PAPP-A - Part 2, Placental Physiology, and the Science of Growth
Low PAPP-A (Pregnancy-Associated Plasma Protein-A) is often treated clinically as a static risk marker
— a reason to increase monitoring or begin low-dose aspirin.
Yet biologically,
it tells us far more:
it reflects early placental function,
vascular remodelling, and the balance of maternal
–fetal growth signalling through the Insulin-Like Growth Factor (IGF) system.
Understanding this physiology helps us explain to women that PAPP-A is not a fixed fate,
but part of a responsive system that continues to adapt throughout pregnancy.
🔬 What PAPP-A Is and What It Does
PAPP-A is a high-molecular-weight zinc-binding metalloproteinase enzyme, secreted primarily by the syncytiotrophoblast (outer placental layer) into maternal circulation.
It acts on Insulin-Like Growth Factor Binding Protein-4 (IGFBP-4) — cleaving it to release free IGF-I and IGF-II, which are then biologically active.
These IGFs are central to early placental development. They regulate:
Trophoblast proliferation and invasion
Uterine spiral artery remodelling
Angiogenesis and vasodilation
Nutrient transport and metabolic signalling between mother and fetus
Low PAPP-A measured between 10–14 weeks (below ~0.4–0.5 MoM) is therefore a proxy marker for reduced early placental activity, which may be associated with restricted growth, pre-eclampsia, or preterm birth.
(References: Christiansen et al., 2013; Smith et al., 2002; Spencer et al., 2008; FASP NHS 2023.)
📈 PAPP-A Across Gestation
While PAPP-A is only measured once for screening, maternal serum levels increase exponentially throughout pregnancy, reaching up to 100-fold higher at term than in the first trimester.
From around 15 weeks onwards,
variability between individuals becomes so great that it loses predictive value for screening
— but physiologically,
this rise reflects continued placental growth and syncytiotrophoblast activity.
In other words, PAPP-A is not static.
A lower first-trimester value indicates how the placenta embedded,
but later placental function remains plastic and modifiable.
This distinction is crucial when discussing risk
— because it leaves room for supportive intervention and positive adaptation, rather than deterministic fear.
(See Bersinger et al., 2004; Sifakis et al., 2010.)
💗 The IGF System: Growth, Angiogenesis, and Metabolic Regulation
The Insulin-Like Growth Factors (IGF-I and IGF-II)
resemble insulin structurally but function primarily as growth mediators rather than glucose regulators.
Once released from their binding proteins via PAPP-A,
they act on IGF-1 receptors in placental and endothelial cells, stimulating:
🩸 1. Angiogenesis and Vascular Expansion
IGFs promote endothelial proliferation and VEGF (Vascular Endothelial Growth Factor) expression,
supporting new capillary growth and widening of uterine arteries.
This improves uteroplacental perfusion and oxygen delivery.
(Han et al., 1996; Forbes & Westwood, 2008)
🌱 2. Cellular Growth and Tissue Formation
They drive trophoblast proliferation and fetal myoblast
(muscle precursor) development
— contributing to fetal growth and placental mass.
⚖️ 3. Nutrient and Metabolic Regulation
IGFs increase placental amino acid and glucose transporter activity
(e.g., System A transporters)
ensuring nutrient transfer meets fetal demand.
💚 4. Endothelial Protection and Anti-Oxidative Action
IGFs maintain endothelial integrity and
reduce oxidative stress within the placental bed
— protective against pre-eclampsia and vascular dysfunction.
🩸 Low PAPP-A, Placental Perfusion, and Aspirin
A number of studies link low first-trimester PAPP-A
with increased uterine artery resistance and reduced diastolic flow in Doppler studies.
Low-dose aspirin (75–150 mg/day,
ideally before 16–20 weeks) is offered because it reduces platelet aggregation
and enhances microvascular flow within the uteroplacental circulation.
Mechanistically, aspirin inhibits thromboxane A2 synthesis,
shifting the balance towards prostacyclin, a vasodilator.
The result is smoother blood flow and improved trophoblastic perfusion
— effectively “unclogging” the small-calibre vessels of the placenta.
However, non-pharmacological factors can influence the same system:
regular low-intensity exercise, hydration, nitric oxide–rich foods (beetroot, leafy greens), and stress reduction (lower cortisol = less vasoconstriction) all support endothelial health and uterine blood flow.
(Rolnik et al., 2017; NICE NG133, 2023.)
🌿 Why This Matters for Birthworkers
Understanding the PAPP-A/IGF axis offers a more nuanced,
less fear-driven way to support women labelled as “high risk.”
Rather than viewing low PAPP-A as an irreversible defect,
we can explain it as a modifiable indicator of placental demand and function
— something the mother’s body continues to influence through nourishment, movement, rest, and emotional environment.
Nutrients (protein, omega-3, antioxidants, magnesium) support IGF pathways.
Movement (yoga, walking) improves uteroplacental flow and vascular tone.
Calm states (meditation, yoga nidra) reduce sympathetic dominance, enhancing perfusion.
This is the intersection of science and body wisdom: a living example of how physiology supports instinct.
📚 Key References
Forbes K & Westwood M. The IGF axis and placental function. Hormone Research, 2008.
Bersinger NA et al. PAPP-A levels rise exponentially during pregnancy. Clinical Chemistry, 2004.
Rolnik DL et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. NEJM, 2017.
Spencer K et al. Low PAPP-A in the first trimester and adverse outcomes. Prenatal Diagnosis, 2008.
NICE NG133 (2023). Hypertension in pregnancy: diagnosis and management.