Aerobe Cycling Training in Women With Unexplained Recurrent Pregnancy Loss (HMOVE)

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.

Study Overview

• Status: Recruiting
• Conditions: Recurrent Pregnancy Loss
• Intervention / Treatment: Other: Exercise

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tess Meuleman, Dr. MD.; Phone Number: 0031-631133392; Email: tess.meuleman@radboudumc.nl
• Study Contact Backup: Name: Denise Habets, Dr.; Phone Number: 0031-623385664; Email: denise.habets@mumc.nl

Study Locations

• Netherlands
  • Maastricht, Netherlands, 6202 AZ
    • Recruiting
    • Maastricht UMC+
    • Contact: Denise Habets, Dr.; Phone Number: 0031-623385664; Email: denise.habets@mumc.nl
  • Nijmegen, Netherlands, 6500 HB
    • Recruiting
    • Radboud UMC
    • Contact: Tess Meuleman, Dr. MD.; Phone Number: 0031-631133392; Email: tess.meuleman@radboudumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: <80% eNK; Women with low eNK bright cell numbers, defined as <80% of the total endometrial NK cell population	Other: Exercise; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Maastricht University Medical Center
• Investigators: Principal Investigator: Tess Meuleman, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2022
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: November 29, 2022
• First Submitted That Met QC Criteria: August 22, 2023
• First Posted (Actual): August 23, 2023

Study Record Updates

• Last Update Posted (Actual): August 23, 2023
• Last Update Submitted That Met QC Criteria: August 22, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Natural Killer cells
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pregnancy Complications; Death; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Recurrence; Abortion, Spontaneous; Abortion, Habitual; Fetal Death
• Other Study ID Numbers: HMOVE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: On reasonable special request only.

Drug and device information, study documents

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