Teratology Flashcards
Principles of Teratology
- developmental timing
- genetic susceptibility
- tissue access
- patterns of malformation
- dosage effects
Critical Periods of Embryonic and Fetal Development
(1) preimplantation or “all or none” period
(2) period of organogenesis
(3) period of growth and maturation.
Preimplantation Phase
- The preimplantation phase of embryonic development occurs during the first 2 weeks after conception (from 2-4 weeks post LMP).
- During this time the early embryo migrates from the fimbrial portion of the fallopian tube to the uterus and begins the process of implantation into the uterine wall. It does not have any attachment to the maternal circulation.
- Potentially teratogenic insults during this stage are believed to result either in embryonic death or intact survival, hence the designation as the “all or none” period.
- Congenital anomalies are not produced during this time. The all or none phenomenon is useful in counseling about very early pregnancy exposures.
Organogenesis
•The period of organogenesis is the most critical period of development for structural malformations. This period occurs from approximately 15 to 60 days after conception. Almost all major organ systems are developing and have completed their general structural development by the end of this time period. For example, the primitive heart tube begins to beat around day 22 and the neural tube closes at about day 28.
Growth and Differentiation
- From day 60 until birth is the period of growth and differentiation. Teratogenic exposures occurring during this period are not thought to cause structural birth defects. They are more likely to result in impairment of growth or function.
- In particular, the central nervous system is susceptible, as CNS growth, neuronal migration and synaptogenesis are important events that continue throughout this period, and even into the postnatal period.
- Issues of poor neonatal adaptation (such as those seen with the use of opioids or SSRI’s) and long-term neurobehavioral effects (such as those seen with fetal alcohol syndrome) are important considerations in this time frame.
Categories of Teratogenic Agents
•infectious agents
-TORCH infections
- maternal disease of metabolic state
- medications
- recreational drugs
- physical agents
Infectious Agents
- TORCH is a mnemonic that stands for Toxoplasmosis, Other, Rubella, Cytomegalovirus, and Herpes simplex virus.
- Of these, two of the more clinically important, historically and presently, are rubella and cytomegalovirus
Rubella
- Rubella infection is of great historical importance and represents a true success story in the prevention of human disease through immunization.
- Prior to rubella immunization becoming a part of routine preventive health care for infants, there were frequently outbreaks of this condition, with resulting problems during pregnancy. However, this condition is rarely encountered in newborns in countries with successful vaccination programs.
- Gestational timing of infection is related to risk, with the incidence of detectable malformations being about 85% in the first 8 weeks after conception, decreasing to about 15% by the 13th to 20th weeks.
- Affected infants are growth deficient and microcephalic, and significant proportions have sensorineural hearing loss and eye abnormalities such as cataracts and glaucoma.
Cytomegalovirus (CMV)
- Cytomegalovirus (CMV) remains a problem for many babies worldwide. About 1-4% of U.S. newborns have evidence of a congenital CMV infection, but the great majority are asymptomatic at birth.
- Some newborns can be very seriously affected, with growth restriction, microcephaly, cerebral calcifications and chorioretinitis (a congenital inflammation of the eye which often results in visual compromise).
- During a maternal primary infection, the rate of fetal infection is about 30-50%, whereas the rate of fetal infection in a mother with a known previous infection is probably no higher than 1%.
- Of infected, asymptomatic newborns, 10- 15% will develop hearing loss or learning difficulties.
- Routine newborn screening can now identify many newborns with hearing loss.
Diabetes Mellitus
- Poor diabetic control in early pregnancy has been associated with an increased risk to the fetus of up to 8% for a specific pattern of malformations. The most common features of the diabetic embryopathy include abnormalities of the spine and lower extremities, heart, and kidney.
- The risk is greatest for those individuals with the poorest long-term glycemic control and is much lower for women who maintain normal control throughout gestation.
Maternal PKU
- Since the inception of newborn screening and dietary treatment for PKU in the late 1960’s, many women have been successfully treated and are now of childbearing age.
- Previous dietary management called for children to go “off diet” at around age 8 years, with the assumption that brain maturation was complete by that time. Therefore, many of these women on normal diets have very high phenylalanine levels. High phenylalanine levels are toxic to the developing brain and heart. In order to have healthy offspring, it is necessary for women with PKU to be on a stringent PKU diet so that their serum phenylalanine levels will be low and not present a risk to fetal development. It is recommended that women with PKU go on diet prior to attempting a pregnancy. This may be difficult as some insurance companies will not pay for the expensive formula or will pay for it only if there is an ongoing pregnancy.
Fetal hydantoin syndrome
- Fetal hydantoin syndrome is a pattern of anomalies present in the children of some women who take diphenylhydantoin (Dilantin) during pregnancy. It is associated with growth deficiency, neurodevelopmental delay, microcephaly, widely spaced eyes, low anterior hairline, and short fingers with nail hypoplasia. The risk for the syndrome is about 10-15% in exposed children. Many anticonvulsants are metabolized through the arene oxide pathway (an enzyme pathway that includes epoxide hydrolase) and some studies suggest a common pathogenetic mechanism for the malformations seen in anticonvulsant-exposed children.
- Children exposed to carbamazepine (Tegretol), another anticonvulsant eliminated through the arene oxide system, have similar phenotypic features to diphenylhydantoin-exposed children. Recent data suggest involvement of other metabolic pathways, although much work still needs to be done in this area.
Valproic acid (Depakene)
•a specific pattern of malformations has been seen, including facial abnormalities similar to those seen in the fetal hydantoin syndrome, heart defects, and neural tube defects. The risk for a neural tube defect is approximately 1-2%. In addition, significant delays in infant neurodevelopment have lead the FDA to recommend against using this medication in reproductive age women unless there are no other choices. In comparison to other anticonvulsants, the highest incidence of neurodevelopmental problems are seen with valproate-exposed babies.
Lithium
•Lithium is used to treat bipolar disease. Initial reports of lithium-exposed pregnancies showed an increased risk of heart defects, especially Ebstein’s anomaly, a serious abnormality of the tricuspid valve. Subsequent reports indicate that this risk is probably very small (1-5%). Serum levels should be monitored throughout pregnancy due to the narrow range of toxicity.
Vitamin A congeners
- It has long been known that high doses of vitamin A can cause birth defects in experimental animals and in humans. Since 1982, a vitamin A analog, isotretinoin (Accutane) has been used for treatment of cystic acne, and in 1985 the first reports of birth defects as a consequence of isotretinoin were published. Exposed infants were found to have microtia/anotia (small or absent ear), central nervous system defects, thymic abnormalities, and cardiac defects. This pattern of anomalies is seen in about 30% of pregnancies exposed in the first trimester. Structurally normal children have also been found to have an increased risk of neurodevelopmental problems.
- A Pregnancy Prevention Program (iPLEDGE) is now in place which requires the physician, pharmacist and patient to register in an online program. In addition, 2 forms of birth control must be used, only one month supply is provided and proof of a negative pregnancy test within 7 days prior to filling the prescription are required. This program has significantly reduced the number of exposed babies.
