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Immunotherapy for recurrent pregnancy loss

https://doi.org/10.1016/j.bpobgyn.2019.07.005Get rights and content

Highlights

  • Immunotherapy, since its inception, has been highly controversial.

  • Randomized trials that do not select subgroups of patients have not shown a beneficial effect.

  • No laboratory tests are available to determine which patients will respond to immunotherapy.

  • When women are selected for a poor prognosis, or immune phenomena, immunotherapy is effective in these subgroups.

  • Embryonic aneuploidy and embryonic structural malformations confound many trials of immunotherapy. These patients should be excluded from future trials of immunotherapy.

Abstract

When immunomodulation is used on an unselected population with recurrent miscarriage (RM), there is no improvement in the live birth rate. However, when the population is selected for a poor prognosis, or immune phenomena, immunotherapy has been shown to be effective. This review discusses four immunomodulatory agents, namely, paternal leukocyte immunization, intravenous immunoglobulin (IVIg), intralipid, and filgrastim. The presence of embryonic aneuploidy may confound the results of treatment, therefore creating an impression of futility when treatment may be highly effective in saving pregnancies that can be saved. Additionally, in an unselected population with RM, there is a relatively good prognosis of 60–80% for a subsequent live birth depending on whether the definition of ≥2 or ≥3 miscarriages is used. Hence, spontaneous prognosis must be taken into account, which has not been the case in previous trials.

This review discusses the possible immune-mediated mechanisms of pregnancy loss and the means whereby immunotherapy may modulate these mechanisms.

Introduction

Recurrent miscarriage (RM) is usually defined in North America, Russia, and Western Europe as two or more miscarriages before 20 weeks of gestation but in the UK as three or more consecutive miscarriages. All treatment modalities used for RM depend on immunomodulation for their effects. Aspirin is used for its anti-inflammatory effects, anticoagulants for their anti-inflammatory and anticoagulant effects, and steroids for their anti-inflammatory effects. This article describes active immunization with paternal leukocytes, passive immunization using intravenous immunoglobulin (IVIg), intralipid, and the use of growth factors such as G-CSF (filgrastim) to enhance placental and fetal growth and increase subsequent live births.

The problem is that all methods of immunotherapy have been assessed by an evidence-based approach in comparative trials, either randomized or blinded, or both, and compared to no treatment. Using this approach, it soon became clear that immunotherapy is not a panacea for treating all patients with RM. Unfortunately, there are no definite laboratory criteria by which immune-mediated mechanisms can be positively identified. Attempts have been made to use antipaternal complement-fixing antibodies and the number and killing activity of natural killer (NK) cells as selection criteria, but neither is sufficiently specific. Additionally, the effect of confounding factors such as embryonic structural malformations and embryonic genetic aberrations has not usually been taken into account.

This chapter discusses the efficacy, mode of action, and side effects associated with immunopotentiation in recurrent pregnancy loss.

Section snippets

Diagnostic criteria

As there are no definitive laboratory criteria for diagnosing immune-mediated miscarriages, immunopotentiation has usually been used on patients with no other established causes of RM. This approach has been used to prevent other presumptive causes of miscarriage from confounding the results. The author's criteria for excluding other presumptive causes of RM are as follows: (1) Normal karyotype of both parents; (2) Normal glucose tolerance test; (3) Normal uterine cavity as shown by

Efficacy of treatment

There are numerous meta-analyses of paternal leukocyte immunization (PLI). However, instead of clarifying the efficacy of treatment, they have obscured the results. The original meta-analysis was conducted by the “Recurrent Miscarriage Immunotherapy Trialists Group” (RMITG) [8]. This meta-analysis was performed on original patient data from an international register of 1753 patients who participated in double-blind trials carried out in 15 centers. The results were analyzed by two independent

Efficacy of treatment

With immunoglobulin (IVIg), there is a similar problem as that with PLI in terms of how to assess treatment. When all patients with three or more miscarriages are treated as one homogeneous group, there is no beneficial effect as shown in a systematic review in the Cochrane database [14]. However, among all the causes of recurrent pregnancy loss, the ones that would be expected to respond to IVIg would be those that involve a mechanism that can be modulated by IVIg. IVIg would not be expected

Efficacy of treatment

In 1988, Johnson et al. [43] carried out a randomized controlled trial involving trophoblast vesicles as active immunization for patients with RMs. As an inert intervention in the control group, intralipid (a 20% intravenous fat emulsion used routinely as parental nutrition) was used. There was no difference in the results between the immunized and control groups. Much of the criticism against Johnson et al.'s [43] study was that intralipid is not immunologically inert. There is evidence that

Efficacy of treatment

Filgrastim is a cytokine growth factor (G-CSF). The main clinical use is in the treatment of neutropenia, such as chronic idiopathic or postchemotherapy neutropenia and to stimulate cell growth in hematopoietic stem cell donation or transplantation. The use of filgrastim in RPL is supported by a randomized controlled study [51]. The live birth rate was 82.8% in women treated with filgrastim compared to that of 48.5% in the control group (p = 0.0061). The number of patients who needed treatment

Summary

All treatment modalities of RM (aspirin, anticoagulants, hormone support) except pregestational testing for aneuploidy (PGT-A) have an immunomodulatory effect. Paternal immunization, IVIg, and filgrastim have been shown to have a beneficial effect in patients with a poor prognosis and when used appropriately. However, the results have been confounded by including a large number of inappropriate patients in trials. Thus, an impression of futility has been created. Because of this impression of

Conflicts of interest

The author has no conflicts of interest to report.

Practice points

  • When used on an unselected population with RM, immunomodulation does not affect the live birth rate.

  • When women with RM are selected for a poor prognosis, or immune phenomena, immunotherapy has been shown to be effective.

  • Embryonic aneuploidy is a prevalent cause of RM, which confounds many trials of immunotherapy. Failure to account for embryonic aneuploidy has precluded showing a positive result of immunotherapy.

  • There is no

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