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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 4 1430-1433
Copyright © 2007 by The Endocrine Society

BRIEF REPORT

Insulin Resistance Increases the Risk of Spontaneous Abortion after Assisted Reproduction Technology Treatment

Li Tian, Huan Shen, Qun Lu, Robert J. Norman and Jim Wang

Reproductive Medical Centre (L.T., H.S., Q.L.), Peking University, People’s Hospital, Xizhimen, Beijing, China 100044; and Research Centre for Reproductive Health (R.J.N., J.W.), Department of Obstetrics and Gynaecology, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia 5011, Australia

Address all correspondence and requests for reprints to: Li Tian, Reproductive Medical Centre, Beijing University, People’s Hospital, No. 11 South Street, Xizhimen, Beijing, China 100044. E-mail: tianli916{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Objective: This study aims to examine the impact of insulin resistance (IR) on the risk of spontaneous abortion in patients who received infertility treatment.

Patients and Methods: This is a cohort study of 107 patients who achieved their first pregnancy after infertility treatment in a tertiary medical center. A homeostasis model assessment of IR (HOMA-IR) was carried out. Patient demographic characteristics and pregnancy outcome were also recorded. Statistical comparison was made between patients with and without IR. Logistical regression analysis was used to assess the effect of IR and several other factors simultaneously on the risk of spontaneous abortion.

Results: The incidence of spontaneous abortion was 17.8%. The association of IR with the risk of spontaneous abortion was significant after adjusting for other risk factors. The effect of overweight/obesity and polycystic ovarian syndrome was not statistically significant in the multivariate model.

Discussion and Conclusion: This study suggested that IR was an independent risk factor for spontaneous abortion. Because of the high prevalence of IR in obese or polycystic ovarian syndrome patients, the risk of spontaneous abortion in these patients can be raised. Patients with IR should be advised to improve their insulin sensitivity through lifestyle change or medical intervention before infertility treatment to reduce their risk of spontaneous abortion.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SPONTANEOUS ABORTION IS a major hazard in pregnancy, both for those naturally conceived and those after assisted reproductive technology (ART) treatment. In recent years, some studies have reported high spontaneous abortion rates in overweight/obese infertile women treated by ART (1). Other reports, however, dispute these results (2). The condition of polycystic ovarian syndrome (PCOS) in many infertile women also contributes to the confusion because it has been reported as a risk factor for spontaneous abortion probably linked with obesity (3). But this may be just due to the high prevalence of overweight/obesity in PCOS women (4). Despite these reports, there is no clear mechanism suggested for the reported association.

We propose that insulin resistance (IR) is a key factor behind the link between PCOS/obesity and the risk of spontaneous abortion. Previous studies have shown that using metformin may reduce the risk of pregnancy loss in PCOS women (5), and IR is a baseline predictor of clinical efficacy of metformin use for improving fertility performance (6). Given the well-known effect of metformin in reducing IR, these results have indirectly suggested that IR was correlated with the risk of spontaneous abortion. IR is often increased in women with PCOS (7) and hyperinsulinemia is an important etiological factor in the pathogenesis of PCOS (8). Obesity, especially android obesity, is also associated with a decrease of hepatic and peripheral insulin sensitivity (9). Hyperinsulinemia has been proposed as the pathway for the effect of obesity on some reproductive abnormalities, probably through its effect on androgen production (10). However, to our knowledge, there has been no report directly linking the level of IR with the risk of spontaneous abortion. The present study aims to examine the relationship in a group of pregnant women after ART treatment.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The study population was ethnic Chinese patients who achieved pregnancy for the first time after receiving in vitro fertilization (IVF) or intracytoplasmic sperm injection treatment in the Reproductive Medicine Centre, Peking University, People’s Hospital, Beijing, China, from June 2003 to July 2005 (n = 107). The primary infertility etiology of the patients included tubal blockage, male factor, PCOS, and other factors. All patients received a standard long protocol of pituitary suppression with GnRH agonist, followed by administration of recombinant FSH, and human chorionic gonadotropin (hCG). Transvaginal follicular aspiration was performed 36 h after administration of hCG. Handling of gametes, fertilization, and embryo culture were according to standard IVF procedures. Embryos were usually transferred on d 3 after oocyte recovery. Two embryos were normally transferred, except for women over 36 yr old, where three embryos were transferred. Luteal phase support up to 14 d after oocyte retrieval consisted of daily im injection of 40 mg progesterone in oil.

Pregnancy was defined as positive serum ß-hCG and the presence of a gestation sac detected by ultrasound 6–8 wk after the last menstrual period. Spontaneous abortion was defined as a pregnancy lost before 20 full weeks of gestation. No patient has been diagnosed with type II diabetes. One month before the GnRH agonist treatment was commenced, a venous blood sample was drawn to determine the concentrations of fasting glucose (FG) and fasting insulin (FI). A homeostasis model assessment of IR index (HOMA-IR) (11) was carried out to assess IR. It was calculated as follows: [FI (µU/ml) x FG (mmol/liter)]/22.5. Patients with HOMA-IR greater than 4.5 were classified as IR, and HOMA-IR of 4.5 or less non-IR (11). Body mass index (BMI) [mass (kg)/height2 (m2)] was used as an indicator of obesity. Patients were stratified into three BMI groups: underweight (<19 kg/m2), normal (19–24.9 kg/m2), and overweight/obese (≥25 kg/m2). PCOS status was determined based on the revised 2003 criteria (12), i.e. they fulfill two of the following three manifestations: 1) oligo- and/or anovulation, 2) clinical and/or biochemical signs of hyperandrogenism, and 3) polycystic ovaries with exclusion of other etiologies (congenital adrenal hyperplasias, androgen-secreting tumors, or Cushing’s syndrome). No patient got hypoglycemic treatments before and after pregnancy.

Student’s t test and {chi}2 or Fisher exact test were used to test the difference between groups where appropriate. Multivariate logistical regression analysis was used to assess the effect of IR, both as a categorical variable and a continuous variable (HOMA-IR), and other risk factors, including age, etiology, number of embryos transferred, BMI, PCOS status, and secondary fertility simultaneously. Adjusted odds ratio (OR) and its 95% confidence interval (CI) have been calculated based on the analysis. A statistical significance level of P < 0.05 was used.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
During the 2 yr, 327 patients received IVF or intracytoplasmic sperm injection treatment, and 107 patients were pregnant. The pregnancy rate was 32.7%. The demographic characteristics of the study population are shown in Table 1Go. The mean age was 30.8 yr, ranging from 21–39 yr, and the mean BMI was 22 kg/m2, ranging from just over 16 to nearly 33 kg/m2. Nineteen patients (18%) were overweight or obese. The mean IR was 3.28, with over 20% (23 of 107) patients who were IR. There were no cases of diabetes in this group of patients. The overall spontaneous abortion rate was 17.8% (19 of 107). There was no significant difference in all variables apart from the concentrations of insulin and glucose, glucose insulin ratio, and the rate of spontaneous abortion between the two groups.


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  		TABLE 1. Demographic characteristics of the patients

 
Table 2Go shows the risk of spontaneous abortion by factors that were included in the logistic regression model. For women aged 35 yr or older, the risk is almost doubled, 26.9 vs. 14.8% in younger women (P < 0.05). Overweight/obesity, compared with normal weight, was also linked with nearly doubling the risk of spontaneous abortion (P < 0.05). PCOS was linked with a significant increase of the risk (P < 0.05). However, none of the associations reached a statistically significant level as shown by the OR calculated from the logistic regression analysis. Patients with IR greater than 4.5 had significantly greater risk of spontaneous abortion compared with those with normal IR. This increase was significant as shown by multivariate logistic regression analysis (OR, 8.32; 95% CI, 2.65–26.13). Another logistic regression analysis, using HOMA-IR as a continuous variable and the same other variables, showed an increase in OR of 0.52 (95% CI, 0.34–0.80) per unit HOMA-IR (P = 0.002).


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  		TABLE 2. Risk of spontaneous abortion (percent) and adjusted risk (OR and 95% CI)

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of this study indicated that the risk of spontaneous abortion was positively related with HOMA-IR level. In women with IR greater than 4.5, the OR is eight times that of those with IR of 4.5 or less. It remained significantly higher after controlling for the possible confounding effect of BMI, age, PCOS status, etc. It suggests that IR is a common factor behind the increased risk of spontaneous abortion in women who are overweight/obese or with PCOS.

An early report has shown that poor metabolic control around conception may cause spontaneous abortion (13). Another study reported an increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss (14). More recently, several studies reported reduced pregnancy loss in PCOS women after treatment of metformin, presumably due to its effect on IR (5). However, this is the first report showing a direct link between the risk of spontaneous abortion and the level of IR. The mechanism explaining the association between IR and the risk of spontaneous abortion may be complicated. Hyperinsulinemia adversely affects the preimplantation environment by decreasing the expression of glycodelin and IGF-binding protein-1 (15). Glycodelin may play a role in inhibiting the endometrial immune response of the embryo, and IGF-binding protein-1 seems to facilitate adhesion processes at the fetomaternal interface (16). One recent report also has shown in patients receiving metformin that plasminogen activator inhibitor 1 positively correlated with the HOMA score (17). Another study showed that higher levels of plasminogen activator inhibitor 1 were related to an increased risk of spontaneous abortion (18). More work is needed to explore the possible mechanism on how IR may cause spontaneous abortion.

Spontaneous abortion is a major loss for pregnant women, especially for those who achieve pregnancy through expensive and stressful ART treatments. Information on potentially remediable risk factors for spontaneous abortion is important in our effort in reducing the risk. The prevalence of increased IR among reproductive-aged women, especially infertile ones, is high, directly relating to the high prevalence of overweight/obesity and/or PCOS. In China, the prevalence of overweight/obesity has also been on the increase in recent decades (19). However, the prevalence of PCOS in the Chinese population has not been reliably reported.

The finding that IR is a possible risk factor for spontaneous abortion may form part of the overall information on lifestyle modification before infertility treatment. Medication, such as metformin, may be used with the additional objective of reducing the risk of spontaneous abortion in some patients. Either through lifestyle modification or metformin, the management of IR in patients can be done at a low cost and easily administrated.

In this study, the relatively small sample size has limited its capacity to detect statistical significance of some known risk factors, such as PCOS and BMI, even though the actual increase in the risk of spontaneous abortion is quite large. On the other hand, this is expected based on our hypothesis that IR is the common factor behind the links. Using HOMA-IR as an indicator for IR may not be as accurate as the euglycemic clamp, but it is a cheaper, noninvasive, and convenient method for evaluating IR that is suitable for a large population screen (20). For patients who are receiving stressful and expensive ART treatment, a simple and cheap screening test would be more acceptable and ensure that patients were willing to participate in the study. Although it is expected that some abortions may be a result of serious genetic defect(s), genetic testing of abortion product is not routinely carried out, and its effect cannot be assessed in this study. A much larger sample size, probably through a collaborative study, will be needed to assess this aspect of abortion. Finally, about one third of the patients (37.4%) were secondary infertile, which was included in the multivariate logistic regression analysis and did not show a significant effect. Some of them may have had previous spontaneous abortions, although it could not be considered in the analysis due to lack of data. These limitations may have affected the sensitivity of the study.

In summary, there seemed to be a positive relationship between HOMA-IR and the risk of spontaneous abortion. Increased IR may be an independent risk factor for spontaneous abortion in pregnant women after ART treatment. Patients with high IR should be advised before ART treatment regarding the need for weight reduction or taking metformin to reduce their risk of spontaneous abortion.


   Footnotes
 
Disclosure Statement: The authors have nothing to disclose.

First Published Online January 23, 2007

Abbreviations: ART, Assisted reproductive technology; BMI, body mass index; CI, confidence interval; FG, fasting glucose; FI, fasting insulin; hCG, human chorionic gonadotropin; HOMA-IR, homeostasis model assessment of IR; IR, insulin resistance; IVF, in vitro fertilization; OR, odds ratio; PCOS, polycystic ovarian syndrome.

Received May 24, 2006.

Accepted January 16, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Wang JX, Davies MJ, Norman RJ 2002 Obesity increases the risk of spontaneous abortion during infertility treatment. Obes Res 10:551–554[Medline]
  2. Styne-Gross A, Elkind-Hirsch K, Scott Jr RT 2005 Obesity does not impact implantation rates or pregnancy outcome in women attempting conception through oocyte donation. Fertil Steril 83:1629–1634[CrossRef][Medline]
  3. Hamilton-Fairley D, Kiddy D, Watson H, Paterson C, Franks S 1992 Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotrophin. Br J Obstet Gynaecol 99:128–131[Medline]
  4. Wang JX, Davies MJ, Norman RJ 2001 Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment. Hum Reprod 16:2606–2609[Abstract/Free Full Text]
  5. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L 2002 Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 17:2858–2864[Abstract/Free Full Text]
  6. Eisenhardt S, Schwarzmann N, Henschel V, Germeyer A, von Wolff M, Hamann A, Strowitzki T 2006 Early effects of metformin in women with polycystic ovary syndrome: a prospective randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 91:946–952[Abstract/Free Full Text]
  7. Anttila L, Karjala K, Penttila RA, Ruutiainen K, Ekblad U 1998 Polycystic ovaries in women with gestational diabetes. Obstet Gynecol 92:13–16[Abstract]
  8. Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN 2006 Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab 91:48–53[Abstract/Free Full Text]
  9. Peiris AN, Hennes MI, Evans DJ, Wilson CR, Lee MB, Kissebah AH 1988 Relationship of anthropometric measurements of body fat distribution to metabolic profile in premenopausal women. Acta Med Scand Suppl 723:179–188[Medline]
  10. Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ 1986 Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 62:904–910[Abstract]
  11. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC 1985 Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419[CrossRef][Medline]
  12. 2004 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19:41–47[CrossRef]
  13. Dicker D, Feldberg D, Samuel N, Yeshaya A, Karp M, Goldman JA 1988 Spontaneous abortion in patients with insulin-dependent diabetes mellitus: the effect of preconceptional diabetic control. Am J Obstet Gynecol 158:1161–1164[Medline]
  14. Craig L, Ke R, Kutteh W 2002 Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss. Fertil Steril 78:487
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  16. Seppala M, Taylor RN, Koistinen H, Koistinen R, Milgrom E 2002 Glycodelin: a major lipocalin protein of the reproductive axis with diverse actions in cell recognition and differentiation. Endocr Rev 23:401–430[Abstract/Free Full Text]
  17. Palomba S, Orio Jr F, Falbo A, Russo T, Tolino A, Zullo F 2005 Plasminogen activator inhibitor 1 and miscarriage after metformin treatment and laparoscopic ovarian drilling in patients with polycystic ovary syndrome. Fertil Steril 84:761–765[CrossRef][Medline]
  18. Kujovich JL 2004 Thrombophilia and pregnancy complications. Am J Obstet Gynecol 191:412–424[CrossRef][Medline]
  19. Wu Y 2006 Overweight and obesity in China. BMJ 333:362–363[Free Full Text]
  20. Ikeda Y, Suehiro T, Nakamura T, Kumon Y, Hashimoto K 2001 Clinical significance of the insulin resistance index as assessed by homeostasis model assessment. Endocr J 48:81–86[Medline]



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