Environmental factors (L14)

main causes of congenital abnormalities (environmental)

maternal/placental infections (e.g. rubella virus)

maternal nutrition and disease (folic acid deficiency, diabetes)

chemicals and drugs (alcohol, retinoic acid)

transcervical (ascending) infections - what

can pass up the cervix into the uterus

mostly acquired from the cervicovaginal route

how fetus gets infected in transcervical infections

inhaling infected amniotic fluid into the lungs shortly before birth or

from the infected birth canal during delivery

what is a common result of infection and how is it caused

preterm birth

damage/rupture of amniotic sac due to inflammation

or infuction of labour by prostaglandins released from infiltrating neutrophils

premature birth as result of infection can cause

neonatal respiratory distress syndrome and other complications

what can inhalation of amniotic fluid cause

pneumonia, sepsis or meningitis

transplacenta infections - what type of pathogen

mostly viral and parasitic

few bacterial

how do transplacental infections cross the placenta

access the fetal bloodstream via the chorionic villi

occasional during delivery by maternal to fetal transfusion - placenta haemmorrhage (e.g. hepatitis B and HIV)

when do transplacenta infections occur

can occur at any time during gestation

occassionally during deliivery

consequences of transplacental infections

can interfere with early development or destroy structures that have already been formed

viruses crossing the placenta

can pass into trophoblast cells which surround the villi

can also get into the hofbauer cells (type of macrophages in the placenta) and replicate inside these, then released and cross into the fetal capillaries

rubella virus

RNA virus, mild disease in children and adults, most serious impact is its teratogenic efect

congential rubella syndrome = neonatal menifestation of infections

when rubella infection

in first trimester - infection rate of fetus is around 85%

after 16 weeks infection rate drops to around 50%

by third trimester fetal ifnections are low and resulting abnormalities are rare

infection at birth does not appear to cause CRS

consequences of maternal rubella infection

abortion, still birth, foetal growth restriction and CRS

congenital malformations in CRS

occular defects - cataract, glaucoma, retinopathy, iris hypoplasia etc

auditory defects - sensorineural deafness

cardiovascular defects - persistent ductus arteriosus, pulmonary artery stenosi, ventricular septal defect, myocarditis

CNS defects - microcephaly, psychomotor retardation, meningoencephalitis

occuluar defects from CRS

cataract, glaucoma, retinopathy, microphthalmia, iris hypoplasia, cloudy cornea

auditory defects from CRS

sensorineural deafness

cardiovascular defects from CRS

persistent ductus arteriosus, pulmonary artery stenosis, ventricular septal defect, myocarditis

CNS defects

microcephaly, psychomotor retardation, meningoencephalitis

molecular mechanisms of CRS

rubella virus infection during critical stages of organ development can result in CRS

RV causes apoptosus in adult cells, vs in feotal fibroblasts no apoptosis so infection persists

downregulation of genes in fetal cells involved in sensory organ development (FGFR2, FZD3, Noggin, MYO7A)

these genes are required for ear and eye development - hence ocular and auditory impairment

disrupts actin filament assembly and can slow cell division in fetal cells

molecular mechanisms od CRS diagram

prevention of rubella

immunisation

universal screening and vaccinaion pre-pregnancy

MMR vaccine for kids at 12 and 15 months

incidence has drastically decreased since vaccine, no reported cases of congenital rubella in NZ since 1998, but still high in developing countries - no vaccine

pregnancy and covid

pregnant women at higher risk of ICU and ventilation

higher rate of preterm birth and c section - electively to improve respiratory condition

chances of vertical transmission is low

no reported teratogenicity so far, but prelimanry evidence that maternal covid may be associated with neurodevelopmental sequalae in some offspring (from dif paper)

covid vaccines safe while pregnant

neural tube

formed from neural ectoderm by week 4

neural tube becomes spinal cord, spine, brain and skull

neural tube - what days do pores close on

anterior pore closes on day 25 - posterior on dat 28

neural tube defects - what

failure of neural tube pores to fuse

connection between amniotic fluid cavity and spinal canal

anencephaly and spina bifida

what causes neural tube defects

genetic mutation or exposure to environmental factors

maternal infection, irradiation, maternal diabetes, low folic acid

anencephaly

underdeveloped brain and incomplete skull

anterior pore doesnt close

spina bifida

spinal cord fails to develop and close normally

range of symptoms depending on the defect - occulta, meningocele, myelomeningocele

mild or no symptoms to paralysis or bowl ddysfunction

can treat with pre or post natal surgery

may still be disabled due to nerve damage

when susceptible to neural tube defects

first month of gestation because this is when the neural tube is forming and closing

spina bifida occulta

gap in vertebrae but spinal cord is normal - this could be completely invisible or have a dimple or patch of hair

meningocele

just have a fluid filled sac which will likely have no effect and can easily be surgically corrected

myelomeningocele

spinal cord protrudes and becomes damaged which can cause paralyss which may even be too severe to correct surgically

how does folic acid deficiency cause NTD

folic acid is a B vitamin needed for synthesis of nucleotides (DNA synthesis, repair, methylation

essential for mitosis in rapidly proliferating cells e.g. neuroectoderm cells - deficiency during gestation can result in neural tube defects

higher incidence in spring pregnancies

folic acid supplementation significantly reduces neural tube defect incidence

conclusions of report about folic acid

fortification of foods with folic acid reduces the prevelance of NTDs

no known adverse effects

the beneficial effects arent limited to pregnant women

in NZ flour now has to be fortified with folic acid

this is during first trimester, now doing research to see if it is also beneficial at second and third trimester

glucose in healthy people

increase glucose = increase from pancreas

so increase in uptake of glucose by cells for energy OR if hyperglycemia increase storage of glucose in liver, muscle and fat cells

glucose levels are controlled

maternal diabetes - what happens

even in normal pregnancy metabolic changes are induced including increased insulin resistance

pre-existing diabetes prevents increasing insulin secretion causing hyperglycemia

high blood glucose causes increased insulin in fetus = fetal hyperinsulinaemia

what can pre-existing diabetes cause in fetus

duration and degree of hyperglycemia and time of onset effect outcome (early is more severe for fetus)

exposure to abnormal mixture of metabolites alters phenotype of cells in developing fetus

can cause: stillbirth, heart defetcs, kidney defects, diabetes, obesity, hypertension, higher risk of attention-dficit hyperactivity disorders and autism

overal maternal diabetes

gestational diabetes mellitus - when

second or third trimester

organs already formed - no major developmental defects

consequences of gestational diabetes

fetal macrosomia

birthing complications

50% of mothers with GDM develop type II diabetes

foetal alcohol spectrum disorder (FASD) - what disorders

group of disorders caused by prenatal exposure to alcohol include:

foetal alcohol syndrome

alcohol related neurodevelopmental disorder

alcohol related birth defect

foetal alcohol syndrome

most severe effects

minor facial anomolies, growth deficiency, brain abnormality, cognitive or behavioural impairment

alcohol related neurodevelopmental disorder (ARND)

cognitive or behavioral development

alcohol-related birth defects (ARBD)

other systemic malformation

FASD when

exposure during first trimester more severe - causes more anatomical defects

later exposure can cause more subtle neurological defects as brain development continues throughout gestation

FASD rates

~3% of births but this varies per country

probably more in NZ as we have higher rates of alcohol drinking and reporting is not very reliable

plus defects may occur early before the person knows they are pregnant

FASD clinical features - physical

discriminating craniofacial anomalies:

• microcephaly

• short palpebral fissures

• smooth philtrum

• thin upper lip

associated features:

• epicanthal folds

• minor ear anomolies

• low nasal bridge

• micrognathia

FASD - other physical features

minor physical anomalies: railroad track ears, altered pa,mar creases, clinodactyly

number of minor features correlates with magnitude and timing of alcohol exposure

• sensory and cognitive processing impariment

• eye development impairments - microphthalmia (small eye), reduced palpebral fissure length, coloboma, retinal dysplasia

• shorter than average height - greoth retardation

FASD clinical features - neurological

hearing, speech and language disorders

developmental delay

cognitive deficits

fine motor deficits

hypoplasia of brain structures e.g. corpus callosum, cerebellum, brainstem

behavioural and emotionl disturbances (e.g. hyperactivity, poor impule control, aggression, poor social skills)

compromises schoola dn work performance and can lead to criminal behaviour

FASD in NZ

leading preventable cause of non-genetic intellectual disability

FASD mechanisms

outcomes depend on amount, frequency, duration and gestational timing of alcohol consumption

ethyl alcohol metabolised by alcohol dehydrogenase enzyme and CYP2E1 which the fetus has low amounts of

EtOH and acetaldehyde are toxic to cells - affect the survival and migration of cranial neural crest cells that form craniofacial structures

EtOH inhibits retinol metabolism to retinoic acid - retinoic acid signalling important for early embryogenesis and patterning of structures

steps of FASD mechanisms

1. ethanol metabolism generates reactive oxygen species (ROS)

2. ethanol metabolism competes for same enzymes as retinol - reduces retinoic acid

3. retinoic acid essential for development of many early embryonic structures

4. acytl-CoA modifies gene expression

5. depleted neural stem cells incluse neural crest cells (craniofacial abnormalities)

6. disrupted neuronal migration (altered brain development)

retinoic acid as a teratogen

when given orally (for acne)

defects related to cranial neural crest cells - e.g. facial structures, outflow tract of the heart, thymus

so when taking this medication have to be careful to not get pregnant