Transcript Methotrexate, SSRI 0608., Down

Methotrexate,
Retinoic acids, SSRI
주산기분과 전임의
이미범
Content
 Methotrexate
 Retinoic acids
 Isotretinoin
 Acitretin
 SSRI
 Fluoxetine
 Paroxetine
Methotrexate (amethopterin)
 Toxicity to human embryonic or trophoblastic
tissues
 Used clinically as an abortifacient and in the
treatment of ectopic pregnancy
 기형발생위험률 : 7-75%
 Critical period : 6-8weeks after fertilization
 Critical dose : 10mg/week
Methotrexate (amethopterin)
 기형발생의 기전
 Folic acid antagonist
 Dihydrofolate reductase activity ↓
 Tetrahydrofolate ↓
 Folic acid : important in replication of nucleic
acids
 Folic acid antagonism or deficiency
 abnormal development
Methotrexate (amethopterin)
 반감기(T1/2) : 7.2시간
 NSAID’s는 금기
 Concomittant use of NSAID's
 Lengthens the elimination half- life
 Could potentially cause sustained levels
 MTX의 혈중농도 증가로 사망했던 사례들이 있음.
Methotrexate (amethopterin)
 Animal teratology studies
 Developmental abnormalities after
methotrexate exposure
 Demonstrated in chicks, mice, rats, and rabbits
 Abnormalities in experimental animal studies
 Central nervous system, palate
Methotrexate (amethopterin)
 Epidemiologic Information
 CNS abnormalities
 Anencephaly
 Hydrocephaly
 Meningomyelocele
 MTX에 의한 특징적인 기형
 Clover-leaf skull with large head, Sweptback hair, Low-set ears, Prominent eyes,
Wide nasal bridge
Methotrexate (amethopterin)
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Limb defects
Absent ossification centers
Developmental delay
Intellectual impairment
 임신 초기에 노출시 기형발생률이 용량에 따라 빈도 증
가됨.
 하지만, 임신 2기 이후의 태아에 미치는 위험도는 알려
져 있지 않음.
Methotrexate (amethopterin)
 한국 마더리스크 프로그램 정보
 MTX에 임신 초기 노출은 1례가 있었으나,
자연유산됨.
 모유수유시 독성 및 적합성 정보
 미국 소아과학회 : 모유 수유시 부적합 약물
 한국 마더리스크프로그램 : 수유부와 수유아 1쌍 중
부작용은 없었음.
Retinoic acids
 기형발생기전
 직접 세포독성과 programmed cell death의 변
형을 발생함.
 Neural crest cell이 특별히 민감.
 Retinoid-associated malformations :
Inhibition of migration of cranial neural
crest cells during early embryonic
development
Isotretinoin
 Retinoids (13-cis-retinoic acid)
 prescription medication taken by mouth to
treat severe disfiguring cystic acne that has
not responded to other treatments
Isotretinoin
Isotretinoin
 작용기전
 일종의 retinoid로 하루 0.51.0mg/kg투여량으로 피지선의 작용과
각질화를 억제시킴.
 명확한 작용기전은 아직까지 알려져 있지는
않음.
Isotretinoin
 Animal teratology studies
 Vitamin A, many retinoids
 produce congenital anomalies in different species
 Central nervous system, head, limbs,
cardiovascular system defect
 All-trans-retinoic acid (tretinoin)
 Isomer of isotretinoin that is readily formed
when isotretinoin is ingested
 craniofacial abnormalities in rats, rabbits, and monkeys
 Isotretinoin
 produces congenital anomalies in a number of species,
including humans
 Hydrocephalus, microcephaly, ear, face,
limb abnormalities
Isotretinoin
 Epidemiologic Information
 more than 80 children whose mothers were treated orally
with isotretinoin in therapeutic doses during early
pregnancy
 very uncommon but strikingly similar pattern of
congenital anomalies
(Anonymous, 1983, 1984; Lammer et al., 1985; Rosa et al.,
1986; Teratology Society, 1991; Coberly et al., 1996).
 Isotretinoin embryopathy
 central nervous system malformations,
microtia/anotia, micrognathia, cleft palate, cardiac
and great vessel defects, thymic abnormalities, and
eye anomalies. Limb reduction defects (Rizzo et al.,
1991)
Isotretinoin
Left-bilateral
microtia or anotia,
Right-flat,
depressed nasal
bridge and ocular
hypertelorism
Isotretinoin
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Spontaneous abortion
Premature delivery
Isotretinoin and other retinoids : effects on behavior
Five-year-old children, first 60 days after conception : 31
47% performed in the subnormal range on standard
intelligence tests
(Adams, 1990; Adams et al., 1991; Adams & Lammer, 1991, 1993)
 Major malformations : 12
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 IQ <70 : 6 (including 4 with major CNS anomalies)
 IQ 70-85 : 4 (including 1 with major CNS anomalies)
 IQ >85 : 2
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no major malformations : 19
 IQ 70-85 : 6
 IQ >85 : 13
Isotretinoin
 Interspecies differences in sensitivity to developmental
effects of isotretinoin
: Species differences in retinoid toxicokinetics
 Case Report : infant with microtia whose mother
stopped five weeks before conception
 18 children during first two weeks after conception :
no retinoid embryopathy
 Persistence of isotretinoin in maternal stores may
occur even after low doses  embryopathy over a
period of days to weeks
 Outcome of 101 pregnancies in women discontinuing
isotretinoin from days to weeks prior to conception
 No apparent increase in the incidence of
miscarriage or birth defects
Isotretinoin
 Miscarriage risk
 40% risk
 Birth defect risk
 35 % risk; 80% of malformations are CNS
Isotretinoin
 반감기: 50시간
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Not found in a woman’s blood 4-5 days after the last dose
By-products : gone within 10 days after the last dose
 Clinical intervention
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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.
Message: Accutane®
blister pack with the
“avoid pregnancy”
warning icons
Isotretinoin
 Topical gel
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Men using excessive doses of the gel  plasma levels of
isotretinoin and its metabolites : below the limits of
detection (20 ng/mL)
By comparison, plasma levels after oral isotretinoin : 60
ng/mL
In a second study, photodamaged skin, high doses of
topical isotretinoin for 42 d  plasma isotretinoin and
metabolites : negligible fraction of retinoid exposures
from normal dietary sources
 In some women, isotretinoin or other retinoids
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Menstrual abnormalities
Isotretinoin
 한국 마더리스크 프로그램 정보
 임신 초기 노출 후 자연유산율은 13.8%이며
인공유산은 17.2%였음.
 37주 이전의 조산률은 0.0%(0/20)이며,
2500gm미만의 저체중증은 0.0%(0/20)이었으며
기형아 발생률은 0.0%(0/20)이었음.
 모유수유시 독성 및 적합성 정보
 인간의 모유로 분비되는지의 여부는 아직 정확하게
밝혀져 있지 않지만 명백한 부작용이 있을 수
있으므로 수유부에서는 복용을 금함.
 한국 마더리스크 프로그램 : 수유부와 수유아 쌍 중
노출된 례는 없었음.
Acitretin
 Acid analog of etretinate
 Treatment of psoriasis
 Animal teratology studies
 In rats, etretinate teratogenicity : due to the
biotransformation to acitretin
 In vitro studies, prevention of the metabolism of
etretinate to acitretin  markedly reduced the
teratogenicity of etretinate
 Acitretin : teratogenic in mice, rats, and rabbits
 Limbs and palate defect
Acitretin
 Epidemiologic information
 Human case report
 1 mg/kg/d, during first trimester
 craniofacial, ear, and cardiac malformations
 severe limb abnormalities
 10 mg/day, beginning of pregnancy ~ 10th week of
gestation
 microcephaly, epicanthal folds, low nasal bridge,
high palate, cup-shaped ears, atrial septal
defect, and bilateral sensorineural deafness
Acitretin
 Stopped 25 and 40 months before delivering
 Two normal pregnancies (with undetectable etretinate
levels)
 36 pregnancies, stopped between 6 weeks to 23 months
before conception
 no defects indicative of retinoid teratogenesis
 44 infants, using between 0 and 2 years before
conception
 Only one case of undescended testicle
 Half-life of 49hr
 Intervention
 Contraception for 2-3 years
Acitretin
 한국 마더리스크 프로그램 정보
 헌혈금지 약물인 acitretin에 노출된 수혈을 받은
임신부에서 자연유산율은 0.0%(0/9)이며,
인공유산률은 11.1%이었음. 37주 이전의 조산률은
12.5(1/8)%이며, 2500g 미만의 저체중증은
12.5(1/8)%이었으며, 기형아 발생률은
0.0%(0/8)이었음.
 모유수유시 독성 및 적합성 정보
 한국마더리스크 프로그램 : 수유뷰와 수유아 쌍 중
노출된 례는 없었음.
SSRI
 임신부에게 처방할 수 있는 SSRI의 종류
 Fluoxetine
 Sertaline
 Paroxetine
 기형아 출산과 장기적 신경발달에 영향을 미치지 않음.
 하지만 임신 20주 이후 사용시 신생아 폐고혈압의 위험을
증가시킬 수 있으며, 또한 신생아에서 중추신경계, 호흡기계,
위장관계의 mild transient withdrawal syndrome을 일으킬 수
있음.
Fluoxetine
 Prozac, Sarafem
 Selective serotonin reuptake inhibitors (SSRIs)
 Depression
 Obsessive-compulsive disorders
 Tourette’s syndrome
 Eating disorders (bulimia nervosa)
 Premenstrual Dysphoric Disorder (PMDD)
 Half-life : 2~3 days
 May be found in your system for several weeks
 Fairly low after one to two weeks
Fluoxetine
 Animal teratology studies
 Placental transfer in the rat
 Doses up to 11 times the maximum daily human
dose in rats and rabbits
 no adverse reproductive or neurotoxic
effects
 17 times the human dose on a mg/kg basis
 Increase in skin hematomas
 Coagulation disturbances
Fluoxetine
 Epidemiologic information
 In 1997, 796 pregnancies with first-trimester
exposure
 Lack of evidence of an increase in miscarriage and
congenital malformation
 28 involving congenital defects, retrospective
case study
 No pattern of defects was evident
Fluoxetine
 Meta- analysis of reports on first trimester
exposures to fluoxetine
 no increase in congenital defects
 California report on 228 fluoxetine exposed
pregnancies
 164 of which were exposed in the first trimester
 no increase in major malformations
Fluoxetine
 More than 100 pregnancies exposed in the third
trimester
 no increase in neonatal problems, including
prematurity
 Neonatal adverse effects (SSRI)
 Respiratory distress and persistent pulmonary
hypertension
 jitteriness, irritability, vomiting, and convulsions
Fluoxetine
 Withdrawal Symptoms in baby
 Problems breathing
 Jitteriness
 Increased muscle tone
 Irritability
 Altered sleep patterns
 Tremors
 Difficulty eating
 Mild and disappear by two weeks of age with no treatment
or with only supportive care
 Occur at all doses of fluoxetine
 More often with higher doses
Fluoxetine
 Prospective study, mother-infant pairs
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fluoxetine (N=40) or tricyclic antidepressants (N=46)
non-medicated comparison group (N=36)
no differences at age 15-71 months in global IQ, language
development or behavior
Significant and negative correlation between duration of
depression and IQ & between the number of episodes of
postpartum depression and language development
This finding may provide a fetal/child
as well as a maternal reason
for treating to remission in perinatal depression
Fluoxetine
 Fluoxetine & norfluoxetine (major active metabolite)
 excreted in human milk
 In one report,
 milk/plasma ratios : about 0.6
 Mean total infant exposure (in fluoxetine equivalents) :
6.81% (range 2.15-12%)
 Two case reports, adverse outcome associated with
fluoxetine exposure through nursing
 One case, colic in an exposed infant
 Another case report, taking fluoxetine 3 months
postpartum  increased irritability during the first two
weeks
 No adverse effects were reported by others.
Fluoxetine
 한국 마더리스크 프로그램
 임신 초기 노출 후 자연유산율은 11.8%이며,
인공유산은 3.9%이었음. 37주 이전의 조산률은
1.6%이며, 2500gm 미만의 저체중증은
1.6%이었으며 기형아 발생률은 3.2%(2/62)이었음.
포함된 기형들은 abdominal cyst(1), liver
mass(1)이었음.
 모유 수유시 독성 및 적합성 정보
 Most reports : no problem
 Small number of case : irritability, vomiting,
diarrhea, decreased sleep
 한국 마터리스크 프로그램 : 수유부와 수유아 2쌍
중 부작용 없었음.
Fluoxetine – summary  Based on experimental animal studies and human
experience, fluoxetine is not expected to increase the
risk of major congenital anomalies.
 Use of fluoxetine late in pregnancy can be associated
with a mild transient neonatal syndrome of central
nervous system, motor, respiratory, or gastrointestinal
signs.
 Use of fluoxetine, sertraline, or paroxetine after 20
weeks gestation has been associated with an increased
risk of neonatal pulmonary hypertension.
 Long-term neurodevelopmental studies suggest that
antenatal fluoxetine exposure, unlike maternal
depression, does not adversely affect outcome.
Paroxetine
 Paxil, Aropax, Seroxat
 Selective serotonin reuptake inhibitors
(SSRIs)
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Depression
Social anxiety disorder
Obsessive compulsive disorder
Panic disorder
Paroxetine
 Animal teratology studies
 In rabbits, 5.1 mg/kg/d
 no increase in congenital abnormalities
 In rabbits, up to 43 mg/kg/d
 without an increase in offspring anomalies
 In rats, 13 mg/kg/d or more
 decrease in fertility
 One study in rats, 10 mg/kg/day during the last
week of gestation
 decreased the length of gestation, birth weight,
and neonatal survival
Paroxetine
 Epidemiologic information
 A report on 463 paroxetine-exposed pregnancies
identified by teratogen information services
 increase in cardiovascular malformations
 after adjustment for potential confounders, a
statistically not significant (adjusted OR 2.66; 95% CI
0.80-8.90)
 Canadian teratology information service, 1013 infants
 Incidence of congenital heart disease : 0.7%
identical to the incidence in a comparison group
 Canadian service, 5 malformed infants among 148
pregnancies exposed to paroxetine
 Pulmonary hypoplasia, ventricular septal defect,
clinodactyly, cleft lip and palate, and omphalocele
CDC National Birth Defects Prevention Study
Alwan S, et al, Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth
defects. N Engl J Med 2007
Paroxetine
 Slone Epidemiology Birth Defects study
 9849 infants with malformations
 5860 control infants
 Statistically significant association between paroxetine
use & right ventricular outflow defects (OR 3.3, 95% CI
1.3-8.8) but not other cardiac abnormalities
 Associated with clubfoot (OR 5.8, 95% CI 2.6-12.8),
undescended testes (OR 2.8, 95% CI 1.0- 7.8), neural
tube defects (OR 3.3, 95% CI 1.1-10.4)
Louik C, et al, First-trimester use of selective serotonin-reuptake inhibitors and the risk
of birth defects. N Engl J Med 2007
Paroxetine
 Swedish Medical Birth Register
 Congenital heart disease
 statistically significant with an odds ratio of 2.22 (95%
CI 1.39-3.55)
 Ventricular and atrial septal defects
 strongest associations : odds ratio 3.23(95% CI 1.30-6.65)
 Canadian group, population-based registry linked to
administrative data bases
 Among 24 infants with cardiac anomalies
 no significant association with recorded maternal
paroxetine usage
Paroxetine
 Meta-analysis in 2007, 7 eligible studies
 Odds ratio of 1.72 (95% CI 1.22-2.42) for
cardiovascular malformation and first-trimester
paroxetine exposure
 Subsequent meta-analysis
 No significant association between paroxetine
exposure during pregnancy and congenital
cardiac malformations
Paroxetine
 In 2007, ACOG Practice Bulletin
 Pregnant women and women planning pregnancy avoid use
of paroxetine when possible but also noted that
treatment decisions should be individualized to minimize
the risk of relapse of depression.
 In 2009, ACOG and the American Psychiatric
Association
 the risk of relapse should be clearly discussed with
women for whom paroxetine has proven to be uniquely
effective in their treatment before substituting an
alternative agent.
Paroxetine
 모유 수유시 독성 및 적합성 정보
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Excreted in human milk in small amounts
milk/plasma ratios : about 0.2
Mean dose : 1.13% (range 0.5-1.7%)
Lactation exposure to paroxetine
 No harmful effects
Paroxetine – summary 
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Associated with cardiovascular abnormalities in some epidemiology
studies, but findings have not been consistent
Experimental animal studies do not suggest an increased risk of
congenital anomalies.
Use of paroxetine late in pregnancy
 mild transient neonatal syndrome
It is possible that neonatal symptoms lead to greater use of
cardiovascular studies in paroxetine-exposed children, thereby
increasing the likelihood of identification of a cardiovascular
anomaly.
Long-term neurodevelopmental studies suggest that antenatal
exposure to fluoxetine, sertraline, or paroxetine, unlike maternal
depression, does not adversely affect outcome.
Thank you for your attention !