Teratology and Medications that Affect the Fetus

Christiana Calagui-Damaso, MD OB-GYN

TERATOLOGY
65 % - etiology of birth defects is unknown Teratogen
derived from the Greek teratos, meaning monster A hadegenafter Hades, the god who possessed a helmet conferring invisibilityis an agent that interferes with normal maturation and function of an organ any agentchemicals, viruses, environmental agents, physical factors, and drugsthat acts during embryonic or fetal development to produce a permanent alteration of form or function

 Trophogen
an agent that alters growth

Hadegens and trophogens generally affect processes occurring after organogenesis or even after birth

Selected Drugs or Substances Suspected or Proven to Be Human Teratogens

Alcohol Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers Aminopterin Androgens Bexarotene Bosentan Carbamazepine Chloramphenicol Chlorbiphenyls Cocaine Corticosteroids Cyclophosphamide Danazol Diethylstilbestrol (DES) Efavirenz Etretinate Isotretinoin Leflunomide Lithium Methimazole Methyl mercury Methotrexate Misoprostol Mycophenolate Paroxetine Penicillamine Phenobarbital Phenytoin Radioactive iodine Ribavirin Streptomycin Tamoxifen Tetracycline Thalidomide Tobacco Toluene Tretinoin Valproate Warfarin

Evaluation of Potential Teratogens

Criteria
1. The defect must be completely characterized
Careful delineation of clinical cases Rare environmental exposure associated with rare defect, with at least three reported caseseasiest if defect is severe This is preferably done by a geneticist or dysmorphologist

Many genetic and environmental factors produce similar anomalies

Identical defects with different etiologies are called phenocopies

2. The agent must cross the placenta

Placental transfer depends on maternal metabolism; on specific characteristics of the drug, such as protein binding and storage, molecular size, electrical charge, and lipid solubility; and on placental metabolism, such as with cytochrome P450 enzyme systems

3. Exposure must occur during a critical developmental period

Proof that the agent acts on the embryo or fetus, directly or indirectly Proven exposure to agent at critical time(s) in prenatal development Syndromes resulting from teratogen exposure are named according to the time of exposure Those within the first 8 weeks result in an embryopathy, and after 8 weeks, a fetopathy

 preimplantation period
2 weeks from fertilization to implantation traditionally been called the "all or none" period. The zygote undergoes cleavage, and an insult damaging a large number of cells usually causes death of the embryo

embryonic period
from the second through the eighth week. It encompasses organogenesis and is thus the most crucial with regard to structural malformations

fetal period
certain organs remain vulnerable
brain remains susceptible throughout pregnancy to environmental influences such as alcohol exposure Alteration in cardiac blood flow during the fetal period can result in deformations such as hypoplastic left heart or aortic coarctation

4. There must be a biologically plausible association

it is always possible that an exposure and a defect are temporally but not causally related

5. Epidemiological findings must be consistent

two or more high-quality epidemiological studies should report similar findings

 (a) Control of confounding factors (b) Sufficient numbers

(c) Exclusion of positive and negative bias factors

(d) Prospective studies, if possible (e) Relative risk of three or more

6. The suspected teratogen causes a defect in an animal

If a drug or environmental exposure causes birth defects in experimental animals, it may be harmful to the human fetus

Food and Drug Administration Categories for Drugs and Medications

Category A: Studies in pregnant women have not shown an increased risk for fetal abnormalities if administered during the first (second, third, or all) trimester(s) of pregnancy, and the possibility of fetal harm appears remote.
Fewer than 1 percent of all medications are in this category levothyroxine, potassium supplementation, and prenatal vitamins, when taken at recommended doses.

 Category B: Animal reproduction studies have been performed and have revealed no evidence of impaired fertility or harm to the fetus.
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
Prescribing information should specify kind of animal and how dose compares with human dose

many antibiotics, such as penicillins, macrolides, and 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 wellcontrolled studies in pregnant women. Prescribing information should specify kind of animal and how dose compares with human dose.
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 lifethreatening medical conditions, such as albuterol for asthma, zidovudine and lamivudine for human immunodeficiency viral infection, and many antihypertensives, including -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 of the potential hazard to the fetus.
This category also contains medications used to treat potentially life-threatening medical conditions, for example: systemic corticosteroids, azathioprine, phenytoin, carbamazepine, valproic acid, and lithium

 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 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

Disruption of Folic Acid Metabolism
Folic acid is essential for the production of methionine, which is required for methylation reactions and thus production of proteins, lipids, and myelin. Hydantoin, carbamazepine, valproic acid, and phenobarbital impair folate absorption or act as antagonists.
They can lead to decreased periconceptional folate levels in women with epilepsy and to fetal malformations

 Fetal Genetic Composition

Examples:
A) mutation of the gene for methylene tetrahydrofolate reductaseMTHFR 677C T
This mutation is associated with neural-tube defects and other malformations, but only when the mother has inadequate folic acid intake

 B) fetuses exposed to hydantoin are most likely to develop anomalies if they are homozygous for a gene mutation resulting in abnormally low levels of epoxide hydrolase C) cigarette smoking and isolated cleft palate, but only in individuals with an uncommon polymorphism in the gene for transforming growth factor-1TGF-1

 Homeobox Genes
These are highly conserved genes that share a region of homology. They are regulatory and encode nuclear proteins that act as transcription factors to control the expression of other developmentally important genes

They are essential for establishing positional identity of various structures along the body axis from the branchial area to the coccyx

 Example: A) retinoic acid

During embryogenesis, retinoids such as vitamin A activate genes essential for normal growth and tissue differentiation. Retinoic acid is a potent teratogen that can activate these genes prematurely, resulting in chaotic gene expression at sensitive stages of development
abnormalities in the hindbrain and limb buds

 B) valproic acid
which is believed to preferentially alter the expression of the homeobox Hox genes. Disregulation of Hox-gene expression by valproic acid may prevent normal closure of the posterior neuropore

 Paternal Exposures
paternal exposures to drugs or environmental influences (ethyl alcohol, cyclophosphamide, lead, and certain opiates) may increase the risk of adverse fetal outcome due to
induction of a gene mutation or chromosomal abnormality in sperm during intercourse a drug in seminal fluid could directly contact the fetus paternal germ cell exposure to drugs or environmental agents may alter gene expression

COUNSELING FOR TERATOGEN EXPOSURE

Questions regarding medication and illicit drug use should be part of routine preconceptional and prenatal care Counseling should include possible fetal risks from drug exposure, as well as possible teratogenic risks or genetic implications of the condition for which the drug was prescribed

EXAMPLES OF KNOWN AND SUSPECTED TERATOGENS

Alcohol
Fetal Alcohol Syndrome Diagnostic Criteriaall required

II. Prenatal and/or postnatal growth impairment III. Central nervous system abnormalities a. Structural: Head size < 10th percentile, significant brain abnormality on imaging b. Neurological c. Functional: Global cognitive or intellectual deficits, functional deficits in at least three domains

I. Dysmorphic facial features a. Small palpebral fissures b. Thin vermilion border c. Smooth philtrum

Alcohol-Related Birth Defects

I.Cardiac: atrial or ventricular septal defect, aberrant great vessels, conotruncal heart defects II. Skeletal: radioulnar synostosis, vertebral segmentation defects, joint contractures, scoliosis III. Renal: aplastic or hypoplastic kidneys, dysplastic kidneys, horseshoe kidney, ureteral duplication

IV. Eyes: strabismus, ptosis, retinal vascular abnormalities, optic nerve hypoplasia V. Ears: conductive or neurosensory hearing loss VI. Minor: hypoplastic nails, clinodactyly, pectus carinatum or excavatum, camptodactyly, "hockey stick" palmar creases, refractive errors, "railroad track" ears

 Anticonvulsant Medications

 Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin-Receptor Blockers

Fetotoxic and embryotoxic enalapril, captopril and lisinopril disrupt the fetal renin-angiotensin system, which is essential for normal renal development may provoke prolonged fetal hypotension and hypoperfusion, thus initiating a sequence of events leading to renal ischemia, renal tubular dysgenesis, and anuria ACE inhibitor fetopathy

 Antifungals
Fluconazole and Itraconazole skull abnormalities, cleft palate, humeral-radial fusion, and other arm abnormalities

 Anti-Inflammatory Agents
A)Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
not considered to be teratogenic, but they can have adverse fetal effects when used in the third trimester Indomethacin - cause constriction of the fetal ductus arteriosus with subsequent pulmonary hypertension
may also decrease fetal urine output and thereby reduce amnionic fluid volume, presumably by increasing vasopressin levels and responsiveness to it

 Leflunomide
This is a pyrimidine-synthesis inhibitor used to treat rheumatoid arthritis It currently is considered contraindicated in pregnancy
in animal studies with multiple species
hydrocephalus, eye anomalies, skeletal abnormalities, and embryo death

 Antimalarials
Chloroquine Quinine and quinidine
no increased rate of congenital anomalies in the offspring of mothers given any of these antimalarial drugs during pregnancy

 Antimicrobials
A)Aminoglycosides
gentamicin or streptomycin Although both nephrotoxicity and ototoxicity congenital defects resulting from prenatal exposure have not been confirmed

 Chloramphenicol
readily crosses the placenta and results in significant fetal blood levels When given to the preterm neonate
gray baby syndrome - cyanosis, vascular collapse, and death

 Sulfonamides
Although these agents readily cross the placenta, fetal blood levels are lower than maternal levels
do not appear to pose any significant teratogenic risk

 Tetracyclines
may cause yellow-brown discoloration of deciduous teeth or be deposited in fetal long bones when used after 25 weeks

 Antineoplastic Agents
A) Cyclophosphamide
cell death and heritable DNA alterations in surviving cells missing and hypoplastic digits, believed to be caused by necrosis of limb buds and DNA damage in surviving cells cleft palate, single coronary artery, imperforate anus, and fetal-growth restriction with microcephaly

 Methotrexate and Aminopterin

alter folic acid metabolism fetal methotrexate-aminopterin syndrome
growth restriction, failure of calvarial ossification, craniosynostosis, hypoplastic supraorbital ridges, small posteriorly rotated ears, micrognathia, and severe limb abnormalities

 Tamoxifen
adjuvant to treat breast cancer pregnancy category D, and it is recommended that exposed offspring be followed for up to 20 years to assess the risk of carcinogenicity

 Antivirals
Amantadine
used in pregnancy to prevent, modify, or treat influenza infections embryotoxic and teratogenic in animals at high doses, but data regarding its safety in pregnancy are limited

 Ribavirin
Category X and contraindicated for use in pregnancy

 Bosentan
This is an endothelin-receptor antagonist used to treat pulmonary hypertension No human data are available category X

 Hormones
Exposure to exogenous sex hormones before 7 completed weeks generally has no effect on external structures Between 7 and 12 weeks, however, female genital tissue is responsive to exogenous androgens and exposure can result in full masculinization. The tissue continues to exhibit some response until 20 weeks, with exposure causing partial masculinization or genital ambiguity

 Androgens
congenital adrenal hyperplasia

Testosterone and Anabolic Steroids

virilization, including labioscrotal fusion after firsttrimester exposure and phallic enlargement from later fetal exposure

 Androgenic Progestins
no association between this agent and any congenital defects in humans has been established

Danazol
endometriosis but also is used to treat immune thrombocytopenic purpura, migraine headaches, premenstrual syndrome, and some breast diseases dose-related pattern of clitoromegaly, fused labia, and urogenital sinus malformation

 Estrogens
Most of the many available estrogen compounds do not affect fetal development Diethylstilbestrol (DES)
prenatally exposed women who developed vaginal clear-cell adenocarcinoma

 Corticosteroids
Hydrocortisone, prednisone, and other corticosteroids are commonly used to treat serious medical conditions such as asthma and autoimmune disease.
systemic corticosteroids are category D if used in the first trimester, however, they are not considered to represent a major teratogenic risk

 Mycophenolate Mofetil
pregnancy category D

Iodine Preparations
Radioactive iodine-131 is used to treat thyroid malignancies and hyperthyroidism contraindicated during pregnancy because it readily crosses the placenta and is avidly concentrated in the fetal thyroid by the end of the first trimester

 Methyl Mercury
Prenatal exposure causes disturbances in neuronal cell division and migration, resulting in a range of defects from developmental delay and mild neurological abnormalities to microcephaly and severe brain damage

 Psychiatric Medications
Lithium
This drug is used for manic-depressive illness Ebstein anomaly, which is characterized by a downward or apical displacement of the tricuspid valve that leads to atrialization of the right ventricle

 Selective Serotonin-Reuptake Inhibitors (SSRIs)

most commonly used antidepressants in pregnancy citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline
Increased risk of cardiac malformations neonatal behavioral syndrome
jitteriness or shivering, increased muscle tone, feeding or digestive disturbances, irritability or agitation, and respiratory distress

 pulmonary hypertension in the newborn (PPHN)

characterized by high pulmonary vascular resistance, right-toleft shunting, and profound hypoxemia

 Retinoids
Vitamin A
Beta-carotene and Retinol high doses of vitamin A is associated with congenital anomalies

Bexarotene
contraindicated during pregnancy

 Isotretinoin
one of the most potent teratogens in common use.

First-trimester exposure is associated with a high rate of fetal loss, and the 26-fold increased malformation rate in survivors is similar to that for thalidomide

 Etretinate
treat psoriasis associated with severe anomalies similar to those with isotretinoin

Tretinoin
When used topically during early pregnancy, there were no observed increases in rates of congenital anomalies

 Thalidomide
Defects primarily are limited to structures derived from the mesodermal layer, such as limbs, ears, cardiovascular system, and bowel musculature
variety of limb-reduction defects

 Warfarin (Coumadin Derivatives)

Anticoagulants which readily cross the placenta, and can cause significant adverse teratogenic and fetal effects If exposed between the sixth and ninth weeks, the fetus is at risk for warfarin embryopathy
characterized by nasal and midface hypoplasia and stippled vertebral and femoral epiphyses vitamin K-dependent clotting factors are not demonstrable in the embryo warfarin derivatives exert their teratogenic effect by inhibiting posttranslational carboxylation of coagulation proteins

Herbal Remedies

 Recreational Drugs
Amphetamines
symmetrical fetal-growth restriction but does not appear to increase the frequency of congenital anomalies

 Cocaine
increased incidence of stillbirth
congenital anomalies resulting from vascular disruption have been described skull defects, cutis aplasia, porencephaly, subependymal and periventricular cysts, ileal atresia, cardiac anomalies, and visceral infarcts

 Opiates (Narcotics)
Heroin
fetal-growth restriction, perinatal death, and several perinatal complications Withdrawal symptoms such as tremors, irritability, sneezing, vomiting, fever, diarrhea, and occasionally seizures

 Methadone
Withdrawal symptoms, however, are frequent, and birthweights are often lower than expected

Marijuana
no evidence, however, that marijuana is associated with human anomalies

 Miscellaneous Drugs
Phencyclidine (PCP), known as angel dust
not associated with congenital anomalies

lysergic acid diethylamide (LSD),

no evidence that this drug is a human teratogen

Toluene
toluene embryopathy

 Tobacco
Cigarette smoke contains a complex mixture of substances including nicotine, cotinine, cyanide, thiocyanate, carbon monoxide, cadmium, lead, and various hydrocarbons doubles the risk of low birthweight and increases the risk of fetal-growth restriction two- to threefold subfertility, spontaneous abortion, placenta previa and abruption, and preterm delivery

Immunizations in Pregnancy

Thank you!!