Фармакологическая безопасность при беременности: современные знания, практика и фармакоэпидемиологические подходы к изучению и признанию лекарственных средств с тератогенным риском

Одним из ключевых вопросов в акушерской практике остается отсутствие или фрагментарность информации о тератогенности большинства используемых беременными женщинами лекарственных средств (ЛС). Неопределенность в отношении тератогенных рисков существенно влияет на качество информации о препаратах, тем не менее консультирование пациенток позволяет прийти к более сбалансированному решению относительно их риска при беременности. Определение наиболее часто принимаемых ЛС (рецептурных или безрецептурных) в первом триместре гестации и повышение знаний об их эмбриофетальных рисках позволяют оптимизировать фармакотерапию во время беременности. Характеристика и эпидемиологический анализ возможных факторов, в частности ЛС, связанных с возникновением врожденных аномалий, имеют решающее значение для разработки профилактических мероприятий, оказывающих воздействие на распространенность дефектов.

1. Charlton RA, Neville AJ, Jordan S, et al. Healthcare databases in Europe for studying medicine use and safety during pregnancy. Pharmacoepidemiol Drug Saf. 2014;23(6):586-594. doi: 10.1002/pds.3613.

2. Mitchell AA. Systematic identification of drugs that cause birth defects: a new opportunity. N Engl J Med. 2003;349(26):2556- 2559. doi: 10.1056/NEJMsb031395.

3. Friedman JM. ABCDXXX: the obscenity of postmarketing surveillance for teratogenic effects. Birth Defects Res A Clin Mol Teratol. 2012;94(8):670-676. doi: 10.1002/bdra.23043.

4. 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.

5. Adam MP, Polifka JE, Friedman JM. Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet C Semin Med Genet. 2011;157C(3):175-182. doi: 10.1002/ajmg.c.30313.

6. Mitchell AA, Gilboa SM, Werler MM, et al. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol. 2011;205(1):51.e1-51.e8. doi: 10.1016/j.ajog.2011.02.029.

7. Lupattelli A, Spigset O, Twigg MJ, et al. Medication use in pregnancy: a cross-sectional, multinational web-based study. BMJ Open. 2014;4(2):e004365. doi: 10.1136/bmjopen-2013-004365.

8. Thorpe PG, Gilboa SM, Hernandez-Diaz S, et al. Medications in the first trimester of pregnancy: most common exposures and critical gaps in understanding fetal risk. Pharmacoepidemiol Drug Saf. 2013;22(9):1013-1018. doi: 10.1002/pds.3495.

9. Andrade SE, Raebel MA, Morse AN, et al. Use of prescription medications with a potential for fetal harm among pregnant women. Pharmacoepidemiol Drug Saf. 2006;15(8):546-554. doi: 10.1002/pds.1235.

10. Daw JR, Mintzes B, Law MR, et al. Prescription drug use in pregnancy: a retrospective, population-based study in British Columbia, Canada (2001-2006). Clin Ther. 2012;34(1):239-249.e2. doi: 10.1016/j.clinthera.2011.11.025.

11. Mitchell AA. Research challenges for drug-induced birth defects. Clin Pharmacol Ther. 2016;100(1):26-28. doi: 10.1002/cpt.374.

12. Friedman JM. Editorial in bed with the devil: recognizing human teratogenic exposures. Birth Defects Res. 2017;109(18):1407- 1413. doi: 10.1002/bdr2.1134.

13. Brent RL. Counseling women and men regarding exposures to reproductive and developmental toxicants before conception or women during pregnancy. Semin Fetal Neonatal Med. 2014;19(3):139- 152. doi: 10.1016/j.siny.2013.09.008.

14. Daston GP. Laboratory models and their role in assessing teratogenesis. Am J Med Genet C Semin Med Genet. 2011;157C (3):183- 187. doi: 10.1002/ajmg.c.30312.

15. Решетько ОВ, Луцевич КА, Клименченко НИ. Фармакологическая безопасность при беременности: принципы тератогенеза и тератогенность лекарственных средств // Педиатрическая фармакология. — 2016. — Т.13. — №2. — С. 105–115. [Reshetko OV, Lutsevich KA, Klimenchenko NI. Pharmacological safety during pregnancy: the principles of teratogenesis and teratogenicity of drugs. Pediatricheskaya farmakologiya — Pediatric pharmacology. 2016;13(2):105-115. (In Russ).] doi: 10.15690/pf.v13i2.1551.

16. Решетько ОВ, Луцевич КА, Санина ИИ. Фармакологическая безопасность при беременности: систематический обзор применения потенциально тератогенных лекарственных средств // Педиатрическая фармакология. — 2017. — Т.14. — №2. — С. 127–141. [Reshetko OV, Lutsevich KA, Sanina II. Pharmacological safety in pregnancy: a systematic review on the use of potentially teratogenic drugs. Pediatricheskaya farmakologiya — Pediatric pharmacology. 2017;14(2):127–141. (In Russ).] doi: 10.15690/pf.v14i2.1727.

17. Obican S, Scialli AR. Teratogenic exposures. Am J Med Genet C Semin Med Genet. 2011;157C(3):150-169. doi: 10.1002/ajmg.c.30310.

18. Feldkamp ML, Botto LD, Carey JC. Reflections on the etiology of structural birth defects: established teratogens and risk factors. Birth Defects Res A Clin Mol Teratol. 2015;103(8):652-655. doi: 10.1002/bdra.23392.

19. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295-300.

20. Shepard TH. Catalog of Teratogenic Agents. 13th ed. Baltimore, Md.: Johns Hopkins University Press, 2010.

21. Holmes LB. Human teratogens: update 2010. Birth Defects Res A Clin Mol Teratol. 2011;91(1):1-7. doi: 10.1002/bdra.20748.

22. Bleyl SB, Schoenwolf GC. What is the timeline of important events during pregnancy that may be disrupted by a teratogenic exposure? In: Hales B, Scialli A, Tassinari MS, eds. Teratology primer: Teratology society. 2nd ed. 2010. рр. 3-5.

23. Adam MP. The all-or-none phenomenon revisited. Birth Defects Res A Clin Mol Teratol. 2012;94(8):664-669. doi: 10.1002/bdra.23029.

24. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry. Reproductive and developmental toxicities — integrating study results to assess concerns [Accessed 25.10.2018]. September, 2011. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079240.pdf.

25. Briggs GG, Polifka J; Research Committee, Organization of Teratology Information Specialists. Better data needed from pregnancy registries. Birth Defects Res A Clin Mol Teratol. 2009;85(2):109-111. doi: 10.1002/bdra.20551.

26. Czeizel AE. Specified critical period of different congenital abnormalities: a new approach for human teratological studies. Congenit Anom (Kyoto). 2008;48(3):103-109. doi: 10.1111/j.1741-4520.2008.00189.x.

27. Rutledge JC. Developmental toxicity induced during early stages of mammalian embryogenesis. Mutat Res. 1997;396(1-2):113-127. doi: 10.1016/S0027-5107(97)00178-4.

28. Saitou M, Kagiwada S, Kurimoto K. Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development. 2012;139(1):15-31. doi: 10.1242/dev.050849.

29. Vassena R, Boué S, González-Roca E, et al. Waves of early transcriptional activation and pluripotency program initiation during human preimplantation development. Development. 2011;138(17):3699-3709. doi: 10.1242/dev.064741.

30. Siffel C, Czeizel AE. Study of developmental abnormalities and deaths after human zygote exposure. Mutat Res. 1995;334(3):293- 300. doi: 10.1016/0165-1161(95)90066-7.

31. Curley JP, Mashoodh R, Champagne FA. Epigenetics and the origins of paternal effects. Horm Behav. 2011;59(3):306-314. doi: 10.1016/j.yhbeh.2010.06.018.

32. Hoeltzenbein M, Weber-Schoendorfer C, Borisch C, et al. Pregnancy outcome after paternal exposure to azathioprine/6- mercaptopurine. Reprod Toxicol. 2012;34(3):364-369. doi: 10.1016/j.reprotox.2012.05.001.

33. Millsop JW, Heller MM, Eliason MJ, Murase JE. Dermatological medication effects on male fertility. Dermatol Ther. 2013;26(4):337- 346. doi: 10.1111/dth.12069.

34. Scialli AR, Buelke-Sam JL, Chambers CD, et al. Communicating risks during pregnancy: a workshop on the use of data from animal developmental toxicity studies in pregnancy labels for drugs. Birth Defects Res A Clin Mol Teratol. 2004;70(1):7-12. doi: 10.1002/bdra.10150.

35. Knudsen TB, Kavlock RJ, Daston GP, et al. Developmental toxicity testing for safety assessment: new approaches and technologies. Birth Defects Res B Dev Reprod Toxicol. 2011;92(5):413-420. doi: 10.1002/bdrb.20315.

36. Van Dyke DC, Ellingrod VL, Berg MJ, et al. Pharmacogenetic screening for susceptibility to fetal malformations in women. Ann Pharmacother. 2000;34(5):639-645. doi: 10.1345/aph.19218.

37. Augustine-Rauch KA. Predictive teratology: teratogenic riskhazard identification partnered in the discovery process. Curr Drug Metab. 2008;9(9):971-977. doi: 10.2174/138920008786485137.

38. Friedman JM. How do we know if an exposure is actually teratogenic in humans? Am J Med Genet Part C Semin Med Genet. 2011;157C(3):170-174. doi: 10.1002/ajmg.c.30302.

39. Eichler HG, Abadie E, Baker M, Rasi G. Fifty years after thalidomide; what role for drug regulators? Br J Clin Pharmacol. 2012;74(5):731-733. doi: 10.1111/j.1365-2125.2012.04255.x.

40. Mazer-Amirshahi M, Samiee-Zafarghandy S, Gray G, van den Anker JN. Trends in pregnancy labeling and data quality for US-approved pharmaceuticals. Am J Obstet Gynecol. 2014;211(6):690.e1–690.e11. doi: 10.1016/j.ajog.2014.06.013.

41. Food and Drug Administration, HHS. Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. Final rule. Fed Regist. 2014;79(233):72063–72103.

42. Ramoz LL, Patel-Shori NM. Recent changes in pregnancy and lactation labeling: retirement of risk categories. Pharmacotherapy. 2014;34(4):389-395. doi: 10.1002/phar.1385.

43. Peters SL, Lind JN, Humphrey JR, et al. Safe lists for medications in pregnancy: inadequate evidence base and inconsistent guidance from Web-based information, 2011. Pharmacoepidemiol Drug Saf. 2013;22(3):324-328. doi: 10.1002/pds.3410.

44. Zomerdijk IM, Ruiter R, Houweling LM, et al. Dispensing of potentially teratogenic drugs before conception and during pregnancy: a population-based study. BJOG. 2015;122(8):1119- 1129. doi: 10.1111/1471-0528.13128.

45. Eltonsy S, Martin B, Ferreira E, Blais L. Systematic procedure for the classification of proven and potential teratogens for use in research. Birth Defects Res A Clin Mol Teratol. 2016;106(4):285- 297. doi: 10.1002/bdra.23491.

46. Fisher B, Rose NC, Carey JC. Principles and practice of teratology for the obstetrician. Clin Obstet Gynecol. 2008;51(1):106-118. doi: 10.1097/GRF.0b013e318161d2c8.

47. Miller MT, Stromland K. Teratogen update: thalidomide: a review, with a focus on ocular findings and new potential uses. Teratology. 1999;60(5):306-321. doi: 10.1002/(SICI)1096-9926(199911)60:5<306::AID-TERA11>3.0.CO;2-Y.

48. Chan M, Wong IC, Sutcliffe AG. Prescription drug use in pregnancy: more evidence of safety is needed. Obstetrician Gynaecologist. 2012;14(2):87-92. doi: 10.1111/j.1744-4667.2012.00096.x.

49. Shahin I, Einarson A. Knowledge transfer and translation: examining how teratogen information is disseminated. Birth Defects Res A Clin Mol Teratol. 2011;91(11):956-961. doi: 10.1002/bdra.22851.

50. Conover EA, Polifka JE. The art and science of teratogen risk communication. Am J Med Genet Part C Semin Med Genet. 2011;157C(3):227-233. doi: 10.1002/ajmg.c.30308.

51. Widnes SF, Schjøtt J. Risk perception regarding drug use in pregnancy. Am J Obstet Gynecol. 2017;216(4):375-378. doi: 10.1016/j.ajog.2016.12.007.

52. Petersen EE, Rasmussen SA, Daniel KL, et al. Prescription medication borrowing and sharing among women of reproductive age. J Womens Health (Larchmt). 2008;17(7):1073-1080. doi: 10.1089/jwh.2007.0769.

53. van Gelder MM, de Jong-van den Berg LT, Roeleveld N. Drugs associated with teratogenic mechanisms. Part II: a literature review of the evidence on human risks. Hum Reprod. 2014;29(1):168-183. doi: 10.1093/humrep/det370.

54. Chambers CD. Value of the small cohort study including a physical examination for minor structural defects in identifying new human teratogens. Congenit Anom (Kyoto). 2011;51(1):16-20. doi: 10.1111/j.1741-4520.2010.00310.x.

55. Carey JC, Martinez L, Balken E, et al. Determination of human teratogenicity by the astute clinician method: review of illustrative agents and a proposal of guidelines. Birth Defects Res A Clin Mol Teratol. 2009;85(1):63-68. doi: 10.1002/bdra.20533.

56. Вишнева Е., Намазова-Баранова Л. Применение будесонида у кормящих грудью матерей, страдающих бронхиальной астмой. Педиатрическая фармакология. 2009;6(5):110-112.

57. Howard TB, Tassinari MS, Feibus KB, Mathis LL. Monitoring for teratogenic signals: pregnancy registries and surveillance methods. Am J Med Genet C Semin Med Genet. 2011;157C(3):209-214. doi: 10.1002/ajmg.c.30304.

58. Pedersen LH, Petersen OB, Nørgaard M, et al. Linkage between the Danish National Health Service Prescription Database, the Danish Fetal Medicine Database, and other Danish registries as a tool for the study of drug safety in pregnancy. Clin Epidemiol. 2016;8:91-95. doi: 10.2147/CLEP.S98139.

59. Ehrenstein V, Sorensen HT, Bakketeig LS, Pedersen L. Medical databases in studies of drug teratogenicity: methodological issues. Clin Epidemiol. 2010;2:37-43. doi: 10.2147/CLEP.S9304.

60. U.S. Department for Health Human Services, Food Drug Administration, Center for Drug Evaluation Research, Center for Biologics Evaluation Research. Guidance for industry: Establishing pregnancy exposure registries. Rockville [Accessed 25.10.2018]. August, 2002. Available from: http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthResearch/ UCM133332.pdf.

61. Gelperin K, Hammad H, Leishear K, et al. A systematic review of pregnancy exposure registries: examination of protocol-specified pregnancy outcomes, target sample size, and comparator selection. Pharmacoepidemiol Drug Saf. 2017;26(2):208-214. doi: 10.1002/pds.4150.

62. Espnes MG, Bjørge T, Engeland A. Comparison of recorded medication use in the Medical Birth Registry of Norway with prescribed medicines registered in the Norwegian Prescription Database. Pharmacoepidemiol Drug Saf. 2011;20(3):243-248. doi: 10.1002/pds.2085.

63. Завидова С., Намазова-Баранова Л., Тополянская С. Клинические исследования лекарственных препаратов в педиатрии: проблемы и достижения. Педиатрическая фармакология. 2010;7(1):6-14.

64. de Jonge L, de Walle HE, de Jong-van den Berg LT, et al. Actual use of medications prescribed during pregnancy: a cross-sectional study using data from a population-based congenital anomaly registry. Drug Saf. 2015;38(8):737-747. doi: 10.1007/s40264-015-0302-z.

65. de Jonge L, Garne E, Gini R, et al. Improving information on maternal medication use by linking prescription data to congenital anomaly registers: a EUROmediCAT Study. Drug Saf. 2015;38(11):1083-1093. doi: 10.1007/s40264-015-0321-9.