Drugs in pregnancy

1. بنام خدا Drugs in pregnancy دارو ها و حاملگی

9. Teratogens • Teratogens are agents used during pregnancy that interfere with development and increase the incidence of congenital malformation: • neural tube defect • cleft lip/palate • cardiac defects and . . . . . . . . • Teratos =غول

10. Teratogenic risk • Baseline risk for major malformations • 3%

11. نقص خلقت مادر زادي حدود 3 در صد هنگام تولد و حدود 5 در صد پس از 5 سال اما و اما . . .

12. چرا رويان و جنين 1 - بسرعت در حال رشد است 2 - عبور داروها از جفت 3 - جنين با دارو چه ميكند 4 - دارو با رويان و جنين چه ميكند 5– اين يك تومور دارد كه تومور نيست

13. كليات خواص فيزيكوشيميايي داروها (وزن ملكولي – حل در چربي ...) سرعت عبور از جفت و در صدي كه به جنين ميرسد مدت مجاورت دارو با جنين نحوه پخش دارو در بدن جنين وضع و درجه رشد رويان و جنين

14. نقص خلقت مادر زادي لطفا به اين موضوعات توجه بفرماييد: • Exact identity and dose of the teratogen • Stage of embryogenesis • Genetic sensitivity of the mother and fetus

15. EMBRYOSرویان FETUS جنین

16. Embryonic period • Period of organogenesis: 2-8 weeks • Time of greatest susceptibility to teratogens • Critical stages for malformations of different organ systems during this period: • Neural tube closes by day 30 • Limb buds develop • Heart

17. Fetal period • Fetus less susceptible to teratogens but still susceptible to toxicity and behavioral teratogenicity • Some agents paradoxically cause more problems in 2nd trimester than in 1st: Varicella

18. Fetal period Birth defects: Oligohydramnios: NSAIDS ACE inhibitors Hypotension/ Cardiac arrhythmia/ Ischemia: Cocaine, phenytoin, anti-arrhythmics

20. مطالعه و بر رسي تراتوژنيك بودن داروها غالبا مطالعات حيواني است. هميشه نميتوان به آن تكيه كرد مطالعات انساني غالبا گزارش تك مورد است اثبات رابطه علت و معلولي آسان نيست

21. Factors determining teratogenic action Dose-response relationship: Every teratogen has a “no-effect” level. Agents are true teratogens only when they disrupt development at doses that are not toxic to the mother. Susceptibility depends on stage of development: Pre-implantation period = “all-or-none” period Organogenesis = 2-8 weeks post conception Fetal period = 9 weeks- delivery Genetic susceptibility

22. علل نقص خلقت مادر زادي فقط در حدود 50 در صد علت معلوم است عواملي كه شناخته اند (نا شناخته هم داريم) : محيطي - فيزيكي - اشعه - اكسيژن و عفونت ها ( تب - سرخجه ) مادر (ديابت – فشار خون – صرع – اعتياد و سن) پدر (پر فشاري خون - سن و ... كوچكترين اثري ندارد) ژنتيك دارو ها

23. اشعه ايكس • Max dose: 10 rads • CXR: 8 rads • Upper GI: 558 rads • IVP: 407 rads • BE: 805 rads • With large doses, if not lethal, get microcephaly and mental retardation

24. عفونت ها • Cytomegalovirus (CMV) • Most common congenital infection No effective therapy • Hydrocephaly, Microcephaly, chorioretinitis, cerebral calcification, symetrical IUGR, microphtalmos, brain damage, hearing loss • Rubella (SOR KHEH JEH) • Microcephaly, mental retardation, cataracts, congenital heart disease, • Cytolytic virus, all organs may be affected

25. عفونت ها • Syphilis • If severe: fetal demise with hydrops • If mild: detectable anomalies of skin, teeth and bones • Penicillin is effective • Toxoplasmosis • All organs mainly CNS, hydrocphaly, microcephaly, cerebral calcifications • Varicella (ABELEH MORGHAN) • Skin scarring, chorioretinitis, cataracts, microcephaly, hypoplasia of the hands and feet, muscle atrophy

26. Genetic Conditions: Chromosomal Abnormalities • Trisomy 21 (Down’s Syndrome) • Trisomy of other chromosomes

27. Critical Period Defect: Cleft Palate • Irreversible congenital abnormality affecting a critical period (palate development) during the embryonic and early fetal stages • May affect pituitary growth as the palate and anterior pituitary are derived from the same embryonic tissue.

28. Critical Period Defect: Anencephaly (absence of brain)

30. Autism A neurodegenerative disorder characterized by impairment in social interaction and communication. فرياد

31. ساير عوامل • Hyperthermia Increased neural tube defects (X 2.8) • Lead Increased abortion rate, stillbirth • Organic mercury Cerebral atrophy, microcephaly, mental retardation, spasticity, seizures, blindness

32. Examples of critical timing • Warfarin • critical period 6-9 weeks gestation • Tetracyclines • safe until 16 weeks • ACE inhibitors • probably safe until 14-16 weeks • NSAIDs • avoid from 30-32/40 until term

33. سد جفت مواد قابل حل در چربي براحتي عبور ميكنند مواد قابل حل در آب راحت عبور نميكنند موضوع اتصال به پروتيين هاي پلاسما

34. Factors determining teratogenic action of drugs Access to the embryo depends on : • lipid solubility • degree of ionisation • protein binding • surface available for diffusion • pH • molecular weight • MW >1000 do not readily cross placenta • MW less than 600 usually cross the placenta

35. FDA classification of drugsused in pregnancy • Category A • Drugs which have been taken by a large number of pregnant women of childbearing age without any proven increase frequency of malformations • Category B • Drugs that have been taken by only a limited number of pregnant women without an increase in frequency of malformation

36. FDA classification of drugsused in pregnancy • B1- studies in animals have not shown evidence of an increased occurrence of fetal damage • B2- Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage • B3- studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans

37. FDA classification of drugsused in pregnancy • Category C • Drugs, which owing to their pharmacological effects, have caused or may be suspected of causing , harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. • Category D • Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects

38. FDA classification of drugsused in pregnancy • Category X • Drugs that have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy • Examples: • Retinoic acid • Misoprostol • Ribavirin

39. Management • COUNSELLING • INVESTIGATION • APPROPRIATE REFERRAL پیشگیری

40. Investigation • Age ايشالا موباراك بادا • Family history, AFP • Ultrasound • Invasive testing : CVS • Follow-up

41. Teratogens and cardiac defects • Valproic acid , Carbamazepine • Thalidomide , Lithium , Phenytoin • Maternal diabetes • Amphetamines

42. Teratogens and skeletal defects • Valproic acid , Thalidomide • Cyclophosphamide • Fluconazole • Maternal diabetes

43. Teratogens and neural tube defects • Valproic acid , Carbamazepine • Maternal diabetes • Hyperthermia • Folate antagonists

44. Preconceptional counselling • Consider drug discontinuation • Try best single agent • Lifestyle modifications : • Sleep , diet • alcohol/cigarettes • Folate supplementation

45. “Drugs of choice” in pregnancy • Some drugs may be safe to take at one stage of pregnancy but not at other times • ACE inhibitors: safe in 1st trimester • Tetracyclines: safe until 17 weeks

46. آنتي بيوتيك ها • Penicillins, Erythromycin, Cyclosporines • no proven teratogenicity • Tetracycline • yellow discoloration decidous teeth • Steptomycin, kanamycin • Hearing loss, eight nerve damage • Gentamycin and vancomycin appear safe

47. Hypertension • Preferable drugs : • methyldopa • beta blockers • hydralazine • Drugs to be avoided if possible : • ACE inhibitors • Calcium channel blockers

48. Coughs, colds, allergies and fevers • Antihistamines are regarded as being safe for use during pregnancy • Ephedrine at usual doses is safe • Paracetamol is safe. • Hyperthermia (>390) may cause fetal damage, encourage patients to take paracetamol if they have a fever

49. Analgesia • Paracetamol and narcotic analgesics are safe for use during pregnancy • High doses of narcotics near term may result in neonatal withdrawal • Avoid aspirin and NSAIDs in last trimester (especially after 32 weeks) • bleeding • premature closure of ductus arteriosus

50. Epilepsy and pregnancy • Over 90% of pregnant patients using anti-convulsants now can expect favorable maternal and infant outcome • Variable effect of pregnancy on seizure frequency, but overall most women do not experience significant changes in seizure frequency • Some causes of increased seizure frequency • sleep deprivation • changes in free-drug levels • poor compliance with drugs • nausea/vomiting in first trimester • fear of anomalies