体重指数对中国多囊卵巢综合征患者体外受精胚胎移植结局的影响:一项回顾性队列研究

Effects of body mass index on the outcomes of in vitro fertilization in Chinese patients with polycystic ovary syndrome: a retrospective cohort study 体重指数对中国多囊卵巢综合征患者体外受精胚胎移植结局的影响:一项回顾性队列研究 1 first-author 2 2 3 1 1 corresp ‡Corresponding Authors ‡Corresponding Authors †E-mail:zhuyim@zju.edu.cnsyqufan@zju.edu.cn †E-mail:zhuyim@zju.edu.cnsyqufan@zju.edu.cn zhuyim@zju.edu.cn 1 corresp ‡Corresponding Authors ‡Corresponding Authors †E-mail:zhuyim@zju.edu.cnsyqufan@zju.edu.cn †E-mail:zhuyim@zju.edu.cnsyqufan@zju.edu.cn zhuyim@zju.edu.cn Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China Department of Reproductive Medicine, Maternal & Child Health Care Hospital of Liuzhou, Liuzhou 545001, China Department of Reproductive Medicine, Maternal & Child Health Care Hospital of Liuzhou, Liuzhou 545001, China Zhejiang Chinese Medical University, Hangzhou 310053, China Zhejiang Chinese Medical University, Hangzhou 310053, China Objective: 2 To investigate the effects of body mass index (BMI) on the outcomes of in vitro fertilization (IVF) in Chinese patients with polycystic ovary syndrome (PCOS). Methods: 2 In the retrospective cohort study, a total of 1074 patients with PCOS undergoing IVF between April 2010 and May 2017 in two reproductive medicine centers, respectively in eastern China (Women’s Hospital, School of Medicine, Zhejiang University, Zhejiang Province) and in southern China (Maternal and Child Health Care Hospital of Liuzhou, Guangxi Province), were included. The patients were divided into four groups according to the recommended Chinese BMI cut-off points: underweight (BMI < 18.5 kg/m 2 ), normal weight (18.5 kg/m 2 ≤BMI < 24.0 kg/m 2 ), overweight (24.0 kg/m 2 ≤BMI < 28.0 kg/m 2 ), and obese (BMI≥28.0 kg/m 2 ). The basic characteristics of the PCOS patients, the details of IVF treatment, and the pregnancy outcomes were collected. Mainresults: 2 There were no significant differences among the normal weight, overweight, and obese PCOS patients undergoing IVF on the biochemical pregnancy rate, clinical pregnancy rate, miscarriage rate, live birth rate, or term delivery rate ( P > 0.05), although the overweight and obese PCOS patients required more gonadotropin (Gn) ( P < 0.001) as well as longer stimulation period ( P < 0.001), and got less retrieved oocytes ( P < 0.05) and fertilized oocytes ( P < 0.05). The underweight PCOS patients required less Gn ( P < 0.05) and achieved higher live birth rate and term delivery rate ( P < 0.05), compared with the normal weight PCOS patients. Conclusions: 2 High BMI had no negative effects on the outcomes of IVF in Chinese patients with PCOS; however, the conclusion may seem a little limited due to the retrospective design and the potential bias. 目的 2 探讨体重指数对中国多囊卵巢综合征(PCOS)患者体外受精胚胎移植结局的影响. 创新点 2 本研究是一项多中心大样本研究,纳入了华东、华南两家生殖中心的患者;本研究根据中国体重指数(BMI)分界点进行分组,而非国际BMI分界点,得出的结论更加适合中国或者亚洲人群. 方法 2 此项回顾性研究纳入2010年4月到2017年5月分别在华东、华南两家生殖中心进行体外受精胚胎移植的患者共1074例.根据推荐的中国BMI分界点,患者被分成四组:低体重组(BMI < 18.5 kg/m 2 ),正常体重组(18.5 kg/m 2 ≤BMI < 24.0 kg/m 2 ),超重组(24.0 kg/m 2 ≤BMI < 28.0 kg/m 2 )和肥胖组(BMI≥28.0 kg/m 2 ).比较各组间的基本信息、体外受精情况和妊娠结局. 结论 2 高BMI对中国PCOS患者的体外受精胚胎移植 结局没有不利影响.因为本研究是回顾性研究及一些潜在的偏差,所以此结论可能存在一定的局限性. Body mass index In vitro fertilization Polycystic ovary syndrome 体重指数 体外受精胚胎移植 多囊卵巢综合征 Introduction 1 Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women, affecting approximately 5%–10% women of reproductive age (Beydoun et al., 2009 2009 ). It is characterized by oligomenorrhea and ovulatory dysfunction, clinical or biochemical hyperandrogenism, and polycystic ovary morphology (Teede et al., 2011 2011 ; Szydlarska et al., 2017 2017 ). This disorder is often associated with insulin resistance, hypertension, infertility, obesity, and weight-related disorders (Bentley-Lewis et al., 2011 2011 ; Stepto et al., 2013 2013 ; Joham et al., 2015 2015 ; Balen et al., 2016 2016 ; Bergh et al., 2016 2016 ). The treatment of PCOS was diversified, which included lifestyle intervention, menstrual cycles regulation, anti-androgen therapy, reproductive promotion, and Chinese traditional treatment. As part of Chinese traditional treatment, acupuncture (WU et al., 2016 2016 ; Robinson, 2017 2017 ) and transcutaneous electrical acupoint stimulation (Qu et al., 2017a 2017a , 2017b 2017b ) played an important role in treating PCOS, which is increasingly recognized by clinicians. Approximately 50% of women with PCOS are overweight or obese, and most of them have the abdominal phenotype (Chen et al., 2010 2010 ). Overweight and obesity are definitely risk factors for adverse pregnancy outcomes (Mantakas and Farrell, 2010 2010 ; Deshmukh et al., 2016 2016 ), which may be induced by the altered metabolic conditions (Meenakshi et al., 2012 2012 ), and the lifestyle intervention can improve the pregnancy outcomes (Oteng-Ntim et al., 2012 2012 ; Martin et al., 2015 2015 ). Although some previous studies associated body mass index (BMI) with in vitro fertilization (IVF) outcomes in PCOS women (Jungheim et al., 2009 2009 ; Ozgun et al., 2011 2011 ; Bailey et al., 2014 2014 ; Huang et al., 2014 2014 ), they had some limitations for these data to be clinically employable to our daily practice. First, these previous studies mainly targeted Caucasian populations. Clinical characteristics of PCOS and also infertility frequently show racial differences (Wang et al., 2018 2018 ). Second, previous researches defined overweight and obese at different BMI cut-off points according to the study populations, which were 25 and 30 kg/m 2 , respectively. This does not accord with the present Chinese criteria, which are 24 and 28 kg/m 2 , respectively. Thus, these previous data were not available to Chinese or Asian populations. In the retrospective cohort study, a total of 1074 patients with PCOS undergoing IVF in two Reproductive Medicine Centers, respectively in eastern China and southern China, were included to investigate the effects of BMI on the outcomes of IVF in Chinese patients with PCOS. Materials and methods 1 The retrospective cohort study was performed in two Reproductive Medicine Centers, respectively in eastern China (Women’s Hospital, School of Medicine, Zhejiang University, Zhejiang Province) and in southern China (Maternal and Child Health Care Hospital of Liuzhou, Guangxi Province). Data were collected from the clinical records between April 2010 and May 2017. A total of 1074 patients with PCOS were chosen using the Rotterdam criteria (Chang et al., 2004 2004 ). To minimize the bias, the age of all the included patients was ≤42 years, and only the first fresh treatment cycle of IVF was included. The patients were excluded if they underwent oocyte or sperm donation, in vitro maturation (IVM), preimplantation genetic diagnosis (PGD), intracytoplasmic sperm injection (ICSI), testicular sperm aspiration, frozen embryo transfer (FET), blastocyst transfer, or have severe endometriosis (III and IV stages) which was diagnosed by laparoscopic surgery. The BMI was defined as weight in kilograms divided by the square of height in meters. Based on the recommended Chinese BMI cut-off points (Barba et al., 2004 2004 ), patients were divided into four groups: underweight (BMI < 18.5 kg/m 2 ), normal weight (18.5 kg/m 2 ≤BMI < 24.0 kg/m 2 ), overweight (24.0 kg/m 2 ≤ BMI < 28.0 kg/m 2 ), and obese (BMI≥28.0 kg/m 2 ). All the included patients underwent controlled ovarian hyperstimulation (COH) using the standard long agonist protocol. Recombinant follicle-stimulating hormone (FSH; Gonal-F, Serono, Switzerland) was administrated with or without highly purified human menopausal gonadotropin (HMG; Lizhu, China). Ovulation was induced with 10 000 IU human chorionic gonadotropin (HCG) or 250 μg recombinant HCG (Ovitrelle, Merck KCaA, Germany) when at least two follicles had reached 18 mm in diameter. Oocytes were retrieved 34–36 h after HCG administration by guidance of vaginal ultrasound. Conventional fertilization was performed in all patients. Embryos were transferred on Day 3, except in cases with few embryos (≤2), which were transferred on Day 2. Although one or two embryos were transferred usually, in women over 35 years old, after counseling the risk of multiple gestation, three embryos were also allowed to transfer. Fertilization rate was calculated as the ratio of number of embryos obtained over the number of oocytes retrieved. Implantation rate was calculated as the ratio of the number of gestational sacs over the number of transferred embryos. Biochemical pregnancy was diagnosed by a rising concentration of serum β-HCG 14 d after embryo transfer (ET). Clinical pregnancy was confirmed by the presence of a gestational sac and fetal cardiac activity on vaginal ultrasound examination six weeks after ET. Ectopic pregnancy was confirmed by positive HCG without evident product of conception within the uterus. Miscarriage was defined as a pregnancy loss before 28 full weeks of gestation (Xie and Gou, 2013 2013 ). Live birth was defined as any deliveries in which at least one baby was born alive. Premature delivery was defined as delivery between 28 to 37 completed weeks of gestation. Term delivery was defined as delivery after 37 completed weeks of gestation. Statistical analysis was performed using SPSS Version 22.0 (SPSS, Chicago, IL, USA). The distribution of continuous data was tested by one-sample Kolmogorov-Smirnov test. The continuous variables were tested by one-way analysis of variance (ANOVA) tests. If ANOVA testing indicated a significant difference among four groups, post-hoc comparisons were performed using the least significant difference (LSD) test. Categorical variables were compared using Chi-square test and logistic regression analysis. Results were presented as mean±standard deviation (SD) or frequency (%). P values less than 0.05 were considered to be significant. Results 1 Descriptive characteristics of the included PCOS patients 2 As shown in Table 1 1 , the underweight group was younger than the normal weight group ( P < 0.05), while there were no significant differences in age among the normal weight, overweight, and obesity groups ( P > 0.05). The duration of infertility was longer in the overweight and obesity groups than in the normal weight group ( P < 0.05). There were no significant differences in primary infertility rate or the luteinizing hormone (LH)/FSH ratio on the 3rd day of menstruation among the four groups ( P > 0.05). PCOS: polycystic ovary syndrome; BMI: body mass index; FSH: follicle-stimulating hormone; LH: luteinizing hormone. Data are expressed as mean±standard deviation or number (percentage). P < 0.05, ** P < 0.001, compared with the normal weight group; P < 0.001, compared with the overweight group Variable Normal weight ( n =606) Underweight ( n =51) Overweight ( n =315) Obesity ( n =102) Age (year) 29.08±3.23 27.78±3.17 * * 29.45±3.53 29.77±3.56 BMI (kg/m 2 ) 21.44±1.50 17.72±0.66 ** ** 25.62±1.08 ** ** 30.01±2.19 ** ** ## ## Duration of infertility (year) 3.75±2.50 3.67±2.25 4.46±3.05 ** ** 4.56±2.90 * * Primary infertility 343 (56.6%) 36 (70.6%) 177 (56.2%) 52 (51.0%) Day 3 LH/FSH 1.46±0.97 1.51±1.25 1.40±0.86 1.26±0.74 Effects of BMI on the characteristics of IVF treatment of PCOS patients 2 As shown in Table 2 2 , compared with the normal weight women with PCOS, overweight women with PCOS required higher dose of gonadotropin (Gn) ( P < 0.001) and longer days of COH ( P < 0.001), retrieved less oocytes ( P < 0.05), got less fertilized oocytes ( P < 0.05), transferred more embryos ( P < 0.05), and froze less embryos ( P < 0.05). As BMI increased, it was the same situation in obese women when compared with the normal weight women. Underweight women required lower dose of Gn ( P < 0.05) than normal weight women, with other variables not significantly different ( P > 0.05). BMI: body mass index; IVF: in vitro fertilization; PCOS: polycystic ovary syndrome; Gn: gonadotropin; COH: controlled ovarian hyperstimulation. Data are expressed as mean±standard deviation. P < 0.05, ** P < 0.001, compared with the normal weight group; P < 0.05, ## P < 0.001, compared with the overweight group Variable Normal weight ( n =606) Underweight ( n =51) Overweight ( n =315) Obesity ( n =102) Total dose of Gn (IU) 1716.16±630.85 1427.70±513.08 * * 2118.73±801.48 ** ** 2574.61±1049.49 ** ** ## ## Duration of COH (d) 10.60±2.19 10.35±1.53 11.84±2.91 ** ** 12.94±3.48 ** ** ## ## Number of retrieved oocytes 17.14±8.37 16.75±6.54 15.59±7.64 * * 11.86±7.53 ** ** ## ## Number of fertilized oocytes 10.33±6.89 9.78±5.35 8.85±6.24 * * 6.58±4.84 ** ** # # Fertilization rate (%) 59.78±25.37 60.43±24.88 56.45±26.43 56.63±26.10 Number of transferred embryos 1.01±0.94 1.06±0.86 1.17±0.95 * * 1.42±0.87 ** ** # # Number of frozen embryos 5.52±5.58 4.82±4.34 4.54±4.90 * * 3.15±3.46 ** ** # # We also conducted comparisons between the obese PCOS women and overweight PCOS women, and found that obese women required higher dose of Gn ( P < 0.001) and longer days of COH ( P < 0.001), retrieved less oocytes ( P < 0.001), got less fertilized oocytes ( P < 0.05), transferred more embryos ( P < 0.05), and froze less embryos ( P < 0.05). Although the fertilization rate decreased with BMI increasing, the difference was not statistically significant. Effects of BMI on the pregnancy outcomes of PCOS patients undergoing IVF 2 As shown in Table 3 3 , the clinical pregnancy rate, miscarriage rate, ectopic pregnancy rate, and preterm delivery rate were comparable in the four groups ( P > 0.05). Although the biochemical pregnancy rate, implantation rate, live birth rate, and term delivery rate decreased with BMI increasing ( P < 0.05), no significant differences were found in overweight women or obese PCOS women when compared with the normal weight PCOS women. The live birth rate and term delivery rate in the underweight group were significantly higher than those in the normal weight group ( P < 0.05). BMI: body mass index; PCOS: polycystic ovary syndrome; IVF: in vitro fertilization. Data are expressed as mean±standard deviation or number (percentage). P < 0.05, compared with the normal weight group Variable Normal weight ( n =606) Underweight ( n =51) Overweight ( n =315) Obesity ( n =102) Number of patients who had embryos transferred 355 (58.6%) 34 (66.7%) 203 (64.6%) 78 (76.5%) Biochemical pregnant rate 180 (50.7%) 22 (64.7%) 87 (42.9%) 33 (42.3%) Clinical pregnant rate 162 (45.6%) 21 (61.8%) 80 (39.4%) 31 (39.7%) Implantation rate 35.92±43.83 50.00±44.38 28.98±40.23 29.70±41.58 Miscarriage rate 31 (8.7%) 0 (0%) 15 (7.4%) 6 (7.7%) Ectopic pregnancy rate 3 (0.8%) 1 (2.9%) 5 (2.5%) 0 (0%) Live birth rate 133 (37.5%) 20 (58.8%) * * 65 (32.0%) 25 (32.1%) Preterm delivery rate 28 (7.9%) 0 (0%) 11 (5.4%) 3 (3.8%) Term delivery rate 105 (29.6%) 20 (58.8%) * * 54 (26.6%) 22 (28.2%) Discussion 1 In the present study, we found that the underweight PCOS patients were much younger, required less Gn, achieved higher live birth rate and term delivery rate when compared with the normal weight patients, while the other pregnancy outcomes were not significantly different. However, other studies found that underweight had a deleterious effect on the pregnancy outcomes such as preterm delivery (Sebire et al., 2001 2001 ; Hoellen et al., 2014 2014 ). As the prevalence of underweight in patients with PCOS was very low (Anastasiou et al., 2017 2017 ), only 51 underweight PCOS patients were included in our study. It needed to be examined whether the inconsistency was caused by the lower sample size of the underweight group.Overweight and obese PCOS patients required more Gn and days of COH, retrieved less oocytes, got less fertilized oocytes, transferred more embryos, froze less embryos than the normal weight patients, which were even more obvious in the obese PCOS patients when compared with overweight PCOS patients. Although the fertilization rate, implantation rate, clinical pregnancy rate, miscarriage rate, live birth rate, preterm delivery rate, and term delivery rate were all lower than those of the normal weight patients, the differences were not statistically significant. Our conclusions were consistent with some studies which showed that BMI was negatively associated with ovarian response, but did not remain for implantation rate (McCormick et al., 2008 2008 ) and live birth rate in PCOS patients (Mulders et al., 2003 2003 ; Ozgun et al., 2011 2011 ; Huang et al., 2014 2014 ). However, our conclusion was contrary to other studies which reported BMI having an adverse effect on the clinical IVF outcomes (Jungheim et al., 2009 2009 ; Bailey et al., 2014 2014 ; Cui et al., 2016 2016 ; Kalem et al., 2016 2016 ). BMI was also found to have a negative relationship with anti-Müllerian hormone levels (Salmassi et al., 2015 2015 ; Bernardi et al., 2017 2017 ; Lefebvre et al., 2017 2017 ), which is one of the widely recognize markers of ovarian reserve (Fleming et al., 2013 2013 ). We found that the fertilization rate and implantation rate in overweight and obese PCOS patients were not significantly different from those of the normal weight patients. As obesity is a state of chronic inflammation and metabolic disorder, markers of inflammation and oxidative stress are increased in the serum and ovarian follicular fluids (Merhi et al., 2015 2015 ; Buyuk et al., 2017 2017 ), which may have a negative impact on the IVF outcomes (Cakiroglu et al., 2016 2016 ). The aberrant serum metabolic changes, such as the increased cholesterol, triglycerides, and apolipoprotein A, were often observed in obesity, which were usually reflected in the follicular fluids (Valckx et al., 2012 2012 ). The studies above suggested that obesity induced an adverse maternal endocrine and metabolic environment both local and general, which then negatively affected the interaction of granulose cell–oocyte, the maturation of oocyte, and the potential developmental competence of embryo, contributing to unsuccessful outcomes for patients with PCOS (Qiao and Feng, 2011 2011 ). In our study, all the oocytes were fertilized in vitro, and embryos were transferred after 2 to 3 d culture in vitro, which made the adverse effects of in vivo environment smaller, contributing to the comparable fertilization rate and implantation rate between different BMI groups. Consequently, the increased BMI did not play an adverse role on the general clinical pregnancy outcomes of PCOS patients undergoing IVF. Conclusions 1 BMI had no negative effects on the outcomes of IVF in the overweight and obese Chinese patients with PCOS; however, the conclusion may seem a little limited due to the retrospective design and the potential bias. To minimize the bias as much as possible, only the first IVF treatment cycles were included, so we were not able to find the relationship between the elevated BMI and cumulative pregnancy outcomes of IVF. More studies should be focused on the incidence of ovarian hyperstimulation syndrome, perinatal and neonatal outcomes of PCOS women undergoing IVF with different BMI levels. Contributors 2 Fan QU designed the research, Xiao-ming PAN and Fan QU performed data analysis and wrote the paper. Zhong LIN, Nan LI, Jia-qi WU, Dan-qing CHEN, and Yi-min ZHU collected and explained the data. References OE Anastasiou , A Canbay , D Fuhrer , 等 . Metabolic and androgen profile in underweight women with polycystic ovary syndrome . 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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 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. 10.1631/jzus.B1800113 Project supported by the Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholars (No. LR16H040001), the Key Project of Science and Technology Department of Zhejiang Province (No. 2018C03010), the Zhejiang Provincial & Ministry of Health Research Fund for Medical Sciences (Nos. WKJ-ZJ-1522 and WKJ-ZJ-1722), the National Key Technology R & D Program of China (No. 2014BAI05B04), the Guangxi Natural Science Foundation (Nos. 2015GXNSFBA139177, 2017GXNSFAA198199, and 2017 GXNSFAA198193), China 2018-02-25 2018-05-08 2022-01-05 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2018 2018 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 06 19