Methotrexate, SSRI 0608., Down
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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)
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
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
IQ <70 : 6 (including 4 with major CNS anomalies)
IQ 70-85 : 4 (including 1 with major CNS anomalies)
IQ >85 : 2
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
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
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
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
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
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)
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
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
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 !