Intravenous Immunoglobulin and Prednisolone for RPL After ART.

  • STATUS
    Recruiting
  • End date
    Aug 1, 2023
  • participants needed
    74
  • sponsor
    Caroline Nørgaard-Pedersen
Updated on 1 August 2021
l-arginine
pregnancy tests

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. 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 volume of the immune system, capillary permeability, and immune cell activity.

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 is definitely effective in patients with unexplained RPL after ART (defined as IVF or ICSI treatment). Potentially, this study will be able to establish a new treatment to women with unexplained RPL after ART, who otherwise have a poor prognosis.

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 undergoing ART treatment. A treatment with such effect is highly desirable, and in addition to increased birth rate, it will potentially improve quality of life and reduce detrimental anxiety and stress symptoms associated with RPL and ART treatment, since 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).

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.

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, a group of 37 healthy female blood donors 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 (low birth weight, preterm birth, stillbirth) and malformations will be recorded after birth.

Details
Condition Recurrent Pregnancy Loss, Pregnancy Complications, recurrent miscarriage, habitual abortion, recurrent abortions, Miscarriage, Spontaneous abortion, Fertility Disorders
Treatment Placebo, Human Intravenous Immunoglobulins, (Privigen (R), CLS Behring), Prednisolone Tablets, Human Albumin Solution
Clinical Study IdentifierNCT04701034
SponsorCaroline Nørgaard-Pedersen
Last Modified on1 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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

Exclusion Criteria

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
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
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