OBSTETRICS

LECTURE: 1.7 Teratology, Teratogens, and Fetotoxic Agents

LECTURER: Dr. Hidalgo
DATE: 9/1/16
TRANSCRIBER: Group 1 Kalaw,Kalaw,Kang,Keller
EDITOR: J. Rosario

OUTLINE  Women use an average of 2 to 3 medications per

I. Studies in pregnant women pregnancy and that 70% take medication in the first
II. Criteria for determining teratogenicity trimester
III. Critical periods of fetal development
IV. Food & drug administration classification
V. Counselling for teratogen exposure Teratology - Study of birth defects and their etiology
VI. Genetic and physiological susceptibility to teratogens
VII. Known and Suspected Teratogens Teratogen
- Alcohol  derived from the Greek teratos, meaning monster
- Anticonvulsant medications  any agent that acts during embryonic or fetal
- ACE Inhibitors and ARBs development to produce a permanent alteration of form
- Antifungal medications
- Anti-inflammatory medications or function
- Antimicrobial drugs
- Antineoplastic agents Table 1. Selected Teratogens and Fetotoxic Agents (no need
- Antiviral agents to memorize according to the lecturer)
- Endothelin-Receptor Antagonists Acitrecin Lenalidomide DES
- Sex Hormones Alcohol Lithium Tobacco
- Immunosuppresant medications Ambrisentan Methimazole Efavirenz
- Radioiodine
- Lead
Ace inhibitors Mercury Toluene
- Mercury ARBs Methotrexat Fluconazole
- Psychiatric Medications Androgens Mycophenolate Topiramate
- Retinoids Bexarotene Phenobarbital Isotretinoin
- Thalidomide and Lenalidomide Carbamazepine Phenytoin Trastuzumab
- Warfarin Chloramphenicol Radioactive iodine Lamotrigine
- Herbal Remedies
- Recreational Drugs Cocaine Ribavirin Tretinoin
- Miscellaneous Drugs Bosentan Misoprostol Lead
- Tobacco Corticosteroids Tamoxifen Valproic acid
Cyclophosphamide Tetracycline Warfarin
OBJECTIVES: Danazol Thalidomide Leflunomide
At the end of the lecture, the student should be able to:
1. Identify criteria for determining teratogenicity
2. Enumerate FDA drug categories as to teratogenic potential  Pregnant women are considered a special population and
3. To discuss the genetic and physiological susceptibility to excluded from trials
teratogens  Reasons:
4. Discuss common teratogenic drugs and their effects - To prevent the embryo and fetus from potentially
harmful effects of a medication
References (APA Bibliography format): - Pregnancy physiology affects medication – its
1.) Lecturer’s Powerpoint
2.) Bloom et al.(2014). Williams Obstetrics 24th ed. USA: McGRw-
pharmacokinetics
Hill Education.
3.) Recording Case Report and Series
- A major limitation of case series is that they lack a
Legend: Italicized – quoted from the lecturer; bold – emphasis, or from control group
references
Pregnancy Registries
I. STUDIES IN PREGNANT WOMEN - Clinicians prospectively enroll exposed pregnancies in
 2 to 3% of all newborns have a major congenital abnormality a registry to monitor potentially harmful agents
detected at birth
 At age 5, another 3% have been diagnosed with Case Control Studies
malformation - Investigators retrospectively assess prenatal
 At age 18, another 8 to 10% have one or more apparent exposure
functional or developmental abnormalities - Two inherent weaknesses:
 About 70% of birth defects = no obvious etiology 1. Potential for recall bias in which the mother of
 Those with identified cause = more likely to be genetic than an affected infant may be more likely to recall
teratogenic exposure
 FDA (2005) estimates less than 1% of all birth defects are 2. It can only evaluate associations rather than
caused by medications causality and thus hypothesis generating

TRANSCRIBER: Trans Group 1 (Issa Kalaw 09276845584) EDITOR: J. Rosario 1

OBSTETRICS: 1.7 TERATOLOGY, TERATOGENS, AND FETOTOXIC AGENTS (2018B)
The National Birth Defects Prevention Study
- A population based case control study involving 10
states with active birth defects surveillance programs
- A collaborative effort of the Centers for Birth Defects
Research and Prevention to evaluate medications as
a cause of birth defects
II. CRITERIA FOR DETERMINING TERATOGENICITY
Essential Criteria
1. Careful delineation of clinical cases, particularly if there is a
specific defect or syndrome
2. Proof that exposure occurred at a critical time during
development
3. Consistent findings by at least 2 epidemiological studies
with:
a. Exclusion of bias
b. Adjustment of confounding variables
c. Adequate sample size (power)
d. Prospective ascertainment if possible
e. Relative risk of 3.0 or >, some recommend RR of
0.6 or >
OR, for a rare environmental exposure associated with a rare
defect, at least 3 cases are reported. This is easiest if defect is
severe.
Ancillary Criteria
4. The association is biologically plausible
5. Teratogenicity in experimental animals is important but not
essential
6. The agent acts in an unaltered form in an experimental
model
The following tenets must be considered (summary of the
criteria):
 The defect has been completely characterized
 The agent must cross the placenta
 Exposure must occur during a critical development
period
 A biologically plausible association is supportive
 Epidemiological findings must be consistent
 The suspected teratogen causes a defect in animal
studies
III. CRITICAL PERIODS OF FETAL DEVELOPMENT
PREIMPLANTATION PERIOD
 2 weeks from fertilization to implantation
 Insult causes either pregnancy loss due to severe cellular
damage or normal development because damaged cells are
replaced (ALL OR NONE LAW)
EMBRYONIC PERIOD
 2nd to 8th week: it encompasses organogenesis
 Most crucial with regard to structural malformation
FETAL PERIOD
 Beyond 8 weeks
 Characterized by continued maturation and functional
development, during this time, certain organs are vulnerable
TRANSCRIBER: Trans Group 1 Issa Kalaw (09276845584) EDITOR: J. Rosario
IV. FOOD AND DRUG ADMINISTRATION CLASSIFICATION
“As much as possible we refrain from giving any medication. The
only recommended that can be given is folic acid at a
recommended level, not even vitamins. Unless is rural areas
that they are nutritionally deficient that we give multivitamins.” -
Hidalgo, 2016
A. Category A
 Studies in pregnant women have not shown any risk for
fetal abnormalities if administered (second, third, or all)
trimester(s) of pregnancy, and the possibility of fetal harm
appears remote
o Fewer than 1% of all medications are in this category
o Examples: levothyroxine, potassium supplements,
prenatal vitamins, when given at recommended doses
B. Category B
 Animal reproduction studies have been performed and have
revealed no evidence of impaired fertility or harm to the
fetus
 Prescribing information should specify kind of animal and
how dose compares with human dose OR
 Animal studies have shown an adverse effect, but adequate
and well-controlled studies in pregnant women have failed
to demonstrate a risk to the fetus during the 1st
trimester of pregnancy, and there is no evidence of a risk
in later trimesters
C. Category C
 Animal reproduction studies have shown that this
medication is teratogenic (embryocidal or has other
adverse effect), and there are no adequate and well-
controlled studies in pregnant women
 Prescribing information should specify kind of animal and
how dose compares with human dose OR
 No animal reproduction studies and no adequate and well-
controlled studies in humans
 Approximately 2/3 of all medications are in this category
 It contains medications commonly used to treat life-
threatening medical conditions such as albuterol and
calcium channel blockers
D. Category D
 This medication can cause fetal harm when administered
to a pregnant woman
 If this drug is used during pregnancy or if a woman becomes
pregnant while taking this medication, she should be
apprised of the potential hazard to the fetus
 This category also contains emergency medications used to
treat potentially life-threatening medical conditions like:
corticosteroids, azathioprine, carbamazepine and lithium
E. Category X
 This medication is contraindicated in women who are or
may become pregnant
 It may cause fetal harm if this drug is used during pregnancy
or if a woman becomes pregnant while taking this
medication, she should be appraised of the potential harm to
the fetus
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The A, B, C, D and X risk categories, in use since 1979, are now
replaced with narrative sections and subsections due to vague
differences to include:
Pregnancy (includes Labor and Delivery)
 Pregnancy Exposure Registry
 Risk Summary
 Clinical Considerations
 Data
Lactation (includes Nursing Mothers)
 Risk Summary
 Clinical Considerations
 Data
Females and Males of Reproductive Potential
 Pregnancy Testing
 Contraception
V. COUNSELLING FOR TERATOGEN EXPOSURE
How do we present Risk Information to our patients?
i.e. pregnant patient with malignancy
 Counselling should include a discussion on the risks and/or
genetic implications of the underlying condition for which
the drug is given with as well as risks associated with not
treating the condition
 Should be part of routine preconceptional and prenatal
care
 Women are usually misinformed regarding level of risk
 Usually, they may underestimate the background for birth
defects in the general population and exaggerate the
potential risks associated with medication exposure
VI. GENETIC AND PHYSIOLOGICAL SUSCEPTIBILITY TO
TERATOGENS
 Teratogens act by disturbing specific physiological processes
– leading to abnormal cellular differentiation, altered tissue
growth or cell death
 Even the most potent teratogen induces birth defects in only a
fraction of exposed embryos
 Reasons why some infants are affected and others are not
remains largely unknown
 Fetal Genome
 Genetic composition has been linked to susceptibility to
teratogenic effects of specific drugs
 Disruption of folic acid metabolism
 Fetal neural tube defects, cardiac defects, and oral clefts
can be a result of folic acid metabolic pathway
disturbances
 Folates are essential for methionine production, required
for gene methylation and thus production of myelin
(giving prophylactic folate even 2 mos before pregnancy)
 Paternal Exposure
 Paternal exposures to drugs or environmental influences
may increase the risk of adverse fetal outcome
 Induction of gene mutation or chromosomal abnormality
in sperm is a proposed mechanism
 In a study, there is an exposure to teratogen during
sexual intercourse in the seminal fluid
TRANSCRIBER: Trans Group 1 Issa Kalaw (09276845584) EDITOR: J. Rosario
VII. KNOWN AND SUSPECTED TERATOGENS
A. ALCOHOL
 Ethyl alcohol is a potent and prevalent teratogen
 One of the most frequent non-genetic causes of
mental retardation as well as leading cause of
preventable birth defects in the US
 Centers for Disease Control and Prevention claims that
8% of women drink alcohol during pregnancy
 NBDPS (National Birth Defects Prevention Study)
identified a prevalence of as high as 30%
 Binge drinking is about 1-2% in pregnant women
Fetal Alcohol Syndrome or FAS
 Prevalence: 0.6-3 per 1000 births
 Spectrum of alcohol-related fetal defects
 Criteria for FAS diagnosis requires all three of the
following findings:
1. Documentation of all three facial abnormalities namely
smooth philtrum, thin vermillion border, and small
palpebral fissure
2. Documentation of growth deficits
3. Documentation of CNS abnormalities
Fetal Alcohol Spectrum Disorder
 Prevalence: estimated to be as high as 1% of births in the
US (CDC, 2012;Guerri, 2009)
 Umbrella term that includes the full range of prenatal
alcohol damage that may not meet the criteria for fetal
alcohol syndrome
Dose Effect:
 The fetal vulnerability to alcohol is modified by:
- Genetic factors
- Nutritional status
- Environmental factors
- Coexisting maternal disease
- Maternal age
 The minimum amount of alcohol required to produce
adverse fetal outcome is unknown
 Binge drinking is believed to pose particularly high risk
for alcohol-related birth defects and also linked to an
increased risk for stillbirth (CDC, 2012;Maier,
2001;Strandberg-Larsen, 2008)
B. ANTICONVULSANT MEDICATIONS
 No anticonvulsant drugs are considered truly “safe” in
pregnancy
 Most medications used to treat epilepsy have been
proven or suspected to confer an increased risk for fetal
malformations
 Traditionally, women taking anti-epileptic drugs were
informed of a 2-3 fold risk for fetal malformation
 More recent data suggest that the risk may not be as
great as once thought with the newer drugs
 Recent studies have shown a 3% malformation risk with
newer anticonvulsant drugs compared to a 2% risk in
unexposed fetuses
 3% risk is the same malformation rate as for those with
untreated epilepsy
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 Exception: Valproic Acid has a significant increased
risk for malformations
- Major malformations occurred in 9% of fetuses with 1st
trimester valproate exposure and a 4% risk of neural
tube defects
- Significantly lower IQ scores at age 3 yrs compared to
those exposed to other anticonvulsant drugs
(phenytoin, carbamazepine, or lamotrigine)
 Most frequent anomalies reported:
- Orofacial clefts
- Cardiac malformations
- Neural tube defects
- Fetal hyantoin syndrome
Topiramate
 North American Anti-Epileptic Drug (NAAED)
Pregnancy Registry and the NBDPS reported a risk of
at least 5 fold higher than in exposed pregnancies for
orofacial clefts
C. Angiotensin-Converting Enzyme Inhibitors and
Angiotensin-Receptor Blocking Drugs
 ACE-inhibitors are fetotoxic resulting in ACE-inhibitor
fetopathy
 Effects: fetal hypotension and renal hypoperfusion
with subsequent ischemia and anuria
 Refused perfusion may cause fetal growth restriction
and calvarium maldevelopment
 Oligohydramnios may result in pulmonary hypoplasia
and limb contractures
 Embryotoxicity of these 2 classes of drugs is less
certain
 1st trimester exposure was associated with a 2-3 fold
increased risk for cardiac and CNS abnormalities
 Findings have not been corroborated
 Recommendation: ACE-Inhibitors and ARB drugs
should be avoided for treating hypertension in
pregnancy
D. ANTIFUNGAL MEDICATIONS
FLUCONAZOLE:
 Has been associated with a pattern of congenital
malformations resembling the autosomal recessive
Antley-Bixler Syndrome
 Oral clefts, abnormal facies, cardiac, skull, long bone and
joint abnormalities
 Only with chronic, high dose treatment in the 1st trimester
= at doses of 400-800mg daily
 3-fold increased risk of Tetralogy of Fallot was
identified (Molgaard-Nielsen, 2013) with 1st trimester
exposure to low dose fluconazole in a population based
cohort of more than 7000 pregnancies.
 FDA categorized fluconazole as Pregnancy Category D
– but states that a single 150mg (prescribed for vaginal
candidiasis) dose does not appear to be teratogenic.
TRANSCRIBER: Trans Group 1 Issa Kalaw (09276845584) EDITOR: J. Rosario
Figure 1. Amniotic Band Syndrome-like syndrome in infant
born to mother on high-dose fluconazole. (Left) Patient at birth
with “pear-shaped” nose, “dysplastic” ears, exorbitism, and
synostosis at elbows. (Right) Radiograph at birth showing
radiohumeral synostosis. (Taken from lecturer’s PPT)
E. ANTI-INFLAMMATORY MEDICATIONS
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
 Aspirin, Ibuprofen, Indomethacin
 Inhibit prostaglandin synthesis
 At least 20% of pregnant women use these drugs during
the 1st trimester but does not appear to be a major risk
factor for birth defects
 Low dose aspirin 100mg (given to prevent pre-
eclampsia) daily does not confer an increased risk for
constriction of the ductus arteriosus or for adverse infant
outcome
 May cause adverse fetal effects when taken late in
pregnancy
 Indomethacin may cause constriction of fetal ductus
arteriosus resulting in pulmonary hypertension
 Fetal ductus constriction is more likely when drug is
taken for more than 72hrs in the 3rd trimester
Leflunomide
 Pyrimidine synthesis inhibitor used to treat rheumatoid
arthritis
 Contraindicated in pregnancy
 Associated with multiple congenital anomalies i.e.
ydrocephalus, eye anomalies, skeletal abnormalities,
and embryonic death
 Active metabolite of leflunomide is detectable in plasma
for up to 2yrs after discontinuation
 Cholestyramine treatment/washout (3x/day for 11
days) is indicated for women of child bearing potential
who discontinued this medication
 Serum levels are measured and undetectable on two
tests, 14 days apart (below 0.02mg/L)
F. ANTIMICROBIAL DRUGS
 One of the most common drugs prescribed in pregnancy
 Except for a few, most of the commonly used
antimicrobial agents are considered safe for the
embryo/fetus
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OBSTETRICS: 1.7 TERATOLOGY, TERATOGENS, AND FETOTOXIC AGENTS (2018B)
 Antimicrobial drugs not safe during pregnancy:
1. Aminoglycosides
- Gentamycin, streptomycin
- Preterm infants treated with the 2 drugs developed
nephrotoxicity (check creatinine) and ototoxicity
- Despite theoretical concern for potential fetal toxicity,
no adverse effects have been demonstrated
2. Chloramphenicol
- Not considered teratogenic
- No longer used in the US
- Gray baby syndrome was described in neonates
3. Nitrofurantoin – 1st line for UTI
- Associated with birth defects
- 4 fold increased risk for hypoplastic left heart
syndrome, microphthalmia/anophthalmia
- 2 fold increased risk for clefts and Autism Syndrome
Disorder (ASD)
- For postexposure counseling exposure, the absolute
risk of these defects remain quite low
- According to the American College of Obstetricians
and Gynecologists (ACOG), 1st trimester
nitrofurantoin use is appropriate if no suitable
alternatives are available
4. Sulfonamides – for treating UTI
- Used in combination with trimethoprim for various
infections like methicillin-resistant Staphylococcus
aureus (MRSA)
- NBDPS found association between 1st trimester
intake and:
 3 fold increased risk for anencephaly and
left ventricular outflow tract obstruction
 8 fold increased risk for choanal atresia
 2 fold increased risk for diaphragmatic
hernia
- ACOG considers sulfonamides appropriate for 1st
trimester use if suitable alternatives are lacking
5. Tetracycline
- Not commonly used anymore in pregnancy
- Associated with yellowish-brown discoloration of
decidiuous teeth when used after 25 weeks
- Risk for dental caries does not appear to be
increased
N. ANTINEOPLASTIC AGENTS
1. Cyclophosphamide
 Alkylating agent which inflicts a chemical insult on
developing fetal tissues, leading to cell death and
heritable DNA alterations in surviving cells
 Pregnancy loss is increased
 Skeletal abnormalities, limb defects, cleft palate,
eye abnormalities
 Surviving infants may have growth abnormablities
and developmental delays
 Environmental exposure among health-care
workers is associated with an increased risk for
spontaneous abortion
TRANSCRIBER: Trans Group 1 Issa Kalaw (09276845584) EDITOR: J. Rosario
2. Methotrexate
 Folic acid antagonist which is a potent teratogen
 Used for cancer therapy
 For immunosuppresion: autoimmune disease,
psoriasis
 Medical management of ectopic pregnancy
(abortifacient) – evaluate well using 2-3 UTZ
 Similar in action to aminopterin – no longer used
 Can cause defects known as methotrexate-
aminopterin syndrome (craniosytosis with “clover
leaf” skull, wide nasal bridge, low set ears,
micrognathia, and limb abnormalities)
3. Tamoxifen
 Nonsteroidal selective estrogen-receptor modulator
(SERM)
 Adjuvant treatment for breast cancer
 Fetotoxic and carcinogenic in rodents –
malformation similar to those caused by
Diethylstilbestrol exposure
 Pregnancy category D
 Recommended for women who become pregnant
while either on therapy or within 2 months of its
discontiuation be apprised of potential long term
risks of a DES like syndrome
 Exposed offspring should be monitored for
carcinogenic effects
4. Trastuzumab
 A recombinant monoclonal antibody directed to the
human epidermal growth factor receptor 2 (HER 2)
protein
 Used to treat breast cancer that over express HER
2 protein
 Not associated with fetal abnormalities
 Oligohydraminos, anhydraminos, fetal renal failure
have been described
 May result in fetal pulmonary hypoplasia, skeletal
abnormalities, or neonatal death
O. ANTIVIRAL AGENTS
1. Ribavirin
 A nucleoside analog
 Component therapy for hepatitis C infection
 Causes birth defects in multiple animal species at
doses lower than those recommended for human
use
 Malformations include: skull, palate, eye, skeleton,
and GI abnormalities
 Has a long half life and persists in extravascular
compartments following discontinuation of therapy
 Recommendation: women use 2 forms of
contraception while on therapy and delay
childbearing for 6 months following
discontinuation of the drug
2. Efavirenz
 Nonnucleoside reverse transcriptase inhibitor
 Used to treat HIV infection
 CNS and ocular abnormalities have been reported
in monkeys treated with human comparable doses
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OBSTETRICS: 1.7 TERATOLOGY, TERATOGENS, AND FETOTOXIC AGENTS (2018B)
 CNS abnormalities following human exposure
N. ENDOTHELIN-RECEPTOR ANTAGONISTS
Bosentan & Ambrisentan
- Are used to treat pulmonary hypertension
- Mice deficient of endothelin receptors develop
abnormalities of the head, face, and large vessels
O. SEX HORMONES
1. Testosterone and Anabolic steroids
 Causes virilization
 May result in ambiguous genitalia
 Labioscrotal fusion with 1st trimester exposure
 Phallic enlargement from later fetal exposure
2. Danazol – adverse effects in long term use i.e.
masculinization of females; no longer used now
 Ethinyl testosterone derivative
 Weak androgenic activity
 Used to treat endometriosis, immune
thrombocytopenic purpura, migraine headaches,
premenstrual syndrome, fibrocycstic breast disease
 Causes virilization in exposed female fetuses
 Dose-related pattern of citoromegaly, fused labia,
and urogenital sinus malformation
3. Dithylstilbestrol
 Synthetic estrogen
 1940-1971, between 2 to 10 million women were
given DES
 A series of women exposed to DES in utero
developed an otherwise rare neoplasm, vaginal
clear cell adenocarcinoma
 The absolute cancer risk in DES-exposed fetuses
was approximately 1/1000, with no relationship to
dosage
 Women with in utero DES exposure also had a 2 fold
increase in vaginal and cervical intraepithelial
neoplasia
 Has been associated with genital tract
abnormalities in exposed fetuses of both genders
 Women: hypoplastic, T-shaped uterine cavity,
cervical collars, hoods, speta, and coxcombs,
“withered” fallopian tubes
 Later in life, women exposed in utero have slightly
higher rates of earlier menopause and breast
cancer
 Men may develop epididymal cysts, microphallus,
hypospadias, cryptochidism, and testicular
hypoplasia
N. IMMUNOSUPPRESANT MEDICATIONS
1. Corticosteroids (CCS)
 Both anti-inflammatory and immunosuppressive
actions
 Used to treat serious disorders such as asthma and
autoimune disease
 Have been associated with clefts in animal studies
TRANSCRIBER: Trans Group 1 Issa Kalaw (09276845584) EDITOR: J. Rosario
 Based on meta-analysis of case control studies by
Motherisk program and a 10 yr prospectivs cohort
study by same group
 CCS are not considered to represent a major
teratogenic risk
 Unlike other CCS, the active metabolite of
prednisone, which is prednisolone, is inactivated
by the placental enzyme 11 beta-hydroxysteroid
dehydrogenase 2 and does not effectively reach the
fetus
2. Mycophenolate Mofetil
 Inosine monophosphate dehydrogenase inhibitor
 Mycophenolic acid, a related agent
 Both are used to prevent rejection in organ-
transplant recipients
 Also used for autoimmune disease such as lupus
nephritis
 Almost half of exposed pregnancies
spontaneously aborted and 1/5 of surviving infants
had malformations – nearly half of which were ear
abnormalities
 A Risk Evaluation and Mitigation Strategy (REMS)
is necessary before mycophenolate is prescribed
O. RADIOIODINE
Radioactive iodine-131
 Used to treat thyroid cancer and thyrotoxicosis
 For diagnostic thyroid scanning a component of iodine-
131 tositumomab therapy for one type of non-Hodgkin’s
lymphoma
 It readily crosses the placenta and concentrated in the
fetal thyroid gland by 12 weeks
 Causes irreversible fetal hypothyroidism
 May increase the risk for thyroid cancer
 Contraindicated in pregnancy
P. LEAD
 Prenatal lead exposure is assocated with fetal-growth
abnormalities
 There is no lead exposure level that is considered safe
in pregnancy (CDC, 2010)
Q. MERCURY
 Prenatal exposure causes disturbances in neuronal cell
division and migration
 Causes defects from developmental delay to
microcephaly and severe brain damage
 Prenatal mercury exposure due to consumption of
certain species of large fish i.e. tuna
R. PSYCHIATRIC MEDICATIONS
1. Lithium
 Associated with Ebstein anomaly - cardiac abnormality
characterized by apical displacement of the tricuspid
valve
 Fetal Echocardiography is recommended for
pregnancies with lithium exposure in the first trimester
 Neonatal lithium toxicity near delivery has been well
documented
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 Abnormal findings may persist for 1 to 2 weeks and may 3. Acitretin

include:  Used to treat psoriasis
- Hypothyroidism  It was introduced to a replace etretinate which has a
- Diabetes insipidus long half life (120 days), birth defects resulted more
- Cardiomegaly than 2 years after discontinuation of the drug
- Bradycardia  Though acitretin has a shorter half life, it is
- Electrocardiogram abnormalities metabolized to etretinate, remaining in the body for a
- Cyanosis long period
- Hypotonia  “Do Your P.A.R.T.” Pregnancy prevention Actively
Required during and after Treatment
2. Selective Serotonin and Norepinephrine-Reuptake  Promotes delay of pregnancy for at least 3 years
Inhibitors (Selective SNRIs) following discontinuation of therapy
 Ex: Desvenlafaxine, Duloxetine (anti-depressants)
 Not considered a major teratogen except paroxetine 4. Bexarotene
- Paroxetine is associated with increased risk of  Used to treat cutaneous T cell lymphoma
cardiac anomalies particularly ASD and VSD  Abnormalities noted are: ear and eye abnormalities,
 Neonatal behavioral syndrome cleft palate, incomplete ossification
 Jitterness  Guidelines when taking this medication:
 Hypoglycemia  2 forms of contraception: beginning 1 month before
 Thermoregularity instability/irritability therapy until one month after discontinuation
 Hyper/hypotonia  Monthly pregnancy test during treatment
 Respiratory abnormalities  Males who have partners who could get pregnant
 Feeding abnormalities should use condom during treatment until 1 month from
 Vomiting the discontinuation of therapy.
 Mild and self limited, lasting for only about 2 days
 Late pregnancy exposure to SSRI is associated with 5. Topical Retinoids
persistent pulmonary hypertension of the newborn  Initially used to treat acne, but became popular to treat
sun damage are called cosmeceuticals
S. ANTIPSYCHOTIC MEDICATIONS  Examples: topical tretinoin, tazarotene
 Not considered teratogenic  Cause cranial neural-crest defects in animals
 Exposed neonates manifest abnormal extrapyramidal
muscle movements and withdrawal symptoms U. Thalidomide and Lenalidomide
 Haloperidol, chlorpromazine, risperidone 1. Thalidomide
 The most notorious human teratogen
T. RETINOIDS  Causes malformation in 20% of fetuses exposed between
 Vitamin A derivatives (Among the most potent human 34 to 50 days menstrual age
teratogens)  Phocomelia is the characteristic malformation
o Isoretinoin  Absence of >1 long bones, resulting to the hands of feet
o Acitretin being attached to the trunk by a small rudimentary bone
o Bexarotene  Cardiac malformation, GI malformations and other limb
o Topical Retinoids reduction defects
 Marketed outside U.S. from 1956-1960 before its
1. Vitamin A teratogenicity was appreciated
 2 natural forms:  Important teratological principles:
 Beta carotene-fruits and vegetables 1. The placenta is not a perfect barrier to the transfer
 Retinol- associated with cranial neural crest defects of toxic substances from mother to fetus
 Avoid doses of preformed preparations higher than 2. Extreme variability in species susceptibility to
the recommended 3000IU daily allowance drugs and chemicals
3. There is close relationship between exposure
2. Isotretinoin timing and defect type
 13-cis-Retinoic acid= vitamin A isomer  Upper-limb phocomelia developed when exposed during
 Stimulates epithelial cell differentiation 27-30 days which coincides with appearance of upper-
 Used for cystic nodular acne limb buds at day 27
 First trimester exposure is associated with high rate of  Lower-limb phocomelia was associated with exposure
pregnancy loss and up to 1/3 of fetuses have during days 30-33
malformations  Gallbladder aplasia at 42-43 days
 iPLEDGE Program (promising not to be pregnant while  Duodenal atresia at 40-47 days
using this)  Was first approved in the US in 1999. Currently used to
treat leprosy and multiple myeloma
 Thalomide REMS-web based restricted distribution
program

TRANSCRIBER: Trans Group 1 Issa Kalaw (09276845584) EDITOR: J. Rosario 7

OBSTETRICS: 1.7 TERATOLOGY, TERATOGENS, AND FETOTOXIC AGENTS (2018B)

2. Lenalidomide  Active metabolite, delta 9-tetrahydrocannabinol is

 Analogue of thalidomide teratogenic in high doses to animals
 Used to treat some types of myelodysplastic syndrome
and multiple myeloma 2. Phencyclidine (PCP) or angel dust – used to be anesthetic
 Not associated with congenital anomalies
V. WARFARIN  Exposed newborns exhibit withdrawal symptoms
 Vitamin K anatogonist, potent anticoagulant
 Low molecular weight thus crosses the placenta readily 3. Toluene
 Embryotoxic and fetotoxic  Solvent in paints and glue
 Exposure between 6 and 9th weeks = cause warfarin  Associated with toluene embryopathy similar to fetal
embryopathy alcohol syndrome
 Characterized by: stippling of the vertebrae and femoral  Up to 40% of exposed children have developmental
epiphysis, nasal hypoplasia with depression of nasal delays
bridge
 This can result in respiratory distress Z. Tobacco
 Contains a mixture of nicotine, cotinine, cyanide,
W. HERBAL REMEDIES thiocyanate, carbon monoxide, cadmium, lead,
 Identity, quality and purity of ingredients are usually hydrocarbons
unknown  Fetotoxic and have vasoactive effects or reduce oxygen
 Not regulated by FDA levels
 Best documented adverse outcome is dose response
X. RECREATIONAL DRUGS reduction in fetal growth
 At least 10% of fetuses are exposed to one or more illicit REVIEW QUESTIONS
drugs. Alcohol a significant teratogen is readily available 1. What classification of medication can cause fetal harm when
 Illegal substances may contain toxic subs like lead, administered to a pregnant woman?
cyanide, herbicide, pesticides a. Category A
b. Category B
1. Amphetamines c. Category C
 Sympathomimetic amines, not considered to be a major d. Category D
2. Which of the following Anti-microbials may be used in the 1st trimester
teratogen if no suitable alternatives are available?
 Used to dilute other illicit drugs a. aminoglycosides
 Methamphetamine is used to treat obesity, narcolepsy b. nitrofurantoin
and attention deficit disorders c. sulfonamides
 Exposure in utero is associated with fetal growth d. a & b
restriction and with behavioral abnormalities in e. b & c
3. Which drug causes amniotic band syndrome-like syndrome in infants?
infancy and early childhood
a. Leflunomide
b. Tetracycline
2. Cocaine c. Fluconazole
 Central nervous system stimulant derived from leaves of d. All of the above
Erythroxylum coca tree e. None of the above
 Adverse outcomes are due to its vasoconstrictive and 4. Which of the ff anti-neoplastic drugs is used as a medical
hypertensive effects management for ectopic pregnancy and is known as an abortifacient
drug?
 Can cause serious maternal complications such as a. Cyclophosphamide
cerebrovascular hemorrhage, myocardial damage, b. Methotrexate
placental abruption c. Tamoxifen
 Associated with fetal growth restriction and preterm d. Trastuzumab
delivery 5. Amphetamine exposure in utero may cause which of the ff:
a. cerebrovascular hemorrhage
3. Ecstasy b. persistent pulmonary hypertension of the newborn
c. fetal alcohol syndrome
 It can contain a wide mixture of substances-from LSD, d. fetal growth restriction
cocaine, heroin, amphetamine and methamphetamine, Answers: D,E,C,B,D
to rat poison, caffeine, dog deworming substances, etc.

Y. MISCELLANEOUS DRUGS
END OF TRANS
1. Marijuana – given for pain management
 Has not been associated with increased risk of human
fetal anomalies

TRANSCRIBER: Trans Group 1 Issa Kalaw (09276845584) EDITOR: J. Rosario 8