614: Teratogens and Common Birth Defect Patterns

What percent of all infants have a major anomaly?

3%

What percent of all infants have a minor abomaly?

15%

Does the percentage of infants with major and minor anomalies differ based on ethnicity?

No- same frequency regardless of ethnicity

Major vs minor anomaly

Major:

-requires medical or surgical treatment

-serious structural impact

Minor:

-do not generally require medical intervention

-may be normal variations, have no serious implications

What are examples of major and minor anomalies?

Major: cardiac defects, clubfoot, cleft lip/palate, gastroschisis

Minor: ear pits, absent nails, extra nipples, cliniodactyly

How many minor anomalies suggest an underlying defect?

3+

malformation

occurs during organogenesis and results in absence of or alteration in normal configuration of a structure

disruption

morphological alteration of already formed structures caused by destructive processes

deformation

results from mechanical process that mold a part of a fetus over time

syndrome

group of anomalies occurring together that have one specific cause

association

nonrandom appearance of 2 or more anomalies that occur together more frequently than by chance alone

Sequence

group of related anomalies that stem from a single initial insult that alters development of other surrounding or related tissues or structures; can be caused by different underlying etiologies

What type of congenital anomaly is cleft lip and palate?

malformation

What are types of destructive events that can cause a disruption?

vascular

infectious

teratogenic

mechanical

What type of congenital anomaly is amniotic band disruption?

disruption

What type of congenital anomaly is clubfoot?

deformation

(low fluid → not enough room to grow properly)

What are potential causes of increased NT?

Trisomy 21, 18, 13

structural anomalies: cardiac defect, hydrocephalus, congenital diaphragmatic hernia, lung and GI anomalies

Other genetic syndromes (>100)

Cystic hygroma

lymphatic fluid accumulation behind the neck, usually characterized by presence of septations

may spontaneously resolve, progress to hydrops, or remain stable and present at birth

cystic hygroma associations

chromosome abnormality (50-60%): most commonly trisomy 21 or monosomy X

structural abnormality (20-30%): most commonly cardiac defects

other genetic syndrome (5-15%): noonan, skeletal dyspasia

remaining cases due to blockage in lymphatic system or unknown etiology

What is recommended for later follow-up if NT or cystic hygroma identified?

fetal echo 22-24 weeks

hydrops

excessive fluid accumulation in at least 2 serous cavities (abdomen, lungs, pericardium) or body tissue (subcutaneous edema)

What are the 2 categories of hydrops?

1. Immune: rhesus isoimmunization

2. non-immune: all others (>90%)

Hydrops prognosis

mortality rate: 70% (80-100% if pleural effusions, buildup space between lung and chest wall)

rarely resolves spontaneously

Hydrops associations

-fetal anemias (alpha thalassemia, hemorrhage, G6PD)

-Chromosomal abnormaly (Turner syndrome, T21, T18, T13, triploidy) prognosis always poor → mortality close to 100%

-infection

-single gene disorders (skeletal dysplasias, inborn errors of metabolism, hematologic disorders)

-congenital heart disease (structural, arrhythmias, fetal tumors)

What is echogenic bowel a soft marker for/has associations with?

soft marker for T21

Chromosome aneuploidy- primarily T21

cystic fibrosis

fetal infection (CMV, toxoplasmosis)

GI abnormality (bowel perforation, bowel atresia, blockage)

fetal growth restriction

80-90% normal outcome when isolated

What is cardiac rhabdomyoma commonly associated with?

tuberous sclerosis

What is duodental atresia commonly associated with

T21

What is thickened nuchal fold commonly associated with?

T21

Potter sequence

Renal agenesis → oligohydramnios → pulmonary hypoplasia → fetal deformations

What is the typical appearance of Potter sequence?

widely spaced eyes

broad nasal bridge

low set ears

receding chin

limb contractures, abnormal positions

hypoplastic lungs

Pierre Robin sequence

hypoplastic mandible (underdeveloped lower jaw, small chin) → posterior displacement of the tongue → palatal closure interrupted → cleft palate

What are postnatal concerns for pierre robin sequence?

upper airway obstruction

feeding difficulties

What genetic diseases is pierre robin sequence associated with?

often isolated

stickler syndrome

velocardiofacial syndrome

amniotic bands syndrome/sequence

highly variable spectrum of congenital anomalies that occur on association with amniotic bands

premature rupture of amnion → loose mesodermic strands adhere to/entangle the embryo

VACTERL association

Vertebral

Anal atresia

Cardiac defect

TracheoEsophageal

Renal anomalies

Limb defect

(H)ydrocephalus)

2+ anomalies needed

CHARGE associateion

Coloboma

Heart defects

Artresia choanae

Restriction of growth

Genital anomalies

Ears

mutation in CHD7

Teratogen

agent that causes an abnormality following a fetal exposure during pregnancy (the non-genetic things that cause birth defects)

What are the 4 types of teratogens

1. substances (medications, drugs, tobacco, alchol)

2. Physical agents (hypethermia, radiation)

3. Infectious exposures

4. Maternal health factors (diabetes, PKU, hypothyroidism)

What are important factors the affect the impact of a teratogen?

Dose & route of consumption/exposure:

level or amount of exposure

theoretical threshold for crossing placenta

route of exposure (orally vs topically) impacts effect on fetus

Duration of exposure:

one time vs prolonged period = different risks for congenital anomaly

Timing of exposure:

all-or-none period vs. organogenesis vs. fetal period

What risks are associated with smoking?

stillbirth (b/c affects placenta): 50% increase risk

preterm premature rupture of membranes/premature delivery (b/c of placenta)

low birth weight/fetal growth restriction

placental abruption

cleft lip +/- palate

gastroschisis

potentially muscoloskeletal defects

Fetal alcohol syndrome

range of physical, behavioral, and neurodevelopmental effects related to alcohol exposure during pregnancy

structural anomalies, neurobehavioral effects, postnatal growth retardation

What risks are associated with anti-seizure medications?

neural tube defects, CHDs, skeletal anomalies, oral clefts

Which anti-sezure medication holds the greatest risk?

Valproate (valproic acid)

Thalidomide

medication used in 50s and 60s to treat nausea in pregnancy

What anomalies are associated with thalidomide?

shortening/absence of limbs

malformation of hands and digits

ear and eye damage; sensory impairment

facial disfigurement/palsy and damage to the brain

What risks are associated with isotretioin?

aka acutane

ear anomalies

CNS malformations

hydrocephalus

neuronal brain migration defects

cerebellum abnormalities

severe intellectual disability

seizures

conotruncal heart defects

dysmorphic features

(Must immediately stop once pregnancy is recognized)

Selective serotonin reuptake inhibitors (SSRIs)

type of antidepressant medication

What risks are associated with SSRIs?

neonatal withdrawal

persistent pulmonary hypertension

pre-eclampsia

growth restriction

preterm birth

(in general, consequences of untreated depression outweighs any potential risk of using antidepressants in pregnancy)

What risks are associated with uncontrolled pregestational diabetes?

first trimester hyperglycemia (high blood sugar) → diabetic embryopathy:

cardiac defects

neural tube defects

contractures

cleft palate

caudal regression

second/third trimester hyperglycemia → diabetic fetopathy

When in pregnancy is the highest risk for transmission to fetus and when is highest risk for severe phenotype?

Highest risk of transmission to fetus when exposure is later in pregnancy

highest risk of sever phenotype when exposure early in pregnancy

What is the best way to confirm if fetus has been exposed to infection?

amniocentesis

What is amniocentesis infectious work-up and what are the pros/cons?

measures presence of infection in the amniotic fluid using PCR to determine if fetal exposure has occured

Pros: definitively tells us if fetus has been exposed

cons: invasive , expensive

What is maternal serum studies infectious work-up and what are the pros/cons?

measurement of maternal immunoglobulins (aka antibodies) to determine if maternal exposure has occured

pros: non-invasive, no risk

cons: hard to tell timing of exposure, doesn’t assess for fetal exposure

IgM vs IgG

immunoglobulin M (IgM): first antibody the body makes when fighting a new infection → indicates recent exposure/acute infection

-present within 1-2 weeks following exposure

-usually undetectable by ~4 months after exposure but can be present up to one year

immunoglobulin G (IgG): antibodies the body makes over time to fight against recurrent infection → indicates past exposure

-present within a few weeks following exposure and usually remain detectable for life

What do you order when maternal serum studies comes back positive for oth IgG and IgM?

avid testing

Avidity testing and result interpretation

Avidity = how strongly the IgG antibodies bind to the antigen (infectious agent)

the longer the antibodies have been present, the stronger the bond

high avidity = infection occurred >3-4 months ago

low avidity = infection occurred <3-4 months ago

What is the most common congenital viral infection?

cytomegalovirus (CMV)

What are CMV ultrasound findings?

microcephaly

ventriculomagaly

intraventricular calcifications

liver calcifications

echogenic bowel*

fetal growth restriction*

hydrops*

polyhdramnios. oroligohydramnios

placental thickening

cerebellar hypoplasia

brain cysts

additional brain anomalies

toxoplasmosis

parasitic infection, common in cats

maternal infection usually causes mild symptoms that last ~3 days or no symptoms at all

What are sources of transmission of toxoplasmosis

raw or undercooked meat

contaminated soil or water (unwashed fruits/veggies)

unpasteurized milk

rawseafood harvested from contaiminated eaters

cat feces/feces other infected host

toxoplasmosis ultrasound findings

intracranial clacifications/densities

ventriculomegaly/hydrocephalus

echogenic bowel

hepatosplenomagaly

liver calcifications

fetal growth rstriction

hydrops

cataracts

parvovirus B19

common childhood infection → 30-60% adults have antibodies

symptoms in children and adults: joint pain, rash, anemia

first exposure in pregnancy puts etus at risk of exposure

Risks associated with parvovirus B19

majority of fetuses exposed will not have adverse effects

sever fetal anemia → hydrops → fetal demise

Differentiation ultrasound finsings and what infections should test for

hydrops: CMV, trophoplasmosis, & parvovirus

any other anolomilies: just CMV & trophoplasmosis

TORCH infections

Toxoplasmosis

Other

Rubella

Cytomegalovirus (CMV)

Herpes simplex virus

hypertelorism

increased interorbital distance

hypotelorism

decreased interorbital distance

What condiions is hypotelorism associated with

frequent underlying abnormalities of brain: commonly microcephaly and holoprosencephaly

T13, T18, T21

maternal PKU

fetal alchohol syndrome

Congenital cataracts

30% congenital eye malformations

infections (rubella, CMV, toxo)