Intravenous Immunoglobulin and Prednisolone for RPL After ART.
Intravenous Immunoglobulin and Prednisolone for RPL After ART.
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.
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 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, pregnancy week 8+0 or
 the time of biochemical pregnancy loss/miscarriage, 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.

 An immediate analysis of the blood sample will quantify NK-cells and T-cell subsets by flow
 cytometry. Also, a TruCulture analysis for activity of leucocyte subsets will be carried out
 in 37 patients. The research/future biobank will store frozen serum and plasma for analysis
 of 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.
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:

 1. BMI ≥35

 2. Age ≥41

 3. Significant uterine malformation(s)

 4. Known parental balanced chromosomal translocations

 5. ≥2 previous pregnancies with fetuses with known abnormal karyotype

 6. Patients with IgA deficiency, IgA-autoantibodies or hyperprolinaemia

 7. 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.

 8. 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.

 9. Patients with a clinical or biochemical profile indicating need for heparin or
 levothyroxine treatment during pregnancy

 10. Previous treatment with IVIg

 11. Allergy to prednisolone and/or IVIg

 12. AMH <4 pmol/L. If transfer of donor egg is planned for her IVF cycle, the AMH value
 will not be an exclusion criterion.