Congenital anomalies
Common congenital anomalies: neural tube, heart, kidney and facial defects, teratogens
Most congenital anomalies arise in weeks 3 to 8 after conception, when organs form and teratogens do most harm. CPSP asks how neural tube defects and clefts arise, which drug or infection causes which defect, and how renal anomalies change amniotic fluid.
Timing and terms
- Weeks 1–2 after conception: all-or-none effect (the embryo dies or recovers fully). Weeks 3–8: organogenesis, the period of greatest sensitivity to teratogens. Fetal period: growth and functional damage (brain, ears, kidneys, teeth).
| Term | Meaning | Example |
|---|---|---|
| Malformation | Intrinsic error in forming a structure | Spina bifida, cleft lip |
| Disruption | A normally formed part is destroyed | Amniotic band amputation; cocaine vasoconstriction |
| Deformation | Mechanical moulding of a normal part | Talipes and hip dysplasia with oligohydramnios |
| Sequence | One primary defect sets off a cascade | Pierre Robin; Potter |
| Syndrome | Several independent defects from one cause | Down, Beckwith–Wiedemann |
| Association | Non-random cluster, no single cause | VACTERL |
- Pierre Robin sequence: the primary defect is mandibular hypoplasia. The small jaw keeps the tongue high and back, so it blocks the palatal shelves from meeting (wide U-shaped cleft) and falls back to obstruct the airway after birth.
Neural tube defects
- The notochord induces overlying ectoderm to form the neural plate (neurulation) in week 3–4. The cranial neuropore closes about day 25 and the caudal about day 28 after conception, roughly 6 weeks after the last period, often before pregnancy is recognised.
- Anencephaly: cranial neuropore fails; absent calvarium; not compatible with life; polyhydramnios (no swallowing).
- Spina bifida occulta: bony defect only, usually L5–S1, tuft of hair or dimple. Meningocele: sac of meninges and CSF without neural tissue, usually no deficit. Myelomeningocele (commonest open defect): cord or roots in the sac, leg paralysis, neurogenic bladder, Chiari II and hydrocephalus.
- Encephalocele: brain and meninges through a skull defect, usually occipital.
- Ultrasound: open spina bifida lets CSF leak, pulling the hindbrain down: lemon skull and banana cerebellum.
- Maternal AFP rises only with open lesions.
- Risk factors: folate deficiency, vitamin B12 deficiency, previous affected child, valproate and carbamazepine, pregestational diabetes, obesity, high fever in weeks 3–4.
- Folate donates one-carbon units for thymidylate and purine synthesis in the rapidly dividing neural folds. B12 is the cofactor of methionine synthase; without it folate is trapped as methyltetrahydrofolate and homocysteine rises. A strict vegetarian can therefore have an affected baby despite folic acid and a normal red cell folate.
- Give 400 micrograms folic acid daily before conception until 12 weeks; 5 mg for high-risk women.
Brain: holoprosencephaly and hydrocephalus
- Holoprosencephaly: failure of the prosencephalon (forebrain) to divide into two hemispheres in weeks 5–6. Severe forms show a single monoventricle, fused thalami, no falx and midline facial defects (cyclopia, single nostril, median cleft). Causes: trisomy 13, poorly controlled maternal diabetes, sonic hedgehog mutations. Absent corpus callosum alone is not holoprosencephaly, because the hemispheres are separate.
- Commonest congenital cause of hydrocephalus: aqueduct stenosis (non-communicating); in boys with adducted thumbs think X-linked L1CAM.
Congenital heart disease
- Commonest lesion overall: ventricular septal defect.
| Cause | Typical lesion |
|---|---|
| Maternal diabetes | VSD, transposition; caudal regression is characteristic but rare |
| Rubella | Patent ductus arteriosus, pulmonary artery stenosis |
| Lithium | Ebstein anomaly (low tricuspid valve, atrialised right ventricle) |
| Trisomy 21 | AVSD |
| Turner syndrome | Coarctation, bicuspid aortic valve |
| 22q11 deletion (DiGeorge) | Conotruncal defects with cleft palate, thymic aplasia (recurrent infections), hypocalcaemia |
| Maternal anti-Ro (SLE, Sjögren) | Congenital heart block |
- Diabetic embryopathy comes from hyperglycaemic oxidative stress; fetal hyperinsulinaemia later causes macrosomia, not malformations.
Kidneys and amniotic fluid
- After 16 weeks, amniotic fluid is mainly fetal urine. Bilateral renal agenesis gives anhydramnios and the Potter sequence: flattened face, limb deformities and fatal pulmonary hypoplasia.
- Autosomal recessive polycystic kidney: large echogenic kidneys, oligohydramnios, congenital hepatic fibrosis.
- Meckel–Gruber syndrome (autosomal recessive, a ciliopathy): occipital encephalocele, large cystic kidneys and polydactyly, recurring in a consanguineous couple. Trisomy 13 also has polydactyly and cystic kidneys but does not usually recur.
- Posterior urethral valves (boys): thick distended bladder with a keyhole sign, bilateral hydronephrosis, oligohydramnios. PUJ obstruction is the commonest antenatal hydronephrosis.
- Polyhydramnios follows failed swallowing or absorption: anencephaly, oesophageal or duodenal atresia, maternal diabetes.
Abdominal wall, lymphatics and imprinting
| Feature | Exomphalos (omphalocele) | Gastroschisis |
|---|---|---|
| Defect | Gut fails to return from the cord in week 10–12 | Paraumbilical (right-sided) wall defect |
| Covering | Peritoneum–amnion sac; cord inserts on sac | None; bowel floats free |
| Associations | Often syndromic or aneuploid (trisomy 18, Beckwith–Wiedemann) | Usually isolated; young mothers |
- Beckwith–Wiedemann syndrome (11p15 imprinting, excess IGF2): exomphalos, macroglossia, hemihypertrophy, neonatal hypoglycaemia from islet hyperplasia, and later Wilms tumour.
- Cystic hygroma: the jugular lymph sacs fail to join the internal jugular veins, so lymph collects as a septated sac behind the neck with hydrops. It is strongly linked to 45,X (Turner) and other aneuploidy.
Clefts
- Cleft lip: failure of the maxillary prominence to fuse with the medial nasal prominence (intermaxillary segment) by week 7; it may extend into the primary palate in front of the incisive foramen.
- Cleft palate: the lateral palatine shelves fail to fuse with each other, the primary palate and the nasal septum (weeks 8–12), so a later insult gives isolated cleft palate. Most clefts are multifactorial.
- Teratogenic causes: phenytoin, topiramate, isotretinoin, valproate; also trisomy 13 and 22q11 deletion. Apert syndrome (FGFR2) adds craniosynostosis, flat midface, proptosis and syndactyly.
Teratogens and infections to know
| Agent | Defect or point |
|---|---|
| Warfarin (6–12 weeks) | Nasal hypoplasia, stippled epiphyses |
| Isotretinoin | Craniofacial, ear, heart and CNS defects |
| Valproate | Neural tube defects, developmental delay |
| Alcohol | Smooth philtrum, thin upper lip, short palpebral fissures |
| ACE inhibitors (later pregnancy) | Fetal renal failure, oligohydramnios, skull hypoplasia |
| Thalidomide | Phocomelia |
| Methotrexate | Skeletal and cranial defects; retained in tissues as polyglutamates, so wait 3 months before conceiving |
| Rubella | Under 12 weeks: cataract, PDA, deafness; at 12–16 weeks mainly sensorineural deafness |
| Varicella before 20 weeks | Dermatomal (zigzag) scarring, limb hypoplasia, cataract, microcephaly |
- Maternal phenylketonuria off diet: phenylalanine is actively transported and concentrated across the placenta, so even a carrier fetus with normal enzyme has brain and heart damage.
- Syphilis treated with erythromycin: macrolides cross the placenta poorly, so the fetus is not treated and the baby needs full treatment after birth. Penicillin is the only reliable fetal treatment.
Remember Fluid tells the story: too little means kidneys or outflow; too much means the fetus cannot swallow.
Exam trap A normal maternal AFP does not exclude a skin-covered spinal defect.
Exam trap Folic acid started at the booking visit is too late: the neural tube has already closed.
How FCPS asks about this
- Commonest congenital heart defect: VSD; lithium causes Ebstein anomaly.
- Unilateral cleft lip with normal palate: maxillary prominence failed to fuse with the medial nasal prominence.
- Sacral swelling with meninges only: spina bifida with meningocele.
- Rubella at 15 weeks: sensorineural deafness.
- Small jaw, tongue obstructing airway, U-shaped cleft: Pierre Robin sequence from mandibular hypoplasia.
- Exomphalos, big tongue, hemihypertrophy, hypoglycaemia: Beckwith–Wiedemann syndrome.
- Neural tube defect despite folic acid in a vegan: vitamin B12 deficiency.
Test yourself on this topic
5 of the 40 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A newborn has an exomphalos containing bowel, a very large tongue, one side of the body larger than the other, and recurrent hypoglycaemia in the first days. Which syndrome is most likely?
Answer: Beckwith–Wiedemann syndrome
Beckwith–Wiedemann syndrome is an overgrowth disorder caused by abnormal imprinting on chromosome 11p15, often with excess IGF2 activity. Features include exomphalos, macroglossia, hemihypertrophy, large organs and neonatal hypoglycaemia from islet cell hyperplasia. Affected children have a raised risk of embryonal tumours, especially Wilms tumour and hepatoblastoma, so they are screened in childhood. Exomphalos also occurs with trisomy 18, but not with overgrowth.
Beckwith–Wiedemann
- Exomphalos
- Macroglossia, hemihypertrophy
- Neonatal hypoglycaemia
- Risk of Wilms tumour
Remember Big tongue, open navel, low sugar.
Exam trap Exomphalos, unlike gastroschisis, is often part of a syndrome, so look for other features.
Why the other options are wrong
- Trisomy 18 Associated with exomphalos but with growth restriction.
- Prader–Willi syndrome Hypotonia and poor feeding in infancy, no exomphalos.
- Turner syndrome Lymphoedema and short stature, no exomphalos.
- Infant of diabetic mother Hypoglycaemia and size, but no macroglossia or exomphalos.
A woman with type 1 diabetes had an HbA1c of 10% (86 mmol/mol) at conception. Which group of malformations is most common in babies of mothers like her?
Answer: Cardiac defects
Poor glucose control around conception and in the first 8 weeks raises the risk of major malformations in proportion to the HbA1c. Congenital heart defects, such as transposition of the great arteries, ventricular septal defect and truncus arteriosus, are the most common group. Neural tube defects are also increased. Caudal regression is the most specific diabetic anomaly but is rare.
Diabetic embryopathy
- Risk rises with periconception HbA1c
- Commonest: heart defects (TGA, VSD)
- Also neural tube defects
- Most specific: caudal regression (rare)
Remember Diabetic mother: check the baby's heart.
Exam trap Caudal regression is the most characteristic, not the most frequent, anomaly.
Why the other options are wrong
- Renal defects Increased but less common than cardiac defects.
- Facial clefts Not the most common group.
- Limb defects Less common than heart defects.
- Neural tube defects Increased, but cardiac defects are commoner.
A 13-week scan shows a large septated fluid-filled sac behind the fetal neck with generalised skin oedema. Karyotype shows 45,X. Which developmental failure best explains the neck swelling?
Answer: Jugular lymph sacs not joining the veins
Lymphatic vessels develop from lymph sacs, the first of which are the paired jugular lymph sacs beside the internal jugular veins. Normally these drain into the venous system around week 6. If the connection fails or is delayed, lymph collects in the neck, forming a septated cystic hygroma, and may spread to cause generalised oedema and hydrops. This is common in Turner syndrome, which explains the webbed neck seen in survivors.
Cystic hygroma
- Jugular lymph sacs fail to drain
- Septated sac behind the neck
- Often Turner syndrome
- Survivors: webbed neck
Remember Blocked neck lymph, webbed neck later.
Exam trap A septated hygroma is more often aneuploid than a simple raised nuchal translucency.
Why the other options are wrong
- Failure of the third pharyngeal pouch Gives thymic and parathyroid defects.
- Persistence of the thyroglossal duct Gives a midline thyroglossal cyst.
- Closure failure of the posterior neuropore Gives spina bifida, not a neck sac.
- Persistence of the second pharyngeal cleft Gives a lateral branchial cyst.
A woman has confirmed primary rubella at 15 weeks. Infection at this stage most often leaves the baby with which defect?
Answer: Sensorineural deafness
The fetal risk from rubella falls as pregnancy advances. Before 12 weeks most infected fetuses are damaged, often with the full syndrome of cataract, heart defects and deafness. Between 13 and 16 weeks the risk is lower and the main effect is sensorineural deafness, because the cochlea remains vulnerable after the eye and heart have formed. After about 20 weeks defects are rare.
Rubella by gestation
- Before 12 weeks: full syndrome
- 13–16 weeks: mainly deafness
- After 20 weeks: defects rare
- Cochlea vulnerable longest
Remember Late rubella damages the ear.
Exam trap Rubella after the first trimester is not harmless; hearing can still be damaged.
Why the other options are wrong
- Patent ductus arteriosus The heart has formed by this stage.
- Congenital cataract Eye defects follow first-trimester infection.
- Microphthalmia An early-pregnancy eye defect.
- Pulmonary artery stenosis Part of the early full syndrome.
A woman with a mechanical mitral valve on warfarin plans pregnancy. To avoid nasal hypoplasia and stippled epiphyses in the baby, during which period of gestation is warfarin most important to avoid?
Answer: 6 to 12 weeks
Warfarin embryopathy, with nasal hypoplasia and stippled epiphyses (chondrodysplasia punctata), follows exposure between about 6 and 12 weeks. Warfarin inhibits vitamin K epoxide reductase, which is needed to carboxylate proteins involved in bone and cartilage mineralisation. Exposure later in pregnancy instead risks fetal intracranial bleeding. Many women switch to heparin from 6 to 12 weeks for this reason.
Warfarin in pregnancy
- Embryopathy: 6–12 weeks
- Nasal hypoplasia, stippled epiphyses
- Later: fetal brain bleeding
- Switch to heparin in this window
Remember Weeks 6 to 12: keep warfarin away.
Exam trap The risk is dose related; it is lower at 5 mg daily or less.
Why the other options are wrong
- 0 to 2 weeks The all-or-none period, before organogenesis.
- 14 to 20 weeks The embryopathy window has passed.
- 28 to 34 weeks Late exposure risks bleeding, not embryopathy.
- Only after 36 weeks Too late; bleeding risk at delivery is the concern.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: Genetics and congenital anomalies, Common congenital anomalies: neural tube defects, cardiac and renal anomalies, teratogenic causes
Read next
Drug dose pages
Doses, cautions and practical tips for drugs in this chapter.