Intravenous Immunoglobulin or Intravenous Lipid Emulsion Therapy in Patients With Elevated NK Cytotoxicity Improves Live Birth Rates in Different Ways.

PROBLEM: Many studies have demonstrated the negative impact of high rates of NK cytotoxicity (NKc) on reproductive outcomes, as well as the beneficial effects of intravenous immunoglobulin or intravenous lipid emulsion, specifically in these patients.

METHOD OF STUDY: NKc was measured in PBMCs against K562 by flow cytometry. For retrospective analysis, 2250 cycles of ET were selected and divided into four groups according to NKc levels and treatment: normal (nNKc, n = 587), elevated (eNKc, n = 615), eNKc with IvIg treatment (n = 231), and eNKc with IL treatment (n = 180). Patients were <36 years old, negative for anticardiolipin antibodies, and did not have insufficient endometrium, thrombotic disorders, uterine abnormalities, or obesity. Patients aged 36-39 years (n = 359) and 39-42 years (n = 279) were analyzed separately using a similar approach.

RESULTS

Patients with eNKc, in addition to having reduced clinical pregnancy rates (CPR) 26.99%, had increased levels of pregnancy failures (PF) 36.7% and a preterm birth rate (PBR) 13.3%, compared to nNKc patients (34.07%, 23.5%, and 3.26%, respectively). As a result, patients with eNKc had a reduced live birth rate (LBR) (17.0%), compared to nNKc patients (26.06%, OR: 1.720, p < 0.0002). Both IvIg and IL treatment resulted in increased CPR (44.15% and 39.44%) and LBR (32.03% and 32.22%) compared to patients with eNKc without treatment. IvIg treatment increased CPR even compared to patients with nNKc. However, the pregnancy failure rate (PFR) in IvIg-treated patients was not significantly reduced compared to non-treated patients with eNKc. In contrast, IL-treated patients had significantly decreased PFR compared to patients with eNKc without treatment. As a result, both treatments (IvIg and IL) led to an LBR similar to that of nNKc. Both therapies (IvIg and IL) did not affect the Preterm birth rate, which remained relatively high (14.86% and 13.79%, respectively). However, the frequency of antenatal or prenatal fetal death was the same in all groups. In patients aged 36-39 years, the results were quite similar, although the PFR in all groups was already significantly higher. However, in patients aged 39-42 years, the negative impact of eNKc was no longer significant, as high PFR and low LBR were also found in patients with nNKc. Nevertheless, even in this group, IvIg therapy led to higher LBR rates compared to eNKc without therapy.

CONCLUSIONS

Our findings highlight the negative impact of high levels of NK cytotoxicity on all stages of the reproductive process. Treatment with IvIg and IL in this group significantly improves LBR. It seems that the strength of IvIg is based on a strong increase in the CPR even compared with nNKc patients, whereas IL's effectiveness is more based on a significantly reduced PF rate. It also appears that the efficacy of IvIg is not limited to the group of patients with eNKc. Combining IvIg and IL treatments may enhance the results in patients with elevated NK activity.