Association Between Plasma Level of Mannose Binding Lectin and Human Reproduction

Is Plasma Level of Mannose Binding Lectin Associated With Reproductive Failure?

A low plasma level of mannose binding lectin (p-MBL) is associated with unexplained recurrent pregnancy loss (RPL), but it is not investigated if it is associated with unexplained reproductive failure in general, including recurrent implantation failure (RIF) after assisted reproductive technology (ART) (including IVF, ICSI and FET), recurrent pregnancy loss (RPL) after spontaneous conception, and RPL after ART.

Study Overview

• Status: Recruiting
• Conditions: Infertility; Recurrent Miscarriage; Recurrent Implantation Failure; Recurrent Pregnancy Loss; Mannose-Binding Lectin Deficiency; Habitual Abortion; Recurrent Spontaneous Abortion

Detailed Description

The prevalence of a low p-MBL level is higher in patients with unexplained RPL than in the background population, while a high level is significantly less frequent in RPL patients (Nørgaard-Pedersen et al., submitted).

Approximately 50% of RPL patients have none of the evidence-based risk factors associated with RPL. Unexplained RPL is more complicated since finding the cause is essential for offering the optimal intervention to improve the patient's chances of a child.

Other conditions characterized by reproductive failure are infertility and recurrent implantation failure (RIF). The underlying mechanisms and the physiologic stage in early pregnancy being complicated and impeding normal pregnancy may probably differ between these pathologic conditions, since theoretically RIF would involve complicated embryo apposition, adhesion and invasion and clinical/visualized pregnancy losses would involve complicated stages later in the implantation process and fetal development. However, these conditions are suggested to have partly overlapping causes since most of the evidence-based risk factor recur; including parental chromosomal abnormalities, and maternal endocrine disorders, acquired thrombophilia, anatomic abnormalities in the uterine cavity, and endometrial and ovarian diseases. In addition, adverse immune responses against the embryo have been suggested as a cause of reproductive failure. If RPL is associated with a low p-MBL level, RIF may be so too.

The investigators aim to explore the p-MBL level in patients suffering from reproductive failure.

If low p-MBL level is associated with all the investigated subgroups of patients suffering from reproductive failure, this would strengthen our theory that MBL is involved in the pathophysiology characterized by reproductive failure in the very early stages of pregnancy and should therefore take part in the exploration of all patients with reproductive failure.

• Study Type: Observational
• Enrollment (Anticipated): 500

Contacts and Locations

• Study Contact: Name: Caroline Noergaard-Pedersen, M.D.; Phone Number: +4541120267; Email: c.noergaardpedersen@rn.dk
• Study Contact Backup: Name: Ole B. Christiansen; Email: olbc@rn.dk

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Recruiting
    • Aagaard Klinik
    • Contact: Aboubakar Cissé, MD; Phone Number: +45 86 12 61 21

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 41 years (Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Danish female population. The centers cover mainly the western region of Denmark, but patients from all over Denmark can be treated at each center.

The Aagaard Klinik is a private IVF clinic and therefore their patients pay for their ART treatments. Patients contact the clinic themself when they need medical support because of reproductive failure.

The RPL center at AaUH (public hospital) is available without costs for the patient. Patients are referred from their practitioner or fertility clinic or gynecologist when they have experienced 3 or more pregnancy losses (including biochemical and clinical pregnancies).

Description

Inclusion Criteria:

fulfil one of the following:

• 3 consecutive pregnancy losses after spontaneous conception
• 3 consecutive pregnancy losses after assisted reproductive technology treatment (ART) including IVF, ICSI and FET
• 3 failed embryo transfers characterized by no achieved pregnancy (after 3 cycles with minimum 1 embryo transfer of a good-quality embryo in each cycle.)

Exclusion Criteria:

• Age <18 or >45 years
• AMH <4.0 pmol/l unless donor egg in previous cycles
• Significant uterine malformation
• Known endometrial pathologies including intrauterine endometriosis, adenomyosis, hyperplasia or polyps
• Known chromosomal abnormalities
• Pregnancy >9 weeks of gestation at the time collecting the blood sample

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Recurrent pregnancy loss after spontaneous conception; Minimum three consecutive losses from pregnancies achieved after spontaneous conception
Recurrent pregnancy loss after assisted reproductive treatment; Minimum three consecutive losses from pregnancies achieved after assisted reproductive treatment (ART), which includes in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and frozen embryo transfer (FER).
Recurrent implantation failure; Minimum three consecutive embryo transfers (ET) of good quality embryos with no hCG production. The patient must not have experienced any clinical pregnancies (i.e. evidence of pregnancy on an US or by histopathological examination) after IVF or spontaneous conception. Biochemical pregnancies after spontaneous conception, which terminated before evidence of a gestational sac on an ultrasonic scan (US) could be visualized and before the series of RIF occurred, are accepted.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Low p-MBL level	Low plasma mannose binding lectin level defined as <500 ug/l	Blood sample collected after admission when the patient is not pregnant or <9 weeks of gestation.
Very low p-MBL level	Very low plasma mannose binding lectin level defined as <100 ug/l	Blood sample collected after admission when the patient is not pregnant or <9 weeks of gestation.
High p-MBL level	High plasma mannose binding lectin level defined as >3000 ug/l	Blood sample collected after admission when the patient is not pregnant or <9 weeks of gestation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Odds ratio for a low p-MBL level	Comparing prevalence in the patient group with danish female background population (n=185)	Blood sample collected after admission when the patient is not pregnant or <9 weeks of gestation.

Collaborators and Investigators

• Sponsor: Aalborg University Hospital
• Investigators: Principal Investigator: Caroline Nørgaard-Pedersen, M.D., Aalborg University Hospital, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2022
• Primary Completion (Anticipated): November 30, 2022
• Study Completion (Anticipated): November 30, 2022

Study Registration Dates

• First Submitted: December 19, 2021
• First Submitted That Met QC Criteria: December 19, 2021
• First Posted (Actual): December 27, 2021

Study Record Updates

• Last Update Posted (Actual): February 3, 2022
• Last Update Submitted That Met QC Criteria: February 2, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pregnancy Complications; Infertility; Recurrence; Abortion, Spontaneous; Abortion, Habitual
• Other Study ID Numbers: MBL_reproduction_2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data obtained through this study may be provided to qualified researchers with academic interest in RPL after approval by the researchers. Data will be coded with no personal identifiers included. Approval of the request and execution of all applicable agreements (i.e. a material transfer agreement) are prerequisites to the sharing of data with the requesting party. Please contact the primary researcher. The researchers maintain the right to reject the request. Data requests can be submitted starting 12 months after article publication.
• IPD Sharing Time Frame: Data requests can be submitted starting 12 months after article publication and up to 36months only on request.
• IPD Sharing Access Criteria: Only on request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

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