Teratology Flashcards
incidence of birth defects
- 3-5% overall risk
- 1% (~1 in 100) babies born with CHDs
percentage of birth defects due to teratogens
5-10%
miscarrying pregnancies
approximately 20% of all recognized pregnancies
risk perception with medication exposure
- 50-90% of all women exposed to meds in pregnancy, but most of these are not teratogenic
- women and providers tend to estimate their risk for teratogenic effects to be about 25%
teratogen
any medication, chemical, infectious disease or environmental agent that might interfere with normal fetal development and may result in miscarriage, birth defects or adverse pregnancy outcomes
possible teratogenic effects
- SAB
- pregnancy complications
- IUGR
- patterns of major, minor malformations
- metabolic dysfunction
- cognitive dysfunction
- altered social behavior
- malignancy
- complications in the neonatal period
thalidomide
- drug used as a sedative
- resulted in 20-50% of exposed pregnancies having sever limb defects
thalidomide critical period
between 30-50 days post-LMP
principles of teratology
- developmental timing
- dose
- genetic susceptibility
- pattern of malformation
- tissue access
developmental timing
most important factor in determining the risk for a birth defect to affect the pregnancy
heart formation
ends at about 6w post-conception, 8w post-LMP
limb formation
complete by the end of the first tri
brain formation
any teratogen that can affect cognition or behavior can cause issues at any point in the pregnancy
warfarin embryopathy
- nasal hypoplasia that can cause respiratory distress in the newborn period
- stippled epiphyses-calcifications of joints that don’t typically cause physical disability
- limb hypoplasia
warfarin critical period
6-9w post-conception, 8-11w post-LMP
-need moms to switch to alternate anti-thrombotic
ACE inhibitor/ARB embryopathy
- renal tubular dysplasia
- IUGR
- hypocalvaria with large anterior fontanelle
ACE inhibitor/ARB critical period
2nd and 3rd trimester of pregnancy
effects of renal tubular dysplasia
- oligohydramnios
- Potter sequence
- pulmonary hypoplasia
ACE inhibitor mechanism of activity
- reduce intrauterine blood flow, causing placental perfusion and severe fetal hypotension
- block fetal angiotensin-converting enzyme in fetus disrupting fetal hemodynamics
Potter sequence
- renal problems lead to oligo
- this can lead to other abnormalities, including club foot, pulmonary hypoplasia, sometimes eye and cardiac anomalies
- facies: low-set abnormal ears, epicentral folds, micrognathia, flattened nose/profile
SSRI effects in the first trimester
-smaller studies showed no increased risk for birth defects
-larger studies found a range of implications, including
+craniosynostosis
+anencephaly
+omphalocele
+2 fold CHD risk (1 in 200)
SSRI effects throughout pregnancy
- can result in mild short-lived neonatal adaptation syndrome-like a less severe version of withdrawal
- potential effects on gross motor and language development
SSRI effects after 20w of pregnancy
variable opinions on increased risk for pulmonary HTN of the newborn
+would lead to the need for a NICU stay
+risk in the past has been thought to be only about 1%
discontinuation of SSRI effects
untreated depression is likely to lead to recurrence in the first trimester
nausea and vomiting in pregnancy
- common-occurs in ~80% of women between weeks 6-12
- 1% will progress to life-threatening hyperemesis gravidarum
hyperemesis gravidarum treatment
-traditionally includes antihistamines, phenothiazines, and antiemetics
+ondansetron (antiemetic) has recently been seen with a two-fold CHD risk
-Diclegis is now the only FDA approved N&V medication
dose
-teratogens tend to exhibit a dose-response relationship
+can be greater in animals than humans
-greater exposure generally leads to a greater effect
+a threshold below which no effect can be seen is sometimes present
methylmercury
-high levels of mercury can lead to neurological problems in women and children-severe CNS and motor effects
+asymptomatic levels are about 8bbp in skin, 2ppm in hair
+affected kids with 5-110ppm in hair
-per FDA, women recommended to eat fish during pregnancy, but avoid those high in mercury
radiation
-pattern of malformations: ID, microcephaly, seizures, minor eye malformations, GR, possible increased risk for carcinogenesis
-no increased risk below 5 rads
+most diagnostic tests do not go above this, only possible with abdominal CTs
+often times affected kids were exposed to 20-25 rads
fluconazole
-antifungal medications
-mostly non-associated with no birth defects
+however some women treated with it in large doses of Valley fever had babies with severe craniofacial, cardiac and limb anomalies
+requires large oral or IV dosage
+possible risk for Antley-Bixler phenocopy
common anti-convulsants
- pheytoin
- valproate
- trimethadione
- barbiturates
- carbamazepines
- anticonvulsant embryopathy usually refers to these older medications
anticonvulsant use
- drug cocktails/polytherapy worse
- increasing use of drugs for other maternal conditions-ex: bipolar
anticonvulsant embryopathy
- dysmorphic features-hypertelorism, broad depressed nasal bridge, short-upturned nose, cupid’s bow lip, nail hypoplasia
- major malformation risk-myelomeningocele, oral clefting, CHDs (aorta, PDA), limb anomalies
- neurobehavioral: DD, dose dependent increased risk for diminished IQ, ASD
anticonvulsant risk values
-highest risks for valproic acid, phenobarbital, carbamazepine, trimethadione
+6-15% risk of major malformations
-possible reduced risk in newer meds
-DD risk independent of additional anomalies
-higher polydrug therapy risk
-best outcomes if optimal lower risk therapy identified prior to conception
tissue access
teratogen present in maternal circulation in high enough amounts to cross the placenta
Organogenesis
Days 18-60 of gestation
-NTD develops between days 23-30
Maternal diabetes risks
- miscarriage, stillbirth, preterm birth
- macrosomia (>10lbs)
- cardiac defects
- NTDs and caudal regression
- polyhydramnios
- other birth defects
- maternal HTN and preeclampsia
- hypoglycemia “knocks out” important cells
MDM counseling and recommendations
-lower risks in controlled and gestational diabetes
+need to consider co-morbidities like HBP
-recommend folic acid beginning preconception
-level II/anatomy scan b/t 18-20w
-msAFP or AFAFP b/t 16-20w
-fetal echo b/t 20-22w
FDA teratogen classification
- A, B, C, D alphabetically least to most concerning
- X is contraindicated, except if benefit to mom significantly outweighs risk
- N is not yet classified
- lettering will be removed because of the medical mismanagement associated with the system
retinoic acid embryopathy
-ID can be seen in absence of additional anomalies (30-60%)
-can lead to CNS, CV (aortic arch anomalies), ear and thymus anomalies in 20-30% of exposed fetuses
+related to disruption of neural crest cell migration/function
retin-A/tretinoin
topically absorbed, and although effects likely less severe or non-existent suggested to be avoided during pregnancy
genetic susceptibility
-teratogenicity related to maternal and fetal DNA and metabolizing enzymes
+cytochrome p450 (CYP)
+only 30% of babies affected by teratogens
-future research may work towards personalized medicine
smoking in pregnancy risks
- infertility
- ectopic pregnancy
- miscarriage
- preterm birth
- IUGR (dose dependent)
- placental abruption & placenta previa
- SIDS
- orofacial clefts
fetal orofacial clefts and cigarettes
-association in some studies but not in others
-thought to be related to polymorphisms in TGF-alpha
+moms more likely to have a child with problems if they are in contact with teratogen and have the particular allele
codeine and breastfeeding
- rare association of use and newborn respiratory failure
- moms were ultra-rapid metabolizers of morphine
CMV incidence
-primary infection occurs in 1-4% of all pregnancies
-most infected newborns are unaffected (85-95%)
+primary maternal infection only results in congenital infection in 30-40% of cases
+secondary infection thought to be related to a different strain of the virus
CMV pattern
in 10-14% of infected pregnancies the following may occur to varying degrees
- IUGR
- cerebral calcifications, ID
- ocular abnormalities, deafness
- hepatosplenomegaly
- petichiae
- most common adverse outcome is hearing loss
vaccines in pregnancy
some can be given in pregnancy, though recommended to be up to date prior to conception
viral and parasitic infections in pregnancy
generally can lead to damaging effect in the CNS and hematopoietic systems
alcohol in pregnancy
no known safe level, but effects only thought to be seen in addicted mothers
FASD implications
-IUGR and postnatal GR
-CNS effects-brain malformations, seizures
-CHD, renal anomalies, skeletal implications
+ID, DD
+behavioral problems-irritability, ADHD, ASD
-facial dysmorphism
+ptosis, SHORT palpebral fissures, micropthalmia
+smooth philtrum
+thin upper vermillion
benzodiazepines
- used mostly to treat anxiety
- some associations with oral clefting in animal models and older studies
- use in the end of pregnancy has a higher risk for neonatal adaptation syndrome
Zika virus
neurotropic flavivirus in the same class as dengue, West Nile, Chikungunya, Yellow Fever, Japanese Encephalitis
Zika symptoms
-usually incubates 3-14d
-80% infected asymptomatic or with mild symptoms
+can get conjunctivitis, fever, joint pain, rash
+muscle pain & headache can also happen
+possible increased risk for Guillan-Barre related to autoimmune disease reaction
-infection and damage to placenta can lead to congenital infection
congenital Zika risks
*highest risks in 1st tri exposures
-microcephaly
+~13% of vertical transmission cases, often not seen until 3rd tri
-brain calcifications
-other brain anomalies (ventriculomegaly, abnormal gyral patterning, cerebellar hypoplasia & cerebellar vermis or brainstem hypoplasia, hypo plastic corpus callosum)
-IUGR
-eye anomalies & hearing loss
-arthrogryposis & club foot
-neuromotor anomalies and seizures
Zika testing
-PCR of serum & urine of RNA
+serum remains positive usually up to 7 days
+urine has delayed positive (3-14d)
-consider asymptomatic travelers may have incubation period
-IgM
+subject to cross-reactivity can be tested 4d-12w post symptom
-PRNT
+infects serum with live virus when IgM positive and measure dilution
+subject to cross-reactivity
-amniotic fluid PCR
+no longer recommended to rule out because a negative result doesn’t exclude risk
fetal kidney development
not complete until 16w
-amniotic fluid may not accurately represent fetal cell makeup until this point
congenital rubella syndrome
- caused by infection exposure in 1st and early 2nd tri, though effects can be seen into 3rd tri
- earlier exposures increase risk for SAB, SNHL, ID, cataracts, CHD, “blueberry muffin” phenotype due to platelet destruction and blood pooling under skin
- later exposure increases risk for ID, microcephaly, ASD, diabetes and autoimmune disease
fetal valproate syndrome
- includes fetal hydantoin syndrome as subtype (kids more dysmorphic); drug cocktails worse
- higher intake correlated with higher risk
- 20 fold ONTD and cardiac anomaly risk increase
- CL+or-P, GU, skeletal anomalies, DD, autism, and endocrine disorders may also occur
toxo
brain and eye anomalies
HSV
increased risk for SAB, blindness, deafness, cerebral palsy, ID
syphilis
increased risk SAB, deafness, ID
Lithium exposure
increased risk for CHD (Ebstein anomaly) in fetuses of exposed mothers
warfarin embryopathy
- SGA
- extremity hypoplasia
- optic atrophy, CHD
maternal HTN
increased risk LBW, preterm labor, still birth and maternal mortality
maternal autoimmune disease
- ex: Lupus
- can lead to IUGR, fetal heart block
