teratogen exposure in pregnancy drugs in pregnancy

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2010. 5. 11

고려의대산부인과학교실

홍순철

Teratogen exposure in pregnancy

Drugs in pregnancy

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28세 G(0)P(0) 6년간 valproic acid로치료중이던간질(epilepsy) 여성이 12주간의무월경을주소로산부인과를방문하였다. 최근피임을시행하지않았으며, 금일 Urine hCG검사상양성소견을보였다. 이여성의임신전가능핚조치는무엇이었으며, 현재이여성에게어떻게조언핛것인가?

Case

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임신중약물에노출시일반적인오해는무엇인가?

임신을계획하고있는여성이피해야핛기형유발약물에는어떠핚것이있고어떻게상담핛것인가?

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Contents

Teratogenic drugs/chemicals

1. Accutane (isotretinoin)

2. Antiepilectic drugs: phenytoin, carbamazepine,

valproic acid

3. Warfarin (coumarine)

4. ACE inhibitors

5. Misoprostol

Summary

Introduction

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0.2%HIV/AIDS

7.1%Rubella seronegative

At risk of getting pregnant

Pregnant or

gave birth

15.9%Received inadequate prenatal Care

69.0%Not taking Folic Acid

30.8%Obese

2.6%On teratogenic drugs

3.8%Diabetic

4.1%Had preexisting medical conditions

10.1%Consumed alcohol in pregnancy

11.0%Smoked during pregnancy

IntroductionPrevalence of Risk Factors

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Introduction

When do birth defects occur?

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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 phenobarbitalall impair folate absorption or act as antagonists.

Introduction

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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

Mechanisms of teratogenicity

Introduction

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검사 및 조치 증명된 효과

엽산제 공급 신경관 결손증을 2/3이상 감소시킨다.

풍진 예방접종 선천성 풍진 증후군을 예방한다.

당뇨 관리당뇨를 앓고 있는 임신부에서 기형확률이 3배정도 증가하므로

임신전 혈당 조절을 통해 기형확률을 낮춘다.

갑상선 기능저하증치료

적절한 갑상선 기능조절은 태아의 정상적인 신경계 발달을 돕는다.

B형 간염 예방접종태아감염을 예방하고, 엄마또한 B형간염의 합병증(간기능부전,

간경화, 간암)으로부터 보호받을 수 있다.

AIDS(에이즈) 선별검사

환자와 보호자에게 에이즈와 관련된 치료 및 임신시기 등적절한 정보제공

성병 선별검사 및치료

클라미디아, 임질과 관련한 자궁외임신, 불임, 만성 골반통증을 줄이고태아합병증 가능성을 줄인다.

항응고제 조절Warfarin과 같은 기형유발가능성있는 항응고제를 임신전에

다른 약제로 바꾼다.

항경련제 조절 간질(epilepsy) 여성의 경우 기형유발가능성이 적은 약제로 교환한다.

Accutane 사용 조절기형유발물질로 알려진 여드름 치료제의 일종인 Accutane사용시

임신을 피하고, 임신전에 Accutane 사용을 중지한다.

금연 상담임신전에 금연을 함으로서, 흡연과 관련된 조산, 저체중아 등의

임신 합병증을 예방한다.

알코올 상담무심코 먹는 일회성 술이나 습관적인 알코올 노출을 피함으로서,

태아알콜증후군 또는 알코올 관련 기형을 예방한다.

비만 조절임신전에 적절한 체중에 도달함으로써, 비만시 증가하는 신경관 결손증,

조산, 당뇨병, 제왕절개증가, 고혈압, 혈전증을 감소시킨다.

효과가 입증된 임신전 상담 및 조치 (ACOG, AAP)

Introduction

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

태아기형 발생 위험에 관한 약물상담 시 FDA 분류: A, B, C, D, X 체계 적용은 오류.

Introduction

• The general consensus is that this FDA

system is not ideal. Many drug ratings are

based on animal data, case reports, and

limited or no human data, with information

rarely updated.

• The FDA acknowledges important limitations

of the system.

(Williams Obstetrics 2010)

Most current & accurate information

On-line reproductive toxicity services

Such as Reprotox and TERIS

Introduction

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Introduction

Reprotox - http://thomsonhc.com

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Introduction

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Introduction

총 빈도: 30,672

Introduction

-관동대 제일병원

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)

Introduction

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Human TeratogensACE inhibitors(captopril, enalapril) Kanamycin

Aminopterin Lithium

Androgens Metal (mercury, lead)

Methimazole

A-II antagonistsb

Methotrexate

Busulfan Misoprostol

Carbamazepine Penicillamine

Chlorbiphenyls Phenytoin

Cocaine Radioactive iodine

Coumarins Streptomycin

Cyclophosphamide Tamoxifen

Danazol Tetracycline

Diethylstilbestrol (DES) Thalidomide

Ethanol Tretinoin

Etretinate Trimethadione

Isotretinoin Valproic acid

Introduction

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Contents

Introduction



valproic acid


4. ACE inhibitors

5. Misoprostol

Summary


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1. Accutane(Isotretinoin)

Isotretinoin(13-cis-retinoic acid, Accutane)→ The treatment of cystic acne

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Fetal adverse effects: Spontaneous abortion; deformities of cranium, ears

(microtia, low-set ears, anotia), face, heart (TGA, TOF, VSD etc), limbs, liver; hydrocephalus, microcephalus.

Cognitive defects

Left-bilateral microtia or anotia,Right-flat, depressed nasal bridge and ocular hypertelorism


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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.


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Message: Accutane®

blister pack with the“avoid pregnancy”warning icons

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The treatment of psoriasis

Fetal adverse effect:

Human case report-Craniofacial, ear and cardiac malformations

Half-life of 120 days

Intervention

Contraception for 2-3 years

Acitretin(etretin, Neotigason)


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Contents

Introduction



valproic acid


4. ACE inhibitors

5. Misoprostol

Summary


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2. Antiepileptic drug(AED)

Fetal anticonvulsant (FAC) syndrome

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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%


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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


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Fetal hydantoin syndrome: Upper facial features including upturned nose, mild midfacial hypoplasia, long upper lip with thin vermilion border.

Lower distal digital hypoplasia.


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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


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Carbamazepine

Fetal adverse effects:

Increased risk for NTDs (1%)

Did not impair intelligence

Clinical intervention:

Periconceptional folate

Level II US

Maternal/amniotic AFP


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Valproic acid

Fetal adverse effects Lumbosacral spina bifida with meningomyelocele

CNS defects, microcephaly

Cardiac defects

Cognitive impairment (2% risk of NTD)

Clinical intervention: Level II US,

Maternal/amniotic AFP


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Teratogenic Effects of Common Anticonvulsant Medications

Drug Abnormalities Described Affected Preg. Category

Valproate Neural-tube defects, clefts, skeletal abnormalities, developmental delay

1–2% with monotherapy,9–12% with polytherapy

D

Phenytoin Fetal hydantoin syndrome: craniofacial anomalies, fingernail hypoplasia, growth deficiency, developmental delay, cardiac defects, clefts

5–11% D

Carbamazepine Fetal hydantoin syndrome, spina bifida 1–2% D

Phenobarbital Clefts, cardiac anomalies, urinary tract malformations

10–20% D

Lamotrigine Inhibits dihydrofolate reductase, lowering fetal folate levels. Registry data suggest increased risk for clefts

4-fold with monotherapy, 10-fold with polytherapy

C

Topiramate Registry data suggest increased risk for clefts 2% C

Levetiracetam Theoretical—skeletal abnormalities and impaired growth in animals at doses similar to or greater than human therapeutic doses

Too few cases reported to assess risk

C

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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.


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Contents

Introduction



valproic acid


4. ACE inhibitors

5. Misoprostol

Summary


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3. Warfarin(Coumarin)

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Fetal adverse effects

Fetal warfarin syndrome (warfarin embryopathy): nasal hypoplasia, chondrodysplasia punctata, brachydactyly, skull defects, abnormal ears, malformed eyes, CNS malformations, microcephaly, hydrocephalus, skeletal deformities, mental retardation, optic atrophy, spasticity, Dandy-Walker malformations

Most susceptible period: GA 6-12 weeks

2nd & 3rd trimester: microcephaly, mental retardation, optic atrophy in addition to teratogenicity due to first trimester exposure.


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Chondrodysplasia punctataFetal warfarin syndrome


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Relative risk for teratogenicity:

Malformations 16%

Hemorrhages 3%

Stillbirth 8%

Clinical intervention

Switch to heparin


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Contents

Introduction



valproic acid


4. ACE inhibitors

5. Misoprostol

Summary


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4. ACE inhibitors: captopril, enalapril

ACE inhibitors

Recent use: Tx of hypertension and congestive heart failure


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

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Contents

Introduction



valproic acid


4. ACE inhibitors

5. Misoprostol

Summary


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5. Misoprostol

Misoprostol (Cytotec, PGE1 analogue)→ The treatment of peptic ulcer disease→ Termination of early pregnancy

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5. Misoprostol

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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.

5. Misoprostol

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5. Misoprostol

Möbius syndrome (paralysis of sixth and seventh cranial nerves)

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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.

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Case

28세 G(0)P(0) 6년간 valproic acid로치료중이던간질(epilepsy) 여성이 12주간의무월경을주소로산부인과를방문하였다. 최근피임을시행하지않았으며, 금일Urine hCG검사상양성소견을보였다. 이여성의임신전가능핚조치는무엇이었으며, 현재이여성에게어떻게조언핛것인가?

→임신최소 3개월전부터는엽산제(5mg) 복용을권유핚다. 하루복용량을나누어투여핚다. Valproic acid는임신 1분기노출시 2%에서신경관결손증(NTD)을동반핚다. 따라서임신 16주경 MSAFP검사와초음파검사를시행후이상소견시양수검사를시행.

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경청해 주셔서 감사합니다.

teratogen exposure in pregnancy drugs in pregnancy

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