Abstract
Purpose
This retrospective cohort study aims to investigate whether high-normal fasting blood glucose (FBG) affects assisted reproductive technology (ART) outcomes undergoing single blastocyst frozen-thawed embryo transfer (FET) cycles in women with normal body mass index (BMI).
Methods
944 women with normal BMI and FBG levels undergoing single blastocyst FET cycles were enrolled. Based on the median of FBG (4.97 mmol/L, 1 mmol/L = 18 mg/dL), the subjects were categorized into the low-normal group (3.90 ≤ FBG ≤ 4.97 mmol/L, n = 472) and the high-normal group (4.97 < FBG < 6.10 mmol/L, n = 472). Multivariable logistic regression and receiver operating characteristic (ROC) were used to analyze the relationship between high-normal FBG and ART outcomes. Primary outcome: live birth rate (LBR).
Results
LBR was significantly lower in the high-normal group than in the low-normal group (36.8% vs. 45.1%, p = 0.010), and the miscarriage rate was considerably higher than that in the low-normal group (23.9% vs. 16.5%, p = 0.041). High-normal FBG of female was an independent predictor of live birth (adjusted OR:0.747, 95% CI: 0.541–0.963, p = 0.027) and miscarriage (adjusted OR:1.610, 95% CI: 1.018–2.547, p = 0.042). ROC analyses showed that the cut-off values of FBG (endpoints: live birth and miscarriage) were 5.07 mmol/L, and 5.01 mmol/L, respectively.
Conclusions
In women with normal BMI, high-normal FBG is an independent risk factor for lower LBR and higher miscarriage rate in single blastocyst FET cycles. Attention to preconception FBG monitoring in this particular population may allow early intervention to improve ART outcomes.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10815-024-03191-w.
Keywords: Fasting blood glucose, Frozen-thawed embryo transfer, Pregnancy outcome, Live birth, Miscarriage
Introduction
Reproductive health has received worldwide attention, and assisted reproductive technology (ART) has rapidly become the most important means of infertility treatment. The outcome of ART is influenced by various factors, among which the female factor plays an important role. In recent years, the incidence of metabolic diseases has increased with sedentary lifestyles and changes in dietary patterns, and the number of metabolic disease-associated infertility cases has also been on the rise [1, 2]. Nevertheless, the influence of female metabolic factors on reproductive function and the efficacy of ART treatment remains poorly understood [3].
The World Health Organization (WHO) defines obesity or overweight in Asians as a body mass index (BMI) greater than 25 kg/m2 [4]. BMI is a common assessment of obesity, and the adverse effects of obesity on female reproduction are well-established [5]. Nevertheless, abnormalities of lipid metabolism and insulin resistance (IR) are present even in individuals with abdominal obesity whose BMI is within the normal range, this population is at a twofold increased risk of metabolic disease compared to the general population [6]. However, the metabolic status of fertile women with a normal BMI is often overlooked in clinical practice. There is a lack of research on whether a normal BMI but a high risk of metabolic indicators affects the outcome of ART in this particular population.
Fasting blood glucose (FBG) is a cost-effective and accessible indicator of metabolism. Numerous studies have demonstrated the adverse effects of maternal hyperglycemia on embryo quality, pregnancy outcome, and the long-term health of the offspring [7, 8]. A study of over 6.4 million Chinese women evaluated the correlation between preconception FBG and spontaneous pregnancy outcomes, for every 1 mmol/L increase in FBG, the risk of spontaneous abortion, preterm delivery, macrosomia, small for gestational age, and perinatal infant death increased by 8%, 3%, 5%, 3%, and 9%, respectively, compared with the reference group (FBG < 5.0 mmol/L) [9].
It is of great value to pay attention to preconception FBG in women preparing for pregnancy, as this can help to prevent the occurrence of adverse pregnancy outcomes. With the increasing number of women undergoing ART, the impact of glucose metabolism on ART outcomes warrants further investigation. However, the effect of high-normal female FBG on ART outcomes, particularly in women with normal BMI, remains unknown. No studies have been conducted to determine the optimal FBG levels associated with ART outcomes in this population.
This study aims to investigate the effect of high-normal FBG on ART outcomes in single blastocyst frozen-thawed embryo transfer (FET) cycles in women with normal BMI. This will facilitate a more comprehensive understanding of the influence of female glycemic metabolism on ART outcomes, thereby enabling the development of more effective clinical treatment strategies and the improvement of ART outcomes.
Materials and methods
Study design and setting
We enrolled 944 female participants from January 2013 to November 2022 at the Medical Center for Human Reproduction, Beijing Chao-Yang Hospital, Beijing, China. The retrospective cohort study was approved by the Human Research Ethics Committee of Beijing Chao-Yang Hospital.
According to the definition of the Chinese Medical Association Diabetes Branch, 3.90 ≤ FBG < 6.10 mmol/L (70.20 ≤ FBG < 109.80 mg/dL) is considered normal, 6.10 ≤ FBG < 7.00 mmol/L (109.80 ≤ FBG < 126.00 mg/dL) is considered impaired fasting glucose (IFG), FBG ≥ 7.00 mmol/L (FBG ≥ 126.00 mg/dL) is considered diabetes mellitus (DM) [10, 11]. Thus, according to the median of female FBG (4.97 mmol/L, 89.46 mg/dL), the cycles with normal FBG levels were divided into the low-normal group (3.9 ≤ FBG ≤ 4.97 mmol/L, 70.20 ≤ FBG ≤ 89.46 mg/dL, n = 472) and the high-normal group (4.97 < FBG < 6.1 mmol/L, 89.46 < FBG < 109.80 mg/dL, n = 472).
Participants
Inclusion criteria were: (1) Female aged between 22 to 38 years both at the stage of oocyte pick-up (OPU) and FET; (2) Female in the first single blastocyst FET cycle; (3) 18.5 kg/m2 ≤ female BMI < 25 kg/m2; (4) Female with normal FBG. Exclusion criteria were: (1) Women having diseases associated with poor ART outcomes, including metabolic diseases such as preconception diabetes, preconception hypertension, abnormal uterine anatomy, and antiphospholipid syndrome; (2) Donor cycles; (3) Any significant information missing.
Couples should complete the necessary assessment before controlled ovarian hyperstimulation (COH), usually within 1–2 months before COH, including basic information and laboratory parameters (FBG, lipids, and reproductive hormones). FBG is one of the essential preconception indicators measured by the Laboratory Department. The indications and techniques for COH protocols, OPU, fertilization method, oocyte and embryo culture, and FET protocols were performed based on the criterion in the center. The procedure of ART was previously described thoroughly in our previous studies [12–14].
Follow-up and outcome measures
The primary outcome was the live birth rate (LBR). The secondary outcomes were embryo laboratory parameters, including fertilization rate, cleavage rate, blastocyst formation rate, quality blastocyst rate, available blastocyst rate and available embryo rate, and pregnancy outcomes, including biochemical pregnancy rate (BPR), clinical pregnancy rate (CPR), miscarriage rate, gestation weeks of delivery and neonatal birth weight [13, 15].
Embryos were graded according to the Gardner and Schoolcraft scoring systems, stages ≥ 4, and ratings of AA, AB, BA, and BB were defined as quality blastocysts [16]. Embryo outcomes were recorded as follows, fertilization rate of in vitro fertilization (IVF) was equal to the number of fertilized embryos divided by the number of obtained oocytes, fertilization rate of intracytoplasmic sperm injection (ICSI) was equal to the number of fertilized embryos divided by the number of injected oocytes, cleavage rate was equal to the number of cleaved embryos divided by the number of fertilized embryos, blastocyst formation rate was equal to the number of blastocysts divided by the number of cultured embryos for blastocyst formation, quality blastocyst rate was equal to the number of quality blastocysts divided by the number of all formed blastocysts, available blastocyst rate was equal to the number of available blastocysts divided by the number of all formed blastocysts, available embryo rate was equal to the number of transferred and frozen embryos divided by the number of cleavage embryos [17].
Maternal and neonatal outcomes were recorded as follows, biochemical pregnancy was defined as human chorionic gonadotropin (HCG) positivity (HCG ≥ 25 IU/mL), while no gestational sac. BPR was defined as the number of biochemical pregnancies divided by the number of FET cycles. Clinical pregnancy was defined as the occurrence of the gestational sac (s) by ultrasound at 7–8 gestation weeks. CPR was defined as the number of clinical pregnancies divided by the number of FET cycles. Miscarriage was defined as clinical pregnancy loss before 28 gestation weeks. The miscarriage rate was defined as the number of miscarriages divided by the number of clinical pregnancies. Live birth was defined as a live birth born after 28 gestation weeks. LBR was defined as the number of live births divided by the number of FET cycles. Preterm, full-term, and post-term delivery were defined as gestation weeks < 37, 37–42, and ≥ 42, respectively. Birth defects were defined as abnormalities in the body structure, function, or metabolism that exist at birth. Low, normal, and high birth weight were defined as birth weight < 2.5 kg, 2.5–4.0 kg, and > 4.0 kg, respectively [18–21]. Obstetric and perinatal outcomes include delivery mode and pregnancy complications, including gestational diabetes, gestational hypertension, premature rupture of membranes, and placenta previa. All the above information was obtained from the medical record.
Statistical analysis
Data were analyzed via SPSS (V27.0). Normally distributed continuous variables were reported as mean ± standard deviation (SD) and analyzed by Student t-test. Non-normally distributed continuous and categorical variables were reported as median (interquartile range) (IQR) or frequency (%), with Mann–Whitney U test or chi-square (χ2) test or Fisher’s exact test to analysis. Multivariable logistic regression and receiver operating characteristic (ROC) were used to analyze the association between FBG and ART outcomes. Values of p < 0.05 for two-sided tests were considered statistically significant.
Results
Baseline characteristic of participants
From January 2013 to November 2022, 1814 single blastocyst FET cycles were incorporated in the center, and 944 cycles were finally selected. Based on the median level of female FBG (4.97 mmol/L, 89.46 mg/dL), the subjects were categorized into the low-normal group (n = 472) and the high-normal group (n = 472). The association of FBG with laboratory embryo outcomes and ART outcomes was analyzed in women with normal BMI undergoing single blastocyst FET cycles (Fig. 1).
Fig. 1.
Flow chart of the subject recruitment. FET frozen-thawed embryo transfer, BMI body mass index, FBG fasting blood glucose, IFG impaired fasting glucose (6.1 mmol/L ≤ FBG < 7 mmol/L), ART assisted reproductive technology
The baseline characteristics of participants were shown in Table 1 (Table 1). Compared with the low-normal group, women in the high-normal group had higher BMI (21.60 ± 1.74 vs. 21.30 ± 1.80, kg/m2), FBG (5.31 ± 0.27 vs. 4.66 ± 0.23, mmol/L), FET age (32.46 ± 3.28 vs. 31.92 ± 3.27, years), while high-density lipoprotein cholesterol (HDL) was lower (1.47 ± 0.38 vs. 1.52 ± 0.35, mmol/L) (all p < 0.05).
Table 1.
Baseline characteristics of participants
| Characteristic | The low-normal group n = 472 |
The high-normal group n = 472 |
p |
|---|---|---|---|
| Female OPU age (y) | 31.59 ± 3.21 | 31.97 ± 3.30 | 0.075 |
| Female BMI (kg/m2) | 21.30 ± 1.80 | 21.60 ± 1.74 | 0.010* |
| Male age (y) | 33.30 ± 4.45 | 33.74 ± 4.79 | 0.149 |
| Male BMI (kg/m2) | 25.46 ± 3.70 | 25.50 ± 3.58 | 0.890 |
| Duration of infertility (y) | 2.50 (1.50–4.00) | 2.50 (2.00–4.00) | 0.198 |
| Category of infertility | 0.337 | ||
| Primary (%) | 64.2 (303/472) | 67.2 (317/472) | |
| Secondary (%) | 35.8 (169/472) | 32.8 (155/472) | |
| Causes of infertility | 0.288 | ||
| Female (%) | 70.1 (331/472) | 67.4 (318/472) | |
| Male (%) | 10.2 (48/472) | 14.2 (67/472) | |
| Female and male (%) | 1.5 (7/472) | 1.7 (8/472) | |
| Unknown (%) | 18.2 (86/472) | 16.7 (79/472) | |
| Years of OPU cycle | 0.109 | ||
| From 2013 to 2014 | 4.4 (21/472) | 6.1 (29/472) | |
| From 2015 to 2016 | 12.1 (57/472) | 14.6 (69/472) | |
| From 2017 to 2018 | 11.9 (56/472) | 15.9 (75/472) | |
| From 2019 to 2020 | 40.9 (193/472) | 36.1 (170/472) | |
| From 2021 to 2022 | 30.7 (145/472) | 27.3 (129/472) | |
| AFC (No.) | 15.0 (11.0–21.0) | 14.5 (11.0–20.0) | 0.276 |
| Basal E2 (pg/mL) | 48.40 ± 19.85 | 46.73 ± 18.86 | 0.188 |
| Basal LH (IU/L) | 4.76 ± 2.66 | 4.49 ± 2.80 | 0.130 |
| Basal FSH (IU/L) | 6.39 ± 2.35 | 6.17 ± 2.33 | 0.159 |
| Basal P (ng/mL) | 0.53 ± 0.40 | 0.53 ± 0.35 | 0.896 |
| Female FBG (mmol/L) | 4.66 ± 0.23 | 5.31 ± 0.27 | < 0.001* |
| Female TC (mmol/L) | 4.56 ± 0.89 | 4.58 ± 0.74 | 0.674 |
| Female TG (mmol/L) | 0.92 (0.70–1.27) | 0.98 (0.74–1.33) | 0.089 |
| Female HDL (mmol/L) | 1.52 ± 0.35 | 1.47 ± 0.38 | 0.027* |
| Female LDL (mmol/L) | 2.60 ± 0.82 | 2.61 ± 0.71 | 0.779 |
| Female FET age (y) | 31.92 ± 3.27 | 32.46 ± 3.28 | 0.010* |
| FET protocols | 0.260 | ||
| NC (%) | 26.5 (125/472) | 30.7 (145/472) | |
| AC (%) | 34.5 (163/472) | 29.2 (138/472) | |
| SC (%) | 11.7 (55/472) | 10.8 (51/472) | |
| DR + AC (%) | 27.3 (129/472) | 29.3 (138/472) | |
| Em thickness (mm) | 9.59 ± 1.92 | 9.71 ± 2.07 | 0.340 |
| Blastocyst Grading | 0.302 | ||
| Quality ratio (%) | 67.8 (320/472) | 64.6 (305/472) | |
| Non-quality ratio (%) | 32.2 (152/472) | 35.4 (167/472) |
Data are shown as mean ± SD, median (IQR), or n (%). *p indicated statistical significance compared with the low-normal group. OPU Oocyte pick-up; BMI Body mass index; AFC Antral follicle count; E2 Estradiol; LH Luteinizing hormone; FSH Follicle stimulating hormone; P Progesterone; FBG Fasting blood glucose; TC Total cholesterol; TG Triglycerides; HDL High-density lipoprotein cholesterol; LDL Low-density lipoprotein cholesterol; FET Frozen-thawed embryo transfer; NC Natural cycle; AC Artificial cycle; SC Stimulation cycle; DR Down-regulation; Em Endometrium. Stages ≥ 4, and ratings of AA, AB, BA, and BB were defined as quality blastocysts
There were no significant differences in the remaining parameters, including female OPU age, male age and BMI, duration of infertility, category of infertility, causes of infertility, years of OPU cycle, antral follicle count (AFC), reproductive hormone, female lipids except HDL, FET protocols, endometrial thickness and quality ratio of blastocyst in FET (all p > 0.05).
Laboratory embryo outcomes according to female FBG
Laboratory embryo outcomes were shown in Table 2 (Table 2). There were no significant differences in the all data between the two groups, including fertilization methods, fertilization rate, cleavage rate, 2PN fertilization rate, 2PN cleavage rate, blastocyst formation rate, quality blastocyst rate, available blastocyst rate, and available embryo rate (all p > 0.05).
Table 2.
The laboratory embryo outcomes according to female FBG
| Outcomes | The low-normal group n = 472 |
The high-normal group n = 472 |
p |
|---|---|---|---|
| Fertilization methods | 0.279 | ||
| IVF (%) | 67.6 (319/472) | 65.0 (307/472) | |
| ICSI (%) | 10.4 (49/472) | 13.8 (65/472) | |
| IVF + ICSI (%) | 22.0 (104/472) | 21.2 (100/472) | |
| Fertilization rate (%) | 83.9 ± 13.6 | 83.4 ± 14.9 | 0.569 |
| Cleavage rate (%) | 98.0 ± 4.3 | 98.4 ± 4.3 | 0.268 |
| 2PN fertilization rate (%) | 66.4 ± 17.7 | 66.0 ± 19.0 | 0.745 |
| 2PN cleavage rate (%) | 98.0 ± 8.1 | 97.8 ± 10.1 | 0.746 |
| Blastocyst formation rate (%) | 66.7 (50.0–90.7) | 66.7 (50.0–87.2) | 0.380 |
| Quality blastocyst rate (%) | 39.2 (0–66.2) | 33.3 (0–66.7) | 0.321 |
| Available blastocyst rate (%) | 66.7 (50.0–100) | 60.0 (40.0–100) | 0.290 |
| Available embryo rate (%) | 50.0 (37.5–63.4) | 50.0 (37.5–66.7) | 0.364 |
Data are shown as mean ± SD, median (IQR), or n (%). IVF In vitro fertilization; ICSI Intracytoplasmic sperm injection; PN Pronucleus
FET clinical outcomes according to female FBG
FET clinical outcomes according to female FBG were shown in Table 3 (Table 3) and supplementary Fig. 1 (Supplementary Fig. 1). In the low-normal group, there were 47 cases of biochemical pregnancy and 255 cases of clinical pregnancy, including 42 cases of miscarriage and 213 cases of live birth. In the high-normal group, there were 42 cases of biochemical pregnancy and 230 cases of clinical pregnancy, including 55 cases of miscarriage, 173 cases of live birth, 1 case of ectopic pregnancy, and 1 case of stillbirth. Ectopic pregnancy and stillbirth were excluded from the statistics due to the low volume.
Table 3.
FET clinical outcomes according to female FBG
| Outcomes | The low-normal group | The high-normal group | p |
|---|---|---|---|
| Biochemical pregnancy rate (%) | 10.0 (47/472) | 8.9 (42/472) | 0.578 |
| Clinical pregnancy rate (%) | 54.0 (255/472) | 48.7 (230/472) | 0.104 |
| Miscarriage rate (%) | 16.5 (42/255) | 23.9 (55/230) | 0.041* |
| Live birth rate (%) | 45.1 (213/472) | 36.8 (173/472) | 0.010* |
| Gestation weeks of delivery | 0.918# | ||
| Preterm delivery (%) | 7.5 (16/213) | 6.9 (12/173) | |
| Full-term delivery (%) | 92.0 (196/213) | 93.1 (161/173) | |
| Post-term delivery (%) | 0.5 (1/213) | 0 (0/173) | |
| Delivery mode | 0.161 | ||
| Cesarean delivery (%) | 62.0 (132/213) | 68.8 (119/173) | |
| Spontaneous delivery (%) | 38.0 (81/213) | 31.2 (54/173) | |
| Birth defects (%) | 0 (0/213) | 0.6 (1/173) | 0.448# |
| Fetal sex | 0.218 | ||
| Male (%) | 60.6 (129/213) | 54.3 (94/173) | |
| Female (%) | 39.4 (84/213) | 45.7 (79/173) | |
| Birth weight | 0.470 | ||
| Low birth weight (%) | 5.1 (11/213) | 3.5 (6/173) | |
| Normal birth weight (%) | 88.3 (188/213) | 87.3 (151/173) | |
| High birth weight (%) | 6.6 (14/213) | 9.2 (16/173) | |
| Pregnancy complication | 0.237# | ||
| Gestational Diabetes (%) | 1.4 (3/213) | 2.3 (4/173) | |
| Gestational Hypertension (%) | 0.5 (1/213) | 2.9 (5/173) | |
| Others (%) | 2.3 (5/213) | 1.7 (3/173) |
Data are shown as n (%). *p indicated statistical significance compared with the low-normal group. #Fisher’s exact test was used
LBR was 45.1% (213/472) in the low-normal group while 36.8% (173/472) in the high-normal group, with a statistical difference (p = 0.010). The miscarriage rate was 16.5% (42/255) in the low-normal group and 23.9% (55/230) in the high-normal group, with a statistical difference (p = 0.041). In addition, there were no significant differences in the remaining parameters, including BPR, CPR, gestation weeks of delivery, delivery mode, birth defects, fetal sex, birth weight, and pregnancy complications (all p > 0.05).
Multivariable binary logistic regression analysis for ART outcomes according to female FBG
Multivariable binary logistic regression was conducted to analyze the relationship between female FBG and ART outcomes in women with normal BMI (Table 4). In the unadjusted model, female FBG was negatively associated with live birth (unadjusted OR:0.694, 95% CI:0.534–0.900, p = 0.006), while positively related with miscarriage (unadjusted OR:1.629, 95% CI:1.040–2.533, p = 0.033). In the adjusted model, after adjusting for female BMI, female HDL, OPU age, FET age, FET protocols, Em thickness, and blastocyst grading in FET cycles, high-normal FBG of female was still an independent predictor of live birth (adjusted OR:0.747, 95% CI:0.541–0.963, p = 0.027) and miscarriage (adjusted OR:1.610, 95% CI:1.018–2.547, p = 0.042).
Table 4.
Multivariable binary logistic regression analysis for ART outcomes according to female FBG
| Model | B | OR | 95%CI | p |
|---|---|---|---|---|
| Live birth | ||||
| Unadjusted Model | -0.366 | 0.694 | 0.534–0.900 | 0.006* |
| Adjusted Model | -0.291 | 0.747 | 0.541–0.963 | 0.027* |
| Miscarriage | ||||
| Unadjusted Model | 0.466 | 1.629 | 1.040–2.533 | 0.033* |
| Adjusted Model | 0.476 | 1.610 | 1.018–2.547 | 0.042* |
Female FBG was included as a categorical variable in the analysis. Adjusted Model: adjusted for female BMI, female HDL, OPU age, FET age, FET protocols, Em thickness, and blastocyst grading in FET cycles. OR Odds ratio; CI Confidence interval, *p indicated statistical significance
In addition, when FBG was included as a continuous variable in the analysis (Supplementary Table 1), in the adjusted model, female FBG was still an independent predictor of live birth (adjusted OR:0.680, 95% CI:0.487–0.949, p = 0.023) and miscarriage (adjusted OR:1.731, 95% CI:1.004–2.983, p = 0.048).
ROC analyses to predict ART outcomes based on female FBG
ROC analyses to predict ART outcomes based on female FBG were shown in Fig. 2 (Fig. 2) and Supplementary Table 2 (Supplementary Table 2). The area under the curve (AUC) values of live birth and miscarriage were 0.561 (95% CI: 0.524–0.598, p = 0.001) and 0.568 (95% CI: 0.505–0.631, p = 0.038), and the threshold values for FBG (endpoints: live birth and miscarriage) were 5.07 mmol/L (91.26 mg/dL), 5.01 mmol/L (90.18 mg/dL), respectively (p < 0.05).
Fig. 2.
Receiver-operating characteristic (ROC) curve for predicting live birth and miscarriage based on female FBG. A Live birth, B Miscarriage. AUC area under the curve
Discussion
The present study aimed to investigate the association between female FBG and ART outcomes. After adjusting for confounding variables, high-normal FBG remained an independent risk factor for lower LBR and higher miscarriage rate in women with normal BMI undergoing single blastocyst FET cycles.
The alterations in human dietary patterns and lifestyle have led to an increase in the prevalence of metabolic disorders, with a concomitant rise in the incidence of female reproductive dysfunction associated with metabolic abnormalities. At present, even when some metabolic indicators are within the normal range, such as high-normal blood pressure (BP) and uric acid (UA), they have a non-negligible impact on the outcome of ART. One study found that high-normal systolic BP was negatively associated with CPR and LBR, and positively associated with miscarriage rate, high-normal diastolic BP was negatively associated with LBR and positively associated with miscarriage rate [22]. Another study evaluated the effect of UA quartiles on ART outcomes, which indicated that the group with high quartile UA levels exhibited decreased CPR and LBR, in addition to an increased risk of low birth weight in the fetus [23]. Our study demonstrated that high-normal FBG affects LBR and miscarriage rate in women with normal BMI. Therefore, we hypothesize that elevated levels of metabolic markers may indicate an underlying metabolic imbalance that has a critical impact on pregnancy outcomes in ART, even if the levels have not yet reached the diagnostic criteria for the disease.
It is often overlooked that metabolic levels in women with normal BMI (18.5kg/m2 ≤ BMI < 25.0 kg/m2) are frequently assessed before ART treatment. This study set strict inclusion and exclusion criteria to minimize the influence of confounding factors on ART outcomes. Women between the ages of 22 to 38 years undergoing their first blastocyst FET cycle were included, which partially excluded the confounding effect of embryo quality. Furthermore, we also excluded women with diseases that could lead to poor ART outcomes. As evidenced by existing studies, certain metabolic markers have been shown to have a detrimental impact on female fertility and pregnancy outcomes [20, 24–26]. To gain further insight into the impact of FBG on ART outcomes, we also compared other metabolic indicators such as lipids between the two groups. The present study indicated that high-normal FBG in men could be regarded as an independent risk factor for lower LBR and higher miscarriage rate.
FBG is a cost-effective indicator for the prevention and diagnosis of diabetes. Abnormalities in glucose metabolism affect female fertility, with reduced LBR in the diabetic group compared to the non-diabetic group, which revealed that abnormal glucose metabolism in infertile women may adversely affect ART outcomes [27, 28]. A cross-sectional study on the Chinese population recommended that routine FBG screening be incorporated into the preconception examination for all women [29]. However, the effect of high-normal FBG has been underestimated in infertile women. Our findings may suggest that high-normal FBG may already adversely affect ART outcomes before the onset of abnormal glucose metabolism.
Regrettably, no guideline or large-scale study has yet revealed optimal FBG thresholds related to live birth and miscarriage in infertile women. Therefore, ROC curves were plotted to establish the FBG thresholds for ART pregnancies (endpoints: live birth and miscarriage), which were 5.07 mmol/L (91.26 mg/dL) and 5.01 mmol/L (90.18 mg/dL), respectively (p < 0.05). It is suggested the threshold for the effect of high-normal FBG on ART outcome is different from that for diabetes. In conclusion, it may be proposed that FBG levels might be more sensitive and lower in infertile women, and it would be beneficial to improve ART outcomes by monitoring high-normal FBG levels in this population. However, the AUC values of live birth and miscarriage were 0.561 (95% CI: 0.524–0.598, p = 0.001) and 0.568 (95% CI: 0.505–0.631, p = 0.038), respectively, which may be low but it was statistically significant (p < 0.05). The relatively small sample size and limited predictive value of FBG alone for ART outcomes may have contributed to the lower AUC values observed. In the future, we will continue to expand the sample size or establish a joint prediction model with a multi-indicator, which will facilitate the exploration of more precise thresholds and personalized biomarkers for women undergoing ART.
There is limited research about the impact of high-normal FBG on pregnancy outcomes, with only a few studies addressing the relationship between abnormal glucose metabolism and female reproduction. In summary, the mechanisms linking abnormal female FBG to reproduction are complex, which may involved in abnormal oocyte development [3], abnormal blastocyst development by the premature programmed cell death of key progenitor cells [30], alterations in endometrial function by attenuating endometrial angiogenesis and inhibiting stromal cell apoptosis [31–33], trophectoderm differentiation and decidual development [34, 35]. Nevertheless, the applicability of the aforementioned mechanisms to individuals with high-normal FBG remains uncertain, necessitating further investigation to ascertain this. Additionally, our research has demonstrated that there was no difference in CPR between the two groups, it is a higher miscarriage rate that may have contributed to the difference in LBR in the high-normal group. Consequently, the underlying mechanisms of the influence of high-normal FBG on ART outcomes require further clinical and basic evidence.
There were no significant differences in embryonic developmental outcomes in our study, the IVF technique itself may have played a role, meanwhile, morphological assessment of embryos is not representative of implantation and developmental potential, the mechanism of the effect of FBG on fertilization and embryonic quality remains to be further investigated. Moreover, no differences were observed in perinatal complications and neonatal outcomes, firstly, our endpoint variable was pregnancy outcome after the first FET cycle, the association between cumulative pregnancy and FBG is still unknown, secondly, we chose populations with normal BMI and FBG levels, so the differences in this population might be very small, and lastly, we could not exclude the factor of self-recovery and correction of the pregnancy.
Although this was a retrospective study, rigorous criteria were implemented to control for confounding factors. We found that high-normal female FBG was an independent risk factor for miscarriage and live birth in normal BMI women with single blastocyst FET cycles. Consequently, according to FBG before ART, it is recommended that women be counseled to improve glucose control and commence insulin-sensitizing agents, which may include comprehensive interventions such as exercise, diet, or drugs, but further studies are required to determine if lowering BMI/FBG will improve ART outcomes. Nonetheless, the effects and specific mechanisms of high-normal FBG on embryo quality and pregnancy outcomes remain unclear, and clinical and fundamental experimental research is needed to investigate its influence on reproductive health.
However, limitations also exist in this study. Firstly, the data collection spans nearly a decade, and there have been many changes in IVF laboratory and clinical techniques in this period, which may be a confounding bias related to the temporal global LBR shifts across the study timeframe. Nevertheless, multivariable models were used to adjust for confounding factors, some unknown factors cannot be ruled out, and further studies are needed. Secondly, it is regrettable that not all patients have AMH levels due to limitations in testing conditions at an earlier stage. Thirdly, due to the retrospective nature, we cannot answer whether lowering FBG before ART in women with high-normal FBG than the cut-off value defined will confer a benefit. Finally, the participants were only included in single blastocyst FET cycles, it is unclear whether the results could be applied to fresh embryo and cleavage-stage embryo transfers.
Conclusion
In women with normal BMI, high-normal FBG is an independent risk factor for lower LBR and higher miscarriage rate in single blastocyst FET cycles. Attention to preconception FBG monitoring in this particular population may allow early intervention to improve ART outcomes.
Supplementary Information
Below is the link to the electronic supplementary material.
Author contributions
L.W. collected data and wrote the manuscript. X.T. researched and edited the manuscript. H.L. and L.Y. verified data and participate in discussions. W.Z. contributed to discussion, reviewed and edited the manuscript.
Funding
This study was supported by Beijing Hospitals Authority Clinical Medicine Development of special funding support (YGLX202311), Clinical incubation project of Beijing Chaoyang Hospital (CYFH202307).
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Code availability
Not applicable.
Declarations
Ethics approval
In accordance with the Declaration of Helsinki, the study protocol was reviewed by the institutional ethics review board of Human Research Ethics Committee of Beijing Chao-Yang Hospital (2022-SCI-632).
Consent to participate
Not applicable.
Consent for publication
All authors have read and approved the manuscript.
Conflicts of interest
The authors declare no competing or financial interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Lina Wang and Xiangming Tian contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Not applicable.