Next Article in Journal
Hemodynamic Comparison of Inferior Vena Cava Collapsibility Index in Patients with Preeclampsia vs. Controls: A Pilot Study
Previous Article in Journal
Assessing Thrombophilic Risk via Placental Histopathology: A Comparative Scoring Analysis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Reprod. Med.
Volume 6
Issue 4
10.3390/reprodmed6040034
reprodmed-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Evaluating the Impact of Intralipid Infusion on Pregnancy Outcomes in Infertility Treatments: A Retrospective Study

by
Shajna Kinarulla Kandi
1,
Osama Oro Shareef
1,
Abdelrahim Obeid
1,
Mandy Abushama
2,3,
Badreldeen Ahmed
2,3,4 and
Justin C. Konje
2,3,5,*
1
Reproductive Medicine Unit, Fetal Medicine Centre, Al Markhiya Street, Doha P.O. Box 34181, Qatar
2
Feto-Maternal Centre, Al Markhiya Street, Doha P.O. Box 34181, Qatar
3
Department of Obstetrics and Gynecology, Weill Cornell Medicine, Doha P.O. Box 24144, Qatar
4
Department of Obstetrics and Gynaecology, Qatar University, Doha P.O. Box 2713, Qatar
5
Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK
*
Author to whom correspondence should be addressed.
Reprod. Med. 2025, 6(4), 34; https://doi.org/10.3390/reprodmed6040034
Submission received: 1 September 2025 / Revised: 15 October 2025 / Accepted: 16 October 2025 / Published: 1 November 2025
Versions Notes

Abstract

Background: Infertility is a multifactorial condition that causes significant emotional distress and financial burden for couples. Despite advances in assisted reproductive technologies (ARTs), many patients experience recurrent implantation failure (RIF) or pregnancy loss. Intralipid, an intravenous lipid emulsion, has been proposed as an adjunctive therapy due to its immune-modulatory effects, particularly in reducing elevated natural killer (NK) cell activity, which may be associated with poor reproductive outcomes. This study evaluated the effect of intralipid infusion on pregnancy rates and miscarriage rates in women with recurrent implantation failure undergoing in vitro fertilization (IVF). Materials and Methods: This was a retrospective study of women who had suffered from recurrent implantation failure and underwent IVF between September 2023 and September 2024. A comparative group undergoing IVF but who did not have recurrent implantation failure matched for age was selected. Outcomes of clinical pregnancy, miscarriage and livebirth rates were compared in both groups. Results: A total of 113 women undergoing IVF were identified and 51 received intralipid. Intralipid was initiated at varying stages of the IVF process, a day before embryo transfer (ET) (18 or 35.3%), on the day of ET (20 or 39.2%) and after ET (13 or 25.5%). The clinical pregnancy rate was 44.2% in the treatment group compared to 29% in the comparator group (p < 0.05) while the miscarriage rates were 13.7% versus 11.3% (p > 0.05). Elevated NK cells were present in 65.4% of the patients who received intralipid, but the correlation between NK cell levels and pregnancy outcomes was weak (Spearman ρ = 0.032). No adverse effects were reported in any of the women. Conclusions: Intralipid infusion increased the successful pregnancy rates in women who had recurrent implantation failure during IVF. The successful pregnancy rate was significantly higher than that in those undergoing ART who had not suffered from RIF. These findings support several studies on the potential benefit and safety of intralipids in women undergoing ART, but the numbers remain small and more prospective studies are needed to confirm these findings

1. Introduction

Infertility is a complex and multifactorial condition affecting a significant proportion of couples globally [1]; often leading to emotional distress and a huge financial burden. Traditional treatments, including hormonal therapies and assisted reproductive technologies, have varying degrees of success which are to an extent influenced by specific indications. The success rates with in vitro fertilization (IVF) are about 15–60% [2,3,4] depending on the age of the woman and other factors (such as the underlying cause of infertility, embryo quality, sperm quality, the uterine anatomy, lifestyle factors like smoking and obesity and the expertise of the fertility clinic and embryology lab) [5,6,7] and about 60–90% with pre-implantation genetic testing and implantation of normal embryos [8]. For most of the unsuccessful IVF-ETs where the embryo is karyotypically normal, various factors have been implicated including impaired endometrial receptivity. Reduced endometrial receptivity is thought in some cases to be secondary to immune dysfunction or immune abnormalities [7]. One such immune abnormality is increased natural killer (NK) cells, although this remains controversial [9,10]. These cells (peripheral and uterine) have been described as the potential culprit in recurrent pregnancy loss and implantation failure, especially in women with high numbers of these cells pre-conception [11] and with demonstrably sustained markers of cytotoxic activity in both the peripheral [12] and uterine NK cells [13]. Increased NK cell cytotoxicity has been associated with recurrent implantation failure and recurrent miscarriages [10,14,15,16]. Inhibiting the cytotoxic activities of these NK cells could potentially increase implantation rates and reduce the risk of miscarriage [17]. Various agents have been tried including aspirin, progesterone, low molecular weight heparin, intravenous immunoglobulin [18,19] and corticosteroids [20], but none of these have been shown to be effective in increasing success pregnancy rates.
An approach that has therefore been proposed to modulate the immune dysfunction associated with high NK cells is the use of intralipids [21,22]. Intralipid® is an emulsion of polyunsaturated fatty acids derived from soybean oil, glycerin and egg phospholipid that is commonly used as a component of parenteral nutrition in patients unable to tolerate an oral diet. Although the exact mechanism by which Intralipid® modulates immune modulation remains unclear, its active ingredient, soya oil, has been reported to be capable of inhibiting pro-inflammatory mediators, specifically Th1 cells [23], thus favouring successful implantation and pregnancy. It has been reported to have a variety of immune-modulatory and anti-inflammatory actions including decreased production of interleukin—2 (IL-2), tumour necrosis factor-α (TNFα), interleukin—1β (IL-1β) and suppression of NK cell activity that may last several weeks after a single infusion [17,23,24]. Additionally, it has been shown that intralipid therapy boosted the serum granulocyte colony-stimulating factor (G-CSF), a cytokine reported to be associated with successful implantation following embryo transfer in IVF cycles [25]. Although there have been several studies on the use of intralipids in assisted reproduction, the data have not been consistent. Having said that, two recent systematic reviews and meta-analyses concluded that intralipid administration may improve IVF outcomes, especially in women with recurrent implantation failure or recurrent spontaneous miscarriages [26,27]. However, they concluded that due to some limitations, intralipid use in women undergoing IVF should be approached with caution until more data becomes available. Such data would ideally be from prospective randomized controlled trials, but it could also come from cases series. We have been using intralipid in women with recurrent implantation failure or recurrent spontaneous miscarriages in our Reproductive Unit for the past few years. The aim of this study was to review the outcomes from these women undergoing assisted reproduction techniques to add to the accumulating data. Apart from the outcomes of the ART in the group with recurrent implantation failure, we also set out to determine how the outcomes compared to those in women who had not had recurrent implantation failure.

2. Materials and Methods

This was a retrospective study of women undergoing assisted reproductive technology (ART)—specifically IVF-ET at the Feto Maternal Medical Centre, Qatar for the period September 2023 to September 2024. Institutional review board approval was obtained (FMC-IRB-004 12 March 2024) and since this was an anonymized review of the records, no patient informed consent was required.
Intralipid® was administered to women who had recurrent implantation failure (RIF) defined as three or more unsuccessful IVF/ICSI-ET of at least three good quality embryo transfers. To be included in the study, the women were thoroughly investigated and no obvious causes of infertility (e.g., tubal factor, anatomical, hormonal, hematological and autoimmune) were identified. Male factor was not an exclusion criterion if good quality sperms were generated after routine preparation. However, we excluded women who had anatomical abnormalities such as uterine fibroids that distort the uterine cavity or endometrial polyps, those with poor quality embryos, and those undergoing donor IVF or with co-morbidities such as diabetes mellitus and acquired thrombophilia.
The electronic records of the women were reviewed and from these, various variables were extracted. These included patient demographics, hormonal (follicle stimulating hormone [FSH] and leuteinising hormone [LH] levels, thyroid stimulating hormone [TSH] and free thyroxine [FT] 4) investigation results (classified as normal and if abnormal-specified), type of reproductive pathology requiring treatment by ART, other laboratory data (AMH levels, NK cells—thrombophilia screen) and ultrasound findings. Other variables collected included past medical and surgical history, co-morbidities (such as diabetes, hypertension, etc.) and other associated conditions (such as polycystic ovary syndrome [PCOS], uterine fibroids).
The ART variables collected included, indication for ART, ovulation induction regimen, timing of the intralipid administration (with relation to embryo replacement) and duration of administration and outcomes of the ART where available. We also collected information on additional medications used (e.g., aspirin or steroids during the ART procedure).
The ART outcomes were classified as (1) chemical pregnancy—where there was a urine positive pregnancy test or serum hCG ≥ 5IU/L but with no ultrasound demonstrating intrauterine pregnancy, (2) clinical pregnancy—where there was a gestational sac with or without a fetal pole demonstrated on ultrasound, (3) miscarriage—where an ultrasound demonstrated loss of a clinical pregnancy <22 weeks after the ET or 24 weeks of gestation and (4) pregnancy progressing beyond 24 weeks (livebirth or otherwise). For each woman who received intralipids a comparative group of women (the case either before or after the index case) matched for age and who had not had recurrent implantation failure was selected.

2.1. Intralipid Protocol

Intralipid 20% was administered as an intravenous infusion, prepared by diluting 100 mL of intralipid in 250 mL of normal saline, and infused over a period of 2 h in an outpatient setting. The intralipid was administered either 1–2 days before ET or on the day of embryo transfer and was continued every 2 weeks until 12 weeks, provided there was a positive BHCG and/or confirmed intrauterine pregnancy. Our regimen was a modification of the regimen of Granto et al. [23] and Singh et al. [24].

2.2. Statistical Analysis

Continuous variables are presented as means and standard deviations (SD) where they are normally distributed, while categorical data are presented as frequences (percentages). Where continuous data are not normally distributed, medians and ranges are used. The independent sample t-test was used to compare outcomes between the study and control groups. p < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS software version 29.

3. Results

A total of 113 women who underwent assisted reproductive treatment at our centre and met the inclusion criteria were included in the study; 51 of these had intralipid and constituted the index group while the 62 who did not receive intralipid constituted the comparator group. The mean (SD) age was 37 (6.2) years for the index group and 35 (6.6) years for the comparative group (p > 0.05).
Table 1 shows the medical and gynecological variables extracted from the records of the cohort. Hypothyroidism and polycystic ovary syndrome (PCOS) were more common in the index than comparative groups but only PCOS was statistically significantly so (p < 0.05). Ovarian reserve (assed by AMH levels) was not significantly different in the two groups. It was normal in 78.8% (n = 41) of the index group and 74.2% (n = 46) in the comparative group (p > 0.05). The pattern of menstrual cycles was similar in both groups. Elevated NK cells were present in 34 (65.4%) of those in the index group. The prevalence of other immunological factors such as antiphospholipid syndrome was too small in both groups to be of any statistical significance.
The indications for ART are shown in Table 2. Most were for secondary infertility (45.1% vs. 51.6%, p > 0.05; in the index and comparative groups, respectively). The only indication that was significantly higher in the index group was PGD (27.5% vs. 3.2%, p < 0.05).
Ovarian stimulation in the index group was commonly completed with the antagonist regimen which consisted of (Cetrotide, Orgalutran, Gonal-F and Ovitrelle). A small number of all the cases (5 = 9.5%) were offered the long-term agonist protocols (Deacetyl). Ovulation induction in the comparative group (n = 34; 54.8%) was primarily completed with the antagonist regimen using Gonal-F, Merional, and Cetrotide.
There was no consistency in the timing of the administration of intralipid. It was initiated either a day or two before embryo transfer in 18 (35.3%) cases, on the day of embryo transfer in 20 (39.2%) cases and after embryo transfer in 13 (25.5%). All those who achieved a pregnancy continued with the intralipid until the 12th week of gestation.
The outcomes of the ART in the cohort are shown in Table 3. The clinical pregnancy rates were significantly higher in the index than in the comparative group [23 (45.1%) vs. 18 (29%), p = 0.043].

4. Discussion

This study demonstrated a statistically significant higher clinical pregnancy rate in women with a history of repeated implantation failure (RIF) who received intralipid while undergoing assisted reproductive treatment (ART). The overall clinical pregnancy rate in the intralipid group (45.1%) was significantly higher than in the comparative group (29%, p = 0.043). Coulam and Acacio [18] reported improved pregnancy outcomes in women with immunological abnormalities, including elevated NK cell activity, following intralipid therapy (1). Similarly, Roussev et al. [17] documented that intralipid therapy significantly reduced NK cell activity and improved live birth rates in patients with prior ART failures [28]. In two systematic reviews by Asif et al. [29] and Han et al. [26] of two randomized controlled trials (RTCs) and RTCs composing of 303 and 800 participants, respectively, intralipid improved the livebirth rate compared to controls by an RR of 2.13 (95%CI 1.35–3.36) and 1.85 (95%CI 1.44–2.38), respectively [17]. Our findings of higher pregnancy rates are consistent with the conclusions from these systematic reviews. This was despite our comparator group not being ideal as the denominator was different. However, our findings indicate that intralipid may not only increase the pregnancy rates in women with recurrent implantation failure (RIF) but may even result in higher pregnancy rates in this sub-population when compared to those who had not experienced recurrent implantation failure.
In our series the intralipid was started at three different time points and continued until 12 weeks of gestation where the pregnancy was ongoing. There is no consistency in the timing of intralipids in published studies. In their randomized studies, Singh et al. administered it on the day of oocyte retrieval and again on the day of ET, Gameleldin et al. [30] 6–7 days before ET and again on the day of a positive pregnancy test and El-Khayat et al. [31] between day 4 and 9 of ovulation stimulation and within a week of a positive pregnancy test. The timing of intralipid in these studies and ours did not have any bearing on the successful pregnancy rates, suggesting perhaps that there may be no need to administer more than two doses (the minimum in all the studies) of intralipids. Moreover, Roussev et al. [17] showed that the effect of intralipids, by way of decreasing NK cell cytotoxicity, lasted for about two weeks post administration. A detailed review of the timing of intralipid in all these studies would indicate that most administered it either on the day of ET or within seven days of a positive pregnancy test. This would suggest that this is likely to be the crucial period of immunological modulation by intralipid. Whether a single dose given during this window will result in similar results is unknown.
Results from our findings and those of most others differed from a few others that showed no difference. In the study by Martin et al. [32] in which the intralipid was administered 7–10 days before embryo transfer or insemination, and again at 6 weeks and at 10 weeks, there were no differences in pregnancy rates when compared to a historical control. Han et al. [26] suggested that this might have been because of the use of a historical for control. Another study that failed to show any difference was in women aged 40–42 years in whom intralipid was administered in the mid-follicular phase [33] but the numbers were very small. These discrepancies emphasize the importance of patient selection and the need for standardized protocols in both diagnostic immunological profiling and timing of intervention. Table 4 shows most of the studies that have explored the benefit of intralipids in recurrent unexplained implantation failure.
One major weakness in other published studies and ours was failure to exclude other possible contributing immunological factors to the recurrent implantation failure or quantify peripheral and uterine NK cells. However, since immune dysfunction in the endometrial milieu is regarded as a possible mechanism resulting in implantation failure and peripheral and uterine NK cells have been suggested as potential culprits, and because their levels and cytotoxic activity are increased pre-conception in women with RIF and RPL [36], with demonstrably sustained markers of cytotoxic activity in both peripheral [37] and uterine NK cells [28], it follows that any therapeutic immunomodulatory agents acting on these cells would most likely benefit the women. Intralipids, as such an immunomodulatory agent, are therefore not surprisingly beneficial in some of these women. So, while the evidence for intralipids making a difference in pregnancy rates is reasonably strong, the precise mechanism of action is yet to be elucidated and may vary on factors including immunological modulation. Some studies that have investigated NK cell activity following the infusion of intralipids have shown changes in toxicity perhaps demonstrating modulation. Since the role of peripheral NK cells (which have been shown to be different in origin, function and phenotype from uterine NK cells) in repeated miscarriages and implantation failure remains controversial [38,39,40,41] we would suggest that there may be other yet to be explored or poorly explored contributing modalities by which this intervention improves pregnancy outcomes.
One such poorly explored mechanism is the possibility that intralipids change the uterine environment from a TH1 to a TH2 cytokines environment and in addition modulate the NK cell phenotype (from one hostile to pregnancy to one that favours pregnancy) [42,43]. Previous studies have also suggested that fatty acids and their metabolites of intralipids act as ligands on G-protein coupled receptors and peroxisome proliferator-activated receptors (PPAR) located on NK cells [44,45,46,47], inhibiting their cytotoxic activity (which has been suggested as contributing to RIF/RPL [14,15]) and producing pro-inflammatory cytokines such as tumour necrosis factor-alpha, interleukin-6 and interleukin-8 [23,28,48] which enhance and maintain pregnancy [35,49,50]. Two studies suggested that an alternative mechanism of action of intralipids is by PPAR stimulation which also plays an important role in implantation, invasion of cytotrophoblasts, embryo growth and formation of the placenta [47,51]. Other studies showed that intralipids significantly decreased NK cell activity [28], an effect that lasted from four to nine weeks [17]. Two in vitro studies reported an effect of intralipids on decreased activation of T lymphocytes and on cytokine secretion (decreased TNF-α, IL-2 and IL-1β levels) [10,23]. Taking all of these together, we feel that it is beneficial to consider intralipids in women with unexplained RIF, taking into consideration the available evidence as well as the biological plausibility of its potential beneficial effects in those who have previously experience recurrent implantation failure.
Finally, there were no serious recorded side effects in our cases and no reported congenital abnormalities. Minor adverse effects that have been reported include flushing, headaches, drowsiness, vomiting, sweating and dizziness [51]. This has been a consistent observation in various studies, although the study by Gamaleldin et al. [30] reported two cases of congenital ear abnormalities. These findings have not been reported in any other study. While it may be safe to conclude from the reported cases that intralipid is not teratogenic and that the reported ear abnormalities may be incidental there is a need to continue to monitor this aspect of intralipids.

Strengths and Limitations

This study’s retrospective nature limits causal inference and introduces potential bias in data interpretation. The small sample size (113 women) reduces the statistical power and generalizability of the findings. The variation in intralipid dosing and timing, lack of standardized NK cell testing and absence of long-term follow-up on live birth outcomes constrain definitive conclusions.
Nevertheless, our findings support existing evidence suggesting that intralipid may be beneficial in selected patient populations, particularly those with immune-related infertility challenges. Larger, well-powered, randomized controlled trials with standardized protocols are essential to validate these results and to determine optimal patient selection criteria and treatment timing.
The timing of initiation of intralipids was variable—from pre-ET to post ET. Furthermore, we did not have a control group. An ideal case–control study would have generated more robust evidence. An ideal control group would have been one in which there had been recurrent implantation failures, matched for age and other factors, who did not receive intralipids.

5. Conclusions

In this retrospective study we have shown that intralipids administration is associated with an increase in pregnancy rates in women who have had recurrent implantation failure, consistent with most other studies. Based on our data and that from other studies, we would recommend consideration of the administration of intralipids in women with RIF, even in those without increased peripheral NK levels and dysregulated endometrial immune profiling. However, there is still a need to undertake randomized controlled trials with large numbers to provide more definite evidence and to try to further unravel the precise mechanism by which intralipids improve IVF-ET outcomes. Such studies must include immunological testing in women who successfully have live birth after intralipid versus women who do not.

Author Contributions

J.C.K. and O.O.S. conceived the study; S.K.K. collected the data; S.K.K. and J.C.K. analyzed the data; S.K.K. wrote the initial draft which was then reviewed by J.C.K. and then by O.O.S., A.O., M.A. and B.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Feto Maternal Centre Institutional Review Board FMC-IRB-004 of 12 March 2024.

Informed Consent Statement

Patient consent was waived due to this being a retrospective study that involved reviewing patient records anonymously.

Data Availability Statement

The data are not publicly available due to the confidentiality of ART procedures but will be shared upon request.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Liang, Y.; Huang, J.; Zhao, Q.; Mo, H.; Su, Z.; Feng, S.; Li, S.; Ruan, X. Global, regional, and national prevalence and trends of infertility among individuals of reproductive age (15–49 years) from 1990 to 2021, with projections to 2040. Hum. Reprod. 2025, 40, 529–544. [Google Scholar] [CrossRef] [PubMed]
  2. IVF Success Rates. February 2025. Available online: https://www.cdc.gov/art/success-rates/index.html (accessed on 26 August 2025).
  3. eClinicalMedicine. The current status of IVF: Are we putting the needs of the individual first? eClinicalMedicine 2023, 65, 102343. [Google Scholar] [CrossRef]
  4. 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. [Google Scholar] [CrossRef]
  5. Yazdani, N.; Shekari Khaniani, M.; Bastami, M.; Ghasemnejad, T.; Afkhami, F.; Mansoori Derakhshan, S. HLA-G regulatory variants and haplotypes with susceptibility to recurrent pregnancy loss. Int. J. Immunogenet. 2018, 45, 181–189. [Google Scholar] [CrossRef] [PubMed]
  6. Fatemi, H.M.; Popovic-Todorovic, B.; Papanikolaou, E.; Donoso, P.; Devroey, P. An update of luteal phase support in stimulated IVF cycles. Hum. Reprod. Update 2007, 13, 581–590. [Google Scholar] [CrossRef]
  7. 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, 87–92. [Google Scholar] [CrossRef] [PubMed]
  8. 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, 473–483. [Google Scholar] [CrossRef] [PubMed]
  9. Zhu, L.Y.; Chen, X.; Xu, Z.Z.; Xu, L.; Mao, T.; Zhang, H. Changes and clinical significance of peripheral blood helper T lymphocyte and natural killer (NK) cells in unexplained recurrent spontaneous abortion (URSA) patients after abortion and successful pregnancy. Clin. Exp. Obstet. Gynecol. 2015, 42, 62–66. [Google Scholar] [CrossRef]
  10. Lédée, N.; Vasseur, C.; Petitbarat, M.; Chevrier, L.; Vezmar, K.; Dray, G.; Chenière, S.; Lobersztajn, A.; Vitoux, D.; Cassuto, G.N.; et al. Intralipid® may represent a new hope for patients with reproductive failures and simultaneously an over-immune endometrial activation. J. Reprod. Immunol. 2018, 130, 18–22. [Google Scholar] [CrossRef] [PubMed]
  11. Faas, M.M.; de Vos, P. Uterine NK cells and macrophages in pregnancy. Placenta 2017, 56, 44–52. [Google Scholar] [CrossRef] [PubMed]
  12. Yamaya, A.; Fukui, A.; Kawai, K.; Yano, M.; Honda, H.; Nakagawa, K.; Kamei, H.; Omote, M.; Wakimoto, Y.; Mabuchi, S. A Comparative Study of Intravenous Immunoglobulin and Lipid Emulsion in Patients With Reproductive Failures Associated With NK Cell Abnormalities. Reprod. Med. Biol. 2025, 24, e12662. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  13. Santillán, I.; Lozano, I.; Illán, J.; Verdú, V.; Coca, S.; Bajo-Arenas, J.M.; Martinez, F. Where and when should natural killer cells be tested in women with repeated implantation failure? J. Reprod. Immunol. 2015, 108, 142–148. [Google Scholar] [CrossRef] [PubMed]
  14. Tang, A.W.; Alfirevic, Z.; Quenby, S. Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: A systematic review. Hum. Reprod. 2011, 26, 1971–1980. [Google Scholar] [CrossRef]
  15. Meng, L.; Lin, J.; Chen, L.; Wang, Z.; Liu, M.; Liu, Y.; Chen, X.; Zhu, L.; Chen, H.; Zhang, J. Effectiveness and potential mechanisms of intralipid in treating unexplained recurrent spontaneous abortion. Arch. Gynecol. Obstet. 2016, 294, 29–39. [Google Scholar] [CrossRef] [PubMed]
  16. Kolanska, K.; Suner, L.; Cohen, J.; Ben Kraiem, Y.; Placais, L.; Fain, O.; Bornes, M.; Selleret, L.; Delhommeau, F.; Feger, F.; et al. Proportion of Cytotoxic Peripheral Blood Natural Killer Cells and T-Cell Large Granular Lymphocytes in Recurrent Miscarriage and Repeated Implantation Failure: Case-Control Study and Meta-analysis. Arch. Immunol. Ther. Exp. 2019, 67, 225–236. [Google Scholar] [CrossRef] [PubMed]
  17. Roussev, R.G.; Acacio, B.; Kaider, B.D.; Jackson, E.; Coulam, C.B. Duration of intralipid’s suppressive effect on NK cell functional activity. Am. J. Reprod. Immunol. 2008, 60, 258–263. [Google Scholar] [CrossRef]
  18. Coulam, C.B.; Acacio, B. Does immunotherapy for treatment of reproductive failure enhance live births? Am. J. Reprod. Immunol. 2012, 67, 296–304. [Google Scholar] [CrossRef]
  19. Moraru, M.; Carbone, J.; Alecsandru, D.; Castillo-Rama, M.; García-Segovia, A.; Gil, J.; Alonso, B.; Aguarón, A.; Ramos-Medina, R.; Martínez de María, J.; et al. Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56+ cells. Am. J. Reprod. Immunol. 2012, 68, 75–84. [Google Scholar] [CrossRef]
  20. Robertson, S.A.; Jin, M.; Yu, D.; Moldenhauer, L.M.; Davies, M.J.; Hull, M.L.; Norman, R.J. Corticosteroid therapy in assisted reproduction—Immune suppression is a faulty premise. Hum. Reprod. 2016, 31, 2164–2173. [Google Scholar] [CrossRef]
  21. Acacio, B.; Coulam, C.; Rinehaert, J.; Rinehart, L.; Ng, S.C.; Roussev, R.G.; Parrett, S. Pregnancy Outcome After Intralipid Infusion Among Women Experiencing Recurrent Pregnancy Loss. Fert. Steril. 2008, 89, S11. [Google Scholar] [CrossRef]
  22. Ndukwe, G. Recurrent embryo implantation failure after in-vitro fertilisation: Improved outcome following intralipid infusion in women with elevated T Helper r response. Hum. Fertil. 2011, 14, 21–22. [Google Scholar] [CrossRef]
  23. Granato, D.; Blum, S.; Rossle, C.; Le Boucher, J.; Malnoe, A.; Dutot, G. Effects of parenteral lipid emulsions with different fatty acid composition on immune cell functions in vitro. J. Parenter. Enteral. Nutr. 2000, 24, 113–118. [Google Scholar] [CrossRef]
  24. Singh, N.; Davis, A.A.; 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. [Google Scholar] [CrossRef]
  25. Henshaw, J.; Tremellen, K. Intralipid infusion therapy as an adjunct treatment in women experiencing adenomyosis-related infertility. SAGE J. 2023, 17, 26334941231181258. [Google Scholar] [CrossRef] [PubMed]
  26. Han, E.J.; Lee, H.N.; Kim, M.K.; Lyu, S.W.; Lee, W.S. Efficacy of intralipid administration to improve in vitro fertilization outcomes: A systematic review and meta-analysis. Clin. Exp. Reprod. Med. 2021, 48, 203–210. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  27. Marchand, G.J.; Masoud, A.T.; Ulibarri, H.; Arroyo, A.; Coriell, C.; Goetz, S.; Moir, C.; Moberly, A.; Gonzalez, D.; Blanco, M.; et al. 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. J. Clin. Transl. Res. 2023, 9, 236–245. [Google Scholar] [PubMed] [PubMed Central]
  28. 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, 262–269. [Google Scholar] [CrossRef] [PubMed]
  29. Asif, S.; AlAhwany, H.; Chittawar, P.B.; Nigdelis, M.P.; Toulis, K.A.; Goulis, D.G.; Kirubakaran, R.; Raine-Fenning, N.; Seshadri, S.; Child, T.; et al. Immune therapies for women with history of unsuccessful implantation undergoing IVF/ICSI treatment: A Cochrane collaboration systematic review. Hum. Reprod. 2018, 33, 85. [Google Scholar]
  30. Gamaleldin, I.; Gomaa, M.F.; 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, 31–32. [Google Scholar]
  31. El-khayat, W.; El Sadek, M. Intralipid for repeated implantation failure (RIF): A randomized controlled trial. Fertil. Steril. 2015, 104, E26. [Google Scholar] [CrossRef]
  32. 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, 261–268. [Google Scholar] [CrossRef]
  33. 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, 14–15. [Google Scholar] [CrossRef]
  34. Ehrlich, R.; Hull, M.J.; Walkley, J.; Sacks, G. Intralipid immunotherapy for repeated IVF failure. Fertil. Reprod. 2019, 1, 154–160. [Google Scholar] [CrossRef]
  35. Peivandi, S.; Mortazavi, L.; Gordani, N.; Zamaniyan, M.; Asgarian-Omran, H.; Ajami, A.; Khademloo, M. Effect of Intralipid Infusion on Pregnancy Outcome in Infertile Women with History of Implantation Failure: A Single Blind Randomized Clinical Trial. J. Mazandaran. Univ. Med. Sci. 2022, 32, 16–26. [Google Scholar]
  36. Lédée, N.; Petitbarat, M.; Chevrier, L.; Vitoux, D.; Vezmar, K.; Rahmati, M.; Dubanchet, S.; Gahéry, H.; Bensussan, A.; Chaouat, G. The Uterine Immune Profile May Help Women With Repeated Unexplained Embryo Implantation Failure After In Vitro Fertilization. Am. J. Reprod. Immunol. 2016, 75, 388–401. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  37. Clark, D.A. Intralipid as treatment for recurrent unexplained abortion? Am. J. Reprod. Immunol. 1994, 32, 290–293. [Google Scholar] [CrossRef]
  38. Manaster, I.; Mandelboim, O. The unique properties of uterine NK cells. Am. J. Reprod. Immunol. 2010, 63, 434–444. [Google Scholar] [CrossRef] [PubMed]
  39. Manaster, I.; Mandelboim, O. The unique properties of human NK cells in the uterine mucosa. Placenta 2008, 29, 60–66. [Google Scholar] [CrossRef] [PubMed]
  40. Melsen, J.E.; Lugthart, G.; Lankester, A.C.; Schilham, M.W. Human Circulating and Tissue-Resident CD56(bright) Natural Killer Cell Populations. Front. Immunol. 2016, 7, 262. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  41. Feyaerts, D.; Kuret, T.; van Cranenbroek, B.; van der Zeeuw-Hingrez, S.; van der Heijden, O.W.H.; van der Meer, A.; Joosten, I.; van der Molen, R.G. Endometrial natural killer (NK) cells reveal a tissue-specific receptor repertoire. Hum. Reprod. 2018, 33, 441–451. [Google Scholar] [CrossRef] [PubMed]
  42. Mukherjee, N.; Sharma, R.; Modi, D. Immune alterations in recurrent implantation failure. Am. J. Reprod. Immunol. 2023, 89, e13563. [Google Scholar] [CrossRef] [PubMed]
  43. Guo, L.; Guo, A.; Yang, F.; Li, L.; Yan, J.; Deng, X.; Dai, C.; Li, Y. Alterations of Cytokine Profiles in Patients With Recurrent Implantation Failure. Front. Endocrinol. 2022, 13, 949123. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  44. Fournier, T.; Therond, P.; Handschuh, K.; Tsatsaris, V.; Evain-Brion, D. PPAR gamma and early human placental development. Curr. Med. Chem. 2008, 15, 3011–3024. [Google Scholar] [CrossRef]
  45. Leslie, D.S.; Dascher, C.C.; Cembrola, K.; Townes, M.A.; Hava, D.L.; Hugendubler, L.C.; Mueller, E.; Fox, L.; Roura-Mir, C.; Moody, D.B.; et al. Serum lipids regulate dendritic cell CD1 expression and function. Immunology 2008, 125, 289–301. [Google Scholar] [CrossRef]
  46. Kostenis, E. A glance at G-protein-coupled receptors for lipid mediators: A growing receptor family with remarkably diverse ligands. Pharmacol. Ther. 2004, 102, 243–257. [Google Scholar] [CrossRef]
  47. Desmarais, J.A.; Lopes, F.L.; Zhang, H.; Das, S.K.; Murphy, B.D. The peroxisome proliferator-activated receptor gamma regulates trophoblast cell differentiation in mink (Mustela vison). Biol. Reprod. 2007, 77, 829–839. [Google Scholar] [CrossRef]
  48. Mayer, K.; Meyer, S.; Reinholz-Muhly, M.; Maus, U.; Merfels, M.; Lohmeyer, J.; Grimminger, F.; Seeger, W. 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, 4837–4843. [Google Scholar] [CrossRef] [PubMed]
  49. Zhang, X.; Rodriguez-Galan, M.C.; Subleski, J.J.; Ortaldo, J.R.; Hodge, D.L.; Wang, J.M.; Shimozato, O.; Reynolds, D.A.; Young, H.A. Peroxisome proliferator-activated receptor-gamma and its ligands attenuate biologic functions of human natural killer cells. Blood 2004, 104, 3276–3284. [Google Scholar] [CrossRef]
  50. Delerive, P.; Fruchart, J.C.; Staels, B. Peroxisome proliferator-activated receptors in inflammation control. J. Endocrinol. 2001, 169, 453–459. [Google Scholar] [CrossRef]
  51. Kowalewski, M.P.; Meyer, A.; Hoffmann, B.; Aslan, S.; Boos, A. Expression and functional implications of peroxisome proliferator-activated receptor gamma (PPARγ) in canine reproductive tissues during normal pregnancy and parturition and at antiprogestin induced abortion. Theriogenology 2011, 75, 877–886. [Google Scholar] [CrossRef] [PubMed]
Table 1. Medical and gynecological variables.
Table 1. Medical and gynecological variables.
Index Group n (%)
n = 51		Comparator Group n (%)
n = 62		p Value
PCOS6 (18%)2 (3.2%)0.02
Hypothyroidism9 (27%12 (19.3%)>0.05
Endometriosis2 (6%)2 (3.2%)>0.05
GDM3 (9%)2 (3.2%)0.3
Regular menstrual cycles40 (78.4%)54 (87.1%)>0.05
Ovarian reserve
Low
Normal
10 (19.2%)
41 (78.8%)
16 (25.8%)
46 (74.2%)
>0.05
>0.05
Table 2. Indication for ART.
Table 2. Indication for ART.
Cause of InfertilityIndex Group
n = 51 No (%)		Comparator Group
n = 62 No (%)		p Value
Primary infertility12 (23.5%)23 (37.1%)0.01
Secondary infertility23 (45.1%)32 (51.6%)0.57
PGS2 (03.9%)4 (06.5%)0.68
PGD14 (27.5%)2 (03.2%)0.0003
Male factor0 (00.0%)1 (01.6%)>0.05
PGS—pre-implantation genetic screening; PGD—Pre-implantation genetic diagnosis.
Table 3. Outcome of ART in the index and comparator groups.
Table 3. Outcome of ART in the index and comparator groups.
OutcomeIndex Group (n = 51)Comparator Group (n = 62)p Value
Chemical pregnancy2 (3.9%)02 (3.2%)>0.05
Clinical pregnancy23 (45.1%)18 (29.0%)0.043
Miscarriage7 (13.7%)07 (11.3%)0.7
Ectopic pregnancy01 (1.96%)000.45
Not pregnant18 (35.3%)35 (56.5%)0.03
Table 4. Summary of studies on intralipids and pregnancy outcomes.
Table 4. Summary of studies on intralipids and pregnancy outcomes.
Study & YearType of Study and Sample SizeStudy PopulationTiming of IntralipidOutcomeResults
Acacio et al., 2008 [21]Cohort study n = 79 women-68 with Recurrent implantation failure (N = 68) Not specifiedPregnancy rates40% pregnancy rates, None of women > 409 achieved pregnancy
Ndukwe G 2011 [22]Cohort studyRecurrent implantation failure with elevated NK cellsNot specifiedPregnancy rate46% clinical pregnancy rate
El Khayat et al., 2015 [31]Randomized controlled (n = 203)Unexplained implantation failure (>2–6 cycles)Between day 4–9 of ovulation stimulation & within 1 weeks of pregnancy testClinical pregnancy, implantation and live birth rates35% clinical pregnancy rate and 33% live birth rate
Check & Check 2016 [33]Matched control Unexplained implantation failure and recurrent pregnancy lossMid-follicular phaseClinical pregnancy and delivery ratesNo pregnancy in those given intralipid compared to 40$ in untreated controls and 30% live births in controls
Gamaleldin et al., 2018 [30] (Abstract only)Randomized double blind controlled (n = 97)Unexplained recurrent implantation failure6–7 days before ET and second dose if positive pregnancy testClinical pregnancy and live birth rates (Treated vs. control)Clinical pregnancy rates 39.6% vs. 26.5% and livebirth rates-29.2% vs. 18.4%. 2 of 14 livebirths in treated group had congenital ear anomalies
Ledee et al., 2018 [10]Prospective cohort study (n = 94) Recurrent implantation failure at 5 week and again at 9 weeksLivebirthLivebirth rate of 54% compared to 20–25% for IFV-ET at time in France
Martini et al., 2018 [32]Retrospective study (n = 127); compared to historical control (n = 20)Unexplained implantation failure/recurrent pregnancy loss7–10 days before ET/insemination and at 6 and 10 weeks if pregnantClinical pregnancy and live birth ratesClinical pregnancy rates of 51% vs. 70% in study and controls and livebirth rates of 37% vs. 40% respectively
Ehrlich et al., 2019 [34]Retrospective case series (Cases n = 85 & aged matched controls n = 558)Recurrent implantation failureDay 5–9 of IVF cycles and again at positive pregnancy test; Or on day of oocyte retrieval in fresh ET or day of ET in FET and then on day of positive pregnancy test Clinical pregnancy and livebirth rates40% versus 35% clinical pregnancy (in treated and controls) and livebirth rate of 35.7% in intralipid group
Singh et al., 2019 [24]Randomized controlled (n = 102)Previous implantation failure (≥1 cycle)Day of oocyte retrieval and on day of ETChemical and clinical pregnancy rates, implantation rates, ongoing and live birth rates34.6% clinical pregnancy rate and 34.6% livebirth rate
Peivandi et al., 2022 [35]Randomised blind controlled trial (n = 80)Recurrent implantation failure2 days before ETClinical pregnancy30% vs. 10% in intralipid versus control groups (p < 0.05)
Kinarullakandi et al. (Current study) 2025Retrospective comparative (n = 113)Recurrent implantation failureBefore ET or at ET and at pregnancy test and weekly until 12 weeksClinical pregnancy, live birth and miscarriage ratesClinical pregnancy-44.2% vs. 29%; Miscarriage-13.7% vs. 11.3%
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kandi, S.K.; Shareef, O.O.; Obeid, A.; Abushama, M.; Ahmed, B.; Konje, J.C. Evaluating the Impact of Intralipid Infusion on Pregnancy Outcomes in Infertility Treatments: A Retrospective Study. Reprod. Med. 2025, 6, 34. https://doi.org/10.3390/reprodmed6040034

AMA Style

Kandi SK, Shareef OO, Obeid A, Abushama M, Ahmed B, Konje JC. Evaluating the Impact of Intralipid Infusion on Pregnancy Outcomes in Infertility Treatments: A Retrospective Study. Reproductive Medicine. 2025; 6(4):34. https://doi.org/10.3390/reprodmed6040034

Chicago/Turabian Style

Kandi, Shajna Kinarulla, Osama Oro Shareef, Abdelrahim Obeid, Mandy Abushama, Badreldeen Ahmed, and Justin C. Konje. 2025. "Evaluating the Impact of Intralipid Infusion on Pregnancy Outcomes in Infertility Treatments: A Retrospective Study" Reproductive Medicine 6, no. 4: 34. https://doi.org/10.3390/reprodmed6040034

APA Style

Kandi, S. K., Shareef, O. O., Obeid, A., Abushama, M., Ahmed, B., & Konje, J. C. (2025). Evaluating the Impact of Intralipid Infusion on Pregnancy Outcomes in Infertility Treatments: A Retrospective Study. Reproductive Medicine, 6(4), 34. https://doi.org/10.3390/reprodmed6040034

Article Metrics

Back to TopTop