Low Dose Prednisone Therapy in Women With Recurrent Pregnancy Loss
NCT ID: NCT04558268
Last Updated: 2020-09-22
Study Results
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Basic Information
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UNKNOWN
PHASE2/PHASE3
242 participants
INTERVENTIONAL
2020-12-31
2021-10-31
Brief Summary
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Detailed Description
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Recently, a few studies were conducted with different protocols to investigate the impact of steroid therapy on women with RPL. Eight studies had reported a positive effect of prednisone on live birth rate. Hasegawa et al (12) found a significantly effective live birth rate of 76.5% compared to 8.3% (p\<0.01) in 17 treated RPL patients with antiphospholipid antibody with Prednisolone (40 mg/day) as soon as pregnancy was diagnosed, for at least 4 weeks together with low dose Aspirin (81 mg/day) until delivery, and 12 untreated patients respectively. They also found decreased antiphospholipid antibody titer and lower IUGR rate in the study group (30.8% compared to 83.3%, p\<0.05). Reznikoff et al (13) reported on the influence of steroid therapy combined with low dose Aspirin on the live birth rate in RPL autoantibody negative pregnant women. In his study he found a 90.7% live birth rate among 214 women treated with Prednisone (20 mg/day) in the first trimester only and low dose Aspirin (100 mg/day) for 7 months, compared with 74.6% birth rate among 63 women receiving aspirin alone (p\<0.001). Bansal et al (14) claimed in his review that a combination of Prednisone with low-dose aspirin can be efficient in preventing RPL, mainly in the first trimester of pregnancy, especially in women with non-APAS autoimmunity. Ogasawara et al (15) reported about a birth of a healthy baby to a woman who experienced 10 unexplained first trimester miscarriages after receiving intra-uterine Prednisolone (8 mg of 2 ml of solumedrol) 2-3 days before ovulation and aspirin (40 mg/day) from 4 until 36 weeks of gestation. Gomaa et al (16) reported an ongoing pregnancy beyond 20 weeks of gestation in 70.3 % of women in the prednisolone treatment group and only 9.2% in the placebo group. In three different studies, Quenby et al have shown a positive effect of steroid therapy on reducing the number of uterine NK cells (from 14% before treatment to 9% after, p=0.0004) by given Prednisone (20 mg/day, from day 1 to 21 of the menstrual cycle) to 28 women with RPL and high number of uterine NK cells(17). She reported about a birth of a healthy baby to a woman that suffered from 19 consecutive miscarriages after receiving prednisolone (20 mg/day) for 6 months prior to conception until 5 weeks gestation(18). In a latest study, a 60% and 40% live birth rate was reported in a small treatment and placebo group respectively both with no pregnancy complications nor serious adverse fetal outcomes, although the results weren't statistically significant (19).
Three studies have shown a probable positive effect of prednisone on birth life rate but have reported complications. Tempefar et al (20)reported 77% and 35% live birth rates in a 52 RPL women group who received a combination of Prednisone (20 mg/day), Progesterone (20 mg/day) for the first 12 weeks, Aspirin (100 mg/day) until 38 weeks of gestation and Folic-acid (5 mg) every second day throughout the pregnancy, and in a 52 RPL women control group respectively. Complications including nausea, depression, and tachycardia were observed. Cushing's disease and IUGR were not observed, neither a difference of mean birth weight nor preterm birth rate. Kumar et al (21)suggested that steroid therapy restricted to the preconception and early pregnancy for women with non-APAS autoimmunity may improve the outcome of the pregnancy. However, Kumar noted that steroid therapy during pregnancy is associated with a higher risk for preterm labor secondary to rupture of membranes and to the development of preeclampsia and gestational diabetes. Wang et al (22) who used high doses Prednisone (40-50 mg/day), reported on the increased risk of preterm labor and recommended not to used high doses prednisone for RPL women.
Two studies didn't show improvement of steroid therapy in the outcome of pregnancy. Laskin et al (23) published a study on 773 women with RPL and autoantibodies (antinuclear, anti-DNA, antilymphocyte, anticardiolipin and lupus anticoagulant antibodies). The women were divided into treatment group (received high dose Prednisone 0.5-0.8 mg/kg/day + Aspirin 100 mg/day) and to a placebo group. No significant difference in live birth was reported between the two groups. However, preterm labor (62% and 12%, p\<0.01), hypertension (13%\&5%, p=0.05) and gestational diabetes (15%\&5%, p=0.02) were more common in the treatment group. Empson et al (24) reviewed the influence of prednisone and aspirin treatment for RPL women with antiphospholipid antibody or lupus anticoagulant. He reported higher rates of prematurity and gestational diabetes in the steroid treatment group without an improvement in pregnancy outcome.
To summarise for many years there is a lack of large randomized controlled trials that study the effect of low dose prednisone in women with RPL and thus the evidence of a probable efficacy of prednisone in RPL women remains limited and unclear. As the ESHRE recommended in 2018 (2) we aim to assess the effect of such treatment in a large trial that includes unexplained and abnormal autoimmune profile RPL patients. we also aim to assess the side effects of the treatment in RPL pregnant women.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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treatment group
Prednisone
Prednisone is a corticosteroid. It prevents the release of substances in the body that cause inflammation. It also suppresses the immune system.
Prednisone is used as an anti-inflammatory or an immunosuppressant medication. Prednisone treats many different conditions such as allergic disorders, skin conditions, ulcerative colitis, arthritis, lupus, psoriasis, or breathing disorders.
Progesterone
Progesterone is a female hormone important for the regulation of ovulation and menstruation.
Progesterone is used to cause menstrual periods in women who have not yet reached menopause but are not having periods due to a lack of progesterone in the body. It is also used to prevent overgrowth in the lining of the uterus in postmenopausal women who are receiving estrogen hormone replacement therapy.
vit D
Vitamin D acts on our bones, intestines, kidneys and parathyroid glands to keep calcium in balance throughout our body. Vitamin D receptors are also located within our cardiovascular system, lungs, pancreas, skeletal muscle, skin, and reproductive organs. In summary, vitamin D is a prohormone that is essential for good health.
Iron Supplement
Iron is one of the minerals in the human body. It is one of the components of hemoglobin, the substance in red blood cells that helps blood carry oxygen throughout the body.
Folic Acid
Folic acid is a type of B vitamin that is normally found in foods such as dried beans, peas, lentils, oranges, whole-wheat products, liver, asparagus, beets, broccoli, brussels sprouts, and spinach.
Folic acid helps your body produce and maintain new cells, and also helps prevent changes to DNA that may lead to cancer.
placebo group
Progesterone
Progesterone is a female hormone important for the regulation of ovulation and menstruation.
Progesterone is used to cause menstrual periods in women who have not yet reached menopause but are not having periods due to a lack of progesterone in the body. It is also used to prevent overgrowth in the lining of the uterus in postmenopausal women who are receiving estrogen hormone replacement therapy.
vit D
Vitamin D acts on our bones, intestines, kidneys and parathyroid glands to keep calcium in balance throughout our body. Vitamin D receptors are also located within our cardiovascular system, lungs, pancreas, skeletal muscle, skin, and reproductive organs. In summary, vitamin D is a prohormone that is essential for good health.
Iron Supplement
Iron is one of the minerals in the human body. It is one of the components of hemoglobin, the substance in red blood cells that helps blood carry oxygen throughout the body.
Folic Acid
Folic acid is a type of B vitamin that is normally found in foods such as dried beans, peas, lentils, oranges, whole-wheat products, liver, asparagus, beets, broccoli, brussels sprouts, and spinach.
Folic acid helps your body produce and maintain new cells, and also helps prevent changes to DNA that may lead to cancer.
Interventions
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Prednisone
Prednisone is a corticosteroid. It prevents the release of substances in the body that cause inflammation. It also suppresses the immune system.
Prednisone is used as an anti-inflammatory or an immunosuppressant medication. Prednisone treats many different conditions such as allergic disorders, skin conditions, ulcerative colitis, arthritis, lupus, psoriasis, or breathing disorders.
Progesterone
Progesterone is a female hormone important for the regulation of ovulation and menstruation.
Progesterone is used to cause menstrual periods in women who have not yet reached menopause but are not having periods due to a lack of progesterone in the body. It is also used to prevent overgrowth in the lining of the uterus in postmenopausal women who are receiving estrogen hormone replacement therapy.
vit D
Vitamin D acts on our bones, intestines, kidneys and parathyroid glands to keep calcium in balance throughout our body. Vitamin D receptors are also located within our cardiovascular system, lungs, pancreas, skeletal muscle, skin, and reproductive organs. In summary, vitamin D is a prohormone that is essential for good health.
Iron Supplement
Iron is one of the minerals in the human body. It is one of the components of hemoglobin, the substance in red blood cells that helps blood carry oxygen throughout the body.
Folic Acid
Folic acid is a type of B vitamin that is normally found in foods such as dried beans, peas, lentils, oranges, whole-wheat products, liver, asparagus, beets, broccoli, brussels sprouts, and spinach.
Folic acid helps your body produce and maintain new cells, and also helps prevent changes to DNA that may lead to cancer.
Eligibility Criteria
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Inclusion Criteria
* Patients with abnormal immunological profile, including ANA, RF, anti-DNA, antilymphocyte, anticardiolipin, antithyroid and lupus anticoagulant antibodies that have no other clinical manifestation.
* Women with three or more pregnancy losses (before 24 weeks of gestation) who referred to the RPL clinic in Soroka hospital.
* An age above 25 years.
* The women agreed to participate in the study and signed on a consent form.
* women with index pregnancy.
Exclusion Criteria
* Diabetes mellitus diagnosed by symptoms of diabetes plus random glucose concentration≥ 200mg/dL or fasting plasma glucose≥ 126mg/dL or hemoglobin A1C≥5.8% or 2-h plasma glucose≥ 200mg/dL during an oral glucose tolerance test.
* Previously untreated tuberculosis, as determined by an abnormal chest film in the previous year or a positive tuberculin skin test.
* Prednisone therapy during pregnancy for other reasons.
* Sensitivity to prednisone.
25 Years
40 Years
FEMALE
Yes
Sponsors
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Soroka University Medical Center
OTHER
Responsible Party
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Locations
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Soroka Medical Center
Beersheba, , Israel
Countries
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Central Contacts
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References
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ESHRE Guideline Group on RPL; Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, Nelen W, Peramo B, Quenby S, Vermeulen N, Goddijn M. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018 Apr 6;2018(2):hoy004. doi: 10.1093/hropen/hoy004. eCollection 2018.
(2) Mehta S, Gupta B. Recurrent Pregnancy Loss. 2018 Apr 20,.
Ford HB, Schust DJ. Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol. 2009 Spring;2(2):76-83.
Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012 Nov;98(5):1103-11. doi: 10.1016/j.fertnstert.2012.06.048. Epub 2012 Jul 24.
Gabbai D, Harlev A, Friger M, Steiner N, Sergienko R, Kreinin A, Bashiri A. Pregnancy outcomes among patients with recurrent pregnancy loss and uterine anatomic abnormalities. J Perinat Med. 2018 Sep 25;46(7):728-734. doi: 10.1515/jpm-2016-0411. No abstract available.
Kabessa M, Harlev A, Friger M, Sergienko R, Litwak B, Koifman A, Steiner N, Bashiri A. Pregnancy outcomes among patients with recurrent pregnancy loss and chromosomal aberration (CA) without PGD. J Perinat Med. 2018 Sep 25;46(7):764-770. doi: 10.1515/jpm-2016-0408. No abstract available.
El Hachem H, Crepaux V, May-Panloup P, Descamps P, Legendre G, Bouet PE. Recurrent pregnancy loss: current perspectives. Int J Womens Health. 2017 May 17;9:331-345. doi: 10.2147/IJWH.S100817. eCollection 2017.
Bashiri A, Gete S, Mazor M, Gete M. [Recurrent pregnancy loss--evaluation and treatment]. Harefuah. 2011 Nov;150(11):852-6, 875. Hebrew.
Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. 2006 Jun;148(3):245-54. doi: 10.1038/sj.bjp.0706736.
Feldman PA, Wolfson D, Barkin JS. Medical management of Crohn's disease. Clin Colon Rectal Surg. 2007 Nov;20(4):269-81. doi: 10.1055/s-2007-991026.
Bandoli G, Palmsten K, Forbess Smith CJ, Chambers CD. A Review of Systemic Corticosteroid Use in Pregnancy and the Risk of Select Pregnancy and Birth Outcomes. Rheum Dis Clin North Am. 2017 Aug;43(3):489-502. doi: 10.1016/j.rdc.2017.04.013.
Hasegawa I, Takakuwa K, Goto S, Yamada K, Sekizuka N, Kanazawa K, Tanaka K. Effectiveness of prednisolone/aspirin therapy for recurrent aborters with antiphospholipid antibody. Hum Reprod. 1992 Feb;7(2):203-7. doi: 10.1093/oxfordjournals.humrep.a137617.
Reznikoff-Etievant MF, Cayol V, Zou GM, Abuaf N, Robert A, Johanet C, Milliez J. Habitual abortions in 678 healthy patients: investigation and prevention. Hum Reprod. 1999 Aug;14(8):2106-9. doi: 10.1093/humrep/14.8.2106.
Bansal AS, Bajardeen B, Thum MY. The basis and value of currently used immunomodulatory therapies in recurrent miscarriage. J Reprod Immunol. 2012 Jan;93(1):41-51. doi: 10.1016/j.jri.2011.10.002. Epub 2011 Dec 21.
Ogasawara M, Aoki K. Successful uterine steroid therapy in a case with a history of ten miscarriages. Am J Reprod Immunol. 2000 Oct;44(4):253-5. doi: 10.1111/j.8755-8920.2000.440411.x.
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 Oct;290(4):757-62. doi: 10.1007/s00404-014-3262-0. Epub 2014 May 13.
Quenby S, Kalumbi C, Bates M, Farquharson R, Vince G. Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. Fertil Steril. 2005 Oct;84(4):980-4. doi: 10.1016/j.fertnstert.2005.05.012.
Quenby S, Farquharson R, Young M, Vince G. Successful pregnancy outcome following 19 consecutive miscarriages: case report. Hum Reprod. 2003 Dec;18(12):2562-4. doi: 10.1093/humrep/deg502.
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 Jul;28(7):1743-52. doi: 10.1093/humrep/det117. Epub 2013 Apr 12.
Tempfer CB, Kurz C, Bentz EK, Unfried G, Walch K, Czizek U, Huber JC. A combination treatment of prednisone, aspirin, folate, and progesterone in women with idiopathic recurrent miscarriage: a matched-pair study. Fertil Steril. 2006 Jul;86(1):145-8. doi: 10.1016/j.fertnstert.2005.12.035. Epub 2006 May 23.
Kumar A. Immunomodulation in recurrent miscarriage. J Obstet Gynaecol India. 2014 Jun;64(3):165-8. doi: 10.1007/s13224-014-0541-4. Epub 2014 May 8.
Wang SW, Zhong SY, Lou LJ, Hu ZF, Sun HY, Zhu HY. The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis. Reprod Biomed Online. 2016 Dec;33(6):720-736. doi: 10.1016/j.rbmo.2016.08.025. Epub 2016 Sep 16.
Laskin CA, Bombardier C, Hannah ME, Mandel FP, Ritchie JW, Farewell V, Farine D, Spitzer K, Fielding L, Soloninka CA, Yeung M. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med. 1997 Jul 17;337(3):148-53. doi: 10.1056/NEJM199707173370302.
Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev. 2005 Apr 18;2005(2):CD002859. doi: 10.1002/14651858.CD002859.pub2.
Other Identifiers
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SOR-0461-18-CTIL
Identifier Type: -
Identifier Source: org_study_id
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