Habitual AbortionPhase 2RPLNCT04701034
Intravenous Immunoglobulin and Prednisolone for RPL After ART.
A Phase 2 study testing Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring), Prednisolone Tablets and Human Albumin Solution in people with Habitual Abortion and Recurrent Pregnancy Loss, run by Aalborg University Hospital at 1 site in Denmark.
Trial summary
Recurrent pregnancy loss (RPL) affects around 5 % of women in reproductive age. The underlying cause of RPL is most often unknown, probably multifactorial, and no treatment with documented effect on chance of live birth exists. Read more about this study
- Who is it for?
- Ages 18 to 41 years, women only
- Conditions the study is for
- Habitual Abortion, Recurrent Pregnancy Loss, Fertility Disorders
- What is being tested?
- Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring), Prednisolone Tablets and Human Albumin Solution
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 80 participants
- Where
- 1 siteDenmark
- Study dates
- 28 Jan 2021to 18 Apr 2024
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 41 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- Women with ≥ 2 consecutive pregnancy losses (miscarriages or biochemical pregnancies) ≤ completed gestational week 10 after ART with the present partner or with an egg/semen donor*
- The gestational week of the non-induced pregnancy losses will be based on the date of clinical signs of miscarriage or the fetus' crown-rump-length of a missed abortion measured on the ultrasonic scan detecting the pregnancy loss. If the participant plan to use egg donation in the study cycle, the previous two pregnancy losses must also have happened with the use of egg donation; however, it is not required to use the same egg donor in all three embryo transfers.
Who cannot join
- BMI ≥35
- Age ≥41
- Significant uterine malformation(s)
- Known parental balanced chromosomal translocations
- ≥2 previous pregnancies with fetuses with known abnormal karyotype
- Patients with IgA deficiency, IgA-autoantibodies or hyperprolinaemia
Show all 13Show fewer
- Treatment with medication interacting with prednisolone
- CYP3A4-inhibitors (fx erythromycin, itraconazole, ritonavir, lopinavir), CYP3A4-inductors (fx phenobarbital, phenytoin og rifampicin), loop diuretics, thiazides, amphotericin B, beta2-agonists, antidiabetics, interleukin-2, somatotropins, anticholinergics and regular treatment with NSAIDs.
- Patients with moderate/severe hypertension, diabetes mellitus, heart insufficiency, severe mental disorders, Cushing syndrome, myasthenia gravis, ocular herpes simplex, pheochromocytoma, systemic sclerosis, and moderate/severe renal dysfunction.
- Patients with a clinical or biochemical profile indicating need for heparin or levothyroxine treatment during pregnancy
- Previous treatment with IVIg
- Allergy to prednisolone and/or IVIg
- AMH <4 pmol/L. If transfer of donor egg is planned for her IVF cycle, the AMH value will not be an exclusion criterion.
Trial locations and contacts
1 site in 1 country.
Denmark1 site
• The Centre for Recurrent Pregnancy Loss of Western Denmark, Department of Obstetrics and Gynaecology, Aalborg University Hospital
Aalborg, 9000
About this study
Official title: Intravenous Immunoglobulin and Prednisolone to Women With Unexplained Recurrent Pregnancy Loss After Assisted Reproductive Technology Treatment: a Randomised, Double-blind, Placebo-controlled Trial
Recurrent pregnancy loss (RPL) affects around 5 % of women in reproductive age. The underlying cause of RPL is most often unknown, probably multifactorial, and no treatment with documented effect on chance of live birth exists. In unexplained cases of RPL, primarily the immune system is hypothesized to play a pivotal, causative role, since autoantibodies and specific human leukocyte antigen (HLA) alleles as well as unbalanced distribution of leucocyte subsets, especially natural killer (NK) cells and T-helper (Th) cells, occurs more frequently in patients with unexplained RPL. For that reason, many treatment regimens used in autoimmune diseases have been tested on RPL patients, as for example prednisolone and intravenous immunoglobulin (IVIg).
IVIg (Privigen) consist of a broad spectrum of structurally and functionally intact IgG antibodies. The mechanism of action is not fully elucidated, but certainly IVIg do help opsonise and neutralize foreign cells and pathogens. Prednisolone support this anti-inflammatory action by suppressing migration of polymorphonuclear leukocytes, and reducing the volume and activity of the immune system and the capillary permeability.
Read more
A retrospective, observational pilot study suggested that a combination of prednisone and IVIg in first trimester improves the chance of a live birth in women with RPL after assisted reproductive technologies (ART) (Nyborg et al., 2014).
A randomized controlled study is necessary for determining if this immunomodulatory treatment definitely is effective in patients with unexplained RPL after ART (defined as IVF or ICSI ad FER). Potentially, this study will be able to establish evidence for an effective treatment to women with unexplained RPL after ART, who otherwise have a poor prognosis.
Read the detailed description
In a randomized, double-blinded, placebo-controlled trial, this study aims to investigate whether treatment with prednisolone and intravenous immunoglobulin (IVIg) before and in early pregnancy improves the chance of a live birth in women undergoing treatment with artificial reproductive technologies (ART) (defined as IVF or ICSI or FER treatment) after previous recurrent pregnancy loss (RPL) after ART.
If an improved live birth rate can be confirmed, the treatment will be the first documented treatment supplement for women with RPL undergoing ART treatment. A treatment with such effect is highly desirable. If the treatment increases the birth rate, it will potentially also improve quality of life and reduce detrimental anxiety and stress symptoms associated with RPL and ART treatment, since the burden (including the number of treatments and the number of losses) will be reduced.
Potential study participants will be identified among patients who are referred to The Center for Recurrent Pregnancy Loss of Western Denmark (in the following called The RPL Center), located at Aalborg University Hospital (AaUH) Denmark.
At the first appointment at The RPL Center, a list of standard health information important for the RPL examination will be collected together with the RPL Center's standard blood sample.
Treatment: The participants will be randomly allocated 1:1 to active immunomodulatory treatment versus placebo treatment (see Arms and Interventions). Study treatment starts on the patient's first day of her menstrual cycle in which her fertility clinic plan to transfer an embryo/blastocyst(s) and continue until a negative pregnancy test, the time of biochemical pregnancy loss/miscarriage or pregnancy week 8+0, whichever comes first.
from first day of cycle and until embryo transfer, one tablet (5mg prednisolone or placebo) per day is taken. First infusion (IVIg or Albumin) is given within 5 workings days before and 2 working days after embryo transfer. On the day of embryo transfer, two tablet per day is taken.
Approximately 14 days after ET, the patient will have a pregnancy test. If positive, the patient will have plasma-hCG measured twice with 1-2 days interval at her local hospital. With adequate increment of plasma-hCG, the patient will be booked for her last 3 infusions in gestational week 5, 6, and 7, and continue tablet intake. If she is not pregnant, study medication will not continue.
On the day of the first infusion treatment and again approximately four weeks later (the day of her third infusion treatment during pregnancy), a study specific blood sample will be taken for our research biobank. In participants who do not achieve pregnancy or have a miscarriage before gestational week 6 (and therefore do not come for the third infusion), we will ask these participants to come for the second blood sample too. The blood samples will be analysed by the Department of Clinical Immunology at AaUH.
In addition, in a separate study performed by the same investigators, a group of 37 healthy females in reproductive age with no prior known pregnancy losses will have one blood sample collected in their luteal phase and analyzed according to the same protocol and will serve as a reference group to the two study groups.
An immediate analysis of the blood sample will quantify NK-cells, B-cells, and T-cell subsets by flow cytometry. Also, a TruCulture analysis for activity of leucocyte subsets will be carried out in 25 patients. The research/future biobank will store frozen serum and plasma for analysis of immune markers including smaller extracellular vesicles.
If the participant is still pregnant after her last infusion of study medicine before week 8+0, she will be offered routine monitoring at The RPL Center at AaUH, at her local fertility clinic, and her local hospital. She will receive a questionnaire 2 weeks after her nuchal scan and 2 weeks after her due date for collection of data regarding her pregnancy, delivery, and perinatal outcome.
Study-relevant data will be collected from medical records, birth records, questionnaires, and the research biobank.
Adverse events will be recorded on all participants from the day of admission and until 6 months after last infusion treatment or until birth of her child if she becomes pregnant. Both adverse events in the participant and her child will be recorded. To support compliance and meticulous reporting of side effects, all participants receive a folder with a list of all known side effects to prednisolone, IVIg and albumin, a diary with boxes to tick of every day the tablet(s) is taken, and a table in which side effects can continuously be noted. According to the child, negative perinatal outcomes (e.g., low birth weight, preterm birth, stillbirth) and malformations will be recorded after birth.
- Being tested
- Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring), Prednisolone Tablets, Human Albumin Solution, Placebo tablet
- Keywords
- Fertility treatment, In vitro fertilization, Intravenous immunoglobulin, Prednisolone, Recurrent pregnancy loss
- Medical subject headings
- Abortion, Habitual, Abortion, Spontaneous
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring)Drug
Also called IVIg
infusion: Initial infusion rate of 0.3 ml/kg BW/hr in about 30 min. If well-tolerated, the infusion rate may gradually be increased to 4.8 ml/kg BW/hr. During the infusion, health care personnel are present to secure immediate action in case of serious AR. Blood pressure and pulse is monitored before, during and after the treatment. In case of anaphylaxis, the treatment is discontinued and the participant is excluded. The hospital ward possess adrenaline 0.1 % solutions ready in case of anaphylaxis.
Prednisolone TabletsDrug
5 mg before ET and 10 mg after ET until gestational week 8+0
Human Albumin SolutionDrug
Also called Albumin infusion
Infusion: Initial infusion rate of 0.3 ml/kg BW/hr in about 30 min. If well-tolerated, the infusion rate may gradually be increased to 4.8 ml/kg BW/hr. During the infusion, health care personnel are present to secure immediate action in case of serious AR. Blood pressure and pulse is monitored before, during and after the treatment. In case of anaphylaxis, the treatment is discontinued and the participant is excluded. The hospital ward possess adrenaline 0.1 % solutions ready in case of anaphylaxis.
Placebo tabletDrug
1 tablet before ET and 2 tablets after ET until gestational week 8+0
| Study group | Role | What they receive |
|---|---|---|
| Active treatment group | Active comparator | Intravenous immunoglobulin(IVIg) and prednisolone. IVIG is administered at the time of embryo/blastocyst transfer (ET) (5 days before to 2 days after ET) and if the participant becomes pregnant, the infusion (same dose) is repeated in gestational week 5, 6, and 7.
Participants with pre-pregnancy weight ≤70 kg will receive 25 g immunoglobulin (250 ml), participants with weight 70-85 kg will receive 30 g immunoglobulin (300 ml), and participants with weight ≥85 kg will receive 35 g immunoglobulin (350 ml) at each infusion, which will approximate 0.4 g IVIg per kg body weight.
Prednisolone, tablets, 5mg. 1 tablet daily started within first 3 days of menstrual cycle and until ET. On the day of ET, the participant will double her dose to 2 tablets daily until a negative pregnancy test, the time of biochemical loss/miscarriage, or pregnancy week 8+0, whichever comes first. Gradual discontinuation four days with one tablet before completing cessation. Receives: Drug: Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring); Drug: Prednisolone Tablets |
| Passive treatment group | Placebo comparator | Human albumin infusion and placebo tablets.
Human albumin, 5%, (CLS Behring). Participants with pre-pregnancy weight ≤70 kg will receive 250 ml, participants with weight 70-85 kg will receive 300 ml, and participants with weight ≥85 kg will receive 350 ml at each infusion. Administration is planned at the time of ET (5 days before to 2 days after ET) and if the participant becomes pregnant, the infusion is repeated in the same volume in gestational week 5, 6, and 7.
Placebo tablets: contain 85 mg of lactose monohydrate, 86 mg potato starch, 8.1 mg talc, 3 mg gelatine, and 0.9 mg magnesium stearate. 1 tablet daily started within first 3 days of menstrual cycle and until ET. On the day of ET, the participant will double her dose to 2 tablets daily until a negative pregnancy test, the time of biochemical loss/miscarriage, or pregnancy week 8+0, whichever comes first. Gradual discontinuation four days with one tablet before completing cessation. Receives: Drug: Human Albumin Solution; Drug: Placebo tablet |
What is being measured
The primary outcome is the main question the study is designed to answer.
A normal live fetus at nuchal scan in ITT population
The frequency of participants with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively.
Here, the primary analyses will be undertaken as an intention-to-treat (ITT) analysis, including all participants who were allocated to either active or placebo treatment at the start of the ART cycle, even if they did not receive infusion with IVIg or albumin due to cancellation of embryo/blastocyst transfer.
Measured: 12 week after embryo transfer
A normal live fetus at nuchal scan in PP population
The frequency of participants with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively.
Here, the primary analyses will be undertaken as a per-protocol (PP) analysis, including patients who were randomized and received the allocated infusion of study medicine at the time of embryo/blastocyst transfer and had this transfer performed.
Measured: 12 week after embryo transfer
Live birth rate in ITT population
The frequency of participants with a liveborn (sign of life immediately af delivery >24 weeks) among all randomized participants
Measured: At delivery
Live birth rate in the PP population
The frequency of participants with a liveborn (sign of life immediately af delivery >24 weeks) among all participants who fulfill criteria for PP-analysis
Measured: At delivery
A normal live fetus at nuchal scan among participants who become pregnant after embryo transfer in the ITT population
The frequency of participants in the ITT population with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively, and who become pregnant after embryo transfer.
Measured: 12 week after embryo transfer
A normal live fetus at nuchal scan among participants who become pregnant after embryo transfer in the PP population
The frequency of participants in the PP population with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively, and who become pregnant after embryo transfer.
Measured: 12 week after embryo transfer
Secondary outcomes (13)
Maternal adverse reactions
Number of participants with adverse reactions including headache, skin rash, and fever that might be associated to study medicine in the ITT population.
Measured: 9 months after embryo transfer.
Negative pregnancy test
Number of participants with a negative pregnancy test after ET in the ITT population.
Measured: 9 months after embryo transfer.
Miscarriage rate
Number of participants with a miscarriage (defined as any loss before 24 weeks of gestation) among the number of participants becoming pregnant (defined as a rise in serum beta hCG concentration >25 UI/L per transfer) in the ITT population.
Measured: Before 24 weeks of gestation
Rate of Abnormal karyotype in Miscarried fetuses
The frequency of pregnancy losses with unknown or normal karyotype among all participants with a pregnancy loss having an evac. and chromosome typing.
Measured: Before 24 weeks of gestation
Rate of Stillbirth rate
Number of participants with a still birth (defined as fetal death at 24 weeks or more or no sign of life after delivery) among the number of participants becoming pregnant (defined as a rise in serum beta hCG concentration >25 UI/L per transfer) in the ITT population.
Measured: 9 months after embryo transfer.
Rate of Congenital deformities
Number of live-born babies with a of congenital deformity among all live-borns in the ITT population.
Measured: 1 week after delivery
Rate of Preterm birth
Number of live-born before 37+0 weeks of gestation among all live-borns in the ITT population.
Measured: 1 week after delivery
Rate of Low birth weight (BW)
Number of live-born with a BW <2500 g among all live-borns in the ITT population.
Measured: 1 week after delivery
Rate of Preeclampsia
Number pregnant participants >24 weeks with hypertension (systolic blood pressure (SBP) greater than or equal to 140 mm Hg or a diastolic blood pressure (DBP) greater than or equal to 90 mm Hg) and proteinuria (>0.3 g per day or urine albumine/creatinine ratio≥ 300 mg/g) among all pregnant participants >24 weeks in the ITT population.
Measured: 1 week after delivery
Rate of Gestational diabetes
Number pregnant participants >24 weeks with gestation diabetes (i.e.efined as an oral glucose challenge test (OGCT) with >9.0 mmol/l 2 hours after oral intake of 75g glucose solution) among all pregnant participants >24 weeks in the ITT population.
Measured: 1 week after delivery
Rate of gestational hypertension
Number pregnant participants >24 weeks with hypertension (i.e. systolic blood pressure (SBP) greater than or equal to 140 mm Hg or a diastolic blood pressure (DBP)) among all pregnant participants >24 weeks in the ITT population.
Measured: 1 week after delivery
Rate of abnormal embryonic/fetal karyotype
Number of miscarriages with a abnormal embryonic/fetal karyotype among all miscarriages having a karyotype test in the ITT population.
Measured: Before 24 weeks of gestation
Frequency of a boy
The percentage of live births that was a boy
Measured: Right after delivery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jan 2021
- Study start28 Jan 2021
- Primary completion18 Apr 2024
- Study completion18 Apr 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Habitual AbortionStudies of the same condition, open and under way.
- More trials run by Aalborg University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 80 participants (actual)
Sponsor and investigators
- Lead sponsor
- Aalborg University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Svend Andersen Fonden, Beckett Foundation, L.F. Foghts Foundation
- Responsible party
- Principal investigator, Caroline Nørgaard-Pedersen, Aalborg University Hospital
- Investigators
- Ole B Christiansen, Principal investigator, Aalborg University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04701034
- Sponsor's protocol ID
- CNPOBC2020
- Other IDs
- 2020-000256-35, U1111-1273-8585
- Acronym
- RPL
- Status last verified
- Nov 2025
- First submitted
- 5 Jan 2021
- Last updated
- 24 Nov 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The data that will be shared includes (due to the danish regulation) an overview of the data results with means, medians and standard deviations on numbers reported in manuscripts (text, tables, figures, and appendices). If allowed, individual data on these variables will be shared after deidentification together with data dictionary upon request. Sharing will be done after publication and will be available up to 5 years after study end. Study protocol will be available. Data will only be shared with researchers who provide a methodologically sound proposal according to CNP and OBC (the two primary investigators). Proposals should be directed to c.noergaardpedersen@rn.dk. To gain access, data requestors will need to sign a data access agreement.
Publications
Norgaard-Pedersen C, Kesmodel US, Jorgensen MM, Christiansen O. Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a randomised, double-blind, placebo-controlled trial. BMJ Open. 2025 Nov 19;15(11):e106024. doi: 10.1136/bmjopen-2025-106024.
PubMed 41263919Norgaard-Pedersen C, Nielsen K, Steffensen R, Eriksen L, Jorgensen MM, Kesmodel US, Christiansen OB. Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a protocol for a randomised, double-blind, placebo-controlled trial. BMJ Open. 2022 Sep 22;12(9):e064780. doi: 10.1136/bmjopen-2022-064780.
PubMed 36137638
Study at a glance
From the registry record, last updated by the sponsor on 24 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Intravenous Immunoglobulin and Prednisolone to Women With Unexplained Recurrent Pregnancy Loss After Assisted Reproductive Technology Treatment: a Randomised, Double-blind, Placebo-controlled Trial
- ClinicalTrials.gov ID
- NCT04701034
- Acronym / sponsor ID
- RPL / CNPOBC2020
- Keywords
- Fertility treatment, In vitro fertilization, Intravenous immunoglobulin, Prednisolone, Recurrent pregnancy loss
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 80 participants (actual)
- Lead sponsor
- Aalborg University HospitalUniversity, hospital or other
- Collaborators
- Svend Andersen Fonden, Beckett Foundation, L.F. Foghts Foundation
- Study start
- 28 Jan 2021 (actual)
- Primary completion
- 18 Apr 2024 (actual)
- Study completion
- 18 Apr 2024 (actual)
- First posted
- 8 Jan 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Recurrent pregnancy loss (RPL) affects around 5 % of women in reproductive age. The underlying cause of RPL is most often unknown, probably multifactorial, and no treatment with documented effect on chance of live birth exists. In unexplained cases of RPL, primarily the immune system is hypothesized to play a pivotal, causative role, since autoantibodies and specific human leukocyte antigen (HLA) alleles as well as unbalanced distribution of leucocyte subsets, especially natural killer (NK) cells and T-helper (Th) cells, occurs more frequently in patients with unexplained RPL. For that reason, many treatment regimens used in autoimmune diseases have been tested on RPL patients, as for example prednisolone and intravenous immunoglobulin (IVIg).
IVIg (Privigen) consist of a broad spectrum of structurally and functionally intact IgG antibodies. The mechanism of action is not fully elucidated, but certainly IVIg do help opsonise and neutralize foreign cells and pathogens. Prednisolone support this anti-inflammatory action by suppressing migration of polymorphonuclear leukocytes, and reducing the volume and activity of the immune system and the capillary permeability.
A retrospective, observational pilot study suggested that a combination of prednisone and IVIg in first trimester improves the chance of a live birth in women with RPL after assisted reproductive technologies (ART) (Nyborg et al., 2014).
A randomized controlled study is necessary for determining if this immunomodulatory treatment definitely is effective in patients with unexplained RPL after ART (defined as IVF or ICSI ad FER). Potentially, this study will be able to establish evidence for an effective treatment to women with unexplained RPL after ART, who otherwise have a poor prognosis.
Detailed description
In a randomized, double-blinded, placebo-controlled trial, this study aims to investigate whether treatment with prednisolone and intravenous immunoglobulin (IVIg) before and in early pregnancy improves the chance of a live birth in women undergoing treatment with artificial reproductive technologies (ART) (defined as IVF or ICSI or FER treatment) after previous recurrent pregnancy loss (RPL) after ART.
If an improved live birth rate can be confirmed, the treatment will be the first documented treatment supplement for women with RPL undergoing ART treatment. A treatment with such effect is highly desirable. If the treatment increases the birth rate, it will potentially also improve quality of life and reduce detrimental anxiety and stress symptoms associated with RPL and ART treatment, since the burden (including the number of treatments and the number of losses) will be reduced.
Potential study participants will be identified among patients who are referred to The Center for Recurrent Pregnancy Loss of Western Denmark (in the following called The RPL Center), located at Aalborg University Hospital (AaUH) Denmark.
At the first appointment at The RPL Center, a list of standard health information important for the RPL examination will be collected together with the RPL Center's standard blood sample.
Treatment: The participants will be randomly allocated 1:1 to active immunomodulatory treatment versus placebo treatment (see Arms and Interventions). Study treatment starts on the patient's first day of her menstrual cycle in which her fertility clinic plan to transfer an embryo/blastocyst(s) and continue until a negative pregnancy test, the time of biochemical pregnancy loss/miscarriage or pregnancy week 8+0, whichever comes first.
from first day of cycle and until embryo transfer, one tablet (5mg prednisolone or placebo) per day is taken. First infusion (IVIg or Albumin) is given within 5 workings days before and 2 working days after embryo transfer. On the day of embryo transfer, two tablet per day is taken.
Approximately 14 days after ET, the patient will have a pregnancy test. If positive, the patient will have plasma-hCG measured twice with 1-2 days interval at her local hospital. With adequate increment of plasma-hCG, the patient will be booked for her last 3 infusions in gestational week 5, 6, and 7, and continue tablet intake. If she is not pregnant, study medication will not continue.
On the day of the first infusion treatment and again approximately four weeks later (the day of her third infusion treatment during pregnancy), a study specific blood sample will be taken for our research biobank. In participants who do not achieve pregnancy or have a miscarriage before gestational week 6 (and therefore do not come for the third infusion), we will ask these participants to come for the second blood sample too. The blood samples will be analysed by the Department of Clinical Immunology at AaUH.
In addition, in a separate study performed by the same investigators, a group of 37 healthy females in reproductive age with no prior known pregnancy losses will have one blood sample collected in their luteal phase and analyzed according to the same protocol and will serve as a reference group to the two study groups.
An immediate analysis of the blood sample will quantify NK-cells, B-cells, and T-cell subsets by flow cytometry. Also, a TruCulture analysis for activity of leucocyte subsets will be carried out in 25 patients. The research/future biobank will store frozen serum and plasma for analysis of immune markers including smaller extracellular vesicles.
If the participant is still pregnant after her last infusion of study medicine before week 8+0, she will be offered routine monitoring at The RPL Center at AaUH, at her local fertility clinic, and her local hospital. She will receive a questionnaire 2 weeks after her nuchal scan and 2 weeks after her due date for collection of data regarding her pregnancy, delivery, and perinatal outcome.
Study-relevant data will be collected from medical records, birth records, questionnaires, and the research biobank.
Adverse events will be recorded on all participants from the day of admission and until 6 months after last infusion treatment or until birth of her child if she becomes pregnant. Both adverse events in the participant and her child will be recorded. To support compliance and meticulous reporting of side effects, all participants receive a folder with a list of all known side effects to prednisolone, IVIg and albumin, a diary with boxes to tick of every day the tablet(s) is taken, and a table in which side effects can continuously be noted. According to the child, negative perinatal outcomes (e.g., low birth weight, preterm birth, stillbirth) and malformations will be recorded after birth.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Active treatment group | Active comparator | Drug: Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring), Drug: Prednisolone TabletsIntravenous immunoglobulin(IVIg) and prednisolone. IVIG is administered at the time of embryo/blastocyst transfer (ET) (5 days before to 2 days after ET) and if the participant becomes pregnant, the infusion (same dose) is repeated in gestational week 5, 6, and 7. Participants with pre-pregnancy weight ≤70 kg will receive 25 g immunoglobulin (250 ml), participants with weight 70-85 kg will receive 30 g immunoglobulin (300 ml), and participants with weight ≥85 kg will receive 35 g immunoglobulin (350 ml) at each infusion, which will approximate 0.4 g IVIg per kg body weight. Prednisolone, tablets, 5mg. 1 tablet daily started within first 3 days of menstrual cycle and until ET. On the day of ET, the participant will double her dose to 2 tablets daily until a negative pregnancy test, the time of biochemical loss/miscarriage, or pregnancy week 8+0, whichever comes first. Gradual discontinuation four days with one tablet before completing cessation. |
| Passive treatment group | Placebo comparator | Drug: Human Albumin Solution, Drug: Placebo tabletHuman albumin infusion and placebo tablets. Human albumin, 5%, (CLS Behring). Participants with pre-pregnancy weight ≤70 kg will receive 250 ml, participants with weight 70-85 kg will receive 300 ml, and participants with weight ≥85 kg will receive 350 ml at each infusion. Administration is planned at the time of ET (5 days before to 2 days after ET) and if the participant becomes pregnant, the infusion is repeated in the same volume in gestational week 5, 6, and 7. Placebo tablets: contain 85 mg of lactose monohydrate, 86 mg potato starch, 8.1 mg talc, 3 mg gelatine, and 0.9 mg magnesium stearate. 1 tablet daily started within first 3 days of menstrual cycle and until ET. On the day of ET, the participant will double her dose to 2 tablets daily until a negative pregnancy test, the time of biochemical loss/miscarriage, or pregnancy week 8+0, whichever comes first. Gradual discontinuation four days with one tablet before completing cessation. |
Who may qualify
- Ages
- 18 to 41 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- Women with ≥ 2 consecutive pregnancy losses (miscarriages or biochemical pregnancies) ≤ completed gestational week 10 after ART with the present partner or with an egg/semen donor*
Key exclusion criteria (13 listed)
- BMI ≥35
- Age ≥41
- Significant uterine malformation(s)
- Known parental balanced chromosomal translocations
- ≥2 previous pregnancies with fetuses with known abnormal karyotype
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring)Also: IVIginfusion: Initial infusion rate of 0.3 ml/kg BW/hr in about 30 min. If well-tolerated, the infusion rate may gradually be increased to 4.8 ml/kg BW/hr. During the infusion, health care personnel are present to secure immediate action in case of serious AR. Blood pressure and pulse is monitored before, during and after the treatment. In case of anaphylaxis, the treatment is discontinued and the participant is excluded. The hospital ward possess adrenaline 0.1 % solutions ready in case of anaphylaxis. | Drug | Active treatment group |
| Prednisolone Tablets5 mg before ET and 10 mg after ET until gestational week 8+0 | Drug | Active treatment group |
| Human Albumin SolutionAlso: Albumin infusionInfusion: Initial infusion rate of 0.3 ml/kg BW/hr in about 30 min. If well-tolerated, the infusion rate may gradually be increased to 4.8 ml/kg BW/hr. During the infusion, health care personnel are present to secure immediate action in case of serious AR. Blood pressure and pulse is monitored before, during and after the treatment. In case of anaphylaxis, the treatment is discontinued and the participant is excluded. The hospital ward possess adrenaline 0.1 % solutions ready in case of anaphylaxis. | Drug | Passive treatment group |
| Placebo tablet1 tablet before ET and 2 tablets after ET until gestational week 8+0 | Drug | Passive treatment group |
Primary outcome
A normal live fetus at nuchal scan in ITT population
Time frame: 12 week after embryo transfer
The frequency of participants with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively. Here, the primary analyses will be undertaken as an intention-to-treat (ITT) analysis, including all participants who were allocated to either active or placebo treatment at the start of the ART cycle, even if they did not receive infusion with IVIg or albumin due to cancellation of embryo/blastocyst transfer.
A normal live fetus at nuchal scan in PP population
Time frame: 12 week after embryo transfer
The frequency of participants with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively. Here, the primary analyses will be undertaken as a per-protocol (PP) analysis, including patients who were randomized and received the allocated infusion of study medicine at the time of embryo/blastocyst transfer and had this transfer performed.
Live birth rate in ITT population
Time frame: At delivery
The frequency of participants with a liveborn (sign of life immediately af delivery >24 weeks) among all randomized participants
Live birth rate in the PP population
Time frame: At delivery
The frequency of participants with a liveborn (sign of life immediately af delivery >24 weeks) among all participants who fulfill criteria for PP-analysis
A normal live fetus at nuchal scan among participants who become pregnant after embryo transfer in the ITT population
Time frame: 12 week after embryo transfer
The frequency of participants in the ITT population with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively, and who become pregnant after embryo transfer.
A normal live fetus at nuchal scan among participants who become pregnant after embryo transfer in the PP population
Time frame: 12 week after embryo transfer
The frequency of participants in the PP population with minimum one apparently normal fetus alive at the time of nuchal scan (approx. week 12) in patients receiving active and placebo treatment, respectively, and who become pregnant after embryo transfer.
13 secondary outcomes
Maternal adverse reactions
Time frame: 9 months after embryo transfer.
Negative pregnancy test
Time frame: 9 months after embryo transfer.
Miscarriage rate
Time frame: Before 24 weeks of gestation
Rate of Abnormal karyotype in Miscarried fetuses
Time frame: Before 24 weeks of gestation
Rate of Stillbirth rate
Time frame: 9 months after embryo transfer.
Rate of Congenital deformities
Time frame: 1 week after delivery
Rate of Preterm birth
Time frame: 1 week after delivery
Rate of Low birth weight (BW)
Time frame: 1 week after delivery
Rate of Preeclampsia
Time frame: 1 week after delivery
Rate of Gestational diabetes
Time frame: 1 week after delivery
Rate of gestational hypertension
Time frame: 1 week after delivery
Rate of abnormal embryonic/fetal karyotype
Time frame: Before 24 weeks of gestation
Frequency of a boy
Time frame: Right after delivery
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Nov 2025.
- Derived from this study: PubMed 41263919Norgaard-Pedersen C, Kesmodel US, Jorgensen MM, Christiansen O. Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a randomised, double-blind, placebo-controlled trial. BMJ Open. 2025 Nov 19;15(11):e106024. doi: 10.1136/bmjopen-2025-106024.
- Derived from this study: PubMed 36137638Norgaard-Pedersen C, Nielsen K, Steffensen R, Eriksen L, Jorgensen MM, Kesmodel US, Christiansen OB. Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a protocol for a randomised, double-blind, placebo-controlled trial. BMJ Open. 2022 Sep 22;12(9):e064780. doi: 10.1136/bmjopen-2022-064780.
- Individual participant dataSharing planned: Yes. The data that will be shared includes (due to the danish regulation) an overview of the data results with means, medians and standard deviations on numbers reported in manuscripts (text, tables, figures, and appendices). If allowed, individual data on these variables will be shared after deidentification together with data dictionary upon request. Sharing will be done after publication and will be available up to 5 years after study end. Study protocol will be available. Data will only be shared with researchers who provide a methodologically sound proposal according to CNP and OBC (the two primary investigators). Proposals should be directed to c.noergaardpedersen@rn.dk. To gain access, data requestors will need to sign a data access agreement.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ole B Christiansen principal investigator
Aalborg University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring), Prednisolone Tablets and Human Albumin Solution in people with Habitual Abortion and Recurrent Pregnancy Loss, run by Aalborg University Hospital at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
A normal live fetus at nuchal scan in ITT population (time frame: 12 week after embryo transfer). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04701034, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Nov 2025.