PAPP-A, or pregnancy-associated plasma protein-A, is a blood marker measured during first-trimester screening, and your result is reported as a “multiple of the median” (MoM) that compares your level to what is typical for your stage of pregnancy. A low PAPP-A, generally below 0.4 MoM, flags a higher chance of certain complications including poor fetal growth, preeclampsia, and preterm birth, while also feeding into the risk calculation for chromosomal conditions like Down syndrome. But a flagged result is not a diagnosis of anything. Most pregnancies with low PAPP-A still end well, and the number is far more useful as a trigger for closer monitoring than as a prediction of what will happen.
What PAPP-A Actually Does
PAPP-A is a metalloproteinase, an enzyme that clips specific proteins in its immediate surroundings. During pregnancy the placenta produces it in large quantities, but it is not unique to pregnancy; many cell types throughout the body make it. Its main job is regulating local insulin-like growth factor (IGF) activity by cutting apart IGF binding proteins, especially one called IGFBP-4. When PAPP-A clips that binding protein, the growth factor is freed up to dock with nearby receptors and promote cell growth and nutrient transfer.1Endocrine Reviews. The Pregnancy-Associated Plasma Protein-A (PAPP-A) Story In practical terms, PAPP-A helps ensure that the placenta develops a robust blood supply and that nutrients flow efficiently to the fetus. When less of it circulates, placental function may be compromised, which is why low levels in the first trimester can foreshadow problems later.
How Results Are Reported
Raw PAPP-A concentrations in your blood change rapidly week by week, so labs do not hand you a number in mU/L and leave you to interpret it. Instead, they convert your result into a “multiple of the median,” or MoM. The median is the midpoint value for all pregnancies at your exact gestational age. A MoM of 1.0 means your level sits right at the average. A MoM of 0.5 means your level is half the average; 2.0 means double.
This conversion matters because raw concentrations climb steeply through the first trimester. Between 11 and 12 weeks, typical levels run roughly 943 to 1,455 mU/L; from 12 to 13 weeks they jump to about 1,455 to 2,243 mU/L; and after 13 weeks they climb higher still.2Journal of Nursing Reports in Clinical Practice. The first-trimester screening to detect chromosomal abnormalities in pregnant women: A retrospective study Without the MoM adjustment, a perfectly normal level at 11 weeks would look alarmingly low compared to the average at 13 weeks. The MoM system also allows labs to correct for factors like maternal weight, which affects how diluted the protein is in your bloodstream. Weight correction alone can shift the population false-positive rate from about 7% down to 6.5% without sacrificing detection.3PubMed. Maternal weight correction of maternal serum PAPP-A and free beta-hCG MoM when screening for trisomy 21 in the first trimester of pregnancy
Where PAPP-A Fits in First-Trimester Screening
Your PAPP-A result is one piece of a package known as the combined first-trimester screen, which also includes a second blood marker (free beta-hCG), an ultrasound measurement of the fluid at the back of the baby’s neck (nuchal translucency), and your age. Together, these inputs generate a risk score for chromosomal conditions, primarily trisomy 21 (Down syndrome). None of them work well in isolation. Nuchal translucency plus age alone detects about 71% of Down syndrome pregnancies at a 5% false-positive rate, but adding PAPP-A and free beta-hCG pushes detection to roughly 87%.4Cochrane Database of Systematic Reviews. First trimester ultrasound alone or in combination with first trimester serum tests for the prediction of Down syndrome Other studies put the combined detection rate in the range of 83 to 90%, depending on gestational timing and the specific markers used.5Obstetrics & Gynecology. Comparison of Serum Markers in First-Trimester Down Syndrome Screening6PubMed Central. A prospective two years study of first trimester screening for Down syndrome
In a pregnancy affected by trisomy 21, PAPP-A tends to be lower than expected while free beta-hCG tends to be higher. The screening algorithm weighs both markers alongside the ultrasound and maternal age to spit out a probability, such as “1 in 1,500” or “1 in 150.” It is that composite probability, not any single marker, that determines whether you are offered further testing like cell-free DNA screening or amniocentesis.
What Counts as Low PAPP-A
There is no universal cutoff carved in stone. Most guidelines and studies define “low” as a MoM below 0.4, which corresponds roughly to the 5th percentile.7PubMed Central. Importance of Low Pregnancy Associated Plasma Protein-A (PAPP-A) Levels During the First Trimester as a Predicting Factor for Adverse Pregnancy Outcomes: A Prospective Cohort Study of 2636 Pregnant Women8European Journal of Medical and Health Sciences. Association of First-Trimester Low PAPP-A Levels (0.2 MoM) with Maternal and Fetal Outcomes Some centers use 0.5 MoM as their threshold and follow those patients more closely through delivery.9PubMed Central. Variation of Papp-A Level in the First Trimester of Pregnancy and Its Clinical Outcome About 5% of pregnancies fall into the low category at any given cutoff, which means it is uncommon but far from rare.2Journal of Nursing Reports in Clinical Practice. The first-trimester screening to detect chromosomal abnormalities in pregnant women: A retrospective study
The lower the MoM, the stronger the statistical link with complications. A result of 0.35 MoM carries modestly elevated risk; a result below 0.2 MoM is taken much more seriously. In one study of women with PAPP-A under 0.2 MoM, rates of growth restriction, gestational hypertension, and preeclampsia were all substantially higher than in the general pregnancy population.8European Journal of Medical and Health Sciences. Association of First-Trimester Low PAPP-A Levels (0.2 MoM) with Maternal and Fetal Outcomes
Low PAPP-A and Fetal Growth
The link between low PAPP-A and babies born smaller than expected is one of the most consistent findings in this area. Because PAPP-A helps regulate growth factor activity in the placenta, less of it may mean less efficient nutrient delivery. A large study found that as first-trimester PAPP-A dropped, the odds of a small-for-gestational-age baby climbed in a dose-response pattern: PAPP-A below the 10th percentile roughly doubled the odds, below the 5th percentile raised them about two and a half times, and below the 1st percentile raised them more than ninefold.10PubMed. First-trimester pregnancy-associated plasma protein A and subsequent abnormalities of fetal growth
A recent study of over 2,600 pregnancies found fetal growth restriction carried an odds ratio of about 2.5 in the low PAPP-A group even after adjusting for other risk factors.11PubMed Central. Relationship Between PAPP-A Levels in the First Trimester of Pregnancy and Complication Risk Some researchers have explored whether early Doppler ultrasound of the umbilical vein can spot growth restriction even earlier in pregnancies already flagged by low PAPP-A, and the initial findings are promising for identifying the most vulnerable fetuses within that group.12PubMed. First-trimester umbilical vein blood flow in pregnancies with low serum pregnancy-associated plasma protein-A levels: an early predictor of fetal growth restriction
Low PAPP-A and Preeclampsia
Preeclampsia, the dangerous combination of high blood pressure and organ stress that can develop in the second half of pregnancy, also shows up more often when first-trimester PAPP-A is low. One study found that preeclampsia occurred in about 8.4% of women with PAPP-A below the 10th percentile, compared with 2.6% in the general population, a relative risk of roughly three times higher. Early-onset preeclampsia, the more severe form appearing before 34 weeks, was about nine times more likely in the low-PAPP-A group.13PubMed Central. Low maternal serum pregnancy-associated plasma protein-A as a risk factor of preeclampsia The same large cohort study mentioned earlier found that the odds of developing hypertensive disorders were roughly five times higher in the low PAPP-A group.11PubMed Central. Relationship Between PAPP-A Levels in the First Trimester of Pregnancy and Complication Risk
This connection between PAPP-A and preeclampsia is not just academic; it directly influences treatment decisions, as covered below.
Other Complications Linked to Low PAPP-A
Growth restriction and preeclampsia get the most attention, but the risk picture extends further. The same cohort study found that spontaneous preterm birth was roughly seven times more likely in the low PAPP-A group, and miscarriage about four times more likely.11PubMed Central. Relationship Between PAPP-A Levels in the First Trimester of Pregnancy and Complication Risk A separate study found that when low PAPP-A was combined with other markers, more than half of affected women experienced at least one serious pregnancy complication, a category that included miscarriage, fetal death, small-for-gestational-age infants, preeclampsia, preterm birth, and fetal anomalies.14American Journal of Obstetrics & Gynecology. Maternal serum low PAPP-A in the first trimester is an independent risk factor for adverse pregnancy outcome
Those numbers sound alarming, and they should be taken seriously. But they also reflect populations already filtered for low PAPP-A; the absolute risk for any individual is still shaped by many other factors, including your medical history, blood pressure, and how the pregnancy develops over time. Low PAPP-A raises the odds of trouble, but the majority of women in these studies still had pregnancies that did not develop the worst complications.
What Your Doctor Will Do About Low PAPP-A
A low PAPP-A result typically triggers two practical changes: more frequent monitoring and, in many cases, low-dose aspirin. If your chromosomal screening came back low-risk but your PAPP-A alone was flagged, you are unlikely to be sent straight for amniocentesis. Instead, your care team will usually schedule extra growth scans in the second and third trimesters to watch for early signs of growth restriction or placental problems.
The aspirin story is particularly encouraging. A meta-analysis of randomized trials found that when low-dose aspirin was started before 16 weeks in women at high risk of preeclampsia, the risk of preeclampsia dropped by roughly half, growth restriction dropped by a similar margin, preterm birth was cut by about 65%, and perinatal death was reduced by nearly 60%. When aspirin was started after 16 weeks, the benefit was much smaller across all those outcomes.15PubMed. Low-dose aspirin for prevention of adverse outcomes related to abnormal placentation A retrospective study in a Taiwanese population reported a 95% risk reduction specifically for early-onset preeclampsia when low-dose aspirin was initiated after positive first-trimester screening.16PubMed Central. Effect of Low-Dose Aspirin in Preventing Early-Onset Preeclampsia in the Taiwanese Population-A Retrospective Cohort Study Doses above 80 mg per day appear to provide better protection than lower doses.15PubMed. Low-dose aspirin for prevention of adverse outcomes related to abnormal placentation
The timing takeaway is clear: because the benefit of aspirin depends on starting early, a low PAPP-A result at 11 to 13 weeks actually arrives at the right moment to act. This is one of the reasons first-trimester screening has value beyond just chromosomal risk assessment.
When PAPP-A Is High
Most of the clinical concern around PAPP-A focuses on low values, and for good reason. High PAPP-A, typically defined as above 2.0 MoM, does not carry the same weight. A study examining pregnancy outcomes in women with high PAPP-A and normal ultrasound findings concluded that the outcomes were good and that counseling in these cases should be reassuring.17PubMed. Clinical consequences of maternal serum PAPP-A and free beta hCG levels above 2.0 multiple of median in the first trimester screening Even at extremely elevated levels, complication rates were not higher than in the general population when the ultrasound looked normal.
There is one exception worth noting. In women already considered high-risk, particularly those with prior uterine surgery, elevated PAPP-A may serve as a marker for placenta accreta spectrum, a condition where the placenta grows too deeply into the uterine wall.18PubMed. Elevated first-trimester PAPP-A is a marker in high-risk pregnancies with an increased risk of placenta accreta in predicting adverse outcomes This is a niche finding relevant mainly to women with specific risk factors, not a general concern for anyone whose PAPP-A happens to be above average.
Factors That Can Skew Your Results
Several things can push PAPP-A levels away from where they would otherwise land, and if your provider does not account for them, you could get a misleadingly low or high reading.
- IVF conception: PAPP-A levels are consistently lower in IVF pregnancies than in those conceived spontaneously. This appears to be a genuine biological difference, not a lab artifact, and it holds across different assay platforms. ICSI (a specific IVF technique) pushes levels even lower, which also increases the false-positive rate on chromosomal screening.19PubMed Central. Low first-trimester PAPP-A in IVF (fresh and frozen-thawed) pregnancies, likely due to a biological cause Interestingly, one study found that when frozen-thawed embryos were transferred in a natural cycle without ovarian stimulation, PAPP-A levels were not significantly different from spontaneous pregnancies, suggesting that the hormonal stimulation itself plays a role.20PubMed. Serum PAPP-A levels at 10-14 weeks of gestation are altered in women after assisted conception
- Smoking: PAPP-A is significantly lower in women who smoke, and the effect is dose-dependent. The more cigarettes per day, the lower the level.21PubMed Central. Serum pregnancy-associated plasma protein A levels in the first, second and third trimester of pregnancy: relation to newborn anthropometric parameters and maternal tobacco smoking Most screening programs ask about smoking status and apply a correction, but if the information is entered inaccurately, the adjusted MoM will be off.
- Maternal weight: Heavier women tend to have lower PAPP-A MoM values before weight correction is applied, because the protein is diluted in a larger blood volume. Labs routinely correct for this, and doing so measurably reduces false-positive rates.3PubMed. Maternal weight correction of maternal serum PAPP-A and free beta-hCG MoM when screening for trisomy 21 in the first trimester of pregnancy
- Twin pregnancies: PAPP-A is naturally higher in twin pregnancies because two placentas (or one larger one) are producing it. Screening labs use twin-specific medians. Even within twin pregnancies, monochorionic twins (sharing one placenta) have lower PAPP-A than dichorionic twins (each with their own), so the type of twin pregnancy needs to be specified for accurate interpretation.22PubMed. Early first-trimester free-β-hCG and PAPP-A serum distributions in monochorionic and dichorionic twins
If you conceived through IVF, smoke, or are carrying twins, ask your provider whether those adjustments were made before your MoM was calculated. A “low” result that does not account for IVF, for instance, may not actually be low for your situation.
When Low PAPP-A Shows Up but Chromosomes Are Fine
A common scenario: your first-trimester screen flags low PAPP-A, but the combined risk for Down syndrome comes back low and cell-free DNA testing (if done) is normal. The chromosomal question is resolved, but the low PAPP-A itself is still clinically meaningful, because the placental risks it signals have nothing to do with the baby’s chromosomes. This is the situation where extra growth scans and possible aspirin become relevant.
Some centers are now pairing early morphology ultrasounds with molecular screening when first-trimester blood markers are atypical but chromosomal risk is low. A retrospective study over five years found that this approach was useful in a small number of cases for detecting severe early growth restriction that raised suspicion for conditions like triploidy.23Elsevier / PubMed Central. Usefulness of early morphological ultrasound in association with cell-free DNA testing in case of atypical serum markers in first trimester of pregnancy: A retrospective study over 5 years In most cases, though, the outcome is reassuring and the early morphology scan confirms normal anatomy.
Combining PAPP-A with Newer Markers
Researchers have been exploring whether combining first-trimester PAPP-A with second- and third-trimester biomarkers can improve prediction of late-onset preeclampsia, the form that develops after 34 weeks and often catches people off guard. One model combined PAPP-A with a second-trimester ratio of two angiogenic markers and detected about 87.5% of late-onset preeclampsia cases at a 5% false-positive rate.24BioMed Central / PubMed Central. Screening models using multiple markers for early detection of late-onset preeclampsia in low-risk pregnancy These multi-marker models are not yet standard of care everywhere, but they point toward a future where first-trimester results are not just a one-time risk assessment but the first data point in a pregnancy-long monitoring strategy.
Uterine artery Doppler is another tool sometimes paired with PAPP-A. First-trimester Doppler readings and low PAPP-A each independently predict a portion of preeclampsia and growth restriction cases. When both are abnormal, the concern is higher; when PAPP-A is low but Doppler is normal, the risk is somewhat attenuated.25PubMed Central. Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler and PAPP-A at 11-14 weeks’ gestation
PAPP-A Outside of Pregnancy
If you see PAPP-A mentioned in a cardiology context, you are not imagining things. The same enzyme the placenta churns out also plays a role in the biology of blood vessel walls. PAPP-A is found in unstable arterial plaques, the kind that rupture and cause heart attacks, and elevated PAPP-A levels have been studied as an early marker for acute coronary syndrome.26PubMed Central. Pregnancy associated plasma protein-A (PAPP-A) as an early marker for the diagnosis of acute coronary syndrome The underlying mechanism is the same: PAPP-A frees up IGF in the local environment, which in an artery wall promotes the kind of cell growth and inflammation that destabilizes plaques. This cardiovascular research is separate from obstetric screening, but it helps explain why PAPP-A was originally described in the context of pregnancy and then surprised researchers by showing up in a completely different disease process. The pregnancy and cardiovascular applications use different assays and different reference ranges, so a cardiac PAPP-A result and an obstetric one are not interchangeable.