To the content
1 . 2023

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

Abstract

Introduction. Recurrent pregnancy loss (RPL), defined as two or more consecutive pregnancy losses in the first trimester, affects around 5% of fertile women. The underlying causes remain unknown in up to 60% of patients; however, most studies point at an immunological pathology in unexplained RPL, and therefore, an effective treatment may be immunomodulatory. This study aims to evaluate the effect of intravenous immunoglobulin (IVIg) and prednisolone on reproductive outcome and the immune system in women with unexplained RPL undergoing assisted reproductive technology treatment.

Methods and analysis. This randomised, placebo-controlled trial with double-blinded randomisation to two parallel arms evaluate if immunomodulatory (active) treatment is superior to placebo in increasing the chance of ongoing pregnancy assessed at nuchal translucency scan in gestational weeks (GW) 11–13 after embryo transfer (ET) in 74 RPL patients with ≥2 pregnancy losses as its primary objective. The active treatment consists of IVIg (one infusion preferably 1–5 days before ET and in GW 5, 6 and 7) and prednisolone (5 mg/day from first day of menstrual bleeding until ET and 10 mg/day from ET to GW 8+0) while the comparator consists of intravenous human albumin (5%) and placebo tablets. Allocation is concealed for participants, caregivers, and investigators until trial termination and is performed in a 1:1 ratio. The secondary objective is to evaluate treatment safety, and the tertiary objective is exploration of the association between treatment, reproductive outcome after ET, and the lymphocyte subset distribution in peripheral blood collected before and after intravenous infusion(s). Excess biological material is stored in a biobank for future research.

Ethics and dissemination. The North Denmark Region Committee on Health Research Ethics (N-20200066) approved this trial. The results will be published in peer-reviewed scientific journals and presented to relevant patient associations, at relevant academic conferences and to key stakeholders.

Trial registration number: NCT04701034.

Norgaard-Pedersen C., Nielsen K., Steffensen R., et al. 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; 12: e064780. DOI: https://doi.org/10.1136/bmjopen-2022-064780

References

1 ESHRE Guideline Group on RPL; Bender Atik R., Christiansen O.B., et al. ESHRE guideline: Recurrent pregnancy loss. Hum Reprod Open. 2018; 2018: 1–12.

2 Bashiri A., Halper K.I., Orvieto R. Recurrent implantation failure: Update overview on etiology, diagnosis, treatment and future directions. Reprod Biol Endocrinol. 2018; 16: 1–18.

3 Egerup P., Lindschou J., Gluud C., et al. The effects of intravenous immunoglobulins in women with recurrent miscarriages: A systematic review of randomised trials with meta-analyses and trial sequential analyses including individual patient data. PLoS One. 2015; 10: e0141588-22.

4 Nyborg K.M., Kolte A.M., Larsen E.C., et al. Immunomodulatory treatment with intravenous immunoglobulin and prednisone in patients with recurrent miscarriage and implantation failure after in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril. 2014; 102: 1650–5.

5 Egerup P., Nielsen H.S., Andersen A.N., et al. Live birth rate in women with recurrent pregnancy loss after in vitro fertilization with concomitant intravenous immunoglobulin and prednisone. J Clin Med. 2022; 11: 1894.

6 Kemeter P., Feichtinger W. Prednisolone supplementation to Clomid and/or gonadotrophin stimulation for in-vitro fertilization: A prospective randomized trial. Hum Reprod. 1986; 1: 441–4.

7 Ando T., Suganuma N., Furuhashi M., et al. Successful glucocorticoid treatment for patients with abnormal autoimmunity on in vitro fertilization and embryo transfer. J Assist Reprod Genet. 1996; 13: 776–81.

8 Hasegawa I., Yamanoto Y., Suzuki M., et al. Prednisolone plus low-dose aspirin improves the implantation rate in women with autoimmune conditions who are undergoing in vitro fertilization. Fertil Steril. 1998; 70: 1044–8.

9 Forges T., Monnier-Barbarino P., Guillet-May F., et al. Corticosteroids in patients with antiovarian antibodies undergoing in vitro fertilization: a prospective pilot study. Eur J Clin Pharmacol. 2006; 62: 699–705.

10 Raghupathy R. Th1-type immunity is incompatible with successful pregnancy. Immunol Today. 1997; 18: 478–82.

11 Quenby S., Bates M., Doig T., et al. Pre-implantation endometrial leukocytes in women with recurrent miscarriage. Hum Reprod. 1999; 14: 2386–91.

12 Tuckerman E., Laird S.M., Prakash A., et al. Prognostic value of the measurement of uterine natural killer cells in the endometrium of women with recurrent miscarriage. Hum Reprod. 2007; 22: 2208–13.

13 Quenby S., Nik H., Innes B., et al. Uterine natural killer cells and angiogenesis in recurrent reproductive failure. Hum Reprod. 2009; 24: 45–54.

14 Clifford K., Flanagan A.M., Regan L. Endometrial CD56+ natural killer cells in women with recurrent miscarriage: A histomorphometric study. Hum Reprod. 1999; 14: 2727–30.

15 Beer A.E., Kwak J.Y., Ruiz J.E. Immunophenotypic profiles of peripheral blood lymphocytes in women with recurrent pregnancy losses and in infertile women with multiple failed in vitro fertilization cycles. Am J Reprod Immunol. 1996; 35: 376–82.

16 King K., Smith S., Chapman M., et al. Detailed analysis of peripheral blood natural killer (NK) cells in women with recurrent miscarriage. Hum Reprod. 2010; 25: 52–8.

17 Karami N., Boroujerdnia M.G., Nikbakht R., et al. Enhancement of peripheral blood CD56(dim) cell and NK cell cytotoxicity in women with recurrent spontaneous abortion or in vitro fertilization failure. J Reprod Immunol. 2012; 95: 87–92.

18 Seshadri S., Sunkara S.K. Natural killer cells in female infertility and recurrent miscarriage: A systematic review and meta-analysis. Hum Reprod Update. 2014; 20: 429–38.

19 Saito S., Nakashima A., Shima T., et al. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol. 2010; 63: 601–10.

20 Ebina Y., Shimada S., Deguchi M., et al. Divergence of helper, cytotoxic, and regulatory T cells in the decidua from miscarriage. Am J Reprod Immunol. 2016; 76: 199–204.

21 Quenby S., Kalumbi C., Bates M., et al. Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. Fertil Steril. 2005; 84: 980–4.

22 Thum M.-Y., Bhaskaran S., Abdalla H.I., et al. Prednisolone suppresses NK cell cytotoxicity in vitro in women with a history of infertility and elevated NK cell cytotoxicity. Am J Reprod Immunol. 2008; 59: 259–65.

23 Fu X.-Q., Cai J.-Y., Huang Q.-Y., et al. Prednisone may induce immunologic tolerance by activating the functions of decidual immune cells in early pregnancy. Oncotarget. 2017; 8: 102 191–8.

24 Elenkov I.J. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci. 2004; 1024: 138–46.

25 Yamada H., Deguchi M., Maesawa Y., et al. Medium-dose intravenous immunoglobulin therapy for women with six or more recurrent miscarriages. J Reprod Immunol. 2015; 109: 48–51.

26 Ahmadi M., Aghdam S.A., Nouri M., et al. Intravenous immunoglobulin (IVIg) treatment modulates peripheral blood Th17 and regulatory T cells in recurrent miscarriage patients: non randomized, open-label clinical trial. Immunol Lett. 2017; 192: 12–9.

27 Ahmadi M., Abdolmohammadi-Vahid S., Ghaebi M., et al. Effect of intravenous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent pregnancy loss (RPL). Biomed Pharmacother. 2017; 92: 1095–102.

28 Stephenson M.D., Fluker M.R. Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: A randomized, placebo-controlled Canadian trial. Fertil Steril. 2000; 74: 1108–13.

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)

CHIEF EDITORS
CHIEF EDITOR
Sukhikh Gennadii Tikhonovich
Academician of the Russian Academy of Medical Sciences, V.I. Kulakov Obstetrics, Gynecology and Perinatology National Medical Research Center of Ministry of Healthсаre of the Russian Federation, Moscow
CHIEF EDITOR
Kurtser Mark Arkadievich
Academician of the Russian Academy of Sciences, MD, Professor, Head of the Obstetrics and Gynecology Subdepartment of the Pediatric Department, N.I. Pirogov Russian National Scientific Research Medical University, Ministry of Health of the Russian Federation
CHIEF EDITOR
Radzinsky Viktor Evseevich
Corresponding Member of the Russian Academy of Sciences, MD, Professor, Head of the Subdepartment of Obstetrics and Gynecology with a Course of Perinatology of the Medical Institute in the Russian People?s Friendship University named after P. Lumumbа

Journals of «GEOTAR-Media»