Interventions to improve reproductive outcomes in women with elevated natural killer cells undergoing assisted reproduction techniques: a systematic review of literature.

STUDY QUESTION: Is there any scientific evidence to support the routine use of adjuvant therapies for women with elevated natural killer (NK) cells undergoing assisted reproduction techniques (ARTs) in order to improve live birth rate? SUMMARY ANSWER: Due to the poor quality evidence, this review does not support the use of described adjuvant treatments in women found to have elevated absolute numbers or activity of NK cells undergoing ART. WHAT IS KNOWN ALREADY: Deregulation in the numbers of NK cells and/or their activity, in the blood as well as in the endometrium, has been associated with various manifestations of reproductive failure. NK cell analysis is becoming increasingly popular as a test offered to investigate the causes of reproductive failure. Adjuvant therapies influencing the NK cells have been postulated as therapeutic options for couples where deregulation of this component of the maternal immune system is suspected as the cause of infertility or implantation failure. STUDY DESIGN, SIZE, DURATION: Systematic review. Embase, LILACS, MEDLINE, PsycINFO, CENTRAL and CINAHL databases from 1946 to present were searched with no language restrictions. PARTICIPANTS/MATERIALS, SETTING,
METHODS: Studies evaluating the use of adjuvant therapies in women undergoing ART where NK cell numbers and/or activity were assessed were considered eligible for inclusion. MAIN RESULTS AND THE ROLE OF CHANCE: Only three studies (one in abstract form only) meeting the inclusion criteria were identified: two reported the use of intravenous immunoglobulins (IVIg) and one the use of oral prednisolone. All studies demonstrated a beneficial effect of the interventions on clinical pregnancy rates with a risk ratio (RR) of 1.63 [95% confidence interval (CI) 1.00-2.66] for prednisolone and 3.41 (95%CI 1.90-6.11) for IVIg. Studies assessing the efficacy of IVIg have also reported live birth rate with an RR of 3.94 (95% CI 2.01-7.69) favoring the intervention. Data heterogeneity was substantial however (I(2) = 66%) suggesting a cautious interpretation of the results. LIMITATIONS, REASONS FOR CAUTION: Differing study populations, lack of statistical power, method of data presentation (per couple or per cycle), the use of additional medications and differing dosage regimes contribute to data heterogeneity and suggest a cautious approach to data interpretation. WIDER IMPLICATIONS OF THE
FINDINGS: This review identified some data showing that adjuvant therapies (mainly IVIg) in this selected population seem to confer some benefit on ART outcome. However, overall, the review does not support the use of prednisolone, IVIg or any other adjuvant treatment in women undergoing ART who are found to have elevated absolute numbers or activity of NK cells, purely due to the paucity of, or poor quality of, the evidence. Agreement as to the most reliable NK cell testing method must be made by the scientific community as well as 'normal' NK cell levels unequivocally defined. Well designed, sufficiently powered RCTs with an appropriate population selection and using the same NK cell testing methodology are required to ascertain the actual benefit of using adjuvant therapy treatment for elevated NK cell levels or activity in the context of pregnancy outcome following IVF. STUDY FUNDING/COMPETING INTEREST(S): None.