Uric acid as a predictor of adverse treatment outcomes in women undergoing in vitro fertilization

doi:10.21203/rs.3.rs-2884543/v1

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Uric acid as a predictor of adverse treatment outcomes in women undergoing in vitro fertilization

https://doi.org/10.21203/rs.3.rs-2884543/v1

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Introduction Current knowledge on the association of uric acid (UA) as a scavenger of free radicals with the reproductive outcomes of in vitro fertilization is largely limited, since most of the available data are focused on pregnancy complications, and high UA concentration was proposed as a risk indicator for adverse maternal and even infant risks. In the reproductive system, several studies have revealed that UA is involved in female reproductive diseases and that UA accumulation may cause reproductive disorders. However, the effect of UA on the progression of the evolution and quality of oocytes or embryos remains unexplored and unknown. This study aimed to explore the relationship between serum uric acid and reproductive outcomes in women undergoing in vitro fertilization procedures.

Methods 1027 women without any intervention on serum UA levels who underwent the COH procedure and treatment with PGT-M and PGT-A were included, leaving a total of 1,177 samples available for analysis. Finally, 1,177 subjects were further divided into 3 groups according to the serum UA levels: the ≤250 μmol/L group (N=347), the 251-360 μmol/L group (N=669), and the >360 μmol/L group (N=161).

Results The number of retrieved oocytes, mature oocyte rate and good-quality blastocyst rate were individually negatively related to hyperuricemia.

Conclusions The presence of high serum uric acid could lead to a change in the follicular microenvironment, insufficient ovarian blood supply and overexposure of ovarian follicles and embryos to hypoxia and inflammation responses, which strengthened the utility of uric acid as a promising biomarker in clinical practice, particularly in in vitro fertilization procedures, that could contribute to early detection, decision-making about intervention, and improvement of reproductive treatment outcomes.

Uric acid

in vitro fertilization

preimplantation genetic testing

number of retrieved oocytes

mature oocyte rate

good quality blastocyst rate

Uric acid (UA), which is produced through the enzymatic action of xanthine oxidase, is the end catabolic product of purine metabolism, has both pro-oxidant and antioxidant properties and plays a central role as a scavenger of free radicals[1, 2]. UA was found to assume oxidant activity depending on the organic microenvironment[3, 4]. In addition, studies have confirmed that UA triggers peripheral inflammation in different independent ways[5]. Clinical studies as well as animal trials have shown that elevated UA is associated with cardiovascular events and risk factors[6]; hence, UA can be used as an early predictor for the disease. In the reproductive system, several studies have revealed that UA is involved in female reproductive diseases and that UA accumulation may cause reproductive disorders. UA is used as a biomarker for placental ischemia[7] and plays a central role in the placental and peripheral stages. Elevated UA could inhibit nitric oxide production, become a proinflammatory factor and result in reproductive problems, including placental hypoxia and impaired endothelial repair, trophoblast syncytial microparticle release in mothers’ bloodstream and dysregulation of trophoblast invasion, and subsequent inefficiency of physiological transformation of spiral arteries[8–10]. The effect of uric acid on nitric oxide production not only compromises placental vasculature but also affects maternal vasculature [11, 12].

Various studies have explored the associations between uric acid in women with adverse perinatal outcomes and proposed that a high serum UA concentration could be used as a risk indicator for these pregnancy complications and adverse maternal and even infant risks[5, 12–14] due to the easy process of measuring and implementing it in patients’ health care and to its low cost among biochemical marker screenings. To the best of our knowledge, no study has yet investigated the relationships between serum UA and reproductive outcomes of in vitro fertilization, since most of the available data were focused on pregnancy complications, and less is known about the effect of UA on the progression of the evolution and quality of oocytes or embryos. Taken together, UA acts as an oxidant/antioxidant based on its biochemical microenvironment and triggers peripheral inflammation in reproductive disorders as well as many other systemic diseases, and the evidence suggests that disequilibrium of hormonal levels influences oocyte development and quality by inducing intracellular stress in the oocyte, which transforms the ovarian environment[15].

We raise the question of whether there is a close relationship between UA and reproductive outcomes of patients undergoing controlled ovarian hyperstimulation (COH) during in vitro fertilization cycles, aiming to explore the proof-of-concept for the potential use of serum UA as a simple, low-cost and effective predictor of reproductive outcomes and to contribute to clinical treatment in the field of reproductive medicine.

Subjects

A total of 1220 patients who visited the Center for Reproductive Medicine, the First Affiliated Hospital, Sun Yat-sen University, from January 2013 to December 2020 for preimplantation genetic testing for monogenic disorders were recruited. Baseline demographic information and medical history were collected at their first visit, and their peripheral blood samples were collected for preoperative routine examinations before COH as well as for serum UA analysis. The records of these patients were carefully reviewed after an 8-year follow-up.

Inclusion criteria included the following: patients undergoing preimplantation genetic testing for monogenic/single gene defects (PGT-M); patients with aneuploid screening results; and patients ranging in age from 22 to 38.

Exclusion criteria included the following: patients taking medications that might interfere with glomerular filtration due to medical illnesses, including diabetes, hypothyroidism, malignancy, hypercortisolism, arthritis, or inflammatory diseases.

A total of 1,066 patients with 1,219 cycles who did not receive any intervention for serum UA levels underwent the COH procedure and preimplantation genetic testing for monogenic/single gene defects (PGT-M). We further excluded 39 women with 42 cycles who had no available serum UA data, and 1,027 women with 1177 cycles were included, leaving a total of 1,177 samples available for analysis. Finally, 1,177 subjects without any intervention for serum UA levels were included. Different parameters were compared among the groups and multivariable linear regression analysis for serum UA status was applied.

Sample collection and serum uric acid analysis

Uric acid (µmol/L) was measured in serum collected at enrollment. Peripheral blood samples were collected in BD Vacutainer tubes, and all the samples were assayed using the same uricase-based colorimetric protocol from Pointe Scientific (Canton, MI) Kit U7581-120 with the lowest detection limit of 88.4 µmol/L in a single laboratory. Quantitation and patterns were concordant in all cases. Readings were made independently by at least two experienced evaluators (blinded to the sample characteristics and time period). The variance coefficient was 9.0%. The presence of more than 360 µmol/L serum UA was considered hyperuricemia according to our laboratory standard.

Controlled ovarian stimulation and PGT-M

Routine controlled ovarian stimulation protocols were implemented, including an agonist long protocol, an antagonist protocol and mild ovarian stimulation cycles. Both recombined and highly purified urinary gonadotropins were utilized. Final oocyte maturation was typically induced with 6,000 to 10,000 IU of human chorionic gonadotropin when at least three follicles had reached a maximal diameter of 18 mm. Transvaginal oocyte retrieval was performed 36 hours after human chorionic gonadotropin administration. The intracytoplasmic sperm injection, embryo culture, and blastocyst culture procedures were routine procedures.

Morphological grading of embryo viability

The assessment method of embryo viability was morphological grading, which could stipulate an evaluation of embryo potential development. The detailed vitrification and thawing procedure was as reported in a previous study[16]. Cleavage-stage embryos were graded according to the Istanbul consensus[17]. Blastocyst quality assessment was based on the scoring system of Gardner and Schoolcraft[18].

Aneuploid screening procedure

Usable blastocysts were biopsied on Days 5 and 6. Monogenetic disease was diagnosed with specific probes. Aneuploid screening was performed through next-generation sequencing (NGS) or a single-nucleotide polymorphism (SNP) microarray platform. All usable euploid blastocysts were cryopreserved for future use.

Statistical methods

Statistical analysis was performed using SPSS version 26 (IBM). The euploid rate was defined as the number of blastocysts biopsied divided by the number of euploids. Continuous data are presented as the mean ± standard deviation, and one-way analysis of variance (ANOVA) was performed for intergroup comparisons. Categorical data are presented as percentages, and the chi-square test was used for intergroup comparisons. Associations between hyperuricemia and reproductive outcomes were assessed using multivariable linear regression with the backward method. The odds ratio was adjusted for baseline parameters, treatment parameters and embryonic parameters. The results were considered to be statistically significant when the P value was less than 0.05 (*P < 0.05, **P < 0.01, **P < 0.001, ***P < 0.0001).

The records of 1,066 patients without any intervention on serum UA levels who underwent the COH procedure and treatment with PGT-M and PGT-A were carefully reviewed after an 8-year follow-up. We further excluded 39 women with 42 cycles who had no available serum UA data, and 1027 women with 1,177 cycles were included, leaving a total of 1,177 samples available for analysis. Finally, 1,177 subjects without any intervention on serum UA levels were included and further divided into 3 groups according to the serum UA levels: the ≤ 250 µmol/L group (N = 347), the 251–360 µmol/L group (N = 669), and the > 360 µmol/L group (N = 161) (Fig. 1).

Patient profiles

The patient characteristics between the two groups are listed in Table 1. Age, BMI, AMH, and basal sex hormone levels between the two groups were within the normal range and compared. BMI between the groups was significantly different, and BMI increased with increasing levels of serum uric acid. The levels of basal FSH were higher in the ≤ 250 µmol/L group than in the > 360 µmol/L group (P < 0.009), and the levels of basal E₂ were higher in the ≤ 250 µmol/L group than in the 251–360 µmol/L group (P < 0.023), while the other parameters were not significantly different among the 3 groups.

Table 1

Baseline characteristics of the study population
Parameter	≤ 250 µmol/L	251–360 µmol/L	> 360 µmol/L	P₁	P₂	P₃
Age (years)	31.65 ± 4.64	31.59 ± 4.41	31.42 ± 4.41	0.845	0.582	0.652
BMI (kg/m2)	20.45 ± 2.35	22.52 ± 2.48	22.77 ± 3.33	0.000	0.000	0.000
AMH (ng/mL)	3.72 ± 2.71	4.27 ± 3.76	4.11 ± 2.87	0.079	0.380	0.712
FSH (IU/L)	5.87 ± 2.08	5.62 ± 1.48	5.40 ± 1.34	0.072	0.009	0.342
LH (IU/L)	3.60 ± 1.98	3.55 ± 2.21	3.32 ± 2.06	0.730	0.165	0.212
E₂ (pg/mL)	35.95 ± 20.39	33.04 ± 18.13	34.37 ± 21.28	0.023	0.390	0.434
PRL (uIU/mL)	16.69 ± 12.40	16.77 ± 13.95	16.05 ± 16.26	0.930	0.626	0.552
T (pmol/L)	0.45 ± 2.50	0.39 ± 1.92	0.30 ± 0.13	0.647	0.443	0.625
BMI: body mass index; AMH: anti-Mullerian hormone; FSH: follicle-stimulating hormone; LH: luteinizing hormone; E2: estradiol; PRL: prolactin; T: testosterone. P₁: P value between ≤ 250 µmol/L group and 251–360 µmol/L group; P₂: P value between ≤ 250 µmol/L group and > 360 µmol/L group; P₃: P value between 251–360 µmol/L group and > 360 µmol/L group; The data are expressed as (Mean ± SD).

Comparisons of treatment parameters between the study population

Routine controlled ovarian stimulation protocols were used in our study, such as agonist, antagonist and mild ovarian stimulation protocols. The proportions of the agonist protocol were higher in the ≤ 250 µmol/L group than in the 251–360 µmol/L group (P = 0.032), while the rest of the protocol proportions compared among the 3 groups were equivalent. The starting stimulation dosage in the study group was not significantly different among the three groups. With a similar stimulation duration, the total gonadotropin usage among the study groups was equivalent; the LH levels on the day of hCG administration in the > 360 µmol/L group were significantly higher than those of the ≤ 250 µmol/L group (P = 0.003) and the 251–360 µmol/L group (P = 0.026). The E2 level on the day of hCG administration and the number of oocytes retrieved were comparable between the three groups. Although two different aneuploid screening platforms were used, the proportions among the three groups were comparable. The details are provided in Table 2.

Comparisons of embryonic parameters between the study population

The mature oocyte rate, fertilization rate, MPN rate, cleavage rate, embryo rate, blastocyst rate, euploid rate, viable blastocyst rate, good quality blastocyst rate, cumulative clinical pregnancy rate, and cumulative live birth rate were similar among the 3 groups. All of the details are provided in Table 3.

Table 2

Treatment Parameters of the Study Population
Parameter	≤ 250 µmol/L	251–360 µmol/L	> 360 µmol/L	P₁	P₂	P₃
Protocol				0.032	0.522	0.112
Agonist	70.61% (245)	67.12% (449)	61.49% (99)
Antagonist	28.24% (98)	31.69% (212)	38.51% (62)
Mild stimulation	1.15% (4)	1.20% (8)	0.00% (0)
Starting GN dosage (IU)	220.57 ± 63.45	222.61 ± 59.47	227.48 ± 60.69	0.612	0.233	0.362
Total GN dosage (IU)	2385.55 ± 869.95	2361.64 ± 875.99	2470.57 ± 912.87	0.681	0.311	0.158
COS duration (day)	10.43 ± 1.83	10.34 ± 1.90	10.45 ± 1.97	0.457	0.907	0.492
FSH on HCG day (IU/L)	14.52 ± 5.44	13.82 ± 5.31	13.36 ± 5.55	0.070	0.037	0.364
LH on HCG day (IU/L)	1.13 ± 1.17	1.25 ± 1.29	1.57 ± 1.90	0.452	0.003	0.026
E₂ on HCG day (pg/mL)	3023.26 ± 1363.79	3001.11 ± 1388.02	2911.48 ± 1405.73	0.809	0.399	0.463
P on HCG day (ng/mL)	0.91 ± 1.15	0.85 ± 0.42	0.84 ± 0.42	0.233	0.308	0.235
No. of oocytes	19.00 ± 9.13	19.45 ± 9.20	18.98 ± 8.26	0.600	0.864	0.796
PGT platform				0.330	0.078	0.231
NGS	67.44% (234)	70.40% (471)	75.16% (121)
SNP	32.56% (113)	29.60% (198)	24.84% (40)
IU: international unit; GN: gonadotropins; COS: controlled ovarian stimulation; FSH: follicle-stimulating hormone; HCG: human chorionic gonadotropin; LU: luteinizing hormone; E₂: estradiol; p: progesterone; No: number; PGT-A: preimplantation genetic testing for aneuploidies; NGS: next-generation sequencing; SNP: single-nucleotide polymorphism; P₁: P value between ≤ 250 µmol/L group and 251–360 µmol/L group; P₂: P value between ≤ 250 µmol/L group and > 360 µmol/L group; P₃: P value between 251–360 µmol/L group and > 360 µmol/L group. Protocol and PGT platform data are presented as percentages (number of subjects), and the rest of data are expressed as mean ± SD.

Table 3

Embryonic parameters of the study population
Parameter	≤ 250 µmol/L	250–360 µmol/L	> 360 µmol/L	P₁	P₂	P₃
Mature oocyte rate	0.834 ± 0.138	0.824 ± 0.138	0.825 ± 0.134	0.253	0.483	0.922
Fertilization rate	0.676 ± 0.165	0.662 ± 0.154	0.653 ± 0.165	0.169	0.123	0.524
MPN rate	0.015 ± 0.048	0.014 ± 0.036	0.010 ± 0.023	0.804	0.189	0.215
Cleavage rate	0.986 ± 0.039	0.988 ± 0.039	0.983 ± 0.066	0.489	0.454	0.182
Embryo rate	0.429 ± 0.181	0.415 ± 0.167	0.400 ± 0.175	0.214	0.071	0.304
Blastocyst rate	0.698 ± 0.194	0.688 ± 0.188	0.685 ± 0.214	0.445	0.487	0.849
Euploid rate	0.537 ± 0.285	0.544 ± 0.272	0.556 ± 0.287	0.722	0.480	0.618
Viable blastocyst rate	0.608 ± 0.221	0.603 ± 0.210	0.579 ± 0.242	0.742	0.164	0.207
Good quality blastocyst rate	0.467 ± 0.224	0.459 ± 0.213	0.442 ± 0.229	0.586	0.231	0.372
Cumulative clinical pregnancy rate	0.732 ± 0.398	0.707 ± 0.401	0.673 ± 0.414	0.396	0.174	0.398
Cumulative live birth rate	0.711 ± 0.477	0.664 ± 0.451	0.605 ± 0.440	0.153	0.028	0.187
MPN: multiple pronuclear; P₁: P value between ≤ 250 µmol/L group and 251–360 µmol/L group; P₂: P value between ≤ 250 µmol/L group and > 360 µmol/L group; P₃: P value between 251–360 µmol/L group and > 360 µmol/L group.

Multivariable linear regression analysis for serum UA status

We used multivariable linear regression to analyze the association between hyperuricemia and reproductive treatment outcomes and further adjusted for basal FSH level, initial stimulating gonadotropin dosage, total gonadotropin dosage and FSH level on the HCG day. Among all the factors, the number of retrieved oocytes, mature oocyte rate, good-quality blastocyst rate were individually negatively related to hyperuricemia. The details are shown in Table 4.

Table 4

Association between hyperuricemia and reproductive treatment outcomes
Characteristic	Elevated serum UA levels
	OR^a	95% CI^a	p value^a
Age of female patients (years)	0.981	0.890–1.080	0.692
BMI (kg/m2)	1.578	1.352–1.843	0.000
Basal FSH concentration (IU/L)	0.080	0.572–1.032	0.080
Basal LH concentration (IU/L)	1.004	0.802–1.257	0.971
Basal E₂ concentration (pg/mL)	1.006	0.986–1.026	0.546
PRL concentration (uIU/mL)	1.012	0.993–1.032	0.219
T concentration (pmol/L)	4.170	0.254–68.387	0.317
Protocol
Agonist	1.180	0.576–2.417	0.651
Antagonist	0.000	0.000–0.000	0.998
Starting dosage (IU)	0.988	0.980–0.995	0.002
Total GN (IU)	1.000	0.998–1.002	0.894
COS duration (day)	1.086	0.847–1.393	0.515
FSH on HCG day (IU/L)	0.935	0.830–1.054	0.271
LH on HCG day (IU/L)	1.128	0.833–1.527	0.435
E₂ on HCG day (pg/mL)	1.000	0.999-1.000	0.241
P on HCG day (ng/mL)	2.010	0.913–4.428	0.083
No. of oocytes	0.948	0.906–0.992	0.022
Mature oocyte rate	0.024	0.002–0.305	0.004
Fertilization rate	0.382	0.015–9.839	0.562
MPN rate	0.076	0.000-429690.085	0.746
Cleavage rate	7.474	0.001-62039.135	0.662
Embryo rate	1.386	0.016-120.799	0.886
Blastocyst rate	1.787	0.061–51.941	0.736
Euploid rate	0.608	0.136–2.730	0.517
Viable blastocyst rate	0.444	0.021–9.348	0.602
Good quality blastocyst rate	0.105	0.017–0.653	0.016
Cumulative clinical pregnancy rate	2.170	0.458–10.288	0.329
Cumulative live birth rate	0.496	0.235–1.046	0.065
^{BMI: body mass index, calculated as weight (kg) divided by the square of height (m2); CI: confidence interval; FSH: follicle stimulating hormone; LH: luteinizing hormone; E}₂: ^{estradiol; PRL: prolactin; T: testosterone; IU: international unit; GN: gonadotropins; COS: controlled ovarian stimulation; FSH: follicle−stimulating hormone; HCG: human chorionic gonadotropin; LH: luteinizing hormone; P: progesterone; No: Number; OR: odds ratio; a: adjusted for BMI, basal FSH;l concentration}.

To our knowledge, this is the first study to date on the relationships between serum UA and reproductive outcomes of in vitro fertilization.

Obesity was confirmed to have an influence on serum uric acid levels, and increased serum uric acid was closely associated with metabolic disorders, including obesity[19, 20]. In obesity, uric acid can be transformed into a pro-oxidant and plays a direct role in the proliferation of fat cells and the oxidative stress response[21]. In regard to reproduction, it was reported that the majority of women with obesity and PCOS had hyperuricemia, which was nearly threefold higher than that in women with PCOS and a normal BMI[22], and it was demonstrated that ovarian follicles from overweight women have increased oxidative stress and reduced antioxidant capacity compared to women with normal weight due to changes in the microenvironment caused by elevated uric acid[15, 23, 24]. In this study, we demonstrated that BMI had a positive correlation with elevated serum uric acid, which was consistent with the findings that BMI was positively correlated with uric acid and that healthy women with high uric acid levels had a higher incidence of obesity than those with normal uric acid levels[24, 25]. There were 12 patients with obesity included in our study, with 2 patients in the ≤ 250 µmol/L group, 3 in the 251–360 µmol/L group and 7 in the > 360 µmol/L group, and the average BMI in the 3 groups was within the normal range. Therefore, we assumed that BMI was independently related to elevated uric acid levels and that the incidence of the oxidative stress response caused by serum uric acid accumulation increased with increasing BMI.

Evidence of the relationship between sex hormones and UA levels seems to be conflicting. Uric acid levels were reported to be lowest during the luteal phase and confirmed to have a positive association with FSH[26], while most studies demonstrated no positive association[22, 27–29]. In addition, E₂ was reported to be negatively associated with uric acid levels[22, 26, 30]. Our study analyzed the effects of serum uric acid levels on basal sex hormones, including FSH, LH, estradiol, prolactin and testosterone, among women undergoing in vitro fertilization. An inverse association between FSH and serum uric acid levels and a negative association between estradiol and serum uric acid levels were observed, while no association between the other basal sex hormones was found. In addition, a positive association between LH levels on the HCG day and serum uric acid levels was found. However, when we adjusted for age and BMI, the aforementioned positive and negative relationships between sex hormone levels and serum uric acid levels disappeared, which indicated that each association was not independent, underscoring the complexity of pregnancy biology. We speculated that high uric acid levels influence sex hormone levels in the following possible ways: i) Changes in sex hormones were associated with changes in plasma sex hormone-binding globulin (SHBG) levels, and SHBG levels could bind free androgens to reduce the levels of sex hormones and control their bioavailability[2, 31], which could indirectly affect the uric acid levels via induced inactivation of AMPK in the liver[32, 33], and steroid hormones might affect serum uric acid levels through mechanisms involving the secretion of uric acid[30]; ii) uric acid may inhibit oocyte maturation as a purine derivative due to oxidative stress[15, 24–26, 34–37], which revealed the association between uric acid and the elevated levels of FSH as well as sporadic anovulation. However, the observed associations between uric acid and sex hormones were not always statistically significant. The reasons for the inconsistency were that uric acid levels reacted to the change in sex hormones within a certain range, which was observed in our study regarding the difference in basal FSH levels and E₂ levels between the groups with lower uric acid levels and that as each sex hormone was not an independent factor in the hypothalamic–pituitary–gonadal (HPO) axis, changes in an individual sex hormone could initiate feedback mechanisms to compensate for impaired follicular development, resulting in the upregulation or regulation of other sex hormones. Therefore, it seemed more significant to investigate the correlations of reproductive treatment outcomes with serum uric acid concentration.

Our study confirmed that the number of retrieved oocytes, mature oocyte rate and good-quality blastocyst rate were individually negatively related to hyperuricemia. The prevalence of hyperuricemia in the study population was not high, which was reflected by the 95% CI and standard errors, which are broader with respect to positive outcomes compared to normal uric acid levels. Both the cumulative clinical pregnancy rate and cumulative live birth rate decreased with increasing serum uric acid levels; however, there were no statistically significant differences. In addition to oxidative stress/antioxidant capacity, we assumed that the actions of uric acid as metabolites of purines in the patients’ bloodstream contribute to endothelial dysfunction and oxidative stress via synthetic enzyme XOR-related reactive oxygen species (ROS) production[2, 38] and via proliferation and apoptosis of vascular smooth muscle cells in an inflammatory state[39], triggering the systemic sterile inflammatory response via IL-1β converted by monosodium urate (MSU)-produced pro-IL-1 in a high serum level state[40] and upregulating interleukin-1, interleukin-6 and tumor necrosis factor-alpha[14], confirming the role of VEGF[38] and leading to changes in the follicular microenvironment and insufficient ovarian blood supply. On the other hand, the overexposure of ovarian follicles and embryos to hypoxia and inflammation responses could result from the aforementioned process, which strengthened the utility of uric acid as a promising biomarker in clinical practice when used in in vitro fertilization procedures. Our study and the growing current evidence on the role of uric acid in the pathophysiology of reproductive disorders encourage future research to elucidate the underlying mechanism behind these findings.

The strengths of our study include the large in vitro fertilization cohort, strict monitoring of renal function, integral reproductive treatment outcomes, consideration of nonlinear relations with respect to serum uric acid levels, separate assessments of embryos with atypical in vitro growth, and prudent modeling with the applications of crossvalidation and bootstrap sample techniques, but we were limited by having only one serum UA measurement and no data on uric acid in follicular fluid, which might have a more direct influence on treatment outcomes. We recommend additional validation studies using both serum and follicular fluid samples for metabolomics analyses and exploring the combination with other clinical or biochemical factors, such as lipid peroxidation and glutathione redox or the ratio in the follicular fluid, to elevate the influence of oxidative stress on in vitro processes.

The findings of our study remain novel. There exists a need for a simple, predictive test regarding treatment outcomes in in vitro fertilization, and detection of uric acid stands out as being a low-cost and easily accessible measurement. The results in our study have suggested that high serum uric acid levels were associated with unfavorable treatment outcomes, including a smaller number of retrieved oocytes, lower mature oocyte rate and worse quality blastocyst rate, which would help clinicians identify women undergoing in vitro fertilization at risk of adverse treatment outcomes and focus on prevention before starting COH, contributing to early detection; decision-making about intervention; improvement of prognosis, including not limited to increasing the number of retrieved oocytes in terms of PGT; and obtaining more viable blastocysts in the in vitro fertilization procedure, and might help revolutionize the way unexplained infertility will be treated in the future, which has been a complex challenge in the field of reproductive medicine[41]. Moreover, serum uric acid has potential in combination with more clinical and biochemical markers to improve the prognosis of in vitro fertilization treatment outcomes, enriching the sample of adverse outcomes in future research studies.

On the basis of our results, we propose that the measurement of uric acid should be applied as a routine protocol in patients undergoing in vitro fertilization. A serum uric acid level greater than 360 µmol/L in the patient should alert clinicians to the higher incidence of unfavorable treatment outcomes and recommend the consideration of treatments to reduce serum uric acid levels. Long-term cohort studies are needed to assess the efficacy.

In conclusion, this study is one of the first to identify UA-associated differences in the reproductive outcomes of in vitro fertilization. An unprecedented finding is that the presence of high serum uric acid, which has been demonstrated to have antioxidant properties and to be a trigger of proinflammatory cytokines, was correlated with unfavorable treatment outcomes, including a smaller number of retrieved oocytes, lower mature oocyte rate and worse quality blastocyst rate, suggesting a reflection of changes in the follicular microenvironment by serum uric acid accumulation.

Acknowledgments

We thank the staff from the Reproductive Medicine Center, The First Affiliated Hospital, Sun Yat-sen University, for their assistance and advice with regard to this project. We thank American Journal Experts Editing Services for English language editing. We thank the staff from the Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University. This work was supported by the Guangdong Basic and Applied Basic Research Foundation (2114050h000636).

Author Contribution

Niwei Yan, Yuan Yuan designed the research. Niwei Yan and Junli Song collected the samples. Yuan Yuan contributed clinical data. Niwei Yan, Junli Song, Huiying Jie, Pingyin Lee, Simin Liu, Yuan Yuan analyzed and interpreted data. Yuan Yuan revised the article. Niwei Yan, Junli Song, Huiying Jie, Pingyin Lee, Simin Liu, Yuan Yuan wrote the manuscript.

Funding

This study was supported by the Guangdong Provincial Key Laboratory of Reproductive Medicine (2012A061400003).

Data Availability

All original data that contributed to this study are available from the corresponding author on reasonable request.

Ethics approval

Research Protocol was approved by Independent Ethics Committee for Clinical Research and Animal Trials of the First Affiliated Hospital of Sun Yat-sen University under approval number IIT-2022-172.

Competing interests

None Declared.

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No competing interests reported.

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Uric acid as a predictor of adverse treatment outcomes in women undergoing in vitro fertilization

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Abstract

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Introduction

Methods

Sample collection and serum uric acid analysis

Results

Patient profiles

Comparisons of embryonic parameters between the study population

Multivariable linear regression analysis for serum UA status

Discussion

Declarations

Acknowledgments

Author Contribution

Funding

Data Availability

References

Additional Declarations

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