[OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS

TERATOLOGY, DRUGS, AND MEDICATIONS
Dr. Ma. Katherina S. Marinas
TERATOLOGY
 TERATOLOGY  Study of birth defects and their
etiology
 Birth defects are common – 2-3% of all newborns have a
major congenital abnormality detectable at birth
 TERATOGEN
 Derived from the Greek teratos, meaning monster
 An agent that produces structural abnormalities
 The agent must cross the placenta sufficiently to directly
influence embryonic or fetal development or to alter
maternal or placental metabolism to exert an indirect effect.
 If not sufficient  May not directly affect the
embryonic or fetal defect
 Placental transfer depends on:
- Maternal metabolism
- Protein binding and storage, molecular size, electrical
charge, and lipid solubility of the drug
- Placental metabolism

 It is an agent that acts during embryonic or fetal

development to produce a permanent alteration of
form or function.
 It may be a drug or other chemical substance, a
physical or environmental factor such a heat or
radiation, a maternal metabolite such as
phenylketonuria or diabetes, a genetic abnormality,
or an infection.

 HADEGEN
 An agent that interferes with normal maturation and
function of an organ

 TROPHOGEN
 An agent that alters growth

 Hadegens and trophogens generally affect processes

occurring after organogenesis or even after birth
 In most circumstances, TERATOGEN is used to refer to
all three types of agents.

CRITERIA FOR PROOF OF HUMAN TERATOGENICITY

 The criteria for determining teratogenicity or guidelines

are proposed by Shepard as a framework for discussion.
 All criteria may not be required to establish  Exposure must occur during a critical developmental period
teratogenicity.

 The defect has been completely characterized.

 This is preferably done by a geneticist or

dysmorphologist because various genetic and
environmental factors may produce similar
anomalies.

 Easiest to prove causation when:

- Rare exposure produces a rare defect
- At least three cases with the same exposure have been
identified
- Defect is severe

LEA THERESE R. PACIS 1

 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS
EXPOSURE MUST OCCUR DURING A CRITICAL
DEVELOPMENTAL PERIOD
 PREIMPLANTATION PERIOD
 Human teratogenicity is more likely if an agent
produces an adverse effect in different animal
species.
 2 weeks from fertilization to implantation
 Called the "all or none" period
 Insult damaging a large number of cells usually causes
death of the embryo
 Animal studies  Can produce a dose-dependent
diminution in body length or size
 As the zygote undergoes cleavage, an insult damaging
a large number of cells typically causes embryonic
death.
 However, if only a few cells are injured, compensation
may be possible, with normal development.
 EMBRYONIC PERIOD
 From the 2nd through the 8th week following conception
 Encompasses organogenesis
 The most crucial with regard to structural malformations
 FETAL PERIOD
 9th week to term
 Functional maturation
 Ex. Brain remains susceptible throughout pregnancy to
environmental influences such as alcohol exposure
 During this time, certain organs remain vulnerable.
CRITERIA FOR DETERMINING TERATOGENICITY
 A biologically plausible association is supportive.
 Because birth defects and medication exposures are
both common, they may be temporally but not
causally related.
 Epidemiological findings must be consistent.
 An important criterion for teratogenicity is that two or more
high-quality epidemiological studies report similar findings.
 The suspected teratogen causes a defect in animal studies.
FOOD AND DRUG ADMINISTRATION CATEGORIES FOR
DRUGS AND MEDICATIONS
 This system for evaluating drug safety in pregnancy was
developed in 1979.
 It was designed to provide therapeutic guidance by
using five categories—A, B, C, D, or X, to simplify risk-
benefit information.
 Category A and B  Can be given to patients
 Category C  Need to determine its risks and if risks are
greater than its benefits
 Category D  Questionable
 Category X  Not given
 CATEGORY A:
 Studies in pregnant women have not shown an increased
risk for fetal abnormalities.
 If administered during the first, (second, third and all)
trimester of pregnancy, and the possibility of fetal harm
appears remote.
 Fewer than 1 percent of all medications are in this
category.
 Examples include:
- Levothyroxine
- Potassium supplementation
- Prenatal multivitamins (when taken at recommended
doses)
 CATEGORY B:
 Animal reproduction studies have been performed and
have revealed no evidence of impaired infertility 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
first trimester of pregnancy, and there is no evidence of
a risk in later trimesters.
 Examples include many antibiotics, such as:
- Penicillins
- Macrolides
- Most cephalosporins
 CATEGORY C:
 Animal reproduction studies have shown that this
medication is teratogenic (or embryocidal or has other
adverse effect), and there are no adequate and well
controlled studies in pregnant women.
LEA THERESE R. PACIS 2
 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS
 Prescribing information should specify kind of animal and
how dose compares with the human dose. OR
 There are no animal reproduction studies and no
adequate and well controlled studies in humans.
 Approximately two thirds of all medications are in this
category. It contains medications commonly used to treat
potentially life-threatening medical conditions, such as:
- Albuterol
- Zidovudine
- Lamivudine
- Anti-hypertensives (Beta Blockers and Calcium Channel
Blockers)
 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 to the potential hazard to the fetus.
 Contains medications used to treat potentially life-
threatening medical conditions
 Examples include:
- Systemic Corticosteroids
- Azathioprine
- Phenytoin
- Carbamazepine
- Valproic acid
- Lithium
 CATEGORY X:
 This medication is contraindicated in women who are or
may become pregnant.
 May cause fetal harm.
 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.
 There are a few medications in this category that have
never been shown to cause fetal harm but should be
avoided nonetheless such as the rubella vaccine.
GENETIC AND PHYSIOLOGICAL MECHANISMS OF
TERATOGENICITY
 Disturbance of specific physiological processes
 Cell death, altered tissue growth, abnormal cellular
differentiation, abnormal development
 Result in multiple effects or similar phenotypic
abnormalities
 The mechanism of most teratogens are mostly unknown
DISRUPTION OF FOLIC ACID METABOLISM
 Folates are essential for methionine production, which
is required for gene methylation and thus production of
proteins, lipids, and myelin.
 Neural tube defects, cardiac defects, cleft lip and palate
 Hydantoin, carbamazepine, valproic acid, phenobarbital
 Periconceptual folate supplementation
PATERNAL EXPOSURES
 Induction of a gene mutation or chromosomal abnormality
in sperm
 Epigenetic pathways suppress germ-cell apoptosis or
interfere with imprinting (Cordier, 2008)
 Exposure to a teratogenic agent in seminal fluid during
intercourse
 In some cases, paternal exposures to drugs or
environmental influences may increase the risk of
adverse fetal outcome.
 Proposed mechanisms include induction of a gene
mutation or chromosomal abnormality in sperm.
 Sperm cells mature into functional spermatogonia takes
64 day. Therefore, drug exposure at any time during 2
months prior to conception could result in mutation.
FETAL GENETIC COMPOSITION (not discussed)
 Multifactorial anomalies are caused by interaction of
environment and gene alterations
 Mutation of gene tetrahydrofolate reductase (MTHFR 677C)
 Neural Tube Defects
 HYDANTOIN  Homozygous gene mutation of low epoxide
hydroxylase activity
 CIGARETTE SMOKING and cleft palate  Polymorphism in
gene for transforming growth factor -1
HOMEOBOX GENES (not discussed)
 Regulatory genes that encode nuclear proteins
(transcription factors) to control expression of other
developmentally important genes
 Establishes positional identity of various structures along the
body axis
 Retinoic acid  Prematurely activate these genes  Severe
hindbrain and limb anomalies
 Valproic acid  Activates homeobox gene that regulates
axial skeletal patterning  Neural tube defects in
lumbosacral region
KNOWN TERATOGENS
 As a general rule, because there are no adequate and
well-controlled studies in pregnant women for most
medications, and because animal reproduction studies
are not always predictive of human response, any
medication in pregnancy must be carefully considered
and only used if clearly needed.
LEA THERESE R. PACIS 3
 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS

 Features of Fetal Alcohol Syndrome

(Picture Above) A. 2 ½ years B. 12 years

 Note persistence of short palpebral fissures,
epicanthal folds, flat midface, hypoplastic philtrum,
and thin upper vermilion border.

ALCOHOL

 Ethyl alcohol is a potent and prevalent teratogen.

 Alcohol is one of the most frequent non-genetic causes
of mental retardation.
 Fetal effects of alcohol abuse has been recognized since
1800s and the spectrum of alcohol-related fetal defects
are known as FETAL ALCOHOL SYNDROME.

 Fetal Alcohol Syndrome

 The minimum amount of alcohol required to produce

adverse fetal consequences is unknown.
 Binge drinking, however, is believed to pose particularly
high risk for alcohol-related birth defects and has also
been linked to an increased risk for stillbirth

ANTICONVULSANTS
 Women with epilepsy have increased risk of fetal
malformations even if they are NOT receiving
anticonvulsants
 Most frequent: orofacial clefts and congenital heart
defects, NTD

 Pragmatically, no anticonvulsant drugs are considered

truly “safe” in pregnancy.
 Of agents in current use, valproic acid confers the
greatest risk.
 Regardless of the anticonvulsant medication used,
specialized sonography should be considered.

LEA THERESE R. PACIS 4

 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS

PHENYTOIN TERATOGENIC EFFECTS OF COMMON ANTICONVULSANT

 Teratogenicity is strongly influenced by genetic make-up  MEDICATIONS
Low activity of fetal epoxide hydroxylase Abnormalities Pregnancy
Drug Affected
Described Category
 7-10% have sufficient features of the FETAL HYDANTOIN
 Neural Tube Defects
SYNDROME and one third show minor craniofacial and  Clefts
1-2% with
digital anomalies monotherapy
 Skeletal
Valproate D
 Fetal Hydantoin Syndrome Abnormalities
9-12% with
 Developmental
polytherapy
 FETAL HYDANTOIN SYNDROME: Delay
 Fetal Hydantoin
 Craniofacial anomalies
Syndrome:
 Fingernail hypoplasia  Craniofacial
 Growth deficiency anomalies
 Developmental delay  Fingernail
Phenytoin hypoplasia 5-11% D
 Cardiac defects
 Growth deficiency
 Clefts  Developmental
delay
 Cardiac defects
 Clefts
 Fetal Hydantoin
Carbamazepine Syndrome 1-2% D
 Spina Bifida
 Clefts
 Cardiac anomalies
Phenobarbital 10-20% D
 Urinary tract
malformations
 Inhibits
dihydrofolate
4-fold with
reductase 
monotherapy
Lowering fetal folate
Lamotrigine C
levels
10-fold with
 Registry data suggest
polytherapy
increased risk for
clefts
 Registry data suggest
Topiramate increase risk for 2% C
clefts
(Picture Above) FETAL HYDANTOIN SYNDROME  Theoretical – skeletal
 Upper facial features including upturned nose, mild abnormalities and
Too few
mid-facial hypoplasia, and long upper lip with thin impaired growth in
cases to
vermilion border. Lower distal digital hypoplasia. Levetiracetam animals at doses C
report to
similar to or greater
assess risk
than human
therapeutic doses
CARBAMAZEPINE
 Used to be considered epileptic drug of choice during ACE INHIBITORS AND ARBS
pregnancy
 Teratogenic potential unclear  Disrupt the Fetal Renin-Angiotensin System that is
essential in normal renal development.
TRIMETHADONE AND PARAMETHADONE
 High potential for teratogenicity  Enalapril, captopril, lisinopril
 Anomalies characteristic of anticonvulsant embryopathy  No structural malformations reported during 1st trimester
exposure
VALPROIC ACID  Anomalies result from prolonged fetal hypotension and
 First trimester exposure 1 to 2 % risk of spina bifida hypoperfusion  Renal ischemia, renal tubular dysgenesis,
(lumbosacral area) anuria Oligohydramnios  Lungs & limbs
 Acts directly on a homeobox gene governing caudal  Occurs during the fetal period
structure development
 Minor facial feature effects also reported

LEA THERESE R. PACIS 5

 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS
ANTIFUNGALS
 FLUCONAZOLE
 Fluconazole has been associated with a pattern of
congenital malformations resembling the autosomal
recessive Antley-Bixler syndrome.
 Abnormalities include oral clefts, abnormal facies, and
cardiac, skull, long-bone, and joint abnormalities.
 It states that a single 150-mg dose to treat
vulvovaginal candidiasis does not appear to be
teratogenic.
 Antley Bixler Syndrome
- Autosomal recessive
- Oral clefts, abnormal facies, and cardiac, skull, long-
bone, and joint abnormalities
 Chronic, high-dose treatment in the first trimester—at
doses of 400 to 800 mg daily
 First trimester exposure: 3 fold increase for tetralogy of
Fallot
 Category D
 Single 150 mg dose to treat vulvovaginal candidiasis – not
teratogenic
ANTI-INFLAMMATORY AGENTS (NSAIDS)
 INDOMETHACIN AND OTHER PG INHIBITORS
 Not considered teratogenic but may have reversible fetal
effects during the 3rd trimester
 Constriction of fetal ductus arteriosus and persistent fetal
circulation and pulmonary hypertension in the neonate
 Decreases urine output and amniotic fluid volume with
prolonged use
ANTIMICROBIALS
 AMINOGLYCOSIDES
 Preterm infants treated with gentamicin or streptomycin
have developed nephrotoxicity and ototoxicity
 No adverse effects have been demonstrated
 No congenital defects resulting from prenatal exposure
 CHLORAMPHENICOL
 Preterm infants were unable to conjugate and excrete
the drug.
 Gray baby syndrome in preterm neonates
– Manifested as abdominal distention, respiratory
abnormalities, an ashen-gray color, and vascular
collapse
 NITROFURANTOIN
 Fourfold increased risk for hypoplastic left heart
syndrome and microphthalmia/anophthalmia
 Twofold increased risk for clefts and atrial septal defects
 Nitrofurantoin could be given during the 1st trimester
if there is no suitable alternative available.
 SULFONAMIDES
 Hyperbilirubinemia if used near delivery of a preterm
infant
 TETRACYCLINES
 Associated with yellowish-brown discoloration of
deciduous teeth when used after 25 weeks
ANTINEOPLASTIC AGENTS
 CYCLOPHOSPHAMIDE
 Alkylating agent that causes cell death or heritable DNA
alterations in surviving cells
 Pregnancy loss is increased, and reported malformations
include skeletal abnormalities, limb defects, cleft palate,
and eye abnormalities
 METHOTREXATE
 This folic-acid antagonist is a potent teratogen.
 It is used for cancer chemotherapy.
 It is similar in action to aminopterin, which is no longer
in clinical use, and can cause defects known
collectively as the fetal methotrexate-aminopterin
syndrome.
 Fetal Methotrexate-Aminopterin Syndrome
- Craniosynostosis with “clover-leaf” skull
- Wide nasal bridge
- Low-set ears
- Micrognathia
- Limb abnormalities
 Critical developmental period: 8 to 10 weeks
 10 mg/week to produce abnormalities
LEA THERESE R. PACIS 6
 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS
 Craniosynostosis: Premature ossification and closure
of the cranial sutures results in abnormal shape and
size of the skull.
 Micrognathia: The mandible forms the floor of the
oral cavity and contains the tongue. If the mandible is
severely hypoplastic (micrognathia) of posteriorly
displaced (retrognathia)
 TAMOXIFEN
 Selective Estrogen receptor modulator (SERM)
 Used as an adjuvant in breast CA
 Fetotoxic and carcinogenic in animal studies
 Similar changes cause by DES exposure
 TRASTUZUMAB
 This is a recombinant monoclonal antibody directed to
the human epidermal growth factor receptor 2 (HER2)
protein.
 Not associated with fetal malformations, but cases of
oligohydramnios, anhydramnios, and fetal renal failure
 Fetal pulmonary hypoplasia, skeletal abnormalities, and
neonatal death
ANTIVIRALS
 RIBAVIRIN
 This nucleoside analogue is a component of therapy
for hepatitis C infection.
 Antiviral drug used as an inhalational agent for RSV
infections in children
 Animal studies  Significant teratogenic potential:
hydrocephalus, limb anomalies
 CDC and the manufacturers consider it contraindicated
for use in pregnancy
 EFAVIRENZ
 Non-nucleoside reverse transcriptase inhibitor
 CNS abnormalities following human exposure
 This is a nonnucleoside reverse transcriptase inhibitor
used to treat HIV infection.
ENDOTHELIN-RECEPTOR ANTAGONISTS
 BOSENTAN
 Endothelin receptor antagonist used to treat pulmonary
hypertension
 Category X
 Causes abnormalities of the head, face and large blood
vessels
 Also carcinogenic
SEX HORMONES
 Exposure to exogenous sex hormones prior to 7 completed
weeks of gestation has no effect on external structures
 Exposure between 7 to 12 weeks can result to full
masculinization of the female fetus and partial effects and
genital ambiguity thereafter up to about 20 weeks
 Hormonal influence on behavior occurs much later than on
the external genitalia and the degree of behavioral
alteration is proportional to the dose and length of exposure
 TESTOSTERONE AND ANABOLIC STEROIDS
 Exposure of a female fetus may cause varying degrees of
virilization and may result in ambiguous genitalia
 Labioscrotal fusion with first trimester exposure and
phallic enlargement from later fetal exposure
 DIETHYLSTILBESTROL
 Absolute cancer risk in DES-exposed fetuses: 1 per 1000
 Twofold increase in vaginal and cervical intraepithelial
neoplasia
 Genital tract abnormalities
 Slightly higher rates of earlier menopause and breast
cancer
 Women may have a hypoplastic, T-shaped uterine
cavity; cervical collars, hoods, septa, and coxcombs;
and “withered” fallopian tubes.
 From 1940 until 1971, between 2 and 10 million
pregnant women were given this synthetic estrogen.
 Subsequently, Herbst and associates (1971) reported a
series of eight women exposed to DES in utero who
developed an otherwise rare neoplasm, vaginal clear-
cell adenocarcinoma.
LEA THERESE R. PACIS 7
 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS

 DANAZOL  Used to prevent rejection in kidney recipients and treatment

 This ethinyl testosterone derivative has weak of autoimmune diseases
androgenic activity.  Category D
 It is used to treat endometriosis.  Increased risks of spontaneous abortions, ear
malformations, bilateral microtia, anotia, atresia of external
 40 percent of exposed female fetuses were virilized auditory canals
 Dose-related pattern of clitoromegaly, fused labia, and
urogenital sinus malformation IODINE PREPARATIONS

LEFLUNOMIDE (not discussed)  Avidly concentrated in fetal thyroid by the end of the first
 Pyrimidine synthesis inhibitor used to treat , rheumatoid trimester
arthritis
 Radioactive iodine 131 used to treat thyroid malignancies
 Contraindicated in pregnancy, causes hydrocephalus, eye
anomalies, skeletal abnormalities, and embryo death in  Readily crosses placenta
animal studies  Ablate the fetal thyroid
 Increase risk of childhood thyroid CA
ANTIMALARIALS (not discussed)
 CHLOROQUINE LEAD
 Valuable as a first-line antimalarial treatment and for  Fetal-growth abnormalities and with childhood
chemoprophylaxis developmental delay and behavioral abnormalities
 In high doses, also effective against rheumatoid arthritis  No lead exposure level that is considered safe in pregnancy
and systemic lupus erythematosus
 Prenatal lead exposure is associated with fetal-growth
 QUININE AND QUINIDINE abnormalities and with childhood developmental delay
 Reserved for severely ill women with chloroquine- and behavioral abnormalities.
resistant malaria
 No increased rate of congenital anomalies in the offspring
MERCURY
of mothers given any of these antimalarial drugs during
 Not a drug, but is a known teratogen
pregnancy in therapeutic doses
 Developing CNS is particularly susceptible to the effects of
 Daily use of chloroquine for lupus and other connective
mercury
tissue diseases has been shown to cause maternal
retinopathy but no adverse fetal effects  Prenatal exposure appears to cause a disturbance in
 CNS anomalies, hearing defects, limb and urogenital neuronal cell division and migration, resulting in a range of
abnormalities reported in large dose exposures to induce defects from developmental delay and mild neurological
abortion (not seen in therapeutic doses) abnormalities to microcephaly and severe brain damage
 May be concentrated in large fishes:
 MEFLOQUINE  Tuna
 For asymptomatic malaria treatment  King mackerel
 Associated with a fivefold increased risk of stillbirth  Tile fish
 FDA recommendation: Pregnant women not eat shark,
IMMUNOSUPPRESSANTS swordfish, king mackerel & tilefish
 Other fishes: Not more than 6 oz of albacore tuna; 12 oz of
 Does not represent a MAJOR TERATOGENIC RISK fish or shellfish low in mercury
 These medications include glucocorticoids and
mineralocorticoids, which have antiinflammatory and PSYCHIATRIC MEDICATIONS
immunosuppressive actions. They are commonly used to  LITHIUM
treat serious disorders such as asthma and autoimmune  Used for manic depressive illness
disease.  Causes Ebstein Anomaly

 Hydrocortisone, prednisone In animal studies causes cleft  Ebstein Anomaly

palate and facial clefts  Cardiac abnormality characterized by apical
 Category D in the First trimester displacement of the tricuspid valve. Results in
severe tricuspid valve regurgitation and marked
MYCOPHENOLATE MOFETIL (not discussed) right atrial enlargement.
 Inosine monophosphate dehydrogenase inhibitor

LEA THERESE R. PACIS 8

 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS
 Causes transient neonatal toxicity such as
hypothyroidism, diabetes insipidus, cardiomegaly,
bradycardia, ECG abnormalities, cyanosis, hypotonia
 Recommendation: Targeted Ultrasound with fetal
echocardiography
 SSRI’s
 Paroxetine and Fluoxetine
 Causes cardiovascular anomalies, omphalocoele,
craniosynostosis and anencephaly
 But the absolute risk of any birth defect is small
 NEONATAL EFFECTS OF MATERNAL SSRI USE:
- Neonatal behavioral syndrome- jitteriness, shivering,
increased muscle tone, feeding or digestive
disturbances, irritability or agitation, and respiratory
distress
- Persistent Pulmonary Hypertension in the Newborn –
high pulmonary vascular resistance, right to left
shunting, and profound hypoxemia
RETINOIDS
 VITAMIN A
 Two forms of vitamin A in nature: Beta carotene and
Retinol
- Beta-carotene  A precursor of provitamin A
 Found in fruits and vegetables and has never been
shown to cause birth defects
- Retinol  Preformed vitamin A
 Associated with cranial neural-crest defects when
more than 10,000 IU per day (1st Trimester)
 Doses higher than the recommended daily allowance of
3000 IU should be avoided
 Vitamin A derivatives are the MOST POTENT HUMAN
TERATOGENS.
 ISOTRETINOIN, ACITRETIN AND BEXAROTENE
 MOA: Inhibit neural-crest cell migration during
embryogenesis, they result in a pattern of cranial neural-
crest defects – termed retinoic acid embryopathy – that
involve the CNS, face, heart and thymus.
 ISOTRETINOIN
 Stimulates epithelial cell differentiation and is used for
dermatological disorders, especially cystic nodular acne
 1st trimester exposure  High rates of fetal loss and
malformations similar to thalidomide
 Most strongly associated crainofacial anomaly is bilateral,
symmetrical microtia or anotia and agenesis or stenosis of
external ear canal
 Most frequent cardiac anomaly are conotruncal
 Most frequent CNS anomaly is hydrocephalus
 Agenesis, aplasia, hypoplasia of thymus
 ETRETINATE (not discussed)
 An antipsoriatic drug which produces similar anomalies to
isotretinoin but does so even when conception occurs
after drug discontinuation
 It is recommended that women stop the use of this drug
for at least two years prior to attempting conception
 ACITRETIN
 Severe psoriasis
 Was introduced to replace etretinate
 Shorter half-life than etretinate, it is metabolized to
etretinate
 Delay of conception for at least 3 years following therapy
discontinuation
 TOPICAL RETINOIDS
 Become popular for the treatment of sun damage, called
cosmeceuticals
 Topical tretinoin and tazarotene
 Low systemic absorption
 No differences in the rate of spontaneous abortion or
birth defects compared with that of non-exposed
pregnancies
THALIDOMIDE
 Anxiolytic and sedative agent that is a notorious teratogen
producing malformations in 20% of exposed pregnancies
 Affects structures derived from mesodermal layer (e.g.
limbs, ears, cardiovascular system and bowel musculature)
 Limb-reduction defects (especially upper limbs)
 Abnormal shape and size of bones to total absence
 CLOSE RELATIONSHIP between time of exposure and the
type of defect
 Days 27 to 30: Upper limb phocomelia
 Days 30 to 33: Lower limb phocomelia
 MOST NOTORIOUS HUMAN TERATOGEN
 Causes malformation in 20% of fetuses exposed
between 34 and 50 days menstrual age
 PHOCOMELIA  Absence of one or more long bones,
which results in the hands or feet being attached to the
trunk by a small rudimentary bone
 MALFORMATIONS DUE TO INGESTION OF THALIDOMIDE
LEA THERESE R. PACIS 9
 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS

WARFARIN RECREATIONAL DRUGS

 Low molecular weight enables passage through placenta  AMPHETAMINES
 Distinct defects with TWO different etiologies result from  Sympathomimetic agent
warfarin exposure during two different periods in gestation  Associated with symmetrical growth restriction,
 Warfarin Exposure at 6th-9th wk behavioral abnormalities in both infancy and early
 WARFARIN childhood
EMBRYOPATHY
 Nasal hypoplasia  COCAINE
 Stippled vertebral and  Vasoconstrictive and hypertensive effects
femoral epiphyses  Serious maternal complications: Cerebrovascular
 Mechanism: (-) hemorrhage
Posttranslational  Myocardial damage
carboxylation of  Placental abruption
coagulation proteins  Fetal: Cleft palate, cardiovascular and urinary tract
(osteocalcins) abnormalities, fetal growth restriction and preterm
 Warfarin Exposure at 2nd-3rd trimester delivery
 Defects result from hemorrhage  Dysharmonic growth
and deformation from scarring in many organs  Most adverse outcomes result from its
 Dorsal midline CNS dysplasias, microphthalmia, optic vasoconstrictive and hypertensive effects.
atrophy, blindness, developmental delay and mental  Serious maternal complications such as
retardation cerebrovascular hemorrhage, myocardial damage
and placental abruption
HERBAL REMEDIES WITH TERATOGENIC POTENTIAL

 Risks associated with various herbal remedies are

difficult to estimate because these compounds are not
regulated by the FDA.  OPIODS are not considered to be major teratogens.
 Knowledge of complications may be limited to reports of  Slightly increase risk for spina bifida, gastroschisis and
acute toxicity. cardiac abnormalities

 Echinacea  OPIATES (NARCOTICS)

 Black cohosh  Heroin
 Methadone
 Gingko
 NEONATAL ABSTINENCE SYNDROME  Neonatal narcotic
 Glycyrrhizin
withdrawal, 90% of exposed infants; characterized by CNS
 Pennyroyal
irritability (that may progress to seizures), tachypnea,

 METHADONE – given
HEROIN – preterm to pregnant
birth, heroin users
placental abruption, to
fetal
obviate uncontrolled narcotic withdrawal,
growth restriction and fetal death preterm
birth and fetal growth restriction

episodes of apnea, poor feeding and failure to thrive

MISCELLANEOUS DRUGS
 Marijuana

 Marijuana use – has not been associated with an

increased risk for human fetal anomalies, active
ingredient Delta-9-THC is teratogenic when given in
high doses to animals

 Phenycyclidine  Jitteriness, tremors, irritability

 Lysergic Acid Diethylamide  Chromosomal breakage

*Bigger picture at the end

LEA THERESE R. PACIS 10

 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS

 Toluene  Toluene embryopathy  Isoniazid

 Ethambutol
 Toluene – common solvent used in paints and glue,
similar to fetal alcohol syndrome
ANTIBIOTICS THAT SHOULD BE AVOIDED DURING
PREGNANCY
TOBACCO
 Chloramphenicol
 Nicotine, continine, cyanide, thiocyanide, carbon monoxide,
 Tetracyclines
cadmium, lead, hydrocarbons
 Aminoglycosides
 Fetotoxic as well as vasoactive (reduces oxygen levels)
 Sulfonamides
 Best documented reproductive effect: FETAL GROWTH
 Metronidazole
RESTRICTION
 Ciprofloxacin
 Subfertility, spontaneous abortion, placenta previa,
abruption, preterm delivery
ANTIPROTOZOALS, ANTIFUNGALS, AND ANTIVIRALS
 Cleft lip and palate in genetically predisposed patients
ANTIPROTOZOALS PDA Category
Lindane B
DRUGS COMMONLY USED IN PREGNANCY Mebendazole C
 Antiemetic Pyrantel C
 Antacids Quinine D
 Antihistamines
 Analgesics ANTIFUNGALS PDA Category
 Antimicrobials Amphotericin B
 Anti-hypertensives Fluconazole C
 Tranquilizers/Hypnotics Itraconazole C
 Diuretics Miconazole C
Nystatin B
CLASSIFICATION OF SOME ANTIMICROBIAL AGENTS
ANTIVIRALS PDA Category
COMMONLY USED IN PREGNANCY
Acyclovir C
ANTIMICROBIALS PDA Category
Didanosine B
Aminoglycosides C/D
Ganciclovir C
Azithromycin B
Stavudine C
Aztreonam C
Zalcitabine C
Cephalosporins B
Zidovudine C
Chloroquine C
Erythromycin B
Fluoroquinolones C CLASSIFICATION OF SOME CARDIOVASCULAR DRUGS
Imipenem C COMMONLY USED IN PREGNANCY
Metronidazole B CARDIOVASCULAR DRUGS PDA Category
Nitrofurantoin B ACE Inhibitors C/D
Penicillines B Adenosine C
Quinolones C Amiodarone D
Rifabutin B Beta Blockers C
Sulfonamides B Calcium Antagonists C
Tetracyclines D Coumarins D
Trimethoprim C Digoxin C
Vancomycin C Furosemide C
Heparin (Conventional) C
ANTIBIOTICS CONSIDERED SAFE DURING PREGNANCY Heparin (Low Molecular Weight) B
Local Anesthetic Antiarrhythmics B/C
 Penicillin G
Methyldopa C
 Penicillin V Quinine C
 Ampicillin Streptokinase C
 Amoxicillin Thiazides D
 Amoxicillin/Clavulanic acid Urokinase B
 Erythromycin
 Floxacillin
 Cephalosporins

LEA THERESE R. PACIS 11

 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS

COMMONLY USED MEDICATIONS FOR PSYCHIATRIC Neonatal dependence,

Barbiturates All
DISORDERS AND THEIR CLASSIFICATION cognitive loss
REGARDING USE IN PREGNANCY Congenital
Busulfan All
TRICYCLIC ANTIDEPRESSANTS PDA Category malformations, LBW
Amitryptiline D Carbamazepine 1st Neural tube defects
Amoxapine C
Prolonged neonatal
Clomipramine C Chlorpropamide All
hypoglycemia
Despiramine C
Doxepin C Neonatal lethargy,
Imipramine D Clomipramine 3rd hypotonia, cyanosis,
Nortriptyline D hypothermia
Spontaneous abortion,
SSRIs PDA Category abruptio, preterm labor,
Fluoxetine B Cocaine All
neonatal cerebral infarct,
Paroxetine B abnormal dev’t
Sertraline B
Congenital
Cyclophosphamide 1st
malformations
MAOIs PDA Category
Isocarboxazid C Congenital
Cytarabine 1st, 2nd
Phenelzine C malformations
Tranylcypromine C Neonatal dependence,
Diazepam All
oral cleft
OTHER PDA Category Vaginal adenosis, clear
Buproprion B DES All
cell adenoCA
Trazodone C
Fetal alcohol syndrome,
Ethanol All neurodevelopmental
ANTIPSYCHOTICS PDA Category
Chlorpromazine C defects
Clozapine B High risk multiple
Etretinate All
Fluphenazine C congenital defects
Haloperidol C Heroin All Neonatal dependence
Loxapine C Congenital goiter,
Perphenazine C Iodide All
hypothyroidism
Thioridazine C
High risk CNS, face, ear &
Trifluporazine C Isotretinoin All
other defects
BENZODIAZEPINES PDA Category Lithium 1st Ebstein’s anomaly
Alprazolam D Methadone All Neonatal dependence
Chlordiazepoxide D Multiple congenital
Methotrexate 1st
Clonazepam C malformations
Diazepam D Methylthiouracil All Hypothyroidism
Lorazepam C Mutagenic in animal
Midazolam D
studies, no evidence for
Oxazepam C Metronidazole 1st
mutagenic/teratogenic
effects in humans
SUMMARY
DRUG TRIMESTER EFFECT Multiple maformations,
Organic solvents 1st
ACE Inhibitors All (2nd, 3rd) Renal damage affect brain development
Aminopterin 1st Multiple gross anomalies Misoprostol 1st Mobious sequence
Abnormal Cutis laxa, other
Amphetamines All Penicillamine 1st congenital
developmental patterns
Masculinization of malformations
Androgens 2nd and 3rd Abnormal neurologic
female
Neonatal withdrawal Phencyclidine All exam, poor suck &
Antidepressants, symptoms feeding
3rd Fetal hydantoin
Tricyclics (clomipramine, Phenytoin All
despramine, imipramine) syndrome

LEA THERESE R. PACIS 12

 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS

Propylthiouracil All Congenital goiter

Streptomycin All 8th nerve toxicity
IUGR, prematurity, SIDS,
Smoking All
perinatal complications
Spontaneous abortion or
Tamoxifen All
fetal damage
Discolorations & defects
Tetracycline All
of teeth
Phocomelia & many
Thalidomide 1st
internal malformations
Multiple congenital
Trimethadione All
malformations
Valproic acid All Neural tube defects
Hypoplastic nasal bridge,
Warfarin 1st
chondrodysplasia
2nd CNS malformation
Bleeding risk (d/c 1
3rd
month before delivery)

LEA THERESE R. PACIS 13

 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS

What the F! 2017 Quiz and Ratio (August 17, 2015) D systemic corticosteroids, azathioprine,
By Precious Angelique Dy phenytoin, carbamazepine, valproic acid, and
1. TRUE OR FALSE. The agent must cross the placenta and must lithium
be of sufficient quantity to directly influence embryonic or X rubella vaccine
fetal development or to alter maternal or placental References: Table 12-3. Pg. 244, William’s 24th ed. and Table
metabolism. 14-3, pg. 315, William’s 23rd ed.

 A: TRUE 9. Name one diagnostic criteria for FETAL ALCOHOL

 R: The agent must cross the placenta. Although SYNDROME
almost all drugs cross the placenta, transport must be
of sufficient quantity to directly influence embryonic
or fetal development or to alter maternal of placental
metabolism to exert and indirect effect. (pg. 242,
William’s 24th ed.)

2. Known as “ALL OR NONE PERIOD”

 A: Preimplantation period
 R: The preimplantation period is the 2 weeks from
fertilization to implantation and is known as the “all
or none” period. (pg. 242, William’s 24th ed.)

3. The most crucial period with regard to structural

malformations

 A: Embryonic period
 R: The embryonic period is from the second through
the eighth (2nd-8th) week. It encompasses
organogenesis and is thus the most crucial period 10.Fetal neural tube defects, cardiac defects and oral clefts can
with regard to structural malformations. (pg. 242,
be prevented by the intake of____
William’s 24th ed.)
 A: Folic Acid
 R: Fetal neural-tube defects, cardiac defects, and oral
IDENTIFY FDA CATEGORY
clefts can be a result of folic acid metabolic pathway
4. Prenatal Vitamins
disturbances. (pg. 245, William’s 24th ed.)
5. Calcium Channel Blockers

6. Valproic Acid

7. Penicillin MATCHING TYPE

8. Rubella Vaccine A. Testosterone
B. Lithium
Answers: A, C, D, B, X C. Thalidomide
Category Medications D. Chloramphenicol
A Levothyroxine, Potassium supplementation, E. Aminoglycosides
and prenatal vitamins, when taken at
recommended doses 11.Ototoxicity
B many antibiotics, such as penicillins, 12.Gray Baby Syndrome
macrolides, and most cephalosporins 13.Masculinization of female fetus
C albuterol for asthma, zidovudine and
14.Ebstein anomaly
lamivudine for human immunodeficiency viral
15.Phocomelia
infection, and many antihypertensives,
including -blockers and calcium-channel
blockers Answers: E, D, A, B, C

LEA THERESE R. PACIS 14

 [OBSTETRICS A] TERATOLOGY, DRUGS, AND MEDICATIONS

11. Aminoglycosides
 Preterm infants treated with gentamicin or
streptomycin have developed nephrotoxicity and
ototoxicity. (pg. 248, William’s 24th ed.)

12. Chloramphenicol
 This antimicrobial is not considered teratogenic and
is no longer routinely used in the United States.
More than 50 years ago, a constellation of findings
termed the gray baby syndrome was described in
neonates who received the medication. (pg. 248,
William’s 24th ed.)

13. Testosterone
 Androgen exposure in reproductive-aged women is
typically anabolic steroid use to increase lean body
mass and muscular strength. Exposure of a female
fetus may cause varying degrees of virilization and
may result in ambiguous genitalia similar to that
encountered in cases of congenital adrenal
hyperplasia. (pg. 249, William’s 24th ed.)

14. Lithium
 This medication has been associated with Ebstein
anomaly, a cardiac abnormality characterized by
apical displacement of the tricuspid valve. Ebstein
anomaly often results in severe tricuspid
regurgitation and marked right atrial enlargement,
which confer significant morbidity. (pg. 250,
William’s 24th ed.)

15.Thalidomide
 The drug thalidomide is likely the most notorious
human teratogen. It causes malformations in 20
percent of fetuses exposed between 34 and 50 days
menstrual age. The characteristic malformation is
phocomelia—an absence of one or more long
bones, which results in the hands or feet being
attached to the trunk by a small rudimentary bone.
(pg. 252, William’s 24th ed.)

LEA THERESE R. PACIS 15