IV immunoglobulin for recurrent pregnancy loss

Adverse reproductive outcomes such as recurrent miscarriage and repeated implantation failure are particularly stressful episodes for couples and challenging situations for physicians to manage. A lack of diagnostic testing, therapeutic options, and controversy regarding the available evidence complicates the issue. The aetiology and treatments involve diverse areas including gynaecology, reproductive endocrinology, obstetrics, and, increasingly, immunology.

Recurrent pregnancy loss (RPL), now classified as ≥2 miscarriages, affects around 2-5 per cent of women, but frustratingly, no identifiable cause is found for over 50 per cent of patients after completion of the recommended diagnostic investigations.¹

Immunological dysfunction is thought to play a role in many of these otherwise unexplained cases. The concept of a paradoxical maternal immune response towards the semi-allograft foetus being central to a successful pregnancy was proposed by Sir Peter Medawar over 70 years ago.

This hypothesis suggested that the maternal immune system does not react against the foetus because of three reasons; anatomical separation of the foetus from the mother, antigenic immaturity of the foetus, and immunological indolence of the maternal immune system.

Abnormal immune responses have subsequently been linked with infertility, miscarriage, and obstetric complications, and many immunotherapies have been studied as potential treatments. A growing area of interest, with increasing amounts of supporting evidence, is the use of intravenous immunoglobulin (IVIg) for the treatment of complex cases.

IVIg is a blood derivative product extracted from the purified plasma of thousands of donors, first used in the 1950s to treat primary immunodeficiency.² Improvements in formulation techniques allowed for greater safety and efficacy, with indications expanding to include neuroinflammatory conditions, autoimmune disease, infection-related disorders, and other alloimmune and chronic inflammatory processes.^3,4

IVIg treatment modulates both the innate and adaptive immune responses, with various therapeutic effects. In obstetrics, the use of IVIg in foetal and neonatal alloimmune thrombocytopenia (NAIT), antiphospholipid syndrome (APS), and immune thrombocytopenic purpura (ITP) aims to replenish IgG antibodies that passively neutralise infectious pathogens, and elicit an active immune response via activation of immune cells, conferring protection against diverse diseases.⁵

The mechanisms of action includes Fc and F(ab’)2 receptor-mediated effects, modulation of cytokine production, complement-mediated damage, and regulation of autoreactive B cell clones by anti-idiotype antibodies.⁶

IVIG has been used off-label for many years in the treatment of patients with poor reproductive outcomes. The main areas of interest have been RPL and repeated implantation failure following IVF treatment with high quality blastocyst transfers.

IVIg has been especially considered with reproductive failure in association with immunological conditions, such as antiphospholipid syndrome refractory to thromboprophylaxis therapy, or cellular immune disorders.^3,4 Many studies, randomised and observational, have been performed, with conflicting results regarding the effectiveness for adverse reproductive outcome patients.^7,8

Most of the published evidence for IVIg in reproductive medicine has been for RPL, with many trials and reviews performed. Understanding which patients may benefit most has been a challenge, but is becoming more apparent. A systematic review and meta-analysis by Hutton et al reported that the benefit of IVIg was significant in secondary recurrent miscarriage (after a previous live birth) but not in primary RPL patients who had no prior successful pregnancies.⁹

Another interesting finding in randomised controlled trials (RCTs) involving IVIg for RPL is that studies where the infusions were initiated before conception reported significantly better outcomes in the treated groups compared to placebo, but no treatment effect was found in trials where infusions were administered after conception.⁹

A 2014 Cochrane review reported no significant benefit with IVIg compared to placebo for improvement in the live birth rate (LBR) for RPL patients.¹⁰ Although the overall meta-analysis suggested that IVIg had no impact on LBR, important sensitivity analyses also showed that IVIg significantly increased the LBR when administered prior to conception rather than after a positive hCG test, and interestingly, when serological signs of autoimmunity were noted.¹¹

The finding of benefit in patients with positive immune risk factors was supported by a meta-analysis involving women with RPL and abnormal natural killer (NK) cell levels and activity.¹² This study identified that IVIg therapy led to significantly higher LBRs than controls (P<0.00001).

Several meta-analyses of RCTs of IVIg therapy for unexplained RPL failed to prove its effectiveness but numerous studies have shown that IVIg treatment of women with RPL reduces NK-cell related parameters.^13,14 In addition, patients with RPL who are positive for at least one autoantibody had a better cumulative LBR after IVF/ICSI treatment when a combination of IVIg and prednisone was used from the start of the next IVF/ICSI cycle.^9,15

A recent high quality RCT by Yamada et al reported that patients with higher order RPL (≥6 previous miscarriages) showed benefit in LBR from IVIg treatment (OR 6.0; 95% CI 1.1-32.6: p=0.05).¹⁶ They found that IVIg given in repeated doses (400mg/kg) for five consecutive days very early in pregnancy in women with four or
more unexplained pregnancy losses increased the LBR significantly (OR 2.60; 95% CI 1.15-5.86).¹⁶

The results of this Japanese study have impacted guidelines for the treatment of RPL, with the European Society of Human Reproduction and Embryology changing their advice in the 2022 update, acknowledging that high doses of IVIg in early pregnancy may improve LBRs after ≥4 miscarriages.

The effectiveness of IVIg in unexplained repeated implantation failure (RIF) has traditionally been regarded as more controversial. The ability to establish an evidence base has been hindered by the lack of a consensus definition of RIF.

A recent systematic review and meta-analysis was performed to assess if there was any evidence to support a role for IVIg therapy in RIF patients. Twelve studies were identified, and significant increases were seen in clinical pregnancy rate (OR 5.14; 95% CI 2.33-11.30: p<0.001), LBR (OR 4.60; 95% CI 2.44-8.68: p<0.001), and implantation rate (OR 2.35; 95% CI 1.04-5.29: p=0.039) in IVIg-treated RIF patients.¹⁷ As with recurrent miscarriage patients, positive immunological risk factors were a predictor for increased benefit.

Public funding for IVIg in RIF is typically not supported, with some exceptions. In Quebec it is subsidised but tightly regulated, with strict criteria including three failed unexplained high-quality blastocyst transfers, age <42, BMI <35, no smoking, and unsuccessful implantation failure therapies.¹⁸

Side effects of IVIg are noted in 5-15 per cent of infusions, but are typically mild and transient. These can include headaches, vasovagal reaction, and mild infusion reactions consisting of myalgia, malaise, fatigue, skin erythema.⁷ Increased risk of side effects, especially severe headache, was experienced using a protocol with four weekly infusions of IVIg.⁷

Severe complications are fortunately rare, but can include anaphylaxis (particularly in IgA deficient patients), renal failure, aseptic meningitis, thromboembolism, neutropenia, and autoimmune haemolytic anaemia. Patients with IgA deficiency need additional screening and need infusions with low IgA IVIg or subcutaneous Ig to prevent anaphylactic reactions. IVIg is generally safe and well tolerated in pregnancy, even at high doses.¹⁹ Reassuring data have shown that IVIg treatment did not increase the rate of obstetric complications or lead to foetal teratogenicity.

Summary

There is a growing body of evidence that IVIg treatment can help patients with immune-mediated RPL or repeated implantation failure. IVIg treatment for poor reproductive outcomes can be considered by physicians with training in reproductive immunology for women with abnormal cellular immune responses, such as increased NK cell levels or cytotoxicity or abnormal autoimmunity associated with high-order recurrent pregnancy losses, or failed transfer of proven euploid embryos. IVIg treatment should be given pre-implantation, as this is more successful than administration post conception. Evaluation for identifiable immunological risk factors, such as abnormal cellular immunity and autoimmunity in women with reproductive failures, is important, as empirical IVIg treatment for women with unexplained RPL and implantation failure is not recommended.

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