Do high human chorionic gonadotropin (hCG) readings indicate trisomy?

High hCG and Trisomy: Understanding the Association

Elevated hCG levels are associated with trisomy 21 (Down syndrome), not with trisomy 18 or trisomy 13, which typically show low hCG levels. The pattern of hCG elevation or reduction depends entirely on which trisomy is present, making it a useful but non-specific screening marker that must be interpreted in context with other biochemical markers and ultrasound findings 1, 2.

Biochemical Marker Patterns by Trisomy Type

Trisomy 21 (Down Syndrome)

• hCG is typically elevated (higher than normal) in Down syndrome pregnancies, making it one of the key screening markers 1, 2
• Free beta-hCG performs better than intact hCG for first-trimester screening, particularly at 11-12 weeks gestation 1, 3
• The elevation of hCG in Down syndrome is part of a characteristic pattern that also includes low AFP and low unconjugated estriol (uE3) 2, 4
• Elevated hCG combined with other markers achieves detection rates of 75-80% for Down syndrome in second-trimester screening 2, 4

Trisomy 18 (Edwards Syndrome)

• hCG is typically low (reduced) in trisomy 18, which is the opposite pattern from Down syndrome 1, 5
• Mean hCG in trisomy 18 pregnancies is approximately 0.62 multiples of the median (MoM), with median values around 0.5 MoM 5
• The ratio of free beta-hCG to alpha-hCG is markedly reduced, with values less than 0.25 MoM in 75% of trisomy 18 cases 6
• Using combined low hCG and low unconjugated estriol (both below 0.70 MoM) can detect 79% of trisomy 18 cases with a 3% false-positive rate 5
• First-trimester screening using NT, PAPP-A, and hCG can detect 75-80% of trisomy 18 fetuses at a 1% false-positive rate 1

Trisomy 13 (Patau Syndrome)

• Biochemical marker patterns in trisomy 13 are less well-characterized than for trisomy 21 or 18 1
• The clinical utility of biochemical screening for trisomy 13 is less certain compared to other trisomies 1

Clinical Interpretation Algorithm

Step 1: Determine Which Trisomy Pattern Is Present

• If hCG is elevated (>1.5 MoM): Consider trisomy 21 as the primary concern 2, 7
• If hCG is reduced (<0.7 MoM): Consider trisomy 18 as the primary concern 5
• If hCG is markedly elevated (≥10 MoM): This occurs in only 0.05% of pregnancies and is associated with a 51% rate of pregnancy complications, including 66% fetal disease (which includes chromosomal abnormalities), 16% maternal disease, and 3.5% placental anomalies 8

Step 2: Evaluate Other Biochemical Markers

• For suspected trisomy 21: Look for elevated hCG combined with low AFP and low uE3 2, 4
• For suspected trisomy 18: Look for low hCG combined with low uE3 and low PAPP-A 5, 1
• In trisomy 21 screening, 85% of cases show elevated free β-hCG (>1.5 MoM), but only 53% show low PAPP-A (<0.5 MoM), indicating these are independent markers 7

Step 3: Incorporate Ultrasound Findings

• Nuchal translucency (NT) measurement is essential and should not be omitted, as biochemical markers alone are insufficient 7
• In trisomy 21, only 44% of fetuses with elevated β-hCG and 26.5% with low PAPP-A show increased NT, demonstrating that ultrasound and biochemical testing are independent factors 7
• The combination of NT with PAPP-A and free beta-hCG increases detection rates by approximately 20-25% compared to NT alone 3

Step 4: Calculate Combined Risk

• First-trimester combined screening (NT + PAPP-A + free β-hCG) achieves detection rates of 83-86% for Down syndrome at a 5% false-positive rate 3
• Second-trimester quad screen detects approximately 75% of Down syndrome in women under 35 and over 80% in women 35 and older 2, 4

Critical Clinical Pitfalls to Avoid

Misinterpretation of Isolated Elevated hCG

• Isolated elevation of hCG (without other abnormal markers) does not confer increased risk of structural fetal anomalies beyond chromosomal abnormalities 9
• However, elevated hCG combined with ultrasound "soft markers" for aneuploidy is associated with high incidence of chromosomal anomalies, even when the calculated Down syndrome risk appears low 9
• In one study, 6 chromosomal anomalies (4 Down syndrome, 2 Turner syndrome) were found among patients with elevated hCG and major malformations on ultrasound, despite normal triple screen risk estimates 9

Failing to Recognize Pattern Differences

• The most common error is assuming all trisomies show the same hCG pattern—trisomy 21 shows high hCG while trisomy 18 shows low hCG 1, 5
• In trisomy 21, characteristic correlation with all first-trimester screening parameters occurs in only 23.5% of cases, with 53% showing atypical results 7

Inadequate Follow-Up for Very High hCG

• When hCG is ≥10 MoM, comprehensive evaluation is mandatory as 51% will have pregnancy complications 8
• This includes detailed ultrasound for fetal anomalies, maternal evaluation for gestational trophoblastic disease, and placental assessment 8

Definitive Diagnosis Recommendations

• Screening tests (including hCG) only provide risk assessment, not diagnosis—only diagnostic testing (CVS or amniocentesis) provides definitive results 1, 4
• Women 35 and older should be counseled about the option of diagnostic testing rather than screening alone, as detection rates exceed 80% but false positives still occur 3
• If first-trimester combined screening shows high risk, CVS can be offered immediately (at 10-13 weeks) rather than waiting for second-trimester amniocentesis (at 15-20 weeks) 3