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Benha University Hospital
Email: [email protected]
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
producing 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
Molecular weight: > 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
classification (1980)
• 5 categories
RCT
Animal
Human
• Varies according to
gestational age
• Updated
1.Category A:
• Controlled studies in
humans demonstrated no
fetal risk.
• E.g.:
Prenatal vitamins, not megavits
K CL, citrate & gluconate,
Thyroxin
2. Category B:
• Animal studies indicate no fetal
risk & no controlled studies in
humans.
• E.g.
Penicillins, terbutaline,
Acetaminophen, cyclizine, antacids,
Prednisone, insulin, ampicilln,
Clindamycin, nitrofurantoin,
Miconazole, spiramycin,.
3.Category C:
• Animal studies indicate fetal risk & no
human studies.
• These drugs are administered only when
their benefits outweighs the potential fetal
harm.
• E.g.
Furosemide, Rifampicin, βblockers,
Phenothiazine, methyl dopa, nifedipine,
Heparin, aminophyllin, gentamycin,
Chloroquin, acyclovir, cyclosporin,.
4.Category D:
• There is evidence of fetal risk in humans
but the benefits may outweigh the risk.
• These drugs are given only in serious
disease because no alternative.
• E.g.
Phenytoin, valporic acid, diazepam,
Imipramine, captopril, thiazides,
Spironolactone, coumarine, chlorpropamide
Progestins, tetracyclin, streptomycin,
Quinine, methotrexate, vinblastin,
Azathioprine.
5. Category X:
• There is clear human risk that
outweigh the benefits.
• These drugs are
contraindicated.
• E.g.
Estrogen, androgens,
Aminopterin, isotretinoin,
Thalidomide
Category Animal
risk
A
No risk
Human Risk
Administration
No risk
Yes
B
No risk
No studies
Yes
C
Risk
No studies
If benefits> Risk
D
Risk< Benefit
If No alternative
X
Risk> Benefit
Contraindicated
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 disorders
1. General anesthesia:
Thiopental: No increase in
malformation
Nitrous oxide, Halothane: No
increase of malformation in
humans but increase in animals
Ketamine {B}
2. Analgesic
B
C
Acetaminophen Aspirin
Codiene
Ibuprofen,
indomethacin,
naproxin,
pentazocine
Mepridine,
morphine
Sulindac
D
Ibuprofen, indomethacin,
naproxin, pentazocine
Mepridine, morphine,
Sulindac {premature closure
of D. arteriosus
Asprin, Codien (if used at
term)
Acetaminophen:
Antiprostaglandin effect is short,
bleeding time is not prolonged in
contrast to aspirin.
It is preferred over aspirin.
Indomethacin
is contraindicated after 34 w
3. Narcotic antagonist:
B
D
Naloxone Nalorphine, levallorphan, cyclazocine
4. Anticonvulsant
B
C
D
Mg sulphate Carbamazepine Phenytoin (Dilantin):
Hydantoin syndrome
Metharbital (tegretol):
Phenobarbital,
carbamazepin
syndrome
Valporic acid:
Clonazepam
valporic syndrome,
(Clonopin)
Trimethadione
barbiturates
Fetal anticonvulsant
syndrome
Craniofacial abnormalities
Broad nasal bridge
Epicanthal fold
Limb defects
Growth deficiency
Mental Deficiency
5. Psychotropic
B
Selective
serotonin
reuptake
inhibitors:
fluoxetine,
paroxetine,
sertraline
Antipsychotic:
Clozapine
Bupropion
C
Monoamine oxidase
inhibitors:
isocarboxazid, phenelzine,
tranylcypromine
Tricyclic antidepressants:
desipramine, doxepin
Antipsychotics:
chlorpromazine, thioridazine,
perphenazine
Benzodiazipines:
clonazepam, lorazepam,
oxazepam
D
Tricyclic
antidepressants:
amitriptylin,
amoxapine,
imipramine
clomipramine,
nortriptyline
Benzodiazipines:
alprazolam,
diazepam
lithium
Chlorpromazine:
Negliably cross the placenta
Diazepam:
1st trimester: cleft lip.
Before delivery: hypotonia,
hypothermia, respiratory depression.
Imipramine:
limb reduction defects
Lithium:
Cardiovascular anomalies
II. Cardiovascular disorders
1. Antihypertensives
C
Methyldopa
Hydralazine, ß blockers,
Nifedipine (adalat)
Clonidine (catapress),
Prazosin (minipress)
Diazoxide (hyperstat)
D
Angiotensin converting
enzyme inhibitors:
(Captopril)
Nitroprusside
Reserpine
Captopril: oligohydramnios, pulmonary hypoplasia, IUGR
ß blockers: propranolol (inderal), atenolol (tenormin),
labetolol (trandate)
2. Anticoagulant
B
Heparine (low
C
D
Heparine Warfarin
mol wt 4000-6000 (conventional) (coumarin):
Streptokinase
hemorrhage &
e.g. enoxaparin
Urokinase
warfarin syndrome
Phenindione
(dindivan)
3. Diuretics:
B
C
Amiloride Furosemide
Ethacrynic
acid
4. Heart:
D
Thiazide: thrmbocytopenia
Spironolactone:
antiandrogenic
Acetazolamide: limb
abnormalities
B
C
Lidocaine Digoxin, Quinidine, Procainamide
III. Pulmonary disorders
1. Asthma
B
Cromolyn
Terbutaline
Ipratropium
bromide
Prednisone,
Prednisolone
C
D
Albuterol,
Triamcinolone
Metaproterenol,
acetonide
Betamethazone,
Beclomethazone,
Dexamethazone,
Flunisolide,
Theophylline,
Aminophylline
Epinephrine, ephidrine
Prednisone & prednisolone are inactivated in the placenta
2. Antihistaminics
B
C
Azatadin, clemastine, Brompheniramine,
Cyclizine, Doxylamine Hydroxzine, pheniramine
3. Cold
B
Pseudoephydrine,
Oxymetazoline
Chlorpheniramine,
Dextrome thorphan
C
D
Phenylephrine Iodide
Pyrilamine
4. Antitussive & expectorants
B
C
Amm. Guaifenesin
D
X
Iodinated
Potassium
glycerol
chloride Hydrocodon iodide,
Sodium iodide
Codeine,
IV. Gastrointestinal disorders
1. Antiemetics
B
Cyclizine
Meclizine
C
Chlorpromazine, promethazine,
prochlorperazine, trimethobenzomide
2. Antiulcer
B
Sucralfate (not absorbed)
Antacids (poorly absorbed)
Ranitidine
Cemetidine (antiandrogenic)
Famotidine, nizatidine
C
X
Omeprazole Misoprostol
(uterine
contraction)
3. Gallstone solubilizing agents
B
Ursodiol
X
Chenodiol
4. Laxatives & purgatives
B
C
Lactulose
Casanthranol, Cascara sagrada, danthron,
Mg sulphate docusate, mineral oil, phenolphthalein, senna
5. Antidiarrheals
B
Loperamide
C
D
Kaolin, pectin, diphenoxylate Paregoric
V. Endocrine disorders
1. Antidiabetics
B
Insulin
Metformin
Acarbose
C
Chlorpropamide, tolazamide,
Tolbutamide, Acetahexamide,
Glyburide, Glibpizide
2. Thyroid & parathyroid disorders
A
B
C
Calcitonin Protirelin
Thyroid,
thyrotropin
levothyroxin
Liothyronin
Thyroglobulin
iodothyrine,
liotrix
D
P.thiouracil
Methimazole
Carbimazole
Lithium
carbonate
Methimazole: scalp defects
Iodides: goiter & hypothyroidism
X
Sod
iodide
I131
3. Adrenal
B
C
Prednisolone, Betamethazone,
prednisone Beclomethazone,
Dexamethazone,
Triamcinolone
D
Cortisone
4. Gynecologic disorders
C
D
X
Bromocriptin Progestagens: Progestagens:
ethisterone,
ethyndiol
hydroxy
progestrone
Tamoxifen
norethindrone,
norethyndrel, norgestrel
Estrogens,
Clomiphene
Androgens, Danazol,
Mifipristone
DES:
•Female:
Uterus: T shaped,
Vagina: adenosis,
Vagina & cervix: adenocarcinoma
(at 20 yr) & abnormalities
•Male:
hypoplastic, un descended tsetse,
epidedmal cysts
VI. Skin disorders
B
Dithranol& tar
Orphermine
Metronidazole
Lindane
Sulphur in
petroleum
Piperonal
butoxide
C
Topical
corticosteroids
D
X
Podophyllin Vit A
Tetracyclin derivatives:
& tretinoin
Methotrexate
Pyrilimine
Azathioprine
Chloroquine,
Grisofulvin
Acyclovir,
zidovuidine
isotretinoin
(Accutane)
etretinate
(Tegison)
Thalidomide
VII. Infections
1. Antibacterial
B
Penicillin, Erythromycin,
Ampicillin, augmentin.
Cephalosporin,
clindamycin, azithromycin
spectinomycin, spiramycin
Nitrofurantoin, nalidexic
acid, S. amide.
Metronidazole
Polymyxin, Aztreonam
C
Trimethoprime
Chloramphenicol
Gentamycin,
Neomycin,
Amikacin,
Vancomycin
Quinolones
D
Tetracyclins
S.amide
Tobramycin
Streptomycin
Kanamycin
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:
in 3rd trimester: hyperblirubinaemia & neonatal
jaundice
2. Antituberculosis
C
B
Ethmbutol Rifampicin, INH, PAS,
Ethionamide, Cycloserin, pyrazinamide
3. Antifungal
B
Miconazole,
clotrimazole
Amphotericin,
Nystatin
C
Griseofulvin, fluconazole,
itraconazole, ketoconazole,
miconazole, teraconazole
5 flucytosine, gentian violet
3. Antimalarial
B
C
D
Proguanil Chloroquine, primaquine, Quinine
Pyrimethamine, Dapsone,
Quinacrine, quinidine
4. Antihelminthic
B
C
Piperazine Mebendazole, thiabendazole
Pyrantel, pyrvinium, quinacrine,
Gentian violet
5. Amebicides
B
Metronidazole
6. Antiviral
B
Didanosine
Famciclovir
Ritonavir
C
Chloroquine,
iodoquinol,
paromomycin
C
Acyclovir,
Ganciclovir,
Zidovudine
D
Carbarsone
X
Ribavirin
IX. Immunosupressive
C
Cyclosporin
D
Azathioprine
VIII. Antineoplastic
B
Prednisone
C
D
X
Aminopterin
Cytosine,
Methotrexate, 5
arabinoside flurouracil, 6M.P
Leuprolide
Dactinomycin Doxorubicin,
Interferon
daunorubicin,
alfa
bleomycin
Cyclophosphamide,
melphalan, busulphan,
Cisplatin, vincristin,
vinblastin, Etopside
IX. Vitamins
A
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
C
D
X
ßCarotene,
Tretinoin Etretinate
systemic Isotretinoin
Leucovorin,
Menadione/X,
Phytonadione,
Tretinoin
topical
Isotretinoin:
•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: (Psoriasis)
•Malformation has been described 13 months
after discontinuation (Lammer, 1988)
Contraception for at least 2 years after treatment
(Geier et al, 1994)
Recommendation
Before pregnancy:
Familiar with teratogenic drugs
Avoid pregnancy if teratogenic drug should be given
Ask about the LMP
In 1st trimester:
Avoid drugs
Exception folic acid & vit C
If absolutely indicated for short time & minimal effective dose
2nd & 3rd trimester:
Beneficial & safe drugs
if indicated for short time & minimal effective dose
Last week:
Avoid drugs that may affect neonates
If needed stop 7-10 days before labor
Teratogenic drugs
ACE inhibitor
Alchol
Aminopterin
Androgens
Busulfan
Carbamazepine
Chlorbiphenyls
Coumarins
Cyclophosphamide
DES
Eteretinate
Isotretinoin
Lithium
Methimazole
Methotrexate
Penicillamine
Phenytoin
Radioactive iodine
Tetracycline
Trimethadione
Valporic acid
Benha University Hospital
E-mail: [email protected]