Low Plasma Mannose Binding Lectin (p-MBL) Level is a Risk Factor for Recurrent Pregnancy Loss (RPL)

Study Overview
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Brief Summary
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The present study is based on the hypothesis, that recurrent pregnancy loss (RPL) is associated with abnormal plasma mannose binding lectin (p-MBL) level. Secondarily, p-MBL level may affect the reproductive and the perinatal outcome in the first pregnancy following RPL. Thus, the present study aim to examine whether MBL should be a biomarker for women at risk for RPL and, secondarily, affect the reproductive and perinatal outcome, and thereby help clinicians identify fragile women who need intensified perinatal care.

Detailed Description
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Recurrent pregnancy loss (RPL), defined as 3 or more consecutive pregnancy losses before 22 weeks of gestation, is a multifactorial disorder affecting 1-3% of all females of reproductive age. The underlying cause of RPL remain unknown in up to 50% of patients. Some of these patients may be affected by an aberrant immune system. Low p-MBL levels have been associated with RPL, while relations to high p-MBL levels have been poorly studied. Reports concerning association between maternal p-MBL levels and perinatal outcomes including birth weight and gestational age are conflicting. Low p-MBL level may possess a negative effect by promoting an unfavorable immune response against foreign cells such as fetal/trophoblast cells. This study is a single center a combined cross-sectional and prospective cohort study, that aims to investigate wether high and/or low p-MBL levels are associated with RPL (primary outcome) and whether it affects reproductive outcome in the first pregnancy following admission and the perinatal outcome in the first birth before and after admission (secondary outcome). If such associations exist, p-MBL could become an biomarker for the early identification of women with need for intensified perinatal care. The study sample consists of Danish women admitted to the Centre for Recurrent Pregnancy Loss of Western Denmark. The study group includes 267 women with RPL. P-MBL levels in patients are compared to those of 185 female blood donors of fertile age with unknown reproductive history. The association between low p-MBL level and successful reproductive outcomes is analyzed with logistic regression adjusted for confounding variables (age, BMI and smoking). The perinatal outcomes in first birth (>22 weeks of gestation) before and after admission are compared between RPL subgroups according to their p-MBL level; low (≤500 ug/l), intermediate (501-3000 ug/l), and high (>3000 ug/l) p-MBL levels. Female patients in the study group will have a blood sample taken at their first meeting in the the Centre for Recurrent Pregnancy Loss of Western Denmark before they become pregnant, and they will be followed until delivery of the first child after RPL, if pregnancy after RPL is achieved, or until end of study March 2021. Data on perinatal outcomes of pregnancies before and after RPL were collected at the first consultation, from hospital records, and, when needed, completed by telephone or e-mail correspondence.

Official Title
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Low Plasma MBL Level is a Risk Factor for Recurrent Pregnancy Loss

Conditions
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Recurrent Miscarriage, Spontaneous Abortion, Mannose-Binding Lectin Deficiency, Habitual Abortion, Pregnancy Complications, Pregnancy Loss, Recurrent Pregnancy Loss

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Women admitted to the Centre for Recurrent Pregnancy Loss of Western Denmark January 2016 to March 2020 Exclusion Criteria: Less than 3 consecutive pregnancy losses Significant uterine malformation on hydrosonography or hysteroscopy Significant chromosomal abnormalities Abnormal menstrual cycle length (<22 or >35 days) or irregular cycle Pregnancy at first meeting in the Recurrent Miscarriage Clinic Age <18 and >45 years

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Study sample<br>In total, 267 women with unexplained recurrent pregnancy loss was included. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses are included. Both biochemical and clinical losses documented in hospital records are accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social reasons are not included in the total number of pregnancy losses. Women are excluded from this study, if they have significant uterine malformations, significant parental chromosomal abnormalities, irregular and/or abnormal length of their menstrual cycle length (<22 and >35 days interval), and/or no MBL measurement. | |
| Reference Group<br>The MBL reference group comprised 185 Danish female blood donors of reproductive age (range 21 to 45 years), about whom we have no other information. After informed approval, all controls had an extra blood sample taken, which was analysed for p-MBL. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma MBL Level (ug/ml) | Manose Binding Lectin level in a blood sample | At first consultation. Results accessible within 3 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Giving Birth After Recurrent Pregnancy Loss (RPL) to a Child With Low Birth Weight | <2500g | at delivery | 
| Participants Giving Birth Before RPL to a Child With Low Birth Weight | <2500g | At first consultation | 
| Participants Giving Birth After RPL to a Child With Very Low Birth Weight | <1500g | at delivery | 
| Participants Giving Birth Before RPL to a Child With Very Low Birth Weight | <1500g | At first consultation | 
| Participants With Preclampsia in Pregnancy After RPL | High blood pressure and proteinuria | Developed from 20 weeks gestation and until 6 weeks postpartum. Data collected at delivery. | 
| Participants With Preclampsia in Pregnancy Before RPL | High blood pressure and proteinuria | Developed from 20 weeks gestation and until 6 weeks postpartum. Data collected at first consultation. | 
| Patients With Emergency Caesarean Section After RPL | A surgical delivery in women who were planned for vaginal delivery initially, but an acute indication for caesarean delivery has since developed. | at delivery | 
| Patients With Emergency Caesarean Section Before RPL | A surgical delivery in women who were planned for vaginal delivery initially, but an acute indication for caesarean delivery has since developed | At first consultation | 
| Patients With Elective Caesarean Section After RPL | A surgical delivery in women who were planned for caesarean delivery | at delivery | 
| Patients With Elective Caesarean Section Before RPL | A surgical delivery in women who were planned for caesarean delivery | At first consultation | 
| Patients With Severe Peripartum Hemorrhage in Birth After RPL | Hemorrhage of >999 ml | During delivery | 
| Patients With Severe Peripartum Hemorrhage in Birth Before RPL | Hemorrhage of >999 ml in minimum one previous birth befor RPL | At first consultation | 
| Patients With Moderate Peripartum Hemorrhage in Birth After RPL | Hemorrhage of 500-1000 ml | During delivery | 
| Patients With Moderate Peripartum Hemorrhage in Birth Before RPL | Hemorrhage of 500-1000 ml in minumum one previous birth before RPL | At first consultation | 
| Patients With a Preterm Birth in Birth After RPL | <37 weeks of gestation | at delivery | 
| Patients With a Preterm Birth in Birth Before RPL | <37 weeks of gestation | At first consultation | 
| Patients With a Very Preterm Birth in Birth After RPL | <32 weeks of gestation | at delivery | 
| Patients With a Very Preterm Birth in Birth Before RPL | <32 weeks of gestation | At first consultation | 
| Gender Ratio of Children Born After RPL | Gender ratio in births before RPL | At delivery | 
| Gender Ratio of Children Born Before RPL | Gender ratio in births after RPL | At first consultation | 
| Patients With a Stillbirth After RPL | Stillbirth are defined as fetal death >22 weeks of gestation and within 1 week after delivery | 1 week after delivery | 
| Patients With a Stillbirth Before RPL | Stillbirth are defined as fetal death >22 weeks of gestation and within 1 week after delivery - all women with min one previous birth are included in this analysis. | At first consultation | 
| Patients With a Liveborn After RPL | Number of women who give birth to a healthy liveborn child after RPL | Follow up at study end. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mannose binding lectin, Perinatal outcome, Recurrent pregnancy loss