5.5 about 30 minDeep Learning viewL5 p.25–31

Congenital infections and teratogens

A teratogen is anything that crosses into the embryo or fetus and disturbs development. What it does depends on the agent and, as much, on when it arrives.

Congenital infections (TORCH and others)

L5 p.25–27

Most congenital infections cross the placenta during a maternal infection (often primary, often mild or silent in the mother). Several share a common picture: growth restriction, microcephaly, hepatosplenomegaly, jaundice, thrombocytopenia with petechiae or a blueberry-muffin rash (dermal extramedullary hematopoiesis). What separates them is a small set of specific findings and the timing of transmission.

Transmission and distinguishing findingsL5 p.26

  • CMV (commonest)

    Transmission and timing
    Transplacental, any trimester; worst after a primary maternal infection
    Distinguishing findings
    Periventricular calcification, microcephaly, sensorineural hearing loss (leading sequela; can appear later), chorioretinitis, petechiae, hepatosplenomegaly; owl's-eye inclusions in renal tubular cells; urine culture/PCR

  • Toxoplasmosis

    Transmission and timing
    Transplacental after a primary infection (cat feces, undercooked meat); transmission ↑ but severity ↓ later in pregnancy
    Distinguishing findings
    Triad: chorioretinitis, hydrocephalus, diffuse (scattered) intracranial calcification; deafness possible

  • Rubella

    Transmission and timing
    Transplacental; greatest risk in the first trimester (< 12 weeks)
    Distinguishing findings
    Cataracts, sensorineural deafness, PDA (and peripheral pulmonary stenosis); blueberry-muffin rash; salt-and-pepper retinopathy; microcephaly

  • Syphilis

    Transmission and timing
    Transplacental at any time; fetal damage mainly after ~16–20 weeks
    Distinguishing findings
    Stillbirth, hydrops; early: rhinitis (“snuffles”), rash on palms and soles, hepatosplenomegaly, periostitis; late: saddle nose, notched (Hutchinson) incisors, mulberry molars, saber shins, interstitial keratitis, CN VIII deafness

  • HSV-2

    Transmission and timing
    Mostly at delivery through the birth canal (intrauterine rare)
    Distinguishing findings
    Vesicles of skin, eye and mouth; encephalitis; disseminated disease with liver failure; cesarean if lesions are active

  • Varicella (VZV)

    Transmission and timing
    Transplacental, mostly maternal infection at 8–20 weeks
    Distinguishing findings
    Dermatomal cicatricial skin scars, limb hypoplasia, chorioretinitis, cataracts, microcephaly

  • Parvovirus B19

    Transmission and timing
    Transplacental; highest risk before 20 weeks
    Distinguishing findings
    Infects erythroid precursors (P antigen) → severe fetal anemia → high-output heart failure → nonimmune hydrops fetalis; no malformations

  • Zika

    Transmission and timing
    Transplacental (mosquito or sexual transmission to the mother)
    Distinguishing findings
    Severe microcephaly with a collapsed skull, subcortical calcification, eye lesions, contractures

  • HIV

    Transmission and timing
    Transplacental, at delivery, and by breastfeeding
    Distinguishing findings
    Thrush, recurrent bacterial infections, failure to thrive, intracranial calcification; prevented by maternal antiretroviral therapy

Zika and parvovirus B19 are not in the lecture table; they are added as supporting context.

Lecture image

Axial CT of an infant's head: enlarged lateral ventricles outlined by bright calcifications along their walls.
Congenital CMV: calcification outlining the ventricles (periventricular), with ventricular enlargement from brain loss.L5 p.27

Lecture image

Kidney histology: an enlarged tubular epithelial cell with a large intranuclear inclusion (arrow) in a distal convoluted tubule.
CMV in a distal convoluted tubule: an enlarged cell with a large eosinophilic intranuclear (owl's-eye) inclusion (arrow). Shed cells make urine the best sample.L5 p.27

Lecture image

Newborn skin with multiple purple-blue papules and macules.
Blueberry-muffin rash: purple dermal papules of extramedullary hematopoiesis (with purpura) in congenital rubella or CMV.L5 p.27

Lecture image

Infant's face with white opacities in both pupils.
Congenital rubella: bilateral cataracts (white pupils).L5 p.27

Lecture image

Mouth with widely spaced, notched, peg-shaped upper incisors.
Late congenital syphilis: notched, peg-shaped Hutchinson incisors.L5 p.27

Lecture image

Radiograph of an infant's long bone with layered new bone along the shaft (arrowheads).
Early congenital syphilis: periostitis, with new bone laid along the shaft (arrowheads).L5 p.27

Core activity · Almost Twins

Almost Twins

Two look-alikes side by side. Decide what they share, then pick the clue that separates them and say why it works.

Look-alike A

Congenital CMV

Periventricular calcification (CMV)calcification lines the ventricles
Calcification lining the ventricles (schematic).
  • Intracranial calcification, microcephaly
  • Periventricular calcification; sensorineural hearing loss is the leading sequela
  • Chorioretinitis possible; petechiae, hepatosplenomegaly
  • Commonest congenital infection; owl's-eye inclusions in urine/renal tubules

Step 1 · What they share

What do they share?

Select every feature that both show.

Drugs and exposures: the lecture's teratogen table

L5 p.25, 29–30

Read each row as exposure → mechanism → defect. Many mechanisms repeat: folate antagonism (valproate, methotrexate, phenytoin) gives neural tube and craniofacial defects; vasoconstriction or vascular disruption (cocaine, misoprostol) destroys tissue that had formed; loss of fetal urine (ACE inhibitors) gives the oligohydramnios sequence; hormones (androgenic progestins, DES) act on the genital tract.

Teratogens (lecture Table 6-4, with teaching notes)L5 p.29–30

  • ACE inhibitors and ARBs

    Defects
    IUGR, renal failure, Potter-like syndrome, pulmonary hypoplasia, hypoplastic calvaria
    Mechanism
    Fetal angiotensin II needed for renal perfusion → no fetal urine → oligohydramnios → renal dysplasia
    Teaching note
    Mainly 2nd–3rd trimester; first-trimester cleft and heart risk is uncertain

  • Alcohol

    Defects
    Microcephaly, intellectual disability, ADHD, VSD/ASD, thin upper lip, smooth philtrum, short palpebral fissures, epicanthal folds, flat nasal bridge
    Mechanism
    Acetaldehyde disrupts cell differentiation, migration and retinoic acid and hedgehog signaling; apoptosis of neural crest
    Teaching note
    Leading preventable cause of intellectual disability; no safe dose (see Ch. 6)

  • Amphetamines

    Defects
    Heart defects, IUGR, cleft, limb defects, learning disability
    Mechanism
    Reactive oxygen and nitrogen species, p53-driven apoptosis, mitochondrial dysfunction in neurons
    Teaching note
    Often combined with other exposures

  • Aspirin / NSAIDs (prostaglandin inhibitors)

    Defects
    Lecture: orofacial clefts and septal defects
    Mechanism
    Irreversible COX inhibition; prostaglandins keep the ductus open and maintain placental flow
    Teaching note
    Main risk is late pregnancy: premature ductus closure and oligohydramnios. Low-dose aspirin is used to prevent preeclampsia. The prostaglandin analog misoprostol causes vascular-disruption defects (limb, Möbius)

  • Carbon monoxide

    Defects
    Cerebral atrophy, microcephaly, seizures
    Mechanism
    Fetal hemoglobin binds CO avidly → hypoxia, inflammation, lipid peroxidation
    Teaching note
    Fetal COHb exceeds maternal

  • Cocaine

    Defects
    Microcephaly, low birth weight, renal agenesis, intestinal atresia, heart disease, hydronephrosis, hypospadias
    Mechanism
    Vasoconstriction → vascular insufficiency (disruption)
    Teaching note
    Also placental abruption

  • Diethylstilbestrol (DES)

    Defects
    Vaginal/cervical clear cell adenocarcinoma in daughters, T-shaped uterus, cervical incompetence
    Mechanism
    Disturbs differentiation of Müllerian (paramesonephric) epithelium (vaginal adenosis)
    Teaching note
    Historical; tumors appear in adolescence

  • Phenytoin

    Defects
    Fetal hydantoin syndrome: distal phalanx and nail hypoplasia, cleft lip/palate, microcephaly; neonatal bleeding
    Mechanism
    Reactive intermediates and oxidative stress; folate and vitamin K antagonism
    Teaching note
    Give vitamin K to the newborn

  • Androgenic and progestational exposure

    Defects
    Virilization of a female fetus (clitoromegaly, labial fusion)
    Mechanism
    Androgenic progestins (19-nortestosterone derivatives), danazol, testosterone act on the genital tubercle
    Teaching note
    The lecture lists “progesterone”; natural progesterone used to prevent preterm birth does not virilize

  • Retinoids (isotretinoin, high-dose vitamin A)

    Defects
    Microtia, cleft palate, conotruncal heart defects, thymic aplasia, CNS malformations, neural tube defects
    Mechanism
    Disrupt HOX-gene patterning and neural crest migration
    Teaching note
    Strict contraception; see vitamin A in Ch. 6

  • Tetracyclines

    Defects
    Tooth discoloration, enamel hypoplasia, slowed bone growth
    Mechanism
    Chelate calcium; deposit in developing teeth and bone
    Teaching note
    2nd–3rd trimester

  • Lithium

    Defects
    Ebstein anomaly (tricuspid valve displaced into the right ventricle)
    Mechanism
    Inhibits GSK-3 in the Wnt pathway
    Teaching note
    Absolute risk is low; fetal echocardiography

  • Streptomycin (aminoglycosides)

    Defects
    Ototoxicity (eighth-nerve deafness)
    Mechanism
    Hair-cell death via free radicals and mitochondrial protein synthesis
    Teaching note
    Also nephrotoxic in the mother

  • Tobacco

    Defects
    IUGR, low birth weight, preterm birth, SIDS
    Mechanism
    Nicotine vasoconstriction, CO hypoxia, oxidative stress
    Teaching note
    The slide says no malformations; a modest rise in orofacial clefts is reported

  • Valproate

    Defects
    Neural tube defects (spina bifida), facial, heart and limb defects, autism, lower IQ
    Mechanism
    Folate antagonism; histone deacetylase inhibition; oxidative stress
    Teaching note
    Avoid in women who may conceive; high-dose folate

  • Warfarin

    Defects
    Nasal hypoplasia, stippled epiphyses (weeks 6–9); CNS defects, fetal hemorrhage, death (later)
    Mechanism
    Blocks vitamin K–dependent bone proteins; later, hemorrhage
    Teaching note
    Switch to heparin, which does not cross the placenta

  • Methotrexate

    Defects
    Craniofacial and limb anomalies, neural tube defects
    Mechanism
    Folate antagonist (dihydrofolate reductase)
    Teaching note
    Also an abortifacient

Fetal alcohol syndrome

L5 p.29, 31Ch. V cases p.2

Alcohol crosses the placenta freely, and the fetus clears it slowly. Ethanol and acetaldehyde disturb proliferation, migration and survival of neural crest and brain cells. The facial features are set by exposure early in the first trimester, while the brain stays vulnerable throughout pregnancy, which is why there is no safe amount or time. Fetal alcohol spectrum disorder is the leading preventable cause of intellectual disability.

  • Face

    Findings
    Short palpebral fissures, smooth philtrum, thin upper lip, epicanthal folds, low nasal bridge, short nose

  • Growth

    Findings
    Prenatal and postnatal growth deficiency

  • Brain

    Findings
    Microcephaly, intellectual disability, attention deficit, poor impulse control and emotional regulation

  • Other

    Findings
    Heart defects (VSD, ASD), joint and renal anomalies

Lecture image

Young girl's face with labels: short palpebral fissure length, smooth philtrum, thin upper lip.
Fetal alcohol syndrome: short palpebral fissures (A–B), smooth philtrum and thin upper lip.L5 p.31

Worked case · An “emotional” 4-year-old

A 4-year-old girl at a preschool check has a small head circumference, a thin upper lip and a low nasal bridge, mild intellectual disability, and her parents say she is often “emotional” (Ch. V Q1).

Which maternal factor best explains the findings?

Ch. V cases p.2

Critical periods: when an exposure arrives

L5 p.28Ref. · Moore, The Developing Human

The same drug can do nothing, kill the embryo, cause a malformation or only slow growth, depending on timing. In the first two weeks after fertilization cells are still interchangeable: an injury either kills enough of them to end the pregnancy or the survivors replace the lost cells (all-or-none). Weeks 3–8 are organogenesis, when each organ has a window of maximal sensitivity to major structural defects. After week 8 (the fetal period) organs grow and mature, so exposures cause growth restriction, functional defects (brain, hearing) and minor anomalies; the brain, palate, ears, teeth and external genitalia remain partly vulnerable.

Teaching schematic

Critical periods of developmentwk 1–2all-or-noneEmbryonic period, wk 3–8organogenesis: major malformationsFetal period, wk 9–38growth, function, minor anomaliesCentral nervous systemHeartLimbsEyesEarsPalate and lipTeethExternal genitalia13581216203038weeks after fertilization (scale compressed after week 16)

Dark bars: highest sensitivity to major structural defects; light bars: functional and minor defects. Approximate, after Moore's embryology charts.

Approximate windows of sensitivity by organ. Dark = major malformations; light = functional or minor defects.L5 p.28Ref. · Moore

Core activity · One Fact Changes

One Fact Changes

Answer a case and name the decisive clue. Then exactly one fact changes. Decide whether the answer moves, and why.

1 · The original case

A 24-year-old woman takes isotretinoin for severe acne. She stops it on discovering she is pregnant, about 5 weeks after conception. She asks what the drug could have done.

What is the main risk?

Which fact matters most for the type of risk?

Knowledge check · 5.5

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 7 correct
  1. Q1Fetal alcohol syndromeCh. V cases p.2L5 p.29, 31

    A 4-year-old girl has a small head circumference, a thin upper lip, a low nasal bridge, mild intellectual disability, and is often “emotional” (Ch. V Q1).

    Which maternal cause of birth defects most likely accounts for these findings?

  2. Q2Congenital CMV (image)L5 p.26–27

    A 3-week-old with petechiae, hepatosplenomegaly and a failed newborn hearing screen has the head CT shown.

    Lecture image

    Axial head CT of an infant: enlarged lateral ventricles outlined by bright calcifications along their walls.

    Which congenital infection is most likely?

  3. Q3Congenital rubellaL5 p.26–27

    An unvaccinated woman had a fever and fine rash at 8 weeks of gestation. Her newborn has white pupils, a continuous machinery murmur and fails the hearing screen.

    Which infection explains the triad?

  4. Q4Parvovirus B19 hydropsRef. · parvovirus B19 hydrops

    At 18 weeks, ultrasound shows fetal ascites, pleural effusions and skin edema. Three weeks earlier the mother cared for a child with a “slapped-cheek” rash.

    What is the mechanism of the fetal findings?

  5. Q5ACE inhibitor fetopathyL5 p.29

    A woman with hypertension continued lisinopril through her second and third trimesters. Her stillborn infant has hypoplastic lungs, a poorly ossified skull and small, dysplastic kidneys; amniotic fluid had been severely reduced.

    What is the main mechanism?

  6. Q6All-or-none periodRef. · Moore, critical periods

    A woman learns she is pregnant when her period is late. Dating shows she took a known teratogen for 3 days, from day 6 to day 9 after conception, and none since.

    What is the most accurate counseling?

  7. Q7Valproate and NTDsL5 p.30

    A woman with epilepsy who takes valproate plans a pregnancy.

    Which defect is her baby at greatest risk of, and what reduces it?

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