Leili Mohebnasab: How Metabolic Signals Shape Immune Tolerance and Placental Health

Leili Mohebnasab, Former Midwife at Shariati Hospital, shared a post on LinkedIn:

“Immunometabolism in Pregnancy: How Metabolic Signals Shape Immune Tolerance and Placental Health (2024–2025)

Pregnancy is often described as an immunological paradox: how does the maternal immune system tolerate a semi-allogeneic fetus without compromising protection against infection?

For decades, this question was framed almost exclusively in immunological terms. But emerging evidence from WHO (2024), NIH Maternal–Fetal Biology programs (2023–2025), CDC surveillance data (2024–2025), and FIGO placental guidelines (2024) now points to a deeper, integrative answer:

Immune tolerance in pregnancy is fundamentally metabolic.

The maternal–fetal interface is not governed by immune signaling alone. It is shaped by nutrient availability, energy sensing, mitochondrial function, and metabolic by-products that actively determine immune cell fate, placental vascular health, and pregnancy outcomes.

This field—immunometabolism—is rapidly reshaping how we understand preeclampsia (PE), gestational diabetes (GDM), fetal growth restriction (FGR), and preterm birth (PTB).

Pregnancy as a State of Controlled Metabolic Stress

Normal pregnancy requires profound metabolic adaptation.

According to WHO (2024), maternal glucose utilization increases by approximately 40–60% by mid-pregnancy. Lipid metabolism shifts toward physiologic insulin resistance in late gestation, ensuring a continuous energy supply for the fetus.

These changes are adaptive—not pathological.

But immune cells at the maternal–fetal interface respond directly to these metabolic conditions. Decidual T cells, macrophages, and trophoblast-associated immune populations alter their metabolic programs to support tolerance rather than inflammation.

When metabolic balance is preserved, immune tolerance is stable.

When metabolic stress exceeds adaptive capacity, immune regulation begins to fail.

T Regulatory Cells: Tolerance Requires Energy Stability

Regulatory T cells (Tregs) are central to maternal–fetal immune tolerance.

NIH data (2024–2025) show that in healthy pregnancy, decidual Tregs preferentially rely on:

• fatty acid oxidation rather than glycolysis,
• intact mitochondrial respiration,
• stable redox balance.

This metabolic profile supports suppressive immune function and prevents excessive effector T-cell activation.

In pregnancies complicated by GDM, obesity, or early-onset PE, this balance shifts.

CDC data (2025) indicate that women with GDM demonstrate a 30–40% reduction in functional Treg activity, accompanied by altered glucose and lipid signaling. The issue is not the absence of Tregs, but their metabolic destabilization.

Tolerance is lost not because immunity “turns hostile,” but because immune cells lose the metabolic environment required to remain tolerant.

Placental Macrophages and Metabolic Polarization

Placental macrophages (including Hofbauer cells) are highly responsive to metabolic cues.

In healthy pregnancies, these cells adopt a regulatory, tissue-supportive phenotype that promotes:

• angiogenesis,
• extracellular matrix remodeling,
• immune quiescence.

WHO and FIGO reports (2024) show that metabolic stress—particularly dysregulated lipid flux, oxidative stress, and intermittent hypoxia—pushes macrophages toward a pro-inflammatory profile, characterized by increased IL-6 and TNF-α signaling.

This shift is consistently observed in early-onset PE and severe FGR, linking metabolic imbalance directly to placental inflammation and vascular dysfunction.

The Tryptophan–IDO Axis: Metabolism as Immune Control

One of the clearest examples of immunometabolism in pregnancy is the tryptophan–indoleamine 2,3-dioxygenase (IDO) pathway.

Placental IDO activity depletes local tryptophan concentrations, suppressing effector T-cell proliferation while supporting immune tolerance.

NIH and FIGO updates (2024–2025) demonstrate that:

• IDO expression is reduced in PE,
• maternal tryptophan metabolites are altered,
• inflammatory signaling increases when this pathway is disrupted.

Importantly, this is not a genetic defect—it reflects a metabolic-immune imbalance at the maternal–fetal interface.

Maternal Metabolism, Gut Microbial Metabolites, and Immune Regulation

While the placenta itself is not colonized, maternal microbial metabolites exert systemic effects.

Short-chain fatty acids (SCFAs), particularly butyrate and propionate, have been shown to:

• stabilize Treg differentiation,
• reduce systemic inflammation,
• support endothelial and placental vascular health.

CDC perinatal data (2024) associate reduced SCFA diversity with increased risk of PE and PTB, especially in pregnancies complicated by obesity or metabolic syndrome.

The placenta does not host microbes—but it is exquisitely sensitive to metabolic signals shaped by the maternal microbiome.

When Immunometabolism Fails: Clinical Consequences

Disrupted immunometabolic regulation contributes to:

• Preeclampsia, affecting 5–8% of pregnancies globally (WHO 2024),
• Gestational diabetes, now impacting 16–18% of pregnancies worldwide (CDC 2025),
• Preterm birth, with a 20–30% increased risk in metabolically inflamed pregnancies.

These conditions are not isolated immune disorders. They reflect systemic metabolic stress that destabilizes immune tolerance long before clinical symptoms emerge.

A Midwifery Perspective: Bridging Biology and Lived Experience

From a clinical and midwifery perspective, immunometabolism explains what is often observed but not always named:

• why metabolic stress amplifies inflammation,
• why placental dysfunction precedes maternal symptoms,
• why PE and FGR rarely emerge “suddenly.”

Immunometabolism connects molecular biology to real pregnancy experiences—fatigue, metabolic strain, vascular stress, and placental vulnerability.

Looking Forward: Prevention Through Metabolic Insight

WHO and NIH now identify immunometabolism as a priority area for:

• early risk stratification,
• placental biomarker development,
• preventive strategies before overt disease develops.

Understanding immune tolerance requires understanding energy balance, nutrient signaling, and metabolic resilience.

Pregnancy is not only an immune state.

It is a metabolic–immune partnership.

References (2024–2025)

• World Health Organization (WHO). Maternal–Fetal Immunology and Metabolic Health Review, 2024.
• Centers for Disease Control and Prevention (CDC). Pregnancy Metabolic Health Surveillance Report, 2025.
• National Institutes of Health (NIH). Maternal–Fetal Immunometabolism Initiative, 2023–2025.
• FIGO. Placental Immune Function and Metabolic Regulation Guidelines, 2024.
• ACOG. Metabolic Disorders in Pregnancy: Practice Update, 2024.

Question for You

If immune tolerance in pregnancy is fundamentally a metabolic process, how early should metabolic risk be addressed in routine prenatal care?”

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