Low Dose Prednisone Therapy in Women With Recurrent Pregnancy Loss

September 21, 2020 updated by: Soroka University Medical Center
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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Recurrent pregnancy loss (RPL) was defined recently by the European society of human reproduction and embryology (ESHRE) as the loss of two or more pregnancies that occur after spontaneous conception and assisted reproductive technology excluding ectopic, molar pregnancies and implantation failure (1,2). The exact prevalence of RPL is difficult to estimate but most studies including the American society for reproductive medicine (ASRM) repost that RPL affects 5% of women. In approximately half of the women with RPL the etiology will remain unexplained while in the remaining half the cause will be defined as one or more of the following, genetic factors, anatomic factors, endocrine factors, autoimmune and infectious (1,3-6). 15% of patients with RPL are diagnosed with antiphospholipid syndrome which is considered as an autoimmune disease (7,8). The ESHRE and ASRM guidelines recommend treatment of prophylactic doses of unfractionated heparin and low-dose aspirin for RPL women with high titers of antiphospholipid antibodies. For RPL women with the remaining immunological conditions glucocorticosteroids, IvIg , TNF inhibitors, and G-CSF treatment are not evidence-based but can be given in research context (1,4,8). Glucocorticosteroids are drugs that reduce inflammation by blocking the expression of proinflammatory cytokines. They suppress the activity of T cells and decrease cytokines levels- IL6, IL1β, TNFα. This drug is a known treatment for inflammatory diseases including asthma, Crohn's disease, and rheumatoid arthritis (9,10). In a recent review in 2017 Bandoli et al (11) summarized that corticosteroids are often necessary to control the symptoms of various medical conditions in pregnancy, including rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. Investigations into adverse pregnancy and birth outcomes following corticosteroid exposure have lacked adequate exploration into confounding by disease or disease severity. The evidence for cleft palate alone is not sufficient to summarize. The estimated risk of cleft lip with or without cleft palate from corticosteroid exposure has weakened over time, and no study published after 2003 has reported a statistically significant risk estimate. This review does not find sufficient evidence to support an increased risk of preterm birth, low birth weight, or preeclampsia following systemic corticosteroid use in pregnancy. There is insufficient evidence to determine whether systemic corticosteroids are linked to gestational diabetes mellitus.

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.

Study Type

Interventional

Enrollment (Anticipated)

242

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Israel
      • Be'er Sheva, Israel
        • Soroka Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

23 years to 38 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Patients with unexplained RPL.
  • 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:

  • Presence of any genetic impairment, Mullerian anomaly, endocrine or metabolic disorders, or a luteal-phase defect (as determined by a timed endometrial biopsy).
  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: placebo group
Drug: 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.

Dietary supplement: 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.
Dietary supplement: 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.
Dietary supplement: 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.
Experimental: treatment group
Drug: 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.

Drug: 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.

Dietary supplement: 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.
Dietary supplement: 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.
Dietary supplement: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Live birth
Time Frame: through study completion, an average of 1 year.
birth that occurs after 24 weeks of gestation.
through study completion, an average of 1 year.
Pregnancy loss
Time Frame: through study completion, an average of 1 year.
birth that occurs up to 24 weeks of gestation.
through study completion, an average of 1 year.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Soroka University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

December 1, 2020

Primary Completion (Anticipated)

July 1, 2021

Study Completion (Anticipated)

October 1, 2021

Study Registration Dates

First Submitted

May 12, 2020

First Submitted That Met QC Criteria

September 21, 2020

First Posted (Actual)

September 22, 2020

Study Record Updates

Last Update Posted (Actual)

September 22, 2020

Last Update Submitted That Met QC Criteria

September 21, 2020

Last Verified

February 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SOR-0461-18-CTIL

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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