Edited by: Yiping Shen, Harvard Medical School, United States
Reviewed by: Lianghui Diao, Shenzhen Zhongshan Urology Hospital, China; Krzysztof Cezary Lewandowski, Medical University of Lodz, Poland
*Correspondence: Cuilian Zhang,
This article was submitted to Reproduction, a section of the journal Frontiers in Endocrinology
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The objective of the study was to explore the effect of insulin resistance on pregnancy outcomes in patients with polycystic ovary syndrome (PCOS) from the first embryo transfer cycle.
This was a single-center, retrospective, observational cohort study.
Included in the study were women with PCOS for the first embryo transfer.
Early miscarriage rate and macrosomia rate were the main outcome measures.
With increased HOMA-IR, the early miscarriage rate (7.14, 13.21, and 16.22%, respectively;
Insulin resistance is an independent risk factor for early miscarriage and macrosomia in PCOS patients during the first embryo transfer cycle. It is essential to give more attention before and after pregnancy for PCOS women with high HOMA-IR.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects about 5–10% reproductive women (
At present, the hyperinsulinemic–euglycemic clamp technique is considered as the gold standard for assessing insulin sensitivity (
This was a single-center retrospective cohort study approved by the Ethics Committee of the People’s Hospital of Zhengzhou University. Enrolled as subjects of the study were PCOS patients who underwent
The exclusion criteria included: 1): cycles with incomplete data; 2) no embryo transfer cycles; 3) with endometrium factors such as intrauterine adhesion and uterine malformation; 4) with recurrent spontaneous abortion and autoimmune disease; 5) with chromosome abnormalities screened by preimplantation genetic screening of preimplantation genetic diagnosis; and 6) other endocrine disorders such as thyroid diseases, diabetes mellitus, impaired fasting glucose and hyperprolactinemia (
Flow chart of patients’ selection and exclusions.
Fasting blood glucose and fasting insulin were included in the routine examination of IVF treatment in our center. The two tests were performed six months before the start of ovarian stimulation, and in the same laboratory. As there is no consensus about the cutoff value of IR at present, the patients was divided into three groups according to 25th and 75th quartile of the HOAM-IR in this study: Group 1: HOMA-IR ≤1.87 (n = 238); group 2: 1.87 <HOMA-IR <4.28 (n = 474); and group 3: HOMA-IR ≥4.28 (n = 236). The insulin resistance index was calculated using the HOMA-IR according to the following formula: HOMA-IR = fasting blood glucose × fasting insulin/22.5. The unit of fasting blood glucose was mmol/L and the unit of fasting insulin was μ U/ml.
In this study, the controlled ovulation induction protocol was conducted by the same team according to the condition of the patients. All the women underwent either GnRH agonist or flexible GnRH antagonist protocol.
For the GnRH agonist protocol, 30 to 35 days after a single injection of 3.75 mg of long-acting GnRH agonist (Diphereline, Ipsen, Tianjin) on the second or third day of menstrual cycle, or injection of the short-acting GnRH agonist (Decapeptyl, 0.1 mg/d, Germany ferring) for 14 to 18 days began in the middle luteal phase of the previous menstrual cycle. Once the condition reached the downregulation standard, a dose of 75–300 IU gonadotropin (Gn) was administered based on the age, ovarian reserve, body mass index (BMI), and anti-Mullerian hormone (AMH) level of the patient. Gonadotropin doses were adjusted according to ovarian response and hormone levels after 4 to 5 days. Urinary human chorionic gonadotropin (hCG) was administered subcutaneously for triggering when at least two follicles measured ≥18 mm or three follicles measured ≥17 mm. A dose of 4,000 to 10,000 IU of hCG (Lizhu Pharmaceutical Trading, China) was given to induce ovulation depending on peak estradiol level and age. Oocyte retrieval guided by vaginal ultrasound was performed 36–37 h later.
Gn was injected from the second or third day of menstruation, and the starting dose of Gn was the same as above. Follicular size and hormone levels were monitored after four or five days of Gn treatment. A daily dose of 0.25 mg GnRH antagonist was initiated when a dominant follicle reached a mean diameter of 12 mm or estrogen level ≥200 ng/L or when blood luteinizing hormone (LH) levels began to show a notable upward trend. The dose was administered until the day of hCG administration. When at least two follicles measured ≥18 mm or three follicles measured ≥17 mm, a dose of 4,000 to 10,000 IU hCG was administered subcutaneously for triggering. Oocyte retrieval guided by vaginal ultrasound was performed 35–36 h later.
IVF/ICSI fertilization was performed depending on male semen parameters. On the 3rd to 5th day after oocyte retrieval, 1–2 high-quality cleavage embryos or blastocysts were selected for embryo transfer. During the frozen embryo transfer cycle, the endometrial preparation protocol was selected individually according to the condition of the patient, and 1–2 cleavage embryos or blastocysts should be transferred timely after the endometrial transformation. The hCG level in peripheral blood was measured on the 14th day after embryo transfer. Clinical pregnancy was defined as the presence of at least one intrauterine gestational sac on the 4–5 weeks after transfer. Luteal support drugs were discontinued in non-pregnant patients, and luteal support drugs were continued in pregnant patients until 8–10 weeks of pregnancy.
The primary outcomes of this study were the early miscarriage rate, macrosomia birth rate, and live birth rate. Live birth was defined as the complete removal or delivery of the fertilized product from the mother after more than 28 weeks of gestation with the presence of respiration or any signs of life (heartbeat, umbilical cord pulsation, voluntary muscle movement) after separation from the mother. Early miscarriage was defined as embryo loss before 12 weeks of pregnancy. Low birth weight was defined as fetal birth weight <2,500 g. Macrosomia was defined as birth weight ≥4,000 g.
All measurement data were expressed by mean ± standard deviation (mean ± SD). One-way ANOVA was used for comparison between groups. All counting data were expressed by percentage (%), and chi-squared test was used to compare the count data between groups. Logistic regression model was used for multivariate analysis.
All statistical management and analyses were performed using SPSS software, version 24.0. A two-sided
A total of 948 PCOS women who underwent first embryo transfer cycle and met the study inclusion and exclusion criteria were enrolled (
Comparison of demographic and clinical characteristics of the three groups.
Item | Group 1 | Group 2 | Group 3 |
|
---|---|---|---|---|
No. of cases | 238 | 474 | 236 | |
Age (year) | 29.1 ± 3.9 | 28.9 ± 3.6 | 28.5 ± 4.2 | 0.208 |
HOMA-IR | 1.43 ± 0.35 | 2.92 ± 0.68 | 6.72 ± 2.78 | <0.001 |
BMI (kg/m2) | 22.1 ± 2.9 | 24.9 ± 3.4 | 28.3 ± 3.4 | <0.001 |
<24 | 76.5 (182/238) | 43.0 (204/474) | 9.3 (22/236) | |
24–27.9 | 19.7 (47/238) | 38.9 (184/474) | 38.6 (91/236) | |
≥28 | 3.8 (9/238) | 18.1 (86/474) | 52.1 (123/236) | |
AMH (ng/ml) | 9.2 ± 4.9 | 8.3 ± 4.5 | 7.2 ± 4.1 | <0.001 |
FSH (IU/L) | 6.1 ± 1.5 | 5.7 ± 1.3 | 5.5 ± 1.4 | <0.001 |
LH (IU/L) | 10.5 ± 5.8 | 8.7 ± 4.7 | 7.6 ± 4.2 | <0.001 |
T (ng/ml) | 0.41 ± 0.2 | 0.42 ± 0.19 | 0.46 ± 0.22 | 0.020 |
Duration of infertility (year) | 2.5 ± 0.1 | 2.5 ± 0.1 | 2.5 ± 0.2 | 0.068 |
Type of infertility (%) | 0.103 | |||
Primary | 63.9 (152/238) | 61.8 (293/474) | 69.9 (165/236) | |
Secondary | 36.1 (86/238) | 38.2 (181/474) | 30.1 (71/236) | |
Methods of ART (%) | 0.314 | |||
IVF | 84.5 (201/238) | 87.6 (415/474) | 89.0 (210/236) | |
ICSI | 15.5 (37/238) | 12.4 (59/474) | 11.0 (26/236) |
As shown in
Ovarian stimulation characteristics among the three groups.
Item | Group 1 | Group 2 | Group 3 |
|
---|---|---|---|---|
No. of cases | 238 | 474 | 236 | |
Protocol (%) | 0.078 | |||
GnRH agonist protocol | 83.2 (198/236) | 86.5 (410/474) | 90.3 (213/236) | |
GnRH antagonist protocol | 16.8 (40/236) | 13.5 (64/474) | 9.7 (13/236) | |
Starting dosage of Gn (IU) | 122.1 ± 27.7 | 131.9 ± 29.2 | 142.9 ± 31.7 | <0.001 |
Total dosage of Gn (IU) | 1,741.4 ± 87.6 | 2,200.8 ± 1,202.6 | 2,880.0 ± 1,254.2 | <0.001 |
Duration of Gn (d) | 11.2 ± 3.2 | 12.2 ± 3.7 | 13.7 ± 3.7 | <0.001 |
No. of oocytes retrieved | 16.0 ± 7.7 | 14.8 ± 7.9 | 13.8 ± 7.8 | 0.011 |
No. of mature oocytes | 13.6 ± 7.0 | 12.7 ± 7.1 | 11.8 ± 6.8 | 0.017 |
No. of normal fertilization oocytes | 9.6 ± 5.6 | 9.0 ± 5.5 | 8.1 ± 5.2 | 0.009 |
No. of available embryos | 7.7 ± 4.8 | 7.6 ± 5.0 | 6.7 ± 4.5 | 0.048 |
No. of good embryos | 4.1 ± 2.5 | 3.8 ± 2.4 | 3.6 ± 2.1 | 0.036 |
After the first embryo transfer, the type of transfer (fresh cycle or frozen cycle), number of embryos transferred and the thickness of endometrium were comparable among the groups (
Outcomes of first embryo transfer cycle.
Item | Group 1 | Group 2 | Group 3 |
|
---|---|---|---|---|
No. of cases | 238 | 474 | 236 | |
Type of transfer (%) | 0.128 | |||
Fresh cycle | 43.3 (103/238) | 47.3 (224/474) | 52.5 (124/236) | |
Frozen cycle | 56.6 (135/238) | 52.7 (250/474) | 47.4 (112/236) | |
No of embryo transferred | 1.47 ± 0.50 | 1.47 ± 0.50 | 1.50 ± 0.50 | 0.631 |
Type of transfer embryos (%) | 0.021 | |||
cleavage | 57.1 (136/238) | 55.9 (265/474) | 66.5 (157/236) | |
blastocyst | 42.9 (102/238) | 44.1 (209/474) | 33.5 (79/236) | |
Endometrium (mm) | 9.8 ± 1.9 | 10.0 ± 2.0 | 10.1 ± 2.2 | 0.337 |
Clinical pregnancy rate (%) | 70.59 (168/238) | 67.09 (318/474) | 62.71 (148/236) | 0.188 |
Early miscarriage rate (%) | 7.14 (12/168) | 13.21 (42/318) | 16.22 (24/148) | 0.039 |
Late miscarriage rate (%) | 2.38 (4/168) | 2.83 (9/318) | 5.41 (8/148) | 0.258 |
Live birth rate (%) | 63.03 (150/238) | 55.27 (262/474) | 47.88 (113/236) | 0.004 |
Single live birth rate (%) | 50.84 (121/238) | 44.73 (212/474) | 38.56 (91/236) | 0.027 |
Low birth weight rate (%) | 5.78 (7/121) | 6.60 (14/212) | 9.89 (9/91) | 0.478 |
Macrosomia rate (%) | 5.78 (7/121) | 11.79 (25/212) | 17.58 (16/91) | 0.026 |
Twin live birth rate (%) | 12.18 (29/238) | 10.55 (50/474) | 9.32 (22/236) | 0.597 |
Low birthweight rate (%) | 31.03 (18/58) | 44 (44/100) | 50 (22/44) | 0.125 |
Macrosomia rate (%) | 0 | 0 | 0 | |
GDM (%) | 10.00 (15/150) | 14.50 (38/262) | 25.67 (29/113) | 0.002 |
Baby gender ratio (male/female) | 1.11 | 1.17 | 1.11 | 0.948 |
Total Male | 94 | 168 | 71 | |
Total Female | 85 | 144 | 64 |
Multivariate logistic regression analysis was performed to explore the risk factors of early miscarriage rate and macrosomia rate. The regression model included the following factors: age, HOMA-IR, BMI, AMH, number of available embryos, number of embryos transferred, type of transfer embryo and endometrial thickness. The results showed that HOMA-IR was an independent risk factor of early miscarriage rate and macrosomia rate. Compared with group 1, the group 2 and group 3 had significantly higher early miscarriage rate (group 2, a
Logistic regression analysis to account for confounding variables of early miscarriage and macrosomia.
Early miscarriage rate | Macrosomia rate | |||||
---|---|---|---|---|---|---|
B |
|
|
B |
|
|
|
HOMA-IR | 0.039 | 0.035 | ||||
Group 1 | Ref ( |
Ref ( |
||||
Group 2 | 0.495 | 1.640 (1.101, 2.443) | 0.015 | 0.685 | 1.983 (1.089, 3.611) | 0.025 |
Group 3 | 0.522 | 1.685 (1.049, 2.708) | 0.031 | 0.779 | 2.218 (1.149, 4.281) | 0.018 |
In the present study, we found that HOMA-IR was associated with early miscarriage, macrosomia, live birth rate, and the incidence of GDM. With increasing of HOMA-IR, the early miscarriage rate, the macrosomia rate and the prevalence of GDM elevated remarkedly, and the live birth rate decreased significantly in their first embryo transfer. The influences still remained after adjusting for the following factors: age, BMI, AMH, number of available embryos, number of embryos transferred, type of transfer embryo and endometrial thickness.
Further, we found that with increased HOMA-IR, there were significant decreasing in number of oocytes retrieved, number of available embryos, and number of good embryos. We suspect that with fewer available embryos and good embryos, reduced chance for embryo selection in the first embryo transfer cycle might lead to adverse pregnancy outcomes, and high HOMA-IR may be detrimental to the oocyte and embryo quality.
Several previous studies have shown that PCOS patients had a higher miscarriage rate than non-PCOS patients in IVF treatment. Su et al. found that women with PCOS had an increased risk miscarriage (aOR 1.629, 95% CI 1.240–2.141) for the first IVF treatment (
IR might affect early miscarriage through downstream physiological changes. IR or hyperinsulinemia may affect the secretion of androgen, and excess androgen can aggravate endocrine disorders and follicular dysplasia, which may further result in poor quality eggs and embryos. Besides, from an
In this study, we found that macrosomia rate and the incidence of GDM significantly increased with HOMA-IR elevation, and the influence was still remained after adjusting for the possible confounding factors. A meta-analysis including fifty-nine studies of Chinese PCOS women suggested that the estimates of GDM and macrosomia among women with PCOS were significantly higher than those in women without PCOS (all
At present, a large number of studies have found that maternal weight was a high-risk factor of macrosomia (
Macrosomia has short-term and long-term adverse health effects and is thus an important public health concern. A murine model suggested that neonatal macrosomia was an independent risk factor of adult metabolic syndrome (
To our best knowledge, this is the first study to explore the effects of insulin resistance both on early miscarriage and macrosomia in PCOS patients during their first embryo transfer cycles. Most of the previous studies have compared the influence of IR on PCOS patients and non-PCOS patients. It provides valuable data support for clinical consultation and new ideas for future clinical and basic research. This study also has certain limitations that should be noticed. First, this study was designed as a retrospective cohort study, and thus limited its scope to explore the relevant biological mechanism by which insulin resistance affects pregnancy outcomes. Additionally, the assessment of HOMA-IR has some limitations (
In summary, this study showed that insulin resistance was an independent risk factor for early miscarriage and macrosomia in PCOS patients during the first embryo transfer cycle. The early miscarriage rate and macrosomia rate were significantly higher with the increasing of HOMA-IR. Therefore, for PCOS patients with high insulin level, it is essential to give effective treatment before pregnancy, and the perinatal period may require more attention from obstetricians and pediatricians.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by the Zhengzhou University and the Henan Provincial People’s Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
YC designed the study. JG and QZ were involved in the data extraction and analysis. CZ was responsible for providing data and guiding research. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
This work was supported by the National Natural Science Foundation of China (NSFC) (project number: U2004130).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
The authors thank all participants involved in this study, and wish to express their thanks to all clinicians and clinical embryologists in the reproductive center of People’s Hospital of Zhengzhou University.