A Comparative Study of Intravenous Immunoglobulin and Lipid Emulsion in Patients With Reproductive Failures Associated With NK Cell Abnormalities

ABSTRACT

Purpose

To compare the effects of intravenous immunoglobulin (IVIG) and lipid emulsion (LE) therapies on reproductive failure such as recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF) associated with natural killer (NK) cell abnormalities.

Methods

NK cell abnormalities were defined as peripheral blood NK (pNK) cell activity of 40% or higher and CD16⁺/CD56^dim uterine NK (uNK) cells at 18% or higher. IVIG and LE were administered to RPL and RIF patients. In patients undergoing IVF‐ET, treatment was initiated either before ET, on ET day, or after ET.

Results

Implantation rates of 48.3% and 47.8% were revealed in the IVIG and LE groups, respectively, with no significant difference. For patients with RPL, live birth rates were 75.0% for the IVIG group and 72.5% for the LE group, with no significant difference. For timings of administration before ET, on ET day, or after ET, the clinical pregnancy rates were 47.6%, 0%, and 0%, respectively, in the IVIG group and 30.0%, 12.5%, and 0%, respectively, in the LE group. Higher clinical pregnancy rates were observed when each treatment was initiated before ET.

Conclusions

Both treatments exhibited comparable therapeutic effects on reproductive disorders associated with NK cell abnormalities.

Intravenous immunoglobulin and lipid emulsion treatment is effective for patients with recurrent implantation failure and recurrent pregnancy loss who have NK cell abnormalities. When embryo transfer is to be performed, IVIG or LE should be administered before embryo transfer. Administration of IVIG or LE reduces NK cell activity, and approximately 80% of pregnancies can be maintained.

1. Introduction

According to a report by the recurrent pregnancy loss (RPL) project of Japan Agency for Medical Research and Development (AMED), the risk factors for reproductive failures such as RPL and recurrent implantation failure (RIF) are still unknown in approximately half of the cases [1], and one of these is reported to be an immune abnormality [2, 3, 4]. Previous studies have reported on the involvement of abnormal NK cells in the peripheral blood and endometrium in reproductive disorders [5, 6], specifically, an increase in CD56⁺ NK cells in the peripheral blood and uterine endometrium [7, 8] and an increase in NK cell activity in the peripheral blood [9]. We have previously reported an increase in peripheral blood NK cells in cases of RPL and RIF, as well as an increase in utrine endometrial CD16⁺/CD56^dim cells, a decrease in CD56⁺/NKp46⁺ cells, and a decrease in CD56⁺/NKp46⁺ cells in the uterine endometrium and decidua [10, 11, 12, 13, 14, 15]. Although the ESHRE Good Practice Recommendations on Recurrent Implantation Failure in 2023 and the Guidelines for Recurrent Pregnancy Loss in 2022 do not recommend testing for NK cell abnormalities, the text states that the involvement of implantation failure and NK cell abnormalities cannot be denied [2, 16]. Therefore, NK cell abnormalities may be risk factors for reproductive abnormalities.

The treatment of reproductive failure associated with NK cell abnormalities may involve the use of immunomodulatory drugs. Intravenous immunoglobulin (IVIG) has been reported to be effective in unexplained RPL [17] and its effects include anti‐inflammatory effects, suppression of autoantibodies and complement, and modulation of NK, T, and B cells [18, 19]. However, the detailed effects of IVIG on reproductive failures, such as RPL and RIF, remain unknown. Since immunoglobulin is a blood product and resources are limited, ESHRE Good Practice Recommendations on Recurrent Implantation Failure recommend avoiding its frequent use [16]. Additionally, immunoglobulins for reproductive failure are not covered by government insurance in Japan and their use costs approximately 1500 dollars per administration, placing a significant financial burden on patients. In contrast, lipid emulsion (LE) is sometimes used for patients with reproductive failures associated with immune dysfunction [20, 21, 22], and they are relatively inexpensive, even when paid out‐of‐pocket, resulting in a lower economic burden for patients. However, although there are reports indicating their effectiveness, there are also studies suggesting that they may not be effective [23], and the evidence is inconsistent. In this study, we compared the effects of IVIG and LE in patients with reproductive failures associated with NK cell abnormalities.

2. Materials and Methods

2.1. Study Population

This study targeted patients with reproductive failure who consented to participate and visited the Hyogo Medical University and Kameda IVF clinic between April 2018 and April 2024. All patients with RIF underwent in vitro fertilization and embryo transfer (IVF‐ET), whereas those with RPL included those who underwent IVF‐ET and attempted natural conception. Among patients with RPL who underwent IVF‐ET rather than natural conception, only those who achieved a clinical pregnancy were included in this study. All ET procedures were performed using frozen–thawed embryo transfer in a hormone replacement cycle. Pre‐implantation genetic testing for aneuploidy (PGT‐A) was not performed for IVF‐ET. RIF was defined in those who underwent three embryo transfers of good‐quality embryos but did not achieve pregnancy. RPL was defined in those who have experienced two or more miscarriages. The following patients were excluded: untreated carriers of thrombotic disorders such as antiphospholipid syndrome (APS) or protein S deficiency, untreated septate uterus, untreated diabetes or thyroid dysfunction, chromosomal abnormalities such as translocations that could cause recurrent miscarriage, and those with a high Th1/Th2 ratio. Patients with thrombotic disorders, septate uterus, diabetes, or thyroid dysfunction were included in this study if they had already received appropriate treatment for these conditions but still had poor outcomes. NK cell abnormalities were defined as peripheral blood NK (pNK) cell activity of 40% or higher during the mid‐luteal phase, and CD16⁺/CD56^dim uterine NK (uNK) cells of 18% or higher during the mid‐luteal phase, according to our previous results [10, 24]. A total of 209 patients participated in the study; 102 had high peripheral blood NK cell activity, 80 had an abnormal uNK cell subpopulation, and 27 had both. Among these, patients with NK cell abnormalities were allocated to the immunoglobulin administration group (IVIG group) and lipid emulsion administration group (LE group). Among the RPL patients, 82 were in the LE group (including 26 who had undergone IVF‐ET), and 31 were in the IVIG group (including 6 who had undergone IVF‐ET). Among the RIF patients, 67 were in the LE group, and 29 were in the IVIG group. Patient characteristics are shown in Table 1 and are presented separately for patients with RPL and RIF.

TABLE 1.

Patient characteristics.

	RPL		p a	RIF		p a
	LE group	IVIG group		LE group	IVIG group
	(n = 82)	(n = 31)		(n = 67)	(n = 29)
Age	35.0 [30.0–38.0]	37.0 [35.0–41.5]	< 0.01	38.0 [36.0–41.0]	40.0 [34.8–41.3]	N.S.
Number of pregnacies	3.0 [2.0–5.0]	3.0 [2.0–5.0]	N.S.	0 [0.0–1.0]	0 [0.0–0.5]	N.S.
Number of deliveries	0.0 [0.0–1.0]	0.0 [0.0–0.0]	N.S.	0 [0.0–0.0]	0 [0.0–0.0]	N.S.
Number of abortions	3.0 [2.0–4.0]	3.0 [2.0–4.0]	N.S.	0 [0.0–1.0]	0 [0.0–0.0]	N.S.
Number of biochemical pregnancy	0.0 [0.0–0.3]	0.0 [0.0–0.0]	N.S.	0 [0.0–0.0]	0 [0.0–0.0]	N.S.
Body mass index (kg/m2)	21.0 [19.1–22.6]	20.7 [19.4–22.1]	N.S.	20.6 [19.0–23.2]	20.8 [18.3–22.5]	N.S.
NK cell abnormalities
pNK cell cytotoxicity (%)	42.0 [26.0–49.5]	45.0 [25.8–52.5]	N.S.	40.0 [26.0–47.0]	40.0 [30.0–55.0]	N.S.
CD16+/CD56dim uNK cell (%)	21.2 [14.0–27.0]	19.8 [5.0–24.5]	N.S.	20.7 [14.4–37.2]	21.0 [10.4–33.5]	N.S.
Managed complications
Thrombotic disorders	26	3		5	0
Septate uterus	2	0		0	0
Thyroid dysfunction	1	0		0	0
Diabetes	0	0		0	0
Embryo transfer cycle data	(n = 26)	(n = 6)
Thickness of the endometrium (mm)	10.0 [9.4–11.1]	10.8 [9.5–13.8]	N.S.	10.6 [8.6–15.0]	11.3 [10.4–14.3]	N.S.
P at the time of ET (ng/mL)	16.6 [12.2–19.5]	13.7 [10.1–19.1]	N.S.	14.9 [12.8–18.7]	20.4 [12.3–25.6]	N.S.
Number of transfered embryo	1.0 [1.0–1.0]	1.0 [1.0–1.0]	N.S.	1.0 [1.0–1.0]	1.0 [1.0–1.0]	N.S.

Abbreviations: APS, antiphospholipid syndrome; ET, embryo transfer; IVIG, intravenous immunoglobulin; LE, lipid emulsion; P, progesterone; RIF, recurrent implantation failure; RPL, recurrent pregnancy loss.

^a Mann–Whitney U test was implemented.

2.2. Mesurement of NK Cell Activity

Peripheral blood samples were collected during the middle luteal phase typically in the morning. The pNK cell activity was measured by an external testing company within 24 h of collection. Briefly, lymphocytes were isolated from the patient's peripheral blood, and ⁵¹Cr‐labeled target cells (K‐562 cells) were added and cultured for a specific period. The NK cell activity was assessed by measuring the amount of ⁵¹Cr released owing to NK cell cytotoxicity and was considered abnormal if it was 40%. If pregnancy was confirmed, pNK cell activity was measured weekly until 12 weeks of gestation and every 4 weeks thereafter until 24 weeks.

2.3. Sample Collections and Measurement of Surface Antigens on Uterine NK Cells

Endometrial samples were collected during the midluteal phase. The percentage of CD16⁺/CD56^dim uNK cells was measured using the method we previously reported [13, 14]. The collected endometrium was placed in sterilized Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin, and 1% streptomycin. After visually eliminating blood, the samples were finely chopped with micro‐scissors, mechanically disrupted using a gentleMACS Dissociator (Miltenyi Biotec, Bergisch Gladbach, Germany), and a single‐cell suspension of endometrial cells was prepared. The final concentration was adjusted to 5 × 10⁶ cells/mL. The surface antigens of endometrial NK cells were stained with the following monoclonal antibodies: anti‐CD45‐APC‐H7, anti‐CD56‐Alexa Fluor 488 (BD Bioscience, San Jose, CA, USA), anti‐CD3‐APC, and anti‐CD16‐BV510 (BioLegend Inc., San Diego, CA, USA). Negative and appropriate isotype controls for each antibody were performed simultaneously with surface antigen staining. Monoclonal antibodies were incubated with 100 μL of the endometrial cell suspension at 4°C in the dark for 20 min, followed by lysis and fixation. The samples were washed twice with phosphate‐buffered saline (PBS) and resuspended in 0.25 mL for subsequent flow cytometry analysis. Immunofluorescence flow cytometry analysis of surface antigens on uNK cells was performed using LSRFortessa X‐20 (Becton, Dickinson and Company Inc., Franklin Lakes, NJ, USA). BD FACSDiva software (Becton, Dickinson and Company Inc., Franklin Lakes, NJ, USA) was used for full list‐mode data storage and retrieval. FlowJo software (Becton, Dickinson and Company Inc., Franklin Lakes, NJ, USA) was used for the analysis. First, the forward and side scatter area parameters were used to exclude adhesion signals, and then a gate was set for anti‐CD45 APC‐H7 positive events, followed by a gate for the lymphocyte region. Samples were evaluated for at least 3 × 10⁴ endometrial lymphocytes. Uterine NK cells were distinguished into CD56^dim and CD56^bright cells, as well as CD16⁺ and CD16⁻ cells, according to the intensity of fluorescent staining, and the proportion of CD16⁺/CD56^dim cells among CD56⁺ cells was analyzed. In our previous report, we diagnosed NK cell abnormalities when the proportion of CD16⁺/CD56^dim uNK cells was 18% or more [10].

2.4. Administration of IVIG and LE

IVIG (Venoglobulin IH 10%, Japan Blood Products Organization, Tokyo, Japan) was administered at a dose of 400 mg/kg over 1.5~2 h. LE (Intralipos, Otsuka Pharmaceutical, Tokyo, Japan) was administered via an intravenous drip at a rate of 50 g (20% in 250 mL) for 4 h. In patients with RPL and RIF undergoing IVF‐ET, the initial administration was performed around the date of embryo transfer. If pregnancy was achieved, LE was administered every 3 weeks and IVIG was administered every 4 weeks. For patients with RPL waiting for natural conception, administration was started as soon as possible after pregnancy confirmation (approximately 4 weeks of gestation) and continued at the same intervals as mentioned above. The endpoint of evaluation was 22 weeks of gestation.

2.5. Statistical Analysis

Data were analyzed using IBM SPSS Statistics version 23 (IBM, Chicago, IL, USA). Age, number of pregnancies, deliveries, miscarriages, body mass index (BMI), thickness of the endometrium, progesterone level at the time of embryo transfer, number of transferred embryos, and biochemical pregnancies in the patient background were analyzed using the Mann–Whitney U test. Clinical pregnancy, miscarriage, and live birth rates, including ongoing pregnancies after treatment, were analyzed using the chi‐squared test. Statistical significance was set at p < 0.05. We analyzed whether the timing of drug administration affected the clinical pregnancy rate in patients with RPL and RIF. Specifically, the patients were divided into three groups: those who received drugs within 3 days before embryo transfer (before ET group), those who received drugs on the day of embryo transfer (on ET day group), and those who received drugs within 3 days after embryo transfer (after ET group). Chi‐squared tests were used to compare groups. The NK cell activity after pregnancy was measured weekly until 12 weeks of gestation and every 4 weeks thereafter until 24 weeks, and the NK cell activity values after each drug administration were analyzed using the Mann–Whitney U test.

3. Results

3.1. Age, Obstetrical Histories, and Immune States of the Study Population

No significant differences were observed in the number of pregnancies, deliveries, miscarriages, biochemical pregnancies, BMI, thickness of the endometrium, progesterone at the time of embryo transfer, number of transferred embryos, pNK cell activity, or percentage of CD16⁺/CD56^dim uNK cells (Table 1). The mean age of the patients in the IVIG group was significantly higher than that of the LE group with RPL.

3.2. Pregnancy Outcomes After Administration of IVIG/LE in Cases of RPL and RIF

In cases of RPL, the live birth rates including ongoing pregnancies were 61.0% and 67.7% in the LE and IVIG groups, respectively. Additionally, the live birth rate, excluding miscarriages due to chromosomal abnormalities and biochemical pregnancies, was 72.5% in the LE group and 75.0% in the IVIG group, with no significant differences between the two groups. Furthermore, when excluding unknown chromosomal abortions and considering only chromosomally normal abortions as abortions, the live birth rate was 84.7% in the LE group and 100% in the IVIG group.

In RIF cases, the implantation rate including biochemical pregnancies was 47.8% in the LE group and 48.3% in the IVIG group. The live birth rate, including ongoing pregnancies, was 53.1% in the LE group and 50.9% in the IVIG group. The live birth rate, excluding miscarriages due to chromosomal abnormalities and biochemical pregnancies, was 81.0% in the LE group and 58.3% in the IVIG group, with no significant differences observed between the two groups (Table 2). Furthermore, when excluding unknown chromosomal abortions and considering only chromosomally normal abortions as abortions, the live birth rate was 94.4% in the LE group and 87.5% in the IVIG group.

TABLE 2.

Treatment outcomes of LE and IVIG for RPL and RIF.

	RPL		p a	RIF		p a
	LE group	IVIG group		LE group	IVIG group
	(n = 82)	(n = 31)		(n = 67)	(n = 29)
Implantation rate (including biochemical pregnancies) (%)	N.A.	N.A.		47.8 (32/67)	48.3 (14/29)	N.S.
Live birth rate (%)	61.0 (50/82)	67.7 (21/31)	N.S.	53.1 (17/32)	50.9 (7/14)	N.S.
Live birth rate (excluding ACC and BP) (%)	72.5 (50/69)	75.0 (21/28)	N.S.	81.0 (17/21)	58.3 (7/12)	N.S.
Live birth rate (excluding ACC, BP and UCC) (%)	84.7 (50/59)	100.0 (21/21)	N.S.	94.4 (17/18)	87.5 (7/8)	N.S.
Abortion rate (%)	34.2 (26/76)	25.9 (8/29)	N.S.	22.7 (5/22)	46.2 (6/13)	N.S.
Abortion rate (excluding ACC) (%)	27.5 (19/69)	25.0 (7/28)	N.S.	19.0 (4/21)	41.7 (5/12)	N.S.
Abortion rate (excluding ACC and UCC) (%)	15.3 (9/59)	0.0 (0/21)	N.S.	5.6 (1/18)	12.5 (1/8)	N.S.

Abbreviations: ACC, abnormal chorionic chromosome; BP, biochemical pregnancy; IVIG, intravenous immunoglobulin; LE, lipid emulsion; RIF, recurrent implantation failure; RPL, recurrent pregnancy loss; UCC, unknown chorionic chromosome.

^a Chi‐squared test was implemented.

3.3. Analysis of Clinical Pregnancy Rates by the Date of IVIG/LE Administration

In the RIF cases, the clinical pregnancy rates were 30.0%, 12.5%, and 0.0% in the before ET, on ET day, and after ET groups, respectively, in the LE group. In the IVIG group, the clinical pregnancy rates were 47.6%, 0.0%, and 0.0%, respectively. Although there were no significant differences among the three groups, the clinical pregnancy rates tended to be higher when the drug was administered before embryo transfer (Table 3).

TABLE 3.

IVIG/LE administration timing and clinical pregnancy rates in patients with RIF.

	Before ET	On ET day	After ET	p a
LE group	30.0 (15/50)	12.5 (1/8)	0.0 (0/3)	N.S.
IVIG group	47.6 (10/21)	0.0 (0/5)	0.0 (0/0)	N.S.
Total	35.2 (25/71)	7.7 (1/13)	0.0 (0/3)	N.S.

Abbreviations: ET, embryo transfer; IVIG, intravenous immunoglobulin; LE, lipid emulsion; RIF, recurrent implantation failure.

^a Chi‐squared test was implemented.

3.4. Changes in NK Cell Activity After Conception

Changes in NK cell activity during the administration of each drug after pregnancy are shown in Figure 1. The NK cell activities were significantly decreased by the administration of IVIG/LE. Although the NK cell activity gradually decreased in the IVIG group, it rapidly decreased in the LE group. Moreover, NK cell activity in the IVIG group increased again 4 weeks after IVIG administration; however, it decreased again after re‐administration of IVIG.

FIGURE 1.

Effects of IVIG/LE on NK cell activity during pregnancy. In patients treated with either IVIG or lipid emulsion (LE), peripheral blood NK cell activity was measured weekly until 12 weeks of gestation and every 4 weeks thereafter until 24 weeks. The solid line represents the IVIG group, the dashed line represents the LE group, and the dotted line indicates the reference threshold for NK cell activity (40%). Statistical comparisons between the two groups at each time point were performed using the Mann–Whitney U test. Asterisks indicate statistically significant differences between the groups (*p < 0.05, **p < 0.005). Data are presented as mean ± standard deviation. Both IVIG and LE were associated with a reduction in NK cell activity following administration, with a more rapid decline observed in the LE group compared to the IVIG group.

4. Discussion

Treatments for reproductive failures associated with immune abnormalities have previously included corticosteroids, immunoglobulins, lipid emulsions, and other therapies [25, 26, 27, 28, 29, 30]. The ESHRE Good Practice Recommendations for RIF and ESHRE RPL Guidelines do not recommend testing for immune abnormalities or advocate the use of immunomodulators, stating that large‐scale controlled studies are necessary [2, 16]. Canadian RIF guidelines suggest that immunotherapies such as immunoglobulins, lipid emulsions, and glucocorticoids should only be used for research purposes [25]. According to South Korean guidelines on the use of IVIG, immunoglobulins should not be administered blindly for unexplained implantation failure but rather based on the results of immunological tests, such as the status of NK cells and the Th1/Th2 ratio [31].

In the present study, we compared the effects of IVIG and LE on RPL and RIF associated with NK cell abnormalities. Peripheral blood NK (pNK) cells and uterine NK (uNK) cells were assessed as independent immunological parameters based on the understanding that they differ in origin, phenotype, and function, and previous studies have shown no consistent correlation between them [32, 33]. Nonetheless, both pNK and uNK cell abnormalities have been individually associated with reproductive failure. Therefore, in this study, we included patients who exhibited abnormalities in either pNK activity (≥ 40%) or uNK subpopulations (CD16⁺/CD56^dim ≥ 18%), or in both. This approach enabled us to capture immune dysregulation present at either the systemic or local level, which may contribute to reproductive failure. Our results showed that the therapeutic effects of LE were comparable to those of IVIG for both RPL and RIF. Coulam et al. [20] compared pregnancy outcomes in patients with reproductive failure and elevated NK cell cytotoxicity, matched for age and indication and treated with either IVIG or LE. They reported live birth rates per treatment cycle of 61% fo LE and 56% for IVIG, with no significant differences observed. Meng et al. [34] demonstrated that in cases of RPL with NK cell abnormalities, IVIG and LE equally reduced the NK cell activity and achieved comparable pregnancy success rates. These findings suggest that LE can be used in the same manner as IVIG.

Furthermore, women aged 35–39 years with a history of three miscarriages have a miscarriage rate of 40%–50% in subsequent pregnancies [35, 36]; in comparison, the miscarriage rates in both treatment groups in this study appear to have decreased. Additionally, the pregnancy rate per embryo transfer in women aged 35–39 years was 25.9% [16]. In this study, the clinical pregnancy rate increased slightly when the drugs were administered before embryo transfer.

Although no significant differene was observed in the examination by administration date, there was a tendency for higher clinical pregnancy rates when LE was administered before embryo transfer. A similar tendency was observed for RPL in the IVIG group. Studies examining the effectiveness of IVIG for RPL with unknown risk factors have indicated that administering it as early as possible after pregnancy is effective [17]. This study suggests that in assited reproductive technology cases, administering IVIG before implantation may be beneficial. On the other hand, it has been reported that the immune status during the implantation window and after implantation in normal pregnancies operates through different mechanisms [37]. In the LE group with RPL in this study, no clear differences based on the administration date were observed, indicating that the administration of IVIG before embryo transfer in RPL remains a topic for discussion. Owing to the small sample size for each time point of administration in this study, further investigation is needed.

After pregnancy, NK cell activity decreased in both the IVIG and LE groups, and the decline occurred earlier in the LE group compared to the IVIG group. Even in patients who had abnormalities only in uNK cells, pNK cell activity was measured after pregnancy. As previously mentioned, several studies have reported a lack of correlation between uNK and pNK cells [32, 33]. However, since uNK cells cannot be assessed during pregnancy, we measured pNK cell activity as a surrogate marker. This parameter is considered a useful monitoring tool in patients with elevated pNK cell activity.

Although the exact mechanism by which LE inhibit NK cell function remains unclear, it has been shown that the effects of fatty acids are mediated through receptors including peroxisome proliferator‐activated receptors (PPARs) [38], G protein‐coupled receptors (GPCRs) [39], and cluster of differentiation (CD1) receptors [40]. LE contains long‐chain polyunsaturated fatty acids, including linoleic and oleic acids, which can rapidly influence immune cell function via intracellular signaling. These fatty acids bind to nuclear receptors in NK cells, such as PPARs and GPCRs, thereby modulating gene expression and suppressing immune activity. In contrast, intravenous immunoglobulin (IVIG) regulates immune responses through more indirect mechanisms, including Fc receptor blockade, cytokine modulation, and effects on dendritic and T cell functions [18, 19]. In our study, both IVIG and LE significantly reduced NK cell activity during early pregnancy, with comparable degrees of suppression. Notably, the LE group exhibited a more rapid decline, which may reflect the faster onset of receptor‐mediated signaling pathways. Furthermore, pregnancy outcomes—including implantation and live birth rates—did not differ significantly between the groups. These findings suggest that despite their distinct mechanisms of action, IVIG and LE may converge in their downstream immunological effects. While we do not assert mechanistic equivalence, the similar clinical and immunological outcomes support the consideration of LE as a potential alternative to IVIG in selected patients with NK cell–associated reproductive failure.

LE is made from egg yolk or soybeans and is primarily used for patients who have difficulty with postoperative nutrition; it is inexpensive and easy to use. However, there are some drawbacks, such as an increased risk of thrombosis if lipid droplets form in the bloodstream owing to rapid infusion, and they cannot be used in individuals with soy or egg yolk allergies. Additionally, hepatomegaly, jaundice, cholestasis, splenomegaly, thrombocytopenia, leukopenia, and fat overload syndrome have been reported [41]. In this study, no significant adverse effects were observed.

Limitation of this study is the lack of a placebo or untreated control group, which prevents us from definitively concluding whether IVIG or LE improves pregnancy outcomes beyond natural expectations. The study was designed to compare the clinical outcomes of two immunomodulatory therapies in a high‐risk population with established NK cell abnormalities, and for ethical reasons, we did not include a no‐treatment group. However, as mentioned above, when compared to historical pregnancy outcomes in women of similar age and reproductive history, our results suggest a potential benefit of both interventions. Future randomized controlled trials with a placebo or untreated control arm are warranted to clarify the true therapeutic value of these treatments.

In conclusion, this study suggests that the administration of LE for reproductive failure associated with NK cell abnormalities has effects comparable to those of IVIG. Because LE is less expensive and more readily available than IVIG, it is considered a treatment option that should be explored before IVIG.

Ethics Statement

This study was approved by the institutional review board of the Hyogo Medical University (IRB number 2740). All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later amendments.

Consent

Informed consent was obtained from all patients for being included in the study.

Conflicts of Interest

Atsushi Fukui is an Editorial Board member of Reproductive Medicine and Biology and a co‐author of this article. Atsushi Fukui was excluded from all editorial decision‐making related to the acceptance of this article for publication. The other authors declare no conflicts of interest.

Animal Rights

This article does not contain any studies with animal subjects performed by any of the authors.

Yamaya A., Fukui A., Kawai K., et al., “A Comparative Study of Intravenous Immunoglobulin and Lipid Emulsion in Patients With Reproductive Failures Associated With NK Cell Abnormalities,” Reproductive Medicine and Biology 24, no. 1 (2025): e12662, 10.1002/rmb2.12662.