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

• Sponsor: Aalborg University Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT04017754
• Collaborator: (none)
• Enrollment: 452
• Location: 1
• Actual Duration (Months): 62.9
• Patients Per Site Per Month: 7.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Miscarriage; Spontaneous Abortion; Mannose-Binding Lectin Deficiency; Habitual Abortion; Pregnancy Complications; Pregnancy Loss; Recurrent Pregnancy Loss

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 Design

• Study Type: Observational
• Actual Enrollment: 452 participants
• Observational Model: Case-Control
• Time Perspective: Cross-Sectional
• Official Title: Low Plasma MBL Level is a Risk Factor for Recurrent Pregnancy Loss
• Actual Study Start Date: Jan 1, 2016
• Actual Primary Completion Date: Mar 29, 2021
• Actual Study Completion Date: Mar 29, 2021

Arms and Interventions

Arm	Intervention/Treatment
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.

Outcome Measures

Primary Outcome Measures

1. Plasma MBL Level (ug/ml) [At first consultation. Results accessible within 3 weeks.]

   Manose Binding Lectin level in a blood sample

Secondary Outcome Measures

1. Participants Giving Birth After Recurrent Pregnancy Loss (RPL) to a Child With Low Birth Weight [at delivery]

   <2500g

2. Participants Giving Birth Before RPL to a Child With Low Birth Weight [At first consultation]

   <2500g

3. Participants Giving Birth After RPL to a Child With Very Low Birth Weight [at delivery]

   <1500g

4. Participants Giving Birth Before RPL to a Child With Very Low Birth Weight [At first consultation]

   <1500g

5. Participants With Preclampsia in Pregnancy After RPL [Developed from 20 weeks gestation and until 6 weeks postpartum. Data collected at delivery.]

   High blood pressure and proteinuria

6. Participants With Preclampsia in Pregnancy Before RPL [Developed from 20 weeks gestation and until 6 weeks postpartum. Data collected at first consultation.]

   High blood pressure and proteinuria

7. Patients With Emergency Caesarean Section After RPL [at delivery]

   A surgical delivery in women who were planned for vaginal delivery initially, but an acute indication for caesarean delivery has since developed.

8. Patients With Emergency Caesarean Section Before RPL [At first consultation]

   A surgical delivery in women who were planned for vaginal delivery initially, but an acute indication for caesarean delivery has since developed

9. Patients With Elective Caesarean Section After RPL [at delivery]

   A surgical delivery in women who were planned for caesarean delivery

10. Patients With Elective Caesarean Section Before RPL [At first consultation]

    A surgical delivery in women who were planned for caesarean delivery

11. Patients With Severe Peripartum Hemorrhage in Birth After RPL [During delivery]

    Hemorrhage of >999 ml

12. Patients With Severe Peripartum Hemorrhage in Birth Before RPL [At first consultation]

    Hemorrhage of >999 ml in minimum one previous birth befor RPL

13. Patients With Moderate Peripartum Hemorrhage in Birth After RPL [During delivery]

    Hemorrhage of 500-1000 ml

14. Patients With Moderate Peripartum Hemorrhage in Birth Before RPL [At first consultation]

    Hemorrhage of 500-1000 ml in minumum one previous birth before RPL

15. Patients With a Preterm Birth in Birth After RPL [at delivery]

    <37 weeks of gestation

16. Patients With a Preterm Birth in Birth Before RPL [At first consultation]

    <37 weeks of gestation

17. Patients With a Very Preterm Birth in Birth After RPL [at delivery]

    <32 weeks of gestation

18. Patients With a Very Preterm Birth in Birth Before RPL [At first consultation]

    <32 weeks of gestation

19. Gender Ratio of Children Born After RPL [At delivery]

    Gender ratio in births before RPL

20. Gender Ratio of Children Born Before RPL [At first consultation]

    Gender ratio in births after RPL

21. Patients With a Stillbirth After RPL [1 week after delivery]

    Stillbirth are defined as fetal death >22 weeks of gestation and within 1 week after delivery

22. Patients With a Stillbirth Before RPL [At first consultation]

    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.

23. Patients With a Liveborn After RPL [Follow up at study end.]

    Number of women who give birth to a healthy liveborn child after RPL

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aalborg University Hospital	Aalborg		Denmark	9000

Sponsors and Collaborators

• Aalborg University Hospital

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 1, 2021

More Information

Publications

None provided.

• Responsible Party: Caroline Nørgaard-Pedersen, MD, Aalborg University Hospital
• ClinicalTrials.gov Identifier: NCT04017754
• Other Study ID Numbers: 36e19au5
• First Posted: Jul 12, 2019
• Last Update Posted: Jul 30, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Caroline Nørgaard-Pedersen, MD, Aalborg University Hospital: Mannose binding lectin; Perinatal outcome; Recurrent pregnancy loss
• Additional relevant MeSH terms: Abortion, Spontaneous; Pregnancy Complications; Fetal Death; Abortion, Habitual; Recurrence

Study Results

Participant Flow

Pre-assignment Detail	The study sample consisted of 267 female patients with RPL fulfilling the inclusion criterias.

Arm/Group Title	Study Sample	Control Group 1
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and additionally a parental chromosomal analysis in most cases.	The MBL control group comprised 185 Danish female blood donors of reproductive age (range 21 to 45 years), about whom we have no other information than their plasma MBL level. After informed approval, all controls had an extra blood sample taken, which was analysed for MBL.
Period Title: Overall Study
STARTED	267	185
COMPLETED	267	185
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Study Sample
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases.
Overall Participants	267
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	267 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.2 (5.3)
Sex: Female, Male (Count of Participants)
Female	267 100%
Male	0 0%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	267 100%
Unknown	0 0%
Region of Enrollment (participants) [Number]
Denmark	267 100%
Body mass index (kg/m²) [Mean (Full Range) ]
Mean (Full Range) [kg/m²]	25.4
Number of consecutive pregnancy losses (consecutive pregnancy losses) [Median (Full Range) ]
Median (Full Range) [consecutive pregnancy losses]	3
Percentage with primary Recurrent pregnancy loss (RPL) (Percentage of all RPL patients) [Number]
Number [Percentage of all RPL patients]	53.9

Outcome Measures

1. Primary Outcome

Title	Plasma MBL Level (ug/ml)
Description	Manose Binding Lectin level in a blood sample
Time Frame	At first consultation. Results accessible within 3 weeks.

Outcome Measure Data

Analysis Population Description

18 women were pregnant <12 weeks when blood sample was collected.

Arm/Group Title	Study Sample	MBL Reference Group
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and additionally a parental chromosomal analysis in most cases.	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 than their plasma MBL level. After informed approval, all controls had an extra blood sample taken, which was analysed for MBL.
Measure Participants	267	185
Median (Inter-Quartile Range) [ug/l]	717	1717

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Study Sample, MBL Reference Group
	Comments	Comparing the risk of low p-MBL level between RPL patients and MBL reference group. We hypothesized that more RPL patients had a low p-MBL level; thus, the null hypothesis was that no difference existed.
	Type of Statistical Test	Equivalence
	Comments	A p-value <0.05 was considered significant for at difference in frequency of low p-MBL level(<500 ug/l) between groups.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Prevalence proportion ratio
	Estimated Value	1.79
	Confidence Interval	(2-Sided) 95%; 1.34 to 2.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	The numerator is the risk of low p-MBL in the study sample with RPL patients and the denominator is the risk of low p-MBL in control group 1 of female blood donors.

2. Secondary Outcome

Title	Participants Giving Birth After Recurrent Pregnancy Loss (RPL) to a Child With Low Birth Weight
Description	<2500g
Time Frame	at delivery

Outcome Measure Data

Analysis Population Description

Patients who have given birth after admission within each p-MBL level subgroup

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 79 RPL patients with p-MBL <500 ug/l gave birth after RPL, but birth weight was missing in 3 patients.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 23 RPL patients with p-MBL >3000 ug/l gave birth after RPL, but birth weight was missing in 2 patients.
Measure Participants	76	21
Number [participants]	3 1.1%	1 NaN

3. Secondary Outcome

Title	Participants Giving Birth Before RPL to a Child With Low Birth Weight
Description	<2500g
Time Frame	At first consultation

Outcome Measure Data

Analysis Population Description

participants who had sRPL; thus, who had given birth before admission to at least one child. Data concerns first delivery.

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 54 RPL patients with p-MBL <500 ug/l gave birth before RPL, but information on three of these births were excluded from this analysis since they were stillbirths.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 26 RPL patients with p-MBL >3000 ug/l gave birth before RPL but 1 was excluded from this analysis since it was a stillbirth.
Measure Participants	51	25
Number [participants]	4 1.5%	2 NaN

4. Secondary Outcome

Title	Participants Giving Birth After RPL to a Child With Very Low Birth Weight
Description	<1500g
Time Frame	at delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 79 RPL patients with p-MBL <500 ug/l gave birth after RPL but birth weight was missing in 3 of these patients	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 23 RPL patients with p-MBL >3000 ug/l gave birth after RPL, but birth weight was missing for 2 of these patients.
Measure Participants	76	21
Number [participants]	0 0%	0 NaN

5. Secondary Outcome

Title	Participants Giving Birth Before RPL to a Child With Very Low Birth Weight
Description	<1500g
Time Frame	At first consultation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 54 RPL patients with p-MBL <500 ug/l gave birth before RPL but information on three of these births were excluded from this analysis since they were stillbirths.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 26 RPL patients with p-MBL >3000 ug/l gave birth before RPL but information on one of these births were excluded from this analysis since it was a stillbirth.
Measure Participants	51	25
Count of Participants [Participants]	0 0%	0 NaN

6. Secondary Outcome

Title	Participants With Preclampsia in Pregnancy After RPL
Description	High blood pressure and proteinuria
Time Frame	Developed from 20 weeks gestation and until 6 weeks postpartum. Data collected at delivery.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 79 RPL patients with p-MBL <500 ug/l gave birth after RPL.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 23 RPL patients with p-MBL >3000 ug/l gave birth after RPL.
Measure Participants	79	23
Count of Participants [Participants]	7 2.6%	0 NaN

7. Secondary Outcome

Title	Participants With Preclampsia in Pregnancy Before RPL
Description	High blood pressure and proteinuria
Time Frame	Developed from 20 weeks gestation and until 6 weeks postpartum. Data collected at first consultation.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 54 RPL patients with p-MBL <500 ug/l gave birth before RPL but information on three of these births were excluded from this analysis since they were stillbirths.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 26 RPL patients with p-MBL >3000 ug/l gave birth before RPL but information on one of these births were excluded from this analysis since was a stillbirth.
Measure Participants	51	25
Count of Participants [Participants]	6 2.2%	2 NaN

8. Secondary Outcome

Title	Patients With Emergency Caesarean Section After RPL
Description	A surgical delivery in women who were planned for vaginal delivery initially, but an acute indication for caesarean delivery has since developed.
Time Frame	at delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 79 RPL patients with p-MBL <500 ug/l gave birth after RPL.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 23 RPL patients with p-MBL >3000 ug/l gave birth after RPL but 1 delivery method was missing.
Measure Participants	79	22
Count of Participants [Participants]	10 3.7%	4 NaN

9. Secondary Outcome

Title	Patients With Emergency Caesarean Section Before RPL
Description	A surgical delivery in women who were planned for vaginal delivery initially, but an acute indication for caesarean delivery has since developed
Time Frame	At first consultation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 54 RPL patients with p-MBL <500 ug/l gave birth before RPL and data on one delivery method is missing.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 26 RPL patients with p-MBL >3000 ug/l gave birth before RPL but data on two delivery methods is missing.
Measure Participants	53	24
Count of Participants [Participants]	12 4.5%	6 NaN

10. Secondary Outcome

Title	Patients With Elective Caesarean Section After RPL
Description	A surgical delivery in women who were planned for caesarean delivery
Time Frame	at delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 79 RPL patients with p-MBL <500 ug/l gave birth after RPL.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 23 RPL patients with p-MBL >3000 ug/l gave birth after RPL but data on one delivery method is missing.
Measure Participants	79	22
Count of Participants [Participants]	13 4.9%	3 NaN

11. Secondary Outcome

Title	Patients With Elective Caesarean Section Before RPL
Description	A surgical delivery in women who were planned for caesarean delivery
Time Frame	At first consultation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 54 RPL patients with p-MBL <500 ug/l gave birth before RPL but data on one delivery method is missing.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 26 RPL patients with p-MBL >3000 ug/l gave birth before RPL but data on two delivery methods were missing.
Measure Participants	53	24
Count of Participants [Participants]	6 2.2%	0 NaN

12. Secondary Outcome

Title	Patients With Severe Peripartum Hemorrhage in Birth After RPL
Description	Hemorrhage of >999 ml
Time Frame	During delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 79 RPL patients with p-MBL <500 ug/l gave birth after RPL but information on peripartum hemorrhage were missing in 1 case.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 23 RPL patients with p-MBL >3000 ug/l gave birth after RPL.
Measure Participants	78	23
Count of Participants [Participants]	6 2.2%	3 NaN

13. Secondary Outcome

Title	Patients With Severe Peripartum Hemorrhage in Birth Before RPL
Description	Hemorrhage of >999 ml in minimum one previous birth befor RPL
Time Frame	At first consultation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 54 RPL patients with p-MBL <500 ug/l gave birth before RPL but information on peripartum hemorrhage were missing for 9 patients.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 26 RPL patients with p-MBL >3000 ug/l gave birth before RPL but information on peripartum hemorrhage were missing for 5 patients.
Measure Participants	45	21
Count of Participants [Participants]	8 3%	0 NaN

14. Secondary Outcome

Title	Patients With Moderate Peripartum Hemorrhage in Birth After RPL
Description	Hemorrhage of 500-1000 ml
Time Frame	During delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 79 RPL patients with p-MBL <500 ug/l gave birth after RPL but data on one hemorrhage was missing.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 23 RPL patients with p-MBL >3000 ug/l gave birth after RPL.
Measure Participants	78	23
Count of Participants [Participants]	21 7.9%	2 NaN

15. Secondary Outcome

Title	Patients With Moderate Peripartum Hemorrhage in Birth Before RPL
Description	Hemorrhage of 500-1000 ml in minumum one previous birth before RPL
Time Frame	At first consultation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 54 RPL patients with p-MBL <500 ug/l gave birth before RPL but information on permpartum hemorrhage was missing for 9 patients.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 26 RPL patients with p-MBL >3000 ug/l gave birth before RPL but information on permpartum hemorrhage was missing for 5 patients.
Measure Participants	45	21
Count of Participants [Participants]	6 2.2%	6 NaN

16. Secondary Outcome

Title	Patients With a Preterm Birth in Birth After RPL
Description	<37 weeks of gestation
Time Frame	at delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 79 RPL patients with p-MBL <500 ug/l gave birth after RPL but information on gestational age was missing in 1 patient.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 23 RPL patients with p-MBL >3000 ug/l gave birth after RPL but information on gestational age was missing in 1 patient.
Measure Participants	78	22
Count of Participants [Participants]	8 3%	3 NaN

17. Secondary Outcome

Title	Patients With a Preterm Birth in Birth Before RPL
Description	<37 weeks of gestation
Time Frame	At first consultation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 54 RPL patients with p-MBL <500 ug/l gave birth before RPL, but information on 2 births were missing and 3 stillbirths were excluded.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 26 RPL patients with p-MBL >3000 ug/l gave birth before RPL but information on 2 births were missing and 1 stillbirth was excluded.
Measure Participants	49	23
Count of Participants [Participants]	4 1.5%	1 NaN

18. Secondary Outcome

Title	Patients With a Very Preterm Birth in Birth After RPL
Description	<32 weeks of gestation
Time Frame	at delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 79 RPL patients with p-MBL <500 ug/l gave birth after RPL but information on gestational age was missing in 1 patient.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 23 RPL patients with p-MBL >3000 ug/l gave birth after RPL but information on gestational age was missing in 2 patients.
Measure Participants	78	21
Count of Participants [Participants]	2 0.7%	0 NaN

19. Secondary Outcome

Title	Patients With a Very Preterm Birth in Birth Before RPL
Description	<32 weeks of gestation
Time Frame	At first consultation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 54 RPL patients with p-MBL <500 ug/l gave birth before RPL, but information on 2 births were missing and 3 stillbirths were excluded.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 26 RPL patients with p-MBL >3000 ug/l gave birth before RPL but information on 2 births were missing and 1 stillbirth was excluded.
Measure Participants	49	23
Count of Participants [Participants]	0 0%	0 NaN

20. Secondary Outcome

Title	Gender Ratio of Children Born After RPL
Description	Gender ratio in births before RPL
Time Frame	At delivery

Outcome Measure Data

Analysis Population Description

male:female ratio

Arm/Group Title	Study sampleRPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 79 RPL patients with p-MBL <500 ug/l gave birth after RPL. One of these births was a twin birth of same gender, which was counted as 1.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 23 RPL patients with p-MBL >3000 ug/l gave birth after RPL. One of these births was a twin birth of same gender, which was counted as 1.
Measure Participants	79	23
Number [male:female ratio]	1.08	2.29

21. Secondary Outcome

Title	Gender Ratio of Children Born Before RPL
Description	Gender ratio in births after RPL
Time Frame	At first consultation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 54 RPL patients with p-MBL <500 ug/l gave birth before RPL and none of these were twins. 7 patients had >1 child birth before RPL of mixed gender and therefore excluded from this analysis.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 26 RPL patients with p-MBL >3000 ug/l gave birth before RPL and 3 patients had >1 child birth before RPL of mixed gender and therefore excluded from this analysis.
Measure Participants	47	23
Number [male:female ratio]	3.27	1.88

22. Secondary Outcome

Title	Patients With a Stillbirth After RPL
Description	Stillbirth are defined as fetal death >22 weeks of gestation and within 1 week after delivery
Time Frame	1 week after delivery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 67 RPL patients with p-MBL <500 ug/l gave birth after RPL.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 20 RPL patients with p-MBL >3000 ug/l gave birth after RPL.
Measure Participants	79	23
Count of Participants [Participants]	0 0%	0 NaN

23. Secondary Outcome

Title	Patients With a Stillbirth Before RPL
Description	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.
Time Frame	At first consultation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 54 RPL patients with p-MBL <500 ug/l gave birth >22 weeks before RPL.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 26 RPL patients with p-MBL >3000 ug/l gave birth >22 weeks before RPL.
Measure Participants	54	26
Count of Participants [Participants]	4 1.5%	3 NaN

24. Secondary Outcome

Title	Patients With a Liveborn After RPL
Description	Number of women who give birth to a healthy liveborn child after RPL
Time Frame	Follow up at study end.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RPL Patients With pMBL <500 ug/l	RPL Patients With p-MBL >3000 ug/l
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 119 RPL patients had MBL>500 ug/l.	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases. 46 patients had MBL>3000.
Measure Participants	119	46
Count of Participants [Participants]	79 29.6%	23 NaN

Adverse Events

Time Frame	From January 2016 until March 2020 patients were admitted and serious adverse events were recorded from the day of admission to the RPL center and until birth (up to 2 years) or the end of the study in March 2020.
Adverse Event Reporting Description	Hospitalization due to abortion or birth was not considered as a serious adverse event. Only serious adverse events were recorded since no study specific intervention was performed.
Arm/Group Title	Study Sample
Arm/Group Description	Women with unexplained recurrent pregnancy loss. Only patients with a history of 3 or more consecutive spontaneous pregnancy losses were included. Both biochemical and clinical losses documented in hospital records were accepted. Verified extrauterine pregnancy losses, complete molar pregnancies, and induced abortions of social and genetic reasons were 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. At the first consultation in The Centre for Recurrent Pregnancy Loss of Western Denmark, all women have a diagnostic work-up, including collection of an obstetric and gynaecologic history, a routine blood analysis, a uterine hydrosonography, hysteroscopy, or hysterosalpingography, and a parental chromosomal analysis in most cases.
All Cause Mortality
	Study Sample
	Affected / at Risk (%)	# Events
Total	0/267 (0%)
Serious Adverse Events
	Study Sample
	Affected / at Risk (%)	# Events
Total	0/267 (0%)
Other (Not Including Serious) Adverse Events
	Study Sample
	Affected / at Risk (%)	# Events
Total	0/267 (0%)

Limitations/Caveats

161 (60.3 %) patients gave birth after RPL during the study period, which limited the possibility to detect clear associations between p-MBL levels and perinatal outcomes after RPL.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.