Obstetrics and Gynaecology chapters
Prenatal screening and diagnosis
How fetal disease is found before birth: screening tests for Down syndrome (combined test, quadruple test, NIPT), the anomaly scan, and the invasive diagnostic tests (CVS, amniocentesis, cordocentesis) with their timing and risks.
- Screening finds women at higher risk; diagnosis confirms. Down syndrome screening: combined test at 11-14 weeks (NT, hCG, PAPP-A and age) or the quadruple test at 14-20 weeks; NIPT detects about 98% but still needs confirmation.
- In Down syndrome hCG and inhibin A are raised; PAPP-A, AFP and oestriol are low; NT is thick.
- Diagnostic tests: CVS from 11 weeks (earliest; about 2% extra loss), amniocentesis from 15 weeks (about 1%), cordocentesis from about 20 weeks for fetal blood.
On this page
Overview
Prenatal diagnosis is the detection of disease in the fetus before birth. It usually follows a screening result or a reason for concern:
- Family history of a genetic disease (e.g. thalassaemia, cystic fibrosis); in Pakistan, consanguineous marriage raises the risk of recessive disorders.
- Past obstetric history (e.g. a previous child with a chromosomal or neural tube defect, rhesus disease).
- A high-risk screening test (combined test, quadruple test, NIPT).
- An abnormal ultrasound (dating scan or anomaly scan).
| Screening test | Diagnostic test |
|---|---|
| Applied to everyone who accepts it | Offered to the high-risk group |
| Gives a risk (e.g. 1 in 50) | Gives a yes or no answer |
| No physical risk to the pregnancy | Invasive tests carry a small miscarriage risk |
| Examples: combined test, quadruple test, NIPT, anomaly scan | Examples: CVS, amniocentesis, cordocentesis, detailed fetal medicine scan |
A good screening test is relevant, changes management, has high sensitivity and specificity, predicts well, is affordable and is available to all.
Non-invasive tests
Ultrasound
| Scan | Timing | Purpose |
|---|---|---|
| Dating / first-trimester scan | 10-14 weeks | Viability, dates (CRL), number and chorionicity, nuchal translucency, gross anomalies (anencephaly, cystic hygroma) |
| Anomaly scan | 18-21 weeks (around 20) | Structural defects: spina bifida, heart defects, diaphragmatic hernia, abdominal wall defects, renal agenesis, skeletal dysplasia, cleft lip; placental site |
- Major structural abnormalities affect about 2-3% of pregnancies.
- Detection at the 20-week scan ranges from 40% to 90% depending on the defect, maternal BMI and fetal position, so a normal scan does not guarantee a normal baby.
- Soft markers (normal variants that raise aneuploidy risk): increased NT, absent nasal bone, and on the anomaly scan a nuchal fold over 6 mm. Two or more soft markers → fetal medicine referral.
Classic ultrasound signs
| Sign | Condition |
|---|---|
| Lemon-shaped skull, banana-shaped cerebellum, ventriculomegaly | Open spina bifida (myelomeningocele) |
| Double bubble | Duodenal atresia (linked to Down syndrome; polyhydramnios) |
| Bowel loops floating in the liquor, right of the cord insertion, no sac | Gastroschisis (usually isolated) |
| Bowel or liver in a membrane-covered sac at the cord insertion | Exomphalos (omphalocele) (linked to chromosomal anomaly) |
| Absent kidneys, anhydramnios | Renal agenesis (Potter sequence) |
| Short long bones, narrow chest | Skeletal dysplasia (e.g. achondroplasia) |
Ultrasound detects at least 90% of neural tube defects and gastroschisis. Structural defects are diagnosed by scan, not by karyotyping.
Maternal serum screening for Down syndrome
First-trimester combined test (preferred):
- Scan at about 11+2 to 14+1 weeks: nuchal translucency (NT) with CRL.
- Blood at 10-14 weeks: hCG (beta subunit) and PAPP-A.
- Combined with maternal age to give an individual risk. Detection about 90% (higher with nasal bone, ductus venosus and tricuspid flow).
Second-trimester quadruple test (for late bookers or when NT cannot be measured): 14+2 to 20+0 weeks: AFP, hCG, inhibin A and unconjugated oestriol (uE3); detection about 80% at a 5% false-positive rate.
| Marker | Source | Down syndrome (trisomy 21) |
|---|---|---|
| NT | Fetal neck fluid | Increased |
| hCG (beta-hCG) | Syncytiotrophoblast | Raised (about 2 MoM) |
| Inhibin A | Placenta | Raised |
| PAPP-A | Syncytiotrophoblast | Low (about 0.5 MoM) |
| AFP | Fetal yolk sac and liver | Low |
| uE3 | Placenta and fetal adrenals | Low |
"HI" goes up: HCG and Inhibin are high in Down syndrome; the rest (PAPP-A, AFP, oestriol) are low.
A raised AFP points away from Down syndrome. Raised maternal serum AFP suggests an open neural tube defect, an abdominal wall defect (gastroschisis, exomphalos), multiple pregnancy, wrong (underestimated) dates or fetal death. AFP screening for spina bifida has now been largely replaced by the anomaly scan.
Non-invasive prenatal testing (NIPT)
- Uses circulating fetal DNA (cffDNA) in maternal blood; it comes mainly from the placenta, rises with gestation (around 10% of the circulating DNA at 10 weeks) and disappears within a day of delivery.
- Detects about 98% of trisomy 21, 18 and 13 with a very low false-positive rate.
- Not diagnostic: a positive result should be confirmed by CVS or amniocentesis.
- Other uses: fetal Rh D status in Rh D-negative women (and Kell), fetal sex in X-linked disorders, some single-gene disorders (e.g. achondroplasia, FGFR3).
- Low fetal fraction (early gestation, maternal obesity) can give a failed result.
Understanding a screening result
Screening result: risk of Down syndrome 1 in 50
Affected = 1 of 50 = 2%; unaffected = 49 of 50 = 98%
So even a high-risk result means most such babies are unaffected; only a diagnostic test can tell
Equally, a low-risk result (e.g. 1 in 10,000) does not exclude Down syndrome. A previous pregnancy with Down syndrome counts as screen positive whatever the markers show.
Invasive diagnostic tests
Before any invasive test
- Confirm the diagnosis suspected, its severity, the real risk and that a laboratory test exists (genetics input).
- Discuss what she would do with the result: continue and plan care, decide about termination, or obtain information for future pregnancies.
- Make sure the choice is hers, made without pressure from family or community; record consent.
- Check HIV and hepatitis status (risk of vertical transmission).
- Afterwards: give anti-D to Rh D-negative women (Kleihauer test after 20 weeks); advise rest from strenuous activity for 24 hours; seek help for fever, bleeding, pain or fluid leakage.
Comparison of invasive tests
| Feature | Chorionic villus sampling (CVS) | Amniocentesis | Cordocentesis (fetal blood sampling) |
|---|---|---|---|
| Sample | Placental villi (trophoblast) | 15-20 mL amniotic fluid (amniocytes, fibroblasts) | Fetal blood from the cord at its placental insertion |
| Route | Transabdominal (commoner) or transcervical, ultrasound-guided | Transabdominal under continuous ultrasound | Transabdominal under ultrasound |
| Earliest timing | 11 weeks (never before 10) | 15 weeks | About 20 weeks |
| Extra miscarriage risk | About 2% | About 1% | 2-5% |
| Results | Rapid PCR for T21, 18, 13, X, Y in about 48 hours; full culture 7-10 days | Same | Rapid full karyotype |
| Main uses | Early karyotype and DNA tests (e.g. thalassaemia, cystic fibrosis) | Karyotype, DNA tests, fetal infection (e.g. CMV) | Fetal anaemia (with transfusion) and fetal thrombocytopenia |
| Special problems | Confined placental mosaicism (about 1%); limb defects if done too early | Early amniocentesis (before 14-15 weeks): more loss, talipes, breathing problems | Cord bleeding; higher loss if done early |
CVS is the earliest invasive test and allows earlier (surgical) termination if the fetus is affected. It also gives more DNA, so it is preferred for haemoglobinopathies such as beta-thalassaemia, which matters in Pakistan.
CVS before 10-11 weeks is linked with limb reduction defects; amniocentesis before 15 weeks carries a higher loss rate and talipes. The safe windows are CVS from 11 weeks and amniocentesis from 15 weeks.
Newer laboratory methods
- Chromosomal microarray detects small deletions and duplications missed by karyotyping; it needs fetal tissue (CVS, amniocentesis or cord blood) and may find uncertain results, so counsel carefully.
- Fetal MRI helps with brain abnormalities such as ventriculomegaly.
- 3D ultrasound shows cleft lip and palate to parents.
Which test for which condition?
| Condition | Usual route to diagnosis |
|---|---|
| Neural tube defect, gastroschisis, twin-to-twin transfusion | Ultrasound |
| Down syndrome, cystic fibrosis, thalassaemia | CVS or amniocentesis |
| Fetal anaemia, alloimmune thrombocytopenia | MCA Doppler, then cordocentesis with transfusion |
| Diaphragmatic hernia, exomphalos, duodenal atresia, ventriculomegaly | Ultrasound, then invasive test (chromosomal links) |
| Fetal cardiac defect in a high-risk mother (e.g. maternal congenital heart disease, diabetes) | Fetal echocardiography |
| Congenital infection (CMV, toxoplasma, parvovirus) | Maternal serology, ultrasound, amniotic fluid PCR |
Neural tube defects: prevention and recurrence
- Recurrence risk after one affected pregnancy is about 5% (higher after two or three).
- Higher risk with maternal diabetes, epilepsy and antiepileptic drugs, and obesity.
- Folic acid 400 micrograms daily before conception and in the first trimester; 5 mg after a previous affected pregnancy, started at least 3 months before conceiving.
After a fetal abnormality is found
- Refer to a fetal medicine unit; involve neonatologists, surgeons and geneticists.
- Explain the outlook honestly: options are to continue with planned delivery and care, or termination where the law allows.
- In Pakistan, termination for fetal anomaly is governed by national law and by religious and ethical considerations; involve senior staff and follow current national guidance.
Expect: the difference between screening and diagnostic tests; the components and timing of the combined test (NT, hCG, PAPP-A at 11-14 weeks) and the quadruple test (14-20 weeks); the direction of each marker in Down syndrome; causes of raised AFP; NIPT as a highly sensitive screening (not diagnostic) test; the earliest diagnostic test (CVS) and the safe gestations for CVS (11 weeks), amniocentesis (15 weeks) and cordocentesis (20 weeks); their miscarriage risks; limb defects after very early CVS and talipes after early amniocentesis; placental mosaicism; CVS for thalassaemia; anomaly scan timing (18-21 weeks); lemon and banana signs and double bubble; fetal echocardiography for cardiac screening; anti-D after invasive tests.
Quick revision
- Screening gives a risk; diagnosis gives an answer.
- Combined test (11-14 weeks): NT + hCG + PAPP-A + age; about 90% detection.
- Quadruple test (14-20 weeks): AFP, hCG, uE3, inhibin A; about 80% detection.
- Down syndrome: hCG and inhibin up; PAPP-A, AFP, uE3 down; NT thick.
- NIPT: cffDNA, about 98% detection, confirm with an invasive test.
- CVS from 11 weeks (about 2% loss, mosaicism, limb defects if early); amniocentesis from 15 weeks (about 1%); cordocentesis from 20 weeks (2-5%).
- Anomaly scan 18-21 weeks; lemon and banana signs = spina bifida; double bubble = duodenal atresia.
- Give anti-D to Rh D-negative women after any invasive test.
Written by The House Job from standard references (Obstetrics by Ten Teachers).
FAQ
Is NIPT a diagnostic test for Down syndrome?
No. It is a very sensitive screening test based on placental DNA in the mother's blood, so a high-risk result should be confirmed by CVS or amniocentesis.
Why is CVS preferred for a couple who are both thalassaemia carriers?
It can be done from 11 weeks, gives plenty of DNA for rapid testing, and leaves time for decisions earlier in pregnancy.
Why should amniocentesis not be done at 12 weeks?
Amniocentesis before about 15 weeks has a higher miscarriage rate and is linked with talipes and neonatal breathing problems; CVS is the test for that gestation.
Can karyotyping detect spina bifida?
No. Spina bifida is a structural defect found on ultrasound; invasive tests diagnose chromosomal and single-gene disorders and some infections.