Teratogenic Exposure of the Fetus

Teratogenic Exposures

This topic is of high practical importance and relevance for exams such as AIIMS, NEET, and final year assessments. This lecture compiles various teratogenic exposures to provide a comprehensive understanding. The discussion will delve into teratogens, their types, effects, radiological exposure during pregnancy (including permissible levels and investigations), drugs in pregnancy (linking specific drugs to congenital malformations), and teratogenic infections (TORCH infections, Zika virus, varicella-zoster virus, and parvovirus).

Teratogen Definition

A teratogen is an agent that can cause abnormalities in the form or function of a developing fetus. Teratogenic exposure can lead to fetal loss, birth defects, fetal growth restriction, and impaired neurological performance, including mental retardation.

Factors Influencing Teratogen Effects

The effect of a teratogen depends on the specific teratogen and the period of pregnancy during which exposure occurs. The entire pregnancy is divided into three fetal growth periods:

Pre-Embryonic Period

  • Defined as from the day of fertilization up to two weeks after. During this period, the fetus follows the "all or none" law.
  • All or None Law: Either the exposure leads to fetal loss, or the fetus completely escapes injury with no congenital malformations or growth restrictions.

Embryonic Period

  • From three to eight weeks after fertilization.
  • The main event is organogenesis. Teratogenic exposure during this period leads to the maximum chance of birth defects. This is considered the most teratogenic period.

Fetal Period

  • From nine weeks after fertilization until delivery.
  • Organogenesis is complete, but growth and neurological development occur. Teratogenic exposure during this period can lead to growth restriction and neurological impairment but typically does not cause birth defects since organogenesis is mostly complete.

Types of Teratogens

Teratogens include drugs, radiation, maternal illnesses (e.g., hyperglycemia in diabetes mellitus), infections (TORCH), alcohol, and even increased body temperature (hyperthermia). A sustained rise in body temperature of more than 1.5∘C1.5^\circ C during the first few weeks of pregnancy can lead to cleft lip or cleft palate.

Imaging in Females of Childbearing Age

Before performing any radiological examination in a female of childbearing age, it is essential to inquire about pregnancy. Non-emergency radiological examinations should be done in the first ten days of the menstrual cycle (Rule of 10) to minimize the risk of exposing an early pregnancy to radiation. Pregnancy tests should be performed if there is any doubt about pregnancy status.

Radiological Exposure in Pregnant Females

  • The maximum permissible radiological exposure during pregnancy is up to five rads.
  • If a pregnant female has a road traffic accident and undergoes a chest x-ray at six weeks of pregnancy, the pregnancy should be continued, as the exposure from a single chest x-ray is less than five rads.
  • One rad is equal to 0.010.01 gray.
  • Radiation exposure less than five rads poses no increased risk of fetal loss, birth defects, growth restriction, neurological impairment, or cancers in the fetus.

Period of Pregnancy and Radiological Exposure Effects

  • First Two Weeks Post-Fertilization:
    • Exposure > 5 rads can lead to fetal loss.
    • Fetal death is more likely with exposure >= 10 rads.
  • Up to Sixteen Weeks:
    • Exposure > 5 rads can lead to:
      • Congenital anomalies, such as microcephaly.
      • Intrauterine growth restriction (IUGR).
      • Neurological impairment.
      • Increased risk of cancers (leukemia if exposure > 20 rads).
  • More than or Equal to Sixteen Weeks:
    • Exposure up to 50 rads is considered safe. However, the general permissible limit is still five rads.

Safe Investigations During Pregnancy

Ultrasound, MRI, dental x-rays, and diagnostic x-rays (e.g., head and neck x-ray, limb x-ray) are considered safe in pregnancy, especially if needed for emergency reasons. Gadolinium MRI and CT scans are generally avoided, but if a CT scan is necessary, an abdominal and pelvic shield should be used.

Drug Exposure During Pregnancy

Drugs are divided into five categories based on their safety profile in pregnancy:

  • Category A: Safety established in human and animal studies.
  • Category B: Safety likely, either because there are no human studies and animal studies show no risk, or human studies show no risk but animal studies show some risk.
  • Category C:
    • Teratogenicity may be a possibility because there are no human studies and animal studies show some risk.
    • If there are no results from studies on humans and animals.
  • Category D: The drug has risk, but it can be given under special circumstances where the benefit outweighs the risk, and the human studies show risk.
  • Category X: Definite fetal risk, and should not be used at all.

Category X Drugs

Category X drugs (contraindicated during pregnancy) include ACE inhibitors, hormones, diethylstilbestrol, danazole, valproate, lithium, isotretinoin, thalidomide, methotrexate, misoprostol, and statins.

Drugs Leading to Limb Defects

  • Thalidomide: Leads to phocomelia (proximal limb defect).
  • Warfarin:
    • Leads to defect in cartilage growth causing warfarin embryopathy, also known as Desalas syndrome or chondrodysplasia punctata.
    • Features include a depressed nasal bridge, choanal atresia, and stippled epiphysis (seen in femurs, humerus, or calcaneum).
    • Latest recommendations suggest that if the dose of warfarin is less than five milligrams per day, it may be used in the first trimester.

Drugs Associated with Cardiac Defects

  • Lithium: Leads to Ebstein anomaly (downward displacement of the posterior and septal leaflet and atrialization of the right ventricle).
  • SSRIs (Selective Serotonin Reuptake Inhibitors):
    • Paroxetine is the most teratogenic SSRI, commonly causing cardiovascular defects, such as atrial septal defects.

Drugs Causing Cardiac Defects and Facial Dysmorphology

  • Isotretinoin: Causes cardiac defects; facial dysmorphology (cleft lip/palate, microtia, anosia, micrognathia); CNS defects; and thymus defects.
  • Phenytoin (Fetal Hydantoin Syndrome):
    • Leads to mid-facial dysmorphology.
    • The facial features include flat faces, depressed nasal bridge, thin vermilion border of the upper lip, smooth philtrum, and upturned nose.
    • Distal limb defects such as hypoplastic phalanges and small nails are likely.
    • Similar to fetal alcohol syndrome with one major difference being that of involvement of distal limbs.
    • Cardiac defects.

Drugs Associated with Nerve Palsies

  • Misoprostol: Leads to Mobius syndrome (sixth and seventh nerve palsy) and limb reduction defects.
  • Methotrexate: Methotrexate, it leads to methotrexate aminopteran syndrome. It leads to facial dysmorphology along with limb defects

Drugs Causing Decreased Urine Output in the Fetus

ACE inhibitors and trastuzumab lead to fetal renal hypoperfusion, decreased urine output, oligohydramnios, pulmonary hypoplasia, and limb reduction defects.

Drugs Leading to Facial Dysmorphology

Methotrexate, phenytoin, isotretinoin, alcohol, and glucocorticoids can lead to facial dysmorphology. Rarely, glucocorticoids used at less than ten weeks of gestation may cause cleft lip and palate.

Drugs Linked to Cancer

  • Diethylstilbestrol (DES): Linked to clear cell adenocarcinoma of the vagina and cervix, hypoplastic uterus, T-shaped uterus, breast cancer, and premature menopause in female fetuses. In male fetuses, DES exposure increases the chances of cryptorchidism and renal defects.

Alcohol-Related Birth Defects (Fetal Alcohol Syndrome)

Fetal alcohol syndrome can happen only if a female is consuming more than or equal to six drinks per week for two weeks or on a particular occasion, she's having more than or equal to three drinks and this she takes on two occasions. On two occasions, she's taking more than or equal to three drinks, then that leads to fetal alcohol syndrome. Please remember, binge drinking is more dangerous in a pregnant female. Mnemonic to remember Goa's famous beer bar.

  • Diagnostic Criteria: Diagnostic criteria include Growth impairment, facial dysmorphological features and abnormal brain growth/physiology. The baby’s head circumference is small and behavioural impairment is there.
  • The growth retardation indicates the baby has growth retardation, (G). The features of facial dysmorphology includes, a 10 vermilion border, the philtrum, this over here. The vermillion border, then there can be a low nasal bridge, then microgranathia.
  • If two facial feature is more present; a thin vermilion border, in distinct philtrum and small palpebral fissures then facial. In most cases that the baby’s head circumference is small (B), there is abnormal brain growth or physiology and there is recurrent non febrile seizures and behavioural impairment is there.* Small palpebral fissure, a thin vermilion border, a smooth philtrum. If two or more than two of these three are present, then we say that, yes, it is facial dysmorphological feature related to alcohol.
    In fetal hydrantoin syndrome it was the distal limb involvement. For example, there were hypoplastic phalanges and small nails which was distinguishing fetal hydantoin syndrome from fetal alcohol syndrome.
    You may get cardiac defects. You may get renal defects. You may get skeletal defects, eye defects, and ear defects as well. But they are not included in the diagnostic criteria.

Teratogenic Infections (TORCH Infections)

Cytomegalovirus (CMV) Infection

  • Most common congenital infection.
  • It is the most common cause of sensorineural hearing loss in neonates
    • DNA virus that does not give life-long immunity.
  • Vertical transmission chances are higher with primary infection versus recurrent infection (hardly 1%).
  • The most common time of transmission of cytomegalovirus is third trimester.
Symptoms and Diagnosis
  • May get history of coming into contact with toddlers
  • Congenital CMV syndrome only occurs in 10−15%10-15\%. CNS calcifications-periventricular calcifications, microcephaly, eye lesions, intellectual disability and sensorineural hearing loss.
  • Maternal infection can be diagnosed via IgM and IgG antibody. PCR and nucleic acid amplification tests can find out whether the baby is infected or not with subsequent ultrasonic detection.
  • If IgM is positive and IgG is positive, comes the importance of doing avidity test. If the test is low avidity, low avidity means less interval between infection and the test indicates a recent infection. And if there is high avidity, it means high interval, long interval between the test and the infection indicates remote infection

Toxoplasma Infection

  • Caused by Toxoplasma gondii, an obligate intracellular protozoan parasite.
  • Involves CNS calcifications especially intracellular calcifications.
  • Hydrocephalus, chorioretinitis and IUGR.
Transmission and Treatment
  • History of coming in contact with cat feces.
  • Most common time of transmission of toxoplasma infection is the third trimester, but the most severe infection happens during first trimester.
  • Toxoplasma infection drug of choice is spironomycin, but cannot cross the placenta so give pyrimethamine and sulfadiazine combination, for fetal infection. They are folic acid antagonist, so supplement with folinic acid

Rubella Infection

  • RNA virus that is most teratogenic, if it happens in first trimester then MTP (medical termination of pregnancy) is to be done.
Clinical Presentation
  • Pregnant female acquiring rubella up till 16 weeks of pregnancy is very difficult. First month is maximum teratogenic. If a mother acquires rubella infection, that is indication for doing MTP (Medical Termination of Pregnancy).
  • Congenital rubella syndrome leads to heart disease such as, pulmonary stenosis, sensory neural hearing loss, and cataracts. A cardiac defect means it has to be rubella specifically PDA
  • Mild fever and a maculopapular rash is shown in the pregnant female.
  • Babies who are born with rubella shed shed rubella infection, rubella virus for a very long time.
  • The long term consequences of rubella are pan encephalitis, insulin dependent diabetes mellitus, thyroid disorders, and precautious puberty
Diagnosis
  • Screening is done in first ante natal visit and screening also involves rubella antibody and avidity. However, vaccination is contraindicated in pregnancy so we advise to get vaccinated during her next pregnancy
  • Pregnant is not advised with a rubella vaccine for a month. If the pregnant has a rubella within the month of the vaccination, there is no need to abort.

Parvovirus B19 Infection

  • DNA virus replicating in erythroblast precursors, leading to fetal anemia.
  • Does not lead to any birth defect. Leads to hydrops fetalis and fetal anemia.
Transmission & Diagnosis
  • History of coming into contact with school going children, with polyarthralgias (joint pains) and potential for polyhydramnios.
  • The most common and infectious cause for hydrops fetalis, and is due to severe fetal anemia. This can lead to abortions and stillbirths
  • Maximal risk is from 13-16 weeks to hydrops fatalis.
  • Evaluation can be every two weeks to check for hydrops fatalis but every two weeks you determine what is the peak systolic velocity of the middle cerebral artery (MCA). If peak systolic velocity is more than equal to 1.5 MOM, then that is severe anemia

Varicella Zoster Infection

  • Pregnant is screened by the person they come in contact with, who has contact with a chickenpox.
Transmission & Diagnosis
  • Most common time when varicella infection is going to happen and when it is going to lead to congenital varicella syndrome, is during second trimester from 13 weeks - 20 weeks..
  • Can cause Congenital varicella syndrome which leads to Cicatricial skin lesions.
  • Diagnosis of skin lesion and limb contraction. An MTP can be done.
  • if Varicella infection, 5 days before delivery or two days after delivery, the neonate can develop pneumonitis, hepatitis, meningoencephalitis, which is very similar to chickenpox in clinical presentation.

To prevent varicella zoster infection in a pregnant female, if she has come in contact with a person having chicken pox, you have to give varicella zoster immunoglobulin. And to treat varicella zoster infection in a pregnant female, you have to give acyclovir

Herpes Infection

  • Multiple painful vesicles are found on vulva.
  • Clinical presentation: multiple grouped, tender ulcers, as well as polycyclic erosion with inguinal lymph nodes that may be enlarged and tender without any bubo formation
Transmission & Diagnosis
  • Multiple painful lesions on the vulva and there is a polycyclic erosion, the inguinal lymph nodes are enlarged and tender.
    *Diagnosis is done by t zank smear and you are going to take fluid from the vesicle, fluid from the vesicle, you are going to stain it GEMSA stain, and you are going to see multinucleated giant cells, and you are going to get acantholytic cells + the vesicle fluid, and you are going to send it for PCR and culture
  • If you have active genital herpes infection during labor, cesarean section is to be done, but there may be prodomal symptoms can also be present. C section HAS to be done in this case
    Drug of choice will be acyclovir which is to be given for seven days, given 3 times a day suppressive therapy has to be given at 36 weeks even for pregnancy.
    Most common time for transmission, for this herpes infection, is during labor.
    Skin lesions as well as mucocutaneous lesions occur.

Zika Virus

  • A virus that belongs to the family of Flavivirus and is a vector borne teratogen.
  • Linked to microcephaly.
Transmission & Diagnosis
  • Spread by the bite of the aedes mosquito, which has special affinity for the central nervous system.
  • Zika virus attaches to receptor TIM-one-receptor and TAM-axl-receptors which are on the epidermal cells.
  • There is cortical atrophy which leads to microcephaly. The babies born will have ventricularly large, intracranial calcifications, and macular scarring. Club foot/limb defect
  • Zika Virus in pregnant females it is going to get attached to the TAM A XL receptors and TIM-one receptors which are also present on the Hofbair cells of placenta. From there, it vertical transmission is going to occur and it is going to reach the CNS of the fetus. And when it is going to reach the CNS of the fetus, it is going to lead to cortical matter atrophy and lead to microcephaly".