ppharmПедиатрическая фармакологияPediatric pharmacology1727-57762500-3089Издательство «ПедиатрЪ»10.15690/pf.v13i2.1551ppharm-1399Research ArticleОБЗОР ЛИТЕРАТУРЫREVIEWФармакологическая безопасность при беременности: принципы тератогенеза и тератогенность лекарственных средствPharmacological safety during pregnancy: the principles of teratogenesis and teratogenicity of drugsРешетькоО. В.Reshet’koO. V.

доктор медицинских наук, заведующая кафедрой фармакологии Саратовского государственного медицинского университета им. В.И. Разумовского Адрес: 410071, Саратов, ул. Большая Казачья, д. 112, тел.: +7 (8452) 51-15-32

reshetko@yandex.ruЛуцевичК. А.LutsevichK. A.КлименченкоН. И.KlimenchenkoN. I.Саратовский государственный медицинский университет им. В.И. Разумовского, Саратов, Российская ФедерацияРоссияSaratov State Medical University named after V.I. Razumovsky, Saratov, Russian FederationRussian FederationНаучный центр акушерства, гинекологии и перинатологии им. академика В.И. Кулакова, Москва, Российская ФедерацияРоссияResearch Center for Obstetrics, Gynecology and Perinatology, Moscow, Russian FederationRussian Federation201617062016132105115Copyright © Решетько О.В., Луцевич К.А., Клименченко Н.И., 20162016Решетько О.В., Луцевич К.А., Клименченко Н.И.Reshet’ko O.V., Lutsevich K.A., Klimenchenko N.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pedpharma.ru/jour/article/view/1399

Используемые во время беременности лекарственные средства оказывают одновременное воздействие на систему мать–будущий ребенок. Статья, посвященная проблеме применения лекарственных препаратов с потенциальными тератогенными свойствами, указывает на необходимость дальнейших исследований в области фармакологической безопасности при беременности. Авторы анализируют различные механизмы развития врожденных дефектов у ребенка в период внутриутробного развития, в т. ч. в результате использования лекарственных средств. По этическим соображениям при беременности трудно проводить исследования безопасности лекарственных средств. По мнению авторов, полезным может быть сбор дополнительной информации в пострегистрационный период как в рамках рутинного фармаконадзора, так и в ходе целенаправленных фармакоэпидемиологических исследований с текущей оценкой тератогенного риска ЛС.

Drugs used during pregnancy simultaneously have an impact on 2 populations — fetal and maternal. The article is devoted to teratogenic drugs exposition; it points out the need for further research in the field of pharmaceutical safety during pregnancy. Authors analyzed the multiplicity of the congenital disorders in infants, including birth defects cuased by drug application. For ethical reasons, researchers can not conduct any studies on the safety of medicines during pregnancy. Authors suppose that collection of additional information during the marketing phase as a part of the routine pharmacovigilance program and the targeted pharmacoepidemiological trials with the current evaluation of the teratogenic risk of drugs will help to achieve the goals.

беременностьлекарственные средствабезопасностьтератогенностьврожденные дефектытератогенные механизмыpregnancydrugssafetyteratogenicitybirth defectsteratogenic mechanisms.ReferencesAlfirevic A, Alfirevic Z, Pirmohamed M. Pharmacogenetics in reproductive and perinatal medicine. Pharmacogenomics. 2010; 11(1):65–79. doi: 10.2217/pgs.09.153.Alfirevic A, Alfirevic Z, Pirmohamed M. Pharmacogenetics in reproductive and perinatal medicine. Pharmacogenomics. 2010; 11(1):65–79. doi: 10.2217/pgs.09.153.Parisi MA, Spong CY, Zajicek A, Guttmacher A. We don’t know what we don’t study: the case for research on medication effects in pregnancy. Am J Med Genet C Semin Med Genet. 2011;157(3): 247–250. doi: 10.1002/ajmg. c.30309.Parisi MA, Spong CY, Zajicek A, Guttmacher A. We don’t know what we don’t study: the case for research on medication effects in pregnancy. Am J Med Genet C Semin Med Genet. 2011;157(3): 247–250. doi: 10.1002/ajmg. c.30309.Wilffert B, Altena J, Tijink L, et al. Pharmacogenetics of druginduced birth defects: what is known so far? Pharmacogenomics. 2011;12(4):547–558. doi: 10.2217/pgs.10.201.Wilffert B, Altena J, Tijink L, et al. Pharmacogenetics of druginduced birth defects: what is known so far? Pharmacogenomics. 2011;12(4):547–558. doi: 10.2217/pgs.10.201.Einarson A. Studying the safety of drugs in pregnancy: and the gold standard is. J Clin Pharmacol Pharmacoepidemiol. 2010;1:3–8.Einarson A. Studying the safety of drugs in pregnancy: and the gold standard is. J Clin Pharmacol Pharmacoepidemiol. 2010;1:3–8.Schachter AD, Kohane IS. Drug target gene signatures that predict teratogenicity are enriched for developmentally related genes. Reprod Toxicol. 2011;31(4):562–569. doi: 10.1016/j.reprotox.2010.11.008.Schachter AD, Kohane IS. Drug target gene signatures that predict teratogenicity are enriched for developmentally related genes. Reprod Toxicol. 2011;31(4):562–569. doi: 10.1016/j.reprotox.2010.11.008.Mitchell AA. Adverse drug reactions in utero: perspectives on teratogens and strategies for the future. Clin Pharmacol Ther. 2011;89(6):781–783. doi: 10.1038/clpt.2011.52.Mitchell AA. Adverse drug reactions in utero: perspectives on teratogens and strategies for the future. Clin Pharmacol Ther. 2011;89(6):781–783. doi: 10.1038/clpt.2011.52.Obican S, Scialli AR. Teratogenic exposures. Am J Med Genet C Semin Med Genet. 2011;157(3):150–169. doi: 10.1002/ajmg. c.30310.Obican S, Scialli AR. Teratogenic exposures. Am J Med Genet C Semin Med Genet. 2011;157(3):150–169. doi: 10.1002/ajmg. c.30310.Шер С. А. Тератогенное воздействие лекарственных средств на организм будущего ребенка на этапе внутриутробного развития // Педиатрическая фармакология. — 2011. — Т. 8. — № 6. —С. 57–60. [Sher SA. Teratogenic effects of drugs on the organism of a future child during fetal stage of development. Pediatricheskaya farmakologiya. 2011;8(6):57–60. (In Rus).]Шер С. А. Тератогенное воздействие лекарственных средств на организм будущего ребенка на этапе внутриутробного развития // Педиатрическая фармакология. — 2011. — Т. 8. — № 6. —С. 57–60. [Sher SA. Teratogenic effects of drugs on the organism of a future child during fetal stage of development. Pediatricheskaya farmakologiya. 2011;8(6):57–60. (In Rus).]Иванова А. А., Михайлов А. В., Колбин А. С. Тератогенные свойства лекарств. История вопроса // Педиатрическая фармакология. — 2013. — Т. 10. — № 1. — С. 46–53. [Ivanova AA, Mikhailov AV, Kolbin AS. Teratogenic properties of drugs. Background information. Pediatricheskaya farmakologiya. 2013;10(1): 46–53. (In Rus).] doi: 10.15690/pf.v10i1.588.Иванова А. А., Михайлов А. В., Колбин А. С. Тератогенные свойства лекарств. История вопроса // Педиатрическая фармакология. — 2013. — Т. 10. — № 1. — С. 46–53. [Ivanova AA, Mikhailov AV, Kolbin AS. Teratogenic properties of drugs. Background information. Pediatricheskaya farmakologiya. 2013;10(1): 46–53. (In Rus).] doi: 10.15690/pf.v10i1.588.WHO/CDC/ICBDSR. Birth defects surveillance: a manual for programme managers [Internet]. Geneva: World Health Organization; 2014. Available from: http://www.cdc.gov/ncbddd/birthdefectscount/documents/bd-surveillance-manual.pdf.WHO/CDC/ICBDSR. Birth defects surveillance: a manual for programme managers [Internet]. Geneva: World Health Organization; 2014. Available from: http://www.cdc.gov/ncbddd/birthdefectscount/documents/bd-surveillance-manual.pdf.De Vane L, Goetzl LM, Ramamoorthy S. Exposing fetal drug exposure. Clin Pharmacol Ther. 2011;89(6):786–788. doi: 10.1038/clpt.2011.67.De Vane L, Goetzl LM, Ramamoorthy S. Exposing fetal drug exposure. Clin Pharmacol Ther. 2011;89(6):786–788. doi: 10.1038/clpt.2011.67.Blumenfeld YJ, Reynolds-May MF, Altman RB, El-Sayed YY. Maternal fetal and neonatal pharmacogenomics: a review of current literature. J Perinatol. 2010;30:571–579. doi: 10.1038/jp.2009.183.Blumenfeld YJ, Reynolds-May MF, Altman RB, El-Sayed YY. Maternal fetal and neonatal pharmacogenomics: a review of current literature. J Perinatol. 2010;30:571–579. doi: 10.1038/jp.2009.183.Nordeng H, Ystrom E, Eberhard-Gran M. Medication safety in pregnancy — Results from the MoBa study. Norsk Epidemiologi. 2014;24:161–168.Nordeng H, Ystrom E, Eberhard-Gran M. Medication safety in pregnancy — Results from the MoBa study. Norsk Epidemiologi. 2014;24:161–168.Jelinek R. The contribution of new findings and ideas to the old principles of teratology. Reprod Toxicol. 2005;20(3):295–300. doi: 10.1016/j.reprotox.2005.03.011.Jelinek R. The contribution of new findings and ideas to the old principles of teratology. Reprod Toxicol. 2005;20(3):295–300. doi: 10.1016/j.reprotox.2005.03.011.Friedman JM. The principles of teratology: are they still true? Birth Defects Res A Clin Mol Teratol. 2010;88(10):766–768. doi: 10.1002/bdra.20697.Friedman JM. The principles of teratology: are they still true? Birth Defects Res A Clin Mol Teratol. 2010;88(10):766–768. doi: 10.1002/bdra.20697.Friedman JM. How do we know if an exposure is actually teratogenic in humans? Am J Med Genet C Semin Med Genet. 2011;157(3):170–174. doi: 10.1002/ajmg. c.30302.Friedman JM. How do we know if an exposure is actually teratogenic in humans? Am J Med Genet C Semin Med Genet. 2011;157(3):170–174. doi: 10.1002/ajmg. c.30302.Shepard TH. «Proof» of human teratogenicity. Teratology. 1994;50:97–98.Shepard TH. «Proof» of human teratogenicity. Teratology. 1994;50:97–98.Holmes LB. Human teratogens: Update 2010. Birth Defects Res A Clin Mol Teratol. 2011;91(1):1–7. doi: 10.1002/bdra.20748.Holmes LB. Human teratogens: Update 2010. Birth Defects Res A Clin Mol Teratol. 2011;91(1):1–7. doi: 10.1002/bdra.20748.Wilson RD, Johnson JA, Summers A, et al. Principles of human teratology: drug, chemical and infectious exposure. SOGC Clinical Practice Guideline. J Obstet Gynaecol Can. 2007;29(11):911–917. doi: 10.1016/s1701-2163(16)32668-8.Wilson RD, Johnson JA, Summers A, et al. Principles of human teratology: drug, chemical and infectious exposure. SOGC Clinical Practice Guideline. J Obstet Gynaecol Can. 2007;29(11):911–917. doi: 10.1016/s1701-2163(16)32668-8.Uhl K, Trontell A, Kennedy D. Risk minimization practices for pregnancy prevention: understanding risk, selecting tools. Pharmacoepidemiol Drug Saf. 2007;16(3):337–348. doi: 10.1002/pds.1312.Uhl K, Trontell A, Kennedy D. Risk minimization practices for pregnancy prevention: understanding risk, selecting tools. Pharmacoepidemiol Drug Saf. 2007;16(3):337–348. doi: 10.1002/pds.1312.Zhu H, Kartiko S, Finnell RH. Importance of gene-environment interactions in the etiology of selected birth defects. Clin Genet. 2009;75(5):409–423. doi: 10.1111/j.1399-0004.2009.01174.x.Zhu H, Kartiko S, Finnell RH. Importance of gene-environment interactions in the etiology of selected birth defects. Clin Genet. 2009;75(5):409–423. doi: 10.1111/j.1399-0004.2009.01174.x.Kalter H. Teratology in the twentieth century. Congenital malformations in humans and how their environmental causes were established. Amsterdam: Elsevier; 2003.Kalter H. Teratology in the twentieth century. Congenital malformations in humans and how their environmental causes were established. Amsterdam: Elsevier; 2003.Van Gelder MMHJ, Van Rooij IALM, Miller RK, et al. Teratogenic mechanisms of medical drugs. Hum Reprod Update. 2010;16(4): 378–394. doi: 10.1093/humupd/dmp052.Van Gelder MMHJ, Van Rooij IALM, Miller RK, et al. Teratogenic mechanisms of medical drugs. Hum Reprod Update. 2010;16(4): 378–394. doi: 10.1093/humupd/dmp052.van der Put NMJ, van Straaten HWM, Trijbels FJM, Blom HJ. Folate, homocysteine and neural tube defects: an overview. Exp Biol Med. 2001;226(4):243–270.van der Put NMJ, van Straaten HWM, Trijbels FJM, Blom HJ. Folate, homocysteine and neural tube defects: an overview. Exp Biol Med. 2001;226(4):243–270.Czeizel AE. Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities. Birth Defects Res A Clin Mol Teratol. 2009;85(4):260–268. doi: 10.1002/bdra.20563.Czeizel AE. Periconceptional folic acid and multivitamin supplementation for the prevention of neural tube defects and other congenital abnormalities. Birth Defects Res A Clin Mol Teratol. 2009;85(4):260–268. doi: 10.1002/bdra.20563.Botto LD, Yang Q. 5,10-methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000;151(9):862–877. doi: 10.1093/oxfordjournals.aje.a010290.Botto LD, Yang Q. 5,10-methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000;151(9):862–877. doi: 10.1093/oxfordjournals.aje.a010290.van der Linden IJM, den Heijer M, Afman LA, et al. The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida. J Mol Med. 2006;84(12):1047–1054. doi: 10.1007/s00109-006-0093-x.van der Linden IJM, den Heijer M, Afman LA, et al. The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida. J Mol Med. 2006;84(12):1047–1054. doi: 10.1007/s00109-006-0093-x.van Beynum IM, Kapusta L, den Heijer M, et al. Maternal MTHFR 677C>T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation. Eur Heart J. 2006;27(8):981–987. doi: 10.1093/eurheartj/ ehi815.van Beynum IM, Kapusta L, den Heijer M, et al. Maternal MTHFR 677C>T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation. Eur Heart J. 2006;27(8):981–987. doi: 10.1093/eurheartj/ ehi815.Hernandez-Diaz S, Werler MM, Walker AM, et al. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med. 2000;343(22):1608–1614. doi: 10.1056/nejm200011303432204.Hernandez-Diaz S, Werler MM, Walker AM, et al. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med. 2000;343(22):1608–1614. doi: 10.1056/nejm200011303432204.Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol. 2001;153(10):961–968. doi: 10.1093/aje/153.10.961.Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol. 2001;153(10):961–968. doi: 10.1093/aje/153.10.961.Meijer WM, de Walle HEK, Kerstjens-Frederikse WS, et al. Folic acid sensitive birth defects in association with intrauterine exposure to folic acid antagonists. Reprod Toxicol. 2005;20(2):203–207. doi: 10.1016/j.reprotox.2005.01.008.Meijer WM, de Walle HEK, Kerstjens-Frederikse WS, et al. Folic acid sensitive birth defects in association with intrauterine exposure to folic acid antagonists. Reprod Toxicol. 2005;20(2):203–207. doi: 10.1016/j.reprotox.2005.01.008.Malm H, Kajantie E, Kivirikko S, et al. Valproate embryopathy in three sets of siblings: further proof of hereditary susceptibility. Neurology. 2002;59(4):630–633. doi: 10.1212/wnl.59.4.630.Malm H, Kajantie E, Kivirikko S, et al. Valproate embryopathy in three sets of siblings: further proof of hereditary susceptibility. Neurology. 2002;59(4):630–633. doi: 10.1212/wnl.59.4.630.Kini U, Lee R, Jones A, et al. Influence of the MTHFR genotype on the rate of malformations following exposure to antiepileptic drugs in utero. Eur J Med Genet. 2007;50(6):411–420. doi: 10.1016/j.ejmg.2007.08.002.Kini U, Lee R, Jones A, et al. Influence of the MTHFR genotype on the rate of malformations following exposure to antiepileptic drugs in utero. Eur J Med Genet. 2007;50(6):411–420. doi: 10.1016/j.ejmg.2007.08.002.Stoller JZ, Epstein JA. Cardiac neural crest. Semin Cell Dev Biol. 2005;16(6):704–715. doi: 10.1016/j.semcdb.2005.06.004.Stoller JZ, Epstein JA. Cardiac neural crest. Semin Cell Dev Biol. 2005;16(6):704–715. doi: 10.1016/j.semcdb.2005.06.004.Duester G. Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid. Eur J Biochem. 2000;267(14):4315–4324. doi: 10.1046/j.1432-1327.2000.01497.x.Duester G. Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid. Eur J Biochem. 2000;267(14):4315–4324. doi: 10.1046/j.1432-1327.2000.01497.x.Fujii H, Sato T, Kaneko S, et al. Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos. EMBO J. 1997;16(14):4163–4173. doi: 10.1093/emboj/16.14.4163.Fujii H, Sato T, Kaneko S, et al. Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos. EMBO J. 1997;16(14):4163–4173. doi: 10.1093/emboj/16.14.4163.Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284(16): 878–881. doi: 10.1056/nejm197104222841604.Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284(16): 878–881. doi: 10.1056/nejm197104222841604.Hernandez-Diaz S, Mitchell AA, Kelley KE, et al. Medications as a potential source of exposure to phthalates in the U. S. population. Environ Health Perspect. 2009;117(2):185–189. doi: 10.1289/ehp.11766.Hernandez-Diaz S, Mitchell AA, Kelley KE, et al. Medications as a potential source of exposure to phthalates in the U. S. population. Environ Health Perspect. 2009;117(2):185–189. doi: 10.1289/ehp.11766.Giwercman A, Rylander L, Giwercman YL. Influence of endocrine disruptors on human male fertility. Reprod Biomed Online. 2007; 15(6):633–642. doi: 10.1016/s1472-6483(10)60530-5.Giwercman A, Rylander L, Giwercman YL. Influence of endocrine disruptors on human male fertility. Reprod Biomed Online. 2007; 15(6):633–642. doi: 10.1016/s1472-6483(10)60530-5.Diav-Citrin O, Park YH, Veerasuntharam G, et al. The safety of mesalamine in human pregnancy: a prospective controlled cohort study. Gastroenterology. 1998;114(1):23–28. doi: 10.1016/s0016-5085(98)70628-6.Diav-Citrin O, Park YH, Veerasuntharam G, et al. The safety of mesalamine in human pregnancy: a prospective controlled cohort study. Gastroenterology. 1998;114(1):23–28. doi: 10.1016/s0016-5085(98)70628-6.Gill SK, O’Brien L, Einarson TR, et al. The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis. Am J Gastroenterol. 2009;104(6):1541–1545. doi: 10.1038/ajg.2009.122.Gill SK, O’Brien L, Einarson TR, et al. The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis. Am J Gastroenterol. 2009;104(6):1541–1545. doi: 10.1038/ajg.2009.122.Sahambi SK, Hales BF. Exposure to 5-bromo-2 deoxyuridine induces oxidative stress and activator protein–1 DNA binding activity in the embryo. Birth Defects Res A Clin Mol Teratol. 2006; 76(8):580–591. doi: 10.1002/bdra.20284.Sahambi SK, Hales BF. Exposure to 5-bromo-2 deoxyuridine induces oxidative stress and activator protein–1 DNA binding activity in the embryo. Birth Defects Res A Clin Mol Teratol. 2006; 76(8):580–591. doi: 10.1002/bdra.20284.Wellfelt K, Skold AC, Wallin A, et al. Teratogenicity of the class III antiarrhythmic drug almokalant. Role of hypoxia and reactive oxygen species. Reprod Toxicol. 1999;13(2):93–101. doi: 10.1016/s0890-6238(98)00066-5.Wellfelt K, Skold AC, Wallin A, et al. Teratogenicity of the class III antiarrhythmic drug almokalant. Role of hypoxia and reactive oxygen species. Reprod Toxicol. 1999;13(2):93–101. doi: 10.1016/s0890-6238(98)00066-5.Hansen JM, Harris C. A novel hypothesis for thalidomideinduced limb teratogenesis: redox misregulation of the NF-kB pathway. Antioxid Redox Signal. 2004;6(1):1–14. doi: 10.1089/152308604771978291.Hansen JM, Harris C. A novel hypothesis for thalidomideinduced limb teratogenesis: redox misregulation of the NF-kB pathway. Antioxid Redox Signal. 2004;6(1):1–14. doi: 10.1089/152308604771978291.Winn LM, Wells PG. Maternal administration of superoxide dismutase and catalase in phenytoin teratogenicity. Free Radic Biol Med. 1999;26(3–4):266–274. doi: 10.1016/s0891-5849(98)00193-2.Winn LM, Wells PG. Maternal administration of superoxide dismutase and catalase in phenytoin teratogenicity. Free Radic Biol Med. 1999;26(3–4):266–274. doi: 10.1016/s0891-5849(98)00193-2.Defoort EN, Kim PM, Winn LM. Valproic acid increases conser vative homologous recombination frequency and reactive oxygen species formation: a potential mechanism for valproic acid-induced neural tube defects. Mol Pharmacol. 2006;69(4): 1304–1310. doi: 10.1124/mol.105.017855.Defoort EN, Kim PM, Winn LM. Valproic acid increases conser vative homologous recombination frequency and reactive oxygen species formation: a potential mechanism for valproic acid-induced neural tube defects. Mol Pharmacol. 2006;69(4): 1304–1310. doi: 10.1124/mol.105.017855.Scholl TO. Iron status during pregnancy: setting the stage for mother and infant. Am J Clin Nutr. 2005;81(5):1218–1222.Scholl TO. Iron status during pregnancy: setting the stage for mother and infant. Am J Clin Nutr. 2005;81(5):1218–1222.Foster W, Myllynen P, Winn LM, et al. Reactive oxygen species, diabetes and toxicity in the placenta: a workshop report. Placenta. 2008;29:105–107. doi: 10.1016/j.placenta.2007.10.014.Foster W, Myllynen P, Winn LM, et al. Reactive oxygen species, diabetes and toxicity in the placenta: a workshop report. Placenta. 2008;29:105–107. doi: 10.1016/j.placenta.2007.10.014.Azzato EM, Chen RA, Wacholder S, et al. Maternal EPHX1 polymorphisms and risk of phenytoin-induced congenital malformations. Pharmacogenet Genomics. 2010;20(1):58–63. doi: 10.1097/FPC.0b013e328334b6a3.Azzato EM, Chen RA, Wacholder S, et al. Maternal EPHX1 polymorphisms and risk of phenytoin-induced congenital malformations. Pharmacogenet Genomics. 2010;20(1):58–63. doi: 10.1097/FPC.0b013e328334b6a3.Chevrier C, Bahuau M, Perret C, et al. Genetic susceptibilities in the association between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft. Am J Med Genet A. 2008; 146A(18):2396–2406. doi: 10.1002/ajmg. a.32505.Chevrier C, Bahuau M, Perret C, et al. Genetic susceptibilities in the association between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft. Am J Med Genet A. 2008; 146A(18):2396–2406. doi: 10.1002/ajmg. a.32505.Shi M, Christensen K, Weinberg CR, et al. Orofacial cleft risk is increased with maternal smoking and specific detoxification gene variants. Am J Hum Genet. 2007;80(1):76–90. doi: 10.1086/510518.Shi M, Christensen K, Weinberg CR, et al. Orofacial cleft risk is increased with maternal smoking and specific detoxification gene variants. Am J Hum Genet. 2007;80(1):76–90. doi: 10.1086/510518.van Rooij I, Wegerif MJ, Roelofs HM, et al. Smoking, genetic polymorphisms in biotransformation enzymes, and nonsyndromic oral clefting: a gene-environment interaction. Epidemiology. 2001;12(5):502–507. doi: 10.1097/00001648-200109000-00007.van Rooij I, Wegerif MJ, Roelofs HM, et al. Smoking, genetic polymorphisms in biotransformation enzymes, and nonsyndromic oral clefting: a gene-environment interaction. Epidemiology. 2001;12(5):502–507. doi: 10.1097/00001648-200109000-00007.Hartsfield JK Jr, Hickman TA, Everett ET, et al. Analysis of the EPHX1 113 polymorphism and GSTM1 homozygous null polymorphism and oral clefting associated with maternal smoking. Am J Med Genet. 2001;102(1):21–24. doi: 10.1002/1096-8628 (20010722)102:1<21::aid-ajmg1409>3.0.co;2-t.Hartsfield JK Jr, Hickman TA, Everett ET, et al. Analysis of the EPHX1 113 polymorphism and GSTM1 homozygous null polymorphism and oral clefting associated with maternal smoking. Am J Med Genet. 2001;102(1):21–24. doi: 10.1002/1096-8628 (20010722)102:1<21::aid-ajmg1409>3.0.co;2-t.Lie RT, Wilcox AJ, Taylor J, et al. Maternal smoking and oral clefts: the role of detoxification pathway genes. Epidemiology.2008;19(4):606–615. doi: 10.1097/ede.0b013e3181690731.Lie RT, Wilcox AJ, Taylor J, et al. Maternal smoking and oral clefts: the role of detoxification pathway genes. Epidemiology.2008;19(4):606–615. doi: 10.1097/ede.0b013e3181690731.Orioli IM, Castilla EE. Epidemiological assessment of misoprostol teratogenicity. BJOG. 2000;107(4):519–523. doi: 10.1111/j.1471-0528.2000.tb13272.x.Orioli IM, Castilla EE. Epidemiological assessment of misoprostol teratogenicity. BJOG. 2000;107(4):519–523. doi: 10.1111/j.1471-0528.2000.tb13272.x.Vargas FR, Schuler-Faccini L, Brunoni D, et al. Prenatal exposure to misoprostol and vascular disruption defects: a case-control study. Am J Med Genet. 2000;95(4):302–306. doi: 10.1002/1096-8628 (20001211)95:4<302: aid-ajmg2>3.0.co;2-b.Vargas FR, Schuler-Faccini L, Brunoni D, et al. Prenatal exposure to misoprostol and vascular disruption defects: a case-control study. Am J Med Genet. 2000;95(4):302–306. doi: 10.1002/1096-8628 (20001211)95:4<302: aid-ajmg2>3.0.co;2-b.Kozer E, Nikfar S, Costei A, et al. Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a metaanalysis. Am J Obstet Gynecol. 2002;187(6):1623–1630. doi: 10.1067/mob.2002.127376.Kozer E, Nikfar S, Costei A, et al. Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a metaanalysis. Am J Obstet Gynecol. 2002;187(6):1623–1630. doi: 10.1067/mob.2002.127376.Werler MM, Mitchell AA, Shapiro S. The relation of aspirin use during the first trimester of pregnancy to congenital cardiac defects. N Engl J Med. 1989;321(24):1639–1642. doi: 10.1056/nejm198912143212404.Werler MM, Mitchell AA, Shapiro S. The relation of aspirin use during the first trimester of pregnancy to congenital cardiac defects. N Engl J Med. 1989;321(24):1639–1642. doi: 10.1056/nejm198912143212404.Raymond GV. Teratogen update: ergot and ergotamine. Teratology. 1995;51(5):344–347. doi: 10.1002/tera.1420510511.Raymond GV. Teratogen update: ergot and ergotamine. Teratology. 1995;51(5):344–347. doi: 10.1002/tera.1420510511.Smets K, Zecic A, Willems J. Ergotamine as a possible cause of Mobius sequence: additional clinical observation. J Child Neurol. 2004;19(5):398. doi: 10.1177/08830738040 1900518.Smets K, Zecic A, Willems J. Ergotamine as a possible cause of Mobius sequence: additional clinical observation. J Child Neurol. 2004;19(5):398. doi: 10.1177/08830738040 1900518.Werler MM, Sheehan JE, Hayes C, et al. Vasoactive exposures, vascular events, and hemifacial microsomia. Birth Defects Res A Clin Mol Teratol. 2004;70(6):389–395. doi: 10.1002/bdra.20022.Werler MM, Sheehan JE, Hayes C, et al. Vasoactive exposures, vascular events, and hemifacial microsomia. Birth Defects Res A Clin Mol Teratol. 2004;70(6):389–395. doi: 10.1002/bdra.20022.Schutz S, Le Moullec JM, Corvol P, Gasc JM. Early expression of all the components of the renin-angiotensin-system in human development. Am J Pathol. 1996;149(6):2067–2079.Schutz S, Le Moullec JM, Corvol P, Gasc JM. Early expression of all the components of the renin-angiotensin-system in human development. Am J Pathol. 1996;149(6):2067–2079.Himmelmann A, Hansson L, Hansson BG, et al. ACE inhibition preserves renal function better than beta-blockade in the treatment of essential hypertension. Blood Press. 1995;4(2):85–90. doi: 10.3109/08037059509077575.Himmelmann A, Hansson L, Hansson BG, et al. ACE inhibition preserves renal function better than beta-blockade in the treatment of essential hypertension. Blood Press. 1995;4(2):85–90. doi: 10.3109/08037059509077575.Shotan A, Widerhorn J, Hurst A, et al. Risks of angiotensinconverting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med. 1994;96(5):451–456. doi: 10.1016/0002-9343(94)90172-4.Shotan A, Widerhorn J, Hurst A, et al. Risks of angiotensinconverting enzyme inhibition during pregnancy: experimental and clinical evidence, potential mechanisms, and recommendations for use. Am J Med. 1994;96(5):451–456. doi: 10.1016/0002-9343(94)90172-4.Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006;354(23):2443–2451. doi: 10.1056/nejmoa055202.Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006;354(23):2443–2451. doi: 10.1056/nejmoa055202.Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol Teratol. 2005;73(2):123–130. doi: 10.1002/bdra.20102.Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol Teratol. 2005;73(2):123–130. doi: 10.1002/bdra.20102.Gofflot F, Hars C, Illien F, et al. Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling. Hum Mol Genet. 2003;12(10):1187–1198. doi: 10.1093/hmg/ddg129.Gofflot F, Hars C, Illien F, et al. Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling. Hum Mol Genet. 2003;12(10):1187–1198. doi: 10.1093/hmg/ddg129.Petersen EE, Mitchell AA, Carey JC, et al. Maternal exposure to statins and risk for birth defects: a case-series approach. Am J Med Genet A. 2008;146A(20):2701–2705. doi: 10.1002/ajmg. a.32493.Petersen EE, Mitchell AA, Carey JC, et al. Maternal exposure to statins and risk for birth defects: a case-series approach. Am J Med Genet A. 2008;146A(20):2701–2705. doi: 10.1002/ajmg. a.32493.Bateman BT, Hernandez-Diaz S, Fischer MA, et al. Statins and congenital malformations: a cohort study. BMJ. 2015;350:h1035. doi: 10.1136/bmj.h1035.Bateman BT, Hernandez-Diaz S, Fischer MA, et al. Statins and congenital malformations: a cohort study. BMJ. 2015;350:h1035. doi: 10.1136/bmj.h1035.Menegola E, Di Renzo F, Broccia ML, et al. Inhibition of histone deacetylase activity on specific embryonic tissues as a new mechanism for teratogenicity. Birth Defects Res B Dev Reprod Toxicol. 2005;74(5):392–398. doi: 10.1002/bdrb.20053.Menegola E, Di Renzo F, Broccia ML, et al. Inhibition of histone deacetylase activity on specific embryonic tissues as a new mechanism for teratogenicity. Birth Defects Res B Dev Reprod Toxicol. 2005;74(5):392–398. doi: 10.1002/bdrb.20053.Di Renzo F, Cappelletti G, Broccia ML, et al. Boric acid inhibits embryonic histone deacetylases: a suggested mechanism to explain boric acid related teratogenicity. Toxicol Appl Pharmacol. 2007; 220(2):178–185. doi: 10.1016/j.taap.2007.01.001.Di Renzo F, Cappelletti G, Broccia ML, et al. Boric acid inhibits embryonic histone deacetylases: a suggested mechanism to explain boric acid related teratogenicity. Toxicol Appl Pharmacol. 2007; 220(2):178–185. doi: 10.1016/j.taap.2007.01.001.Eikel D, Lampen A, Nau H. Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives. Chem Res Toxicol. 2006;19(2):272–278. doi: 10.1021/tx0502241.Eikel D, Lampen A, Nau H. Teratogenic effects mediated by inhibition of histone deacetylases: evidence from quantitative structure activity relationships of 20 valproic acid derivatives. Chem Res Toxicol. 2006;19(2):272–278. doi: 10.1021/tx0502241.Phiel CJ, Zhang F, Huang EY, et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001;276:36734– 36741. doi 10.1074/jbc.M101287200.Phiel CJ, Zhang F, Huang EY, et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001;276:36734– 36741. doi 10.1074/jbc.M101287200.Yoshida M, Kijima M, Akita M, et al. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem. 1990;265(28):17174–17179.Yoshida M, Kijima M, Akita M, et al. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem. 1990;265(28):17174–17179.Di Renzo F, Cappelletti G, Broccia ML, et al. The inhibition of embryonic histone deacetylases as the possible mechanism accounting for axial skeletal malformations induced by sodium salicylate. Toxicol Sci. 2008;104:397–404. doi: 10.1093/ toxsci/kfn094.Di Renzo F, Cappelletti G, Broccia ML, et al. The inhibition of embryonic histone deacetylases as the possible mechanism accounting for axial skeletal malformations induced by sodium salicylate. Toxicol Sci. 2008;104:397–404. doi: 10.1093/ toxsci/kfn094.Streck RD, Kumpf SW, Ozolins TR, et al. Rat embryos express transcripts for cyclooxygenase-1 and carbonic anhydrase-4, but not for cyclooxygenase-2, during organogenesis. Birth Defects Res B Dev Reprod Toxicol. 2003;68(1):57–69. doi: 10.1002/bdrb.10006.Streck RD, Kumpf SW, Ozolins TR, et al. Rat embryos express transcripts for cyclooxygenase-1 and carbonic anhydrase-4, but not for cyclooxygenase-2, during organogenesis. Birth Defects Res B Dev Reprod Toxicol. 2003;68(1):57–69. doi: 10.1002/bdrb.10006.Cappon GD, Cook JC, Hurtt ME. Relationship between cyclooxygenase 1 and 2 selective inhibitors and fetal development when administered to rats and rabbits during the sensitive periods for heart development and midline closure. Birth Defects Res B Dev Reprod Toxicol. 2003;68(1):47–56. doi: 10.1002/bdrb.10008.Cappon GD, Cook JC, Hurtt ME. Relationship between cyclooxygenase 1 and 2 selective inhibitors and fetal development when administered to rats and rabbits during the sensitive periods for heart development and midline closure. Birth Defects Res B Dev Reprod Toxicol. 2003;68(1):47–56. doi: 10.1002/bdrb.10008.Nielsen GL, Sorensen HT, Larsen H, et al. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. BMJ. 2001;322(7281):266–270. doi: 10.1136/bmj.322.7281.266.Nielsen GL, Sorensen HT, Larsen H, et al. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. BMJ. 2001;322(7281):266–270. doi: 10.1136/bmj.322.7281.266.Cleves MA, Savell VH, Raj S, et al. Maternal use of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), and muscular ventricular septal defects. Birth Defects Res A Clin Mol Teratol. 2004;70(3):107–113. doi: 10.1002/bdra.20005.Cleves MA, Savell VH, Raj S, et al. Maternal use of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), and muscular ventricular septal defects. Birth Defects Res A Clin Mol Teratol. 2004;70(3):107–113. doi: 10.1002/bdra.20005.Ofori B, Oraichi D, Blais L, et al. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-control study. Birth Defects Res B Dev Reprod Toxicol. 2006;77(4):268–279. doi: 10.1002/bdrb.20085.Ofori B, Oraichi D, Blais L, et al. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-control study. Birth Defects Res B Dev Reprod Toxicol. 2006;77(4):268–279. doi: 10.1002/bdrb.20085.Cook JC, Jacobson CF, Gao F, et al. Analysis of the nonsteroidal anti-inflammatory drug literature for potential developmental toxicity in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol. 2003;68(1):5–26. doi: 10.1002/bdrb.10005.Cook JC, Jacobson CF, Gao F, et al. Analysis of the nonsteroidal anti-inflammatory drug literature for potential developmental toxicity in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol. 2003;68(1):5–26. doi: 10.1002/bdrb.10005.Kallio H, Pastorekova S, Pastorek J, et al. Expression of carbonic anhydrases IX and XII during mouse embryonic development. BMC Dev Biol. 2006;6(1):22. doi: 10.1186/1471-213x-6-22.Kallio H, Pastorekova S, Pastorek J, et al. Expression of carbonic anhydrases IX and XII during mouse embryonic development. BMC Dev Biol. 2006;6(1):22. doi: 10.1186/1471-213x-6-22.Scott WJ, Duggan CA, Schreiner CM, et al. Reduction of embryonic intracellular pH: a potential mechanism of acetazolamide induced limb malformations. Toxicol Appl Pharmacol. 1990;103(2):238–254. doi: 10.1016/0041-008x(90)90227-l.Scott WJ, Duggan CA, Schreiner CM, et al. Reduction of embryonic intracellular pH: a potential mechanism of acetazolamide induced limb malformations. Toxicol Appl Pharmacol. 1990;103(2):238–254. doi: 10.1016/0041-008x(90)90227-l.Monyer H, Burnashev N, Laurie DJ, et al. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. 1994;12(3):529–540. doi: 10.1016/0896-6273(94)90210-0.Monyer H, Burnashev N, Laurie DJ, et al. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. 1994;12(3):529–540. doi: 10.1016/0896-6273(94)90210-0.Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA recep tors and apoptotic neurodegeneration in the developing brain. Science. 1999;283(5398):70–74. doi: 10.1126/science. 283.5398.70.Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA recep tors and apoptotic neurodegeneration in the developing brain. Science. 1999;283(5398):70–74. doi: 10.1126/science. 283.5398.70.Kornhuber J, Bormann J, Hubers M, et al. Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDAreceptor-gated ion channel: a human postmortem brain study. Eur J Pharmacol. 1991;206(4):297–300. doi: 10.1016/0922- 4106(91)90113-v.Kornhuber J, Bormann J, Hubers M, et al. Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDAreceptor-gated ion channel: a human postmortem brain study. Eur J Pharmacol. 1991;206(4):297–300. doi: 10.1016/0922- 4106(91)90113-v.Andaloro VJ, Monaghan DT, Rosenquist TH. Dextromethorphan and other N-methyl-D-aspartate receptor antagonists are teratogenic in the avian embryo model. Pediatr Res. 1998;43(1):1–7. doi: 10.1203/00006450-199801000-00001.Andaloro VJ, Monaghan DT, Rosenquist TH. Dextromethorphan and other N-methyl-D-aspartate receptor antagonists are teratogenic in the avian embryo model. Pediatr Res. 1998;43(1):1–7. doi: 10.1203/00006450-199801000-00001.Bennett GD, VanWaes J, Moser K, et al. Failure of homocysteine to induce neural tube defects in a mouse model. Birth Defects Res B Dev Reprod Toxicol. 2006;77(2):89–94. doi: 10.1002/bdrb.20071.Bennett GD, VanWaes J, Moser K, et al. Failure of homocysteine to induce neural tube defects in a mouse model. Birth Defects Res B Dev Reprod Toxicol. 2006;77(2):89–94. doi: 10.1002/bdrb.20071.Akesson E, Kjaeldgaard A, Samuelsson EB, et al. Ionotropic glutamate receptor expression in human spinal cord during first trimester development. Brain Res Dev Brain Res. 2000;119(1): 55–63. doi: 10.1016/s0165-3806(99)00158-3.Akesson E, Kjaeldgaard A, Samuelsson EB, et al. Ionotropic glutamate receptor expression in human spinal cord during first trimester development. Brain Res Dev Brain Res. 2000;119(1): 55–63. doi: 10.1016/s0165-3806(99)00158-3.Varju P, Katarova Z, Madarasz E, et al. GABA signalling during development: new data and old questions. Cell Tissue Res. 2001; 305(2):239–246. doi: 10.1007/s004410100356.Varju P, Katarova Z, Madarasz E, et al. GABA signalling during development: new data and old questions. Cell Tissue Res. 2001; 305(2):239–246. doi: 10.1007/s004410100356.Dolovich LR, Addis A, Vaillancourt JM, et al. Benzodiazepine use in pregnancy and major malformations of oral cleft: metaanalysis of cohort and case-control studies. BMJ. 1998;317(7162): 839–843. doi: 10.1136/bmj.317.7162.839.Dolovich LR, Addis A, Vaillancourt JM, et al. Benzodiazepine use in pregnancy and major malformations of oral cleft: metaanalysis of cohort and case-control studies. BMJ. 1998;317(7162): 839–843. doi: 10.1136/bmj.317.7162.839.Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A populationbased case-control study of oral chlordiazepoxide use during pregnancy and risk of congenital abnormalities. Neurotoxicol Teratol. 2004;26(4):593–598. doi: 10.1016/j.ntt.2004.03.009.Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A populationbased case-control study of oral chlordiazepoxide use during pregnancy and risk of congenital abnormalities. Neurotoxicol Teratol. 2004;26(4):593–598. doi: 10.1016/j.ntt.2004.03.009.Wikner BN, Stiller CO, Bergman U, et al. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol Drug Saf. 2007;16(11):1203–1210. doi: 10.1002/pds.1457.Wikner BN, Stiller CO, Bergman U, et al. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol Drug Saf. 2007;16(11):1203–1210. doi: 10.1002/pds.1457.Lin AE, Peller AJ, Westgate MN, et al. Clonazepam use in pregnancy and the risk of malformations. Birth Defects Res A Clin Mol Teratol. 2004;70(8):534–536. doi: 10.1002/bdra.20051.Lin AE, Peller AJ, Westgate MN, et al. Clonazepam use in pregnancy and the risk of malformations. Birth Defects Res A Clin Mol Teratol. 2004;70(8):534–536. doi: 10.1002/bdra.20051.Nebigil CG, Hickel P, Messaddeq N, et al. Ablation of serotonin 5-HT2B receptors in mice leads to abnormal cardiac structure and function. Circulation. 2001;103(24):2973–2979. doi: 10.1161/01.cir.103.24.2973.Nebigil CG, Hickel P, Messaddeq N, et al. Ablation of serotonin 5-HT2B receptors in mice leads to abnormal cardiac structure and function. Circulation. 2001;103(24):2973–2979. doi: 10.1161/01.cir.103.24.2973.Shuey DL, Sadler TW, Lauder JM. Serotonin as a regulator of craniofacial morphogenesis: site specific malformations following exposure to serotonin uptake inhibitors. Teratology. 1992;46(4): 367–378. doi: 10.1002/tera.1420460407.Shuey DL, Sadler TW, Lauder JM. Serotonin as a regulator of craniofacial morphogenesis: site specific malformations following exposure to serotonin uptake inhibitors. Teratology. 1992;46(4): 367–378. doi: 10.1002/tera.1420460407.Sari Y, Zhou FC. Serotonin and its transporter on proliferation of fetal heart cells. Int J Dev Neurosci. 2003;21(8):417–424. doi: 10.1016/j.ijdevneu.2003.10.002.Sari Y, Zhou FC. Serotonin and its transporter on proliferation of fetal heart cells. Int J Dev Neurosci. 2003;21(8):417–424. doi: 10.1016/j.ijdevneu.2003.10.002.Alwan S, Reefhuis J, Rasmussen SA, et al. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med. 2007;356(26):2684–2692. doi: 10.1056/nejmoa066584.Alwan S, Reefhuis J, Rasmussen SA, et al. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med. 2007;356(26):2684–2692. doi: 10.1056/nejmoa066584.Louik C, Lin AE, Werler MM, et al. First trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007;356(26):2675–2683. doi: 10.1056/nejmoa067407.Louik C, Lin AE, Werler MM, et al. First trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007;356(26):2675–2683. doi: 10.1056/nejmoa067407.Berard A, Ramos E, Rey E, et al. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol. 2007;80(1):18–27. doi: 10.1002/bdrb.20099.Berard A, Ramos E, Rey E, et al. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol. 2007;80(1):18–27. doi: 10.1002/bdrb.20099.Kallen BA, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol. 2007;79(4): 301–308. doi: 10.1002/bdra.20327.Kallen BA, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol. 2007;79(4): 301–308. doi: 10.1002/bdra.20327.Einarson A, Pistelli A, DeSantis M, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry. 2008;165(6): 749–752. doi: 10.1176/appi.ajp.2007.07060879.Einarson A, Pistelli A, DeSantis M, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry. 2008;165(6): 749–752. doi: 10.1176/appi.ajp.2007.07060879.Diav-Citrin O, Shechtman S, Weinbaum D, et al. Paroxetine and fluoxetine in pregnancy: a prospective, multicentre, controlled, observational study. Br J Clin Pharmacol. 2008;66:695–705. doi: 10.1111/j.1365-2125.2008.03261.x.Diav-Citrin O, Shechtman S, Weinbaum D, et al. Paroxetine and fluoxetine in pregnancy: a prospective, multicentre, controlled, observational study. Br J Clin Pharmacol. 2008;66:695–705. doi: 10.1111/j.1365-2125.2008.03261.x.Reefhuis J, Devine O, Friedman JM, et al. Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports. BMJ. 2015;350: h3190. doi: 10.1136/bmj.h3190.Reefhuis J, Devine O, Friedman JM, et al. Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports. BMJ. 2015;350: h3190. doi: 10.1136/bmj.h3190.Sadler TW. Selective serotonin reuptake inhibitors (SSRIs) and heart defects: potential mechanisms for the observed associations. Reprod Toxicol. 2011;32(4):484–489. doi: 10.1016/j.reprotox.2011.09.004.Sadler TW. Selective serotonin reuptake inhibitors (SSRIs) and heart defects: potential mechanisms for the observed associations. Reprod Toxicol. 2011;32(4):484–489. doi: 10.1016/j.reprotox.2011.09.004.Vahakangas K, Myllynen P. Drug transporters in the human blood-placental barrier. Br J Pharmacol. 2009;158(3):665–678. doi: 10.1111/j.1476-5381.2009.00336.x.Vahakangas K, Myllynen P. Drug transporters in the human blood-placental barrier. Br J Pharmacol. 2009;158(3):665–678. doi: 10.1111/j.1476-5381.2009.00336.x.Кукес В. Г., Сокова Е. А., Игнатьев И. В. и др. Гликопротеин P и здоровье плода. Проблемы репродукции. 2010;5:78–84. [Kukes VG, Sokova EA, Ignat’ev IV, et al. Glycoprotein P and fetal condition. Problemy reproduktsii. 2010;5:78–84. (In Rus).]Кукес В. Г., Сокова Е. А., Игнатьев И. В. и др. Гликопротеин P и здоровье плода. Проблемы репродукции. 2010;5:78–84. [Kukes VG, Sokova EA, Ignat’ev IV, et al. Glycoprotein P and fetal condition. Problemy reproduktsii. 2010;5:78–84. (In Rus).]Atkinson DE, Brice-Bennett S, D’Souza SW. Antiepileptic medication during pregnancy: does fetal genotype affect outcome? Pediatr Res. 2007;62(2):120–127. doi: 10.1203/pdr.0b013e3180a02e50.Atkinson DE, Brice-Bennett S, D’Souza SW. Antiepileptic medication during pregnancy: does fetal genotype affect outcome? Pediatr Res. 2007;62(2):120–127. doi: 10.1203/pdr.0b013e3180a02e50.Lankas GR, Wise LD, Cartwright ME. Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod Toxicol. 1998;12(4):457–463. doi: 10.1016/s0890-6238(98)00027-6.Lankas GR, Wise LD, Cartwright ME. Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod Toxicol. 1998;12(4):457–463. doi: 10.1016/s0890-6238(98)00027-6.Smit JW, Huisman MT, van Tellingen O, et al. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest. 1999;104(10): 1441–1447. doi: 10.1172/jci7963.Smit JW, Huisman MT, van Tellingen O, et al. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest. 1999;104(10): 1441–1447. doi: 10.1172/jci7963.Bliek BJ, van Schaik RH, van der Heiden I, et al. Maternal medication use, carriership of the ABCB1 3435C>T polymorphism and the risk of a child with cleft lip with or without cleft palate. Am J Med Genet A. 2009;149(10):2088–2092. doi: 10.1002/ajmg. a.33036.Bliek BJ, van Schaik RH, van der Heiden I, et al. Maternal medication use, carriership of the ABCB1 3435C>T polymorphism and the risk of a child with cleft lip with or without cleft palate. Am J Med Genet A. 2009;149(10):2088–2092. doi: 10.1002/ajmg. a.33036.Martinelli M, Carinci F, Morselli PG, et al. Study of ABCB1 multidrug resistance protein in a common orofacial malformation.Int J Immunopathol Pharmacol. 2011;24(2):1–5.Martinelli M, Carinci F, Morselli PG, et al. Study of ABCB1 multidrug resistance protein in a common orofacial malformation.Int J Immunopathol Pharmacol. 2011;24(2):1–5.Wang C, Xie L, Zhou K, et al. Increased risk for congenital heart defects in children carrying the ABCB1 gene C3435T polymorphism and maternal periconceptional toxicants exposure. PLoS ONE. 2013;8(7): e68807. doi: 10.1371/journal.pone.0068807.Wang C, Xie L, Zhou K, et al. Increased risk for congenital heart defects in children carrying the ABCB1 gene C3435T polymorphism and maternal periconceptional toxicants exposure. PLoS ONE. 2013;8(7): e68807. doi: 10.1371/journal.pone.0068807.Wang C, Zhou K, Xie L, et al. Maternal medication use, fetal 3435 C>T polymorphism of the ABCB1 gene, and risk of isolated septal defects in a Han Chinese population. Pediatric Cardiology. 2014;35(7):1132–1141. doi: 10.1007/s00246-014-0906-6.Wang C, Zhou K, Xie L, et al. Maternal medication use, fetal 3435 C>T polymorphism of the ABCB1 gene, and risk of isolated septal defects in a Han Chinese population. Pediatric Cardiology. 2014;35(7):1132–1141. doi: 10.1007/s00246-014-0906-6.

The authors declare that there are no conflicts of interest present.