8. Environmental Causes Of Birth Defects

Question 1

Define and discuss terms including teratogen and teratology (objective)

Answer 1

Answer later

Question 2

Discuss the basic principles of teratology (objective)

Answer 2

Answer later

Question 3

Discuss medications with possible teratogenic effects, including methotrexate (objective)

Answer 3

Answer later

Question 4

Discuss the clinical features of fetal alcohol syndrome (objective)

Answer 4

Answer later

Question 5

Discuss the teratogenic effects of some of the TORCH infections, maternal conditions and chemicals (objective)

Answer 5

Answer later

Question 6

Teratogen

Answer 6

A drug or other agent that causes abnormal development in the embryo or fetus

An exposure in pregnancy that has a harmful fetal effect

Question 7

Teratology

Answer 7

The study of environmentally induced congenital anomalies

Question 8

Human Teratogens (list)

Answer 8

1. Drugs (medical: anticonvulsants; recreational- EtOH, cocaine)
2. Heavy metals: mercury
3. Radiation: cancer therapy
4. Maternal Conditions: diabetes/obesity
5. Infections: viral
6. In vitro fertilization
7. Hyperthermia

Question 9

Teratology Principles

Answer 9

1. Prenatal development is sequential process
2. Most sensitive to teratogens during organogenesis
3. No agent is 100% teratogenic
4. Factors affecting teratogenicity: timing, dose (amount/frequency/duration), fetal and maternal metabolism, genetic susceptibility
5. Association does not prove causation

Question 10

Thalidomide

Answer 10

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)

Question 11

Prenatal development is a sequential process

Answer 11

1st trimester exposure: congenital malformations

2nd and 3rd trimester exposure: IQ issues

Question 12

Organogenesis

Answer 12

Growing individual is most sensitive to teratogens during the period of organogenesis

***2-9 weeks post-conception (approximately 1st trimester)

Question 13

Medications: Known Teratogens (list)

Answer 13

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

Question 14

Methotrexate/Misoprostol Embryopathy

Answer 14

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

Question 15

ACE Inhibitors

Answer 15

Angiotensin converting enzyme inhibitors for hypertension: 2 and 3 trimester

Decreased fetal renal blood flow
Reversible or irreversible renal failure, hypotension, anuria, skull hypoplasia

Question 16

Lithium

Answer 16

Ebstein’s anomaly: tricuspid valve inferiorly displaced

1. 5-3x RR for all congenital anomalies
2. 2-7.7x RR for cardiac malformations

Clinical management of women with bipolar disorder should be modified

Usually see women pregnant and bipolar

Question 17

Isotretinoin (accutane)

Answer 17

Vitamin A, retinoids (derivative)

CNS, cardiac, ear, thymic, branchial arch anomalies

Studies hard to do because lots of death

Cerebellar hypoplasia

Question 18

Anticonvulsants

Answer 18

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

Question 19

Fetal Alcohol Syndrome

Answer 19

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

Question 20

Growth Deficiency Fetal Alcohol Syndrome

Answer 20

May not be clear at start

Weight, length, head circumference

Question 21

FAS Tip of Iceberg (Prenatal Alcohol)

Answer 21

FAS
Fetal Alcohol Effects
Clinically Suspect or Abnormal
Apparently Normal but Unable to Meet Potential

Question 22

How does ethanol disturb normal gene expression in the embryo?

Answer 22

Ethanol exposure cause changes in intracellular calcium
Alter numerous signaling cascades and results in dysmorphogenesis

Gene targets: SHH, Fgf-8, Pax6

Question 23

Other Drugs of Abuse

Answer 23

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

Question 24

Dosage Effect: Cigarettes and IQ

Answer 24

Increased cigarettes, decreased IQ

Income may be a confounding variable

Question 25

Maternal Exposure

Answer 25

Timing

Dose

Genetic predisposition of embryo/fetus

• mother’s metabolism
• physiology of the placenta

Question 26

Maternal Infections: TORCH

Answer 26

Toxoplasmosis
Other-varicella, syphilis
Rubella
Cytomegalovirus
Herpes
TORCHZ (Zika)

Question 27

TORCH infections: clinical manifestations

Answer 27

General: intrauterine growth restriction (IUGR), prematurity

Vital signs: hypo-/hyperthermia, apnea, tachypnea

CNS: hypo-/hypertonia, seizures, microcephaly, hydrocephalus

Question 28

TORCH Clinical Manifestations (continued)

Answer 28

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

Question 29

Congenital Rubella Syndrome

Answer 29

85% risk of this if infection in 1st trimester

IUGR, microcephaly, cataracts, senorineural hearing loss, chorioretinitis, meningoencephalitis, ID

Vaccine refusal, immigration

Question 30

Congenital Cytomegalovirus Infection

Answer 30

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)

Question 31

Maternal Metabolic Disorders: Diabetes

Answer 31

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”

Question 32

Maternal Metabolic Disorders: PKU

Answer 32

Dose response seen to increasing PHE levels

Microcephaly, ID, cardiac defects, pregnancy loss

Question 33

Chemicals which are teratogenic

Answer 33

Methylmercury-microcephaly, MR, cerebral palsy: Minamata disease (shellfish in Japan)

Lead- impairs CNS function

Question 34

Minamata Disease

Answer 34

Methylmercury in shellfish in Japan

Neurologic impairment

Question 35

Association Does Not Prove Causation

Answer 35

Bendectin-morning sickness medication with an antihistamine, antispasmotic and vitamin B6.

Medication is effective and not be bad based on data