2. Case
28세 G(0)P(0) 6년간 valproic acid로 치료 중이던
간질(epilepsy) 여성이 12주간의 무월경을 주소로
산부인과를 방문하였다. 최근 피임을 시행하지 않
았으며, 금일 Urine hCG검사상 양성 소견을 보였
다. 이 여성의 임신전 가능핚 조치는 무엇이었으
며, 현재 이 여성에게 어떻게 조언핛 것인가?
2
3. 임신중 약물에 노출시 일반적인 오해는 무엇인
가?
임신을 계획하고 있는 여성이 피해야 핛 기형유
발 약물에는 어떠핚 것이 있고 어떻게 상담핛 것
인가?
3
5. Introduction
Prevalence of Risk Factors
Pregnant Smoked during pregnancy 11.0%
or Consumed alcohol in pregnancy 10.1%
gave birth Had preexisting medical conditions 4.1%
Rubella seronegative 7.1%
HIV/AIDS 0.2%
Received inadequate prenatal Care 15.9%
At risk of Diabetic 3.8%
getting On teratogenic drugs 2.6%
pregnant
Obese 30.8%
5 Not taking Folic Acid 69.0%
7. Introduction
Mechanisms of teratogenicity
Two major mechanisms of teratogenesis
1. Disruption of folic acid metabolism
Several congenital anomalies, including neural-tube defects,
cardiac defects, cleft lip and palate, and even Down
syndrome
Hydantoin, carbamazepine, valproic acid, and phenobarbital
all impair folate absorption or act as antagonists.
7
8. Introduction
Mechanisms of teratogenicity
2. Oxidative intermediates
Hydantoin, carbamazepine, and phenobarbital are
metabolized by microsomes to arene oxides or epoxides.
Detoxified by cytoplasmic epoxide hydrolase, but because
fetal epoxide hydrolase activity is weak, oxidative
intermediates accumulate in fetal tissue.
Carcinogenic, mutagenic, and other toxic effects
8
9. Introduction
효과가 입증된 임신전 상담 및 조치 (ACOG, AAP)
검사 및 조치 증명된 효과
엽산제 공급 신경관 결손증을 2/3이상 감소시킨다.
풍진 예방접종 선천성 풍진 증후군을 예방한다.
당뇨를 앓고 있는 임신부에서 기형확률이 3배정도 증가하므로
당뇨 관리
임신전 혈당 조절을 통해 기형확률을 낮춘다.
갑상선 기능저하증
적절한 갑상선 기능조절은 태아의 정상적인 신경계 발달을 돕는다.
치료
태아감염을 예방하고, 엄마또한 B형간염의 합병증(간기능부전,
B형 간염 예방접종
간경화, 간암)으로부터 보호받을 수 있다.
AIDS(에이즈) 환자와 보호자에게 에이즈와 관련된 치료 및 임신시기 등
선별검사 적절한 정보제공
성병 선별검사 및 클라미디아, 임질과 관련한 자궁외임신, 불임, 만성 골반통증을 줄이고
치료 태아합병증 가능성을 줄인다.
Warfarin과 같은 기형유발가능성있는 항응고제를 임신전에
항응고제 조절
다른 약제로 바꾼다.
항경련제 조절 간질(epilepsy) 여성의 경우 기형유발가능성이 적은 약제로 교환한다.
기형유발물질로 알려진 여드름 치료제의 일종인 Accutane사용시
Accutane 사용 조절
임신을 피하고, 임신전에 Accutane 사용을 중지한다.
임신전에 금연을 함으로서, 흡연과 관련된 조산, 저체중아 등의
금연 상담
임신 합병증을 예방한다.
무심코 먹는 일회성 술이나 습관적인 알코올 노출을 피함으로서,
알코올 상담
태아알콜증후군 또는 알코올 관련 기형을 예방한다.
임신전에 적절한 체중에 도달함으로써, 비만시 증가하는 신경관 결손증,
비만 조절
9 조산, 당뇨병, 제왕절개증가, 고혈압, 혈전증을 감소시킨다.
10. Introduction
태아기형 발생 위험에 관한 약물상담 시 FDA 분류:
A, B, C, D, X 체계 적용은 오류.
FDA Classification
A Controlled Studies show no risk
B No evidence of risk in humans
C Risk cannot be ruled out
D Positive evidence of risk
X Contraindicated in pregnancy
11. Introduction
• The general consensus is that this FDA
system is not ideal. Many drug ratings are
based on animal data, case reports, and
Most current & accurate information
limited or no human data, with services
On-line reproductive toxicity information
rarely updated. as Reprotox and TERIS
Such
• The FDA acknowledges important limitations
of the system.
(Williams Obstetrics 2010)
16. Introduction
Criteria for Teratogen
1. Careful delineation of clinical cases
2. Rare environmental exposure associated with rare defect,
with at least three reported cases-easiest if defect is severe
3. Proof that agent acts on embryo or fetus, directly or indirectly
4. Proven exposure to agent at critical time(s) in prenatal development
5. Association must be biologically plausible
6. Consistent findings by two or more epidemiological studies of high quality
: Control of confounding factors
Sufficient numbers
Exclusion of positive and negative bias factors
Prospective studies, if possible
Relative risk of three or more
7. Teratogenicity in experimental, animals, especially primates
(Williams Obstetrics 2010)
22. 1. Accutane(Isotretinoin)
Relative risk for teratogenicity
38 % risk; 80% of malformations are CNS
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.
22
23. 1. Accutane(Isotretinoin)
Message: Accutane®
blister pack with the
“avoid pregnancy”
warning icons
23
24. 1. Accutane(Isotretinoin)
Acitretin(etretin, Neotigason)
Fetal adverse effect:
Human case report-
Craniofacial, ear and
cardiac malformations
Half-life of 120 days
Intervention
The treatment of psoriasis Contraception for 2-3
years
24
28. 2. Antiepileptic drug(AED)
Anticonvulsants
The most frequently reported defects: Orofacial
clefts, Cardiac malformations and NTD
The rate of major fetal malformations:
Epilepsy & no medication: 3%
Epilepsy with monotherapy: 3%
Two/ three/ four medication: 5%/10%/20%
28
29. 2. Antiepileptic drug(AED)
Phenytoin
Fetal hydantoin syndrome
Craniofacial anomalies: low nasal bridge, inner
epicanthal folds, ptosis, strabismus, hypertelorism,
large fontanel,
Hypoplasia of distal phalanges and nails
Microcephaly and mental retardation,
Growth deficiency, developmental delay
Cardiac defects, cleft palate and/or lip
29
30. 2. Antiepileptic drug(AED)
Fetal hydantoin syndrome:
Upper facial features
including upturned nose,
mild midfacial hypoplasia,
long upper lip with thin
vermilion border.
Lower distal digital
hypoplasia.
30
31. 2. Antiepileptic drug(AED)
Phenytoin
Relative risk for teratogenicity
5-10% of typical syndrome(FHS)
Relative risk for offspring IQ≤84 : 7
Clinical intervention
Neurologist should consider changing to other
medication
Keep phenytoin concentration at lower effective
levels
Level II US
Vit K to neonate
31
32. 2. Antiepileptic drug(AED)
Carbamazepine
Fetal adverse effects:
Increased risk for NTDs (1%)
Did not impair intelligence
Clinical intervention:
Periconceptional folate
Level II US
Maternal/amniotic AFP
32
34. 2. Antiepileptic drug(AED)
Teratogenic Effects of Common Anticonvulsant Medications
Drug Abnormalities Described Affected Preg. Cat
egory
Valproate Neural-tube defects, clefts, skeletal abnormalitie 1–2% with monotherapy, D
s, developmental delay 9–12% with polytherapy
Phenytoin Fetal hydantoin syndrome: craniofacial anomalie 5–11% D
s, fingernail hypoplasia, growth deficiency, devel
opmental delay, cardiac defects, clefts
Carbamazepine Fetal hydantoin syndrome, spina bifida 1–2% D
Phenobarbital Clefts, cardiac anomalies, urinary tract malforma 10–20% D
tions
Lamotrigine Inhibits dihydrofolate reductase, lowering fetal f 4-fold with monotherapy, C
olate levels. Registry data suggest increased risk 10-fold with polytherapy
for clefts
Topiramate Registry data suggest increased risk for clefts 2% C
Levetiracetam Theoretical—skeletal abnormalities and impaire Too few cases reported to C
d growth in animals at doses similar to or great assess risk
34 er than human therapeutic doses
35. 2. Antiepileptic drug(AED)
Preconceptional counseling
Proper seizure control is the primary goal
Patient education as to the risks of uncontrolled seizures and the
possible teratogenicity of AEDs.
Seizure control should be achieved at least 6 months prior to
conception
The lowest effective dose of a single AED according to the type of
epilepsy.
The new AEDs are not recommended in pregnancy.
If valproic acid is indicated, divided doses are preferred to avoid
high levels of valproic acid in plasma.
Folate supplementation: 5mg/day, 3 months before conception.
35
42. 4. ACE inhibitors: captopril, enalapril
ACE inhibitors
Recent use: Tx of hypertension and congestive heart failure
Fetal adverse effects
During the second or third trimesters:
act on the renal and circulatory systems of exposed fetus
→ produce hypotension, anuria, death
In a report on the use of captopril in 15 human pregnancies:
two spontaneous abortions,
two voluntary abortions(one of which demonstrated malformations),
one intrauterine death at 28 weeks,
two neonatal deaths with anuria
three instance of neonatal distress attributed to premature delivery
42
46. 5. Misoprostol
Fetal adverse effects
Spontaneous abortion, fetal death (RR 3.15)
Möbius syndrome-paralysis of sixth and seventh cranial
nerves (OR 25.7)
Transverse terminal limb defects, abnormalities of frontal
and temporal bones in the skull, omphalocele,
gastroschisis, bladder exstrophy
Clinical intervention
Increase the awareness of teratogenicity of the drug.
46
47. 5. Misoprostol
Möbius syndrome (paralysis of sixth and seventh cranial nerves)
47
48. Summary
The use of retinoic acid (Accutane) is absolutely
contraindicated in pregnancy, and treatment of acne can
be postponed without risk to the mother.
In epilepsy, patients should understand the risks associated
uncontrolled seizures as well as the potential for
teratogenicity of the anticonvulsive medication.
Heparin, which does not cross the placenta, may substitute
for warfarin during the first trimester.
Misoprostol use is associated with abortion, fetal death
and Möbius syndrome.
48
49. Case
28세 G(0)P(0) 6년간 valproic acid로 치료 중이던 간질
(epilepsy) 여성이 12주간의 무월경을 주소로 산부인과
를 방문하였다. 최근 피임을 시행하지 않았으며, 금일
Urine hCG검사상 양성 소견을 보였다. 이 여성의 임신
전 가능핚 조치는 무엇이었으며, 현재 이 여성에게 어
떻게 조언핛 것인가?
→임신 최소 3개월전부터는 엽산제(5mg) 복용을 권유핚
다. 하루 복용량을 나누어 투여핚다. Valproic acid는 임
신 1분기 노출시 2%에서 신경관 결손증(NTD)을 동반
핚다. 따라서 임신 16주경 MSAFP검사와 초음파 검사를
시행 후 이상 소견시 양수 검사를 시행.
49
