2025.03.03 | Questions 92-93
Prenatal genetics (1/3): Teratogens (& 2025 ABMGG Bootcamp Registration!)
Hello,
This is the 1st in a series of 3 posts related to prenatal genetics. This month’s post will focus on teratogens.
While it is tempting to study teratogens as a long list, there are a few principles that we discuss in this post that can help structure your learning on this topic. We also uploaded a video to YouTube to complement the written post (“Top 30 teratogens for board exams”) .
We are also excited to announce that registration is open for our new ABMGG board review bootcamp, which will take place between March 25 - June 19, 2025. This bootcamp is for clinical and laboratory geneticists taking the ABMGG general exam in August 2025. We will cover topics from all 11 domains and 115 subdomains on the ABMGG content outline. An early-bird discount is available through March 24, 2025. For more information and to register, please visit our website.
Note that we will share information about the schedule for our summer ABGC board review bootcamp for genetic counselors in an upcoming newsletter post.
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I hope you have a great week!
-Daniel
Questions
Question 92
A pregnant woman at 8 weeks gestation presents for her first prenatal visit. She is taking lisinopril for hypertension and is otherwise healthy with no medical conditions. If she remains on this medication throughout pregnancy, her fetus would be at risk for which of the following complications?
Question 93
A pregnant woman at 20 weeks gestation presents for prenatal care. She has a history of Graves disease and has been taking methimazole for hyperthyroidism throughout her pregnancy. Her fetus is at increased risk for which complication?
Explanations
Question 92: Pulmonary hypoplasia
Question 93: Areas of missing skin (aplasia cutis)
Teratogens are environmental factors that can disrupt normal fetal development. In order to understand their effects on the fetus, there are three important principles to keep in mind:
Timing: The first trimester is particularly vulnerable to teratogenic effects, as this is when vital organs like the heart and neural tube form. Exposure during this period typically results in the most severe developmental complications.
Dose-response relationships: The severity of teratogenic effects generally correlates with both the dose and duration of exposure. Higher doses or longer exposure periods typically increase the risk of fetal complications.
Individual genetic susceptibility: There is significant variation in how different pregnancies respond to teratogenic exposure. Two pregnancies exposed to the same dose of the same teratogen may have completely different outcomes. This may be due in part to underlying genetic factors in both the mother and fetus that are not well understood in most cases.
[Note: These 3 principles were derived for clinical relevance and brevity from Wilson’s original 6 principles of teratology, which was first published in 1959.]
Teratogen classification and safety databases
For many years, the FDA categorized the risk of drugs to a fetus using a five-letter system (A, B, C, D, and X). Each letter indicated the teratogenic potential of a drug based on available safety data, with “X” being clearly teratogenic. This 5-letter system has since been replaced with the Pregnancy and Lactation Labeling Rule (PLLR), which includes a description on the safety of drug in pregnancy, lactation, and in people of reproductive age. Safety information for FDA-approved medications can be found on the drug labels at the Drugs@FDA website. Subscription databases like Reprotox and TERIS also contain information on teratogens, and Mother-to-baby is a reliable resource on teratogens for patients.
Classification of teratogens
For board exams, think about teratogens as belonging into one of 4 categories: medications, recreational substances, maternal infections, and maternal illness.
1. Medications
There are multiple classes of medications that have well-documented teratogenic effects. During pregnancy, teratogenic medications should be discontinued or substituted for an alternative, when available. When this is not possible, the benefits of the mother taking a teratogenic medication should be weighed against the risk that their fetus would be affected by the medication. Below are a few examples:
Angiotensin-converting enzyme (ACE) inhibitors (e.g. lisinopril) can cause fetal renal failure, which leads to oligohydramnios. This is because fetal urine forms the amniotic fluid, especially in the 2nd half of pregnancy. Fetal lung development requires the presence of amniotic fluid, and so pulmonary hypoplasia (underdevelopment of the lungs; Question 92) can result if amniotic fluid levels are low.
Methimazole, an antithyroid medication, can cause aplasia cutis (Question 93) and micrognathia.
Warfarin, an anticoagulant, can cause nasal hypoplasia and skeletal anomalies (e.g. short limbs and digits).
Valproate is an antiepileptic that can cause neural tube defects and cardiac defects.
Isotretinoin, a vitamin A derivative used to treat severe acne, affects the development of cranial neural crest cells, which causes craniofacial, cardiac, and thymic malformations.
Lithium is a mood stabilizer used to treat bipolar disorder that can cause congenital heart defects (e.g. Ebstein anomaly, which presents with a malformed tricuspid valve, a large right atrium, and a small right ventricle).
2. Recreational substances
The use of recreational substances is relatively common nationwide among both pregnant and non-pregnant individuals. However, recreational substance use is particularly discouraged during pregnancy due to the risks to the fetus.
Alcohol use causes fetal alcohol spectrum disorder (FASD), which can present with “FAS”: Facial differences (short palpebral fissures, epicanthal folds, thin upper lip, smooth philtrum), Altered CNS development (DD/ID, behavior), and Small size (body and head). FASD is the most common preventable cause of intellectual disability.
Note that FASD presents similarly to Down syndrome (epicanthal folds, short stature, DD/ID).
There are no safe levels of alcohol during pregnancy.
Smoking cigarettes increases the risk of preterm birth, fetal growth restriction, cleft lip and palate, and jejunoilial atresia (like cocaine).
Cocaine is a vasoconstrictor and is associated with vascular accidents (e.g. jejunoileal atresia) in the fetus.
Duodenal (not jejunoileal) atresia is more commonly associated with Down syndrome.
3. Maternal infections
Maternal infections can also impair fetal development. Primary infections (i.e., the mother’s first infection) typically carry the greatest risk for fetal teratogenesis (as the mother lacks protective antibodies that form after the first infection). In some cases, an infection may cause minimal or no symptoms in the mother. Medications that treat the maternal infection are available in some cases, though treatment may not necessarily prevent symptoms in the fetus. Skin rashes, hepatomegaly, or lymphadenopathy in a newborn should raise concern for a congenital infection. The main teratogenic infections can be remembered with the mnemonic "TORCHES":
Toxoplasmosis, which is caused by a parasite acquired from cat feces, can cause intracranial calcifications and chorioretinitis in the fetus.
“Other” reminds us that there are other infections (e.g. Zika, varicella) that can cause congenital birth defects.
Congenital Rubella presents with a classic triad of deafness, cataracts, and cardiac defects.
CMV (cytomegalovirus) can cause microcephaly, periventricular calcifications (CMV = “Calcify My Ventricles“), cataracts, chorioretinitis (think “Sight”omegalovirus), and hearing loss.
Herpes simplex virus is typically acquired upon passage through birth canal. Babies may present within a few days after birth with a vesicular rash and temporal lobe hemorrhage (herpes encephalitis).
Syphilis is a bacteria that can cause rhinorrhea (“syphilitic snuffles”), anemia, thrombocytopenia, hepatomegaly, skin rash, and skeletal anomalies.
4. Maternal illness
Certain non-infectious maternal illness can affect fetal development. Below are a few examples:
Maternal diabetes, both pre-gestational and gestational, can impact the development of a fetus. This topic was also discussed in a prior post.
Pre-gestational diabetes (type 1 or 2) is associated with an increased risk of congenital heart disease, lower extremity anomalies (e.g. caudal regression syndrome), and holoprosencephaly. The risk of a major fetal anomaly or stillbirth correlates with maternal glucose control.
Gestational diabetes (defined as diabetes that develops after 20 weeks gestation) can present with macrosomia and neonatal hypoglycemia after delivery. There is a lower risk of major congenital anomalies compared to pre-gestational diabetes.
Maternal phenylketonuria is due to high levels of phenylalanine and can cause cardiac defects, fetal growth restriction, and microcephaly.
Obesity increases the risk of CHiN (Cleft lip/palate, Heart defect, and Neural tube defects) in the fetus.
Hyperthermia (e.g. maternal fever) increases the risk for neural tube defects if this happens early in the first trimester (recall that the neural tube closes at 6 weeks gestation).
Disclaimer: This overview provides examples of teratogens that may be tested on exams and represents only a subset of all known teratogens. Our understanding of teratogens and the risks they pose continues to evolve as new research emerges.
Learning objectives
Teratogens can be classified into four main categories: medications, recreational substances, maternal illnesses, and maternal infections. In most cases, the risk of severe congenital anomalies is highest during critical periods of organogenesis in early pregnancy. Remember the 3 key factors that determine the effects of teratogens on the fetus: timing of exposure, dose-response relationships, and individual susceptibility due to polygenic factors.
2025 ABMGG General Exam Blueprint | VI. Gene environment interactions → c) Teratology
2023 ABGC Exam Content Outline | Domain 1A. Clinical information → 2. Teratogens, exposure, and other non-genetic risk factors
References
Teratogenesis (2017, Vargesson and Fraga)
Handbook of Teratology: General Principles and Etiology (Wilson, 1977)