Successful pregnancy requires a finely regulated maternal immune response that promotes tolerance toward fetal antigens while maintaining adequate defense mechanisms. Several immunological abnormalities have been associated with miscarriage:

• Autoimmune disorders, particularly antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE), are strongly linked to pregnancy loss^(9,10).
• Alloimmune dysfunction, including inadequate maternal tolerance to paternal antigens, may impair implantation and placental development⁽⁶⁾.
• Abnormal NK cell activity, especially elevated cytotoxic uterine NK cells, has been observed in women with RPL⁽¹¹⁾.
• Cytokine imbalance, particularly a shift toward a Th1-dominant inflammatory profile, is associated with early pregnancy failure⁽¹²⁾.
• Complement activation, a mechanism implicated in placental injury in autoimmune diseases⁽¹³⁾.

These findings provide the rationale for immunomodu­latory therapies such as IVIG.

3. Mechanisms of action of IVIG in pregnancy

IVIG is a purified IgG preparation derived from pooled donor plasma. Its mechanisms of action are diverse, and may support pregnancy maintenance.

3.1. Modulation of NK cell activity

IVIG reduces NK cell cytotoxicity and alters receptor expression, promoting a more tolerant uterine environment⁽¹⁴⁾.

3.2. Cytokine regulation

IVIG shifts the immune response from a Th1-domi­nant to a Th2-dominant profile, which is essential for implantation and placental development⁽¹⁵⁾.

3.3. Fc receptor blockade

By saturating Fc receptors, IVIG reduces the activity of pathogenic autoantibodies and immune complexes, particularly relevant in APS and SLE⁽¹⁶⁾.

3.4. Complement inhibition

IVIG contains anti-idiotypic antibodies that inhibit complement activation, reducing inflammation at the maternal-fetal interface⁽¹⁷⁾.

3.5. Enhancement of regulatory T cells

Regulatory T cells (Tregs) are essential for maternal tolerance; IVIG has been shown to increase their number and function⁽¹⁸⁾.

These mechanisms collectively support the hypothe­sis that IVIG may benefit women with immunemediated pregnancy loss.

3.6. Anti-immunoglobulin antibodies – anti-idiotype and anti-F(ab)2 antibodies

Idiotype anti‑idiotype networks create a natural regulatory loop in which antibodies neutralize each other’s antigen‑binding sites, dampening excessive immune activation. Anti‑idiotype antibodies can mimic fetal antigens and induce tolerance by promoting regulatory T‑cell expansion and reducing Th1‑type inflammation⁽¹⁹⁾. Anti‑F(ab’)2 antibodies further down‑regulate autoreactive B‑cell clones by binding to their antigen‑binding fragments, limiting harmful autoantibody production⁽²⁰⁾. Together, these mechanisms reduce NK‑cell cytotoxicity, complement activation and inflammatory cytokines at the maternal-fetal interface. This immunomodulation explains why IVIG – rich in anti‑idiotype and anti‑F(ab’)2 antibodies – may help restore immune tolerance in women with recurrent spontaneous abortion of suspected immune origin⁽²¹⁾.

4. Clinical evidence for IVIG in preventing spontaneous abortion

4.1. IVIG in autoimmune-related pregnancy loss

In APS, standard therapy consists of low-dose aspirin and heparin, which significantly improve the outcomes⁽²²⁾. IVIG has been used as an adjunct in refractory cases, with some studies reporting improved live birth rates⁽²³⁾.

4.2. IVIG in unexplained recurrent pregnancy loss (uRPL)

This is the most debated indication. Early uncontrolled studies suggested live birth rates of 70-80% with IVIG⁽⁷⁾. However, randomized controlled trials (RCTs) have produced mixed results:

• Some RCTs found no significant benefit compared with placebo⁽²⁴⁾.
• Others demonstrated improved outcomes in specific subgroups, such as women with more than three miscarriages⁽²⁵⁾.

A 2021 metaanalysis concluded that IVIG may improve live birth rates in selected high-risk women, but heterogeneity across studies limits firm conclusions⁽²⁶⁾.

4.3. IVIG in alloimmune disorders

Women with abnormal alloimmune profiles (e.g., low blocking antibodies, high Th1/Th2 ratios) may benefit from IVIG, although these tests lack standardization⁽²⁷⁾.

4.4. Timing and dosage

Protocols vary widely:

• Early pregnancy administration (peri-implantation) appears more effective⁽²⁴⁾.
• Doses range from 0.2 g/kg to 1 g/kg, given monthly or biweekly⁽²⁸⁾.

Lack of standardization complicates the interpretation of results.

5. Safety and adverse effects

IVIG is generally well tolerated. Common adverse effects include headache, fever and chills, while rare complications include thromboembolic events, aseptic meningitis and hemolysis⁽²⁹⁾.

In pregnancy, IVIG is considered relatively safe, with no evidence of teratogenicity⁽³⁰⁾.

6. Controversies and limitations

6.1. Heterogeneity of patient populations

Studies include women with autoimmune, alloimmune and unexplained RPL, making comparisons difficult^(7,12).

6.2. Lack of standardized immunological testing

Markers such as NK cell levels or cytokine ratios vary by laboratory and lack universal cutoffs^(11,12).

6.3. High cost and resource use

IVIG is expensive and requires infusion facilities, raising concerns about cost-effectiveness⁽³²⁾.

6.4. Ethical considerations

Major reproductive societies, including ASRM and ESHRE, do not recommend routine IVIG use outside research settings due to insufficient evidence^(33,34).

7. Future directions

Future research should focus on:

• Identifying reliable biomarkers to select women who may benefit^(21,35).
• Standardizing IVIG protocols (dose, timing, duration)⁽²⁵⁾.
• Conducting large RCTs targeting immunologically defined subgroups⁽²⁵⁾.
• Exploring alternative immunotherapies (e.g., intralipid therapy, TNF-a inhibitors, Treg-based therapies)^(36,37).

8. Conclusions

Intravenous immunoglobulin is a promising but controversial therapy for preventing spontaneous abortion, particularly in women with recurrent pregnancy loss of suspected immunological origin. While mechanistic studies support its potential benefits, clinical evidence remains inconsistent due to heterogeneous study designs and patient populations. At present, IVIG should be considered only in selected high-risk cases or within clinical research protocols. Continued investigation is essential to clarify which women may truly benefit and to establish standardized treatment guidelines.

Autor corespondent:   Dan Navolan E-mail: navolan@yahoo.com 

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.