Lucan · Conditions

Fetal anomaly screening

Australian guidance: RANZCOG C-Obs 35 Fetal Structural Anomalies (2024)

1. Definition and epidemiology

Foetal anomaly screening encompasses the antenatal detection of structural malformations and chromosomal conditions using ultrasound, serum biochemistry, and cell-free deoxyribonucleic acid (cfDNA) analysis. In Australia, trisomy 21 (Down syndrome) occurs in approximately 1 in 400 pregnancies and is the most common aneuploidy detected prenatally, comprising roughly half of all chromosomal abnormalities identified at prenatal diagnosis in Victoria. Trisomies 18 and 13 are the next most frequent autosomal aneuploidies; together with trisomy 21 they accounted for 58% of all major chromosomal conditions detected by prenatal diagnosis in Victoria in 2022. Australia has no national screening unit, so uptake of aneuploidy screening varies by jurisdiction and socioeconomic status, with a Victorian statewide study finding that 84% of women accessed some form of aneuploidy screening in 2015.

2. Pathophysiology

The majority of clinically significant foetal anomalies arise from one of three broad mechanisms. First, numerical chromosomal abnormalities (aneuploidies) result from meiotic non-disjunction, most commonly in maternal meiosis I; the risk increases sharply with advancing maternal age because oocytes are arrested in prophase I for decades, accumulating cohesin degradation and spindle assembly checkpoint errors. Trisomy 21 produces characteristic overexpression of chromosome 21 gene products that disrupt neuronal migration, cardiac septation, and facial morphogenesis, explaining the intellectual disability, atrioventricular septal defects, and dysmorphic facies seen in affected neonates (Robbins Ch 10). Trisomy 18 and 13 involve more severe dosage imbalance and disrupt organogenesis across multiple systems, leading to high rates of intrauterine death and early infantile mortality. Second, copy number variants (CNVs) arise from unequal crossover or replication errors, producing microdeletions or microduplications; the 22q11.2 deletion (DiGeorge or velocardiofacial syndrome) is the most clinically common pathogenic CNV. Third, structural anomalies without a detectable chromosomal cause reflect multifactorial developmental disruption, including teratogen exposure, single gene mutations, or stochastic errors in morphogenesis.

3. Clinical presentation and diagnostic criteria

Most foetal structural anomalies are asymptomatic in the mother and are identified exclusively through screening. First trimester ultrasound at 11 to 14 weeks may reveal an increased nuchal translucency (NT) of 3.5 mm or greater, absent nasal bone, early cardiac defects such as atrioventricular septal defect, or major structural lesions including anencephaly, holoprosencephaly, and large abdominal wall defects. Second trimester morphology ultrasound at 18 to 22 weeks allows more complete structural survey and detects anomalies not visible at 11 to 14 weeks, including cardiac outflow tract defects, renal agenesis, diaphragmatic hernia, and neural tube defects. Soft markers identified at the morphology scan that warrant further assessment include echogenic bowel, mild cerebral ventriculomegaly, aberrant right subclavian artery, mild renal pelvis dilatation, short humerus or femur more than two standard deviations below the mean, thickened nuchal fold, and hypoplastic nasal bone. Isolated soft markers that are no longer reported as pathological include echogenic intracardiac focus, choroid plexus cysts, sandal gap toe, and clinodactyly.

4. Investigations and AU-specific cutoffs

Investigations follow a sequential screening-to-diagnosis pathway per C-Obs 35:

First-tier screening (before 14 weeks): Non-invasive prenatal testing (NIPT) using cfDNA from maternal plasma is the most accurate primary screening test for trisomies 21, 18, and 13, with pooled sensitivity of 98.8% for T21 and a false positive rate of 0.04% in singleton pregnancies. NIPT is available from 10 weeks gestation but is not currently Medicare-funded in Australia as a primary screen, so out-of-pocket cost remains a significant access barrier. Combined first trimester screening (CFTS, also called MSS1) incorporates maternal age, foetal crown-rump length (CRL), nuchal translucency (NT measured at 11+0 to 13+6 weeks), free beta human chorionic gonadotrophin (beta-hCG), and pregnancy-associated plasma protein A (PAPP-A) collected at 9+0 to 13+6 weeks. The conventional threshold for an increased chance result on CFTS is 1:300 across Australia; results of 1:10 or higher are generally referred directly to diagnostic testing rather than contingent NIPT. CFTS has pooled sensitivity of 87% for T21 with a 5% false positive rate.

Second-tier screening (from 14 weeks): For women presenting after the first trimester, NIPT is the most accurate option. Second trimester maternal serum screening (MSS2, also called triple or quadruple test) uses alpha-fetoprotein (AFP), hCG, and unconjugated oestriol (uE3), with Victoria and New Zealand also including inhibin-A.

Ultrasound: All pregnant women should be offered two ultrasounds: one at 11 to 14 weeks and one at 18 to 22 weeks (RANZCOG Recommendation 11, GRADE: Moderate). NT of greater than 3.5 mm at 11 to 14 weeks should prompt referral and chromosomal microarray (CMA) irrespective of a prior low probability aneuploidy screening result.

Diagnostic testing: A high chance screening result requires diagnostic confirmation before further management decisions. Chorionic villus sampling (CVS) is performed transabdominally or transcervically at 11 to 14 weeks; amniocentesis is performed from 15 weeks. Pregnancy loss risk is not substantially different between the two procedures. CMA is recommended in the presence of any foetal anomaly on ultrasound and offers higher genomic resolution than G-banded karyotype, detecting CNVs less than 3 Mb in size.

5. Management

Management is guided by the nature of the anomaly detected, gestational age, and informed patient preference. The overarching goal per C-Obs 35 is to maximise reproductive autonomy through timely, balanced information and access to appropriate downstream services.

When an anomaly or increased chance screening result is identified, the woman should be offered diagnostic confirmation (CVS or amniocentesis) before management decisions are made (Good Practice Point 4). Referral to a clinician with appropriate expertise in foetal medicine and prenatal diagnosis is recommended when a foetal structural condition is identified on ultrasound (Good Practice Point 11); this may include a maternal-foetal medicine specialist, clinical geneticist, or operator with diagnostic and dating ultrasound (DDU) credentials.

Where a foetal anomaly is confirmed diagnostically, management options include continuation of pregnancy with planned perinatal care, or termination of pregnancy. Termination in the second trimester is associated with greater medical complexity and maternal morbidity than first trimester termination, reinforcing the value of early anomaly detection.

A multidisciplinary team approach is appropriate for complex anomalies, particularly cardiac defects, neural tube defects, skeletal dysplasias, and conditions likely to require neonatal surgical or intensive care. Referral to a tertiary centre should be considered depending on the condition identified.

When a foetal structural anomaly is detected at greater than 20 weeks with a previously low probability NIPT result, specialist referral for detailed assessment and an offer of diagnostic testing with CMA is appropriate.

6. Pharmacology and AU PBS notes

There are no pharmacological treatments that modify the underlying chromosomal or structural anomalies detected through prenatal screening. Pharmacological relevance to this topic is indirect:

Folate supplementation at 400 to 500 micrograms daily starting one month before conception and continuing through the first trimester reduces the risk of neural tube defects by approximately 70%. Women with a prior affected pregnancy or on antiepileptic drugs require high-dose folate (5 mg daily) available as prescription-only tablets. This is not PBS subsidised for standard dose but is available over the counter (e.g. Folinic, Blackmores Folate). There is no PBS streamlined authority code specific to neural tube defect prevention.

RhD immunoglobulin (anti-D; e.g. RhoGAM, Rhophylac) is relevant because invasive diagnostic procedures (CVS, amniocentesis) in RhD-negative women require anti-D prophylaxis to prevent alloimmunisation. Rhophylac 1500 IU is available; dosing follows the RANZCOG and NHMRC anti-D guidelines.

7. Complications and monitoring

Complications of screening and diagnosis: Invasive diagnostic procedures (CVS and amniocentesis) carry a procedure-related pregnancy loss risk that is not substantially different between the two methods (RANZCOG Recommendation 8, GRADE: Low). CVS carries an additional risk of confined placental mosaicism, which may require follow-up amniocentesis to clarify foetal karyotype (Good Practice Point 9). NIPT failure (no call result) occurs in 1 to 6% of tests and is more common with maternal body mass index greater than 30; women with a no call result have a higher baseline rate of foetal abnormality, particularly trisomies 13 and 18, and should be offered detailed ultrasound and the option of repeat NIPT or alternative screening.

False positive screening results create significant parental anxiety and may lead to invasive testing in unaffected pregnancies. Confined placental mosaicism is the most common cause of false positive NIPT.

Psychosocial complications: Receipt of a foetal anomaly diagnosis is associated with post-traumatic stress symptoms and complicated grief, particularly when diagnosis occurs late in the second trimester. Timely psychological support and access to genetic counselling should be arranged.

Surveillance schedule: Women with a structural anomaly identified on foetal ultrasound require serial growth and anatomy surveillance, with frequency determined by the nature of the anomaly and multidisciplinary team recommendations. Conditions with associated growth restriction (e.g. trisomy 18, skeletal dysplasias) require more intensive growth monitoring. Structural cardiac anomalies require foetal echocardiography and neonatology input for delivery planning.

Women with a low probability first trimester screening result but second trimester soft markers should be reviewed for residual aneuploidy risk and offered NIPT (if not yet performed) or amniocentesis per local protocol and individual preference.

Written for Australian practice and grounded in the guidance named above. Study material only — not medical advice. Always check against current guidelines.