Experience with Intralipid in early reproductive losses

DOI

https://dx.doi.org/10.18565/aig.2021.11.194-201

Bespalova O.N., Zhernakova T.S.
D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductology, Saint Petersburg, Russia

The fat emulsion Intralipid containing ω-6 and ω-3 fatty acids has been the gold standard of parenteral nutrition for 60 years. To date, there have been thirty years of experience with Intralipid in the immunological factor of early reproductive losses; ω-6 and ω-3 polyunsaturated fatty acids (PUFA) have been proven to play a role in oocyte maturation and embryo implantation, in the balance of synthesis of pro- and anti-inflammatory cytokines, and in the reduction of natural killer (NK) cytotoxicity. Considering the comparable efficacy of Intralipid and intravenous immunoglobulins, the fat emulsion was presented as a promising and affordable method for the treatment of recurrent abortion and implantation failures in IVF programs. Scientific sources have contradictory data on the efficacy of Intralipid in repeated implantation failures. This is due to the determination of indications for its prescription and to the choice of criteria for evaluating the efficiency of this therapy. The paper includes data from 25 original investigations from 1991 to 2021, which present different results of Intralipid therapy. It describes the proposed mechanism of its action in the early stages of pregnancy and presents materials on the history of the discovery, classification, and metabolism of fat emulsions.
Conclusion: The accumulated depot of essential ω-3 PUFA during the pre-conception period contributes to the optimal development of the fetal brain and visual organs and, as shown by numerous studies, prevents the development of great obstetric syndromes. Thus, the intravenous administration of fat emulsions has a positive effect on the onset and prolongation of pregnancy.

Intralipid

early reproductive losses

recurrent miscarriage

repeated implantation failures

immunotherapy

Full text (in Russian)

Drakopoulos P., Errázuriz J., Santos-Ribeiro S., Tournaye H., Vaiarelli A., Pluchino N., Blockeel C., Polyzos N.P. Cumulative live birth rates in in-vitro fertilization. Minerva Ginecol. 2019; 71(3): 207-10. https://dx.doi.org/10.23736/S0026-4784.18.04347-2.
Donoso P., Staessen C., Fauser B.C., Devroey P. Current value of preimplantation genetic aneuploidy screening in IVF. Hum. Reprod. Update. 2007; 13: 15-25. https://dx.doi.org/10.1093/humupd/dml043.
Lee E., Illingworth P., Wilton L., Chambers G.M. The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review. Hum. Reprod. 2015; 30(2): 473-83. https://dx.doi.org/10.1093/humrep/deu303.
Van den Boogaard E., Hermens R.P.M.G., Franssen A.M.H.W., Doornbos J.P.R., Kremer J.A.M., van der Veen F., Goddijn M. Recurrent miscarriage: do professionals adhere to their guidelines. Hum. Reprod. 2013; 28(11): 2898-904. https://dx.doi.org/10.1093/humrep/det329.
Mak W. BMJ best practice topic. Yale recurrent pregnancy loss program. Yale School of Medicine, New Haven, CT. 2017. 46p.
Сидельникова В.М., Сухих Г.Т. Невынашивание беременности. М.: МИА; 2010. 534c. [Sidelnikova V.M., Sukhikh G.T. Miscarriage of pregnancy. M.; 2010. 534p. (in Russian)].
Jeve Y.B., Davies W. Evidence-based management of recurrent miscarriages. J. Hum. Reprod. Sci. 2014; 7(3): 159-69. https://dx.doi.org/10.4103/0974-1208.142475.
Сидельникова В.М. Невынашивание беременности – современный взгляд на проблему. Российский вестник акушера-гинеколога. 2007; 7(2): 62-4. [Sidelnikova V.M. Miscarriage – a modern view of the problem. Russian Bulletin of Obstetrician-Gynecologist. 2007; 2: 62-5.(in Russian)].
Серов В.Н., Сидельникова В.М., Жаров Е.В. Привычное невынашивание беременности: современные представления о патогенезе, диагностике и лечении. Журнал Российского общества акушеров-гинекологов. 2008; 3: 28-41. [Serov V.N., Sidelnikova V.M., Zharov E.V. Habitual miscarriage: current understanding of the pathogenesis, diagnosis and treatment. M., 2008; 28-41. (in Russian)].
Агаджанова А.А. Современные методы терапии женщин с привычным невынашиванием беременности. Русский медицинский журнал. 2003; 1: 3-6. [Agadzhanova A.A. Modern methods of therapy for women with recurrent miscarriage. Russian medical journal. 2003; 1: 3-6. (in Russian)].
Pandey M.K., Thakur S., Agrawal S. Lymphocyte immunotherapy and its probable mechanism in the maintenance of pregnancy in women with recurrent spontaneous abortion. Arch. Gynecol. Obstet. 2004; 269(3): 161-72. https://dx.doi.org/10.1007/s00404-003-0560-3.
Christiansen O., Larsen E., Egerup P., Lunoee L., Egestad L., Nielsen H. Intravenous immunoglobulin treatment for secondary recurrent miscarriage: a randomized, double-blind, placebo-controlled trial. BJOG. 2015; 122(4): 500-8. https://dx.doi.org/10.1111/1471-0528.13192.
Бельских А.Н., Костюченко А.Л., Жибурт Е.Б., Сизов Д.Н. Новые возможности оценки эффективности экстракорпоральных методов гемокоррекции в лечении больных с острыми гнойно-деструктивными заболеваниями легких и плевры. Клиническая лабораторная диагностика. 1996; 1: 42-3. [Belskikh A.N., Kostyuchenko A.L., Zhiburt E.B., Sizov D.N. New possibilities for assessing the effectiveness of extracorporeal methods of hemocorrection. 1996; 1: 42-3. (in Russian)].
Plaçais L., Kolanska K., Kraiem Y.B., Cohen J., Suner L., Bornes M. et al. Intralipid therapy for unexplained recurrent miscarriage and implantation failure: Case-series and literature review. Eur. J. Obstet. Gynecol. Reprod. Biol. 2020; 252: 100-4. https://dx.doi.org/10.1016/j.ejogrb.2020.06.017.
Roussev R.G., Ng S.C., Coulam C.B. Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G. Am. J. Reprod. Immunol. 2007; 57(4): 262-9. https://dx.doi.org/10.1111/j.1600-0897.2007.00473.x.
Guo F., Zhou M.-J., Zhang A.-J. Advances in the treatment of recurrent implantation failure. Reprod. Dev. Med. 2017; 1: 123-6. https://dx.doi.org/10.4103/2096-2924.216860.
Khan L., Qureshi V.F., Jabeen T., Qureshi S.A. Use of intralipid in the management of recurrent implantation failure: An overview. J. Nat. Sci. Biol. Med. 2018; 9(2): 111-4. https://dx.doi.org/10.4103/jnsbm.JNSBM_246_17.
Лейдерман И.Н., Ярошецкий А.И., Кокарев Е.А., Мазурок В.А. Парентеральное питание: вопросы и ответы. Руководство для врачей. СПб.: Онли-Пресс; 2016. 191 c. [Leiderman I.N., Yaroshetskiy A.I., Kokarev E.A., Mazurok V.A. Parenteral Nutrition: Questions and Answers: A Guide for Physicians. SPb.: Onli-Press; 2016. 191 p. (in Russian)].
Serhan C.N., Chiang N., Dalli J. The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution. Semin. Immunol. 2015; 27(3): 200-15. https://dx.doi.org/10.1016/j.smim.2015.03.004.
Gogos C.A., Kalfarentzos F.E., Zoumbos N.C. Effect of different types of total parenteral nutrition on T-lympho- cyte subpopulations and NK cells. Am. J. Clin. Nutr. 1990; 51(1): 119-22. https://dx.doi.org/10.1093/ajcn/51.1.119.
Ton M.N., Chang C., Carpentier Y.A., Deckelbaum R.J. In vivo and in vitro properties of an intravenous lipid emulsion containing only medium chain and fish oil triglycerides. Clin. Nutr. 2005; 24(4): 492-501. https://dx.doi.org/10.1016/j.clnu.2005.03.001.
Adolph M. Lipid emulsions in total parenteral nutrition-state of the art and futureperspectives. Clin. Nutr. (Edinburgh, Scotland). 2001; 20: 11-4.
Wachtler P., König W., Senkal M., Kemen M., Köller M. Influence of a total parenteral nutrition enriched with omega-3 fatty acids on leukotriene synthesis of peripheral leukocytesan systemic cytokine levels in patients with major surgery. J. Trauma. 1997; 42(2): 191-8. https://dx.doi.org/10.1097/00005373-199702000-00004.
Makrigiannakis A., Petsas G., Toth B., Relakis K., Jeschke U. Recent advances in understanding immunology of reproductive failure. J. Reprod. Immunol. 2011; 90(1): 96-104. https://dx.doi.org/10.1016/j.jri.2011.03.006.
Inagaki N., Stern C., McBain J., Lopata A., Kornman L., Wilkinson D. Analysis of intra-uterine cytokine concentration and matrix-metalloproteinase activity in women with recurrent failed embryo transfer. Hum. Reprod. 2003; 18(3):608-15. https://dx.doi.org/10.1093/humrep/deg139.
Ledee-Bataille N., Bonnet-Chea K., Hosny G., Dubanchet S., Frydman R., Chaouat G. Role of the endometrial tripod interleukin-18, -15, and -12 in inadequate uterine receptivity in patients with a history of repeated in vitro fertilization–embryo transfer failure. Fertil. Steril. 2005; 83(3): 598-605. https://dx.doi.org/10.1016/j.fertnstert.2004.11.021.
Kwak-Kim J.Y.H., Chung-Bang H.S., Ng S.C., Ntrivalas E.I., Mangubat C.P., Beaman K.D. et al. Increased T helper 1cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum. Reprod. 2003; 18(4): 767-73. https://dx.doi.org/10.1093/humrep/deg156.
Karami N., Boroujerdnia M.G., Nikbakht R., Khodadadi A. Enhancement of peripheral blood CD56(dim) cell and NK cell cytotoxicity in women with recurrent spontaneous abortion or in vitro fertilization failure. J. Reprod. Immunol. 2012; 95(1-2): 87-92. https://dx.doi.org/10.1016/j.jri.2012.06.005.
Fukui A., Fujii S., Yamaguchi E., Kimura H., Sato S., Saito Y. Natural killer cell subpopulations and cytotoxicity for infertile patients undergoing in vitro fertilization. Am. J. Reprod. Immunol. 1999; 41(6): 413-22. https://dx.doi.org/10.1111/j.1600-0897.1999.tb00456.x.
Roussev R.G., Acacio B., Ng S.C., Coulam C.B. Duration of intralipid’s suppressive effect on NK cell’s functional activity. Am. J. Reprod. Immunol. 2008; 60(3): 258-63. https://dx.doi.org/10.1111/j.1600-0897.2008.00621.x.
Громова О.А., Торшин И.Ю. Витамины и минералы: между Сциллой и Харибдой: о мисконцепциях и других чудовищах. М.: МЦНМО; 2013. 693c. [Gromova O.A., Torshin I.Yu. Vitamins and Minerals: Between Scylla and Charybdis: About Misconceptions and Other Monsters. M.; 2013. 764p. (in Russian)].
Johnson P.M., Ramsden G.H., Chia K.V., Hart C.A., Farquharson R.G., Francis W.J.A. A combined randomised double-blind and open study of trophoblast membrane infusion (TMI) in unexplained recurrent miscarriage. Cell. Mol. Biol. Mat. Fetal Relation. 1991; 212: 277-84.
Clark D.A. Intralipid as treatment for recurrent unexplained abortion? Am. J. Reprod. Immunol. 1994; 32(4): 290-3. https://dx.doi.org/10.1111/j.1600-0897.1994.tb01128.x.
Acacio B., Coulam C.B., Rinehart J.S., Rinehart L., Ng S.C., Roussev R., Parrett S. Pregnancy outcome after intralipid infusion among women experiencing recurrent pregnancy loss. Fertil. Steril. 2008; 89(4, Suppl.): S11. https://dx.doi.org/10.1016/j.fertnstert.2008.02.034.
Ndukwe G. Recurrent embryo implantation failure after in vitro fertilisation: Improved outcome following intralipid infusion in women with elevated T Helper 1 response. Hum. Fertil. (Camb.). 2011; 14(2): 21-2.
Holschbach V., Kuon R.J., Goeggl T., Daniel V., Weber M., Markert U.R. et al. Intravenous lipid administration in RPL and RIF patients with elevated uterine natural killer cells. Hum. Reprod. 2014; 29(Suppl. 1): i1-i389. (Abstract book of the 30th ESHRE Annual Meeting, Munich, Germany, 29 June - 2 July 2014). https://dx.doi.org/10.1093/humrep/29.Supplement_1.1.
Kaul V., Lolatgis N., Osianlis T., Sorby K., Vollenhoven B. et al. The use of intralipid in IVF cycles in poor responders with repeated implantation failure who were positive for Natural Killer (NK) cells. Hum. Reprod. 2014; 29(Suppl. 1): i1-i389. (Abstract book of the 30th ESHRE Annual Meeting, Munich, Germany, 29 June–2 July 2014). https://dx.doi.org/10.1093/humrep/29.Supplement_1.1.
El-Khayat W., El Sadek M. Intralipid for repeated implantation failure (RIF): a randomized controlled trial. Fertil. Steril. 2015; 104(3, Suppl.): 26. https://dx.doi.org/10.1016/j.fertnstert.2015.07.080.
Dakhly D.M.R., Bayoumi Y.A., Sharkawy M., Allah S.H.G., Hassan M.A., Gouda H.M. et al. Intralipid supplementation in women with recurrent spontaneous abortion and elevated levels. Int. J. Gynaecol. Obstet. 2016; 135(3): 324-7. https://dx.doi.org/10.1016/j.ijgo.2016.06.026.
Meng L., Lin J., Chen L., Wang Z., Liu M., Liu Y. et al. Effectiveness and potential mechanisms of intralipid in treating unexplained recurrent spontaneous abortion. Arch. Gynecol. Obstet. 2016; 294(1): 29-39.
Benschop L., Seshadri S., Toulis K.A., Vincent K., Child T., Granne I.E. et al. Immune therapies for women with history of failed implantation undergoing IVF treatment. Cochrane Database Syst. Rev. 2012; (1): CD009602.
Singh N., Davis A., Kriplani A., Kumar S. Effect of administration of intravenous intralipid on implantation rate in women with implantation failure after IVF/ICSI: a randomized controlled trial. Hum. Reprod. 2014; 29(Suppl. 1): i1-i389. (Abstract book of the 30th ESHRE Annual Meeting, Munich, Germany, 29 June–2 July 2014). https://dx.doi.org/10.1093/humrep/29.Supplement_1.1.
Ehrlich R., Hull M.L., Walkley J., Sacks G. Intralipid immunotherapy for repeated IVF failure. Fertil. Reprod. 2019; 1(4): 1-7. https://dx.doi.org/10.1142/S2661318219500178.
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. 2020; 36(2): 131-4. https://dx.doi.org/10.1080/09513590.2019.1631280.
Check J.H., Check D.L. Intravenous intralipid therapy is not beneficial in having a live delivery in women aged 40-42 years with a previous history of miscarriage or failure To conceive despite embryo transfer undergoing in vitro fertilization-embryo transfer. Clin. Exp. Obstet. Gynecol. 2016; 43(1): 14-5.
Hirshfeld-Cytron J.E., Martini A., Jasulaitis S., Uhler M.L. Does intralipid infusion improve outcomes in RPL (recurrent pregnancy loss)/RIF (recurrent implantation failure) patients undergoing IVF? Is it costeffective? Fertil Steril. 2016; 106(3): e342. https://dx.doi.org/10.1016/j.fertnstert.2016.07.968.
Gamaleldin I., Lenguerrand E., Akande V., Fouad M. Intralipid in women with recurrent implantation failure in IVF/ ICSI cycles. A double blinded randomised controlled trial. Hum Reprod. 2016; 31(Suppl. 1.1): i284-5. https://doi.org/10.1093/humrep/31.Supplement_1.1.
Shirlow R.H., Healey M., Volovsky M., MacLachlan V.B., Vollenhoven B.J. The effect of intralipid on pregnancy rates in in vitro fertilisation (IVF). Fertil. Steril. 2016; 106(3): e337-8. https://dx.doi.org/10.1016/j.fertnstert.2016.07.956.
Martini A.E., Jasulaitis S., Fogg L.F., Uhler M.L., Hirshfeld-Cytron J.E. 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(3): 261-8. https://dx.doi.org/10.4103/jhrs.JHRS_28_18.
Deepika K., Vohra A. Uterine NK cell activity in recurrent implantation failure- role of intralipids. Fertil. Steril. 2019; 112(3, Suppl.): E105-6. https://dx.doi.org/10.1016/j.fertnstert.2019.07.396
BRI Reproductive immunology and endometriosis surgical centre [Электронный ресурс] URL: https://www.preventmiscarriage.com/reproductive-immunology.html (дата обращения: 27.07.2021).
Rimmer M.P., Black N., Keay S., Quenby S., Al Wattar B.H. Intralipid infusion at time of embryo transfer in women with history of recurrent implantation failure: A systematic review and meta-analysis. J. Obstet. Gynaecol. Res. 2021; 47(6): 2149-56. https://dx.doi.org/10.1111/jog.14763.

Received 14.05.2021

Accepted 11.10.2021

Olesya N. Bespalova, MD, PhD, DSci (Medicine), Deputy Director for Research, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology,
shiggerra@mail.ru, https://orcid.org/0000-0002-6542-5953, eLibrary SPIN: 4732-8089, 3, Mendeleevskaya line, Saint-Petersburg, 199034, Russia.
Tatiana S. Zhernakova, graduate student, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, tatazhernakova@gmail.com, 3,
Mendeleevskaya line, Saint-Petersburg, 199034, Russia.

Authors' contributions: Zhernakova T.S. – review of publications on the topic of the article; writing the text of the manuscript; Bespalova O.N. – development of the concept of the article, writing the text and editing the manuscript.
Conflicts of interest: The authors declare that there are no possible conflicts of interest.
Funding: The investigation has not been sponsored.
Patient Consent for Publication: All patients provided informed consent for the publication of their data.
Authors' Data Sharing Statement: The data supporting the findings of this study are available on request from the corresponding author after approval from the principal investigator.
For citation: Bespalova O.N., Zhernakova T.S.
Experience with Intralipid in early reproductive losses.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2021; 11: 194-201 (in Russian)
https://dx.doi.org/10.18565/aig.2021.11.194-201

Experience with Intralipid in early reproductive losses

Bespalova O.N., Zhernakova T.S.

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