|Year : 2018 | Volume
| Issue : 2 | Page : 111-114
Use of intralipid in the management of recurrent implantation failure: An overview
Lubna Khan1, Viquar Fatima Qureshi1, Tahira Jabeen1, Shoeb Qureshi2
1 Department of Obstetrics and Gynecology, National Guard Health Affairs, Kind Abdulaziz Medical City, Riyadh, Saudi Arabia
2 Department of Research, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
|Date of Web Publication||20-Jun-2018|
Department of Research, College of Applied Medical Sciences, Kind Saud bin Abdul-Aziz University for Health Sciences, Riyadh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Recurrent embryo implantation failure is a disorder with potentially dreadful physiological and psychological manifestations for those who are affected. Embryo implantation and formation of a functional placenta are processes that require a plethora of regulatory mechanisms involving both maternal and embryonic cells. In the ensuing overview, an attempt is made to understand (1) the pathophysiology of recurrent unexplained implantation failure (2) the available evidence for the two popular treatment modalities, i.e., intravenous immune globulin and intralipid, (3) the limitation of current available data, (4) the pathophysiology and immunomodulatory treatment options for recurrent implantation failure to address the pathological, psychological, and financial distress, and associated impact on couple's quality of life.
Keywords: Intralipid, intravenous immune globulin, natural killer cells, recurrent implantation failure, reproductive immunology
|How to cite this article:|
Khan L, Qureshi VF, Jabeen T, Qureshi S. Use of intralipid in the management of recurrent implantation failure: An overview. J Nat Sc Biol Med 2018;9:111-4
|How to cite this URL:|
Khan L, Qureshi VF, Jabeen T, Qureshi S. Use of intralipid in the management of recurrent implantation failure: An overview. J Nat Sc Biol Med [serial online] 2018 [cited 2019 Nov 14];9:111-4. Available from: http://www.jnsbm.org/text.asp?2018/9/2/111/234725
| Introduction|| |
Repeated implantation failure (RIF) is determined when transferred embryos fail to implant following several in vitro fertilization (IVF) treatment cycles. However, there are no formal criteria defining the number of failed cycles or the total number of embryos transferred in these IVF attempts. Accordingly, different fertility centers practicing IVF may use different definitions for RIF. Considering the current success rate of IVF treatments and the mean number of embryos transferred in each cycle, Simon and Laufer  recommended defining RIF as failure of implantation in at least three consecutive IVF attempts, in which 1–2 embryos of high-grade quality are transferred in each cycle.
Any abnormality attributed to the embryo, the endometrium or the immune system will result in implantation failure. Therefore, treatment of RIF should be targeted to the abnormality detected, and the correction of any potential malfunction that might contribute to the failure of implantation.
Implantation failure will contribute to patient anxiety and increase the couple's psychological distress and have emotional and financial impact on their life. Clinicians are trying to find a solution to overcome this barrier and to have more information about the pathophysiology to find the best possible treatment option.
It is been postulated that abnormal immunological response, human leukocyte antigen incompatibility between couples, the absence of maternal leukocytotoxic antibodies or the absence of maternal-blocking antibodies as a contributory factor in RIF. Growth factors are important for regulating a variety of cellular processes. Growth factors typically act as signaling molecules between cells. Examples are cytokines and hormones that bind to specific receptors on the surface of their target cells.
Cytokines are immune molecules that control both immune and other cells. Cytokine responses are generally characterized either as T-helper-1 (Th-1) type, with production of the pro-inflammatory cytokines interleukin 2, interferon and tumor necrosis factor alpha, or as T-helper-2 (Th-2) type, with production of the anti-inflammatory cytokines interleukins 4, 6, and 10. It was found that women with recurrent unexplained implantation failure have imbalance TH1/TH2 response.
Uterine natural killer (uNK) cells may play a role in trophoblastic invasion and angiogenesis in addition to being an important component of the local maternal immune response to pathogens.
NK cells are found in peripheral blood and the uterine mucosa. Peripheral blood NK cells are phenotypically and functionally different from uNK cells. It has been suggested that uNK cells may play a role in trophoblastic invasion and angiogenesis in addition to being an important component of the local maternal immune response to pathogens. High dose of intravenous immune globulin (IVIG) has been used for patient who shares same human leukocyte antigen (HLA) alleles with their partners.
The infusion of 20% intralipid solution has been suggested to improve outcomes in women with RIF. It has been implied that intralipid, administered intravenously, may enhance implantation and maintenance of pregnancy in the patient with abnormal NK cell levels or function.
We reviewed the current available evidence through Medline database regarding the use of intralipid mainly, to understand its efficacy and proven benefit for routine recommendation of its use.
Pathophysiology of repeated implantation failure
The immune system has been highlighted for its major role in the process of implantation and in the subsequent maintenance of pregnancy. One idea is that a conception must be recognized as nonself to trigger immunological processes that prevent the maternal immune system from rejecting it. The HLA compatibility system plays a role in this recognition and couples that share common HLA alleles may experience higher rates of RIF. However, it is not at all clear how an “inadequate” response of the maternal immune system to stimulation by paternal antigens, due to HLA sharing, might be implicated in implantation failure. Advocates of abnormal immune responses point to studies suggesting that systemic cytokine concentrations are altered in patients with RIF and propose that this involves the imbalance of TH1:TH2 responses.
Although it is not known whether altered cytokine responses are generated systemically or locally in the decidua where maternal leukocytes encounter allogeneic extravillous trophoblasts. What is clear is that extravillous trophoblasts express a unique combination of class 1 major histocompatibility complex (MHC) molecules including HLA-C and the nonpolymorphic polymorphic HLA-E, and HLA-G molecules. These are believed to perform immunoregulatory functions associated with local maternal tolerance to the extravillous trophoblasts within the decidua. However, to date, there is no proven mechanism described in humans by which these MHC molecules might be involved in implantation failure through a failure to regulate T-cell responses either systemically or locally in the decidua. The rationale for any therapy based on modulating maternal T-cell responses to fetal alloantigen thus remains unclear.
It has been suggested that uNK cells may play a role in trophoblastic invasion and angiogenesis in addition to being an important component of the local maternal immune response to pathogens. NK cells are found in peripheral blood and the uterine mucosa. Peripheral blood NK cells are phenotypically and functionally different from uNK cells. It has been suggested that uNK cells may play a role in trophoblastic invasion and angiogenesis in addition to being an important component of the local maternal immune response to pathogens.
Intravenous immunoglobulin in the management of repeated implantation failure
High-dose IVIG administration has been found to benefit patients with RIF who share HLA alleles with their partner. The number of shared alleles justifying the administration of IVIG treatment has not been determined. One study demonstrated an improvement in patients with as few as one shared allele. Treatment consisted of 30 g of IVIG before embryo transfer and a second similar dose when a fetal heart rate was noticed. Other studies in which IVIG was administered to patients reported to have abnormal cytokine profiles have reported benefits, but patient numbers were limited. As the authors themselves state: “Prospective controlled studies (preferably double-blind, stratified, and randomized) are needed for confirmation. In the absence of clear evidence of efficacy or understanding of which patient groups might benefit, empirical treatment of patients with IVIG is not recommended due to lack of large randomized controlled trials.”
Intralipid in the management of repeated implantation failure
Intralipid is a 20% intravenous fat emulsion that is usually used as a source of fat and calories for patients requiring parenteral nutrition. Intralipid consists of soybean oil as well as egg yolk phospholipids, glycerin, and water. In a small and still unpublished nonrandomized trial, presented at a scientific meeting in the UK. A 50% pregnancy rate and 46% clinical pregnancy rate were achieved in patients with RIF who had an elevated TH1 cytokine response. Intralipid infusion was administered once between days 4 and 9 of ovarian stimulation, and again within 7 days of a positive pregnancy test. This alteration of TH1:TH2 cytokine activity ratio, which decreased in all cases, appeared to correlate with the successful outcome that resulted. The mechanism by which intralipid modulates the immune system is still unclear. It has been postulated that fatty acids within the emulsion serve as ligands to activate peroxisome proliferator-activated receptors expressed by the NK cells. Activation of such nuclear receptors has been shown to decrease NK cytotoxic activity, enhancing implantation.
When comparing the effect of IVIG and intralipid on NK cell activity and trophoblasts activation, no difference was found in the two studies. Chazara et al. also observed no difference in pregnancy outcome after intralipid or IVIG administration in women with a history of reproductive failure and elevated NK cytotoxicity. Moreover, immunotherapy for the treatment of reproductive failure only benefits those with immunologic dysfunction.
As far as intralipid administration is concerned, there are conflicting evidences available regarding the efficacy and proven benefit in women with recurrent implantation failure, while some states that the activation of decidual NK cell by MHC ligands on trophoblasts has beneficial effect on pregnancy outcome. However, Shreeve and Sadek  found that large-scale confirmatory studies are still necessary to prove the efficacy of intralipid before it should be recommended for routine use.
Dakhly et al. performed an RTC as well to investigate the efficacy of intralipid administration in patient with recurrent implantation failure and elevated NK cell activity and found out no increase in chemical pregnancy rates.
Check and Check  stopped his study prematurely after 10 maternal cycle because of no clinical pregnancies achieved in those who received intralipid versus 40% clinical and a 30% live birth rate in untreated controls. This study had some limitations because they included only advanced maternal age group (40–42 years), perhaps he founds this therapy detrimental to this age group.
In the recent clinical guidelines, RCOG states that there is a paucity of available data and evidence to recommend routine measurement of cytokine level in patients with recurrent implantation failure. There is no agreed protocol for time and duration of treatment. We need to have strong clinical evidence before subjecting our patients to this treatment option. It should be noted that the largest study Bombell and McGuire  examining the relationship between uNK cell numbers and future pregnancy outcome reported that raised uNK cell numbers in women with recurrent miscarriage was not associated with an increased risk of miscarriage. Recent green top guideline for recurrent miscarriage said testing for uNK cells should not be offered routinely in the investigation of recurrent miscarriage.
Psychological impact of repeated implantation failure on the patient
There is significant, and often unrecognized, psychological and psychiatric trauma for the mother – for many, miscarriage represents the loss of a future child, of motherhood, and engenders doubts regarding her ability to procreate. Studies have shown that a significant percentage of women experience grief, depression, and anxiety and that there is an increased risk of major depressive disorder following a miscarriage. The psychological effects can persist for 6 months to 3 years and tend to deepen with additional miscarriages.
In fact, the most effective therapy for patients with unexplained recurrent pregnancy loss is often the most simple: antenatal counseling and psychological support. These measures have been shown to have subsequent pregnancy success rates of 86% as compared to 33% provided with no additional antenatal care.
| Summary|| |
One active research question is the possibility that abnormal maternal immune responses to paternal antigens may contribute to implantation failure. There is currently considerable confusion about the possible role of altered T-cell responses in patients with RIF. Some studies report changes in so-called TH1:TH2 cytokines in peripheral blood and on the basis of this suggest benefits from IVIG or intralipid infusions in such patients. However, the definition of which patients might benefit and the actual efficacy of such treatments have not been subjected to large-scale rigorous double-blind trials and thus remain largely unproven. This must be weighed against the significant costs and risks for the patients undertaking such treatments. Similarly, preliminary results using intralipid infusion to support implantation are encouraging. However, the real benefit of such treatment in patients with increased NK cytotoxic activity experiencing RIF has not yet been proven in large-scale randomized controlled studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Madkour WA, Moawad A. Does sequential embryo transfer improve pregnancy rate in patients with repeated implantation failure? A randomized control study. Middle East Fertil Soc J 2015;20:255-61.
Simon A, Laufer N. Assessment and treatment of repeated implantation failure (RIF). J Assist Reprod Genet 2012;29:1227-39.
Rockliff HE, Lightman SL, Rhidian E, Buchanan H, Gordon U, Vedhara K, et al.
Asystematic review of psychosocial factors associated with emotional adjustment in in vitro
fertilization patients. Hum Reprod Update 2014;20:594-613.
Berger A. Th1 and Th2 responses: What are they? BMJ 2000;321:424.
Sharma S. Natural killer cells and regulatory T cells in early pregnancy loss. Int J Dev Biol 2014;58:219-29.
Singh M, Chaudhry P, Asselin E. Bridging endometrial receptivity and implantation: Network of hormones, cytokines, and growth factors. J Endocrinol 2011;210:5-14.
Elram T, Simon A, Israel S, Revel A, Shveiky D, Laufer N, et al.
Treatment of recurrent IVF failure and human leukocyte antigen similarity by intravenous immunoglobulin. Reprod Biomed Online 2005;11:745-9.
Dahl M, Hviid TV. Human leucocyte antigen class Ib molecules in pregnancy success and early pregnancy loss. Hum Reprod Update 2012;18:92-109.
Trowsdale J, Betz AG. Mother's little helpers: Mechanisms of maternal-fetal tolerance. Nat Immunol 2006;7:241-6.
Lash GE, Otun HA, Innes BA, Percival K, Searle RF, Robson SC, et al.
Regulation of extravillous trophoblast invasion by uterine natural killer cells is dependent on gestational age. Hum Reprod 2010;25:1137-45.
Winger EE, Reed JL, Ashoush S, El-Toukhy T, Ahuja S, Taranissi M, et al.
Elevated preconception CD56+16+and/or Th1: Th2 levels predict benefit from IVIG therapy in subfertile women undergoing IVF. Am J Reprod Immunol 2011;66:394-403.
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.
Allahbadia GN. Intralipid infusion is the current favorite of gynecologists for immunotherapy. J Obstet Gynaecol India 2015;65:213-7.
Coulam CB, Acacio B. Does immunotherapy for treatment of reproductive failure enhance live births? Am J Reprod Immunol 2012;67:296-304.
Chazara O, Xiong S, Moffett A. Maternal KIR and fetal HLA-C: A fi ne balance. J Leukoc Biol 2011;90:703-16.
Shreeve N, Sadek K. Intralipid therapy for recurrent implantation failure: New hope or false dawn? J Reprod Immunol 2012;93:38-40.
Dakhly DM, Bayoumi YA, Sharkawy M, Gad 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 Gynaecol Obstet 2016;135:324-7.
Check JH, Check DL. 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;43:14-5.
Bombell S, McGuire W. Cytokine polymorphisms in women with recurrent pregnancy loss: Meta-analysis. Aust N
Z J Obstet Gynaecol 2008;48:147-54.
Royal College of Obstetricians and Gynaecologists (RCOG). The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. Green-top Guideline No. 17; April, 2011.
Lok IH, Neugebauer R. Psychological morbidity following miscarriage. Best Pract Res Clin Obstet Gynaecol 2007;21:229-47.
Jeve YB, Neugebauer R. Evidence-based management of recurrent miscarriages. J Hum Reprod Sci 2014;7:159-69.
] [Full text]
Ford HB, Schust DJ. Recurrent pregnancy loss: Etiology, diagnosis, and therapy. Rev Obstet Gynecol 2009;2:76-83.