8. Environmental Causes Of Birth Defects Flashcards
Define and discuss terms including teratogen and teratology (objective)
Answer later
Discuss the basic principles of teratology (objective)
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Discuss medications with possible teratogenic effects, including methotrexate (objective)
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Discuss the clinical features of fetal alcohol syndrome (objective)
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Discuss the teratogenic effects of some of the TORCH infections, maternal conditions and chemicals (objective)
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Teratogen
A drug or other agent that causes abnormal development in the embryo or fetus
An exposure in pregnancy that has a harmful fetal effect
Teratology
The study of environmentally induced congenital anomalies
Human Teratogens (list)
- Drugs (medical: anticonvulsants; recreational- EtOH, cocaine)
- Heavy metals: mercury
- Radiation: cancer therapy
- Maternal Conditions: diabetes/obesity
- Infections: viral
- In vitro fertilization
- Hyperthermia
Teratology Principles
- Prenatal development is sequential process
- Most sensitive to teratogens during organogenesis
- No agent is 100% teratogenic
- Factors affecting teratogenicity: timing, dose (amount/frequency/duration), fetal and maternal metabolism, genetic susceptibility
- Association does not prove causation
Thalidomide
Use: sleeping and anti-nausea in pregnancy
Stunts growth of fetal arms and legs
Phocomelia: congenital deformity with extremely shortened limbs: feet and hands arise close to the trunk
Highest risk at 3-8 weeks of gestation (organogenesis)
Prenatal development is a sequential process
1st trimester exposure: congenital malformations
2nd and 3rd trimester exposure: IQ issues
Organogenesis
Growing individual is most sensitive to teratogens during the period of organogenesis
***2-9 weeks post-conception (approximately 1st trimester)
Medications: Known Teratogens (list)
New medications: anti-depressants, SSRIs
ACE inhibitors- renal failure, skull defects
Lithium- Ebstein’s anomaly of tricuspid valve
Isotretinoin (accutane)- brain, face, ear, heart
Carbamazepine- neural tube defects
Methotrexate/Misoprostol Embryopathy
Indications for use: cancers and dermatomyositis
Anomalies observed in multiple organ systems/structures
Timing is key: most cases 38% in 1st trimester
Dose response effect
ACE Inhibitors
Angiotensin converting enzyme inhibitors for hypertension: 2 and 3 trimester
Decreased fetal renal blood flow
Reversible or irreversible renal failure, hypotension, anuria, skull hypoplasia
Lithium
Ebstein’s anomaly: tricuspid valve inferiorly displaced
- 5-3x RR for all congenital anomalies
- 2-7.7x RR for cardiac malformations
Clinical management of women with bipolar disorder should be modified
Usually see women pregnant and bipolar
Isotretinoin (accutane)
Vitamin A, retinoids (derivative)
CNS, cardiac, ear, thymic, branchial arch anomalies
Studies hard to do because lots of death
Cerebellar hypoplasia
Anticonvulsants
Up to 3x background risk for anomalies- 10%
Polypharmacy increases risk for malformations
Phenytoin- Fetal Dilantin Syndrome- nail hypoplasia
Valproic acid and carbamazepine-neural tube defect (1-3% risk)
No safe anticonvulsant, but mostly mild teratogens
Fetal Alcohol Syndrome
1/2000 births
Global growth deficiency, microcephaly
Small increased risk for birth defects (heart)
LD, mild/moderate ID
ADHD, impulsive, poor memory, conduct disorder
Smooth and thin upper lip
Hockey stick crease, ears
Seen in families with multigenerational alcoholism; adoptees
Growth Deficiency Fetal Alcohol Syndrome
May not be clear at start
Weight, length, head circumference
FAS Tip of Iceberg (Prenatal Alcohol)
FAS
Fetal Alcohol Effects
Clinically Suspect or Abnormal
Apparently Normal but Unable to Meet Potential
How does ethanol disturb normal gene expression in the embryo?
Ethanol exposure cause changes in intracellular calcium
Alter numerous signaling cascades and results in dysmorphogenesis
Gene targets: SHH, Fgf-8, Pax6
Other Drugs of Abuse
Cocaine: pregnancy loss, abruption, uterine growth retardation (IUGR), microcephaly, vascular anomalies (limb loss)
Methamphetamine: inconclusive
Marijuana: no consistent link, but effect on higher executive function
Tobacco: poor fetal growth, behavior teratogenicity, IQ, cong anomalies
Dosage Effect: Cigarettes and IQ
Increased cigarettes, decreased IQ
Income may be a confounding variable
Maternal Exposure
Timing
Dose
Genetic predisposition of embryo/fetus
- mother’s metabolism
- physiology of the placenta
Maternal Infections: TORCH
Toxoplasmosis Other-varicella, syphilis Rubella Cytomegalovirus Herpes TORCHZ (Zika)
TORCH infections: clinical manifestations
General: intrauterine growth restriction (IUGR), prematurity
Vital signs: hypo-/hyperthermia, apnea, tachypnea
CNS: hypo-/hypertonia, seizures, microcephaly, hydrocephalus
TORCH Clinical Manifestations (continued)
Eyes: chorioretinitis, cataracts, glaucoma, microphthalmia
Ears: hearing loss
Lungs: pneumonia
Cardiovascular: structural defects
Liver/spleen: hepatosplenomegaly (immune system; large liver/spleen)
Skin: petechiae, purpura, rash, jaundice
Congenital Rubella Syndrome
85% risk of this if infection in 1st trimester
IUGR, microcephaly, cataracts, senorineural hearing loss, chorioretinitis, meningoencephalitis, ID
Vaccine refusal, immigration
Congenital Cytomegalovirus Infection
1% US newborns
Only 10% symptomatic
-Primary CMV: more severe sequelae
SNHL, chorioretinitis, microcephaly, MR
5-17% asymptomatic newborns will develop hearing loss (could be genetic/environment)
Maternal Metabolic Disorders: Diabetes
Maternal
Type 1 in 1st trimester: cardiac, sacral defects, NTD, pregnancy loss
-termed embryopathy (affected embryo, early in pregnancy), 10% risk of birth defects
Gestational diabetes- 2nd or 3rd trimester- fetus receives abundant fuel
-fetal macrosomia (big), high insulin levels and can develop hypoglycemia after birth, polycythemia/plethoric (blood), hypertrophic cariomyopathy, microcolon.
Most features resolve
Termed a “fetopathy”
Maternal Metabolic Disorders: PKU
Dose response seen to increasing PHE levels
Microcephaly, ID, cardiac defects, pregnancy loss
Chemicals which are teratogenic
Methylmercury-microcephaly, MR, cerebral palsy: Minamata disease (shellfish in Japan)
Lead- impairs CNS function
Minamata Disease
Methylmercury in shellfish in Japan
Neurologic impairment
Association Does Not Prove Causation
Bendectin-morning sickness medication with an antihistamine, antispasmotic and vitamin B6.
Medication is effective and not be bad based on data
