1. 1 2010. 5. 11 고려의대 산부인과학 교실 홍 순 철

2. 2  28 세 G(0)P(0) 6 년간 valproic acid 로 치료 중이던 간질 (epilepsy) 여성이 12 주간의 무월경을 주소로 산부인과를 방문하였다. 최근 피임을 시행하지 않 았으며, 금일 Urine hCG 검사상 양성 소견을 보였 다. 이 여성의 임신전 가능한 조치는 무엇이었으 며, 현재 이 여성에게 어떻게 조언할 것인가 ?

3. 3 임신중 약물에 노출시 일반적인 오해는 무엇인 가 ? 임신을 계획하고 있는 여성이 피해야 할 기형유 발 약물에는 어떠한 것이 있고 어떻게 상담할 것 인가 ?

4. 4  Teratogenic drugs/chemicals 1. Accutane (isotretinoin) 2. Antiepilectic drugs: phenytoin, carbamazepine, valproic acid 3. Warfarin (coumarine) 4. ACE inhibitors 5. Misoprostol  Summary

5. 5 0.2%HIV/AIDS 7.1%Rubella seronegative At risk of getting pregnant Pregnant or gave birth 15.9%Received inadequate prenatal Care 69.0%Not taking Folic Acid 30.8%Obese 2.6%On teratogenic drugs 3.8%Diabetic 4.1%Had preexisting medical conditions 10.1%Consumed alcohol in pregnancy 11.0%Smoked during pregnancy Prevalence of Risk Factors

6. 6 When do birth defects occur?

7. 7  Two major mechanisms of teratogenesis 1. Disruption of folic acid metabolism Several congenital anomalies, including neural-tube defects, cardiac defects, cleft lip and palate, and even Down syndrome Hydantoin, carbamazepine, valproic acid, and phenobarbital all impair folate absorption or act as antagonists.

8. 8 2. Oxidative intermediates Hydantoin, carbamazepine, and phenobarbital are metabolized by microsomes to arene oxides or epoxides. Detoxified by cytoplasmic epoxide hydrolase, but because fetal epoxide hydrolase activity is weak, oxidative intermediates accumulate in fetal tissue. Carcinogenic, mutagenic, and other toxic effects

9. 9 검사 및 조치증명된 효과 엽산제 공급신경관 결손증을 2/3 이상 감소시킨다. 풍진 예방접종선천성 풍진 증후군을 예방한다. 당뇨 관리 당뇨를 앓고 있는 임신부에서 기형확률이 3 배정도 증가하므로 임신전 혈당 조절을 통해 기형확률을 낮춘다. 갑상선 기능저하증 치료 적절한 갑상선 기능조절은 태아의 정상적인 신경계 발달을 돕는다. B 형 간염 예방접종 태아감염을 예방하고, 엄마또한 B 형간염의 합병증 ( 간기능부전, 간경화, 간암 ) 으로부터 보호받을 수 있다. AIDS( 에이즈 ) 선별검사 환자와 보호자에게 에이즈와 관련된 치료 및 임신시기 등 적절한 정보제공 성병 선별검사 및 치료 클라미디아, 임질과 관련한 자궁외임신, 불임, 만성 골반통증을 줄이고 태아합병증 가능성을 줄인다. 항응고제 조절 Warfarin 과 같은 기형유발가능성있는 항응고제를 임신전에 다른 약제로 바꾼다. 항경련제 조절간질 (epilepsy) 여성의 경우 기형유발가능성이 적은 약제로 교환한다. Accutane 사용 조절 기형유발물질로 알려진 여드름 치료제의 일종인 Accutane 사용시 임신을 피하고, 임신전에 Accutane 사용을 중지한다. 금연 상담 임신전에 금연을 함으로서, 흡연과 관련된 조산, 저체중아 등의 임신 합병증을 예방한다. 알코올 상담 무심코 먹는 일회성 술이나 습관적인 알코올 노출을 피함으로서, 태아알콜증후군 또는 알코올 관련 기형을 예방한다. 비만 조절 임신전에 적절한 체중에 도달함으로써, 비만시 증가하는 신경관 결손증, 조산, 당뇨병, 제왕절개증가, 고혈압, 혈전증을 감소시킨다. 효과가 입증된 임신전 상담 및 조치 (ACOG, AAP)

10. FDA Classification A Controlled Studies show no risk B No evidence of risk in humans C Risk cannot be ruled out D Positive evidence of risk X Contraindicated in pregnancy 태아기형 발생 위험에 관한 약물상담 시 FDA 분류 : A, B, C, D, X 체계 적용은 오류.

11. The general consensus is that this FDA system is not ideal. Many drug ratings are based on animal data, case reports, and limited or no human data, with information rarely updated. The FDA acknowledges important limitations of the system. (Williams Obstetrics 2010) Most current & accurate information On-line reproductive toxicity services Such as Reprotox and TERIS

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15. 총 빈도 : 30,672 - 관동대 제일병원

16. 1. Careful delineation of clinical cases 2. Rare environmental exposure associated with rare defect, with at least three reported cases-easiest if defect is severe 3. Proof that agent acts on embryo or fetus, directly or indirectly 4. Proven exposure to agent at critical time(s) in prenatal development 5. Association must be biologically plausible 6. Consistent findings by two or more epidemiological studies of high quality : Control of confounding factors Sufficient numbers Exclusion of positive and negative bias factors Prospective studies, if possible Relative risk of three or more 7. Teratogenicity in experimental, animals, especially primates (Williams Obstetrics 2010)

17. 17 Human Teratogens ACE inhibitors(captopril, enalapril)Kanamycin AminopterinLithium AndrogensMetal (mercury, lead) Methimazole A-II antagonists b Methotrexate BusulfanMisoprostol CarbamazepinePenicillamine ChlorbiphenylsPhenytoin CocaineRadioactive iodine CoumarinsStreptomycin CyclophosphamideTamoxifen DanazolTetracycline Diethylstilbestrol (DES)Thalidomide EthanolTretinoin EtretinateTrimethadione IsotretinoinValproic acid

18. 18  Introduction 1. Accutane (isotretinoin) 2. Antiepilectic drugs: phenytoin, carbamazepine, valproic acid 3. Warfarin (coumarine) 4. ACE inhibitors 5. Misoprostol  Summary

19. 19 Isotretinoin(13-cis-retinoic acid, Accutane) → The treatment of cystic acne

20. 20

21. 21  Fetal adverse effects: Spontaneous abortion; deformities of cranium, ears (microtia, low-set ears, anotia), face, heart (TGA, TOF, VSD etc), limbs, liver; hydrocephalus, microcephalus. Cognitive defects Left-bilateral microtia or anotia, Right-flat, depressed nasal bridge and ocular hypertelorism

22. 22  Relative risk for teratogenicity 38 % risk; 80% of malformations are CNS  Clinical intervention Women discontinuing isotretinoin are advised not to conceive before 1 month has elapsed. Treatment of acne can be postponed Treated women should have an effective method of contraception.

23. 23 Message: Accutane® blister pack with the “avoid pregnancy” warning icons

24. 24 The treatment of psoriasis  Fetal adverse effect: Human case report- Craniofacial, ear and cardiac malformations Half-life of 120 days  Intervention Contraception for 2-3 years

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26. 26  Introduction 1. Accutane (isotretinoin) 2. Antiepilectic drugs: phenytoin, carbamazepine, valproic acid 3. Warfarin (coumarine) 4. ACE inhibitors 5. Misoprostol  Summary

27. 27 Fetal anticonvulsant (FAC) syndrome

28. 28  Anticonvulsants The most frequently reported defects: Orofacial clefts, Cardiac malformations and NTD The rate of major fetal malformations: Epilepsy & no medication: 3% Epilepsy with monotherapy: 3% Two/ three/ four medication: 5%/10%/20%

29. 29  Phenytoin  Fetal hydantoin syndrome Craniofacial anomalies: low nasal bridge, inner epicanthal folds, ptosis, strabismus, hypertelorism, large fontanel, Hypoplasia of distal phalanges and nails Microcephaly and mental retardation, Growth deficiency, developmental delay Cardiac defects, cleft palate and/or lip

30. 30 Fetal hydantoin syndrome: Upper facial features including upturned nose, mild midfacial hypoplasia, long upper lip with thin vermilion border. Lower distal digital hypoplasia.

31. 31  Phenytoin  Relative risk for teratogenicity 5-10% of typical syndrome(FHS) Relative risk for offspring IQ≤84 : 7  Clinical intervention Neurologist should consider changing to other medication Keep phenytoin concentration at lower effective levels Level II US Vit K to neonate

32. 32  Carbamazepine  Fetal adverse effects: Increased risk for NTDs (1%) Did not impair intelligence  Clinical intervention: Periconceptional folate Level II US Maternal/amniotic AFP

33. 33  Valproic acid  Fetal adverse effects Lumbosacral spina bifida with meningomyelocele CNS defects, microcephaly Cardiac defects Cognitive impairment (2% risk of NTD)  Clinical intervention: Level II US, Maternal/amniotic AFP

34. 34 Teratogenic Effects of Common Anticonvulsant Medications DrugAbnormalities DescribedAffectedPreg. Cat egory ValproateNeural-tube defects, clefts, skeletal abnormalities, developmental delay 1–2% with monotherapy, 9–12% with polytherapy D PhenytoinFetal hydantoin syndrome: craniofacial anomalies, fingernail hypoplasia, growth deficiency, develop mental delay, cardiac defects, clefts 5–11%D CarbamazepineFetal hydantoin syndrome, spina bifida1–2%D PhenobarbitalClefts, cardiac anomalies, urinary tract malformati ons 10–20%D LamotrigineInhibits dihydrofolate reductase, lowering fetal fol ate levels. Registry data suggest increased risk fo r clefts 4-fold with monotherapy, 10-fold with polytherapy C TopiramateRegistry data suggest increased risk for clefts2%C LevetiracetamTheoretical—skeletal abnormalities and impaired growth in animals at doses similar to or greater th an human therapeutic doses Too few cases reported to assess risk C

35. 35  Preconceptional counseling Proper seizure control is the primary goal Patient education as to the risks of uncontrolled seizures and the possible teratogenicity of AEDs. Seizure control should be achieved at least 6 months prior to conception The lowest effective dose of a single AED according to the type of epilepsy. The new AEDs are not recommended in pregnancy. If valproic acid is indicated, divided doses are preferred to avoid high levels of valproic acid in plasma. Folate supplementation: 5mg/day, 3 months before conception.

36. 36  Introduction 1. Accutane (isotretinoin) 2. Antiepilectic drugs: phenytoin, carbamazepine, valproic acid 3. Warfarin (coumarine) 4. ACE inhibitors 5. Misoprostol  Summary

37. 37

38. 38  Fetal adverse effects Fetal warfarin syndrome (warfarin embryopathy): nasal hypoplasia, chondrodysplasia punctata, brachydactyly, skull defects, abnormal ears, malformed eyes, CNS malformations, microcephaly, hydrocephalus, skeletal deformities, mental retardation, optic atrophy, spasticity, Dandy-Walker malformations Most susceptible period: GA 6-12 weeks 2 nd & 3 rd trimester: microcephaly, mental retardation, optic atrophy in addition to teratogenicity due to first trimester exposure.

39. 39 Chondrodysplasia punctataFetal warfarin syndrome

40. 40  Relative risk for teratogenicity: Malformations 16% Hemorrhages 3% Stillbirth 8%  Clinical intervention Switch to heparin

41. 41  Introduction 1. Accutane (isotretinoin) 2. Antiepilectic drugs: phenytoin, carbamazepine, valproic acid 3. Warfarin (coumarine) 4. ACE inhibitors 5. Misoprostol  Summary

42. 42  ACE inhibitors  Recent use: Tx of hypertension and congestive heart failure  Fetal adverse effects During the second or third trimesters: act on the renal and circulatory systems of exposed fetus → produce hypotension, anuria, death In a report on the use of captopril in 15 human pregnancies: two spontaneous abortions, two voluntary abortions(one of which demonstrated malformations), one intrauterine death at 28 weeks, two neonatal deaths with anuria three instance of neonatal distress attributed to premature delivery

43. 43  Introduction 1. Accutane (isotretinoin) 2. Antiepilectic drugs: phenytoin, carbamazepine, valproic acid 3. Warfarin (coumarine) 4. ACE inhibitors 5. Misoprostol  Summary

44. 44 Misoprostol (Cytotec, PGE1 analogue) → The treatment of peptic ulcer disease → Termination of early pregnancy

45. 45

46. 46  Fetal adverse effects Spontaneous abortion, fetal death (RR 3.15) Möbius syndrome-paralysis of sixth and seventh cranial nerves (OR 25.7) Transverse terminal limb defects, abnormalities of frontal and temporal bones in the skull, omphalocele, gastroschisis, bladder exstrophy  Clinical intervention Increase the awareness of teratogenicity of the drug.

47. 47 Möbius syndrome (paralysis of sixth and seventh cranial nerves)

48. 48 The use of retinoic acid (Accutane) is absolutely contraindicated in pregnancy, and treatment of acne can be postponed without risk to the mother. In epilepsy, patients should understand the risks associated uncontrolled seizures as well as the potential for teratogenicity of the anticonvulsive medication. Heparin, which does not cross the placenta, may substitute for warfarin during the first trimester. Misoprostol use is associated with abortion, fetal death and Möbius syndrome.

49. 49  28 세 G(0)P(0) 6 년간 valproic acid 로 치료 중이던 간질 (epilepsy) 여성이 12 주간의 무월경을 주소로 산부인과 를 방문하였다. 최근 피임을 시행하지 않았으며, 금일 Urine hCG 검사상 양성 소견을 보였다. 이 여성의 임신 전 가능한 조치는 무엇이었으며, 현재 이 여성에게 어 떻게 조언할 것인가 ? → 임신 최소 3 개월전부터는 엽산제 (5mg) 복용을 권유한 다. 하루 복용량을 나누어 투여한다. Valproic acid 는 임 신 1 분기 노출시 2% 에서 신경관 결손증 (NTD) 을 동반 한다. 따라서 임신 16 주경 MSAFP 검사와 초음파 검사를 시행 후 이상 소견시 양수 검사를 시행.

50. 50 경청해 주셔서 감사합니다.