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Teratogenicity and Drug Use During Pregnancy and Lactation: Andrada Catrinoiu Diana Avram Erasmus Canakkale 1/04/2019

This document discusses teratogenicity and drug use during pregnancy and lactation. It defines teratogenesis and teratogens, and notes that approximately 10-15% of congenital anomalies result from environmental exposures. Various factors that influence teratogenesis are described, including the specificity of the agent, dosage, genotype, stage of development, and drug interactions. Examples of teratogens like radiation, infectious agents, hyperthermia, and various drugs including alcohol, tobacco, antibiotics, anticonvulsants, and chemotherapy agents are provided along with their potential risks. Considerations for drug use during lactation focus on minimizing infant drug exposure.

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191 views19 pages

Teratogenicity and Drug Use During Pregnancy and Lactation: Andrada Catrinoiu Diana Avram Erasmus Canakkale 1/04/2019

This document discusses teratogenicity and drug use during pregnancy and lactation. It defines teratogenesis and teratogens, and notes that approximately 10-15% of congenital anomalies result from environmental exposures. Various factors that influence teratogenesis are described, including the specificity of the agent, dosage, genotype, stage of development, and drug interactions. Examples of teratogens like radiation, infectious agents, hyperthermia, and various drugs including alcohol, tobacco, antibiotics, anticonvulsants, and chemotherapy agents are provided along with their potential risks. Considerations for drug use during lactation focus on minimizing infant drug exposure.

Uploaded by

Diana Avram
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Teratogenicity and drug use

during pregnancy and


lactation
Andrada Catrinoiu
Diana Avram

Erasmus Canakkale
1/04/2019
Teratogenesis- production of defects in the fetus.

Teratogenic agent-any environmental factor that can produce a


permanent abnormality in structure or function, restriction of
growth, or death of the embryo or fetus

Teratogens: irradiation, chemicals (drugs), and infectious agents


*approximately 10–15% of congenital structural anomalies are the result of
the adverse effect of environmental factors on prenatal development
-Most structural defects caused by teratogenic exposures occur during the embryonic
period.
-Different organ systems have different periods of susceptibility to exogenous agents
VARIABLES AFFECTING
TERATOGENESIS

1.Specificity of the agent :


some organ systems are preferentially affected
2. Dosage:
an agent may be teratogenic only at a higher or lower dose at a different stage.
Small doses administered over several days may produce a different effect
than an equal total amount administered at one time
3. Genotype :
polygenic / monogenic inheritance.
steps involved in drug catabolism : (1) maternal ability to absorb or
metabolize a teratogen (2) placental transfer (3) fetal metabolism
4. Stage of embryonic development – 3 stages
-1 the embryo is relatively resistant (first 2 w)
-2 organogenesis (3-8w) susceptibility to teratogens is maximal
-3 teratogen can affect the overall
growth of the embryo or the size
of a specific organ (8-10 w)
5. Drug Interactions
6.Other factors : maternal or fetal weight,
fetus position, diet
Radiation

-Ionizing radiation - cell death or chromosome injury.


-Diagnostic levels-no proof of human congenital malformations
- the central nervous system (CNS) retains the greatest
sensitivity to the detrimental effects of radiation through the later
fetal stages.
In utero radiation produces microcephaly and mental
retardation.
Later in life there is increased incidence of hematopoietic
malignancies and leukemia
Infectious Agents

-Lethal or developmental effects ← mitotic inhibition, direct


cytotoxic effects, or a vascular disruptive event on the embryo or
fetus.
-repair process → scarring or calcification → histogenesis
-may cause fetal or neonatal death : enteroviruses
(coxsackievirus, poliovirus ,and echovirus) , hepatitis, variola,
vaccina, and mumps viruses.
Thermodisruptions

• Hyperthermia is defined as a body t >38.9°C →antimitotic


teratogen after exposure between weeks 4 and 14.
>Severe mental deficiency, seizures in infancy, microphthalmia,
midface hypoplasia, and mild distal limb abnormalities .
• Hypothermia is defined as a core body t <35°C.
>disruptive defects of the brain and distal spinal cord, suggesting
hypoperfusion
Ethanol, Smoking, and Various
Drugs
1.Fetal Alcohol Syndrome (FAS). 1-2 oz of absolute ethanol /day
3characteristics: prenatal and postnatal growth retardation (>2
SD for L and W), facial anomalies, and CNS dysfunction

2. Tobacco smoking. Nicotine- vasoconstriction- uterine vascular


constriction and intrauterine growth retardation (IUGR)-
decreased perfusion of fetal tissues.
The increased mortality is attributed to abruptio placentae,
placenta previa, spontaneous abortion, prematurity, and IUGR
FDA Rating System for the
Teratogenic Effects on Drugs

• First regulations were implemented in 1962, after exposure of over 10.000


children to thalidomide.

• The 5-letter classification system (A, B, C, D, E, X) was introduced in 1979


by the FDA.

• Because of the limited information about the safety of some medications (in
category C), the 5-letter system is being phased out in favor of a more
comprehensive system with a narrative summary of the risks posed by drugs.
The pregnancy subsection

• Is now presented under the following


subheadings:

– Pregnancy Exposure Registry


– Risk summary
– Clinical considerations
– Data
1. Antibiotics
• Aminoglycosides:
– Amikacin, Gentamycin, Kanamycin, Tobramycin, Neomicin,
Strepto

Old categorization: D
Risk summary: hearing defects, vestibular problems, ear damage
Data: since 1950, approx. 50 cases of fetal ototoxicity have been
described after maternal exposure to Streptomycin. These cases
occurred when high doses were used to treat tuberculosis.
2. Antiretrovirals
– Abacavir, Didanosine, Lamivudine, Tenofovir, Zidovudine,
Indinavir

Old categorization: B or C
Risk summary: Didanosine had increased risk of birth defects in 1st
trimester. No specific pattern of defects was noted and clinical
relevance is uncertain.
Data: studies in monkeys for Tenofovir show decreased fetal growth
and reduction in fetal bone porosity. Human studies demonstrate no
effect on intrauterine growth, but data are conflicting about potential
outcomes in later infancy.
3. Cardiovascular Medications

• ACE inhibitors: Captopril, Enalopril, Fosinopril, Ramipril

Old categorization: C or D
Risk summary: first three trimesters.
Reported complications in pregnancy: oligohydramnios, intrauterine
growth restriction, neonatal renal failure.
Reported birth defects: bony malf, limb contractures, pulmonary
hypoplasia, patent ductus arteriosus
Clinical consideration: stop ACE inhibitor asap if a patient is discovered to be
pregnant.
4. Neurologic Medications

• Anticonvulsivants, 1st generation: Phenytoin, Carbamazepine, Valproate,


Primidone

Old categorization: D
Risk summary: first three trimesters.
Associated defects and complications: facial dysmorphia, gingival hyperplasia,
neurological hyperexcitability, temporal atrophy in the left brain hemisphere.
Data: NEJM- retrospective cohort study:
20% of neonates exposed to 1 drug had birth defects.
28% of neonates exposed to 2 or more drugs had birth defects.
5. Psychiatric Medications

• Benzodiazepines: Alprazolam, Clobazam, Clonazepam, Diazepam,


Lorazepam, Midazolam

Old categorization: D or X
Risk summary: first three semesters. Associated defects and
complications: unclear, potential for isolated oral cleft.
Clinical considerations: avoid Triazolam, use the other with caution
Data: the information currently available is insufficient
6. Respiratory Medications
• Leukotriene receptor antagonists: Montelukast, Pranlukast, Zafirlukast

Old categorization: B
Risk summary: congenital limb defects (rare)
Clinical consideration: they should be used in pregnancy only if clearly needed
Data: Bakhireva: perinatal outcomes among:
96 women who took MLK or ZLK
122 women who took SABA
346 women without asthma

-> no specific pattern of structural anomalies was found.


Animal data: no teratogenicity was observed in rats and rabbits
at the maximum recommended daily oral dose in adults
7. Oncologic Medications

• Antineoplastics: Busulfan, Chlorambucil, Cyclophosphamide,


Mechloretamine

Old categorization: D and X


Risk summary: first three trimesters. Associated defects and
complications: intrauterine growth reduction, cleft palate, renal agenesis,
cardiac anomalies, cloudy corneas.
Data: 10-50% of fetuses exposed to antineoplastic alkylating agents are
malformed. The malformation rate for first trimester exposure- 11.6%.
Drugs during lactation
• milk-to-plasma-drug-concentration ratio
• shorter half-life
• To minimize infant exposure, choose medication with: • poorer oral absorbtion
• lower lipid solubilty
Drugs absolutely contraindicated while breastfeeding:
Cytotoxic drugs: cause immune suppression, neutropenia,
affect growth, increase risk of childhood cancer

Radioactive isotopes of copper, gallium, iodine, technetium


consultation with a nuclear medicine specialist before
performing a diagnostic study with these isotopes

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