The impact of previous live births on peripheral and uterine natural killer cells in patients with recurrent miscarriage

Abstract

Background Peripheral and uterine natural killer cells (pNK and uNK cells) are key players in the establishment and maintenance of pregnancy and are disturbed in patients with recurrent miscarriage (RM). Different immunologic risk factors have been proposed between patients with primary RM (pRM, no previous live birth) and secondary RM (sRM, ≥ 1 previous live birth). However, so far, the study populations mainly consisted of small subgroups. Therefore, we aimed to analyse pNK and uNK cells in a large, well defined study population within a prospective study. Methods In total, n = 575 RM patients ( n = 393 pRM, n = 182 sRM) were screened according to a standard protocol for established risk factors as well as pNK and uNK cells. Peripheral blood levels of CD45 + CD3 − CD56 + CD16 + NK cells were determined by flow cytometry and uterine CD56 + NK cells by immunohistochemistry in mid-luteal non-pregnant RM patients. Exclusion of patients with ≥1 established risk factor revealed n = 248 idiopathic RM patients (iRM, n = 167 primary iRM (ipRM), n = 81 secondary iRM (isRM)). Results Patients with pRM and ipRM showed significant higher absolute numbers and percentages of pNK cells compared to sRM and isRM patients (pRM/ipRM vs sRM/isRM, mean ± SD /μl: 239.1 ± 118.7/244.9 ± 112.9 vs 205.1 ± 107.9/206.0 ± 105.6, p = 0.004/ p = 0.009; mean ± SD %: 12.4 ± 5.5/12.8 ± 5.4 vs 11.1 ± 4.6/11.1 ± 4.3, p = 0.001; p = 0.002). Only patients with isRM showed significantly higher uNK levels compared to patients with ipRM (mean ± SD /mm 2 288.4 ± 239.3 vs 218.2 ± 184.5, p = 0.044). Conclusions The demonstrated differences in pNK and uNK cells in RM patients depending on previous live birth might indicate differences in NK cell recruitment and potentially different underlying immune disorders between pRM and sRM. As there is an overlap in the distribution of the NK cell results, further studies with focus on NK cell function are needed in order to clearly identify RM patients with distinct immune abnormalities. The clinical relevance of our findings should be interpreted cautiously until specificity and sensitivity are further evaluated.

Different Background: Natural Killer Cell Profiles in Secondary versus Primary Recurrent Pregnancy Loss

“…We have shown that in pRPL ( n = 151), significantly higher absolute numbers but not percentages were detected in comparison to sRPL ( n = 85) [ 20 ]. Lately, we confirmed these results in a large, well-defined cohort (pRPL= 393, sRPL = 182), showing significantly higher absolute numbers as well as percentages of pNK in idiopathic pRPL ( n = 167) compared to idiopathic sRPL ( n = 81) patients [ 21 ].…”

“…So far, diagnostic protocols proposed by current guidelines do not emphasize on a distinction of pRPL and sRPL [ 2 , 22 , 23 , 24 ]. However, previous studies of several groups have shown intriguing differences in the composition of clinical and immunological risk factors [ 20 , 21 , 25 , 26 ]. Recently we have shown that patients with idiopathic sRPL present higher uNK-cells, but lower pNK-cells compared to women with idiopathic pRPL and suspected a possible abnormal recruitment of NK-cells from peripheral blood to the endometrium [ 21 ].…”

“…However, previous studies of several groups have shown intriguing differences in the composition of clinical and immunological risk factors [ 20 , 21 , 25 , 26 ]. Recently we have shown that patients with idiopathic sRPL present higher uNK-cells, but lower pNK-cells compared to women with idiopathic pRPL and suspected a possible abnormal recruitment of NK-cells from peripheral blood to the endometrium [ 21 ]. However, due to a lack of a control group in this study, it remained unclear whether the changes in the RPL groups were caused by the physiological antigenic challenge during and after birth in the sRPL patients or representing an immune disorder in these patients.…”

Recurrent Spontaneous Miscarriage: a Comparison of International Guidelines

“…Furthermore, according to the ESHRE, possible testing for HLA-DRB1 can be performed in Scandinavian women with secondary spontaneous miscarriage. A distinction between primary and secondary RM with regard to immunological risk factors with reference to possible testing for HLA-DRB1 is discussed only in the guideline of the ESHRE but appears reasonable in light of recent studies [68,69].…”

“…Dennoch enthält aktuell nur die Leitlinie der ESHRE die Empfehlung Testung von ANA im Falle von RSAwenn auch nur zur möglichen Ursachenerklärung. Da höhere ANA-Titer mit Autoimmunerkrankungen wie Lupus erythematodes und dem Sjögren-Syndrom in Verbindung gebracht werden[66,67], empfiehlt die DGGG/SGGG/OEGGG im Falle des Nachweises von erhöhten ANA eine intensivierte Diagnostik zum Aus-DRB1 in der Leitlinie der ESHRE diskutiert, erscheint aber vor dem Hintergrund aktueller Studien sinnvoll[68,69].AntiphospholipidsyndromAlle Leitlinien raten zur Therapie des APLS durch die Gabe von Low Dose Aspirin (75-100 mg täglich) in Kombination mit unfraktioniertem/niedermolekularem Heparin, was auch von einer aktuellen Cochrane-Analyse unterstützt wird[70]. Nur die DGGG/ OEGGG/SGGG und die ESHRE konkretisieren die Einnahme: Die Therapie sollte zeitgleich mit dem positiven Schwangerschaftstest begonnen werden.…”