What are the risk factors for having a child with Down syndrome?

Risk Factors for Having a Child with Down Syndrome

Advanced maternal age is the single most important risk factor for having a child with Down syndrome, with risk increasing exponentially after age 35. 1, 2

Primary Risk Factor: Maternal Age

Maternal age represents the dominant risk factor, accounting for the vast majority of Down syndrome cases through sporadic chromosomal nondisjunction during meiosis. 1

• At age 35, the baseline risk is approximately 1 in 380 at term (or 1 in 220 in the first trimester), serving as the traditional threshold for offering diagnostic testing. 1, 2
• The risk increases dramatically with each advancing year beyond age 35, reflecting the age-dependent nature of maternal meiotic errors. 1, 2
• Approximately 95% of Down syndrome cases result from sporadic nondisjunction during parental meiosis, with 95% of these being maternal in origin. 1
• Of maternal nondisjunction events, 77% occur during Meiosis I, making this the critical error point. 1

Secondary Risk Factors

Parental Translocation Carrier Status

When a parent carries a chromosomal translocation involving chromosome 21, the inheritance risk depends on the specific translocation type and which parent is the carrier. 1

• Robertsonian translocations involving chromosome 21 create recurrence risks that vary by sex of the carrier parent (unless it is a 21:21 translocation, which carries nearly 100% risk). 1
• This accounts for approximately 3-4% of Down syndrome cases and represents the only truly heritable form. 1

Advanced Paternal Age (Emerging Evidence)

Advanced paternal age contributes to Down syndrome risk, particularly when combined with maternal age of 35 years or older. 3

• The paternal age effect becomes most pronounced when maternal age is 40 years and older, where the paternal contribution reaches 50%. 3
• No significant paternal age influence is observed until age 35 years and older. 3

Maternal Grandmother's Age (Controversial)

Some evidence suggests that advanced age of the maternal grandmother at the time she gave birth to the mother may increase risk, though this remains less established. 4

• For every year of advancement in maternal grandmother's age, one study reported a 30% increase in odds of Down syndrome in the grandchild. 4
• This effect appears independent of the mother's own age at conception. 4

Important Clinical Considerations

Age Distribution and Screening

Despite higher individual risk in older mothers, the majority of Down syndrome births occur to younger mothers (under age 35) due to higher birth rates in this age group. 5

• In one study, 56% of mothers of Down syndrome children were age 35 or older, but this still means 44% were younger. 5
• This demographic reality underscores why universal screening (not just age-based) is recommended. 1, 2, 6

Fetal Loss Rates

Down syndrome pregnancies have higher spontaneous fetal loss rates that increase with maternal age, affecting risk calculations. 7

• Between CVS and term, the average fetal loss rate is 32%, increasing from 23% at age 25 to 44% at age 45. 7
• Between amniocentesis and term, the average loss rate is 25%, increasing from 19% at age 25 to 33% at age 45. 7
• Approximately 43% of Down syndrome pregnancies are lost between late first trimester and term. 1

Common Pitfalls to Avoid

• Do not assume younger women have negligible risk—while lower than older women, they still account for a substantial proportion of Down syndrome births due to higher overall birth rates. 5
• Do not overlook family history of translocations, as this represents the only truly recurrent risk factor independent of age. 1
• Do not dismiss paternal age, particularly when maternal age is also advanced, as this compounds risk. 3
• Recognize that age 35 functions as a psychological anchor for patients, often overriding actual calculated risk from screening results in decision-making about diagnostic testing. 8