25. Causes of the congenital malformations (with examples!)

Learning objectives

  • What is TORCH?
  • How does maternal hyperthermia affect the foetus?
  • How does ionizing radiation affect the foetus?
  • Name some medications which are teratogenic, and some examples of congenital malformations
  • How does maternal alcohol consumption affect the foetus?
  • How does maternal cigarette smoking affect the foetus?
  • What is the scandal surrounding thalidomide and congenital malformations?
  • Name some maternal diseases which increase the risk for congenital malformations, and give some examples
  • Name some heavy metals which increase the risk for congenital malformations

Causes of congenital malformations with examples

Factors which cause congenital malformations are called teratogens.

TORCH

TORCH is an acronym for maternal infections which can be transmitted to the foetus in utero or during birth, which can cause significant morbidity or even death. The various infections can cause a wide variety of congenital malformations.

T stands for toxoplasmosis, a disease caused by a parasite called toxoplasma gondii. Foetal toxoplasmosis can cause microcephaly and hydrocephalus in the neonate. Some neonates are born normal but develop problems later. Toxoplasma is found in uncooked meat and cat faeces, both of which pregnant women should avoid.

O stands for “other”, which includes syphilis, varicella, parvovirus B19, and listeriosis.

R stands for rubella, a disease caused by the rubella virus. Thanks to the MMR vaccine, congenital rubella is very rare in developed countries where the vaccine is available.

C stands for cytomegalovirus (CMV). Maternal CMV is often asymptomatic, but congenital CMV infection is serious. It can cause problems with the liver, brain, and can potentially be lethal.

H stands for herpes simplex virus, the virus which causes cold sores and genital sores. It can cause severe disseminated infection in the neonate. The foetus is usually exposed to the virus when it comes in contact with genital sores during vaginal delivery.

Hyperthermia

Elevated maternal body temperature, either due to maternal fever or due to external sources like hot tubs, is teratogenic. Neurulation is influenced by temperature, and so hyperthermia increases the risk for neural tube defects.

Ionizing radiation

Ionizing radiation, whether from x-ray or from a nuclear accident, is highly teratogenic. Radiation kills rapidly proliferating cells and can cause virtually any type of birth defect.

Medications

Many medications are teratogenic and must be avoided by pregnant women.

Retinoids are drugs which resemble vitamin A, of which isotretinoin is the most important type. These drugs are used in the treatment of severe acne, and can cause many malformations, most commonly skeletal malformations. Women who want isotretinoin must document that they’re using a safe contraceptive, and that they’re not pregnant before getting the prescription.

Several antiepileptic drugs, like phenytoin, valproate, and carbamazepine, are teratogenic. Phenytoin causes a syndrome of congenital malformations called foetal hydantoin syndrome, which includes cleft palate, hand hypoplasia, and excessive hair growth.

Warfarin, a widely used anticoagulant, is teratogenic. It can cause foetal haemorrhage and skeletal abnormalities.

Several drugs given orally against diabetes are teratogenic. Pregnant women with diabetes must temporarily stop taking any of these drugs and instead treat their diabetes with insulin as long as the pregnancy lasts.

Alcohol

Alcohol is a well-known teratogen which all pregnant women should avoid. It causes a syndrome called foetal alcohol syndrome, which includes certain characteristic facial features, as well as severe organ defects. These facial features include a thin upper lip, low nasal bridge, a smooth philtrum, and small palpebral fissures.

Maternal alcohol consumption can cause malformations of virtually all organs, but especially the heart. Intellectual disability is very common in affected children.

Cigarette smoking

Maternal cigarette smoking during pregnancy increases the risk for low birth weight, preterm birth, and miscarriage. Live-born infants are at higher risk of death during the first weeks.

Thalidomide

Thalidomide is a drug which was originally used to treat morning sickness in pregnant women in the late 1950s. Before this time, drugs weren’t tested for harmful effects on foetuses of pregnant women. It was quickly discovered that thalidomide was highly teratogenic, as incidence of certain rare congenital malformations suddenly increased in the years after the drug was introduced. The most notable of these were the total or partial absence of extremities, or extremities which were abnormal in other ways. Thalidomide also causes other malformations.

This scandal led to the development of much stricter drug regulations and monitoring.

Thalidomide is still used today, but for different reasons. It’s used in multiple cancers, especially multiple myeloma, as well as a couple of other diseases.

Maternal diseases

Several maternal diseases increase the risk for congenital malformations.

Maternal diabetes increases the risk for stillbirth, neonatal death, abnormally large infants, as well as numerous congenital malformations. Congenital heart malformations and neural tube defects are among the most common.

Phenylketonuria is a disease where the enzyme phenylalanine hydroxylase is deficient, causing the amino acid phenylalanine to accumulate. Pregnant women with this disease who are not properly treated have increased risk of having infants with intellectual disability, microcephaly, and cardiac malformations.

Maternal obesity increases the risk for neural tube defects, cardiac malformations, among others.

Heavy metals

Organic mercury is mostly found in seafood which is high on the food pyramid, like tuna. Maternal ingestion of organic mercury causes various neurological defects in the infant.

Lead is another heavy metal which causes congenital malformations and stillbirths.

Summary

  • What is TORCH?
    • An acronym for maternal infections which can cause congenital malformations
    • T is toxoplasma, a parasite found in cat faeces and undercooked meat which can cause microcephaly and hydrocephalus
    • O is others, including syphilis, varicella, parvovirus B19, and listeriosis
    • R is rubella, a rare virus nowadays thanks to the MMR vaccine
    • C is cytomegalovirus, which causes asymptomatic infection in the mother but can cause severe infection in the infant
    • H is herpes simplex virus, which can cause severe infection in the infant
  • How does maternal hyperthermia affect the foetus?
    • Neurulation is temperature-dependent, and so maternal hyperthermia causes neural tube defects
  • How does ionizing radiation affect the foetus?
    • Ionizing radiation kills rapidly proliferating cells and can cause any congenital malformation
  • Name some medications which are teratogenic, and some examples of congenital malformations
    • Retinoids, especially isotretinoin, is used to treat severe acne but causes skeletal malformations
    • Several antiepileptic drugs cause congenital malformations, including cleft palate
    • Warfarin, an anticoagulant, causes foetal bleeding and skeletal abnormalities
    • Oral antidiabetic drugs
  • How does maternal alcohol consumption affect the foetus?
    • It causes foetal alcohol syndrome, which has certain characteristic facial features as well as organ defects and intellectual disability
  • How does maternal cigarette smoking affect the foetus?
    • It increases the risk for miscarriage, preterm birth, and early death
  • What is the scandal surrounding thalidomide and congenital malformations?
    • Thalidomide was used against morning sickness in the late 1950s, but it was quickly discovered that it caused severe congenital malformations, most notable the partial or complete absence of extremities
  • Name some maternal diseases which increase the risk for congenital malformations, and give some examples of malformations
    • Maternal diabetes increases risk for foetal and neonatal death, as well as heart and neurological malformation
    • Maternal phenylketonuria increases risk for intellectual disability and heart malformations
    • Maternal obesity increases risk for neural tube defects and heart malformations
  • Name some heavy metals which increase the risk for congenital malformations
    • Organic mercury and lead

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