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Marchand et al. | Journal of Clinical and Translational Research 2023; 9(4): 236-245 243

Figure 7. Forest plot of the live birth rate.

correlations between certain NK cell receptors and RPL [42]. found that there was a benefit to fat emulsion therapy in RIF
At present, in the United States, intravenous 20% fat emulsion patients who exhibited an over-immune activation of uNK
therapy is administered by many fertility clinics for patients cells. They found an improvement to a 54% live birth rate
with RPL/RIF, especially in the setting of empiric treatment of with fat emulsion therapy in RIF patients [16]. Gamaleldin
suspected fertility-related immunological dysfunction [43,44]. et al. [28] found that fat emulsion therapy did not create any
This may be secondary to the high cost of other investigations. significant improvement in live birth and clinical pregnancy
IVIG therapy, for example, is extremely expensive, with a single rates in cases with RIF, and Cohen et al. [30] reported a similar
course of therapy costing up to $14,000 [43]. In addition, the lack of efficacy in patients aged 40–42 years with history of
efficacy of IVIG for improving pregnancy outcomes (clinical miscarriage [30].
pregnancy, ongoing pregnancy, and live birth rates) in RPL/RIF To the best of our knowledge, this meta-analysis is the first
remains unproven. Risks with IVIG administration include the to investigate the effect of intravenous fat emulsion therapy
possibility of anaphylaxis and a low—but possible—risk for on different pregnancy outcomes in women suffering from
transmission of infections [44]. Thus, many clinicians feel that recurrent miscarriage or implantation failure. Strengths of our
intravenous fat emulsion therapy may be safer, in addition, to study include that the characteristics of most of the included
being less expensive. There is, however, no universal consensus. RCTs were extremely similar, with relatively few variables to
Martini et al., [10] for example, failed to find that fat emulsion control for. Other strengths include our strict adherence to the
therapy was cost-effective despite an average cost of only PRISMA guidelines and accepted principles of a systematic
$681.00 for the therapy in their case series. The lack of cost review.
effectiveness was a result of finding very little efficacy versus Our main limitation was the heterogeneity of inclusion criteria
their control [10]. in some of the included studies, although as stated above, we noted
Some of the most compelling evidence for fat emulsion therapy great similarity in the adhered protocols. Secondary to this increased
came from Singh et al., [25] which demonstrated a significant heterogeneity, our strict grading of the studies led to a higher than
improvement in clinical pregnancy, ongoing pregnancy, and live expected risk of bias. This ultimately resulted in a moderate level of
birth rates in women with a history of RIF undergoing intravenous evidence. As noted in our quality of evidence assessment (Figure 4),
fat emulsion therapy. The adjusted odds ratio for clinical pregnancy this is almost entirely due to concerns of a lack of proper blinding
in the fat emulsion therapy group, compared to placebo, was 3.1, of participants and personnel in four of the included studies. This
95% CI [1.02–9.70], P = 0.046. Another RCT, El-Khayat and El led to an increased risk of bias and, thus, lowered the quality of our
Sadek [26] agreed with these findings by concluding a significant overall evidence. It is likely that if more well-designed RCTs are
improvement in clinical pregnancy, implantation, and live birth undertaken, this level of evidence would increase, especially if the
rates among women receiving the intravenous fat emulsion researchers were able to specifically document that correct patient
therapy [26]. In addition, Coulam and Acacio [24] proposed an and personnel blinding procedures were followed.
estimated 61% increase in live birth rates after treatment with Another limitation of this study was the necessity to combine
the intravenous fat emulsion therapy in cases of RPL/RIF with the RPL and RIF groups to reach statistical significance among
increased NK activity. Moreover, this effect was not different the included RCTs. A greater wealth of RCTs on this topic would
when compared against a cohort of IVIG. allow for subgroup analysis or individual analysis to ascertain
Several of the analyzed RCTs had different conclusions. Al- exactly which condition, if either, benefits more from fat emulsion
Zebeidi et al. [27] failed to demonstrate a significant difference therapies.
between the intravenous fat emulsion and control groups in Furthermore, complicating our understanding of the usage of
terms of clinical pregnancy, miscarriage, and live birth rates. fat emulsion therapy, there is still no universal consensus as to
Similarly, Dakhly et al. [29] did not illustrate any significant the mechanism of action of intravenous fat emulsion therapy in
difference in chemical pregnancy among women with RPL after patients with RPL and RIF, which may be limiting the interest in
intravenous fat emulsion therapy (58.3% vs. 50.0%, P = 0.129 developing future RCTs. We would also recommend that future
for intravenous fat emulsion vs. control group, respectively). studies could focus on the cost-effectiveness of the fat emulsion
Furthermore, in a recent retrospective study, Lédée et al. [16] therapy, as this is an important factor for many clinicians.
DOI: http://dx.doi.org/10.18053/jctres.09.202304.23-00060