What is PAPP-A (Pregnancy Associated Plasma Protein-A)?

Pregnancy-Associated Plasma Protein-A (PAPP-A): Clinical Significance and Applications

PAPP-A is a placental glycoprotein that serves as a key biomarker in first-trimester prenatal screening for chromosomal abnormalities and is associated with adverse pregnancy outcomes when levels are abnormal.

Definition and Biology

PAPP-A (Pregnancy-Associated Plasma Protein-A) is a glycoprotein primarily produced by placental trophoblast cells during pregnancy. It functions as:

• A metalloprotease that regulates insulin-like growth factor (IGF) bioavailability, which is essential for normal fetal development 1
• A protein that increases in maternal circulation throughout pregnancy, with levels rising from implantation until peaking at 8-10 weeks gestation 1
• A component of the maternal serum that can be detected shortly after implantation

Clinical Applications in Prenatal Screening

First Trimester Screening for Chromosomal Abnormalities

PAPP-A is a crucial component of first-trimester screening for fetal aneuploidy:

• Down Syndrome (Trisomy 21): PAPP-A levels are significantly decreased during the first trimester in pregnancies affected by Down syndrome 2

  • Median PAPP-A in Down syndrome pregnancies is approximately 0.30 MoM (multiples of the median) 3
  • When combined with maternal age alone, PAPP-A has a detection rate of 62% for Down syndrome with a 5% false-positive rate 3

• Other Aneuploidies:

  • In Trisomy 18, PAPP-A levels are sharply decreased throughout pregnancy 2
  • In Trisomy 13, PAPP-A levels are also decreased but less dramatically than in Trisomy 18 2

Combined First Trimester Screening

The American College of Medical Genetics recommends first trimester screening that includes:

• Maternal age
• Nuchal translucency (NT) measurement
• PAPP-A
• hCG or free beta-hCG 4

This combination achieves:

• Detection rate of approximately 70% for Down syndrome with a 5% false-positive rate when using NT alone 4
• Detection rate of 85-90% with a 1-2% false-positive rate when using the full integrated test (NT, PAPP-A, and second-trimester markers) 4

Role in Predicting Adverse Pregnancy Outcomes

Low PAPP-A levels in the first trimester are associated with:

• Increased risk of preterm delivery
• Intrauterine growth restriction (IUGR)
• Preeclampsia
• Stillbirth 1

Several national guidelines recognize low PAPP-A as a risk factor for fetal growth restriction:

• UK guidelines define PAPP-A <0.415 MoM as a risk factor
• New Zealand considers PAPP-A <0.2 MoM a major risk factor
• Ireland identifies PAPP-A <0.4 MoM as a risk factor for fetal growth restriction 4

Measurement and Interpretation

• PAPP-A should be expressed as Multiples of Median (MoM) for screening purposes, adjusted for gestational age
• Laboratories should establish their own normative data rather than relying on commercial medians 5
• Accurate gestational dating is critical for proper interpretation:
  • Ultrasound measurement of crown-rump length in the first trimester is preferred over last menstrual period dating 4
  • PAPP-A levels increase rapidly during late first trimester, making accurate dating essential 4

Integrated and Sequential Screening Protocols

Several screening protocols incorporate PAPP-A:

1. Serum Integrated Test (when NT measurement is not available):

   • PAPP-A measured in first trimester
   • Second-trimester markers (AFP, uE3, hCG/free beta-hCG, DIA) added later
   • Detection rate of 89% at 5% false-positive rate 4

2. Full Integrated Test (with NT measurement):

   • Includes NT, PAPP-A, and second-trimester markers
   • Detection rate of 92% at 5% false-positive rate 4

3. Sequential Screening:

   • First-trimester results (including PAPP-A) used to identify high-risk patients
   • Second-trimester testing offered to remaining patients 4

Clinical Considerations and Pitfalls

• PAPP-A measurement is most discriminatory earlier in the first trimester (around 10 weeks) 4

• Laboratory variations exist in PAPP-A assays and reference ranges, which should be considered when interpreting results 5

• PAPP-A levels in maternal serum are affected by:

  • Gestational age (increases with advancing gestation)
  • Maternal weight (decreased in heavier women)
  • Smoking status (decreased in smokers)
  • Diabetes status (decreased in diabetic women)

• Important caveat: While low PAPP-A is associated with adverse pregnancy outcomes, it should be combined with other clinical factors and ultrasound findings for comprehensive risk assessment 4

Conclusion

PAPP-A is a valuable biomarker in first-trimester screening for fetal aneuploidy and adverse pregnancy outcomes. Its measurement, when combined with other markers and ultrasound findings, provides important information for clinical decision-making in prenatal care.