Immulology in Pregnancy

SWARAJ HOSPITAL & RESEARCH INSTITUTE

BOLANGIR, ODISHA  •  OBSTETRICS & GYNAECOLOGY CLINICAL PATHWAY SERIES

Clinician Reference Infographic

Immunology of Normal Pregnancy — How the Fetus Escapes Rejection

A baby is half foreign to its mother, yet pregnancy normally proceeds without rejection. The explanation is active, regulated tolerance at the placental interface — combined with a mother whose general defences stay on guard. Understanding it explains pre-eclampsia, recurrent loss, Rh disease, autoimmune flares and infection risk.

🎯 AT A GLANCE — THE PARADOX

The fetus carries 50% paternal antigens, so it is a semi-allograft inside the mother — yet it is not rejected. Medawar posed this paradox in 1953

The answer is not that pregnancy switches off the maternal immune system. Immunity is modulated: tolerance is built locally at the placental interface, and the mother's systemic defences stay largely intact

The tolerance rests on three ideas: a trophoblast with little to recognise, a decidua full of regulatory cells, and molecular brakes on T cells and complement

Pregnancy is immunologically active, not suppressed. That is why it can still reject a virus, a Rh-positive red cell, or — when tolerance fails — the pregnancy itself.

🧬 THE MATERNAL–FETAL INTERFACE — WHO IS IN THE DECIDUA?

Uterine NK cells (about 70%)

CD56-bright, CD16-negative — different from blood NK cells

Not killers here: they secrete VEGF, PlGF and IL-10

Help remodel spiral arteries and guide trophoblast invasion

Decidual Macrophages (20–25%)

Mostly M2-like (anti-inflammatory) phenotype

Clear apoptotic cells and tissue debris

Make IL-10 and support tissue remodelling

T Cells (3–10%)

Regulatory T cells (CD4⁺ CD25⁺ FOXP3⁺) expand in pregnancy and suppress anti-fetal responses

CD8 cells are held in a restrained state

Dendritic Cells & Others

Few DCs — and immature, tolerogenic

Very few B cells

Decidual stromal cells shape the cytokine climate

In early pregnancy, about a third of decidual cells are leukocytes — the decidua is an immune organ built for tolerance, not for rejection.

👁️ TROPHOBLAST — AN IMMUNOLOGICALLY QUIET TISSUE

The syncytiotrophoblast, bathed directly in maternal blood, carries no classical HLA molecules (no class I or II) — there is nothing for T cells to recognise

Extravillous trophoblast (EVT), which invades the decidua and touches maternal cells, switches off HLA-A, HLA-B and class II, but expresses a special set: HLA-C, HLA-E and HLA-G

Trophoblast type	HLA-A / B	HLA-C	HLA-E	HLA-G	Class II
Syncytiotrophoblast (villous)	✗	✗	✗	✗	✗
Extravillous trophoblast	✗	✓	✓	✓	✗

HLA-G binds inhibitory receptors (ILT2, ILT4) on NK cells and T cells — a “don't attack” signal; HLA-E engages NKG2A; HLA-C talks to KIR receptors on uterine NK cells

KIR/HLA-C match matters: a mother with the inhibitory KIR AA genotype carrying a fetus with HLA-C2 has a higher risk of pre-eclampsia, growth restriction and recurrent loss — trophoblast invasion is too shallow

🛡️ MOLECULAR BRAKES ON THE MATERNAL IMMUNE SYSTEM

1

IDO (indoleamine 2,3-dioxygenase) breaks down tryptophan and starves activated T cells

2

PD-L1 on trophoblast engages PD-1 on T cells and switches them off

3

Fas ligand triggers apoptosis of activated maternal T cells at the interface

4

Complement regulators CD55 (DAF), CD46 (MCP) and CD59 protect trophoblast from complement attack

5

Hormones: hCG draws Tregs to the decidua; progesterone acts through PIBF to favour tolerance

6

Galectins and trophoblast exosomes carry anti-inflammatory signals into the maternal circulation

⏱️ THREE IMMUNE PHASES OF PREGNANCY

Phase 1 — ImplantationPro-inflammatory. Controlled inflammation helps the embryo attach, invade and repair the endometrium; macrophages, NK cells and cytokines (IL-1, IL-6, TNF-α) rise. Too little or too much impairs implantation

Phase 2 — GrowthAnti-inflammatory. From the end of the first trimester, Tregs and M2 macrophages dominate with IL-10 and TGF-β; this is the calm phase that supports fetal growth

Phase 3 — LabourPro-inflammatory again. Neutrophils and macrophages enter the myometrium and cervix; IL-1β, IL-6, IL-8 and prostaglandins drive contractions, cervical ripening and membrane rupture

The old Th1 versus Th2 idea is too simple. Pregnancy is not just a Th2 state — the immune balance changes with the stage of pregnancy. Infection or inflammation in phase 2 can trigger preterm labour.

🌡️ SYSTEMIC IMMUNITY — WHAT CHANGES IN THE MOTHER

Innate Immunity — Up

Neutrophils and monocytes are activated

Physiological leukocytosis: WBC about 10,000–16,000/µL, higher in labour

Complement and acute-phase proteins rise

Cell-Mediated Immunity — Down

Th1 responses are reduced and Treg activity is increased

Weaker defence against intracellular pathogens

Shifts back to normal after delivery

Humoral Immunity — Preserved

B-cell function is maintained and vaccines work

Total IgG falls slightly through haemodilution

IgG is actively transferred to the fetus

Postpartum Rebound

Immune function returns to baseline within weeks

Autoimmune flares often follow delivery (RA, MS, thyroid disease)

Postpartum thyroiditis fits this pattern

🦠 WHY SOME INFECTIONS HIT HARDER IN PREGNANCY

Influenza and COVID-19 — higher risk of pneumonia, ICU admission and preterm birth

Varicella — severe pneumonia in the mother; hepatitis E — fulminant liver failure, especially in the third trimester

Malaria — more severe disease, placental malaria and anaemia; listeriosis — intracellular infection, with stillbirth risk

Low threshold to test and treat early, and to vaccinate with inactivated vaccines (influenza, Tdap, COVID-19) — live vaccines are avoided

🔄 AUTOIMMUNE DISEASE IN PREGNANCY — WHAT TO EXPECT

Improve in pregnancy (Th1 / cell-mediated): rheumatoid arthritis (about 60% improve), multiple sclerosis (relapses fall, especially in the third trimester), and Graves' disease

May worsen (antibody-mediated): systemic lupus erythematosus, particularly with active disease at conception

Postpartum flare is common in nearly all of them — plan follow-up and drug review before and after delivery

Plan pregnancy for quiet disease, and check antibodies (anti-Ro/La, antiphospholipid) that affect the fetus

🚚 ANTIBODY TRANSFER ACROSS THE PLACENTA

Only IgG crosses, using the neonatal Fc receptor (FcRn) on the syncytiotrophoblast — IgM, IgA and IgE do not cross

Transfer begins at about 13 weeks, rises steeply after 28 weeks, and fetal IgG may exceed maternal levels at term; the order of efficiency is IgG1 > IgG4 > IgG3 > IgG2

Preterm babies receive less antibody — they are more vulnerable to infection

Clinical use: Tdap at 27–36 weeks of each pregnancy and influenza vaccination in any trimester protect the newborn; raised IgM in cord blood suggests intrauterine infection, because maternal IgM cannot cross

Harm: the same pathway carries anti-D antibodies (Rh disease), anti-HPA-1a (fetal thrombocytopenia), and anti-Ro/La (congenital heart block)

⚠️ WHEN TOLERANCE FAILS

Pre-eclampsia

Poor trophoblast invasion; KIR AA + HLA-C2 risk

Fewer Tregs, more inflammatory cytokines and antiangiogenic factors

Higher risk with a new partner or short sperm exposure

Miscarriage & RPL

Reduced Tregs and altered uNK function in some cases

Antiphospholipid syndrome — an immune cause with proven treatment

See our RPL and Miscarriage guides

Alloimmunisation

Rh disease: anti-D from fetomaternal bleed

FNAIT: anti-HPA-1a destroys fetal platelets; first pregnancy may be affected

Prevention: anti-D immunoglobulin

Preterm Labour

Infection or inflammation triggers phase 3 early

Chorioamnionitis and bacterial vaginosis are classic drivers

Immune activation precedes cervical change

🧫 FETAL MICROCHIMERISM

Fetal cells enter the mother from early pregnancy and can persist for decades; maternal cells also enter the fetus

They may help wound repair and tissue maintenance, but are also being studied in autoimmune disease such as scleroderma

A reminder that the maternal–fetal border is a controlled exchange, not a wall

⛔ MYTHS AND WHAT NOT TO DO

“Pregnancy is immunosuppressed” — wrong; it is immune-modulated, and infections can be severe

Routine NK-cell, cytokine or HLA testing in recurrent loss — no proven value and not recommended

IVIG, steroids, intralipid or paternal lymphocyte immunisation for unexplained loss — not supported by trials

Withholding inactivated vaccines in pregnancy — they protect mother and baby

Memory Aid

SHIELD

Six ways the fetus escapes rejection.

S

Syncytiotrophoblast barrier — no classical HLA to recognise

H

HLA-G, -C and -E on extravillous trophoblast — inhibitory signals to NK and T cells

I

IDO and PD-L1 — brakes that switch off activated T cells

E

Expanded Tregs — FOXP3⁺ regulatory cells under the influence of hCG and progesterone

L

Local uNK cells and M2 macrophages — remodel arteries rather than attack

D

Decidual defences — FasL and complement regulators (CD55, CD46, CD59)

Remember: when tolerance is too weak the result is pre-eclampsia, loss or alloimmune disease; when it is too strong, the mother is exposed to infection. Normal pregnancy sits between the two.

Swaraj Hospital & Research Institute · Department of Obstetrics & Gynaecology, Bolangir, Odisha

Educational summary of current reproductive immunology; many mechanisms are still under study and several findings come from mouse or in-vitro work — they explain clinical patterns but do not yet change routine management.