Teratology and Medications that Affect the Fetus

Christiana Calagui-Damaso, MDOB-GYN

TERATOLOGY• 65 % - etiology of birth defects is unknown

• Teratogen– derived from the Greek teratos, meaning monster

A hadegen—after Hades, the god who possessed a helmet conferring invisibility—is an agent that interferes with normal maturation and function of an organ

– any agent—chemicals, viruses, environmental agents, physical factors, and drugs—that 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

• Criteria1. The defect must be completely characterized

• Careful delineation of clinical cases• Rare environmental exposure associated with rare defect,

with at least three reported cases—easiest 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 well-controlled 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 life-threatening 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

reductase—MTHFR 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-1—TGF-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

AlcoholFetal Alcohol Syndrome Diagnostic Criteria—all required

• I. Dysmorphic facial features– a. Small palpebral

fissures– b. Thin vermilion border– c. Smooth philtrum

• 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

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 first-

trimester 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-to-

left 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

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