What are the implications and management strategies for a pregnant woman at 12-13 weeks of gestation with a Pregnancy-Associated Plasma Protein-A (PAPP-A) level of less than 0.4 Multiple of Median (MoM)?

PAPP-A <0.4 MoM at 12-13 Weeks: Causes and Clinical Implications

A PAPP-A level below 0.4 MoM at 12-13 weeks indicates increased risk for fetal growth restriction, preeclampsia, preterm delivery, and stillbirth, even in chromosomally normal pregnancies, and warrants enhanced surveillance throughout pregnancy. 1

Primary Causes and Associations

Placental Insufficiency (Most Common)

• Low PAPP-A fundamentally reflects impaired placental function and inadequate trophoblast invasion, which manifests as reduced placental volume and decreased vascularization indices on 3D power Doppler ultrasound. 2
• The placental vascular indices (vascularization index, flow index, and vascularization-flow index) are significantly reduced in pregnancies with PAPP-A <0.4 MoM that subsequently develop severe fetal growth restriction with abnormal umbilical artery Doppler. 2
• This placental dysfunction is detectable at 11-13 weeks, well before clinical manifestations appear later in pregnancy. 2

Chromosomal Abnormalities

• PAPP-A <0.4 MoM is associated with increased risk of trisomy 21,13,18, triploidy, and sex chromosome aneuploidy. 3
• The risk of karyotypic abnormality increases progressively as PAPP-A levels decrease, with the highest risk when PAPP-A is ≤0.1 MoM. 4
• International guidelines recognize PAPP-A <0.4 MoM as a risk factor requiring consideration of diagnostic testing (CVS or amniocentesis). 1

Adverse Pregnancy Outcomes in Chromosomally Normal Fetuses

Fetal Growth Restriction:

• Pregnancies with PAPP-A ≤0.25 MoM have a 3.12-fold increased risk of FGR. 3
• Even with PAPP-A between 0.26-0.50 MoM, the risk of FGR remains elevated at 3.30-fold. 3
• The incidence of growth restriction is double that of the normal population across all PAPP-A levels <0.2 MoM. 4

Preeclampsia:

• PAPP-A ≤0.25 MoM confers a 6.09-fold increased risk of proteinuric pregnancy-induced hypertension. 3
• Low first-trimester PAPP-A is particularly predictive of early-onset preeclampsia (<34 weeks). 5
• PAPP-A should be combined with uterine artery Doppler pulsatility index and maternal risk factors to achieve optimal detection rates for preeclampsia. 5

Preterm Delivery:

• The incidence of prematurity is significantly higher than the statewide average across all PAPP-A levels <0.2 MoM. 4
• Extreme prematurity risk appears directly related to decreasing PAPP-A levels. 4
• PAPP-A <0.5 MoM is a useful indicator for future risk of preterm delivery. 6

Pregnancy Loss:

• PAPP-A ≤0.25 MoM carries an 8.76-fold increased risk of spontaneous miscarriage. 3
• PAPP-A ≤0.50 MoM still confers a 3.78-fold increased risk of spontaneous miscarriage. 3

Stillbirth:

• Low PAPP-A at 11-13 weeks is associated with increased stillbirth risk in chromosomally normal fetuses. 6

Management Algorithm

Immediate Actions at Detection (12-13 Weeks)

Genetic Counseling and Karyotype Assessment:

• Offer genetic counseling and discuss diagnostic testing (CVS or amniocentesis) given the increased risk of chromosomal abnormalities. 1
• Multiple international guidelines (UK, New Zealand, Ireland) recognize PAPP-A <0.4 MoM as a risk factor warranting this discussion. 1

Detailed Fetal Anatomy Survey:

• Perform careful morphological assessment at 18-22 weeks, as low PAPP-A is associated with structural abnormalities. 4

Surveillance Protocol for Chromosomally Normal Pregnancies

Uterine Artery Doppler:

• Perform uterine artery Doppler at 19-24 weeks in all women with PAPP-A <0.4 MoM. 1
• This identifies women at highest risk for early-onset preeclampsia and severe FGR. 1

Serial Growth Monitoring:

• Initiate serial ultrasound for fetal growth assessment starting at 26-28 weeks. 1
• Repeat growth scans every 2-4 weeks depending on findings and additional risk factors. 1
• Monitor for growth velocity reduction (AC or EFW crossing centiles by >30% or >2 quartiles). 1

Umbilical Artery Doppler:

• Begin umbilical artery Doppler surveillance from 26-28 weeks if fetus is small on biometry or shows reduced growth velocity. 1
• Repeat every 2 weeks if normal, at least weekly if abnormal. 1

Aspirin Prophylaxis:

• Consider low-dose aspirin 75-100 mg daily if PAPP-A <0.4 MoM is identified before 16 weeks gestation, particularly if combined with other risk factors for preeclampsia or FGR. 1
• Evidence supports aspirin started ≤16 weeks at doses of 100-160 mg for prevention of early-onset preeclampsia and FGR. 1
• Some guidelines recommend aspirin specifically for women at high risk of growth restriction starting <20 weeks. 1

Prognostic Counseling

Risk Stratification by PAPP-A Level

PAPP-A ≤0.1 MoM (Highest Risk):

• Even with normal karyotype, expect a "good" outcome in only 60% of cases and "normal" outcome in 30%. 4
• Highest risk for extreme prematurity and severe adverse outcomes. 4

PAPP-A 0.11-0.2 MoM (Intermediate Risk):

• "Good" outcome expected in at least 60% and "normal" outcome in at least 30%, with percentages increasing as PAPP-A rises. 4

PAPP-A 0.2-0.4 MoM (Lower Risk):

• Better prognosis than lower levels, but still warrants enhanced surveillance. 1

Critical Counseling Points

• Reassure patients that even with PAPP-A <0.1 MoM and normal karyotype, the majority (60%) will have good outcomes. 4
• Low PAPP-A has poor positive predictive value—most pregnancies will not develop complications despite the increased risk. 6
• The severity of placental vascular dysfunction (measured by 3D Doppler indices) correlates with adverse outcomes more strongly than the absolute PAPP-A level. 2
• Enhanced surveillance allows early detection and timely intervention for complications, potentially improving outcomes. 1

Common Pitfalls to Avoid

• Do not dismiss PAPP-A <0.4 MoM as clinically insignificant after normal karyotype—the association with placental insufficiency and adverse outcomes persists regardless of fetal chromosomes. 6, 4, 3
• Do not delay aspirin initiation—prophylaxis is most effective when started before 16 weeks. 1
• Do not rely solely on fundal height measurements—serial ultrasound is essential for detecting growth restriction in high-risk pregnancies. 1
• Do not wait for clinical symptoms before initiating surveillance—placental dysfunction is present from the first trimester and requires proactive monitoring. 2