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Marchand et al. | Journal of Clinical and Translational Research 2023; 9(4): 236-245 237
in vitro fertilization (IVF) cycles [7]. Kumar et al. [8] established In light of this data, we found that there were sufficient
that the failure of implantation occurs in approximately 10% of RCTs performed on this topic to perform a meta-analysis, if the
IVF/intracytoplasmic sperm injection (ICSI) cycles. RCTs on RPL and RIF were combined (There was insufficient
Many factors can be responsible for RPL/RIF. These include data separately.) Therefore, to see if a true difference exists, we
abnormal embryonic karyotype (41%), uterine abnormalities (5%), aimed to design a meta-analysis to assess all of the available data
endocrine dysfunction (6%), and antiphospholipid antibody (APA) regarding the effect of the 20% intravenous fat emulsion therapy
syndrome (6%). Furthermore, it is estimated that the 25% of the on different pregnancy outcomes in women with RPL or RIF
time, the cause is unexplained or that 4% of the cases occur from undergoing IVF/ICSI.
mixed causes [9]. Different studies have proposed an immunological
explanation for the RIF/RPL phenomenon, especially in those cases 2. Materials and Methods
that lack an identified cause [6,10]. There is no consensus whether We performed this systematic review and meta-analysis
the most common cause is the failure of the apposition, adhesion, or accurately with the Cochrane Handbook for Systematic Reviews
invasion of the placenta into the uterine lining [11]. Immunological of Interventions [31]. We reported our findings according to the
causes suspected to be responsible for RPL/RIF are extensive, Preferred Reporting Items for Systematic Reviews and Meta-
and a full discussion is outside the realm of the present work. Analyses (PRISMA) statement [32].
However, commonly suspected abnormalities include T-helper We performed a computerized search in different databases
cells ratio imbalance, the deregulation of T-cells, the deregulation (PubMed, Cochrane Library, Scopus and ISI Web of Science,
of dendritic cells, natural killer (NK) cells in the uterus, APA, and MEDLINE, and ClinicalTrials.gov) during February of 2020.
disorders of adaptive immunity and innate immunity, [12]. Various We used the following search strategy: (intralipid OR intralipid
other biochemical factors have also been investigated, such as infusion OR soybean oil based lipid emulsion) AND (control
inflammatory mediators and human leukocyte antigens [13]. OR comparator OR placebo OR saline OR no intervention)
Accordingly, many immunomodulatory agents have been
studied to reduce RPL/RIF rates. These therapies include low- AND (pregnancy OR pregnant OR gestation OR recurrent
molecular-weight heparin, aspirin, intravenous immunoglobulin pregnancy loss OR recurrent implantation failure OR RPL OR
(IVIG), corticosteroids, and 20% intravenous fat emulsion RIF) AND (clinical trial OR clinical trials OR trial OR random
therapy [14-17]. Despite numerous studies, there is no clear OR random allocation OR RCT OR randomized controlled trial
consensus regarding the efficacy of these therapies in improving OR controlled clinical trial). Two investigators performed the
different pregnancy outcomes. This includes unclear efficacy search strategy. There were no restrictions by language or year
in rates of achieving clinical pregnancy, maintaining ongoing of publication.
pregnancies, and effect on live birth rates in patients with RPL Randomized controlled trials (RCTs) were included using this
and RIF [18]. criteria:
Intralipid™ (20% intravenous fat emulsion) is a fat emulsion (I) population: Women with RPL or RIF; (II) intervention: the
solution that consists of soybean oil, glycerin, egg phospholipid, 20% intravenous fat emulsion therapy; (III) comparator: placebo
water, and glycerol [15]. The medication is Food and Drug (normal saline) or no intervention; and (IV) study design: RCTs.
Administration approved for the administration of parenteral We excluded studies for the following reasons: (1) reviews,
nutrition in patients with ingestion problems and is administered (2) irrelevant studies, (3) letters to editors, and (4) studies whose
intravenously. It supplies the body with essential fatty acids, data could not be extracted or entered into the analysis. Title and
α-linolenic acid, and omega-3 fatty acids [19]. Interestingly, abstract screening and full-text screening were conducted by
several studies have reported on benefits of intravenous fat appropriate step by step analysis by the same two authors.
emulsion therapy outside of the field of parenteral nutrition and Our data were initially extracted by the two authors on a data
the medications intended indication. These include a reduction in extraction sheet. The extracted data included: list of authors,
platelet aggregation, decline in interleukin-2 (IL-2) production, year of publication, sample size, and summary of included
suppression of NK cell activity, and inhibition of TH1 cell studies. In addition, we extracted our primary outcome (clinical
activity [20]. Clearly, these properties spark an interest in the pregnancy rate) and our secondary outcomes (ongoing pregnancy,
efficacy of this medication in the treatment of RPL and RIF. miscarriage, live birth rates, and any adverse events of the 20%
While there is ample evidence that intravenous fat emulsion intravenous fat emulsion therapy). The category of adverse events
therapy is effective in reducing the production of proinflammatory was expanded to include reports of headache, dizziness, flushing,
cytokines and the production of NK cells [21-23], whether the drowsiness, nausea, vomiting, and sweating.
medication actually improves outcomes in patients with RPL Clinical pregnancies were defined as confirmation of fetal
and RIF remains unclear. Before embarking on this review, we cardiac activity through sonography or Doppler, and this was
found conflicting bodies of evidence, with some studies reporting found to be universally accepted in all included studies. Ongoing
improved reproductive outcomes among patients with RPL/RIF pregnancy was defined as a pregnancy that had reached more than
undergoing IVF/ICSI when receiving the 20% intravenous fat or equal to 20 gestational weeks. Miscarriage was determined
emulsion therapy [24-26], and others failing to show any as spontaneous abortion or pregnancy loss prior to 20 weeks of
significant difference [27-30]. gestation. Live birth was defined as the total number of deliveries
DOI: http://dx.doi.org/10.18053/jctres.09.202304.23-00060