Effect of a 20% intravenous fat emulsion therapy on pregnancy outcomes in women with RPL or RIF undergoing IVF/ICSI: a systematic review and meta-analysis
Background and aim: To evaluate the efficacy a 20% intravenous fat emulsion therapy in women suffering from recurrent pregnancy loss or recurrent implantation failure (RPL/RIF) who are undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).
Methods: We searched Cochrane Library, ISI Web of Science, MEDLINE, ClinicalTrials.gov, PubMed, and Scopus using relevant keywords during February 2020 for randomized controlled trials (RCTs) comparing the therapy versus placebo or no intervention in women suffering from RPL/RIF and undergoing IVF/ICSI.
Results: We included five RCTs with 840 patients. The intravenous fat emulsion therapy was significantly effective in increasing clinical pregnancy rates compared to the control group (RR=1.48, 95% CI [1.23,1.79], p<0.001). Furthermore, ongoing pregnancy and live birth rates were significantly higher with 20% intravenous fat emulsion therapy (RR=1.71, 95% CI [1.27,2.32], p=0.005) and (RR= 1.85, 95% CI [1.44, 2.38], p<0.001). Despite the statistically significant differences, the quality of evidence was only considered moderate, and this was primarily due to high risk of bias in the included RCTs. Conclusion: Our review provides a moderate level of evidence that intravenous fat emulsion therapy is effective in improving reproductive outcomes among women with RPL/RIF performing IVF/ICSI techniques. Further investigation is required to ascertain optimal dosage and timing of administration.
Relevance for Patients: Women suffering from RPL or RIF may wish to consider discussing with their reproductive endocrinologist the addition of a 20% fat emulsion therapy to planned IVF or ICSI cycles, which may improve outcomes.
[1] Practice Committee of the American Society for Reproductive Medicine. Definitions of Infertility and Recurrent Pregnancy Loss: A Committee Opinion. Fertil Steril 2013;99:63.
[2] ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, et al. ESHRE Guideline: Recurrent Pregnancy Loss: An Update in 2022. Hum Reprod Open 2023;2023:hoad002.
[3] McBride KL, Beirne JP. Recurrent Miscarriage. InnovAiT 2014;7:25-34.
[4] Kutteh WH. Recurrent Pregnancy Loss. Semin Reprod Med 2006;24:54-66.
[5] Zinaman MJ, Clegg ED, Brown CC, O’Connor J, Selevan SG. Estimates of Human Fertility and Pregnancy Loss. Fertil Steril 1996;65:503-9.
[6] Dimitriadis E, Menkhorst E, Saito S, Kutteh WH, Brosens JJ. Recurrent Pregnancy Loss. Nat Rev Dis Primers 2020;6:98.
[7] Coughlan C, Ledger W, Wang Q, Liu F, Demirol A, Gurgan T, et al. Recurrent Implantation Failure: Definition and Management. Reprod Biomed Online 2014;28:14-38.
[8] Kumar P, Mahajan S. Preimplantation and Postimplantation Therapy for the Treatment of Reproductive Failure. J Hum Reprod Sci 2013;6:88-92.
[9] Sugiura-Ogasawara M. Recurrent Pregnancy Loss and Obesity. Best Pract Res Clin Obstet Gynaecol 2015; 29:489-97.
[10] Martini AE, Jasulaitis S, Fogg LF, Uhler ML, HirshfeldCytron JE. Evaluating the Utility of Intralipid Infusion to Improve Live Birth Rates in Patients with Recurrent Pregnancy Loss or Recurrent Implantation Failure. J Hum Reprod Sci 2018;11:261-8.
[11] Bashiri A, Halper KI, Orvieto R. Recurrent Implantation Failure-update Overview on Etiology, Diagnosis, Treatment and Future Directions. Reprod Biol Endocrinol 2018;16:121.
[12] Boomsma CM, Kamath MS, Keay SD, Macklon NS. Periimplantation Glucocorticoid Administration for Assisted Reproductive Technology Cycles. Cochrane Database Syst Rev 2022;6:CD005996.
[13] Porter TF, Scott JR. Alloimmune Causes of Recurrent Pregnancy Loss. Semin Reprod Med 2000;18:393-400.
[14] Allahbadia GN. Low-Molecular-Weight Heparin (LMWH) in Women with Repeated Implantation Failure. J Obstet Gynaecol India 2012;62:381-3.
[15] Gelbaya TA, Kyrgiou M, Li TC, Stern C, Nardo LG. Lowdose Aspirin for in Vitro Fertilization: ASystematic Review and Meta-analysis. Hum Reprod Update 2007;13:357-64.
[16] Lédée N, Prat-Ellenberg L, Petitbarat M, Chevrier L, Simon C, Irani EE, et al. Impact of Prednisone in Patients with Repeated Embryo Implantation Failures: Beneficial or Deleterious? J Reprod Immunol 2018;127:11-5.
[17] Li J, Chen Y, Liu C, Hu Y, Li L. Intravenous Immunoglobulin Treatment for Repeated IVF/ICSI Failure and Unexplained Infertility: A Systematic Review and a Meta-Analysis. Am J Reprod Immunol 2013;70:434-47.
[18] Wong LF, Porter TF, Scott JR. Immunotherapy for Recurrent Miscarriage. Cochrane Database Systemat Rev 2014;2014:CD000112.
[19] Shreeve N, Sadek K. Intralipid Therapy for Recurrent Implantation Failure: New Hope or False Dawn? J Reprod Immunol 2012;93:38-40.
[20] Beaulieu LM, Vitseva O, Tanriverdi K, Kucukural A, Mick E, Hamburg N, et al. Platelet Functional and Transcriptional Changes Induced by Intralipid Infusion. Thromb Haemost 2016;115:1147-56.
[21] Granato D, Blum S, Rössle C, Le Boucher J, Malnoë A, Dutot G. Effects of Parenteral Lipid Emulsions with Different Fatty Acid Composition on Immune Cell Functions in Vitro. JPEN J Parenter Enteral Nutr 2000;24:113-8.
[22] Mayer K, Meyer S, Reinholz-Muhly M, Maus U, Merfels M, Lohmeyer J, et al. Short-time Infusion of Fish Oil-Based Lipid Emulsions, Approved for Parenteral Nutrition, Reduces Monocyte Proinflammatory Cytokine Generation and Adhesive Interaction with Endothelium in Humans. J Immunol 2003;171:4837-43.
[23] Roussev RG, Acacio B, Ng SC, Coulam CB. Duration of Intralipid’s Suppressive Effect on NK Cell’s Functional Activity. Am J Reprod Immunol 2008;60:258-63.
[24] Coulam CB, Acacio B. Does Immunotherapy for Treatment of Reproductive Failure Enhance Live Births? Am J Reprod Immunol 2012;67:296-304.
[25] Singh N, Davis AA, Kumar S, Kriplani A. The Effect of Administration of Intravenous Intralipid on Pregnancy Outcomes in Women with Implantation Failure After IVF/ ICSI with Non-donor Oocytes: A Randomised Controlled Trial. Eur J Obstet Gynecol Reprod Biol 2019;240:45-51.
[26] El-Khayat W, El Sadek M. Intralipid for Repeated Implantation Failure (RIF): A Randomized Controlled Trial. Fertil Steril 2015;104:e26.
[27] Al-Zebeidi J, Agdi M, Lary S, Al-Obaid S, Salim G, Al-Jaroudi D. Effect of Empiric Intravenous Intralipid Therapy on Pregnancy Outcome in Women with Unexplained Recurrent Implantation Failure Undergoing Intracytoplasmic Sperm Injection-embryo Transfer Cycle: A Randomized Controlled Trial. Gynecol Endocrinol 2019;36:131-4.
[28] Gamaleldin I, Gomaa MF, Shafik A, Akande V. Intralipid Infusion does not Improve Live Birth Rates in Women with Unexplained Recurrent Implantation Failure and May Increase the Risk of Congenital Malformations, a Double-Blinded Randomised Controlled Trial. BJOG 2018; 125:31-2.
[29] Dakhly DM, Bayoumi YA, Sharkawy M, Allah SH, Hassan MA, Gouda HM, et al. Intralipid Supplementation in Women with Recurrent Spontaneous Abortion and Elevated Levels of Natural Killer Cells. Int J Gynecol Obstet 2016;135:324-7.
[30] Cohen R, Check JH, Wilson C, Choe JK. Intravenous Intralipid Therapy is not Beneficial in Having a Live Delivery in Women Aged 40-42 with Previous History of Miscarriage Undergoing in Vitro Fertilization-Embryo Transfer. Fertil Steril 2009;92:S20-1.
[31] O’Connor D, Green S. Higgins JP Cochrane Handbook for Systematic Reviews of Interventions: Cochrane Book Series. Chichester (UK): John Wiley & Sons; 2008. p. 81-94.
[32] Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 2009;6:e1000097.
[33] Green S, Higgins JP, Alderson P, Clarke M, Mulrow DC. Cochrane handbook: Cochrane Reviews: Assessing risk of bias in included studies. In: Systematic Reviews of Interventions. Ch. 8. United States: John Wiley & Sons; 2011. p. 3-10.
[34] Egger M, Smith GD, Schneider M, Minder C. Bias in Meta-Analysis Detected by a Simple, Graphical Test. BMJ 2015;14:1-16.
[35] Terrin N, Schmid CH, Lau J, Olkin I. Adjusting for Publication Bias in the Presence of Heterogeneity. Stat Med 2003;22:2113-26.
[36] Moffett A, Colucci F. Uterine NK Cells: Active Regulators at the Maternal-Fetal Interface. J Clin Investig 2014;124:1872-9.
[37] Seshadri S, Sunkara SK. Natural Killer Cells in Female Infertility and Recurrent Miscarriage: ASystematic Review and Meta-Analysis. Hum Reprod Update 2014;20:429-38.
[38] Zheng L, Feng Y, Shi Y, Zhang J, Mu Q, Qin L, et al. Intralipid Decreases Apolipoprotein M Levels and Insulin Sensitivity in Rats. PLoS One 2014;9:e105681.
[39] Aviram M, Deckelbaum RJ. Intralipid Infusion into Humans Reduces in Vitro Platelet Aggregation and Alters Platelet Lipid Composition. Metabolism 1989;38:343-7.
[40] Moffett A, Shreeve N. First do no Harm: Uterine Natural Killer (NK) Cells in Assisted Reproduction. Hum Reprod 2015;30:1519-25.
[41] Aoki K, Kajiura S, Matsumoto Y, Ogasawara M, Okada S, Yagami Y, et al. Preconceptional NaturalKiller-Cell Activity as a Predictor of Miscarriage. Lancet 1995;345:1340-2.
[42] Habets DH, Schlütter A, van Kuijk SM, Spaanderman ME, Al-Nasiry S, Wieten L. Natural Killer Cell Profiles in Recurrent Pregnancy Loss: Increased Expression and Positive Associations with TACTILE and LILRB1. Am J Reprod Immunol 2022;88:e13612.
43] Practice Committee of the American Society for [Reproductive Medicine. Intravenous Immunoglobulin (IVIG) and Recurrent Spontaneous Pregnancy Loss. Fertil Steril 2006;86:S226-7.
[44] Katz U, Achiron A, Sherer Y, Shoenfeld Y. Safety of Intravenous Immunoglobulin (IVIG) Therapy. Autoimmun Rev 2007;6:257-9.