What is the recurrence risk of Down syndrome in a woman of childbearing age with a previous child diagnosed with Down syndrome?

Recurrence Risk of Down Syndrome in Subsequent Pregnancy

The recurrence risk after one child with Down syndrome is approximately 1% above the baseline maternal age-related risk, with this excess risk being higher for younger women (0.62% excess at age 20) compared to older women (0.04% excess at age 40). 1

Understanding the Baseline Risk

The recurrence risk depends critically on the type of chromosomal abnormality in the previous child:

Free Trisomy 21 (95% of cases)

• Women with a previous Down syndrome pregnancy have a constant absolute excess risk above their age-related baseline risk 1
• This excess risk is age-dependent at the time of the affected pregnancy:
  • After an affected pregnancy at age 20: 0.62% excess risk (95% CI: 0.24-1.15%) 1
  • After an affected pregnancy at age 40: 0.04% excess risk (95% CI: 0.01-0.07%) 1
• The traditional counseling figure of "approximately 1% recurrence risk" represents an average across all maternal ages 2

Inherited Translocation (3-4% of cases)

• For mothers under 30 with inherited translocation: approximately 0.3% recurrence risk 3
• For mothers 30 and over with inherited translocation: approximately 0.05% recurrence risk 3
• De novo (21;21) translocation carries minimal recurrence risk unless parental gonadal mosaicism is present 2

Critical Caveat: Parental Mosaicism

After two pregnancies with trisomy 21, thorough cytogenetic study of both parents is mandatory to detect gonadal mosaicism, which dramatically elevates recurrence risk 2:

• In one documented case series, mosaicism was detected in 47% of ovarian cells in a parent with multiple affected pregnancies 2
• Gonadal mosaicism can occur even when peripheral blood lymphocytes and fibroblasts appear normal 2
• After two affected pregnancies, the probability of parental mosaicism increases substantially, warranting investigation of lymphocytes, fibroblasts, and potentially gonadal tissue 2

Genetic Counseling Imperatives

Immediate genetic counseling is essential and should address 4:

• 50% recurrence risk if the mother herself has 22q11.2 deletion syndrome (though this applies to that specific condition, the principle of determining parental karyotype applies to Down syndrome) 4
• Family history assessment: Multiple affected family members suggest possible familial translocation requiring urgent evaluation 5, 6
• Unpredictable intrafamilial variability in phenotypic expression 4
• Karyotype analysis of the previous affected child (if not already performed) to distinguish free trisomy from translocation 6
• Parental karyotyping is indicated after two affected pregnancies to detect mosaicism or balanced translocations 2

Prenatal Testing Options for Subsequent Pregnancy

Diagnostic testing should be strongly considered rather than screening alone given the elevated baseline risk 5:

First Trimester (10-13 weeks)

• Chorionic villus sampling (CVS) for chromosomal microarray or karyotype 4, 5
• Combined with nuchal translucency measurement if desired 4

Second Trimester (≥15 weeks)

• Amniocentesis remains the gold standard for diagnostic confirmation 5, 7
• Carries approximately 1 in 300-600 risk of pregnancy loss 7

Emerging Technology

• Noninvasive prenatal testing (NIPT) is available but represents screening, not diagnosis 4
• Given elevated recurrence risk, diagnostic testing provides definitive answers 5

Screening Marker Correlations Between Pregnancies

Women at increased screening risk in one pregnancy are 2-3 times more likely to have increased risk in subsequent pregnancies due to biological variability 8:

• Maternal serum free β-hCG shows significant correlation between pregnancies (r = 0.3976, p < 0.001) 8
• PAPP-A demonstrates even stronger correlation (r = 0.4371, p < 0.001) 8
• Fetal nuchal translucency shows no correlation between pregnancies (r = 0.0959, p > 0.10) 8

This information is relevant when counseling about screening results in subsequent pregnancies, as persistently abnormal biochemical markers may reflect maternal physiology rather than fetal aneuploidy 8.

Risk Calculation Algorithm

To calculate patient-specific recurrence risk:

1. Determine current maternal age in decimal years 4
2. Add the age-related baseline risk (e.g., 1:380 at age 35) 4
3. Add the absolute excess risk based on maternal age at previous affected pregnancy 1
4. Multiply by 50 if parental translocation carrier (for robertsonian translocations involving chromosome 21) 4
5. Consider substantially elevated risk if two previous affected pregnancies warrant parental karyotyping 2

Common Pitfalls to Avoid

• Do not assume 1% applies universally: The excess risk varies significantly by maternal age at the time of the previous affected pregnancy 1
• Do not overlook translocation screening: Karyotype the previous affected child if not already done 6, 3
• Do not dismiss family history: Multiple affected relatives suggest familial translocation requiring immediate genetic evaluation 5, 6
• Do not rely on screening alone: Given elevated baseline risk, diagnostic testing provides definitive answers 5
• Do not forget to investigate after two affected pregnancies: This mandates thorough parental cytogenetic evaluation including potential gonadal tissue assessment 2