Drugs and Medications

Pregnancy
Dawit Desalegn, MD
November 2010
 Teratology/Teratogens
• A birth defect is defined as a major deviation from normal
morphology or function that is congenital in origin
• 3% of all deliveries
• Most malformations are not inherited <1/3rd
• Only 10 % congenital abnormalities are caused by teratogens
• Only a small number of teratogens have been confirmed
• Teratogen is any agent that acts during embryonic or fetal
development to produce a permanent alteration of form or function
– The word teratogen is derived from the Greek teratos, meaning
monster.
• Teratology is the study of all environmental contributions to
abnormal development
• Currently recognized teratogens include
 chemicals,
 viruses,
 environmental agents,
 physical factors, and
 drugs
• Pregnant women receive an average of 3.1 prescriptions
for drugs other than vitamins
• 40% are taken in the 1st trimester
• Commonly used drugs include :-
 antiemetics, - antacids,
 antihistamines, - analgesics,
 antimicrobials, - antihypertensive,
 tranquilizers, - hypnotics,
• women also abuse recreational drugs:-
 Alcohol, amphetamine, cigarettes
 Criteria for Proof of Human Teratogenicity
1. It is more often associated with individuals having a specific
defect than with appropriately matched controls.
2. A specific malformation is consistently associated with exposure
to the teratogen (two or more epidemiological studies of high
quality)
3. Biologic plausibility;
- Cleft palate in 3rd trimester
4. The anomaly was less common before the presumptive
teratogen was introduced.
- Phocomelia Vs thalidomide.
5. Experimental animals will develop the anomaly if exposed
1. The Defect Must Be Completely
Characterized:-
• Identical defects with different etiologies
are called phenocopies
• Cleft palate Vs Hydantoid Vs 200 others
2. The Agent Must Cross the Placenta
• transfer depends on both :-
A. maternal metabolism and
B. specific characteristics of the drug,
– such as protein binding and storage,
– molecular size,
– electrical charge, and
– lipid solubility
• Placental enzymes cyt P450,
• Placental thickness in 1st Trimester
3. Exposure Must Occur during a Critical
Developmental Period
• Gestation is divided into three periods, and
syndromes resulting from teratogen
exposure are named accordingly.
• embryopathy = Exposures within 8 weeks
• fetopathy = after 8 weeks
The preimplantation period
• 2 weeks from fertilization to implantation
• traditionally called the "all or none" period
• insult damaging a large number of cells usually
causes death of the embryo.
• If only a few cells = compensation is usually
possible with continued normal development
• The embryonic period,
• from 2 - 8 weeks following conception,
• encompasses organogenesis
• thus the most crucial with regard to
structural malformations
• Fetal period
• after 9 weeks till delivery
• Maturation and functional development
continue after 9 weeks,
• certain organs remain vulnerable
• Ex. the brain remains susceptible
throughout pregnancy to environmental
influences such as alcohol exposure
• The Suspected Teratogen Causes a
Defect in an Animal
• especially subhuman primates
• thalidomide and corticosteroids
 Food and Drug Administration Classifications

• a system for rating drug safety in pregnancy (1980)

• system is problematic
• Fertility and Lactation not addressed
• OCP as category X previously
 CATEGORY A
• Controlled studies in humans have demonstrated no
fetal risks
• There are few category A drugs
• Examples include prenatal vitamins, but not massive
dosages of vitamins.
 CATEGORY B
• Animal studies indicate no fetal risks, but there are
no human studies; or
• adverse effects have been demonstrated in animals,
but not in well-controlled human studies
• Ex. Penicillin
 CATEGORY C
• There are either no adequate studies, either animal or
human, or
• there are adverse fetal effects in animal studies but
no available human data.
• Many medications pregnant women use fall into this
category.
 CATEGORY D
• There is evidence of fetal risk, but benefits are
thought to outweigh the risks
• Ex. Phenitoin
• Ex. Carbamzepine
 CATEGORY X

• Proven fetal risks clearly outweigh any benefit

• Ex. Isotretinoin
 Mechanisms of Teratogenicity
• Teratogens likely act by disturbing specific pathogenetic
processes, leading to :-
 cell death,
 altered tissue growth, or
 abnormal cellular differentiation

• teratogenic exposure commonly results in multiple effects

• different drugs can produce similar phenotypes if they
disturb similar pathophysiological processes
• Ex. fetal hydantoin syndrome
 Two major mechanisms of teratogenesis
1. Disruption of Folic Acid Metabolism
• Folic acid is essential for the production of methionine,
( RNA and DNA synthesis)
• FA required for methylation reactions
• Anti convulsants impair folate absorption or act as
antagonists
• neural-tube defects, cardiac defects, cleft lip and palate,
and even Down syndrome
• Prenatal deficiency Vs supplements
2. Oxidative Intermediates
• Hydantoin, carbamazepine, and phenobarbital are metabolized by
microsomes to arene oxides or epoxides.
• These oxidative intermediates normally are detoxified by cytoplasmic
epoxide hydrolase,
• because fetal epoxide hydrolase activity is weak,
• oxidative intermediates accumulate in fetal tissue
• These free oxide radicals have :-
– carcinogenic, mutagenic, and other toxic effects
• These effects are dose related and increase with multidrug therapy
Fetal Genetic Composition
• many anomalies now categorized as multifactorial are
caused by the interaction of environment and certain
altered genes
 Ex. MTHFR mutation,
• NTD & other malformations,
• but only when the mother has inadequate folic acid
intake
 Ex. mutation of epoxide hydrolase
• hydantoin exposure plus homozygous for a gene
mutation resulting in abnormally low levels of epoxide
hydrolase = malformation
Paternal Exposures
• paternal exposures to drugs may increase the
risk of adverse fetal outcome
• Mechanisms:-
1. gene mutation in sperm (two months before
conception)
2. a drug in seminal fluid could directly contact the
fetus during intercourse

3. agents may alter gene expression

 Known Teratogens
Fortunately:-
• medications strongly suspected or proven to be
human teratogens is small
• there are several alternate drugs that can be
given with relative safety
• If uncertain about the drug – give only if the
benefits clearly outweigh any theoretical risks
 Anti-infectives
• Penicillin • Sulfonamides
• Cephalosporins • Miscellaneous Antibiotics
• Carbapenems • Antivirals
• Fluoroquinolones • Antiretrovirals
• Macrolides • Antifungals
• Aminoglycosides
 Penicillins

• Category B in pregnancy
– Cross the placenta easily and rapidly
– Concentrations equal maternal levels

• Lactation
– Crosses in low concentrations
– Compatible with breastfeeding
 Cephalosporins
• Category B in pregnancy
• Cross the placenta during pregnancy
– Some reports of increased anomalies with specific
cephalosporins
• (cefaclor, cephalexin, cephradrine)
– Primarily cardiac and oral cleft defects
• Lactation
– Excreted into breastmilk in low concentrations
– Considered compatible with breastfeeding
 Fluoroquinolones
• Pregnancy Category C
– Not recommended in pregnancy
– Cartilage damage in animals
– Safer alternatives usually exist
– Ciprofloxacin, ofloxacin, norfloxacin
• Lactation
– Excreted into breast milk
– Limited human data
– FDA says compatible with breastfeeding
 Macrolides
(azithromycin, clarithromycin, erythromycin)

• Pregnancy Categories B/C/B

– Cross the placenta in low amounts
– Limited data = azithromycin & clarithromycin

• Lactation
– Erythromycin compatible
– Others probably compatible
 Aminoglycosides
(amikacin, gentamicin, streptomycin)

• Pregnancy Category C
– Rapidly cross placenta
– Enter amniotic fluid through fetal circulation
– Ototoxicity (CN-VIII)
• Lactation
– Compatible with breastfeeding
– Not absorbed through GI tract
 Sulfonamides
• Pregnancy Category C
– Readily cross the placenta
– Concerns of use at term
– Compete for bilirubin binding sites
– Hyperbilirubinemia if used near delivery in preterm
infants
• Lactation
– Excreted into breastmilk in low levels
– Use should be avoided in premature infants
 Tetracyclines
(doxycycline, minocycline, tetracycline)

• Pregnancy Category D
– Can cause problems with teeth and bone and other
defects/effects
– Have been linked to maternal liver toxicity
• Lactation
– Compatible with breastfeeding
– Serum levels in infants undetectable
 Clindamycin

• Pregnancy Category B,
– commonly used during pregnancy

• Lactation – Compatible
 Metronidazole

• Pregnancy Category B,
– carcinogenic in animals,
– avoid in 1st trimester if possible
• Lactation –
– hold feeds for 12-24hrs afterward
 Nitrofurantoin
• Pregnancy Category B,
– possible hemolytic anemia with use at term
• Lactation –
– Compatible
– avoid with G-6-PD deficiency
 Antimalarials
• Chloroquine
• Quinine and quinidine
• mefloquine
• no increased rate of congenital anomalies in the offspring
 ARV
• There are several antiretroviral drugs that should not be used in
pregnancy:
• Efavirenz;
– Malformation (NTD)
• d4T + ddI (stavudine/didanosine);
– Lactic asidosis
• Nevirapine in women with CD4 count >250/mm3
– Hepatotoxic

• The benefit outweighs the potential risk!!!!

 Hormons
• Androgens
– Masculinization in female fetus
• Progesterone
– Virilization in female fetus
• Estrogen
– No effect
 Alcohol
• Fetal alcohol syndrome
 IUGR
 Behavioral disturbance
 Brain and spinal defects
 Craniofacial anomalies
Absent philtrum
Broad upper lip
Flattened nasal bridge
Micrognathia
Short nose
microophthalmia
FAS
 anticonvulsants
• Fetal Hydantoin Syndrome
• Higher risk with polytherapy
Craniofacial defect
Limb abnormality
Mental deficiency
 anticoagulants
• Warfarine Vs Heparine
– Warfarine embryopathy
• ASA
 Others
• ACE inhibiters
– IUGR
– Oligohydraminios
– Renal tubular dysgenesis
– Pulmonary hypopasia
– Limb contracture
– Perinatal death
• Other anti hypertensives
– Methyldopa, b-blockers, Ca++ CB,
– Diuretics
• The list continues….
 Remember!!!!!
• When prescribing drugs in pregnancy :-
 try to use drugs or drug classes known to be of low
teratogenic potential,
 avoid critical periods of toxicity (eg, during
organogenesis for all drugs, near delivery for some
drugs), and
 consult
Thank You