Aerobe Cycling Training in Women With Unexplained Recurrent Pregnancy Loss

Study Overview
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Brief Summary
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In 50% of women with recurrent pregnancy loss (RPL) miscarriages are unexplained, therefore no therapeutic intervention is possible. In a pilot study, women with unexplained RPL showed less endometrial NK cells (eNK) compared to women with a previously uncomplicated pregnancy. It is known that eNK cells are important for embryo implantation during early pregnancy. Investigators presume that high sympathetic activity in these women is related to eNK cell number, function and phenotype and that exercise is an effective intervention to lower sympathetic activity and to influence the immune system, as especially peripheral NK cells have been assumed to be responsive to physical training. The investigators hypothesize that moderate exercise can lower the adrenergic tone of the sympathetic nervous system hereby influencing endometrial NK cells in women with RPL and eventually pregnancy outcome.

Official Title
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Aerobe Cycling Training in Women With Unexplained Recurrent Pregnancy Loss

Conditions
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Recurrent Pregnancy Loss

Intervention / Treatment
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* Other: Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: RPL defined as 2 or more unexplained pregnancy losses from the time of conception until 24 weeks of gestation, known cause for the miscarriages are the presence of thyroid abnormalities, anti-phospholipid syndrome, uterine malformation, and abnormal parental karyotype according to international guideline. Couples should not be aiming to conceive during the time course of the exercise intervention. Exclusion Criteria: Age above 40 years BMI above 40 Current use of immunosuppressive or biological drugs Current use of hormone conceptive HIV positivity Current or recent (<2 weeks) symptomatic genital infection such as chlamydia, gonorroa, or pelvic inflammatory disease Pre-existent diabetes mellitus, autoimmune disease or overt cardiovascular disease Vaccination (i.e Covid) within 1 month prior to or during sampling and intervention New pregnancy at time of measurements, breastfeeding Current or recent (<2-3 months ago) pregnancy (Physical) inabilities to follow moderate aerobe cycling training Participants who are not capable of signing the informed consent

Ages Eligible for Study
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Maximum Age: 40 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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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: <80% eNK<br>Women with low eNK bright cell numbers, defined as <80% of the total endometrial NK cell population | Other: Exercise<br>* Aerobe cycling training consisting of 12-weeks of HR-controlled training at 50-60% of VO2max (maximal oxygen uptake) for 1 hour, for 2 times (week: 1-6) to 3 times (week: 7-12) per week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD56 endometrial NK cell frequency | Change in CD56 eNK cell frequency measured as percentage of total lymphocyte or total CD56 population by flowcytometry. | 3 months | 
| CD56 endometrial NK cell function | Change in CD56 eNK cell function measured as percentage of CD56 degranulation by flowcytometry. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD56 endometrial NK cell phenotype | Change in CD56 eNK cell phenotype measured as percentage of (sub)population or mean fluorescent intensity respectively by flowcytometry. | 3 months | 
| CD56 peripheral NK cell frequency | Change in CD56 pNK cell frequency measured as percentage of total lymphocyte or CD56 population by flowcytometry. | 3 months | 
| CD56 peripheral NK cell function | Change in CD56 pNK cell function measured as percentage of CD56 degranulation by flowcytometry. | 3 months | 
| CD56 peripheral NK cell phenotype | Change in CD56 pNK cell phenotype measured as percentage of (sub)population or mean fluorescent intensity respectively by flowcytometry. | 3 months | 
| Vaginal microbiome | Change in taxonomic classification of vaginal microbiota of different subtypes but also classified in clustering of different subtypes. | 3 months | 
| Metabolic syndrome parameters I | Change in cm waist circumference. | 3 months | 
| Metabolic syndrome parameters II | Chance in mmHg blood pressure, both systolic as diastolic. | 3 months | 
| Metabolic syndrome parameters III | Change in concentration (mg/dL) triglyceride. | 3 months | 
| Metabolic syndrome parameters IV | Change in concentration (mg/dL) cholesterol levels. | 3 months | 
| Metabolic syndrome parameters V | Change in concentration (mg/dL) blood sugar levels. | 3 months | 
| Sympathetic activity | Change in baroreceptor sensitivity in ms/mmHg. | 3 months | 
| Uterine blood flow | Change in pulsatility index, lower indicates better outcome. | 3 months | 
| Physical fitness | Change in VO2max. | 3 months | 
| Pregnancy rate and live birth rate after one year of intervention, higher rater indicate better outcome. | Questionnaire. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Natural Killer cells