Benha University Hospital, Egypt Email: elnashar53@hotmail.com

Impact of the problem

Egypt: 86% takes drugs without prescription (Rizk et al,

1993)

KSA:

60% takes drugs (Alkhawaja,1991)

USA: 2%: Category A drugs 50%: Category B drugs 40%: Category C drugs 4%: Category D drugs 4%: Category X drugs (Andrade et al, 2004)

Teratogens • Teratos= monster, in Greek

• Any agent

{drug, infection, physical condition or deficiency} that

acts on embryo or fetus:

permanent alteration of morphology or function (Shepard, 1998).

Causes of congenital malformation Unknown or multifactorial: 70%

Genetic: 20%

Environmental: 10%

Drugs & chemicals: 5% Infection: 2%

Maternal disorders: 2%

Irradiation: 1%

Factors affecting the teratogenic

effect of the drug A. Fetal factors: I. Developmental stage :

1.Predifferentiation stage (0-7 days of gestation):

Death or no effect.

2.Differentiation stage (7-57 days of gestation):

Malformation

3.Post differentiation stage (after 57 days of

gestation):

Functional defects, Growth retardation

II. Genetic susceptibility : 1. Species differences: Thalidomide is teratogenic in human & not in

animals.

2. Individual differences: difference in maternal or fetal metabolism of the drug

B. Drug factors: I. The route, dose & duration of administration II. Effect of other agents: Excess vit. A: cleft palate & exencephaly in rats.

Excess vit A + Cortisone: Increased incidence

Excess Vit A+ Vit B: No teratogenic effect

III. Access to fetoplacental unit: Lipid solubility

Mol wt: > 600 not cross the placenta

Protein binding

Thickness of the placental membrane

Drugs not cross the placental membrane:

Erythromycin, TSH, ACTH

Drugs negliably cross: Insulin, Heparin, Thyroxin

S. choline, T. curarine, Guanthidine

Furadandin, Chlorapromazine

Appearance of teratogenic effect: • Immediate: Death & abortion

• At birth: Malformation

Functional defects (Streptomycin: nephrotoxic & ototoxic)

• Delayed: Carcinogenesis: DES

Mutagenesis:

Food & Drug Administration

(FDA) classification • 5 categories

RCT Animal Human • Varies according to gestational age • Updated

1. Category A: • RCT in humans: no fetal risk.

• E.g.:

Prenatal vitamins, not megavits K CL, citrate & gluconate,

Thyroxin

2. Category B: • Animal studies: no fetal risk &

No RCT in humans.

• E.g.

Penicillins, terbutaline,

Acetaminophen, cyclizine, antacids,

Prednisone, insulin, ampicilln,

Clindamycin, nitrofurantoin,

Miconazole, spiramycin,.

3.Category C: • Animal studies: fetal risk &

No human studies. • Given only when benefits outweighs the potential fetal harm. • E.g.

Furosemide, Rifampicin, βblockers,

Phenothiazine, methyl dopa, nifedipine,

Heparin, aminophyllin, gentamycin,

Chloroquin, acyclovir, cyclosporin,.

4.Category D: • Fetal risk in humans but the benefits may

outweigh the risk.

• Given only in serious disease , when no alternative. • E.g.

Phenytoin, valporic acid, diazepam,

Imipramine, captopril, thiazides,

Spironolactone, coumarine, chlorpropamide

Progestins, tetracyclin, streptomycin,

Quinine, methotrexate, vinblastin,

Azathioprine.

5. Category X: • Clear human risk that outweigh the benefits. • Contraindicated. • E.g.

Estrogen, androgens,

Aminopterin, isotretinoin,

Thalidomide

Administration Human Risk Animal

risk

Category

Yes No No A

Yes No studies No B

If benefits> Risk No studies Yes C

If No alternative Risk< Benefit D

Contraindicated Risk> Benefit X

T shaped uterus of

DES

Fetal alcohol syndrome

IUGR

Behavior disturbance

Brain defects

Cardiac defects

Spinal defects

Craniofacial anomalies

Phocomelia (limb reduction defects)

Bone defects

Anomalies of ear, CVS

www.perinatology.com

I. CNS

II. CV

III. Pulmonary

IV. GIT

V. Endocrine

VI. Skin

VII. Infections

VIII. Immunosuppresive

IX. Antineoplastic

X. Vitamins

I. CNS 1. General anesthesia: Thiopental: No increase in malformation

Nitrous oxide, Halothane: No increase of

malformation in humans but increase in animals

Ketamine {B}

D C B

Ibuprofen, indomethacin,

naproxin, pentazocine

Mepridine, morphine, Sulindac

{premature closure of D.

arteriosus}

Asprin, Codien (if used at term)

Aspirin

Codiene

Acetaminophen

Ibuprofen,

indomethacin,

naproxin,

pentazocine

Mepridine, morphine

Sulindac

2. Analgesic

Acetaminophen Vs asprin?: Acetaminophen

{Antiprostaglandin effect is short

bleeding time is not prolonged

Indomethacin

contraindicated after 34 w

D B

Nalorphine, levallorphan, cyclazocine Naloxone

D C B

Phenytoin (Dilantin):

Hydantoin syndrome

Phenobarbital, Valporic

acid: valporic syndrome,

Trimethadione

Carbamazepine

(tegretol):

carbamazepin

syndrome

Clonazepam

(Clonopin)

barbiturates

Mg sulphate

Metharbital

3. Narcotic antagonist:

4. Anticonvulsant

Fetal anticonvulsant

syndrome

Craniofacial

abnormalities

Broad nasal bridge

Epicanthal fold

Limb defects

Growth deficiency

Mental Deficiency

D C B

Tricyclic

antidepressants:

amitriptylin,

amoxapine,

imipramine

clomipramine,

nortriptyline

Benzodiazipines:

alprazolam,

diazepam

lithium

Monoamine oxidase

inhibitors:

isocarboxazid, phenelzine,

tranylcypromine

Tricyclic antidepressants:

desipramine, doxepin

Antipsychotics:

chlorpromazine, thioridazine,

perphenazine

Benzodiazipines:

clonazepam, lorazepam,

oxazepam

Selective

serotonin

reuptake

inhibitors:

fluoxetine,

paroxetine,

sertraline

Antipsychotic:

Clozapine

Bupropion

5. Psychotropic

Chlorpromazine: Negliably cross the placenta

Diazepam: 1st T: cleft lip.

Before delivery: hypotonia, hypothermia, respiratory

depression.

Imipramine: limb reduction defects

Lithium: Cardiovascular anomalies

II. Cardiovascular 1. Antihypertensives

D C

Angiotensin converting enzyme

inhibitors: (Captopril)

Nitroprusside

Reserpine

Methyldopa

Hydralazine, ß blockers,

Nifedipine (adalat)

Clonidine (catapress),

Prazosin (minipress)

Diazoxide (hyperstat)

Captopril: oligohydramnios, pulmonary hypoplasia, IUGR

ß blockers: propranolol (inderal), atenolol (tenormin), labetolol

(trandate)

2. Anticoagulant

D C B

Warfarin (coumarin):

warfarin syndrome&hge

Phenindione (dindivan)

Heparine

(conventional)

Streptokinase

Heparine (low mol wt

4000-6000 e.g.

enoxaparin

Urokinase

Exposure

6-13 w: 5% risk of F warfarin synd

nasal hypoplasia

stippled epiphyses

limb deformities

mental retardation

seizures.

2nd or 3rd T: 5% risk of fetal intracerebral hge.

If warfarin therapy is essential:

Avoid during 1st T {teratogenicity}

Avoid 2 to 4 w before delivery {reduce risk of hge}.

Women who conceive on warfarin& wish to

continue the pregnancy:

Vit K 10mg orally {reverse warfarin effect }

immediately therapeutic LMWH dose

3. Diuretics:

D C B

Thiazide: thrmbocytopenia

Spironolactone: antiandrogenic

Acetazolamide: limb abnormalities

Furosemide

Ethacrynic acid

Amiloride

4. Heart:

C B Digoxin, Quinidine, Procainamide Lidocaine

III. Pulmonary 1. Asthma

D C B

Triamcinolone

acetonide

Albuterol, Metaproterenol,

Betamethazone,

Beclomethazone,

Dexamethazone, Flunisolide,

Theophylline, Aminophylline

Epinephrine, ephidrine

Cromolyn

Terbutaline

Ipratropium

bromide

Prednisone,

Prednisolone

Prednisone & prednisolone are inactivated in the placenta

2. Antihistaminics

C B

Brompheniramine, Hydroxzine,

pheniramine

Azatadin, clemastine,

Cyclizine, Doxylamine

3. Cold

D C B

Iodide Phenylephrine

Pyrilamine

Pseudoephydrine, Oxymetazoline

Chlorpheniramine, Dextrome

thorphan

4. Antitussive & expectorants

X D C B

Iodinated

glycerol

Potassium iodide,

Sodium iodide

Codeine,

Guaifenesin

Hydrocodon

Amm.

chloride

IV. Gastrointestinal 1. Antiemetics

C B

Chlorpromazine, promethazine,

prochlorperazine, trimethobenzomide

Cyclizine

Meclizine

2. Antiulcer

X C B

Misoprostol

(uterine

contraction)

Omeprazole Sucralfate (not absorbed)

Antacids (poorly absorbed)

Ranitidine

Cemetidine (antiandrogenic)

Famotidine, nizatidine

3. Gallstone solubilizing agents

X B

Chenodiol Ursodiol

4. Laxatives & purgatives

C B

Casanthranol, Cascara sagrada, danthron,

docusate, mineral oil, phenolphthalein, senna

Lactulose

Mg sulphate

5. Antidiarrheals

D C B

Paregoric Kaolin, pectin, diphenoxylate Loperamide

V. Endocrine 1. Antidiabetics

C B

Chlorpropamide, tolazamide, Tolbutamide,

Acetahexamide, Glyburide, Glibpizide

Insulin

Metformin

Acarbose

2. Thyroid & parathyroid disorders

X D C B A

Sod

iodide

I131

P.thiouracil

Methimazole

Carbimazole

Lithium

carbonate

Protirelin

thyrotropin

Calcitonin Thyroid,

levothyroxin

Liothyronin

Thyroglobulinio

dothyrine,

liotrix

Methimazole: scalp defects

PTU 150 mg/d or carb 15 mg/d: unlikely to cause problems in the

fetus.

Iodides: goiter & hypothyroidism

3. Adrenal

D C B

Cortisone Betamethazone,

Beclomethazone,

Dexamethazone,

Triamcinolone

Prednisolone,

prednisone

4. Gynecologic disorders

X D C

Progestagens: norethindrone,

norethyndrel, norgestrel

Estrogens, Clomiphene

Androgens, Danazol,

Mifipristone

Progestagens:

ethisterone,

ethyndiol hydroxy

progestrone

Tamoxifen

Bromocriptin

DES: •Female: Uterus: T shaped, Vagina: adenosis, Vagina & cervix: adenocarcinoma (at 20 y) & abnormalities •Male: hypoplastic, un descended tsetse, epidedmal cysts

VI. Skin

X D C B

Vit A

derivatives: isotretinoin

(Accutane)

etretinate

(Tegison)

Thalidomide

Podophyllin

Tetracyclin Methotrexate

Azathioprine

Topical

corticosteroids

& tretinoin

Pyrilimine

Chloroquine,

Grisofulvin

Acyclovir,

zidovuidine

Dithranol& tar

Orphermine

Metronidazole

Lindane

Sulphur in

petroleum

Piperonal

butoxide

VII. Infections 1. Antibacterial

D C B

Tetracyclins

S.amide

Tobramycin

StreptomycinK

anamycin

Trimethoprime

Chloramphenicol

Gentamycin,

Neomycin,

Amikacin,

Vancomycin

Quinolones

Penicillin, Erythromycin,

Ampicillin, augmentin.

Cephalosporin, clindamycin,

azithromycin spectinomycin,

spiramycin

Nitrofurantoin, nalidexic acid,

S. amide.

Metronidazole

Polymyxin, Aztreonam

Tetracyclin: After 4th month when calcium starts to deposit in

bone:

yellow or brown discoloration of deciduous teeth,

hypoplasia of enamel

delayed bone development.

Chloramphenicol: Gray baby syndrome: cyanosis, collapse, death.

Trimethoprime: Folate antagonist

Sulphonamides: 3rd T: hyperblirubinaemia & neonatal jaundice

2. Antituberculosis

C B

Rifampicin, INH, PAS,

Ethionamide, Cycloserin, pyrazinamide

Ethmbutol

3. Antifungal

C B

Griseofulvin, fluconazole, itraconazole,

ketoconazole, miconazole, teraconazole

5 flucytosine, gentian violet

Miconazole,

clotrimazole

Amphotericin,

Nystatin

3. Antimalarial

D C B

Quinine Chloroquine, primaquine,

Pyrimethamine, Dapsone,

Quinacrine, quinidine

Proguanil

4. Antihelminthic

C B

Mebendazole, thiabendazole

Pyrantel, pyrvinium, quinacrine, Gentian violet

Piperazine

5. Amebicides

D C B

Carbarsone Chloroquine, iodoquinol,

paromomycin

Metronidazole

6. Antiviral

X C B

Ribavirin Acyclovir, Ganciclovir,

Zidovudine

Didanosine

Famciclovir

Ritonavir

VIII. Immunosupressive

D C

Azathioprine Cyclosporin

IX. Antineoplastic

X D C B

Aminopterin

Leuprolide

Methotrexate, 5

flurouracil, 6M.P

Doxorubicin,

daunorubicin, bleomycin

Cyclophosphamide,

melphalan, busulphan,

Cisplatin, vincristin,

vinblastin, Etopside

Cytosine,

arabinoside

Dactinomycin

Interferon alfa

Prednisone

X. Vitamins

X D C A

Etretinate

Isotretinoin

Tretinoin

systemic

ßCarotene,

Leucovorin,

Menadione/X,

Phytonadione,

Tretinoin

topical

Vitamins, multiple

Folic acid/C, Niacin/C,

Niacinamide/C,

Pantothenic acid/C,

Pyridoxine/C, Riboflavin/C,

Thiamin/C, Vitamin B12/C,

Vitamin C/C, Vitamin E/C

Calcefediol/D, calcitriol/D,

Cholecalciferol/D,

Dihydrotachysterol/D

Vitamin D/D, Vitamin A/X

Isotretinoin (Accutane) •Craniofacial malformation

Microtia or anotia, flat depressed nasal bridge

Malformation of the heart, CNS, & thymus

•Avoid pregnancy during treatment

Long acting contraceptive method is required

Etretinate (Tegison): (Psoriasis)

•Malformation has been described 13 ms after

discontinuation (Lammer, 1988)

Contraception for at least 2 y after TT (Geier et al, 1994)

Recommendation Before pregnancy: Familiar with teratogenic drugs

Avoid pregnancy if teratogenic drug

should be given

Ask about the LMP

1st T: Avoid drugs

Exception folic acid & vit C

If absolutely indicated: lowest number of drugs,

short time & minimal effective dose

2nd & 3rd T:

Beneficial & safe drugs

if indicated: short time & minimal effective dose

Last week: Avoid drugs that may affect neonates

If needed: stop 7-10 d before labor

ACE inhibitor

Alchol

Aminopterin

Androgens

Busulfan Carbamazepine Chlorbiphenyls Coumarins Cyclophosphamide

DES

Eteretinate

Isotretinoin

Lithium

Methimazole

Methotrexate

Penicillamine

Phenytoin

Radioactive iodine

Tetracycline

Trimethadione

Valporic acid

Teratogenic drugs

Aboubakr Elnashar

Benha University Hospital E-mail: elnashar53@hotmail.com