PAPP-A

Medical analysis

PAPP-A

Pregnancy-Associated Plasma Protein A

By: Dr. Dipak Ladda, M.D. Pregnancy hormone module documentation.

Introduction

Pregnancy-associated plasma protein A (PAPP-A) is a key regulator of insulin-like growth factor bioavailability essential for normal fetal development. Structurally, it is a large glycoprotein, produced by placental trophoblasts and found in maternal serum. This protein is most important in first trimester screening. In maternal blood, this protein increases with gestational age and then rapidly decreases after delivery, reflecting its strict dependency on active placental tissue.

It serves as one of two biochemical markers in double marker testing; which are used for the comprehensive risk calculation of chromosomal aneuploidies. The screening relies heavily on the co-evaluation of PAPP-A and free β-hCG. Decreased levels of PAPP-A before the 14th week of gestation are associated with an increased risk for Down syndrome or Trisomy 21, trisomy 18, and trisomy 13; which cause severe mental and physical challenges in the baby. While decreased PAPP-A points toward these genetic anomalies, increased levels of hCG always remains associated with an increased risk of Down syndrome, providing an effective reciprocal biochemical pattern for modern clinical prenatal diagnostics.

FUNCTIONS OF PAPP-A

Biochemically, there are two pregnancy associated plasma proteins discovered, designated as A & B. PAPP-A is a highly specialized metalloproteinase enzyme. It carries robust proteolytic activity, so it functions in the insulin-like growth factor system; by which it directly governs placental formation and regulation of fetal growth. PAPP-A has the distinct biological ability to cleave IGFBP-4, IGFBP-2, and IGFBP-5 and exerts its proteolytic properties primarily at the cellular level, i.e. close to the IGF-1 receptor. Meanwhile, its structural relative PAPP-A2 cleaves IGFBP-3 and -5, thereby releasing IGF-1 from its ternary complex with IGFBP-3 or -5 and ALS (acid-labile subunit). This coordinated enzymatic cascade ensures that free insulin-like growth factors are released at the cellular level to trigger the growth and proliferative pathways necessary for embryonic and placental expansion.

Pathophysiology

The physiological balance of this pregnancy-associated plasma protein A (PAPP-A) is fundamental for a healthy gestation lifecycle. Low levels of PAPP-A possibly remains responsible for abnormal placentation, which is a critical pathogenic concern for the development of preeclampsia during late gestation. Abnormal levels are strongly associated with an increased risk for chromosome abnormality, making it a reliable early metabolic indicator. Low maternal serum PAPP-A levels in the first trimester are explicitly associated with poor fetal growth and development of pregnancy-induced hypertension, preeclampsia, and stillbirth. Clinical research shows that very low PAPP-A levels are frequently related to adverse pregnancy outcome, reflecting underlying placental insufficiency or defective trophoblastic invasion.

PAPP-A test

The PAPP-A test is a specialized diagnostic assay that detects proteins produced by placenta in early pregnancy; necessary for normal fetal growth and placental placement. By quantifying this circulating glycoprotein, clinicians can gain insight into the functional performance of the trophoblasts, sharing responsibility of well being of fetus. Interestingly, this enzyme is also useful with applications in many areas in cardiology, acting as an electronic marker of cardiovascular plaque structural breakdown.

Indications

The PAPP-A assay is primarily performed as part of a comprehensive prenatal evaluation. It is a part of Dual Marker Study; which is usually performed between the 8th and 14th weeks of pregnancy as part of a full-fledged screening panel. The blood sample for this test is collected between the 11th and 13th week, which is the ideal time for combined risk assessment when synchronized with fetal ultrasound findings.

METHODS OF ESTIMATION

Laboratory medicine utilizes highly precise biochemical techniques to quantify maternal serum PAPP-A. The standard methods of estimation include:

• 01. Enzyme-linked immunosorbent assay (ELISA) for manual or semi-automated detection.

• 02. Automated serum analyzers capable of high-throughput clinical processing.

• 03. Chemiluminescent immunoassay (CLIA), providing superior analytical sensitivity and accuracy.

• 04. Part of first trimester dual screening panel integrations where risk estimation algorithms are utilized.

BEFORE SAMPLE COLLECTION

Medication Consultation: It is critical that patients consult with their Gynecologist for medications which may affect the PAPP A level before blood sample collection; which you may need to discontinue to prevent analytical interference.

No Other Preparation: There is no other preparation required, meaning fasting is not mandatory.

Sample collection

Sample: Blood sample extraction follows routine phlebotomy guidelines. Collect 3.0 ml blood in plain tube (Red capped). Separate serum as early as possible & send it to lab immediately to ensure protein stability.

Additional information what Lab needs?

To execute the screening algorithm, the laboratory requires extensive maternal metadata. This includes the patient’s date of birth, current weight, number of fetuses present, H/O diabetes, if there is a known family history of neural tube defects, if the patient has had a previous pregnancy with a trisomy, if the patient is currently smoking, if the patient is taking valproic acid or carbamazepine (Tegretol), if this is a repeat sample, and the age of the egg donor if in vitro fertilization (IVF) was utilized.

Furthermore, the lab requires a recently done ultrasound with authentic and qualified Radiologist; along with hard copy of report which must clearly state the date of ultrasound, the CRL (crown-rump length) measurement, and the nuchal translucency (NT) measurement. The NT must be measured when the CRL is between 38-83.9 mm. In case if NT measurement is not performed before sample collection; a due date or CRL measurement with the date of ultrasound is required.

Normal Reference Range – PAPP A

Clinical Significance – Pregnancy

PAPP-A serves as a major biomarker (Screening) for fetal and maternal health in the first trimester of pregnancy. When it is measured with β-hCG & NT scan, it achieves an excellent sensitivity pattern. Monitoring PAPP-A levels in conjunction with other markers helps identify high-risk pregnancies, allowing for increased surveillance and personalized care.

High PAPP A Levels

Low PAPP A Levels

Clinical Utility

The clinical utility of measuring PAPP-A is concentrated into three primary domains of prenatal medicine:

1. Aneuploidy screening: Calculating patient-specific risks for autosomal trisomies.

2. Pre-eclampsia prediction: Determining vascular health and hypertensive risk indices early.

3. Intrauterine growth restriction (IUGR): Identifying fetuses at risk of chronic nutrient and oxygen deprivation due to poor placental efficiency.

Clinical Significance – Cardiology

Beyond fetal health, elevated PAPP-A serves as a critical biomarker of plaque instability and a reliable marker of atherosclerosis progression. In non-pregnant cohorts, it stands as a strong predictor of adverse cardiovascular events and all-cause mortality, functioning as an objective marker of disease progression and extent. It is currently being explored extensively as a potential therapeutic target and risk stratification tool in patients presenting with stable and acute coronary heart disease, where vascular inflammation upregulates its synthesis.

LIMITATIONS

Every screening algorithm possesses mathematical boundaries. If the screening marker value is greater (or lesser) than the specified upper (or lower) truncation limit, the limit is used in risk estimation to prevent extreme statistical distortion. In antenatal screening for trisomy 18, lower truncation limits of 0.15 and 0.30 multiples of the median (MoM) for PAPP-A and free β-hCG are currently in use. This may vary in some patients and affect the interpretation sometimes, requiring careful clinical correlation by specialized genetic counselors.

References:

• Smith, G. C., Stenhouse, E. J., Crossley, J. A., Aitken, D. A., Cameron, A. D., & Connor, J. M. (2002). Early pregnancy levels of pregnancy-associated plasma protein A and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth. The Journal of Clinical Endocrinology & Metabolism, 87(4), 1762-1767.
• Malone, F. D., Canick, J. A., Nyberg, D. A., Comstock, C. H., Bukowski, R., Berkowitz, R. L., … & D’Alton, M. E. (2005). First-trimester or second-trimester screening, or both, for Down’s syndrome. New England Journal of Medicine, 353(19), 2001-2011.
• Bayes-Genis, A., Conover, C. A., Overgaard, M. T., Bailey, K. R., Boerwinkle, E., Camoreau, J. J., … & Schwartz, R. S. (2001). Pregnancy-associated plasma protein A as a marker of acute coronary syndromes. New England Journal of Medicine, 345(14), 1022-1029.
• Conover, C. A. (2012). Key roles for pregnancy-associated plasma protein-A in insulin-like growth factor action. Endocrine Reviews, 33(4), 665-687.
• Wald, N. J., Rodeck, C., Hackshaw, A. K., Walters, J., Chitty, L., & Mackinson, A. M. (2003). First and second trimester antenatal screening for Down’s syndrome: the Results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Journal of Medical Screening, 10(2), 56-104.
• Overgaard, M. T., Haaning, J., Boldt, H. B., Olsen, I. M., Laursen, L. S., Oxvig, C., & Conover, C. A. (2001). Expression of recombinant human pregnancy-associated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor. Journal of Biological Chemistry, 276(24), 21849-21853.
• Spencer, K., Cowans, N. J., Chefetz, I., Tal, J., & Meiri, H. (2007). First-trimester uterine artery Doppler and PP13, PAPP-A, and fβ-hCG in the screening for pre-eclampsia. Prenatal Diagnosis: Published in Affiliation with the International Society for Prenatal Diagnosis, 27(3), 258-263.
• Coskun, A., Erbagci, A. B., & Mumbuc, S. (2005). Assay methods for pregnancy-associated plasma protein-A (PAPP-A) in clinical diagnostics. Journal of Immunoassay and Immunochemistry, 26(3), 211-224.
• Heeschen, C., Dimmeler, S., Hamm, C. W., Fichtlscherer, S., Boersma, E., Simoons, M. L., & Zeiher, A. M. (2005). Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes: comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis. Journal of the American College of Cardiology, 45(1), 22-29.
• Kagan, K. O., Wright, D., Baker, A., Sahota, D., & Nicolaides, K. H. (2008). Screening for trisomy 21 by maternal age, fetal nuchal translucency, pregnancy-associated plasma protein-A and free β-human chorionic gonadotropin at 11–13 weeks. Ultrasound in Obstetrics & Gynecology, 31(6), 618-624.
• Lawrence, J. B., Oxvig, C., Overgaard, M. T., Sottrup-Jensen, L., Gleich, G. J., Hays, L. G., … & Conover, C. A. (1999). The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proceedings of the National Academy of Sciences, 96(6), 3149-3153.
• Nicolaides, K. H. (2011). Screening for fetal aneuploidies at 11 to 13 weeks. Prenatal Diagnosis, 31(1), 7-15.
• Poon, L. C., Maiz, N., Valencia, C., Syngelaki, A., & Nicolaides, K. H. (2009). First-trimester prediction of hypertensive disorders in pregnancy. Hypertension, 53(5), 812-818.
• Goetzl, L., Krantz, D. A., Simpson, J. L., Silver, R. K., Zachary, J. M., Fernandez, P., … & First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study Group. (2004). First-trimester screening for Down syndrome: underlying assumptions and performance within a heterogeneous clinical population. American Journal of Obstetrics and Genetics, 191(1), 359-365.
• Iversen, K. K., Teisner, B., Dalsgaard, M., Nielsen, H., Hansen, S., Kliem, A., … & Clemmensen, O. (2008). Pregnancy-associated plasma protein-A (PAPP-A) as a marker of plaque instability in patients with stable coronary artery disease. Coronary Artery Disease, 19(4), 245-251.

FAQ:

• What is PAPP-A structurally? It is a large glycoprotein produced by placental trophoblasts and found in maternal serum.
• What does PAPP-A regulate? It regulates insulin-like growth factor bioavailability essential for normal fetal development.
• Which test uses PAPP-A? It is a vital component of first trimester dual marker screening panels.
• What do low levels indicate? They indicate increased risk for Down syndrome, trisomy 18, and trisomy 13.
• What enzyme category is PAPP-A? It is a metalloproteinase enzyme carrying specific proteolytic activity.
• What does PAPP-A specifically cleave? It cleaves IGFBP-4, IGFBP-2, and IGFBP-5 at the cellular level.
• Can low levels cause preeclampsia? Yes, low levels can lead to abnormal placentation and late-gestation preeclampsia.
• What does the test detect? It detects placental proteins necessary for normal fetal growth and placement.
• When is blood sample collected? Ideally, the blood sample is collected between weeks 11 and 13.
• What is its role in cardiology? Elevated PAPP-A serves as a biomarker for atherosclerosis progression and plaque instability.

For Non-Medicos:

Overview

Pregnancy-associated plasma protein A, commonly known as PAPP-A, is a large glycoprotein produced by placental trophoblasts and released into maternal serum during pregnancy. It is most important in first-trimester screening and plays a key role in regulating insulin-like growth factor bioavailability, which is essential for normal placental development and fetal growth. PAPP-A levels normally increase with advancing gestational age and fall rapidly after delivery. It is one of the two markers used in the dual marker test, along with free beta hCG, for early risk assessment of chromosomal abnormalities and pregnancy-related complications.

Symptoms

PAPP-A itself does not produce direct symptoms, but abnormal levels are associated with clinical outcomes affecting the mother and fetus. Low PAPP-A levels in early pregnancy are linked with poor fetal growth, pregnancy-induced hypertension, preeclampsia, preterm delivery, intrauterine growth restriction, and stillbirth. Very low levels are frequently associated with adverse pregnancy outcomes. Abnormal PAPP-A levels may also indicate an increased risk of chromosomal abnormalities such as Down syndrome, trisomy 18, and trisomy 13.

Causes

Low PAPP-A levels are caused by abnormal placentation and impaired trophoblast invasion in early pregnancy. Reduced proteolytic activity of PAPP-A affects the insulin-like growth factor system, leading to impaired placental development and fetal growth restriction. Low levels are strongly associated with chromosomal abnormalities and pregnancy-related hypertensive disorders. Elevated PAPP-A levels may occur in normal pregnancies with healthy placental function, while increased levels outside pregnancy are associated with atherosclerosis, plaque instability, and acute coronary syndromes.

Risk Factors

Risk factors for abnormal PAPP-A levels include chromosomal abnormalities, placental dysfunction, and a history of adverse pregnancy outcomes. Pregnant women with a history of preeclampsia, intrauterine growth restriction, or stillbirth are at higher risk of low PAPP-A levels. Advanced maternal age, underlying vascular disease, and metabolic disorders may also influence PAPP-A levels. Inaccurate gestational dating or a lack of proper ultrasound correlation can affect interpretation.

Prevention

Prevention focuses on early screening and close monitoring rather than direct prevention of abnormal PAPP-A levels. Performing the dual marker test within the recommended gestational window allows early identification of high-risk pregnancies. Combining PAPP-A results with free beta hCG levels and nuchal translucency measurement improves risk assessment accuracy. Pregnancies identified as high risk require increased surveillance, timely intervention, and individualized prenatal care to reduce complications and improve maternal and fetal outcomes.