Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2020

Open Access 01-12-2020 | Anticoagulant | Study protocol

A three-arm, multicenter, open-label randomized controlled trial of hydroxychloroquine and low-dose prednisone to treat recurrent pregnancy loss in women with undifferentiated connective tissue diseases: protocol for the Immunosuppressant regimens for LIving FEtuses (ILIFE) trial

Authors: Shaoying Yang, Ruoning Ni, Yikang Lu, Suli Wang, Feng Xie, Chunyan Zhang, Liangjing Lu

Published in: Trials | Issue 1/2020

Login to get access

Abstract

Background

Undifferentiated connective tissue disease (UCTD) is known to induce adverse pregnancy outcomes and even recurrent spontaneous abortion (RSA) by placental vascular damage and inflammation activation. Anticoagulation can prevent pregnancy morbidities. However, it is unknown whether the addition of immune suppressants to anticoagulation can prevent spontaneous pregnancy loss in UCTD patients. The purpose of this study is to evaluate the efficacy of hydroxychloroquine (HCQ) and low-dose prednisone on recurrent pregnancy loss for women with UCTD.

Methods

The Immunosuppressant for Living Fetuses (ILIFE) Trial is a three-arm, multicenter, open-label randomized controlled trial with the primary objective of comparing hydroxychloroquine combined with low-dose prednisone and anticoagulation with anticoagulation alone in treating UCTD women with recurrent spontaneous abortion. The third arm of using hydroxychloroquine combined with anticoagulant for secondary comparison. A total of 426 eligible patients will be randomly assigned to each of the three arms with a 1:1:1 allocation ratio. The primary outcome is the rate of live births. Secondary outcomes include adverse pregnancy outcomes and progression of UCTD.

Discussion

This is the first multi-center, open-label, randomized controlled trial which evaluates the efficacy of immunosuppressant regimens on pregnancy outcomes and UCTD progression. It will provide evidence on whether the immunosuppressant ameliorates the pregnancy prognosis in UCTD patients with RSA and the progression into defined connective tissue disease.

Trial registration

ClinicalTrials.gov NCT03671174. Registered on 14 September 2018.
Appendix
Available only for authorised users
Literature
1.
Antunes M, Scirè CA, Talarico R, Alexander T, Avcin T, Belocchi C, et al. Undifferentiated connective tissue disease: state of the art on clinical practice guidelines. RMD Open. 2019;4(Suppl 1):e786.
2.
Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol. 1999;17(5):615–20.PubMed
3.
Vaz CC, Couto M, Medeiros D, Miranda L, Costa J, Nero P, et al. Undifferentiated connective tissue disease: a seven-center cross-sectional study of 184 patients. Clin Rheumatol. 2009;28(8):915–21.PubMed
4.
Guerrero LF, Rueda JC, Arciniegas R, Rueda JM. Undifferentiated connective tissue disease in a rheumatology center in Cali, Colombia: clinical features of 94 patients followed for a year. Rheumatol Int. 2013;33(4):1085–8.PubMed
5.
Spinillo A, Beneventi F, Ramoni V, Caporali R, Locatelli E, Simonetta M, et al. Prevalence and significance of previously undiagnosed rheumatic diseases in pregnancy. Ann Rheum Dis. 2012;71(6):918–23.PubMed
6.
Mosca M, Tani C, Neri C, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases (UCTD). Autoimmun Rev. 2006;6(1):1–4.PubMed
7.
Spinillo A, Beneventi F, Locatelli E, Ramoni V, Caporali R, Alpini C, et al. The impact of unrecognized autoimmune rheumatic diseases on the incidence of preeclampsia and fetal growth restriction: a longitudinal cohort study. Bmc Pregnancy Childb. 2016;16(1):313.
8.
Pandey MK, Rani R, Agrawal S. An update in recurrent spontaneous abortion. Arch Gynecol Obstet. 2005;272(2):95–108.PubMed
9.
Laczik R, Soltesz P, Szodoray P, Szekanecz Z, Kerekes G, Paragh G, et al. Impaired endothelial function in patients with undifferentiated connective tissue disease: a follow-up study. Rheumatology. 2014;53(11):2035–43.PubMed
10.
Spinillo A, Beneventi F, Caporali R, Ramoni V, Montecucco C. Undifferentiated connective tissue diseases and adverse pregnancy outcomes. An undervalued association? Am J Reprod Immunol. 2017;78(6):e12762.
11.
Dubova EA, Klimantsev IV, Pavlov KA, Kulikova GV, Kan NE, Shchyogolev AI, et al. The expression of matrix metalloproteinases in placental tissue depends on the severity of undifferentiated connective tissue dysplasia. Bull Exp Biol Med. 2013;156(1):110–3.PubMed
12.
Beneventi F, Locatelli E, Ramoni V, Caporali R, Montecucco CM, Simonetta M, et al. Uterine artery Doppler velocimetry and obstetric outcomes in connective tissue diseases diagnosed during the first trimester of pregnancy. Prenatal Diag. 2012;32(11):1094–101.PubMed
13.
Mosca M, Neri R, Strigini F, Carmignani A, Totti D, Tavoni A, et al. Pregnancy outcome in patients with undifferentiated connective tissue disease: a preliminary study on 25 pregnancies. Lupus. 2002;11(5):304–7.PubMed
14.
Spinillo A, Beneventi F, Epis OM, Montanari L, Mammoliti D, Ramoni V, et al. The effect of newly diagnosed undifferentiated connective tissue disease on pregnancy outcome. Am J Obstet Gynecol. 2008;199(6):631–2.
15.
Radin M, Schreiber K, Cecchi I, Bortoluzzi A, Crisafulli F, de Freitas CM, et al. A multicentre study of 244 pregnancies in undifferentiated connective tissue disease: maternal/fetal outcomes and disease evolution. Rheumatology. 2020;0:1–7.
16.
Castellino G, Capucci R, Bernardi S, Padovan M, Giacuzzo S, Pivato E, et al. Pregnancy in patients with undifferentiated connective tissue disease: a prospective case-control study. Lupus. 2011;20(12):1305–11.PubMed
17.
Pepmueller PH. Undifferentiated connective tissue disease, mixed connective tissue disease, and overlap syndromes in rheumatology. Mo Med. 2016;113(2):136–40.PubMedPubMedCentral
18.
Mosca M, Tani C, Carli L, Bombardieri S. Undifferentiated CTD: a wide spectrum of autoimmune diseases. Best Pract Res Clin Rheumatol. 2012;26(1):73–7.PubMed
19.
Bodolay E, Csiki Z, Szekanecz Z, Ben T, Kiss E, Zeher M, et al. Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol. 2003;21(3):313–20.PubMed
20.
Mosca M, Tani C, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a new frontier for rheumatology. Best Pract Res Clin Rheumatol. 2007;21(6):1011–23.PubMed
21.
Cavazzana I, Franceschini F, Belfiore N, Quinzanini M, Caporali R, Calzavara-Pinton P, et al. Undifferentiated connective tissue disease with antibodies to Ro/SSa: clinical features and follow-up of 148 patients. Clin Exp Rheumatol. 2001;19(4):403–9.PubMed
22.
Mekinian A, Costedoat-Chalumeau N, Masseau A, Tincani A, De Caroli S, Alijotas-Reig J, et al. Obstetrical APS: is there a place for hydroxychloroquine to improve the pregnancy outcome? Autoimmun Rev. 2015;14(1):23–9.PubMed
23.
Kano T, Shimizu M, Kanda T. Differences in individual efficacy of two Sairei-to preparations (Sojyutu-Sairei-to and Byakujyutu-Sairei-to) on recurrent spontaneous abortions of autoimmune etiologies evaluated by antinuclear antibody and anticardiolipin antibody titers. Am J Chin Med. 2010;38(1):27–36.PubMed
24.
Badawy AM, Khiary M, Sherif LS, Hassan M, Ragab A, Abdelall I. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol. 2008;28(3):280–4.PubMed
25.
Laskin CA, Spitzer KA, Clark CA, Crowther MR, Ginsberg JS, Hawker GA, et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA trial. J Rheumatol. 2009;36(2):279–87.PubMed
26.
Tempfer CB, Kurz C, Bentz E, Unfried G, Walch K, Czizek U, et al. A combination treatment of prednisone, aspirin, folate, and progesterone in women with idiopathic recurrent miscarriage: a matched-pair study. Fertil Steril. 2006;86(1):145–8.PubMed
27.
Flint J, Panchal S, Hurrell A, van de Venne M, Gayed M, Schreiber K, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding—part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology. 2016;55(9):1693–7.PubMed
28.
Tang AW, Alfirevic Z, Turner MA, Drury JA, Small R, Quenby S. A feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant. Hum Reprod. 2013;28(7):1743–52.
29.
Bansal AS. Joining the immunological dots in recurrent miscarriage. Am J Reprod Immunol. 2010;64(5):307–15.PubMed
30.
Gomaa MF, Elkholy AG, El-Said MM, Abdel-Salam NE. Combined oral prednisolone and heparin versus heparin: the effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial. Arch Gynecol Obstet. 2014;290(4):757–62.PubMedPubMedCentral
31.
Bramham K, Thomas M, Nelson-Piercy C, Khamashta M, Hunt BJ. First-trimester low-dose prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood. 2011;117(25):6948–51.PubMed
32.
Kemp MW, Newnham JP, Challis JG, Jobe AH, Stock SJ. The clinical use of corticosteroids in pregnancy. Hum Reprod Update. 2015;2(22):240–59.
33.
Fawzy M, Shokeir T, El-Tatongy M, Warda O, El-Refaiey AA, Mosbah A. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study. Arch Gynecol Obstet. 2008;278(1):33–8.PubMed
34.
James JA, Kim-Howard XR, Bruner BF, Jonsson MK, McClain MT, Arbuckle MR, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2016;16(6):401–9.
35.
Clowse MEB, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum. 2006;54(11):3640–7.PubMed
36.
Koh JH, Ko HS, Kwok S, Ju JH, Park S. Hydroxychloroquine and pregnancy on lupus flares in Korean patients with systemic lupus erythematosus. Lupus. 2014;24(2):210–7.PubMed
37.
Luo Y, Zhang L, Fei Y, Li Y, Hao D, Liu Y, et al. Pregnancy outcome of 126 anti-SSA/Ro-positive patients during the past 24 years—a retrospective cohort study. Clin Rheumatol. 2015;34(10):1721–8.PubMed
38.
Sciascia S, Hunt BJ, Talavera-Garcia E, Lliso G, Khamashta MA, Cuadrado MJ. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am J Obstet Gynecol. 2016;214(2):271–3.
39.
Izmirly PM, Kim MY, Llanos C, Le PU, Guerra MM, Askanase AD, et al. Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis. 2010;69(10):1827–30.PubMedPubMedCentral
40.
Costedoat-Chalumeau N, Amoura Z, Duhaut P, Huong DLT, Sebbough D, Wechsler B, et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: a study of one hundred thirty-three cases compared with a control group. Arthritis Rheum. 2003;48(11):3207–11.PubMed
41.
Abarientos C, Sperber K, Shapiro DL, Aronow WS, Chao CP, Ash JY. Hydroxychloroquine in systemic lupus erythematosus and rheumatoid arthritis and its safety in pregnancy. Expert Opin Drug Saf. 2011;10(5):705–14.PubMed
42.
Practice Committee of American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. 2013;99(1):63.
43.
Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyak K, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010;362(17):1586–96.PubMed
44.
Wong LF, Schliep KC, Silver RM, Mumford SL, Perkins NJ, Ye A, et al. The effect of a very short interpregnancy interval and pregnancy outcomes following a previous pregnancy loss. Am J Obstet Gynecol. 2015;212(3):371–5.
45.
de Groot CJM, van der Mast BJ, Visser W, De Kuiper P, Weimar W, Van Besouw NM. Preeclampsia is associated with increased cytotoxic T-cell capacity to paternal antigens. Am J Obstet Gynecol. 2010;203(5):491–6.
Metadata
Title
A three-arm, multicenter, open-label randomized controlled trial of hydroxychloroquine and low-dose prednisone to treat recurrent pregnancy loss in women with undifferentiated connective tissue diseases: protocol for the Immunosuppressant regimens for LIving FEtuses (ILIFE) trial
Authors
Shaoying Yang
Ruoning Ni
Yikang Lu
Suli Wang
Feng Xie
Chunyan Zhang
Liangjing Lu
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Trials / Issue 1/2020
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-020-04716-1

Other articles of this Issue 1/2020

Trials 1/2020 Go to the issue

Letter

Hydroxychloroquine plus personal protective equipment versus standard personal protective equipment alone for the prevention of COVID-19 infections among frontline healthcare workers: the HydrOxychloroquine Prophylaxis Evaluation(HOPE) trial: A structured summary of a study protocol for a randomized controlled trial

Study protocol

PALLiON – PALLiative care Integrated in ONcology: study protocol for a Norwegian national cluster-randomized control trial with a complex intervention of early integration of palliative care

Study protocol

Robotic radical antegrade modular pancreatosplenectomy (RAMPS) versus standard retrograde pancreatosplenectomy (SRPS): study protocol for a randomized controlled trial

Study protocol

Mesenteric excision surgery or conservative limited resection in Crohn’s disease: study protocol for an international, multicenter, randomized controlled trial

Methodology

A simulation study comparing the power of nine tests of the treatment effect in randomized controlled trials with a time-to-event outcome

Update

First-line support for assistance in breathing in children: statistical and health economic analysis plan for the FIRST-ABC trial