Teratogens: Impact on Fetal Development

The FDA rules on drug pregnancy risk info

- 6/30/2015 - More consistent way to include relevant information regarding risks, benefits and limitations of prescription drugs and biological products during pregnancy and lactation - 3 detailed subsections to include human and animal data, specific adverse reactions • Pregnancy • Lactation • Male and female reproduction potential - Each must include summary of the risks, discussion of supporting data and relevant information to assist providers in making prescribing and counseling decisions - Information regarding pregnancy exposure registry, if available

physical agents: radiation

- Increased risk associated with exposures of 10-20 rads or greater • Dose-response manner • Diagnostic x-ray <5 rads is not known to be teratogenic • Radiation therapy - 1000 rads or more- very high risk of teratogenic effect • Anomalies include: - Central nervous system (CNS) - Microcephaly, mental retardation, seizures - Growth retardation - Minor anomalies of the eyes - Controversial increase in carcinogenesis

Cytomegalovirus (CMV)

- Most women have been exposed at some point prior to pregnancy - 0.7-4% have primary exposure during the pregnancy • 40% risk of transmission to fetus • 10% of infected fetuses show symptoms of congenital CMV at birth • 5-15% of fetal infections with no symptoms at birth may develop long-term effects • Central Nervous System (CNS) - Hydrocephalus in some, microcephaly, cerebral calcifications, mental retardation • Eye - Chorioretinitis, blindness, microphthalmia • Other - Growth retardation, hearing loss, heart defects

characteristics of teratogens

-increased occurrence: exposure during pregnancy is associated with an increased phenotypic effect over the general pop -supportive animal model: aminal models should duplicate human effect, ideally should use same route of exposure -a dose-response relationship: liklihood and magnitude of response should increase with dose of teratogen, certain threshold must be reached -biologic plausibility: plausible biologic explanation for the mechanism of action of the teratogen

categories of teratogens

-infectious agents (ex herpes) -physical agents (ex hypothermia, radiation) -chemical agents/drugs (ex medications, recreational drugs/alcohol) -maternal metabolic and genetic factors (ex diabetes, maternal phenylketonuria. disirders of folate metabolism)

DES (Diethylstilbesterol)

-medication given to prevent pregnancy complications/loss in 1938-1971 - 5-10 million pregnancies exposed Effects seen in the fetuses as adult women: • Internal anomalies of the reproductive tract --> (vaginal adenosis, cervical hoods, T-shaped uterus in at least 1/3 of all exposed • Increased risk of vaginal cancer (clear cell adenocarcinoma) in adult female children (risk= ~1/1000) • Increased risk of infertility **effects of teratogen may not be evident until years after birth**

reprotox

-online database of teratogens -contains summaries on the effects of medications, chemicals, infections and physical agents on pregnancy, reproduction and development

A newborn is evaluated for a heart murmur and found to have a ventricular septal defect (VSD). The history is notable for lack of prenatal care. Near delivery, an ultrasound evaluation showed intrauterine growth retardation. On physical examination, the child is noted to have symmetric growth retardation, small palpebral fissures, thin upper lip, and smooth philtrum. What is the most likely teratogen??

Alcohol - One of the most common teratogen - Produces a spectrum of teratogenic effects - Some children born with only behavioral effects, others with fetal alcohol syndrome (FAS) • FAS has been noted only for regular users of alcohol • Centers for Disease Control: Major risk to the fetus is reported to require chronic, daily alcohol consumption • Lower alcohol intake has been implicated with more subtle abnormalities of development *** No safe level of alcohol consumption ***

A preterm baby is born. Prenatal sonograms were significant for intrauterine growth retardation. She has low birth weight and has an abnormally small head circumference (microcephaly). The baby has seizures on day 2 of life and head imaging reveals evidence of a stroke. What is the most likely teratogen?

Cocaine •readily crosses the placenta and concentrates in the amniotic fluid •Associated with: -Placental abruption -Premature rupture of membranes (PROM) & preterm delivery -Vascular malformations -Microcephaly -Neurobehavioral and learning disorders

Mother has a history of seizures, baby born with the following dysmorohic features: - Microcephaly and intrauterine growth retardation (IUGR) - Hirsutism - Broad and depressed nasal bridge - Short nose - Hypertelorism - Hypoplastic nails - Long, tapering digits - On cardiovascular evaluation, you appreciate a holosystolic murmur What is the teratogen?

Dilantin -- anticonvulsant medication

infections

affect embryogenesis and fetal development: -brain -eyes -ears -heart -growth retardation

teratogen

any substance, agent or process that interferes with normal development

Cigarette Smoking

associated with: -increased miscarriage risk -reduced fetal growth -abnormal placentation • An increase in risk of congenital malformations has been identified in some but not all studies --> If there is such a risk, it appears to be small (e.g., an increase in facial clefting from 1/500 to 1/183).

You are in your continuity clinic and see a baby with Ebstein's anomaly. What question should you ask the infant's mother about her medical history?

Prenatal use of Lithium? Mood stabilizers can contain Lithium, which has an increased risk of heart defects (0.1-0.2%) including Ebstein's anomaly

Multiple exposures

many women are taking multiple medications or have multiple exposures during their pregnancies, which can interact: -additive: combined effect the same as sum of individual effects -antagonism:combined agents counteract each other and have less of an effect -synergism: combined effect is significantly greater then individual effects *very difficult to predict

teratology

the study of environmentally-induced birth defects

Exception: Monoamine oxidase inhibitors (MAOIs)

• Nardil, Emsam, Parnate, Marplan • Limited human and experimental animal data • Contraindicated due to suspected decreased uterine blood flow and increased risk of adverse pregnancy outcome • Data to substantiate this suspicion have not been conclusive

factors affecting potential effect of teratogen

•not all exposed pregnancies will have harmful effects -->dose of agent -->amount, route of administration, duration -->timing (was the exposure during a time of high sensitivity and organ development?) •interactions with other environmental factors •host susceptibility: individual differences in metabolism of teratogenic agents (genetic differences in metabolism of a drug by the mother, the placenta and fetus)

congential rubella

•viral illness known as German Measles •abnormalities vary in frequency, severity and type according to time of exposure: - Abortion/late fetal death - Growth retardation - Microcephaly - Cataracts - Deafness - Congenital heart defects - All organs can be affected

Developmental period: 0-15 days post conception

"all or nothing" period -developing embryo is NOT susceptible to teratogens (not connected to mother yet) -exposure will result in spontaneous miscarriage or will have no effect

Tegretol

*another mood stabilizer* - Neural tube defects - Craniofacial abnormalities - Developmental delay

Carbamazepine (Tegretol)

*anticonvulsant medication* - Increased risk of neural tube defects - Craniofacial abnormalities - Developmental delay

Hydantoin (Dilantin, Phenytoin)

*anticonvulsant medication* 10% risk of anomalies (fetal hydantonin syndrome) - Dysmorphic faces - Microcephaly - IUGR continuing into infancy - Congenital heart defects - Hypoplastic distal phalanges & abnormal nails - Short, webbed neck - Low hairline - Hirsutism - Developmental delay

phenobarbitol

*anticonvulsant medication* 10-20% incidence of birth defects

Relatively benign exposures

-marijuana -caffeine -oral contraceptives

Hyperthermia

Increase in a pregnant women's body temperature above 101 degrees • Fever or exposure to extreme heat conditions (hot tubs or saunas) • Risk of neural tube defects when exposed in the first 4 weeks of pregnancy (3-4 weeks

Diabetes mellitus

Increased risk of: - Neural tube defects (NTD) - heart defects - skeletal defects (caudal regression, sacral agenesis) - macrosomia - 6-10% is a generally used risk The better controlled, the lower the risk: • >20% risk if poorly controlled in the first trimester • Control is difficult as pregnancy is characterized by increased insulin resistance and reduced sensitivity to insulin action

Your patient's prenatal ultrasound reveals fetal macrosomia, a heart defect and spina bifida. Your patient is 250 pounds and noncompliant. What is the most likely teratogen?

Maternal type II diabetes

Developmental period: 3-8 weeks post-conception

Organogenesis -when tissues and organs are forming -embryo is most easily disrupted -fetal death, major malformations, growth retardation, impaired IQ *this is a very vulnerable time* **exposure after an organ is formed will NOT cause a structural defect**

psychiatric medications

Overall, not a strong teratogenic component -Generally considered safe -Limited clinical/human data for some -Biggest risks for mild, transient neonatal syndrome of central nervous system, motor, respiratory or gastrointestinal signs -Some associated with neonatal pulmonary hypertension and withdrawal

Why is this important?

teratogen-induced adverse fetal effects are potentially reversible

valproate (depakote)

*anticonvulsant medication* 6-18% of anomalies and developmental delay (fetal valproate syndrome) - Microcephaly - Spina bifida (1-2%) - Developmental delay - Cardiac defects - Facial clefts - Hypospadias - Craniosynostosis - Limb defects -dysmorphic faces

Vigabitrin, Topimax and Trileptal

*anticonvulsant medication* Unclear if there is an increase in the incidence of congenital anomalies

Clonazepam (Klonopin)

*anticonvulsant medication* not associated with increased risk of anomalies

anticonvulsant medications

-In general, considered teratogenic --> 5-10% with a single medication --> Risk doubles if exposure to two or more medications -Fetal Anticonvulsant Syndromes (FACS)- dysmorphology, developmental delay, neural tube defects, genitourinary anomalies, limb and heart defects -Folic acid antagonists; recommend folic acid supplementation -Recommend vitamin K treatment near term (newborn hemorrhagic disease) -In 1/3 of cases, seizure activity increases in pregnancy -Difficulty in balancing teratogenic risks of medications with risks of seizures during pregnancy **Optimal seizure control is imperative during pregnancy despite teratogenic risks** -Patients should be encouraged to take meds under care by neurology, maternal-fetal-management specialist

manifestations of a teratogen

-death -growth retardation -malformation (structural abnormality) -functional deficit (cognitive impairment, behavioral abnormalities)

Fetal Alcohol Syndrome

3 categories of findings: - Prenatal and postnatal growth restriction (height, weight and head circumference <10th percentile) - Characteristic facial features • narrow palpebral fissures, long, smooth philtrum with thin upper lip - CNS abnormalities (microcephaly, mental retardation, behavioral abnormalities)

This medication was initially introduced in the mid 1950s as a mild sedative to help combat nausea. It was taken off the market in the 1960s due to unexpected effects on fetuses. The anomaly it is best known to cause is phocomelia. What is the teratogen?

Thalidomide (phocomelia = severe limb reduction defect)