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

Mostafa F Gomaa, Abdellatif G Elkholy, Mourrad M El-Said, Nermine E Abdel-Salam, Mostafa F Gomaa, Abdellatif G Elkholy, Mourrad M El-Said, Nermine E Abdel-Salam

Abstract

Purpose: To evaluate the efficacy of the use of oral Prednisolone and heparin versus the use of heparin alone in treatment of patients with unexplained recurrent miscarriage.

Methodology: The study was a double-blind placebo randomized control trial conducted on 160 patients with unexplained recurrent miscarriage. Patients recruited were randomized into two groups. The first group received oral Prednisolone in addition to low dose aspirin and heparin, while the other group received a placebo in addition to low dose aspirin and heparin. A peripheral venous blood sample was taken from all included patients before starting treatment and collected in heparinized tubes. Natural Killer (NK) cells were checked in each sample and then re-checked in another sample at 20 weeks of gestation.

Results: We found that in the prednisolone group, 70.3 % of women had successful outcome (defined as an ongoing pregnancy beyond 20 weeks gestation), while 29.7 % miscarried before this gestation. On the contrary, among women in the placebo group, 9.2 % had successful outcome while 90.8 % miscarried before 20 weeks, which was statistically significant. On the other hand, we found that there were no significant paired differences between initial serum levels of the NK cells markers CD16 and CD56 and their levels at 20 weeks gestation in both groups.

Conclusion: The addition of prednisolone to heparin and low dose aspirin might be beneficial in patients with unexplained recurrent miscarriage, and this effect might be due to a suppressive effect of steroids on the peripheral CD16 NK cells concentration.

Figures

Fig. 1
Fig. 1
Participant flow in the study

References

    1. Practice Committee of the American Society for Reproductive Medicine Definitions of infertility and recurrent pregnancy loss. Fertil Steril. 2008;89:1603. doi: 10.1016/j.fertnstert.2008.03.002.
    1. Egozcue S, Balanco J, Vendrell JM. Human male infertility: chromosomal abnormalities, meiotic disorders, abnormal spermatozoa and recurrent abortion. Hum Reprod. 2000;6:9–105.
    1. Regan L, Jivraj S. Infection and pregnancy loss. In: MacLean A, Regan L, Carrington D, editors. Infection and pregnancy. London: RCOG Press; 2001. pp. 291–304.
    1. Wilcox AJ, Weinberg CR, O’Connor JF. Incidence of early loss of pregnancy. N Engl J Med. 1988;319:189–194. doi: 10.1056/NEJM198807283190401.
    1. Bricker L, Farquharson RG. Types of pregnancy loss in recurrent miscarriage: implications for research and clinical practice. Hum Reprod. 2002;17:1345–1350. doi: 10.1093/humrep/17.5.1345.
    1. Rai R, Regan L. Recurent miscarriage. Lancet. 2006;368:601–611. doi: 10.1016/S0140-6736(06)69204-0.
    1. Hill JA (1999) Recurrent pregnancy loss. In: Rayan KJ., Berkowitz RS., Barbieri RL., Dunaif A. (eds), Kistner’s gynecology and women’s health, 7th edition. Mosby, St Louis pp 396
    1. Summers PR. Microbiology relevant to recurrent miscarriage. Clin Obstet Gynecol. 1994;37:722–729. doi: 10.1097/00003081-199409000-00023.
    1. Matovina M, Husnjak K, Milutin N, Ciglar S, Grce M. Possible role of bacterial and viral infections in miscarriages. Fertil Steril. 2004;81:662–669. doi: 10.1016/j.fertnstert.2003.08.020.
    1. Abramson J, Stagnaro-Green A. Thyroid antibodies and fetal loss: an evolving story. Thyroid. 2001;11:57–63. doi: 10.1089/10507250150500676.
    1. Moffett-King A. Natural Killer cells and pregnancy. Nat Rev Immunol. 2002;2:656–663. doi: 10.1038/nri886.
    1. Yovel G, Shakhar K, Ben-Eliyahu S. The effects of sex, menstrual cycle, and oral contraceptives on the number and activity of natural killer cells. Gynecol Oncol. 2001;81:254–262. doi: 10.1006/gyno.2001.6153.
    1. Lee RM, Silver RM. Recurrent pregnancy loss: summary and clinical recommendations. Semin Reprod Med. 2000;18:433–440. doi: 10.1055/s-2000-13733.
    1. Royal College of Obstetricians and Gynaecologists . Guideline no. 17. The management of recurrent miscarriage. London: RCOG press; 2003. p. 22.
    1. American College of Obstetricians and Gynecologists (2002) Management of recurrent early pregnancy loss. ACOG practice bulletin. Int J Gynaecol Obstet 78:179–190
    1. Bansal AS. Joining the immunological dots in recurrent miscarriage. Am J Reprod Immunol. 2010;64:307–315.
    1. Thum M, Bhaskaran S, Abdallah HI, Ford B, Sumar N, Bansal AS. Prednisolone suppresses NK cell cytotoxicity in vitro in women with a history of infertility and elevated NK cell cytotoxicity. Am J Reprod Immunol. 2008;59:259–265. doi: 10.1111/j.1600-0897.2007.00574.x.
    1. Lash GE, Robson SC, Bulmer JN. Functional role of uterine natural killer (uNK) cells in human early pregnancy deciduas. Placenta. 2011;31:S87–S92. doi: 10.1016/j.placenta.2009.12.022.
    1. Aoki K, Kajiura S, Matsumoto Y, Ogasawara M, Okada S, Yagami Y, Gleicher N. Preconceptional natural-killer-cell activity as a predictor of miscarriage. Lancet. 1995;345:1340–1342. doi: 10.1016/S0140-6736(95)92539-2.
    1. Emmer PM, Nelen WL, Steegers EA, Hendriks JC, Veerhoek M, Joosten L. Peripheral natural killer cytotoxicity and CD 56(pos) CD16 (pos) cells increase during early pregnancy in women with a history of recurrent spontaneous abortion. Hum Reprod. 2000;15:1163–1169. doi: 10.1093/humrep/15.5.1163.
    1. King A, Balendran N, Wooding P, Carter NP, Loke YW. CD3-leukocytes present in the human uterus during early placentation: phenotypic and morphologic characterization of the CD56+ population. Dev Immunol. 1991;1:169–190. doi: 10.1155/1991/83493.
    1. Nagler A, Lanier LL, Cwirla S, Phillips JH. Comparative studies of human FcRIII-positive and negative natural killer cells. J Immunol. 1989;143:3183–3191.
    1. Chrysoula D, Linda CG. Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives. Endocrine Rev. 2005;26:44–62. doi: 10.1210/er.2003-0021.
    1. Badawy AM, Khairy M, Sherif LS, Hassan M, Ragab A, Abdelall I. Low- molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J obstet and gynaecol. 2008;28:280–284. doi: 10.1080/01443610802042688.
    1. Fawzy M, Shokeir T, El-Tongy M, Warda O, El-Refaiey A, Mosbah A. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study. Arch Gynecol Obstet. 2008;278:33–38. doi: 10.1007/s00404-007-0527-x.
    1. Thum MY, Haskaran SB, Bansal AS, Shehata H, Ford B, Sumar N, Abdallah HI. Simple enumerations of peripheral blood natural killer (CD56+ NK) cells, B cells and T cells have no predictive value in IVF treatment outcome. Hum Reprod. 2005;20:1272–1276. doi: 10.1093/humrep/deh774.
    1. Gilman-Sachs A, Duchateau BK, AslaKson CJ, Wohlgmuth GP, Kwak JY, Beer AE, Beaman KD. Natural Killer (NK) cell subsets and NK cell cytotoxicity in women with histories of recurrent spontaneous abortions. Am J Reprod Immunol. 1999;41:99–105. doi: 10.1111/j.1600-0897.1999.tb00081.x.
    1. 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;28:1743–1752. doi: 10.1093/humrep/det117.

Source: PubMed

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