제17차 대한산과마취과학회 강의

1. 한국마더세이프전문상담센터
한정열
마취약물과 태아독성
2013.6.15대한산과마취학회

2. I. 한국마더세이프전문상담센터 소개
II. 임신중 약물
III. 마취약물과 태아독성
내 용

3. I. 한국마더세이프전문상담센터

4. Inadvertently drug exposure
in Pregnancy

5. Unintended pregnancy
0
0.5
1
1.5
2
2.5
3
알코올 흡연 방사선 약물
노출 빈도 (OR)
Han JY et al. Birth Defects Res A Clin Mol Teratol. 2005
 Unintended pregnancy : 48%

6. 한정렬 등 대한산부회지 2002
Perceived teratogenic risk after
inadvertently drug exposure

7. 인공임신중절 이유 N=3,384(명) %
건강문제 부모의 건강문제 98 2.9
태아의 건강문제 126 3.7
임신 중 약물복용 427 12.6
가족계획 더 이상 자녀를 원치 않아서 2,368 70.0
터울 조절을 위해서 208 6.2
원하는 태아의 성별이 아니어서 42 1.2
사회경제적 이유 경제적 어려움 591 17.5
미성년자 혹은 혼인상의 문제 68 2.0
기타 141 4.2
(김해중 등. 인공임신중절 실태조사 및 종합대책수립: 보건복지부 2004년)
인공임신중절의 이유

8. “태아동산”
약물로 인한 인공임신중절 2005년 기준(34만건) : 4만건

9. OTIS

10. 한국마더세이프전문상담센터

12. 한국마더세이프전문상담센터
☎1588-7309

13. 서울 및 지역거점센터의 네트워크 구축 및 활성화

14. 서울 및 지역거점센터의 스텝 및 상담원

15. 상담 사례들
종류 횟수 Percent 사 례
약물 476 85% 가슴확대술, 간수치상승, 간질, 감기, 구충제, 갑상선항진증, 게실염, 결핵, 고
혈압, 골반염, 공황장애, 구충제, 근육통, 다이어트, 기관지염, 눈다래끼, 두드러기,
두통, 루푸스, 류마티스관절염, 멀미, 머릿니, 무좀, 방광염, 변비, 부비동염, 불면
증, 사후피임약, 소화불양, 손목통증, 수면내시경, 수면제, 습진, 아토피, 여드름,
우울증, 위내시경, 유선염, 이석증, 입덧, 치과치료, 장염, 중이염, 질염, 천식, 피임,
허리디스크, 화상, 후두염, B형간염, MRI조영제, 헬리코박터균
음주 3 0.5% 음주후 수유 언제부터 가능한지, 모유수유중 맥주 200ml 마심, 임신초반(6주) 하
루 1500cc의 맥주를 주 3~4회 마심
흡연 4 0.7% 흡연 10년전 부터 하루 10개피, 임신중 흡연(하루 1~2개피)이 아이에 영향이 있는
지, 6년동안 하루 10~14개피 흡연, 6주초까지
감염 1 0.1% 중환자실에서 근무하는 간호사- 손에 상처가 있었는데 VDRL환자의 혈액이 팔에
튀었고 며칠후 피부에 뭐가 나기 시작함
유해물질 4 0.7% 파마,염색,비듬,12~16주사이염색,펌을했어요괜찮을까요?
산과지식 62 11.1% 모유수유 중단, 방법, 혼합수유, 수유시 영양제, 임신중 영양제, 수유자세, 유두통증,
젖양 늘리는방법, 피임방법
방사선 10 1.8% 계획중 다리골절로 x-ray 촬영하려하는데 괜찮은지, 첫아이 X-ray촬영시 간접촬영, 디
스크로 x-ray 촬영, 건강검진으로 방사선노출(X-ray, CT, Mammography), Chest PA
찍을 예정인데 괜찮나요?
계 560 100

16. 마더세이프전문상담센터의 연도별 상담건수
7,329건
8,338건
3,547건 누적상담건수 : 19,214건

17. 지역별 마데세이프 콜 분포 (중앙 콜센터)
2011

18. 상담종류별 상담건수 분포

19. 마더세이프 콜의 인지 경로
2012.03.14 ~ 2012.04.19 N=384

20. II. 임신 중 약물

21. Historical case I.
1960’s Anxiolytic and sedative drug
Malformations : 20 percent
Specific time window :
34 to 50 days menstrual age
Upper limb more seriously affected.
Phocomelia formed limb
THALIDOMIDE

22. THALIDOMIDE VICTIMS
『구족화가 앨리슨래퍼와 그녀의 아들 패리스』

23. Justice delayed is justice denied <영국 선데이타임즈>
THALIDOMIDE APOLOGY

24. Bendectin
Historical case II.
1983.06.10 경향신문 4면 사회 기사(뉴스)
1987.07.16 경향신문 4면 사회 기사(뉴스)

25. U.S.A. Temporal Trends for Limb Reduction Deformities, Bendectin Sales
and Hospitalizations for NVP
Bendectin
Historical case II.

26. Bendectin
Historical case II.
Canada Temporal Trends for Limb Reduction Deformities, Bendectin Sales
and Hospitalizations for NVP

27. 1940-1971, 10milion pregnant women to “support” high risk pregnancies.
But no beneficial effects.
Herbst(1971) : 8 cases of vaginal clear cell adenocarcinoma
Incomplete carcinogen:
absolute cancer risk 1 per1000, not related by dose
no relationship between location of tumor & timing
of exposure.
Structural and functional abnormality:
ectropion, adenosis – malignant potential (2 fold increase)
Diethylstilbestrol (DES)
Historical case III.

28. 임신 중 약물 안전성 평가 및 체계
VS
FDA TERIS

29. Adverse influences to developing
tissues depends on the nature of agent
 Chemical characteristics :
size, lipid solubility
ionization, protein binding
concentration gradients
 Placental barrier, BBB
 Metabolic capability- maternal, placental,
embryo/fetal, neonatal

30. Teratogenesis follows
a toxicological dose response curve%ofsurvivorswith
Rdproductivetoxicity
Dose of Teratogen or mutagen
Background incidence of
Human reproductive toxicity
Teratogenesis
Mutagenesis
R.L. Brent 2001
0
30
100

31. Critical period of Development-prenatal

32. Period of developmental susceptibility
& Deviant development
Germ cell
Development
Organogenesis Fetal period Neonatal period Adolescence
Fertilization Birth Sexual Maturity
Prenatal/Neonatal death
Structural abnormalities
Functional deficits
Altered growth
Carcinogenesis

33. Most teratogens have a confined group
of congenital malformations
• MTX: growth retardation, microsephaly, meningomyelocele,
mental retardation, hydrocephalus
• Coumarine derivatives: nasal hypoplasia, stippling of secondary
epiphysis, IUGR
• Alcohol: Fetal alcohol syndrome
• DES : Clear cell adenocarcinoma, adenosis, genital abnomalities

34. 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
From 1979

35. Nava-Ocampo AA et al 2007
Graphical representation of risk of
drugs in pregnancy
TERIS

36. 사례로 본 임신 중 약물상담

37. 32세 G2 P0
생리 연장 위해서 임신 5주경까지
마이보라를 복용하였음.
아기만 괜찮다면 낳고 싶습니다.
경구용 피임약 (Oral contraceptives)
[임신부 사례 1]

38. FDA : X
경구용 피임약 (Oral contraceptives)

39. 33세 G1P0 임신 6주
임신인지 모른 상태에서 위궤양으로
미소프로스톨정 4T/day 복용
태아에 영향을 미치지 않을지요?
Misoprostol 증례 :
[임신부 사례 2]

40. Misoprostol

41. Reprotox® Quick take: Misoprostol use during early pregnancy has been
associated with abortion and with congenital malformations in surviving infants.
A meta-analysis concluded that misoprostol use in early pregnancy
increases the risk of Moebius sequence and transverse terminal limb
defects.

43. Moebius syndrome
BMJ Case Rep. 2009

44. BMJ Case Rep. 2009

45. While there is no doubt that misoprostol is a cause of Mebius sequence, the
absolute risk is very minimal, and in our prospective series-not a single case
was found. There is however one case described in the literature.
I believe the advice should mention a very small risk. Some of the features may
be detected by detailed ultrasound.
All the best
gidi
Gideon Koren MD, FRCPC, FACMT
Director, The Motherisk Program
The Hospital for Sick Children,
Professor of Pediatrics,Pharmacology, Pharmacy and Medical Genetics
The University of Toronto,

46. III. 마취약물과 태아독성

47. Q : 마취유도제 Pentothal(thiopental sodium),
Propofol 현재 유럽에서 마취유도제로 쓰이지만 미
국에선 FDA 승인이 나지 않은 약물입니다. 따라서,
FDA 미승인 이므로 쓰지 말아야 한다는 의견과 마취
유도제로 별문제 없다는 의견이 있습니다.
또한, 태아에게 안전성이 입증되어 있는지요? 이 부
분에 대해 약물독성학적 입장에서의 의견을 주시면
좋겠습니다.

48. Pentothal(thiopental sodium)
 Ultrashort-acting, barbiturate sedative
 Used in the induction phase of anesthesia
Pharmacokinetics :
T1/2 : 3-8hours
MW : 264 g/mol
Protein binding 60-96%
Bioavailability : variable

49. Quick take: Based on experimental animal studies and
human experience, thiopental is not anticipated to
increase the risk of congenital anomalies.
Pregnancy Risk Category : C

50. Thiopental did not increase congenital anomalies in
teratology studies in rats and mice
Persaud TVN 1965, Tanimura T et al 1967
The Collaborative Perinatal Project : the frequency of
congenital anomalies was not increased in children of
152 women treated with thiopental during the first 4
lunar months of pregnancy Friedman JM 1988

51. Propofol
 frequently used drug to induce anesthesia
 sedation for diagnostic & therapeutic procedures
Pharmacokinetics :
T1/2 : 30-60min
MW : 264 g/mol
Vd 60 l/kg
Protein binding 99%
Bioavailability : variable

52. Quick take: Based on experimental animal studies, induction of
anesthesia with propofol during pregnancy is not expected to
increase the risk of congenital malformations.
Pregnancy Risk Category : B

53. Q : Succinylcholine, Rocuronium,
Vecuronium
산과 영역에서 많이 쓰이는 근이완제 임
태아에 미치는 독성은 어떤가요?

54. Succinylcholine
Short-term muscle relaxation in anesthesia
for facilitation of endotracheal intubation
Pharmacokinetics :
T1/2 : unknown
MW : 290 g/mol
Bioavailability : NA
Protein binding : unknown
Excretion : Renal

55. Quick take: Succinylcholine has not been associated with
adverse effects on the fetus.
Pregnancy Risk Category : C

56.  No malformations were observed among 26 children
born to women treated with succinylcholine during
the first four lunar months of pregnancy in the
Collaborative Perinatal Project
(Heinonen et al., 1977)
.
 No animal teratology studies of succinylcholine
have been published

57. Rocuronium
 an muscle relaxant used in modern
anesthesia, to facilitate endotracheal
intubation
Pharmacokinetics :
T1/2 : 66-80min
MW : 557 g/mol
Protein binding : ~30%
Bioavailability : NA
Excretion : bile & urine

58. Quick take: A rat study did not suggest an increase in
congenital anomaly risk with rocuronium. Published
human experience in pregnancy has been restricted to use
for cesarean section.
Pregnancy Risk Category : C

59. a muscle relaxant to facilitate endotracheal intubation
& to provide skeletal muscle relaxation during surgery
Vecuronium
Pharmacokinetics :
T1/2 : 51-80min
MW : 557 g/mol
Bioavailability : 100%(IV)
Protein binding : ? %
Excretion : fecal and renal

60. Quick take: Vecuronium has been used during late human
pregnancy without apparent adverse effects on the
fetus. There are no data on early human pregnancy effects
of this agent.
Pregnancy Risk Category : C

61.  No animal teratology studies of vecuronium have been
published.
Vecuronium has been administered directly to the
fetus(17 cases) at 22~35 weeks to facilitate intrauterine
transfusion. No adverse fetal effect of such treatment
was observed. (Leveque et al., 1992)
 Use of vecuronium during maternal anesthesia for
cesarean section has not been associated with any
clinically important adverse effect on the newborn infant.
(Hawkins et al., 1990, Iwama et al., 1999)

62. Q : Sugammadex의 태아독성 어떤가요?
http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4346s1-01-Schering-Plough-corebackup.pdf

63. Sugammadex
 an agent for reversal of neuromuscular blockade by
rocuronium in general anesthesia
Pharmacokinetics :
T1/2 : 2.2 hours
MW : 2,178 g/mol
Lipophilic core & hydrophilic periphery
Bioavailability : ? %
Protein binding : low %
Excretion : renal

64.  Pregnancy risk category : ?
 Placental transfer :
< 2-6% in rat and rabbit
 No relevant reproductive toxicity
or teratogenicity
Sugammadex
http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4346s1-01-Schering-Plough-corebackup.pdf

65. Q : 혈압강하제 esmolol, labetalol, nicardipine,
그리고 ACE inhibitor는 태아에 어떤 영향을
줄 수 있나요?

66. Esmolol
 a cardioselective beta receptor blocker
 Ultra short-acting beta blocker with low lipid solubility
Pharmacokinetics :
T1/2 : 9 min
MW : 295 g/mol
Bioavailability : poor
Protein binding : 60 %
Excretion : renal

67. Quick take: Esmolol is a beta-blocker and may produce
signs of beta blockade in the fetus after treatment of the
mother. Ex) bradycardia
Pregnancy Risk Category : C

68. a mixed alpha/beta adrenergic antagonist
Labetalol
Pharmacokinetics :
T1/2 : 6-8hours
MW : 328 g/mol
Bioavailability : 40%
Protein binding : 50%
Excretion : urine

69. Quick take: Based on experimental animal studies and
human reports, labetalol therapy does not appear to
increase the risk of congenital anomalies
Pregnancy Risk Category : C

70. a typical calcium channel blocker
Nicardipine
Pharmacokinetics :
T1/2 : 8.6 hours
MW : 479 g/mol
Bioavailability : 35%
Protein binding : >95%
Excretion : ?

71. Quick take: Nicardipine and other calcium channel blockers may
interfere with embryo development in experimental animal species.
Human pregnancy outcome data after exposure are not adequate
to assess possible risk. Later pregnancy use for tocolysis or
hypertension has sometimes been associated with pulmonary
edema.
Pregnancy Risk Category : C

72. an ACE inhibitor
Captopril
Pharmacokinetics :
T1/2 : 1.9 hours
MW : 217 g/mol
Bioavailability : 70-75 %
Protein binding : 30%
Excretion : renal

73. Quick take: Captopril is not used during the second
and third trimester of pregnancy because of
associated fetal oliguria, skull defects, and death.
Pregnancy Risk Category : C in the 1st trimester
D in the 2nd & 3rd trimester

74. Valsartan
a new angiotensin II receptor antagonist
Pharmacokinetics :
T1/2 : 9 hours
MW : 435 g/mol
Bioavailability : 23%
Protein binding : 97%
Excretion : renal and biliary

75. Quick take: Valsartan is believed to have potential for adverse
pregnancy effects consistent with ACE inhibitor embryopathy,
featuring oligohydramnios, abnormal development, and fetal
death.
Pregnancy Risk Category : C in the 1st trimester
D in the 2nd & 3rd trimester

76. Q : Benzodiazepine계 약물 임신초기에 노출 시
언청이 발생과 관련이 있는가요?

77. Diazepam
 a benzodiazepine drug
Pharmacokinetics :
T1/2 : 43 hours
MW : 285 g/mol
Bioavailability : 100%
Protein binding : 99 %
Excretion : renal

78. Quick take: Diazepam increases the incidence of cleft palate in mice. Most
human studies do not show an increase in cleft palate or other
defects in babies exposed during pregnancy. A neonatal
withdrawal syndrome has been described. It may be preferable to use
benzodiazepines that are less likely to accumulate in the fetus and infant
such as lorazepam .
Pregnancy Risk Category : D

79.  a short-acting benzodiazepine
Alprazolam
Pharmacokinetics :
T1/2 : 11-15 hours
MW : 308 g/mol
Bioavailability : 80-90 %
Protein binding : ? %
Excretion : renal

80. Quick take: Human experience with alprazolam does not suggest
an increase in congenital anomaly risk. Experimental animal
studies did not show an increase in birth defects except with very high
dose exposure. Withdrawal symptoms may occur after pregnancy or
lactation exposure to benzodiazepines.
Pregnancy Risk Category : D

81. Q : 진통관리에 쓰이는 Ketorolac은 태아 및
모유수유아에 어떤 영향을 줄 수 있나요?

82. Ketorolac
 a NSAID for short-term management
of moderate to severe pain
Pharmacokinetics :
T1/2 : 3.5-9.2 hours
MW : 255 g/mol
Bioavailability : 100%
Protein binding : 99 %
Excretion : renal and biliary

83. Quick take: Based on experimental animal studies, ketorolac is
not expected to increase the risk of congenital anomalies.
Nonsteroidal anti-inflammatory drugs are avoided in later
pregnancy due to concerns about constriction of the ductus
arteriosus.
Pregnancy Risk Category : C in the 1st trimester
D in the 2nd & 3rd trimester
Lactation Risk Category : L2 (safer)

84. Q : 임신부에서 비산과적인 복강경수술시 사용하는
CO2 insufflation시 태아에 문제되지 않나요?

85. CO2 insufflation
Properties :
MW : 40.01 g/mol
Appearance : colorless gas
Odor : odorless

86.  When given at 6% to pregnant rats, carbon dioxide
induced cardiac malformations in the offspring
(Haring, 1960)
 Exposure to 10-13% CO2 was associated with vertebral
defects in rabbits (HSDB , 1997)
 Maternal and fetal effects of laparoscopic insufflation in
the gravid baboon : mothers and fetuses had no adverse
effects at an IAP of 10 mm Hg, but may have significant
cardiovascular and respiratory alterations associated with
IAP of 20 mm Hg. (Reedy MB, 1995)
IN ANIMAL

87. Laparoscopic surgery in pregnancy: long-term follow-up
 11 laparoscopic cases in pregnancy 16th to 28th week
 follow-up of 1 to 8 years
 No fetal distress or demise occurred, nor were any tocolytics
used. The resultant children were then monitored, and no
evidence of developmental or physical abnormalities was
detected during the study period.
(Rizzo AG, 2003)
IN HUMAN

88. 정 리
임신부에서 마취 약물 :
 대부분의 마취 관련 약물은 기형을 유발하지 않음
 기형유발 우려 약물에 노출 시 적절한 상담 필요
[☎ 1588-7309 (한국마더세이프전문상담센터)]

89. 감사합니다 !!!
임산부 약물상담 전문가 과정