Association Between Plasma Level of Mannose Binding Lectin and Human Reproduction

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Mannose-Binding Lectin Deficiency, Recurrent Pregnancy Loss, Recurrent Implantation Failure, Infertility, Habitual Abortion, Recurrent Miscarriage, Recurrent Spontaneous Abortion

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 41 Years

Sexes Eligible for Study
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Female

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Recurrent pregnancy loss after spontaneous conception<br>Minimum three consecutive losses from pregnancies achieved after spontaneous conception | |
| Recurrent pregnancy loss after assisted reproductive treatment<br>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<br>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?
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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. |