Habitual Abortion, Mannose-Binding Lectin Deficiency, Pregnancy Complications, Pregnancy Loss, Recurrent Miscarriage, Recurrent Pregnancy Loss, Spontaneous Abortion
Conditions
Keywords
Mannose binding lectin, Perinatal outcome, Recurrent pregnancy loss
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.
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.
Interventions
None listed
Sponsors
Study design
Eligibility
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma MBL Level (ug/ml) | At first consultation. Results accessible within 3 weeks. | Manose Binding Lectin level in a blood sample |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants Giving Birth After RPL to a Child With Very Low Birth Weight | at delivery | \<1500g |
| Participants Giving Birth Before RPL to a Child With Very Low Birth Weight | At first consultation | \<1500g |
| Participants Giving Birth After Recurrent Pregnancy Loss (RPL) to a Child With Low Birth Weight | at delivery | \<2500g |
| 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 |
| 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 |
| 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. |
| 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 |
| Patients With Elective Caesarean Section After RPL | at delivery | A surgical delivery in women who were planned for caesarean delivery |
| Patients With Elective Caesarean Section Before RPL | At first consultation | A surgical delivery in women who were planned for caesarean delivery |
| Patients With Severe Peripartum Hemorrhage in Birth After RPL | During delivery | Hemorrhage of \>999 ml |
| Patients With Severe Peripartum Hemorrhage in Birth Before RPL | At first consultation | Hemorrhage of \>999 ml in minimum one previous birth befor RPL |
| Participants Giving Birth Before RPL to a Child With Low Birth Weight | At first consultation | \<2500g |
| Patients With Moderate Peripartum Hemorrhage in Birth Before RPL | At first consultation | Hemorrhage of 500-1000 ml in minumum one previous birth before RPL |
| Patients With a Preterm Birth in Birth After RPL | at delivery | \<37 weeks of gestation |
| Patients With a Preterm Birth in Birth Before RPL | At first consultation | \<37 weeks of gestation |
| Patients With a Very Preterm Birth in Birth After RPL | at delivery | \<32 weeks of gestation |
| Patients With a Very Preterm Birth in Birth Before RPL | At first consultation | \<32 weeks of gestation |
| Gender Ratio of Children Born After RPL | At delivery | Gender ratio in births before RPL |
| Gender Ratio of Children Born Before RPL | At first consultation | Gender ratio in births after RPL |
| 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 |
| 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. |
| Patients With a Liveborn After RPL | Follow up at study end. | Number of women who give birth to a healthy liveborn child after RPL |
| Patients With Moderate Peripartum Hemorrhage in Birth After RPL | During delivery | Hemorrhage of 500-1000 ml |
Countries
Denmark
Participant flow
Pre-assignment details
The study sample consisted of 267 female patients with RPL fulfilling the inclusion criterias.
Participants by arm
| Arm | Count |
|---|---|
| Study Sample 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. | 267 |
| Total | 267 |
Baseline characteristics
| Characteristic | Study Sample |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 267 Participants |
| Age, Continuous | 33.2 years STANDARD_DEVIATION 5.3 |
| Body mass index | 25.4 kg/m² |
| Number of consecutive pregnancy losses | 3 consecutive pregnancy losses |
| Percentage with primary Recurrent pregnancy loss (RPL) | 53.9 Percentage of all RPL patients |
| Race/Ethnicity, Customized Caucasian | 267 participants |
| Race/Ethnicity, Customized Unknown | 0 participants |
| Region of Enrollment Denmark | 267 participants |
| Sex: Female, Male Female | 267 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 267 |
| other Total, other adverse events | 0 / 267 |
| serious Total, serious adverse events | 0 / 267 |
Outcome results
Plasma MBL Level (ug/ml)
Manose Binding Lectin level in a blood sample
Time frame: At first consultation. Results accessible within 3 weeks.
Population: 18 women were pregnant \<12 weeks when blood sample was collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Study Sample | Plasma MBL Level (ug/ml) | 717 ug/l |
| MBL Reference Group | Plasma MBL Level (ug/ml) | 1717 ug/l |
Gender Ratio of Children Born After RPL
Gender ratio in births before RPL
Time frame: At delivery
Population: male:female ratio
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Sample | Gender Ratio of Children Born After RPL | 1.08 male:female ratio |
| MBL Reference Group | Gender Ratio of Children Born After RPL | 2.29 male:female ratio |
Gender Ratio of Children Born Before RPL
Gender ratio in births after RPL
Time frame: At first consultation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Sample | Gender Ratio of Children Born Before RPL | 3.27 male:female ratio |
| MBL Reference Group | Gender Ratio of Children Born Before RPL | 1.88 male:female ratio |
Participants Giving Birth After Recurrent Pregnancy Loss (RPL) to a Child With Low Birth Weight
\<2500g
Time frame: at delivery
Population: Patients who have given birth after admission within each p-MBL level subgroup
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Sample | Participants Giving Birth After Recurrent Pregnancy Loss (RPL) to a Child With Low Birth Weight | 3 participants |
| MBL Reference Group | Participants Giving Birth After Recurrent Pregnancy Loss (RPL) to a Child With Low Birth Weight | 1 participants |
Participants Giving Birth After RPL to a Child With Very Low Birth Weight
\<1500g
Time frame: at delivery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Sample | Participants Giving Birth After RPL to a Child With Very Low Birth Weight | 0 participants |
| MBL Reference Group | Participants Giving Birth After RPL to a Child With Very Low Birth Weight | 0 participants |
Participants Giving Birth Before RPL to a Child With Low Birth Weight
\<2500g
Time frame: At first consultation
Population: participants who had sRPL; thus, who had given birth before admission to at least one child. Data concerns first delivery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Study Sample | Participants Giving Birth Before RPL to a Child With Low Birth Weight | 4 participants |
| MBL Reference Group | Participants Giving Birth Before RPL to a Child With Low Birth Weight | 2 participants |
Participants Giving Birth Before RPL to a Child With Very Low Birth Weight
\<1500g
Time frame: At first consultation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Participants Giving Birth Before RPL to a Child With Very Low Birth Weight | 0 Participants |
| MBL Reference Group | Participants Giving Birth Before RPL to a Child With Very Low Birth Weight | 0 Participants |
Participants With Preclampsia in Pregnancy After RPL
High blood pressure and proteinuria
Time frame: Developed from 20 weeks gestation and until 6 weeks postpartum. Data collected at delivery.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Participants With Preclampsia in Pregnancy After RPL | 7 Participants |
| MBL Reference Group | Participants With Preclampsia in Pregnancy After RPL | 0 Participants |
Participants With Preclampsia in Pregnancy Before RPL
High blood pressure and proteinuria
Time frame: Developed from 20 weeks gestation and until 6 weeks postpartum. Data collected at first consultation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Participants With Preclampsia in Pregnancy Before RPL | 6 Participants |
| MBL Reference Group | Participants With Preclampsia in Pregnancy Before RPL | 2 Participants |
Patients With a Liveborn After RPL
Number of women who give birth to a healthy liveborn child after RPL
Time frame: Follow up at study end.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With a Liveborn After RPL | 79 Participants |
| MBL Reference Group | Patients With a Liveborn After RPL | 23 Participants |
Patients With a Preterm Birth in Birth After RPL
\<37 weeks of gestation
Time frame: at delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With a Preterm Birth in Birth After RPL | 8 Participants |
| MBL Reference Group | Patients With a Preterm Birth in Birth After RPL | 3 Participants |
Patients With a Preterm Birth in Birth Before RPL
\<37 weeks of gestation
Time frame: At first consultation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With a Preterm Birth in Birth Before RPL | 4 Participants |
| MBL Reference Group | Patients With a Preterm Birth in Birth Before RPL | 1 Participants |
Patients With a Stillbirth After RPL
Stillbirth are defined as fetal death \>22 weeks of gestation and within 1 week after delivery
Time frame: 1 week after delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With a Stillbirth After RPL | 0 Participants |
| MBL Reference Group | Patients With a Stillbirth After RPL | 0 Participants |
Patients With a Stillbirth Before RPL
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With a Stillbirth Before RPL | 4 Participants |
| MBL Reference Group | Patients With a Stillbirth Before RPL | 3 Participants |
Patients With a Very Preterm Birth in Birth After RPL
\<32 weeks of gestation
Time frame: at delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With a Very Preterm Birth in Birth After RPL | 2 Participants |
| MBL Reference Group | Patients With a Very Preterm Birth in Birth After RPL | 0 Participants |
Patients With a Very Preterm Birth in Birth Before RPL
\<32 weeks of gestation
Time frame: At first consultation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With a Very Preterm Birth in Birth Before RPL | 0 Participants |
| MBL Reference Group | Patients With a Very Preterm Birth in Birth Before RPL | 0 Participants |
Patients With Elective Caesarean Section After RPL
A surgical delivery in women who were planned for caesarean delivery
Time frame: at delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With Elective Caesarean Section After RPL | 13 Participants |
| MBL Reference Group | Patients With Elective Caesarean Section After RPL | 3 Participants |
Patients With Elective Caesarean Section Before RPL
A surgical delivery in women who were planned for caesarean delivery
Time frame: At first consultation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With Elective Caesarean Section Before RPL | 6 Participants |
| MBL Reference Group | Patients With Elective Caesarean Section Before RPL | 0 Participants |
Patients With Emergency Caesarean Section After RPL
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With Emergency Caesarean Section After RPL | 10 Participants |
| MBL Reference Group | Patients With Emergency Caesarean Section After RPL | 4 Participants |
Patients With Emergency Caesarean Section Before RPL
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With Emergency Caesarean Section Before RPL | 12 Participants |
| MBL Reference Group | Patients With Emergency Caesarean Section Before RPL | 6 Participants |
Patients With Moderate Peripartum Hemorrhage in Birth After RPL
Hemorrhage of 500-1000 ml
Time frame: During delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With Moderate Peripartum Hemorrhage in Birth After RPL | 21 Participants |
| MBL Reference Group | Patients With Moderate Peripartum Hemorrhage in Birth After RPL | 2 Participants |
Patients With Moderate Peripartum Hemorrhage in Birth Before RPL
Hemorrhage of 500-1000 ml in minumum one previous birth before RPL
Time frame: At first consultation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With Moderate Peripartum Hemorrhage in Birth Before RPL | 6 Participants |
| MBL Reference Group | Patients With Moderate Peripartum Hemorrhage in Birth Before RPL | 6 Participants |
Patients With Severe Peripartum Hemorrhage in Birth After RPL
Hemorrhage of \>999 ml
Time frame: During delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With Severe Peripartum Hemorrhage in Birth After RPL | 6 Participants |
| MBL Reference Group | Patients With Severe Peripartum Hemorrhage in Birth After RPL | 3 Participants |
Patients With Severe Peripartum Hemorrhage in Birth Before RPL
Hemorrhage of \>999 ml in minimum one previous birth befor RPL
Time frame: At first consultation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Sample | Patients With Severe Peripartum Hemorrhage in Birth Before RPL | 8 Participants |
| MBL Reference Group | Patients With Severe Peripartum Hemorrhage in Birth Before RPL | 0 Participants |