|Year : 2018 | Volume
| Issue : 2 | Page : 105-110
Logistic Regression Analysis of Risk Factors Associated with Spontaneous Abortion after In Vitro Fertilization/Intracytoplasmic Sperm Injection-Embryo Transfer in Polycystic Ovary Syndrome Patients
Xiao-Lan Li, Rui Huang, Cong Fang, Yan-Fang Wang, Xiao-Yan Liang
Reproductive Medicine Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510655, China
|Date of Submission||30-Apr-2018|
|Date of Web Publication||4-Oct-2018|
Reproductive Medicine Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, 17 Shougouling Road, Tianhe District, Guangzhou 510655
Source of Support: None, Conflict of Interest: None
Objective: To analyze spontaneous abortion rate and its associated risk factors in patients with polycystic ovary syndrome (PCOS) after in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET).
Methods: This was a retrospective cohort study on 2,231 PCOS patients undergoing IVF/ICSI treatment. For comparison, we enrolled another 2,231 patients with tubular factors in control group. Spontaneous abortion rate and chromosomal abnormality rate were compared between the two groups. Furthermore, clinical data were compared between the patients with spontaneous abortion and those with ongoing pregnancy using univariate and multivariate analysis for risk factors of spontaneous abortion in PCOS patients.
Results: Patients in the PCOS group had significantly higher spontaneous abortion rate (24.15%) than that in the control group (12.75%, P < 0.001). Chromosomal abnormality rate was significantly lower in the PCOS group (36.05%, 31/86) than in the control group (55.56%, 50/90, P = 0.009). In the PCOS group, patients with spontaneous abortion had significantly elder age, higher body mass index (BMI), and homeostasis model assessment for insulin resistance (HOMA-IR) than those with ongoing pregnancy. The logistic regression analysis confirmed that the age, BMI, and HOMA-IR were the risk factors of spontaneous abortion in the PCOS patients. There were no significant differences between groups in the type of cycles, the quality of embryos transferred, the number of embryos transferred, fasting blood glucose, fasting insulin, and so on.
Conclusions: Compared with non-PCOS patients, PCOS patients had higher spontaneous abortion rate, but the chromosomal abnormality was not a major factor for the high spontaneous abortion rate in the PCOS patients. Age, BMI, and HOMA-IR were risk factors for spontaneous abortion after IVF/ICSI-ET in PCOS patients.
Keywords: Polycystic Ovary Syndrome; Risk Factors; Spontaneous Abortion
|How to cite this article:|
Li XL, Huang R, Fang C, Wang YF, Liang XY. Logistic Regression Analysis of Risk Factors Associated with Spontaneous Abortion after In Vitro Fertilization/Intracytoplasmic Sperm Injection-Embryo Transfer in Polycystic Ovary Syndrome Patients. Reprod Dev Med 2018;2:105-10
|How to cite this URL:|
Li XL, Huang R, Fang C, Wang YF, Liang XY. Logistic Regression Analysis of Risk Factors Associated with Spontaneous Abortion after In Vitro Fertilization/Intracytoplasmic Sperm Injection-Embryo Transfer in Polycystic Ovary Syndrome Patients. Reprod Dev Med [serial online] 2018 [cited 2019 Oct 17];2:105-10. Available from: http://www.repdevmed.org/text.asp?2018/2/2/105/242758
| Introduction|| |
Polycystic ovary syndrome (PCOS) is a common female disease caused by endocrine and metabolic disorders, and the reported incidence of women in childbearing period is 7–15.2%., The clinical manifestations of the disease mainly include oligomenorrhea, amenorrhea, ovulatory dysfunction, acne, hirsutism, and obesity. The patients often ask for assisted reproductive technology because of ovulatory dysfunction or combination with other infertility factors. In 1993, Balen et al. reported that the spontaneous abortion rate after in vitro fertilization-embryo transfer (IVF-ET) was up to 50%. The rate of early-stage abortion was also up to 35% for the pregnant PCOS patients after ovulation induction. The clinical manifestations of PCOS are various based on the Rotterdam criteria, from single hyperandrogenism to systemic metabolic and endocrine changes, and the diseases have great heterogeneity. Thus, the pathogenesis for embryonic miscarriage of PCOS patients may be more complicated than the general spontaneous abortion. The results of reports are inconsistent so far, so there is still no confirmed conclusion. Currently, except for chromosomal abnormality, infection, and genital tract abnormality, the spontaneous abortion of PCOS patients has its specificity, such as influence of metabolic and endocrine disorder on the embryo and mother. Abnormality of embryonic chromosome is considered as the most common reason for spontaneous abortion, and more than 50% of the spontaneous abortion is related with genetic abnormality. However, the effect of embryonic chromosomal abnormality on the miscarriage cause of PCOS patients is still controversial. There is only one literature reporting the miscarried embryonic chromosome of PCOS patients complying with Rotterdam criteria. Herein, we retrospectively analyzed the embryonic chromosome of PCOS miscarriage, explored the ratio of abnormality of embryonic chromosome in the miscarriage pathogenesis, and discussed the high-risk factors of PCOS miscarriage, which provided theoretical basis for reducing PCOS spontaneous abortion rate in clinic.
| Methods|| |
PCOS patients who received IVF/intracytoplasmic sperm injection (ICSI)-ET treatment in the Reproductive Medicine Center from January 2013 to August 2017 were retrospectively analyzed, and non-PCOS patients who received IVF/ICSI-ET treatment due to tubular factors were taken as control. The diagnostic criteria for PCOS followed the Rotterdam criteria: (1) oligo-ovulation or no ovulation; (2) hyperandrogenism clinical manifestations and/or hyperandrogenism; (3) polycystic ovary, that was, number of follicles with diameter 2–9 mm ≥12 and/or ovarian volume ≥10 cm3 in unilateral or bilateral ovaries observed by B ultrasound. PCOS could be confirmed if any two of the above three criteria were met. Exclusion criteria of this study were as follows: (1) both or one of the parents having chromosomal abnormality, (2) combination with immune system disease, (3) disease history of repeated transfer failure, and (4) deformity in the genital tract.
Controlled ovarian hyperstimulation protocol
Based on the age, body mass index (BMI), basal sex hormone, anti-Müllerian hormone (AMH), and antral follicle count (AFC), the appropriate ovulation induction protocol and initial dose were individually selected. Long agonist protocol was chosen for the patients with normal ovarian reserve and antagonist protocol for those with lean body type and AFC ≥15 to prevent from ovarian hyperstimulation syndrome. Mild stimulation protocol (if AFC >3, antagonist protocol could be considered) was chosen for the patients with low ovarian reserve (such as bilateral ovarian AFC ≤3 on the 2nd day of menstruation during the ovulation-promoting cycle). The initial dose of gonadotropin (Gn, Gonal-F, Merck, Switzerland) in the long agonist protocol and antagonist protocol mainly depended on the age, BMI, and AMH of patients. The Gn dose was adjusted according to the follicular diameter and sex hormone level monitored by vaginal ultrasound until the application day of human chorionic gonadotropin (hCG). In the mild stimulation protocol, clomiphene (Shanghai Hengshan Pharmaceutical Co., Ltd.)/letrozole (Jiangsu Hengrui Medicine Co., Ltd.) was orally administrated on the 2nd day of menstruation for 4–5 days. Then, Gn was given based on the follicle development. When necessary, gonadotropin-releasing hormone antagonist (GnRH-ant, Cetrotide, Merck, Switzerland) was given to prevent premature luteinizing hormone surge until hCG injection day. When the diameter of 2–3 follicles grew to 16–18 mm, hCG (Livzon Pharmaceutical Group Inc.) was administrated by intramuscular injection at 4,000–10,000 U. After 34–38 h, the egg was retrieved by puncture through vagina under the guidance of ultrasound. The follicles with diameter >10 mm were taken out to perform IVF or ICSI.
Embryo culture observation and transfer
IVF/ICSI was chosen based on the condition of sperm. The fertilization condition at 16–20 h after egg retrieval was observed, and the embryonic cleavage was observed at 72 h. The embryos were graded according to morphological grading system:, Grade I, even appearance of blastomere, transparent and even cell plasma, and no fragmentation; Grade II, even appearance of blastomere, fragmentation of cell plasma <20%; Grade III, uneven appearance of blastomere, fragmentation of cell plasma 20 ~ 50%; and Grade IV, uneven appearance of blastomere, fragmentation of cell plasma >50%. Embryos of Grade I–II are defined as high-quality embryos, and embryos of Grade I–III are transferable. In fresh cycle, 1–2 embryos were transferred at the day 3 or 5 after egg retrieval, and the rest embryos were vitrified. Otherwise, all the embryos were frozen at day 3 or 5.
Frozen embryo transfer and luteal support
The individual endometrial preparation protocol was selected according to the patient's characters, such as menstrual cycle, and infertility reason, including natural cycle, hormone replacement cycle, downregulation and hormone replacement cycle, and stimulation cycle. The thickness of endometrium was monitored by vaginal ultrasound, and the embryo was transferred when endometrial thickness was thicker than 7 mm. The luteal support protocol was administration of progesterone (Zhejiang Xianju Pharmaceutical Co., Ltd., 40 mg/d, muscular injection) and progesterone capsules (Capsugel, 200 mg/d, vaginal administration). At the 12th day of transfer, a patient with blood β-hCG ≥25 U/L was diagnosed as biochemical pregnancy. At the 5th week of transfer, the patient with gestational sac observed under vaginal ultrasound was diagnosed as clinical pregnancy.
The primary observation indices were spontaneous abortion rate and villus chromosomal abnormality rate. The secondary observation index was clinical pregnancy rate. The calculation of observation indices was as follows:
- Spontaneous abortion rate = Number of patients with spontaneous abortion <20 weeks/number of patients with clinical pregnancy × 100%
- Clinical pregnancy rate = Number of patients with clinical pregnancy/transfer cycle × 100%
- Chromosomal abnormality rate = Number of karyotype abnormality/total number of villus chromosome × 100%.
The sterile villus tissues were taken from the patients receiving karyotype analysis because of spontaneous abortion after conventional complete curettage of uterine cavity. The villus cells were cultured followed by g-banding karyotype analysis. Multiplex ligation-dependent probe amplification was used to validate the results.
SPSS 19.0 (IBM Corporation, Armonk, NY, USA) was used to analyze the data. Measurement data were expressed as mean ± standard division if complied with normal distribution. The comparison between groups was analyzed by t-test. Enumeration data were expressed as percentage, and the comparison between groups was analyzed by Chi-square test. Multivariate analysis was performed by two-variable logistic regression method. P < 0.05 was termed as statistical significance.
| Results|| |
Clinical basic information and pregnancy outcomes
Totally 4,462 patients were enrolled, and there were 2,231 patients in PCOS group and control group each. The age, BMI, duration of infertility, and AFC had no statistical differences between the groups [Table 1], so the patients from the two groups were comparable. The clinical pregnancy rate of control group (56.97%) was lower than that of PCOS group (59.39%) but without statistical significance (P = 0.101). However, the patients in the PCOS group had significantly higher spontaneous abortion rate (24.15%) than that of control group (12.75%, P < 0.001).
|Table 1: The clinical characteristics and pregnancy outcomes of two groups (x̄ ± s)|
Click here to view
Chromosomal abnormality ratio of patients with spontaneous abortion
There were 86 and 90 patients with spontaneous abortion receiving karyotype analysis in the PCOS group and the control group, respectively. The average age of patients in the PCOS group was 31.5 ± 3.4 years, and that in the control group was 31.5 ± 3.2 years. There was no statistical difference between the two groups (P = 0.691). The chromosomal abnormality rate of patients in the PCOS group was 36.05% (31/86), significantly lower than that in the control group (55.56% [50/90], P = 0.009).
High-risk factor analysis of spontaneous abortion
There were 307 patients in the PCOS group having spontaneous abortion, and the rest 964 patients were pregnant over 20 weeks. The age, BMI, and homeostasis model assessment (HOMA) level of the spontaneous abortion group were significantly higher than those in ongoing pregnancy group (P < 0.05) [Table 2].
|Table 2: Multivariate analysis for risk factors of spontaneous abortion after IVF/ICSI-ET in PCOS patients (x̄ ± s)|
Click here to view
As shown in [Table 3], the logistic regression analysis indicates that age, HOMA, and BMI are closely related with spontaneous abortion occurrence. There are no statistical differences in type of cycle, quality of embryo transferred, number of embryos transferred, fasting glucose, fasting insulin, and basal sex hormone level (P > 0.05).
|Table 3: Multivariate analysis for risk factors of spontaneous abortion in PCOS patients|
Click here to view
| Discussion|| |
The aim of the assisted reproductive technology is to help women in childbearing age give live births and reduce spontaneous abortion rate as much as possible. Miscarriage is a huge physical and mental hit to the women. Thus, how to reduce the spontaneous abortion rate has become a research spot in clinic. Currently, most of the investigations have indicated that the miscarriage rate of PCOS patients is relatively high (up to 20%–50%)., Through a 1:3 case–control study, Luo et al. reported that the miscarriage rate of PCOS patients was significantly higher than that of non-PCOS patients after IVF. A retrospective analysis with large sample size compared 564 transfer cycles of PCOS patients and 7,494 transfer cycles of non-PCOS patients. The results indicated that there was no statistical difference in the miscarriage rate. Through the 1:1 case–control study, we retrospectively analyzed the spontaneous abortion rate of 2,231 PCOS patients in our hospital. The spontaneous abortion rate of PCOS patients was significantly higher than that of non-PCOS patients, which was consistent with most of the reports.,,
Embryonic chromosomal abnormality is one of the important reasons for occurrence of spontaneous abortion. It is widely known that the incidence of embryonic chromosomal abnormality in the sporadic miscarriage patients is up to 60%–70%. There is still no agreement on the embryonic chromosome of PCOS miscarriage. An investigation on the preimplantation genetic diagnosis (PGD) enrolled 74 PCOS patients and 100 non-PCOS patients. The results of PGD analysis on the embryos after IVF indicated that the embryonic aneuploidy rate was similar between the two groups (about 50%). Besides, there was no statistical difference in different ages (<38 years old and ≥38 years old) and number of retrieved oocytes (10–20, >20). Other investigations demonstrated that the ovum and embryonic morphology of PCOS patients receiving assisted reproduction had no statistical difference with that of non-PCOS patients. It indicated that the embryonic chromosomal abnormality might be not the critical factor for the high miscarriage rate of PCOS patients. Wang et al. analyzed the embryonic chromosome of spontaneous abortion from 32 PCOS patients and 68 non-PCOS patients. The results demonstrated that only 28.1% of the PCOS patients' miscarriage was caused by chromosomal abnormality, and 72.1% of the non-PCOS patients' miscarriage was caused by this. Thus, the embryonic chromosomal abnormality was not the major reason for PCOS patients' miscarriage. In our study, the comparison between 86 PCOS patients and 90 non-PCOS patients in the chromosome of miscarried embryo indicated that the abnormality rate of PCOS patients was significantly lower than that of non-PCOS patients. It also suggested that the abnormality of embryonic chromosome might be not the major reason for the miscarriage. The systemic and local endocrine and metabolic disorder of PCOS patients might involve in the PCOS miscarriage.
PCOS is a common and complicated disease caused by endocrine and metabolic disorder. As we discussed above, the systemic and local endocrine and metabolic disorder may involve in the occurrence of PCOS miscarriage. The multivariate analysis indicated that age, BMI, and HOMA were closely related with miscarriage of PCOS patients, which were high-risk factors for the miscarriage. Current studies on the miscarriage of PCOS patients mainly focus on obesity, hyperandrogenism, hyperinsulinemia, and insulin resistance (IR). Some clinical investigators believed that,, hyperinsulinemia and IR may be the risk factors for early-stage embryonic miscarriage of PCOS patients. As a sensitizer of insulin, metformin has been reported to be conducive to improvement on IR and reduction of miscarriage rate during gestation period., The important role of insulin sensitizer also proves that IR is the high-risk factor for miscarriage of PCOS patients. HOMA is used to evaluate individual IR level. Our study showed that the HMOA of PCOS patients was significantly higher than that of ongoing pregnancy group. The further multivariate analysis confirmed that HOMA was one of the high-risk factors for miscarriage, which was in line with previous study.
Besides, it has been consistently believed that obesity is an independent risk factor for miscarriage. The PCOS patients easily have high incidence of obesity. Hyperandrogenism of the PCOS patients is always correlated with IR and obesity. A retrospective analysis with large sample size indicated that progestational obesity had important influence on the pregnancy and miscarriage rate. After eliminating the influence of obesity, PCOS had no predictive value on the miscarriage. Thus, PCOS is not the risk factor for miscarriage, but obesity is. In oocyte donation cycle, Bellver et al. found that BMI was correlated with miscarriage rate when obese people were the oocyte donees. Thus, it was deduced that the influence of obesity on the mother (such as endometrium) might cause the miscarriage. We also observed that BMI was closely related with miscarriage of PCOS patients, which was in line with above studies.
Above all, compared with non-PCOS patients, the spontaneous abortion rate of PCOS patients was higher. The abnormality of chromosome karyotype was not the major factor for the high spontaneous abortion rate of PCOS patients. Elder age, high BMI, and HOMA were the risk factors for spontaneous abortion in the PCOS patients after IVF/ICSI-ET.
Financial support and sponsorship
We thank the financial support from National Key R&D Plan (2017YFC1001600) and National Natural Science Foundation of China (81471507).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Khaduri MA, Farsi YA, Najjar TA, Gowri V. Hospital-based prevalence of polycystic ovarian syndrome among Omani women. Middle East Fertil Soc J 2014;19:135-8. doi: 10.1016/j.mefs.2013.06.006.
Rashidi H, Ramezani Tehrani F, Bahri Khomami M, Tohidi M, Azizi F. To what extent does the use of the Rotterdam criteria affect the prevalence of polycystic ovary syndrome? A community-based study from the Southwest of Iran. Eur J Obstet Gynecol Reprod Biol 2014;174:100-5. doi: 10.1016/j.ejogrb.2013.12.018.
Balen AH, Tan SL, MacDougall J, Jacobs HS. Miscarriage rates following in vitro
fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin. Hum Reprod 1993;8:959-64. doi: 10.1093/oxfordjournals.humrep.a138174.
Arredondo F, Noble LS. Endocrinology of recurrent pregnancy loss. Semin Reprod Med 2006;24:33-9. doi: 10.1055/s-2006-931799.
Group ESPCW. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Fertil Steril 2004;19:41-7. doi: 10.1016/j.fertnstert.2003.10.004.
Morales C, Sánchez A, Bruguera J, Margarit E, Borrell A, Borobio V, et al.
Cytogenetic study of spontaneous abortions using semi-direct analysis of chorionic villi samples detects the broadest spectrum of chromosome abnormalities. Am J Med Genet A 2008;146A:66-70. doi: 10.1002/ajmg.a.32058.
Wang Q, Luo L, Lei Q, Lin MM, Huang X, Chen MH, et al.
Low aneuploidy rate in early pregnancy loss abortuses from patients with polycystic ovary syndrome. Reprod Biomed Online 2016;33:85-92. doi: 10.1016/j.rbmo.2016.04.006.
ALPHA Scientists in Reproductive Medicine, ESHRE Special Interest Group Embryology. Istanbul consensus workshop on embryo assessment: Proceedings of an expert meeting. Reprod Biomed Online 2011;22:632-46. doi: 10.1093/humrep/der037.
Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, et al.
International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertil Steril 2009;92:1520-4. doi: 10.1016/j.fertnstert.2009.09.009.
Smith ML, Schust DJ. Endocrinology and recurrent early pregnancy loss. Semin Reprod Med 2011;29:482-90. doi: 10.1055/s-0031-1293202.
Luo L, Gu F, Jie H, Ding C, Zhao Q, Wang Q, et al.
Early miscarriage rate in lean polycystic ovary syndrome women after euploid embryo transfer – A matched-pair study. Reprod Biomed Online 2017;35:576-82. doi: 10.1016/j.rbmo.2017.07.010.
Liu L, Tong X, Jiang L, Li TC, Zhou F, Zhang S. A comparison of the miscarriage rate between women with and without polycystic ovarian syndrome undergoing IVF treatment. Eur J Obstet Gynecol Reprod Biol 2014;176:178-82. doi: 10.1016/j.ejogrb.2014.02.041.
Sánchez JM, Franzi L, Collia F, De Díaz SL, Panal M, Dubner M. Cytogenetic study of spontaneous abortions by transabdominal villus sampling and direct analysis of villi. Prenat Diagn 1999;19:601-3. doi: 10.1002/(SICI)1097-0223(199907)19:7<601::AID-PD564>3.3.CO; 2-S.
Weghofer A, Munne S, Chen S, Barad D, Gleicher N. Lack of association between polycystic ovary syndrome and embryonic aneuploidy. Fertil Steril 2007;88:900-5. doi: 10.1016/j.fertnstert.2006.12.018.
Esmailzadeh S, Faramarzi M, Jorsarai G. Comparison of in vitro
fertilization outcome in women with and without sonographic evidence of polycystic ovarian morphology. Eur J Obstet Gynecol Reprod Biol 2005;121:67-70. doi: 10.1016/j.ejogrb.2004.12.002.
Ke RW. Endocrine basis for recurrent pregnancy loss. Obstet Gynecol Clin North Am 2014;41:103-12. doi: 10.1016/j.ogc.2013.10.003.
Palomba S, Falbo A, Orio F Jr., Russo T, Tolino A, Zullo F. Metformin hydrochloride and recurrent miscarriage in a woman with polycystic ovary syndrome. Fertil Steril 2006;85:1511.e3-5. doi: 10.1016/j.fertnstert.2005.09.063.
Morin-Papunen L, Rantala AS, Unkila-Kallio L, Tiitinen A, Hippeläinen M, Perheentupa A, et al.
Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): A multicenter, double-blind, placebo-controlled randomized trial. J Clin Endocrinol Metab 2012;97:1492-500. doi: 10.1210/jc.2011-3061.
Metwally M, Li TC, Ledger WL. The impact of obesity on female reproductive function. Obes Rev 2007;8:515-23. doi: 10.1111/j.1467-789X.2007.00460.x.
Fedorcsák P, Storeng R, Dale PO, Tanbo T, Abyholm T. Obesity is a risk factor for early pregnancy loss after IVF or ICSI. Acta Obstet Gynecol Scand 2000;79:43-8. doi: 10.1034/j.1600-0412.2000.079001043.x.
Bellver J, Rossal LP, Bosch E, Zúñiga A, Corona JT, Meléndez F, et al.
Obesity and the risk of spontaneous abortion after oocyte donation. Fertil Steril 2003;79:1136-40. doi: 10.1016/S0015-0282(03)00176-6.
[Table 1], [Table 2], [Table 3]