, Kwak H-S, Han HJ, Joo SH, Choi J-S, Chun K-C, Kim Y-A, Koh J-W, Han JY: Pregnancy and neonatal outcomes after periconceptional exposure to isotretinoin in Koreans. Obstet Gynecol Sci 65(2):166-175, 2022. [E]


Chen DT, Jacobson MM, Kuntzman RG: Experience with the retinoids in human pregnancy. In: Volans GN (ed). Basic Science in Toxicology. London: Francis Taylor Publishing Co., 1990, pp 473-482. [R]


Choi EJ, Kim N, Kwak H-S, Han HJ, Chun K-C, Kim Y-A, Koh J-W, Han JY, Joo SH, Lee JS, Koren G: The rates of major malformations after gestational exposure to isotretinoin: a systematic review and meta-analysis. Obstet Gynecol Sci 64(4):364-373, 2021. [R]


Coberly S, Lammer E, Alashari M: Retinoic acid embryopathy: case report and review of literature. Pediatr Pathol Lab Med 16(5):823-836, 1996. [R] & [C]


Dai WS, Hsu M-A, Itri LM: Safety of pregnancy after discontinuation of isotretinoin. Arch Dermatol 125(3):362-365, 1989. [E]


Dai WS, LaBraico JM, Stern RS: Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 26(4):599-606, 1992. [S]


Garcia-Bournissen F, Tsur L, Goldstein LH, Staroselsky A, Avner M, Asrar F, Berkovitch M, Straface G, Koren G, De Santis M: Fetal exposure to isotretinoin--an international problem. Reprod Toxicol 25(1):124-128, 2008. [S]


Hendrickx AG, Peterson P, Hartman D, Hummler H: Vitamin A teratogenicity and risk assessment in the macaque retinoid model. Reprod Toxicol 14(4):311-323, 2000. [A]


Henry D, Dormuth C, Winquist B, Carney G, Bugden S, Teare G, Levesque LE, Berard A, Paterson JM, Platt RW: Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy. CMAJ 188(10):723-730, 2016. [S]


Jones KL, Jones MC, del Campo M: Environmental agents: Retinoic acid embryopathy (Accutane embryopathy). In: Jones KL, Jones MC, del Campo M (eds). Smith’s Recognizable Patterns of Human Malformation, 8th ed. Philadelphia, Pa.: Elsevier, 2022, pp 800-801. [R]


Kallen B: Restriction of the use of drugs with teratogenic properties: Swedish experiences with isotretinoin. Teratology 60(2):53, 1999. [E]


Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, Curry CJ, Fernhoff PM, Grix AW Jr, Lott IT, Richard JM, Sun SC: Retinoic acid embryopathy. N Engl J Med 313(14):837-841, 1985. [S]


Lee SM, Kim HM, Lee JS, Yoon CS, Park MS, Park KI, Namgung R, Lee C: A case of suspected isotretinoin-induced malformation in a baby of a mother who became pregnant one month after discontinuation of the drug. Yonsei Med J 50(3):445-447, 2009. [C]


Makori N, Peterson PE, Lantz K, Hendrickx AG: Exposure of cynomolgus monkey embryos to retinoic acid causes thymic defects: effects on peripheral lymphoid organ development. J Med Perinatol 31(2):91-97, 2002. [A]


Nau H: Teratogenicity of isotretinoin revisited: species variation and the role of all-trans-retinoic acid. J Am Acad Dermatol 45(5):S183-S187, 2001. [R]


Rizzo R, Lammer EJ, Parano E, Pavone L, Argyle JC: Limb reduction defects in humans associated with prenatal isotretinoin exposure. Teratology 44(6):599-604, 1991. [C]


Robertson J, Polifka JE, Avner M, Chambers C, Delevan G, Koren G, Lavigne SV, Martinez LP, Miller RK, Carey JC: A survey of pregnant women using isotretinoin. Birth Defects Res A Clin Mol Teratol 73(11):881-887, 2005. [S]


Rosa FW, Wilk AL, Kelsey FO: Teratogen update: vitamin A congeners. Teratology 33(3):355-364, 1986. [R]


Sarici D, Akin MA, Kurtoglu S, Uzum K, Kiraz A: Asymmetric crying face in a newborn with isotretinoin embryopathy. Pediatr Dermatol 30(6):e289-e290, 2013. [C]


Schaefer C, Meister R, Weber-Schoendorfer C: Isotretinoin exposure and pregnancy outcome: an observational study of the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy. Arch Gynecol Obstet 281(2):221-227, 2010. [S]


Shirazi M, Abbariki E, Pirjani R, Akhavan S, Dastgerdy E: Congenital microtia in a neonate due to maternal isotretinoin exposure 1 month before pregnancy: case report. J Obstet Gynaecol Res 41(6):975-978, 2015. [C]


Wiegand U-W, Chou RC: Pharmacokinetics or oral isotretinoin. J Am Acad Dermatol 39(2 Pt 3):S8-S12, 1998. [R]


Yook J-H, Han J-Y, Choi J-S, Ahn H-K, Lee S-W, Kim M-Y, Ryu H-M, Nava-Ocampo AA: Pregnancy outcomes and factors associated with voluntary pregnancy termination in women who had been treated for acne with isotretinoin. Clin Toxicol 50(10):896-901, 2012. [E]


Zomerdijk IM, Ruiter R, Houweling LMA, Herings RMC, Sturkenboom MCJM, Straus SMJM, Stricker BH: Isotretinoin exposure during pregnancy: a population-based study in The Netherlands. BMJ Open 4(11):e005602, 2014. [E]