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

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

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.

Study Overview

• Status: Completed
• Conditions: Pregnancy Complications; Recurrent Miscarriage; Pregnancy Loss; Recurrent Pregnancy Loss; Spontaneous Abortion; Mannose-Binding Lectin Deficiency; Habitual Abortion

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 452

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Aalborg University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Women fulfilling the eligibility criteria will have p-MBL level measured from a blood sample when first admitted to the Centre for Recurrent Pregnancy Loss of Western Denmark and will be followed until delivery of the first child following the consecutive pregnancy losses, if pregnancy is achieved during the study period.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Study sample; 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; 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?

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.

Collaborators and Investigators

• Sponsor: Aalborg University Hospital
• Investigators: Principal Investigator: Caroline Nørgaard-Pedersen, Aalborg University Hospital

Publications and helpful links

General Publications

• Norgaard-Pedersen C, Rom LH, Steffensen R, Kesmodel US, Christiansen OB. Plasma level of mannose-binding lectin is associated with the risk of recurrent pregnancy loss but not pregnancy outcome after the diagnosis. Hum Reprod Open. 2022 Jun 7;2022(3):hoac024. doi: 10.1093/hropen/hoac024. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): March 29, 2021
• Study Completion (Actual): March 29, 2021

Study Registration Dates

• First Submitted: July 9, 2019
• First Submitted That Met QC Criteria: July 10, 2019
• First Posted (Actual): July 12, 2019

Study Record Updates

• Last Update Posted (Actual): July 30, 2021
• Last Update Submitted That Met QC Criteria: July 6, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Perinatal outcome; Mannose binding lectin; Recurrent pregnancy loss
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Death; Recurrence; Abortion, Spontaneous; Abortion, Habitual; Pregnancy Complications; Fetal Death
• Other Study ID Numbers: 36e19au5

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No