P-478 The decreases in serum soluble programmed cell death ligand −1 level are associated with missed miscarriage in humans
Authors: Qin L , Chen C , Wu J , Poon L C , Wang C , Guo X , Song L , Wang X , Zhang Q , Ye Z , Yang Y , Lu J , Yao J , Ye D , Wang Y 
Published: June 2023

Abstract

Study question
The perturbations in serum levels of soluble forms of programmed cell death-1 (sPD-1) and its ligand (sPD-L1) in missed miscarriage (MM) are unknown.

Summary answer
Dysfunction in PD-L1 signal has been demonstrated in MM as evidenced by a lower circulating sPD-L1 level and declined expressions of PD-L1 in placenta.

What is known already
Programmed cell death-1 (PD-1) and its ligand (PD-L1) comprise important immune inhibitory checkpoint signaling to maintain pregnancy. During pregnancy, PD-L1 is highly expressed in the trophoblasts of the placenta. The reduced placental PD-L1 expression is associated with the risk of miscarriage. Therefore, disturbance of PD-1/PD-L1 axis in the fetomaternal interface is susceptible to be an important pathogenesis for pregnancy loss. Interestingly, the soluble form of these immune checkpoint molecules is detectable and associated with immunosuppression, it raises the diagnostic potential to monitor their level to monitor pregnancy health.

Study design, size, duration
In the discovery cohort, we enrolled 108 patients with MM and 115 body mass index (BMI)-matched, healthy women with a full-term pregnancy at 6 to 13 weeks of gestation. Another cohort of 25 MM patients and 25 subjects with induced abortion was recruited for validation.

Participants/materials, setting, methods
Blood samples were collected at the ﬁrst prenatal visit for HP women or on the day of dilatation and curettage surgery (D&C) for subjects with MM or IA to measure serum sPD-1 and sPD-L1 levels. Placenta samples were harvested during the D&C within cohort 2 to examine related gene and protein expression.

Main results and the role of chance
Our results showed that circulating sPD-L1 levels were reduced by 50% in patients with MM (55.71 ± 1.54 pg/mL) compared to HP controls (107.27 ± 5.48 pg/mL, P&lt;0.001) and remained significant after adjusting for maternal age and gestational age, whereas no significant differences in sPD-1 were observed between the two groups. Applying serum sPD-L1 levels achieved an area under the receiver operating characteristics curve (AUROC) of 0.83 (95% CI: 0.77 to 0.88, P&lt;0.001) with the optimal cut-off value of 81.52 pg/ml to detect MM. Our data in the validation cohort further demonstrated that sPD-L1 was lower in MM patients relative to IA subjects. Likewise, placental PD-L1-related gene expressions were downregulated at both mRNA and protein levels in miscarriage samples relative to samples in IA groups and were positively associated with sPD-L1 levels in maternal circulation

Limitations, reasons for caution
This study was conducted in East Asian women, further studies are required for the evaluation of the serum PD-1 and sPD-L1 levels in different ethnic groups. Secondly, due to the cross-sectional nature of the study design, whether the sPD-L1 levels could utilize as a predictive biomarker is questioned.

Wider implications of the findings
The maternal serum sPD-L1 level has the potential to be a diagnostic aid for pregnancy maintenance. Moreover, insufficient PD-L1 expression in the feto-maternal interface may act as one of the potential pathogenic events to trigger early pregnancy loss.

Trial registration number
not applicable