P–424 Evaluating the relationship between endoplasmic reticulum stress and recurrent pregnancy loss in a young population cohort
Authors: Topba. Selcuki N F , Cakmak K , Yilmaz S , Ozdemir I , Oral E 
Published: August 2021

Abstract

Study question
Does endoplasmic reticulum (ER) stress evaluated by X-box binding protein 1 (XBP–1) among patients aged 18–30 years play a role in recurrent pregnancy loss (RPL)?

Summary answer
High levels of XBP–1 observed in patients with known RPL indicate that ER stress plays an important role in RPL.

What is known already
Female reproductive tract undergoes dynamic changes during oogenesis which require protein synthesis, folding, maturation, which take place in the ER. ER is also responsible for destruction of unfolded/misfolded proteins. Excess accumulation of these faulty proteins leads to ER stress, which actives unfolded protein response (UPR). XBP–1 is a transcription factor involved in UPR and regulates ER stress-mediated apoptosis. Regulation of ER homeostasis is important in folliculogenesis, oocyte maturation and embryogenesis. It is also known that ER stress has a positive correlation with age and it is associated with age-related diseases.

Study design, size, duration
This prospective case-controlled study was conducted at University of Health Sciences Turkey, Istanbul Kanuni Sultan Suleyman Training and Research Hospital Department of Obstetrics and Gynecology between March 2020 – September 2020. A total of 70 subjects were included in the study. All patients gave their written informed consent before their enrollment in the study.

Participants/materials, setting, methods
38 patients aged 18–30 years with a history of RPL were included in the study. Patients who had miscarriages due to fetal abnormalities, patients with infections, endocrine or genetic disorders, smokers, alcohol and/or drug abusers, with acute/chronic inflammatory diseases, patients using steroids, anti-inflammatory and antioxidant medications were excluded from the study. Age-matched 32 healthy subjects without RPL were included in the control group. XBP–1 levels were determined using Human XBP–1 ELISA Kit (Elabscience Co., USA).

Main results and the role of chance
The mean age in the control group and in the study group were 25.21±3.3 and 25.26±2.6, respectively and they were statistically similar (p = 0.324). When groups were compared according to thyroid stimulating hormone (TSH) levels and body mass index (BMI), which are additional risk factors of RPL both groups were statistically similar (p = 0.642 and 0.942, respectively). As expected gravidity and abortus numbers were significantly higher in the study group (p &lt; 0.001). A mean XBP–1 level of 1233.41± 3902.97 was determined in the control group. The mean value of the study group was calculated to be 2251.49± 9621.12. Mean XBP–1 level in the study group was significantly high (p &lt; 0.001). A receiver operating curve (ROC) analysis was conducted in the study group. The area under the curve was found to be 87% (95% CI: 79% - 95%). The specificity was 75%, sensitivity was 89%, positive LR was 3.5, negative LR was 0.15, positive predictive value was 80% and negative predictive value was 87% for the cut-off XBP–1 level at 1364.68 pg/mL.

Limitations, reasons for caution
Small sample size is an important limitation of this study. In addition, evaluating XBP–1 only in serum samples does not let us drive any conclusions on the local changes of ER stress. Studies with larger samples sizes and studying XBP–1 levels in tissue samples of endometrial material is needed.
Wider implications of the findings: The significantly high levels of XBP–1 in RPL patients younger than 30 years, indicate higher ER stress in this group even when age dependent increase in ER stress is calculated out of the equation. XBP–1 can be a promising marker in evaluating patients with a fertility wish for RPL risk.

Trial registration number
NCT04455256