Unintended pregnancy00.511.522.53알코올 흡연 방사선 약물노출 빈도 (OR)Han JY et al. Birth Defects Res A Clin Mol Teratol. 2005 Unintended pregnancy : 48%
한정렬 등 대한산부회지 2002Perceived teratogenic risk afterinadvertently drug exposure
인공임신중절 이유 N=3,384(명) %건강문제 부모의 건강문제 98 2.9태아의 건강문제 126 3.7임신 중 약물복용 427 12.6가족계획 더 이상 자녀를 원치 않아서 2,368 70.0터울 조절을 위해서 208 6.2원하는 태아의 성별이 아니어서 42 1.2사회경제적 이유 경제적 어려움 591 17.5미성년자 혹은 혼인상의 문제 68 2.0기타 141 4.2(김해중 등. 인공임신중절 실태조사 및 종합대책수립: 보건복지부 2004년)인공임신중절의 이유
Justice delayed is justice denied <영국 선데이타임즈>THALIDOMIDE APOLOGY
BendectinHistorical case II.1983.06.10 경향신문 4면 사회 기사(뉴스)1987.07.16 경향신문 4면 사회 기사(뉴스)
U.S.A. Temporal Trends for Limb Reduction Deformities, Bendectin Salesand Hospitalizations for NVPBendectinHistorical case II.
BendectinHistorical case II.Canada Temporal Trends for Limb Reduction Deformities, Bendectin Salesand Hospitalizations for NVP
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.
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
Teratogenesis followsa toxicological dose response curve%ofsurvivorswithRdproductivetoxicityDose of Teratogen or mutagenBackground incidence ofHuman reproductive toxicityTeratogenesisMutagenesisR.L. Brent 2001030100
Period of developmental susceptibility& Deviant developmentGerm cellDevelopmentOrganogenesis Fetal period Neonatal period AdolescenceFertilization Birth Sexual MaturityPrenatal/Neonatal deathStructural abnormalitiesFunctional deficitsAltered growthCarcinogenesis
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
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
Nava-Ocampo AA et al 2007Graphical representation of risk ofdrugs in pregnancyTERIS
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.
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,
Q : 마취유도제 Pentothal(thiopental sodium),Propofol 현재 유럽에서 마취유도제로 쓰이지만 미국에선 FDA 승인이 나지 않은 약물입니다. 따라서,FDA 미승인 이므로 쓰지 말아야 한다는 의견과 마취유도제로 별문제 없다는 의견이 있습니다.또한, 태아에게 안전성이 입증되어 있는지요? 이 부분에 대해 약물독성학적 입장에서의 의견을 주시면좋겠습니다.
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
Quick take: Based on experimental animal studies andhuman experience, thiopental is not anticipated toincrease the risk of congenital anomalies.Pregnancy Risk Category : C
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
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
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
Q : Succinylcholine, Rocuronium,Vecuronium산과 영역에서 많이 쓰이는 근이완제 임태아에 미치는 독성은 어떤가요?
Quick take: Succinylcholine has not been associated withadverse effects on the fetus.Pregnancy Risk Category : C
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
Rocuronium an muscle relaxant used in modernanesthesia, to facilitate endotrachealintubationPharmacokinetics :T1/2 : 66-80minMW : 557 g/molProtein binding : ~30%Bioavailability : NAExcretion : bile & urine
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
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
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
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)
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
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
Q : 혈압강하제 esmolol, labetalol, nicardipine,그리고 ACE inhibitor는 태아에 어떤 영향을줄 수 있나요?
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
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
Valsartana new angiotensin II receptor antagonistPharmacokinetics :T1/2 : 9 hoursMW : 435 g/molBioavailability : 23%Protein binding : 97%Excretion : renal and biliary
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
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
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
Q : 진통관리에 쓰이는 Ketorolac은 태아 및모유수유아에 어떤 영향을 줄 수 있나요?
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
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)
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
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
정 리임신부에서 마취 약물 : 대부분의 마취 관련 약물은 기형을 유발하지 않음 기형유발 우려 약물에 노출 시 적절한 상담 필요[☎ 1588-7309 (한국마더세이프전문상담센터)]