Different fetal effects on fingers from exposure to phenytoin, phenobarbital, and carbamazepine.

Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 101235741 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4833 (Electronic) Linking ISSN: 15524825 NLM ISO Abbreviation: Am J Med Genet A Subsets: MEDLINE

Publication: Hoboken, N.J. : Wiley-Blackwell
Original Publication: Hoboken, N.J. : Wiley-Liss, c2003-

Carbamazepine*/adverse effects ; Phenytoin*/adverse effects ; Phenobarbital*/adverse effects ; Fingers*/abnormalities ; Anticonvulsants*/adverse effects ; Anticonvulsants*/therapeutic use ; Prenatal Exposure Delayed Effects*/chemically induced ; Prenatal Exposure Delayed Effects*/pathology; Humans ; Female ; Pregnancy ; Male ; Child ; Abnormalities, Drug-Induced/pathology ; Child, Preschool ; Nails/drug effects ; Nails/pathology ; Infant

Exposure at conception to phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) has been associated with several different effects on the fetus, including hypoplasia of the distal phalanges, dysmorphic facial features, and structural abnormalities such as oral clefts and neural tube defects. One question is whether each of these antiepileptic drugs (AEDs) has the same effects or just similar effects. A systematic examination of the fingers of children exposed at conception to PHT, PB, or CBZ, as monotherapy, has been used to address this question. The findings in the examinations of the fingers of 115 AED-exposed children (40, PHT; 34, PB; 41, CBZ) and their parents were compared to the findings in 111 age- and sex-matched children and their parents. The evaluations used were both subjective assessments and objective measurements. Shortening and narrowing of the fifth fingernail and an increased frequency of arch patterns in the dermal ridges were more common in PHT-exposed children. A significant decrease in the length of the nail, but not width, occurred in the PB-exposed children. Stiffness of the interphalangeal joints was more common in the CBZ-exposed children. The findings in children exposed to PHT, PB, or CBZ, as monotherapy, showed that all three exposures in early pregnancy affected the fingers, but the effects were not the same. The most striking effects were present in PHT-exposed children.
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Adams, J., Janulewicz, P. A., Macklin, E. A., Dhillon, R., Phillips, C., Schomer, D. E., Touches, W. A., Carlson, J. M., & Holmes, L. B. (2022). Neuropsychological effects in children exposed to anticonvulsant monotherapy during gestation: Phenobarbital, carbamazepine and phenytoin. Epilepsy and Behavior, 127, 108533. https://doi.org/10.1016/j.yebeh.2021.108533.
Barr, M., Poznanski, A. K., & Schmickel, R. D. (1974). Digit hypoplasia and anticonvulsants during gestation: A teratogenic syndrome? The Journal of Pediatrics, 84, 254–256. https://doi.org/10.1016/s0022-3476(74)80615-3.
Bokhari, A., Connolly, S., Harvey, E. A., & Holmes, L. B. (2002). Effects on toes produced by prenatal exposure to antiepileptic drugs (AED) are common, but subtle. Teratology, 66, 122–126.
Bokhari, A., Coull, B. A., & Holmes, L. B. (2002). Effect of prenatal exposure to anticonvulsant drugs on dermal ridge patterns of fingers. Teratology, 66, 19–23. https://doi.org/10.1002/tera.10044.
Cummins, H., & Midlo, C. (1961). Finger prints, palms and soles. Dover Publishers.
Danielsson, B. R., Danielson, K., & Tomson, T. (1995). Phenytoin causes phalangeal hypoplasia in a rabbit fetus at clinically relevant free plasma concentrations. Teratology, 52, 252–259.
Danielsson, B. R., Johansson, A., Danielsson, C., Azarbayjani, F., Blomgren, B., & Sköld, A.‐C. (2005). Phenytoin teratogenicity: Hypoxia marker and effects on embryonic heart rhythm suggest an hERG‐related mechanism. Birth Defects Research (Part A), 73, 146–153. https://doi.org/10.1002/bdra.20124.
Finnell, R. H., Shields, H. E., Taylor, S. M., & Chernoff, G. F. (1987). Strain differences in phenobarbital‐induced teratogenesis in mice. Teratology, 35, 177–185.
Gaily, E. (1990). Distal phalangeal hypoplasia in children with prenatal phenytoin exposure: Results of a controlled anthropometric study. American Journal of Medical Genetics, 35, 574–578. https://doi.org/10.1002/ajmg.1320350425.
Hanson, J. W., Myrianthopoulos, N. C., Sedgwick Harvey, M. A., & Smith, D. W. (1976). Risks to the offspring of women treated with hydantoin anticonvulsants, with emphasis on the fetal hydantoin syndrome. The Journal of Pediatrics, 89(4), 662–668. https://doi.org/10.1016/s0022-3476(76)80414-3.
Hanson, J. W., & Smith, D. W. (1975). The fetal hydantoin syndrome. The Journal of Pediatrics, 87, 285–290. https://doi.org/10.1016/s0022-3476(75)80604-4.
Hill, R. M., Verniaud, W. M., Horning, M. G., McCulley, L. B., & Morgan, N. F. (1974). Infants exposed in utero to antiepileptic drugs: A prospective study. American Journal of Diseases of Children, 127, 645–653. https://doi.org/10.1001/archpedi.1974.02110240031002.
Holmes, L. B., Coull, B. A., Dorfman, J., & Rosenberger, P. B. (2005). The correlation of deficits in IQ with midface and digit hypoplasia in children exposed in utero to anticonvulsant drugs. The Journal of Pediatrics, 146, 118–122. https://doi.org/10.1016/j.jpeds.2004.08.048.
Holmes, L. B., Harvey, E. A., Coull, B. A., Huntington, K. B., Khoshbin, S., Hayes, A. M., & Ryan, L. M. (2001). The teratogenicity of anticonvulsant drugs. The New England Journal of Medicine, 344, 1132–1138. https://doi.org/10.1056/NEJM200104123441504.
Holmes, L. B., Hunt, A.‐T., Will, L. A., Dhillon, R., Deutsch, C., & Adams, J. (2024). Facial dysmorphology in children exposed in pregnancy to anticonvulsant medications correlates with deficits in IQ. American Journal of Medical Genetics Part A, 194A:e63511. https://doi.org/10.1002/ajmg.a.635111.
Holmes, L. B., MacDonald, N. R., & Abbott, W. M. (1999). Normal digital artery blood flow in antiepileptic drug embryopathy. Teratology, 59, 130–131. https://doi.org/10.1002/(SICI)1096-9926(199903)59:3<130::AID-TERA2>3.0.CO;2-1.
Holmes, L. B., Quinn, M., Conant, S., Lyons, A., Hauser, W. A., Yerby, M., & Hernandez‐Diaz, S. (2023). Ascertainment of malformations in pregnancy registries: Lessons learned in the North American AED pregnancy registry. Birth Defects Research, 115, 1274–1283. https://doi.org/10.1002/bdr2.2188.
Howe, A. M., Lipson, A. H., Sheffield, L. J., Haan, E. A., Halliday, J. L., Jenson, F., David, D. J., & Webster, W. S. (1995). Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K. American Journal of Medical Genetics, 58, 238–244. https://doi.org/10.1002/ajmg.1320580309.
Jentink, J., Dolk, H., Loane, M. A., Morris, J. K., Wellesley, D., Garne, E., de Jong‐van den Berg, L., & for the EUROCAT Antiepileptic Study Working Group. (2010). Intrauterine exposure to carbamazepine and specific malformations: Systematic review and case‐control study. BMJ, 341, e6581. https://doi.org/10.1136/bmj.e6581.
Jones, K. L., Johnson, K. A., & Chambers, C. C. (1992). Pregnancy outcome in women treated with phenobarbital monotherapy. Teratology, 45, 452–453.
Jones, K. L., Lacro, R. V., Johnson, K. A., & Adams, J. (1989). Pattern of malformations in the children of women treated with carbamazepine during pregnancy. The New England Journal of Medicine, 320, 1661–1666.
Källén, A. J. (1994). Maternal carbamazepine and infant spina bifida. Reproductive Toxicology, 8, 203–205. https://doi.org/10.1016/0890-6238(94)90003-5.
Kelly, T. E. (1984). Teratogenicity of anticonvulsant drugs. III: Radiographic hand analysis of children exposed in utero to diphenylhydantoin. American Journal of Medical Genetics, 19, 445–450.
Kim, S.‐J. (1992). The metrically trimmed mean as a robust estimator of location. The Annals of Statistics, 20, 1534–1547.
Loughnan, P. M., Gold, H., & Vance, J. C. (1973). Phenytoin teratogenicity in man. Lancet, 1, 70–72. https://doi.org/10.1016/s0140-6736(73)90467-4.
Lu, M. C. K., Sammel, M. D., Cleveland, R. H., Ryan, L. M., & Holmes, L. B. (2000). Digit effects produced by prenatal exposure to antiepileptic drugs. Teratology, 61, 277–283.
Lyon, H. M., Holmes, L. B., & Huang, T. (2003). Multiple congenital anomalies associated with in utero exposure to phenytoin: Possible hypoxic ischemic mechanism? Birth Defects Research Part A: Clinical and Molecular Teratology, 67, 993–996. https://doi.org/10.1002/bdra.10100.
Miller, J. R., & Giroux, J. (1966). Dermatoglyphics in pediatric practice. Journal of Pediatrics, 69, 302–312.
Niesen, M., & Fröscher, W. (1985). Finger‐ and toenail hypoplasia after carbamazepine monotherapy in late pregnancy. Neuropediatrics, 16, 167–168.
Nulman, I., Scolnik, D., Chitayat, D., Farkas, L. D., & Koren, G. (1997). Findings in children exposed in utero to phenytoin and carbamazepine monotherapy: Independent effects of epilepsy and medication. American Journal of Medical Genetics, 68, 18–24.
Pagano, M., & Gauvreau, K. (2000). Principles of biostatistics (2nd ed.). Brooks.
Sabry, M. A., & Farag, T. I. (1996). Hand anomalies in fetal‐hydantoin syndrome: From nail/phalangeal hypoplasia to unilateral acheiria. American Journal of Medical Genetics, 62, 410–412. https://doi.org/10.1002/ajmg.1320620403.
Smith, D. W. (1977). Distal limb hypoplasia in the fetal hydantoin syndrome. Birth Defects Original Article Series, 13, 355–359.

Parke-Davis

Keywords: arch patterns; carbamazepine; phenobarbital; phenytoin; small fingernails

33CM23913M (Carbamazepine)
6158TKW0C5 (Phenytoin)
YQE403BP4D (Phenobarbital)
0 (Anticonvulsants)

Date Created: 20240426 Date Completed: 20240809 Latest Revision: 20240813

20240813

10.1002/ajmg.a.63620

38666724