What is the role of intravenous immunoglobulin (IVIG) in treating recurrent pregnancy loss (RPL), particularly in patients with suspected immunological factors or antiphospholipid syndrome?

IVIG Should Not Be Used Routinely in Recurrent Pregnancy Loss

IVIG is not recommended for recurrent pregnancy loss, including cases with antiphospholipid syndrome (APS), based on the strongest guideline evidence showing no demonstrable benefit and significant costs/burdens. 1

Standard Treatment for APS-Related RPL

For patients meeting criteria for obstetric APS, the evidence-based approach is:

• Combined low-dose aspirin (81-100 mg daily) plus prophylactic-dose LMWH (typically enoxaparin 40 mg daily) is strongly recommended as first-line therapy, with treatment starting before 16 weeks gestation and continuing through delivery 1
• Hydroxychloroquine may be conditionally added to aspirin plus LMWH for patients with primary APS, as recent small studies suggest decreased complications 1
• This standard regimen achieves live birth rates of approximately 75% in obstetric APS, though pregnancy loss still occurs in 25% despite treatment 1

Evidence Against IVIG in Refractory APS

The 2020 American College of Rheumatology guidelines conditionally recommend AGAINST IVIG for patients who fail standard therapy with aspirin and prophylactic heparin/LMWH 1. The rationale is clear:

• No controlled data demonstrate improved outcomes with IVIG in refractory obstetric APS 1
• Only anecdotal evidence supports its use 1
• High certainty of harms exists, including increased costs and burden related to drug administration 1

The 2018 GLADEL-PANLAR guidelines provide a strong recommendation AGAINST adding IVIG to standard therapy (HCQ plus LMWH plus aspirin) for pregnant patients with SLE and antiphospholipid antibodies with recurrent pregnancy loss 1

Alternative Approaches for Treatment Failures

When standard therapy fails, consider these evidence-based alternatives instead of IVIG:

• Hydroxychloroquine addition to standard therapy (if not already prescribed) 1
• High-dose methylprednisolone (1000 mg) possibly combined with azathioprine, though this carries risks 1
• Strongly recommend AGAINST adding prednisone to standard therapy, as no controlled studies show benefit and potential risks are significant 1

Unexplained RPL Without APS

For patients with positive antiphospholipid antibodies who do NOT meet criteria for APS:

• Prophylactic aspirin alone (81-100 mg daily) is conditionally recommended starting before 16 weeks gestation for preeclampsia prophylaxis 1
• Prophylactic heparin plus aspirin is conditionally recommended AGAINST unless high-risk features exist (triple-positive aPL, strongly positive LAC, advanced maternal age, IVF pregnancy) 1
• IVIG is not recommended for this population 1

Critical Caveats About Research vs. Guidelines

While recent research studies 2, 3, 4 suggest potential benefit of IVIG in selected subgroups (particularly those with elevated NK cells >12%, ≥5 prior losses, or primary RPL), these are non-randomized observational studies with serious methodological limitations 3. The highest-quality guideline evidence from major rheumatology societies explicitly recommends against IVIG use 1.

The 2025 meta-analysis of randomized trials found no significant improvement in live birth rates with intention-to-treat analysis (RR 1.02,95% CI 0.86-1.22) 4, supporting the guideline recommendations.

Common Pitfalls to Avoid

• Do not use IVIG as first-line therapy for any form of RPL—standard therapy with aspirin plus LMWH is more effective and evidence-based 1
• Do not add IVIG to standard therapy in refractory cases without exhausting other options like hydroxychloroquine 1
• Do not prescribe IVIG based solely on elevated NK cells or Th1/Th2 ratios in clinical practice, as this remains investigational despite research interest 5, 3
• Recognize that IVIG is a blood product subject to shortages, and unrestricted off-label use depletes supply for patients with proven indications 2

When IVIG Might Be Considered (Off-Guideline)

If all standard therapies have failed and shared decision-making supports a trial:

• Consider only in patients with ≥5 prior losses and primary RPL who have failed aspirin, LMWH, and hydroxychloroquine 2
• Dosing would be 0.6-0.8 g/kg prior to conception and monthly until 16-20 weeks gestation 2
• Document informed consent regarding lack of guideline support, costs, and uncertain benefit 1, 2