What is the significance of pregnancy‑associated plasma protein A (PAPP‑A) levels in the first‑trimester dual‑marker screen and what are the normal reference ranges?

Significance and Normal Values of PAPP-A in First-Trimester Dual-Marker Screening

PAPP-A (pregnancy-associated plasma protein A) is a critical first-trimester biochemical marker that, when combined with free β-hCG and nuchal translucency measurement between 11–13+6 weeks gestation, achieves 85–92% detection of Down syndrome with a 5% false-positive rate—substantially outperforming maternal age alone or second-trimester screening. 1, 2

Core Clinical Significance

Role in Aneuploidy Screening

• PAPP-A concentrations are typically reduced (median 0.30–0.44 MoM) in pregnancies affected by Down syndrome, making it the most discriminatory biochemical marker in the first trimester. 1, 3, 4
• The dual-marker test combines PAPP-A with either free β-hCG (preferred at 11 weeks) or intact hCG (preferred at 13 weeks), along with maternal age and nuchal translucency measurement. 5, 1
• When PAPP-A is combined with free β-hCG and NT measurement, the detection rate for trisomy 21 increases from approximately 70% (NT alone) to 85–92%, demonstrating the critical additive value of biochemical markers. 1, 2, 3

Biochemical Characteristics

• PAPP-A is a large glycoprotein (approximately 500 kDa) produced by the placenta and exists in maternal circulation primarily as a 2:2 complex with the proform of eosinophil major basic protein (proMBP). 6, 4
• It functions as a metalloproteinase in the insulin-like growth factor system, playing a crucial role in placental formation and fetal growth regulation. 6
• Maternal serum PAPP-A concentrations increase progressively throughout pregnancy by a factor of approximately 150 compared to the non-pregnant state, with the highest levels occurring in peripheral maternal circulation. 4

Normal Reference Ranges and Interpretation

Gestational Age-Specific Values

• PAPP-A levels are reported as multiples of the median (MoM) for gestational age, with normal pregnancies typically ranging from 0.4–2.5 MoM between 11–13+6 weeks. 1, 3
• The median PAPP-A MoM in Down syndrome pregnancies is approximately 0.30 (quartile range 0.17–0.54), representing a significant reduction compared to unaffected pregnancies. 3
• PAPP-A logMoMs in Down syndrome pregnancies follow a normal distribution with a mean of approximately -0.59 and standard deviation of 0.36, allowing for statistical risk calculation. 3

Assay Considerations

• Modern PAPP-A assays use sandwich enzyme immunoassay techniques with polyclonal and monoclonal antibodies, achieving assay ranges of 2–500 mIU/L with intra- and inter-assay coefficients of variation <10%. 3
• The choice between free β-hCG and intact hCG depends on gestational age: free β-hCG performs 2–3% better at 11 weeks, while intact hCG may perform 1–2% better at 13 weeks. 5

Beyond Aneuploidy: Additional Clinical Significance

Adverse Pregnancy Outcomes

• Low first-trimester PAPP-A levels (<0.4 MoM) are associated with increased risk of preeclampsia, fetal growth restriction, preterm delivery, and stillbirth, even when fetal karyotype is normal. 6, 7, 4
• In pregnancies resulting in preeclampsia, median PAPP-A is significantly lower (0.844 MoM) than in normal outcomes, and when combined with second-trimester uterine artery Doppler, detection rates for preeclampsia reach 62% at a 5% false-positive rate. 7
• For fetal growth restriction, median first-trimester PAPP-A is reduced to 0.813 MoM, providing early risk stratification. 7

Screening Performance Metrics

• Using PAPP-A and maternal age alone for Down syndrome screening achieves a 62% detection rate at a 5% screen-positive rate, but this increases to 90% when combined with free β-hCG and nuchal translucency. 3
• Low PAPP-A levels are found not only in trisomy 21 but also in other fetal aneuploidies including trisomy 18 and trisomy 13. 1, 4

Critical Implementation Requirements

Quality Assurance

• All pregnant women, regardless of maternal age, should be offered first-trimester combined screening between 11 weeks 0 days and 13 weeks 6 days. 1, 2
• Nuchal translucency measurement requires rigorous operator training and certification due to significant inter- and intra-observer variability; programs without established quality assurance should not offer NT screening. 1, 2
• Laboratories must provide educational materials about test performance, interpretation, and the availability of invasive diagnostic testing (CVS or amniocentesis) regardless of screening results. 5, 1

Common Pitfalls to Avoid

• Never rely on PAPP-A measurement alone without combining it with free β-hCG/hCG and nuchal translucency, as this reduces detection rates from 85–92% to approximately 62%. 1, 3
• Failing to offer second-trimester maternal serum alpha-fetoprotein (MSAFP) screening after first-trimester combined screening leaves neural tube defects undetected, as PAPP-A does not screen for these conditions. 1, 2
• Do not use predetermined age-based cutoffs for offering invasive testing; all patients with elevated risk should be offered diagnostic testing regardless of maternal age. 1, 2
• Gestational age must be accurately established by crown-rump length (45–84 mm) before interpreting PAPP-A values, as incorrect dating significantly affects MoM calculations. 2

Special Populations

• In twin pregnancies, combined ultrasound and serum screening (including PAPP-A) is less sensitive than in singleton pregnancies because serum marker concentrations represent an average of both fetuses, resulting in higher false-positive rates. 1, 2
• Patients who decline information about fetal chromosomal status may opt out after appropriate documentation, but should still be counseled about the association between low PAPP-A and adverse pregnancy outcomes. 1, 2