정 의 기형학 (Teratology) : 배아나 태아기에 구조나 기능의 발달 이상의 원인과 기전 그리고 징후를 다루는 과학 발달 독성학 (Developmental toxicology) 임신 전(양친) , 임신 중, 출산 후부터 sexual maturation까지 노출에 기인한 developing organism에 미치는 adverse effects의 과학
Malformations : alterations in normal development that occur as a result of an intrinsic abnormality in the developmental process. Deformations : result from an abnormal mechanical force on an otherwise normal fetus (eg, clubbed foot in the setting of oligohydramnios). Disruptions : due to the disruption of an otherwise normal developmental process (eg, gastroschisis, which is thought to result from a vascular disruption in the fetal anterior abdominal wall).
Principles – 1 Susceptibility to teratogenesis/developmental toxicity depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors Maternal/paternal genetic influences Genetic polymorphism Genomic imprinting Gene-environmental interactions JG Wilson, 1977
Principles – 2Susceptibility to teratogenesis/developmetaltoxicity varies with the developmental stageat the time of exposure to an adverse influence Stage specificity has been defined for several developing organs and for exposures at several different developmental stages
Period of developmental susceptibility to pre-and postnatal exposures Carcinogenesis Altered growth Functional deficits Structural abnormalities Prenatal/Neonatal deathGerm cell Organogenesis Fetal period Neonatal period AdolescenceDevelopment Fertilization Birth Sexual Maturity
Principles – 3 Teratogenic agents act in specific ways (mechanism) on developing cells and tissues to initiate sequences of abnormal developments(pathogenesis)- Pathogenesis is a process – early effects may be repaired / compensated- Mechanistic studies, especially related to alterations in gene expression, are helping to understand how agents acts/interact ex) valproic acid
Principles – 4 The access of adverse influences to developing tissues depends on the nature of the influence(agent) - Chemical characteristics- size, charge, lipid solubility, ionization, protein binding, concentration gradients - Placental barrier, BBB - Metabolic capability- maternal, placental, embryo/fetal, neonatal
Principles – 5 Four manifestations of deviant development : death, malformation, growth retardation, and functional deficit - Types of effect depend on susceptibility, timing of exposure, interrelationship among effects
Principles – 6Manifestations of deviant developmentincrease in frequency and degree asdosage increases, from the no-effects tothe totally lethal level. High dose may result in fewer malformations due to increased death Dose-response relationship for different types of effects. Determination of the no observed adverse effect level(NOAEL) or benchmark dose(BMD)
Teratogenesis follows a toxicological dose response curve 100 TeratogenesisRdproductive toxicity% of survivors with Mutagenesis 30 Background incidence of Human reproductive toxicity 0 Dose of Teratogens or mutagen R.L. Brent 2001
Principles – 7 Even the most potent teratogenic agent cannot produce every malformations
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
In human : post marketing surveillance • Case report rare exposure/ rare malformation • Case-control study less costly, recall bias • Prospective cohort study • Meta-analysis
Safety and risk of drugs in pregnancy Limitations• Is there association between safety and long term usage? Thalidomide : in 4 years Phenytoin : in 30 years Valproic acid : in 22 years Carbamazepine : in 31 years• Sample size?• Is there methodology to detect less potent teratogen? (Reproductive Toxicology 2001)
Criteria for Proof of Human Teratogenicity (Modified from Shepard 2001)
Drugs or Substances Suspected or Proven to Be Human Teratogen Williams Obstetrics 23rd ed. 2010
FDA classificationA Controlled Studies show no riskB No evidence of risk in humansC Risk cannot be ruled outD Positive evidence of riskX Contraindicated in pregnancy From 1979
FDA system is not ideal:• Onus on the clinician to interpret category information• Drugs in categores D & X, and a certain extent those in C may pose similar risksFDA new rules : remove the A-X categories a narrative fetal risk summary, clinical considerations and inadvertent exposure including registries availableMost current and accurate information : online reproductive toxicity services, Reprotox, TERIS
Graphical representation of risk of drugs in pregnancy Nava-Ocampo AA et al 2007
Unintended pregnancy Unintended pregnancy : 48%32 노출 빈도 (OR)10 알코올 흡연 방사선 약물 Han JY et al. Birth Defects Res A Clin Mol Teratol. 2005
Perceived teratogenic risk after inadvertently drug exposure 한정렬 등 대한산부회지 2002
IV. Practical counselling of major teratogens : Misoprostol / Isotretinoin/ Methotrexate
Misoprostol 증례 :G1P0임신 8주에 약물상담외래 방문 : Fetal pole : 1.9cm Good FHB미국의 한 OBGyn clinic에서임신 5주에 vaginal bleeding과 G-sac 모양 좋지 않아임신 중절 위해 싸이토텍 2T 복용함.임신 중절되지 않고 출혈 있어 제일병원 방문
MisoprostolMisoprostol is a drug that is used for the prevention of non steroidalanti inflammatory drug (NSAID) induced gastric ulcers, for earlyabortion, to treat missed miscarriage, and to induce labor. The latteruse is controversial in the United states. Misoprostol was invented andmarketed by Pfizer under the trade name Cytotec (often misspelledCyotec).Pharmacologically, misoprostol is a synthetic prostaglandin E1(PGE1)analogue.
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 limb defects.
Dear Han: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 featuresmay be 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,
Isotretinoin 증례G2P1L1얼굴의 피지 조절 위해3년전 부터 이소트레티노인 간헐적으로 복용함.마지막 복용: 임신 3주, 이소트레티노인 1T
IsotretinoinIsotretinoin is a medication used mostly for cystic acne.It was first developed for brain, pancreatic and other cancers.It is used to treat harlequin-type ichthyosis, a usually lethal skindisease, and lamellar ichthyosis.Its effects are systemic and nonselective.It is a retinoid, meaning it is related to vitamin A,and is found in small quantities naturally in the body.
Quick take: Isotretinoin use during pregnancy increases theincidence of congenital anomalies.Vitamin A and many retinoids produce congenital anomalies indifferent species; defects produced involve the central nervoussystem, the head, limbs, and cardiovascular system
Isotretinoin 연도 별 상담 건수 25 24 총 상담건수: 79건 20 15 11 10 8 8 7 7 5 5 4 3 1 1 0 2001년 2002년 2003년 2004년 2005년 2006년 2007년 2008년 2009년 2010년 2011년상담 시 Maternal age : 29.7±3.4 yrs(23~41 yrs) Gravidity 2.0± 1.4(1~7)
Isotretinoin 노출 시기별 분포(n=79) 45.6%5040 29.1%30 22.8%20100 conception>1Mo conception<1Mo conception during after isotretinoin after isotretinoin isotretinoin discontinuation discontinuation treatment
Isotretinoin 노출 후 임신 경과 39.73±1.05주 분맊주수: (37.50-41.50주) 출생체중:3,251±322gm 임신결과 빈도 (%) (2,600-3,960gm) 출산 41 (51.9) 자연유산 10 (12.7) 인공유산 20 (25.3) 임신유지 중 1 (1.2) 추적실패 7 (8.9) 총 79 (100.0) [2001-2011.04]
수정 후 Isotretinoin 노출군 (n=23) 노출기간: 23.43±27.51일(1-90일) 마지막 노출 시 수정일 기준 임신령: 20.43±18.59일(1-71일)추적실패 분맊주수: 39.48±1.27주(37.50-41.00주)3명(13%) 출생체중: 3370.00±207.04gm(3,200-3,700gm) 정상아 7명(31%) 인공유산 자연유산 9명(39%) 4명(17%)
MethotrexateMethotrexate , abbreviated MTX and formerly known asamethopterin, is an antimetabolite and antifolate drug.It is used in treatment of cancer, autoimmune diseases,ectopic pregnancy, and for the induction of medicalabortions. It acts by inhibiting the metabolism of folicacid. Methotrexate began to replace the more toxicantifolate aminopterin starting in the 1950s
Quick take: Methotrexate increases the incidence of congenitalanomalies in experimental animals and appears to do so in humansas well.A critical period for exposure of 6-8 weeks after fertilization and acritical dose of 10 mg/week have been described, although notuniversally accepted.
Hello,This is a great question, we have looked at case reports and case seriesin the literature to try and answer this. We evaluated whether amalformation or closely related group of malformations occurred moreoften in case reports and case series than would be expected bychance. We compared the proportion of all malformations representedby each specific malformation with the same proportion derived fromthe Metropolitan Atlanta Congenital Defects Program (MACDP).Our disproportionality analysis supported pulmonary atresia,craniosynostosis, and limb deficiencies as possibly associated withmethotrexate exposure.
Please note that our study (Hyoun et al. in press) included bothmothers inadvertently exposed to MTX for presumed ectopicpregnancy as well as those being treated for Rheumatoid arthritis.To help you I have included a portion of a table from our study thatlists the cases in the literature that may be most similar to yourpatient. There is a limited reference list as well which I hope can helpyou. I was hoping to answer you more succinctly than this, but I justdont think we have that information yet.Let me know if you have any other questions.Sarah Obican