Decrease in peripheral natural killer cell level during early pregnancy predicts live birth among women with unexplained recurrent pregnancy loss: a prospective cohort study

Previous studies have suggested that the trophoblast cells inhibit the proliferation of peripheral natural killer (pNK) cells and the level of pNK cells decrease in middle and late pregnancy stage among healthy women. The change of pNK cells level during early pregnancy and the relationship between the change of pNK level and pregnancy outcomes in women with unexplained recurrent pregnancy loss (URPL) has not been sufficiently explored.This study aims to characterize the level of pre-pregnancy pNK to early pregnancy among women with URPL and whether the change in the level of pNK cells in early pregnancy from pre-pregnancy can predict pregnancy outcomes.In this prospective cohort study, 1758 women with recurrent pregnancy loss were recruited between January 2017 and December 2021, of which 252 URPL women had pre-pregnancy and early pregnancy (4-6 weeks gestation) pNK measurements. These 252 women were divided into two groups: those with a lower gestational pNK levels (Group 1) compared to pre pregnancy, and those without (Group 2). Their respective outcomes on live birth and pregnancy loss were comparatively analyzed using Chi-square and Student's t test. Candidate influence factors for live birth were selected using the Akaike information criterion (AIC). Then the participates were randomly divided into training and testing groups. Multivariable logistic regression model was performed, and nomogram was calculated to assess the possibility of live birth. Predictive accuracy was discriminated by area under the receiver operating characteristic curve (ROC), validated by plotting the predicted probabilities and the observed probabilities. Hosmer-Lemeshow test was used to assess the goodsess of fit.When early gestational pNK cells levels were compared with pre pregnancy pNK cells levels, 61.5% (154) women had a comparatively lower early gestational pNK cells levels versus 38.9% (98) women with increase or no change of their pNK cells levels. The live birth rate in Group 1 was 89.0% (137/154), which was significantly higher than 49.0% (48/98) of Group 2 (p<0.001). Decrease of pNK cells level (odds ratio [OR]=1.36, 95% CI 1.22-1.55, p<0.001) and anti-Muellerian hormone (AMH) (OR=1.41, 95% CI 1.14-1.81, p=0.003) were important predicting factors for higher live birth. Female BMI (OR=0.97, 95% CI 0.82-1.15, p=0.763) and parity (OR=1.61, 95% CI 0.71-4.12, p=0.287) were also predicting factors. Furthermore, the area under the ROC curve of the model to diagnose of live birth was 0.853 with a sensitivity of 81.6% and specificity of 78.0% using the training dataset. And the Hosmer-Lemeshow test showed that the model was a good fit (p = 6.068).We report a comparative decrease in pNK cells levels in over 60% URPL women at 4-6 weeks of gestation, when compared to their pre-pregnancy pNK cells level. Compared to pre pregnancy pNK cells levels, a decrease pNK cells level during early pregnancy might be a useful predictor for LBR in women with URPL.