Plasma level of mannose-binding lectin is associated with the risk of recurrent pregnancy loss but not pregnancy outcome after the diagnosis

Abstract

STUDY QUESTION Are low or high plasma mannose binding lectin (p-MBL) levels associated with recurrent pregnancy loss (RPL) and the reproductive and perinatal outcomes before and after RPL? SUMMARY ANSWER The prevalence of low p-MBL levels was significantly higher in RPL patients while high levels were significantly less prevalent. No association was found between p-MBL level and reproductive and perinatal outcomes before and after RPL. WHAT IS KNOWN ALREADY MBL is an important component in the innate immune system. Low p-MBL levels have been associated with RPL, while the correlation with high levels has been poorly studied. Adverse perinatal outcomes are generally more frequent among RPL patients, but reports concerning the association between maternal p-MBL levels and perinatal outcomes, including birth weight and gestational age, are conflicting. STUDY DESIGN, SIZE, DURATION This study was a combined cross-sectional and cohort study of 267 RPL patients admitted to the RPL Center of Western Denmark between January 2016 and March 2020. RPL patients were followed until birth of a liveborn child or until end of follow-up, March 2021. A sample of 185 healthy female blood donors of reproductive age was used as a MBL reference group. PARTICIPANTS/MATERIALS, SETTING, METHODS All RPL patients had ≥3 consecutive pregnancy losses, a regular menstrual cycle, and no known significant chromosomal or uterine malformations. At the first consultation, routine blood samples including p-MBL measurement and detailed obstetrical and perinatal information were collected. p-MBL levels in RPL patients were compared to the MBL reference group. A logistic regression analysis adjusted for relevant confounders assessed the association between low p-MBL levels and an unsuccessful reproductive outcome in RPL patients in first pregnancy after admission. Perinatal outcomes before and after RPL were compared between RPL subgroups according to low (≤500 µg/l), intermediate (501-3000 µg/l), and high (>3000 µg/l) p-MBL levels. MAIN RESULTS AND THE ROLE OF CHANCE Significantly more RPL patients had low p-MBL levels (prevalence proportion ratio [PPR]: 1.79, 95% CI: 1.34–2.38) and fewer had high p-MBL levels (PPR: 0.56, 95% CI: 0.40–0.79) compared to the reference group, while the prevalence of intermediate p-MBL level was not different between the groups (PPR: 0.86, 95% CI: 0.69-1.08). In the prospective study, low p-MBL level was not a significant risk factor for a pregnancy loss in the first pregnancy after admission after adjustment for age, BMI, and smoking. Neither before nor after the RPL diagnosis were maternal p-MBL levels significantly associated with birth weight or gestational age. LIMITATIONS, REASONS FOR CAUTION Only 161 (60.3%) patients had given birth after RPL during the follow-up period, which limited the possibility to detect clear associations between p-MBL levels and perinatal outcomes after RPL. WIDER IMPLICATIONS OF THE FINDINGS In agreement with several previous studies, low p-MBL levels are strongly associated with RPL, while this study for the first time documents that high levels may play a protective role, which suggests a causal relationship. We suggest that larger prospective studies evaluate the association between p-MBL levels and RPL prognosis. STUDY FUNDING/COMPETING INTEREST(S) No external funding was received. We acknowledge the Department of Obstetrics and Gynaecology at Aalborg University Hospital for financial support. U.S.K. has reported personal fees from Merck, consulting fees from IBSA Nordic, and a grant from Gedeon Richter, Merck and IBSA Nordic outside of the submitted work. TRIAL REGISTRATION NUMBER ID from clinicaltrials.gov is NCT04017754.

A combination of the HLA-DRB1*03 phenotype and low plasma mannose-binding lectin predisposes to autoantibody formation in women with recurrent pregnancy loss

“…We have in repeated studies in different populations of RPL patients and controls found that low levels of p-MBL are associated with increased risk of RPL with ORs between 1.46 and 1.79 ( 23 , 24 ). Moreover, the most recent study high p-MBL levels (≥3000µg/l) seemed to protect against RPL ( 23 ). In the present study, most blood samples were taken prior to pregnancy whereas 10.2% were taken in the first trimester.…”

“…The p-MBL level was determined with the enzyme-linked immunosorbent assay (ELISA) method as described by Nørgaard-Pedersen et al. ( 23 ). A low p-MBL level was defined as ≤500 µg/l, which is the cut-off value used routinely in Danish laboratories.…”

“…Anti-nuclear antibodies (ANA), anti-thyroid peroxidase (TPO) antibodies and anti-phospholipid (APL) antibodies are associated with significantly increased odds ratios (OR) for RPL ( 16 – 20 ). Maternal carriage of HLA-DRB1*03 ( 21 ) and HLA-DRB1*07 ( 22 ) alleles and p-MBL deficiency ( 23 , 24 ) have also been reported to be associated with RPL.…”

Is the Complement System Dysregulated in Preeclampsia Comorbid with HIV Infection?

“…MBL concentration is largely inherited from parents, and its concentration is typically low in normal plasma [ 81 ]. The liver plays a crucial role in increasing MBL production during the acute-phase reaction of the innate immune response [ 20 ].…”

“…Early childhood infections are more common in those with MBL deficiencies, highlighting the importance of the MBL pathway for host defence [ 80 ]. The age range during which infections linked to MBL deficiency may occur demonstrates the significance of innate host defence mechanisms during childhood, before the child’s adaptive immune response reaches its full potential [ 81 ].…”