Impact of a detailed ultrasound in pregnancies with high-risk cell-free DNA for common autosomal aneuploidies: a systematic review and meta-analysis.

OBJECTIVES

To systematically evaluate the diagnostic performance of a detailed ultrasound (US) in pregnancies with high-risk cell-free DNA (cfDNA) results for trisomy 21 (T21), trisomy 18 (T18), and trisomy 13 (T13).

METHODS

PubMed, EMBASE, and CINAHL were searched up to April 2025. Singleton pregnancies with high-risk cfDNA for T21, T18, or T13 were included. The index test was a detailed US performed by experienced sonographers, and the reference standard was prenatal or postnatal karyotyping. Risk of bias was assessed using QUADAS-2. Data were extracted into 2 × 2 tables and pooled using a bivariate generalized linear mixed model. Summary receiver operating characteristic (ROC) curves were generated in RevMan5. The protocol was registered with PROSPERO (CRD42024527960).

RESULTS

Eight studies encompassing 858 scans after high-risk cfDNA for T21, T18 and T13 were included. For T21, pooled US sensitivity and specificity were 75.9% (95% CI 64.8-84.4) and 95.1% (95% CI 79.4-98.9; τ2 = 0.146). For T18 and T13, pooled sensitivities were 86.6% (95% CI 76.3-92.8) and 91.4% (95% CI 75.3-97.4), with specificities of 94.5% (95% CI 78.5-98.7) and 92.1% (95% CI 76.8-97.6). Combining US with cfDNA significantly improved the absolute positive predictive value by up to 12% for T21, 40% for T18, and 71% for T13 compared with cfDNA alone. Risk of bias was highest in the index test domain, as operators were typically unblinded to cfDNA results.

CONCLUSIONS

Detailed US shows excellent diagnostic accuracy for T18 and T13 after high-risk cfDNA results, markedly enhancing PPV. Conversely, since the PPV of cfDNA for T21 is already very high, the additive value of US for this condition is more limited although still helpful.