7 drugs in pregnancy2010

Drugs in PregnancyDrugs in Pregnancy

2010.04.13

Liu Yinglin M.D. & PhD / Associate Professor

The 2nd affiliated hospital of S.Y.S.U.

Drugs in Pregnancy

□ Metabolism of drug in pregnancy□ Influence of Drugs on fetuses□ Teratology□ Classifications of Medicine □ Counseling for Teratogen Exposure□ Known Teratogens□ Drugs Commonly Used in Pregnancy

□ Quiz

Metabolism of drug in pregnancy

Pharmacokinetics & pharmacodynamics is quite different!

• Intestines: enterocinesia↓ absorption ↑

• Liver : Detoxifcation ↓

Combining Power (with glucuronic acid) ↓

drug accumulate in body

• Kidney: GFR↑ drug cleen up↑

But if kidney function impaired retention ↑

Influence of Drugs on fetuses

• Indirectly :

by affecting the mother’s endocrine/ metabolism

• Directly:

pass the placental barrier to affect the fetus

Evaluation of Potential Teratogens1.The Defect Must Be Completely Characterized

2.The Agent Must Cross the Placenta

3.Exposure Must Occur during a Critical Developmental Period

preimplantation period-- the "all or none" period

embryonic period-- structural malformations

fetal period-- certain organs remain vulnerable

Teratology

TeratologyEvaluation of Potential Teratogens

4.There Must Be a Biologically Plausible Association

5.Epidemiological Findings Must Be Consistent

6.The Suspected Teratogen Causes a Defect in an Animal

Teratology

• Evaluation of Potential Teratogens

• Evaluation of Potential Teratogens

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

Teratology

Teratology

• Evaluation of Potential Teratogens 6. Consistent findings by two or more epidemiological

studies of high quality:

a. Control of confounding factors

b. Sufficient numbers

c. Exclusion of positive and negative bias factors

d. Prospective studies, if possible

e. Relative risk of three or more

7. Teratogenicity in experimental, animals, especially primates

Category A—SAFEST, show no risk to fetus in the 1st trimester and later in controlled studies in women.

(Appropriate Vitamin)

Category B—Show no risk to fetus in animals, but there’s no controlled studies. Or show adverse effect in animal-reproduction studies which is not confirmed in controlled studies in women.

(Penicillin, Erythromycin, Digoxin ,Insulin,ect)

Classifications of Medicine by FDA (Food and Drug Administration)

Category C—Show adverse effect in animal-reproduction studies while no controlled studies in women. Or studies in animals and women are unavailable. These dugs should be given only when the potential benefits justifies the risk to the fetus.

Gentamycin, Phenergan/Promethazine, INH(Isoniazid),ect

　

Classifications of Medicine

Classifications of Medicine• Category D—Positive evidence of human fetal risk exists.

These drugs are available only when it’s needed in life-threatening situation, or for serious disease without safer effective drugs.

Streptamycin Sulfate, tetracycline hydrochloride,ect

• Category X—Dangerous!! Category X—Dangerous!! Confirmed risks was shown in animals or human, or both. The risks of the use in pregnant women clearly outweighs any possible benefit.(Forbidden!!!)

　 MTX(Methotrexate) Estrobene

Category C,D,X should be avoid in early pregnancy.

1.Disruption of Folic Acid Metabolism Folic acid –essential for the production of methionine

essential for normal meiosis and mitosis

Methylation –PRODUCTION OF proteins, lipids,

and myelin.

Hydantoin( 乙内酰脲 ), Carbamazepine( 卡马西平 ),

Valproic acid( 丙戊酸 ), Phenobarbital( 苯巴比妥 )

Impair folate absorption or act as antagonists

Genetic and Physiological Mechanisms

2.Oxidative Intermediates a. In adults, oxidative intermediates normally are

detoxified by cytoplasmic epoxide hydrolase.

b. Fetal epoxide hydrolase is much weaker. Oxidative intermediates accumulate in fetal tissue.

c. Free oxide radicals have carcinogenic, mutagenic, and other toxic effects

Hydantoin, Carbamazepine, Phenobarbital


3. Effects of Maternal Diseases The interaction of maternal disease and maternal

and fetal genetic composition will determine some drug effects.

e.g. Alcoholic women with poor nutrition and abuse other drugs.

fetus at higher risk of malformation


Questions regarding medication and illicit drug use should be part of routine preconceptional and prenatal care.

-- ACOG, 1999

Counseling should include possible fetal risks from drug exposure, as well as possible teratogenic risks or genetic implications of the condition for which the drug was prescribed.

Counseling for Teratogen Exposure

The manner in which information is presented affects the perception of risk.

Negative information—a 1 to 3 percent chance of having a malformed newborn— perceive an exaggerated risk.

Positive information—the 97 to 99 percent chance of having a normal child.


Counseling should emphasize relative risk.relative risk.

All women have about a 3% chance of having a neonate with a birth defect, and although exposure to a confirmed teratogen may increase this risk, it is usually increased by only 1 or 2 percent, or at most doubled or tripled.

The concept of risk versus benefitrisk versus benefit also should be introduced. Some untreated diseases pose a more serious threat to both mother and fetus than any theoretical risks from medication exposure.


A.A. Alcohol

Known Teratogens

Table 3. Features of Fetal Alcohol Fetal Alcohol SyndromeSyndromeBehavior disturbancesBrain defectsCardiac defectsSpinal defectsCraniofacial anomalies Absent or hypoplastic philtrum Broad upper lip Flattened nasal bridge Hypoplastic upper lip vermilion Micrognathia Microphthalmia Short nose Short palpebral tissues

A.A. Alcohol

Known Teratogens

A. At 2 ½ years. B, C. At 12 years. Note persistence of short palpebral fissures, epicanthal folds, flat midface, hypoplastic philtrum, and thin upper vermilion border.

B.B. Anticonvulsant

Medications

Known Teratogens

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

Known Teratogens

Table 4. Teratogenic Effects of Common Antiepileptic DrugsDrug Teratogenesis Affecte

dPhenytoin Fetal hydantoin syndrome: craniofacial anomalies,

fingernail hypoplasia, growth deficiency, developmental delay, cardiac defects, facial clefts

5–11%

Carbamazepine Fetal hydantoin syndrome; spina bifida 1–2%Valproate Neural-tube defects 1–2%Trimethadione, paramethadione

Craniofacial anomalies, including cleft palate, V-shaped eyebrows, microcephaly, growth deficiency, mental retardation, speech disturbance, cardiac defects

70%

Phenobarbital Clefts, cardiac anomalies, urinary tract malformations 10–20%Lamotrigine Theoretical—lowers fetal folate levels by inhibiting

dihydrofolate reductase?

Topiramate Theoretical—has produced defects or abnormal pregnancy outcomes in all animals tested, even at low or therapeutic doses

?

C.C. Warfarin Compounds

with a low molecular weight, cross the placenta, cause significant adverse teratogenic and fetal effects.

2 different developmental periods, 2 OUTCOMES.

Exposed at 6th ~ 9th week, the fetus is at increased risk of warfarin embryopathy. This is characterized by nasal and midface hypoplasia and stippled vertebral and femoral epiphyses.

Known Teratogens


Warfarin embryopathy

Inhibiting posttranslational carboxylation of coagulation proteins– osteocalcins-- embryonic control of calcification.

Aberrant calcification of cartilage and premature calcification of bone happen.

A phenocopy of chondrodysplasia punctata.

Known Teratogens



Known Teratogens



Dose dependent

Over 5 mg/day

72%-- Spontaneous abortion

8%-- Warfarin embryopathy

Known Teratogens


During the 2nd and 3rd trimester

Hemorrhage -- disharmonic growth and deformation from scarring several organs.

a.a.DDorsal midline central nervous system dysplasia, such as agenesis of the corpus callosum, Dandy–Walker malformation.

b.b.Midline cerebellar atrophy; ventral midline dysplasia such as microphthalmia, optic atrophy, and blindness; and developmental delay and mental retardation.

Known Teratogens

D.D. ACEI -- ACE inhibitor fetopathyACE inhibitor fetopathy

Papillary and tubular atrophy

-- impairment in urinary concentrating ability

Prolonged fetal hypotension and hypoperfusion -- renal ischemia, renal tubular dysgenesis

-- anuria, oligohydramnios

--prevents normal lung development and causes limb contractures

-- growth restriction, relative limb shortening, and maldevelopment of the calvarium

Known Teratogens

E.E. Retinoids

a.Vitamin A-- Doses higher than the recommended daily allowance of 5000 IU （ 1000mcg ） should be avoided.

b.Isotretinoin-- 13-cis-retinoic acid, is effective for treatment of cystic acne.

Isotretinoin embryopathy-- Bilateral microtia or anotia with stenosis of external ear canal, Flat, depressed nasal bridge and ocular hypertelorism.

Known Teratogens

E.E. Retinoids

Isotretinoin embryopathy

Known Teratogens

F.F. Hormones

1.Androgens--autosomal recessive congenital adrenal hyperplasia and masculinization from exogenous.

a.a. Testosterone and Anabolic Steroids--Exposure of a female fetus results in varying degrees of virilization, including labioscrotal fusion after first-trimester exposure and phallic enlargement with later fetal exposure .

b. b. Androgenic Progestins--female fetus masculinization(1%).

Known Teratogens

F.F. Hormones

2.Estrogens

a. a. Diethylstilbestrol (DES)

excess cervical eversion (ectropion 外翻 ) and ectopic vaginal glandular epithelium (adenosis 腺病 )-- malignant potential-- up to 50%

abnormalities of the cervix or vagina—1/4

a hypoplastic, T-shaped uterine cavity; cervical collars, hoods, septa, and coxcombs; and "withered" fallopian tubes

Known Teratogens

G.G. Antineoplastic Agents

a. a. Cyclophosphamide( 环磷酰胺 )

--resulting in cell death and heritable DNA alterations in surviving cells.

--missing and hypoplastic digits on hands and feet.

--cleft palate( 腭裂 ), single coronary artery, imperforate anus( 肛门闭锁 ), and fetal growth restriction with microcephaly( 小头畸形 ).

Known Teratogens

G.G. Antineoplastic Agents

b. b. Methotrexate and Aminopterin

--alter normal folic acid metabolism.

--growth restriction, failure of calvarial ossification, anencephaly （无脑儿）， hydrocephalus （脑积水）， cleft palat （腭裂）， craniosynostosis, hypoplastic supraorbital ridges, small posteriorly rotated ears, micrognathia, and severe limb abnormalities.

Known Teratogens

H.H. Antimicrobials

a. a. Tetracyclines

--cause yellow-brown discoloration of deciduous teeth( 乳牙 ) or be deposited in fetal long bones.

b. b. Aminoglycosides （氨基糖甙类）----nephrotoxicity and ototoxicity （耳毒性） have

been reported in preterm newborns and adults. congenital defects resulting from prenatal exposure have not been confirmed.

Known Teratogens

A. A. Anticoagulants

a. Warfarin Compounds

AVOID!! （ in early pregnancy ）b. heparin

c. Alteplase （阿替普酶） , tissue plasminogen activator (t-PA) （组织纤维蛋白溶酶原激活剂）

d. Streptokinase （链激酶） e. low-molecular-weight heparins

ALL b,c,d and e are SAFE!!

Drugs Commonly Used in Pregnancy

B. B. Antimicrobials

a. Antibacterial Agents

Penicillins are probably the safest.

Cephalosporins, Erythromycin—SAFE!!

Aztreonam （氨曲南， β- 内酰胺类）— NOT teratogenic in ANIMALS.

Chloramphenicol—POSSIBLE gray baby syndrome, manifested by cyanosis, vascular collapse, and death.

Drugs in Pregnancy Drugs Commonly Used in Pregnancy

C. C. Psychotropic Drugs

b. Antidepressant Drugs

Selective serotonin reuptake inhibitors (SSRIs), a good choice for pregnant women.

Tricyclic antidepressants, no increase in the rate of fetal malformation was found.

Venlafaxine, FEW DATA.

Bupropion, FEW DATA.

Drugs in Pregnancy Drugs Commonly Used in Pregnancy

Principal of drug usage in pregnant women

• Using single medicine is safer than drug combination.

• The medicine with certainly positive effect is better than that with suspicious effect.

• Small dosage is safer than large dosage.• Strict control the dosage and duration of

administration is very important. Administration should be stopped timely.

Key points

• In which period fetuses/embryos are the most sensitive to the drug adverse effect?

• How dose the Food and Drug Administration(FDA) classify the drugs ?

• What should we do in Counseling for Teratogen(drug) Exposure?

• How to evaluate the effect of drug in fetuses/embryos?

[1]Which could be the best choise for pregnant women with hypertension?

A. ACEI B. Nitroglycerin

C. Sodium nitroprusside D.CCB

[2]A woman needs cesarean section, which drug could be used in anesthesia?

A. lidocaine B. procaine

C. isoflurane D. all above

Drugs in Pregnancy Quiz

[3]A pregnant woman with lower limb deep venous thromboses needs anticoagulant, which should be chosen?

A. warferin B. heparin

C. t-PA D. streptokinase

[4]Case discuss: A woman with mechanical valve comes to the prenatal clinic. She accepted warferin 2.5mg/d continuously since 3years before. What should you emphasize to her as a doctor on prenatal care?

Drugs in Pregnancy Quiz

[1] Williams Obstetrics 22ND edition

The McGraw-Hill Companies, 2005

[2] Current Diagnosis & Treatment Obstetrics & Gynecology 10th edition

The McGraw-Hill Companies, 2006

Drugs in Pregnancy Reference

Thank You !

7 drugs in pregnancy2010

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