Unexplained recurrent miscarriages: predictive value of immune biomarkers and immunomodulatory therapies for live birth
A retrospective multicenter study was carried out in women with unexplained recurrent miscarriage’s to assess the potential of immune biomarkers and compare pregnancy outcomes following various immunomodulatory treatments (aspirin, low molecular weighted heparin (LMWH), prednisone, hydroxychloroquine and intralipid infusions).
In total of 101 women were recruited from 3 hospitals in France: Saint-Antoine Hospital, Tenon Hospital and Trousseau Hospital between December 2015 and October 2018. Recurrent miscarriage was defined as a minimum of 3 consecutive spontaneous miscarriage’s, before 12 weeks gestation, with the same partner.
All women underwent extensive screening for known causes of recurrent miscarriages (e.g. uterine, genetic, hormonal, infectious, thrombophilia, autoimmune) before being diagnosed with unexplained recurrent miscarriage.
Assessment of immune biomarkers included: serum protein electrophoresis, IL-1, IL-6, IL-10, TNFα, antinuclear, anti-dsDNA, anti-extractable nuclear antigen, anti-thyroperoxydase, anti-thyroglobulin, Natural Killer levels, Vitamin D and endometrial receptivity (IL-15/Fn-14 mRNA, IL-18/TWEAK mRNA to define hypo/hyper activation status).
Selection of immunomodulatory treatment was based on the presence of antinuclear or antithyroid antiobides, hyperactive endometrial recptivity status, and previous treatment (progesterone, aspirin or LMWH).
Clinical pregnancy was confirmed by ultrasound on week 5 of gestation while miscarriage was defined as spontaneous abortion before week 12 of gestation. Voluntary abortions, extra-uterine pregnancies, therapeutic abortions and in-utero death was excluded from analysis.
Patient characteristics showed a mean age of 35 ±5, median number of previous pregnancies equal to 5 and previous miscarriages 4. Thirteen women were overweight (BMI > 25 kg/m2). Median AMH was 1.80 ng/ml and TSH 1.73 UI/L. All women came back negative for antiphospholipid antibodies.
Interestingly immune testing showed that median blood levels of IL-1 and IL-6 were elevated (16.1 pg/ml and 9.4 pg/ml respectively) while TNFα and IL-10 was normal. One in ten women had thyroiditis and endometrial analysis of 21 women confirmed 14% as hypoactive, 42% hyperactive and 42% as normal.
Next across the 101 women, 681 pregnancies were reported with 652 pregnancies included in the final analysis. Of these 652 pregnancies, 92 resulted in live births (14%).
Comparing immune biomarkers in women who did not achieve a live birth with those who did, found that the positive rate of antinuclear antibodies in these women was lower compared to the live birth group (7% vs 13%), while all other biomarkers were similar.
Treatment wise, statistical analysis confirmed a significantly higher rate of cumulative live birth (43.0% vs 34.8%) for women under treatment vs no treatment. More specifically women on steroids (prednisone) doubled their chance of a live birth, possibly a result of prednisone effect on Natural Killer cell concentrations.
On the other hand while treatment with aspirin and/or LMWH improved the chances of a live birth by 40%, and similarly intralipids by 80%, this was not found to be statistically significant due to the small study size (p > 0.1). Interestingly the effect of hydroxychloroquine was also shown to be marginal at best, odds ratio 1.0.
SUMMARY: RECURRENT MISCARRIAGE TREATMENT
Steroid (prednisone) treatment of unexplained recurrent miscarriage significantly doubles the chances of live birth (p = 0.02), while aspirin and/or low molecular weighted heparin did not show a statistically significant increase (p = 0.1) suggesting prednisone treatment may in fact be superior.
- Retrospective study
- Small study size (hydroxychloroquine, intralipids)
Liang P Y, et al. (2015). The pro-inflammatory and anti-inflammatory cytokine profile in peripheral blood of women with recurrent implantation failure. https://doi.org/10.1016/j.rbmo.2015.08.009
Otun H A, et al. (2011). Effect of tumour necrosis factor-α in combination with interferon-γ on first trimester extravillous trophoblast invasion. https://doi.org/10.1016/j.jri.2010.10.003
Haddad E K, et al. (1997). Role of interferon-gamma in the priming of decidual macrophages for nitric oxide production and early pregnancy loss. https://doi.org/10.1006/cimm.1997.1199
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