2. I. II. III. 3. I. 4. Inadvertently drug exposurein Pregnancy
5. Unintended pregnancy00.511.522.53 (OR)Han JY et al. Birth
Defects Res A Clin Mol Teratol. 2005 Unintended pregnancy : 48% 6.
2002Perceived teratogenic risk afterinadvertently drug exposure 7.
N=3,384() % 98 2.9 126 3.7 427 12.6 2,368 70.0 208 6.2 42 1.2 591
17.5 68 2.0 141 4.2( . : 2004) 8. 2005 (34) : 4 9. OTIS 10. 11.
1588-7309 12. 13. 14. Percent 476 85% , , , , , , , , , , , , , , ,
, ,, , , , , , , , , , , , , , , , , ,, , , , , , , , , , ,, , , B,
MRI, 3 0.5% , 200ml , (6) 1500cc 3~4 4 0.7% 10 10, ( 1~2) , 6 10~14
, 6 1 0.1% - VDRL 4 0.7% ,,,12~16,? 62 11.1% , , , , , , , , 10
1.8% x-ray , X-ray , x-ray , (X-ray, CT, Mammography), Chest PA ?
560 100 15. 7,3298,3383,547 : 19,214 16. ( )2011 17. 18. 2012.03.14
~ 2012.04.19 N=384 19. II. 20. Historical case I.1960s Anxiolytic
and sedative drugMalformations : 20 percentSpecific time window :34
to 50 days menstrual ageUpper limb more seriously
affected.Phocomelia formed limbTHALIDOMIDE 21. THALIDOMIDE VICTIMS
22. Justice delayed is justice denied < >THALIDOMIDE APOLOGY
23. BendectinHistorical case II.1983.06.10 4 ()1987.07.16 4 () 24.
U.S.A. Temporal Trends for Limb Reduction Deformities, Bendectin
Salesand Hospitalizations for NVPBendectinHistorical case II. 25.
BendectinHistorical case II.Canada Temporal Trends for Limb
Reduction Deformities, Bendectin Salesand Hospitalizations for NVP
26. 1940-1971, 10milion pregnant women to support high risk
pregnancies.But no beneficial effects.Herbst(1971) : 8 cases of
vaginal clear cell adenocarcinomaIncomplete carcinogen:absolute
cancer risk 1 per1000, not related by doseno relationship between
location of tumor & timingof exposure.Structural and functional
abnormality:ectropion, adenosis malignant potential (2 fold
increase)Diethylstilbestrol (DES)Historical case III. 27. VSFDA
TERIS 28. Adverse influences to developingtissues depends on the
nature of agent Chemical characteristics :size, lipid
solubilityionization, protein bindingconcentration gradients
Placental barrier, BBB Metabolic capability- maternal,
placental,embryo/fetal, neonatal 29. Teratogenesis followsa
toxicological dose response
curve%ofsurvivorswithRdproductivetoxicityDose of Teratogen or
mutagenBackground incidence ofHuman reproductive
toxicityTeratogenesisMutagenesisR.L. Brent 2001030100 30. Critical
period of Development-prenatal 31. Period of developmental
susceptibility& Deviant developmentGerm
cellDevelopmentOrganogenesis Fetal period Neonatal period
AdolescenceFertilization Birth Sexual MaturityPrenatal/Neonatal
deathStructural abnormalitiesFunctional deficitsAltered
growthCarcinogenesis 32. Most teratogens have a confined groupof
congenital malformations MTX: growth retardation, microsephaly,
meningomyelocele,mental retardation, hydrocephalus Coumarine
derivatives: nasal hypoplasia, stippling of secondaryepiphysis,
IUGR Alcohol: Fetal alcohol syndrome DES : Clear cell
adenocarcinoma, adenosis, genital abnomalities 33. FDA
classificationA Controlled Studies show no riskB No evidence of
risk in humansC Risk cannot be ruled outD Positive evidence of
riskX Contraindicated in pregnancyFrom 1979 34. Nava-Ocampo AA et
al 2007Graphical representation of risk ofdrugs in pregnancyTERIS
35. 36. 32 G2 P0 5 . . (Oral contraceptives)[ 1] 37. FDA : X (Oral
contraceptives) 38. 33 G1P0 6 4T/day ?Misoprostol :[ 2] 39.
Misoprostol 40. Reprotox Quick take: Misoprostol use during early
pregnancy has beenassociated with abortion and with congenital
malformations in surviving infants.A meta-analysis concluded that
misoprostol use in early pregnancyincreases the risk of Moebius
sequence and transverse terminal limbdefects. 41. Moebius
syndromeBMJ Case Rep. 2009 42. BMJ Case Rep. 2009 43. While there
is no doubt that misoprostol is a cause of Mebius sequence,
theabsolute risk is very minimal, and in our prospective series-not
a single casewas found. There is however one case described in the
literature.I believe the advice should mention a very small risk.
Some of the features maybe detected by detailed ultrasound.All the
bestgidiGideon Koren MD, FRCPC, FACMTDirector, The Motherisk
ProgramThe Hospital for Sick Children,Professor of
Pediatrics,Pharmacology, Pharmacy and Medical GeneticsThe
University of Toronto, 44. III. 45. Q : Pentothal(thiopental
sodium),Propofol FDA . ,FDA ., ? . 46. Pentothal(thiopental sodium)
Ultrashort-acting, barbiturate sedative Used in the induction phase
of anesthesiaPharmacokinetics :T1/2 : 3-8hoursMW : 264 g/molProtein
binding 60-96%Bioavailability : variable 47. Quick take: Based on
experimental animal studies andhuman experience, thiopental is not
anticipated toincrease the risk of congenital anomalies.Pregnancy
Risk Category : C 48. Thiopental did not increase congenital
anomalies interatology studies in rats and micePersaud TVN 1965,
Tanimura T et al 1967The Collaborative Perinatal Project : the
frequency ofcongenital anomalies was not increased in children
of152 women treated with thiopental during the first 4lunar months
of pregnancy Friedman JM 1988 49. Propofol frequently used drug to
induce anesthesia sedation for diagnostic & therapeutic
proceduresPharmacokinetics :T1/2 : 30-60minMW : 264 g/molVd 60
l/kgProtein binding 99%Bioavailability : variable 50. Quick take:
Based on experimental animal studies, induction ofanesthesia with
propofol during pregnancy is not expected toincrease the risk of
congenital malformations.Pregnancy Risk Category : B 51. Q :
Succinylcholine, Rocuronium,Vecuronium ? 52.
SuccinylcholineShort-term muscle relaxation in anesthesiafor
facilitation of endotracheal intubationPharmacokinetics :T1/2 :
unknownMW : 290 g/molBioavailability : NAProtein binding :
unknownExcretion : Renal 53. Quick take: Succinylcholine has not
been associated withadverse effects on the fetus.Pregnancy Risk
Category : C 54. No malformations were observed among 26
childrenborn to women treated with succinylcholine duringthe first
four lunar months of pregnancy in theCollaborative Perinatal
Project(Heinonen et al., 1977). No animal teratology studies of
succinylcholinehave been published 55. Rocuronium an muscle
relaxant used in modernanesthesia, to facilitate
endotrachealintubationPharmacokinetics :T1/2 : 66-80minMW : 557
g/molProtein binding : ~30%Bioavailability : NAExcretion : bile
& urine 56. Quick take: A rat study did not suggest an increase
incongenital anomaly risk with rocuronium. Publishedhuman
experience in pregnancy has been restricted to usefor cesarean
section.Pregnancy Risk Category : C 57. a muscle relaxant to
facilitate endotracheal intubation& to provide skeletal muscle
relaxation during surgeryVecuroniumPharmacokinetics :T1/2 :
51-80minMW : 557 g/molBioavailability : 100%(IV)Protein binding : ?
%Excretion : fecal and renal 58. Quick take: Vecuronium has been
used during late humanpregnancy without apparent adverse effects on
thefetus. There are no data on early human pregnancy effectsof this
agent.Pregnancy Risk Category : C 59. No animal teratology studies
of vecuronium have beenpublished.Vecuronium has been administered
directly to thefetus(17 cases) at 22~35 weeks to facilitate
intrauterinetransfusion. No adverse fetal effect of such
treatmentwas observed. (Leveque et al., 1992) Use of vecuronium
during maternal anesthesia forcesarean section has not been
associated with anyclinically important adverse effect on the
newborn infant.(Hawkins et al., 1990, Iwama et al., 1999) 60. Q :
Sugammadex
?http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4346s1-01-Schering-Plough-corebackup.pdf
61. Sugammadex an agent for reversal of neuromuscular blockade
byrocuronium in general anesthesiaPharmacokinetics :T1/2 : 2.2
hoursMW : 2,178 g/molLipophilic core & hydrophilic
peripheryBioavailability : ? %Protein binding : low %Excretion :
renal 62. Pregnancy risk category : ? Placental transfer :< 2-6%
in rat and rabbit No relevant reproductive toxicityor
teratogenicitySugammadexhttp://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4346s1-01-Schering-Plough-corebackup.pdf
63. Q : esmolol, labetalol, nicardipine, ACE inhibitor ? 64.
Esmolol a cardioselective beta receptor blocker Ultra short-acting
beta blocker with low lipid solubilityPharmacokinetics :T1/2 : 9
minMW : 295 g/molBioavailability : poorProtein binding : 60
%Excretion : renal 65. Quick take: Esmolol is a beta-blocker and
may producesigns of beta blockade in the fetus after treatment of
themother. Ex) bradycardiaPregnancy Risk Category : C 66. a mixed
alpha/beta adrenergic antagonistLabetalolPharmacokinetics :T1/2 :
6-8hoursMW : 328 g/molBioavailability : 40%Protein binding :
50%Excretion : urine 67. Quick take: Based on experimental animal
studies andhuman reports, labetalol therapy does not appear
toincrease the risk of congenital anomaliesPregnancy Risk Category
: C 68. a typical calcium channel
blockerNicardipinePharmacokinetics :T1/2 : 8.6 hoursMW : 479
g/molBioavailability : 35%Protein binding : >95%Excretion : ?
69. Quick take: Nicardipine and other calcium channel blockers
mayinterfere with embryo development in experimental animal
species.Human pregnancy outcome data after exposure are not
adequateto assess possible risk. Later pregnancy use for tocolysis
orhypertension has sometimes been associated with
pulmonaryedema.Pregnancy Risk Category : C 70. an ACE
inhibitorCaptoprilPharmacokinetics :T1/2 : 1.9 hoursMW : 217
g/molBioavailability : 70-75 %Protein binding : 30%Excretion :
renal 71. Quick take: Captopril is not used during the secondand
third trimester of pregnancy because ofassociated fetal oliguria,
skull defects, and death.Pregnancy Risk Category : C in the 1st
trimesterD in the 2nd & 3rd trimester 72. Valsartana new
angiotensin II receptor antagonistPharmacokinetics :T1/2 : 9
hoursMW : 435 g/molBioavailability : 23%Protein binding :
97%Excretion : renal and biliary 73. Quick take: Valsartan is
believed to have potential for adversepregnancy effects consistent
with ACE inhibitor embryopathy,featuring oligohydramnios, abnormal
development, and fetaldeath.Pregnancy Risk Category : C in the 1st
trimesterD in the 2nd & 3rd trimester 74. Q : Benzodiazepine ?
75. Diazepam a benzodiazepine drugPharmacokinetics :T1/2 : 43
hoursMW : 285 g/molBioavailability : 100%Protein binding : 99
%Excretion : renal 76. Quick take: Diazepam increases the incidence
of cleft palate in mice. Mosthuman studies do not show an increase
in cleft palate or otherdefects in babies exposed during pregnancy.
A neonatalwithdrawal syndrome has been described. It may be
preferable to usebenzodiazepines that are less likely to accumulate
in the fetus and infantsuch as lorazepam .Pregnancy Risk Category :
D 77. a short-acting benzodiazepineAlprazolamPharmacokinetics :T1/2
: 11-15 hoursMW : 308 g/molBioavailability : 80-90 %Protein binding
: ? %Excretion : renal 78. Quick take: Human experience with
alprazolam does not suggestan increase in congenital anomaly risk.
Experimental animalstudies did not show an increase in birth
defects except with very highdose exposure. Withdrawal symptoms may
occur after pregnancy orlactation exposure to
benzodiazepines.Pregnancy Risk Category : D 79. Q : Ketorolac ? 80.
Ketorolac a NSAID for short-term managementof moderate to severe
painPharmacokinetics :T1/2 : 3.5-9.2 hoursMW : 255
g/molBioavailability : 100%Protein binding : 99 %Excretion : renal
and biliary 81. Quick take: Based on experimental animal studies,
ketorolac isnot expected to increase the risk of congenital
anomalies.Nonsteroidal anti-inflammatory drugs are avoided in
laterpregnancy due to concerns about constriction of the
ductusarteriosus.Pregnancy Risk Category : C in the 1st trimesterD
in the 2nd & 3rd trimesterLactation Risk Category : L2 (safer)
82. Q : CO2 insufflation ? 83. CO2 insufflationProperties :MW :
40.01 g/molAppearance : colorless gasOdor : odorless 84. When given
at 6% to pregnant rats, carbon dioxideinduced cardiac malformations
in the offspring(Haring, 1960) Exposure to 10-13% CO2 was
associated with vertebraldefects in rabbits (HSDB , 1997) Maternal
and fetal effects of laparoscopic insufflation inthe gravid baboon
: mothers and fetuses had no adverseeffects at an IAP of 10 mm Hg,
but may have significantcardiovascular and respiratory alterations
associated withIAP of 20 mm Hg. (Reedy MB, 1995)IN ANIMAL 85.
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
tocolyticsused. The resultant children were then monitored, and
noevidence of developmental or physical abnormalities wasdetected
during the study period.(Rizzo AG, 2003)IN HUMAN 86. : [ 1588-7309
()] 87. !!!
