EFFECT OF MATERNAL
DRUGS ON FETUS
Congenital Malformations
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3-4% of all babies are born with a major
birth defect
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Of these, 50% are of unknown cause
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Consider teratogen exposure and
realize genetics plays a role
TERATOGENS
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A substance, organism, physical agents or
deficiency state capable of inducing
abnormal structure or function such as:
 Gross structural abnormalities
 Functional deficiencies
 Intrauterine growth restriction
 Behavioral aberrations
Teratogenic agents
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1) Drugs and chemicals
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2) Infectious agents
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3) Radiation
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4) Other
Teratogenic Factors
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Time of exposure
Developmental stage during exposure
Maternal dose and duration
Maternal pharmacokinetics
Genetic factors/phenotypes
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Interactions between agents
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TERATOGENIC EFFECT
Drug Transfer to the Fetus
Placental transfer may occur by:
 Passive diffusion
 Facilitated diffusion
 Active transport
 Placental surface area
 Placental metabolism
Drug use in pregnancy
Drugs can be harmful for the unborn fetus
 Across Placenta
 Molecular weight
 Lipid solubility
 Ionization
 Protein binding
 Chemical Structure
Fetal Drug Disposition
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60 – 80% passes through liver, the rest travels
through ductus venosus to heart and brain
Hepatic drug metabolism
Adrenal gland metabolism
Recirculation through amniotic fluid
Drug use in pregnancy
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Effects of toxic drugs
• malformation
• growth retardation
• fetal death
• functional defects in newborn
• premature birth
Risk classifications
• Different risk classifications have been
proposed.
• The FDA risk classification is widely used
Risk classification of FDA
drug risks to the fetus runs from:
Category A (safest) →
Category X (known danger--do not
use!)
FDA Risk Categories
A- Studies on humans; no risk
B- Animal studies- no risk; No human studies
C- Either animal studies show adverse effect and
no
human studies or no
animal or human studies
(benefit should
outweigh risk)
Drugs should be given only if the potential
benefit justifies the potential risk to the fetus.
FDA Categories (cont)
D- Positive evidence of human risk(drug is needed
in a life-threatening situation or
for a serious disease for which safer drugs
cannot
be used or are ineffective).
X- Positive evidence of human risk; risk
outweighs benefit and drug is contraindicated
Thalidomide, DES (diethylstilboestrol).
,
Anti-infectives
Penicillins
Cephalosporins
Carbapenems
Fluoroquinolones
Macrolides
Aminoglycosides
Sulfonamides
Antivirals
Antiretrovirals
Antifungals
Penicillins
Category B in pregnancy
Cross the placenta easily and rapidly
Concentrations increased in maternal levels
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
Carbapenems
(ertapenem, imipenem,
meropenem)
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Category B/C/B in pregnancy
 Likely cross the placenta
 Very little human data
Fluoroquinolones
(floxins)
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Pregnancy Category C
 Not recommended in pregnancy
 Cartilage damage
Macrolides
(azithromycin, clarithromycin,
erythromycin)
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Pregnancy Categories B/C/B
 Cross the placenta in low amounts
 Limited data with azithromycin and
clarithromycin
Aminoglycosides
(amikacin, gentamicin,
tobramycin)
• Pregnancy Category C
Rapidly cross placenta
Enter amniotic fluid through fetal circulation
Sulfonamides
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Pregnancy Category C
 Readily cross the placenta
 Concerns of use at term
Antiepileptics
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Risk for syndrome 10%
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Dilantin- phenytoin syndrome
Microcephaly
Nail dysplasia
Developmental delay
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Risk for some adverse effect (low IQ)- 30%
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Accutane
X
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Vitamin A derivative
Retinoic acid
Timing is key- beyond
15 days
postconception
Dose specific
Accutane
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Risk of syndrome- 10-30%
Microcephaly/hydrocephaly
CHD
Microtia
Cleft lip/palate
Risk of spontaneous abortion- 25%
Risk of stillborn
Anticoagulants
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Warfarin: D
Exposure- 4-7 weeks
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Fetal warfarin syndrome: 10%
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Hemorrhage
Depressed nasal bridge
Spontaneous abortion / stillbirth- 25%
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Heparin
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Not teratogenic
Angiotensin-converting
enzyme
inhibitor D
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Reduced fetal renal blood flow
Fetal anuria
IUGR
Oligohydramnios
Tetracyclines
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MaternalIV use in pregnancy: acute fatty liver,
hepatotoxicity
decidual bone/teeth: forms a complex
calcium orthophospphate complications
Minor anomalies?
Quinolone
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Animal studies
Fetal death, neonatal death, preterm
delivery, IUGR
Anomalies: nonspecific
1000 exposed women: no increase in
adverse effects
Birth Registry: No increased risk
Use alternatives:
Lithium
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11% malformations rate- 1st trimester exposure
Most were CV defects
Risk of rare Ebstein’s anomaly
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Neonatal toxicity (1-2 weeks)
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Antivirals
(acyclovir, famciclovir,
valacyclovir)
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Pregnancy Category B
 Acyclovir and valacyclovir readily cross the
placenta
 Can be used for HIV treatment and
suppression
Antiretrovirals
zidovudine
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Pregnancy Category C
 Maternal benefit usually outweighs fetal risk
 Cross the placenta by simple diffusion
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Zidovudine is commonly used, but may cause
neonatal anemia
Antiretrovirals( nevirapine)
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Pregnancy Category C
 Maternal risk usually outweighs fetal
risk
 Likely cross into fetus Nevirapine can
cause hepatotoxicity and rash
 Nevirapine can be used as a single
dose in labor to prevent HIV
transmission
Antifungals/Azoles
(fluconazole, ketoconazole)
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Pregnancy Categories C/D
 Likely cross placenta
 Fluconazole > 400mg/day seems to be
associated with cranio-facial abnormalities
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Ketoconazole can impair cortisol synthesis
Ergots
(Dihydroergotamine,
ergotamine)
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Pregnancy Category X
 Oxytocic properties could cause IUGR by
vascular disruption or increased uterine tone
 Early exposure appears safe, not teratogens
 Chronic exposure is contraindicated
Frequently used teratogenic
agents
• Alcohol
• Smoking
orofacial clefts 1/500 – 1/183
lower birth weight
premature birth
Alcohol
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1-2% women of child-bearing age have an
alcohol abuse problem
Fetal alcohol syndrome- most common
cause of mental retardation in the US
Craniofacial skeletal abnormalities
growth retardation
mental disorders
Nicotine is a Neuroteratogen
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Cell damage and deficits in cell number
Impaired synaptic activity
Receptor-Mediated, therefore low
threshold
Affects Cell Replication/Differentiation
Switchover
Initiates the Program for Cell Death
Morphological changes subtle but
detectable in adulthood
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Maternal Cigarette Smoking
Nicotine in Fetus
Effects on Fetal Brain
General Development
Perinatal Morbidity/Mortality
Growth Retardation
Behavioral Anomalies
Maternal-Fetal Unit
Hypoxia/Ischemia
CO, HCN
Anorexia
Risky Behaviors:
Other drugs/alcohol
Prenatal Care
Socioeconomic
Frequently used teratogenic
agents
• Coffee
> 300 mg caffein/day (>3-6 cups of coffee)
↑ risk of fetal death
advice: limit coffee to 3 cups/day
• Vitamin A
teratogenic in animal model, in human beings?
avoid > 3 mg = 10.000 IE
liver contains large amounts of vitamin A
Herbs use in pregnancy
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Herbs not recommended
nettle root
• alkaloid-containing herbs
coffee, mandrake (podophyllin) …
• essential oils
rosemary …
• anthraquinone laxatives
senna …
• herbs with potential hormonal action
hops, ginseng, licorice …
Drug use in pregnancy
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Use of drugs in pregnancy is not
always wrong
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Drugs should be used with caution
during pregnancy
Thank you