Low Dose Prednisone Therapy in Women With Recurrent Pregnancy Loss

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.

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.

Eligibility Criteria:
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.