IV Intralipid Therapy for In Vitro Fertilization: Does it Help?

Written by: Taylor J. Graber MD

­­­­­­­Background

In vitro fertilization is an increasingly common medical procedure, responsible for the birth of more than 6 million babies each year. It is a scientific, data driven field, and has treatment applications for nearly every issue which may affect male or female fertility. However, it is also expensive, with cycles costing anywhere from $5,000 to $30,000 per cycle, depending on the techniques used and geographic location. Most insurance plans do not cover IVF, leaving the burden of payment on the couple who are trying to conceive. With most success rates only at 50%, this can create a large economic and psychologic burden on the couple going through the process. Therefore, it is advisable to do everything possible to improve chances of success with each cycle, to minimize these negative effects and improve chances at success.

There is evidence that altered maternal immunologic function is a factor which can lead to recurrent implantation loss and miscarriage, although this is not easily diagnosed and clinically identified. Clinically treating this altered maternal immunologic function is the target for various therapies (lymphocyte immunotherapy, prednisolone, intravenous immunoglobulin, anti-tumor necrosis factor alpha antagonists, and intralipid therapy). Recurrent pregnancy loss has historically been described as 3 or more miscarriages before 20 weeks of gestation, and a more recent definition includes having two or more failed pregnancies which do not have to be consecutive. Recurrent implantation failure is frequently cited as three or more failed treatment cycles as well as failure to achieve a clinical pregnancy after transfer of 4 or more good quality embryos over three separate transfer cycles.

Intralipid, a 20% fat emulsion which is comprised of soybean oil, egg phospholipids, and glycerine, was initially used as a form of IV nutrition. It was incidentally found to have an immunosuppressive effects when patients receiving it were found to have elevated rates of bacteremia (the intralipid was thought to reduce the immune systems ability to fight bacteria, leading to an increased amount of bacteria in the blood, called bacteremia). Since this discovery, it has been implemented in several protocols to help immunosuppress the body and reduce the expression and activity of natural killer cells, a type of white blood cell which can interfere with the transfer and implantation process. Intralipid has been touted as a less expensive, safer, and equivalent therapy to more expensive treatments like IVIG (can be $7,000 to $14,000 for a single treatment, and carries with it a risk of anaphylaxis).

Literature Review

Study 1

Ehrlich et al. performed a study between 2011 and 2016 to analyze the effect of intralipid on successful implantation. Their study investigated 93 patients in the treatment group, and 558 patients in the control group. Their outcomes measured live birth rates between groups, defined as a fetal heart rate on ultrasound.

Treatment Protocol: Consisted of giving Intralipid 20%, 100mL of solution diluted into 500mL and administered as an IV infusion. Group A received an intralipid infusion on Day 5-9 of the cycle and again following the detection of a positive beta-HCG, for two total infusions. Group B received an intralipid infusion on the day of oocyte retrieval for a fresh embryo transfer or during the day of embryo transfer for a frozen embryo transfer.

Results: In their study, they found 34 pregnancies (as defined by normal fetal heartbeat by ultrasound) in 85 women who underwent an intralipid treatment, which corresponds to a clinical pregnancy rate of 40%. This was after a single cycle. Their control group (women who did not receive IV intralipid treatment) had a clinical pregnancy rate of 35%. The difference between groups was not statistically significant, although its possible this was due to a low power in the study (too few patients in the intervention arm). Women who underwent 1 cycle had a clinical pregnancy 49% of the time, those who underwent 2 cycles had a 52% chance of being pregnant, and those who underwent 3 transfers had an 80% chance of becoming pregnant. Subgroup analysis showed the largest benefits were found in those women who had higher levels of NK cells in peripheral blood testing, and there was no correlation with uterine NK cell levels.

Conclusions: They found that in women who had a history of extremely poor fertility outcomes, the livebirth rate was statistically non-inferior to the control clinical pregnancy group (35.7% vs. 35.0%). They did not find that intralipid hindered conception. There was an excellent safety profile. Their data provides evidence that intralipid does not negatively impact pregnancy outcomes or safety in women of advanced maternal age. There were no congenital abnormalities identified in women who received intralipid (indicating no increased risk of teratogenicity in embryos treated with intralipid).

Study 2

Martini et al. evaluated the use of intralipid and its ability to improve clinical pregnancy outcomes in women with recurrent pregnancy loss or recurrent implantation failure with elevated NK cells.

Methods: Retrospective cohort study of 127 patients in a large REI private practice from 2012-2015. Data recorded included cycle statistics, clinical pregnancy rates, live birth rates, and cost analyses. Their infusion was 4mL of 20% intralipid solution injected into 250mL of normal saline and were administered over 90-120 minutes.

Results: Neither clinical pregnancy nor live birth rates were significantly improved from baseline. Intralipid increased costs by $681 per live birth.

Conclusion: Intralipid does not improve live birth rates for patients with recurrent pregnancy loss or recurrent implantation failure with elevated NK cells. Their use of intralipid was only 4mL, compared to standard protocols which were 100mL of 20% intralipid solution. This may be an additional reason for their low effects.

Our take: Low doses of intralipid (4mL of 20% intralipid solution) administered 7-10 days before embryo transfer in women with elevated peripheral blood NK cells are not effective at improving clinical pregnancy rates. Studies with higher doses of intralipid should be examined for their effect.

Martini AE, Jasulaitis S, Fogg LF, Uhler ML, Hirshfeld-Cytron 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(3):261-268. doi:10.4103/jhrs.JHRS_28_18

Study 3

Han et al. evaluated the use of IV intralipid to improve outcomes for in vitro fertilization. They performed a systematic review and meta-analysis of the available literature.

Methods: Systematic review of 5 different randomized controlled trials including 840 patients (3 RCTs: women with repeated implantation failure, 1 RCT: women with recurrent spontaneous abortion, 1 RCT: women who had experienced implantation failure more than once). They looked at clinical pregnancy rate (defined as a positive heart beat by ultrasound) and live birth rates (defined as the delivery of a live neonate after 24 weeks gestational age) for treatment and control groups

Results: When compared with control groups, intralipid administration treatment groups showed the following:

1: Clinical pregnancy rate (risk ratio [RR], 1.48; 95% confidence interval [CI], 1.23–1.79)

2: Ongoing pregnancy rate (RR, 1.82; 95% CI, 1.31–2.53)

3: Live birth rate (RR, 1.85; 95% CI, 1.44–2.38).

4: Intralipid administration had no effect on the miscarriage rate (RR, 0.75; 95% CI, 0.48–1.17).

Conclusions: Intralipid administration may benefit women undergoing IVF, especially those who have experienced repeated or recurrent spontaneous abortions. No significant adverse events were noted in any of the treatment groups.

Han EJ, Lee HN, Kim MK, Lyu SW, Lee WS. Efficacy of intralipid administration to improve in vitro fertilization outcomes: A systematic review and meta-analysis. Clin Exp Reprod Med. 2021;48(3):203-210. doi:10.5653/cerm.2020.04266

Study 4

Kumar et al. evaluated the use of IV intralipid to improve outcomes for in vitro fertilization. They performed a systematic review and meta-analysis of the available literature.

Methods: Systematic review of twelve studies comprising 2676 total patients, (1592 controls and 1084 interventions who received intralipid treatment). Outcome measures were clinic pregnancy rate, live birth rate, implantation rate, and miscarriage rate. Patients with recurrent pregnancy loss and/or recurrent implantation failure were selected.

Results: Treatment of the target population with intralipid led to an improvement in IR (Odds Ratio (OR): 2.97, 2.05–4.29), pregnancy rate (OR: 1.64, 1.31–2.04), and LBR (OR: 2.36, 1.75–3.17), with a reduction in MR (OR: 0.2, 0.14–0.30).

Conclusions: Intralipid is clinically helpful for improvements in implantation rate, clinical pregnancy rate, live birth rate, and reducing miscarriage rate. Peripheral blood NK cell activity can be significantly decreased by Intralipid. Pregnancy outcomes following intralipid show a significantly low number of adverse events, indicating it is safe to use in these populations. Although these findings are not enough to establish intralipid use as a routine intervention for RIF/RPL yet, there is a role for strong consideration in selected cases, especially when standard treatment has failed, and identifiable risk factors are present.

Kumar P, Marron K, Harrity C. Intralipid therapy and adverse reproductive outcome: is there any evidence?. Reprod Fertil. 2021;2(3):173-186. Published 2021 Jun 3. doi:10.1530/RAF-20-0052

Our take at ASAP IVs

Following a review of the literature, we have formulated our own decision making at ASAP IVs. From the studies presented (looking at Study 2 by Martini et. al), it seems as though low doses of intralipid (2mL or 4mL of 20% solution into a 250mL saline infusion) are not helpful at improving implantation rate, clinical pregnancy rate, live birth rate, or miscarriage rate.

However, when one looks at the larger pooled studies (Study 3 by Han et al. and Study 4 by Kumar et al.) which incorporate multiple studies with more patients (in both intervention and control arms), it appears that there is a benefit to Intralipid therapy. Especially when using Study 4, which had 1084 patients in the intervention arm (those receiving the intralipid treatment, compared to the 1592 controls who did not), there seem to be multiple clinical benefits which surface. These benefits include improvements in implantation rate (OR ~3, that is 3x more likely to have a successful embryo implantation compared to control), pregnancy rate (OR 1.6, that is 1.6x more likely to have a clinical pregnancy as defined by the presence of a fetal heart beat by ultrasound compared to control groups who did not receive intralipid), live birth rate (OR ~2.4, that is 2.4x more likely to have a successful live birth of an baby in group treated with intralipid, compared to control), and finally a reduction in the miscarriage rate (OR 0.2, that is, the group treated with intralipid was 20% as likely to miscarry as compared to the control group not treated with intralipid). These data were all extrapolated from multiple studies with several protocols (single vs. multiple infusions, low dose vs. higher dose intralipid) and a heterogeneous patient population suffering from recurrent implantation failure or recurrent pregnancy loss.

Although we wouldn’t propose that intralipid be used as the new “standard of care” for every woman undergoing embryo transfer, it does seem as though there are multiple benefits to this treatment in the right population.

Given the above data, we have begun offering the convenience of our IV therapy services at ASAP IVs with this intralipid therapy. We are happy to work in conjunction with your Reproductive Endocrinologist to help you receive the care that you need. Our protocol is modeled after the higher dosed intralipid treatments (this was decided after the above studies showed less effect in the lower dose groups) and is as follows:

1. 100mL of 20% Intralipid Emulsion Therapy diluted into 250mL or 500mL IV Fluid (Normal Saline or Lactated ringers)

2. IV access is established and the therapy is started. The infusion will take approximately 60-120 minutes, depending on patient comfort (the occurrence of any side effects is very rare. These infusions are well tolerated). You will be monitored for safety and comfort during this time.

3. IV Intralipid can be done in conjunction with the discussions with your Reproductive Endocrinologist based on desired timing, or can be scheduled 1-7 days before your Embryo transfer.

We will be offering these treatments at our clinics in San Diego (La Jolla, CA), Phoenix/Scottsdale (Arcadia, AZ), and the San Francisco Bay Area (Pleasanton, CA).

Interested in scheduling an appointment for IV Intralipid Therapy with ASAP IVs? Click on the link below.