Does Cardiometabolic Health Determine IVF Treatment Outcomes?

Background

Infertility is a global health concern that affects approximately 50 million people worldwide or those with the inability to start an integrated family [1]. It has been defined as the failure to conceive (as in pregnancy) after continuous non-contraceptive intercourse for twelve months or longer and subjected to several implications in terms of culturally, socially and also economically [2]. The prevalence rate varied across geographic factors [1], wherein the UK has been estimated at 12-14% while developing countries including Asia reported to 3.5-16%. In western-Africa however, the incidence of infertility is quite high at 50% [3], [4]. As with the difference of incidence in the geographic regions, the causes of infertility too vary in accordance. In Western countries such as the UK or US, the main cause of infertility is increased age while in Africa the main cause has been attributed to the high prevalence of sexually transmitted diseases [1]. These rates of increased prevalence have thus increased the need for assisted reproductive techniques (ART) such as In-vitro Fertilisation (IVF) [5].

Another very important causative factor for infertility that has been warranting IVF is the presence of obesity in women of the childbearing age [6]. In the UK figures demonstrate that 29% of the women aged 16-44 years of age are overweight with BMI of >25kg/m2 but <30kg/m2, while 19% were obese, i.e., >30kg/m2 [6]. Contrastingly in the US more than two-thirds of women of reproductive age have been found to be obese [7]. Obesity is not only a leading cause of infertility but has also been found to have implications for the outcomes of IVF [9]. The main implicating factors of obesity include the development Polycystic Ovaries (PCOS), along with anovulatory fertility and ovulatory subfertility [8]–[10]. Beside this, obesity has also been known to have negative impacts on the oocyte quality and early embryo growth [9], [11] and is strongly related to premature birth and the birth of a macrosomic neonate [12].

One of the major repercussions of obesity remains cardiometabolic risk (CMR) and subsequently metabolic syndrome (MS). In view of this there exists a strong association between MS and the development of insulin resistance (IR) (akin to diabetes) and coronary artery disease (CAD) [13] which defines the concept of CMR. Apart from this, obese women also suffer from other factors of CMR such as hypertension, altered lipid profiles (elevated LDL, dyslipidaemia) and inflammation [8], [9], [14]. However, it is not clear how far cardiometabolic health has been associated with IVF success. Chang et al. [15] have demonstrated the association of IR to assisted reproduction outcomes. The study findings revealed that while hyperinsulinemia and IR do not cause changes in oocyte and embryo development, rather it bears a negative association with the endometrial function and the implantation process. Similarly, the study by Salzer [16] postulated that the mechanism of IR in obese pregnant women is strongly associated with the development of hypertension due to the excess weight which leads to an increase in the sympathetic activity.

Hypertension has in turn been demonstrated to cause defects in placentation and therefore, it is hypothesised that it does play an important role in IVF outcomes [17]. On the other hand, dyslipidaemia and altered lipid profiles, are known to alter the development of oocytes, in terms of the size, number and the quality. Evidence suggests that among obese pregnant women with dyslipidaemia have smaller oocytes than those who do not but these findings are based on few studies [9]. However, the more substantial evidence is required to associate dyslipidaemia and the outcomes of IVF.

The other factors associated with obesity, pregnancy and IVF outcomes are the intake of gonadotropins to increase follicle stimulation[18]. Studies showed that this, in turn, leads to the reduction of Estradiol (E2) levels which is suggestive that obesity does play a role in the impaired metabolism of gonadotropins too [9], [18]. Thus, it can be stated that although obesity is a causative factor for negative outcomes of IVF, it is still a reversible process [10]. However, approaching obesity in terms of a reduced BMI and weight loss is a long drawn process and one that may or may not be successful. Therefore, it is imperative to look into whether treating the various CMR factors can improve the outcomes of IVF.

In line with this, the study by Jinno at al [19] demonstrated that metformin can be used to adequately correct IR, thereby improve the outcome of IVF. Similarly, Tso et al. [20] also showed similar findings where the author demonstrated that metformin can decrease IR and also reduce the risk of Ovarian Hyperstimulation Syndrome (OHSS). On thecontrary , other studies (for example [21], [22]) consider myoinositol as a viable alternative to adjuvant therapy for reduction of IR. Rosiglitazone has been suggested to not only reduce the effects of lipotoxicity caused by dyslipidaemia in obese pregnant women, but also enhances the quality of the oocyte, embryo, and other ovarian functions [23], [24].

Despite the above positive findings, it is important to note, that British Fertility Society (BFS) does not still recommend the use of adjuvants in IVF due to lack of substantial evidence. The guidelines however further state that metformin may be considered as an adjuvant (although not expressly recommended) [25]. Further, it is noted that especially for dyslipidaemia statins are still not recommended, even though they have demonstrated to have no teratogenic effects in pregnancy [26]–[28]. Although CMR factors do have an association with the outcome of IVF and that the correction of these factors may enable for better IVF outcomes but it is still inconclusive due to lack of substantial evidence. Therefore, the area of providing adjuvants in the form of pharmacological therapy during the IVF treatment procedure needs to be explored further.

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Reference

[1] Z. Roupa, M. Polikandrioti, P. Sotiropoulou, E. Faros, A. Koulouri, G. Wozniak, and M. Gourni, “Causes of Infertility in Women at Productive Age,” Heal. Sci. J., vol. 32, no. 2, pp. 80–87, 2009.

[2] World Health Organisation, “Global prevalence of infertility, infecundity and childlessness,” WHO, 2016. [Online]. Available: [Accessed: 15-Feb-2016].

[3] S. Pandey, A. Maheshwari, and S. Bhattacharya, “Should access to fertility treatment be determined by female body mass index?,” Hum. Reprod., vol. 25, no. 4, pp. 815–820, Apr. 2010.

[4] J.-A. Johnson, S. Tough, and Society of Obstetricians and Gynaecologists of Canada, “Delayed child-bearing.,” J. Obstet. Gynaecol. Canada JOGC = J. d’obstétrique gynécologie du Canada JOGC, vol. 34, no. 1, pp. 80–93, 2012.

[5] World Health Organization, “Sexual and reproductive health,” WHO, 2012. [Online]. Available: [Accessed: 15-Feb-2016].

[6] Public Health England, “Trends in the UK,” 2016. [Online]. Available: [Accessed: 15-Feb-2016].

[7] M. M. Hillemeier, C. S. Weisman, C. Chuang, D. S. Downs, J. McCall-Hosenfeld, and F. Camacho, “Transition to overweight or obesity among women of reproductive age.,” J. Womens. Health (Larchmt)., vol. 20, no. 5, pp. 703–10, May 2011.

[8] S. Bhattacharya, S. Pandey, S. Pandey, and A. Maheshwari, “The impact of female obesity on the outcome of fertility treatment,” J. Hum. Reprod. Sci., vol. 3, no. 2, p. 62, 2010.

[9] L. L.-Y. Wu, R. J. Norman, and R. L. Robker, “The impact of obesity on oocytes: evidence for lipotoxicity mechanisms,” Reprod. Fertil. Dev., vol. 24, no. 1, p. 29, 2012.

[10] A. B. Crujeiras and F. F. Casanueva, “Obesity and the reproductive system disorders: epigenetics as a potential bridge,” Hum. Reprod. Update, vol. 21, no. 2, pp. 249–261, Mar. 2015.

[11] A. Legge, R. Bouzayen, L. Hamilton, and D. Young, “The impact of maternal body mass index on in vitro fertilization outcomes,” J Obs. Gynaecol Can, vol. 36, no. 7, pp. 613–619, 2014.

[12] D. L. Zander-Fox, R. Henshaw, H. Hamilton, and M. Lane, “Does obesity really matter? The impact of BMI on embryo quality and pregnancy outcomes after IVF in women aged ≤38 years,” Aust. New Zeal. J. Obstet. Gynaecol., vol. 52, no. 3, pp. 270–276, Jun. 2012.

[13] E. Cardozo, M. E. Pavone, and J. E. Hirshfeld-Cytron, “Metabolic syndrome and oocyte quality,” Trends Endocrinol. Metab., vol. 22, no. 3, pp. 103–109, 2011.

[14] J. L. Bartha, F. Gonz??lez-Bugatto, R. Fern??ndez-Mac??as, N. L. Gonz??lez-Gonz??lez, R. Comino-Delgado, and B. Herv??as-Vivancos, “Metabolic syndrome in normal and complicated pregnancies,” Eur. J. Obstet. Gynecol. Reprod. Biol., vol. 137, no. 2, pp. 178–184, 2008.

[15] E. M. Chang, J. E. Han, H. H. Seok, D. R. Lee, T. K. Yoon, and W. S. Lee, “Insulin resistance does not affect early embryo development but lowers implantation rate in in vitro maturation-in vitro fertilization-embryo transfer cycle,” Clin. Endocrinol. (Oxf)., vol. 79, no. 1, pp. 93–99, 2013.

[16] L. Salzer, K. Tenenbaum-Gavish, and M. Hod, “Metabolic disorder of pregnancy (understanding pathophysiology of diabetes and preeclampsia),” Best Pract. Res. Clin. Obstet. Gynaecol., vol. 29, no. 3, pp. 328–338, Apr. 2015.

[17] D. B. Ehrenthal, N. D. Goldstein, P. Wu, S. Rogers, R. R. Townsend, and D. G. Edwards, “Arterial stiffness and wave reflection 1 year after a pregnancy complicated by hypertension,” J. Clin. Hypertens., vol. 16, no. 10, pp. 695–699, 2014.

[18] F. Vural, B. Vural, and Y. Çakıroğlu, “The Role of Overweight and Obesity in In Vitro Fertilization Outcomes of Poor Ovarian Responders,” Biomed Res. Int., vol. 2015, pp. 1–5, 2015.

[19] M. Jinno, K. Kondou, and K. Teruya, “Low-dose metformin improves pregnancy rate in in vitro fertilization repeaters without polycystic ovary syndrome: Prediction of effectiveness by multiple parameters related to insulin resistance,” Hormones, vol. 9, no. 2, pp. 161–170, 2010.

[20] L. O. Tso, M. F. Costello, L. E. T. Albuquerque, R. B. Andriolo, J. Marjoribanks, and C. R. MacEdo, “Metformin treatment before and during in vitro fertilization or intracytoplasmic sperm injection in women with polycystic ovary syndrome: Summary of a Cochrane review,” Fertility and Sterility, vol. 104, no. 3. pp. 542–544, 2015.

[21] L. Ciotta, M. Stracquadanio, I. Pagano, A. Carbonaro, M. Palumbo, and F. Gulino, “Effects of Myo-Inositol supplementation on oocyte’s quality in PCOS patients: A double blind trial,” Eur. Rev. Med. Pharmacol. Sci., vol. 15, no. 5, pp. 509–514, 2011.

[22] A. Pacchiarotti, G. Carlomagno, G. Antonini, and A. Pacchiarotti, “Effect of myo-inositol and melatonin versus myo-inositol, in a randomized controlled trial, for improving in vitro fertilization of patients with polycystic ovarian syndrome.,” Gynecol. Endocrinol., vol. 32, no. 1, pp. 1–5, 2015.

[23] C.-H. Kim, Y.-J. Lee, J.-B. Kim, K.-H. Lee, S.-K. Kwon, J.-W. Ahn, S.-H. Kim, H.-D. Chae, and B.-M. Kang, “Effect of Pioglitazone on Production of Regulated upon Activation Normal T-cell Expressed and Secreted (RANTES) and IVF Outcomes in Infertile Women with Endometriosis,” Dev. Reprod., vol. 17, no. 3, pp. 207–213, Sep. 2013.

[24] C. E. Minge, B. D. Bennett, R. J. Norman, and R. L. Robker, “Peroxisome proliferator-activated receptor-?? agonist rosiglitazone reverses the adverse effects of diet-induced obesity on oocyte quality,” Endocrinology, vol. 149, no. 5, pp. 2646–2656, 2008.

[25] L. G. Nardo, T. El-Toukhy, J. Stewart, A. H. Balen, and N. Potdar, “British Fertility Society Policy and Practice Committee: Adjuvants in IVF: Evidence for good clinical practice,” Hum. Fertil., vol. 18, no. 1, pp. 2–15, 2014.

[26] B. T. Bateman, S. Hernandez-Diaz, M. A. Fischer, E. W. Seely, J. L. Ecker, J. M. Franklin, R. J. Desai, C. Allen-Coleman, H. Mogun, J. Avorn, and K. F. Huybrechts, “Statins and congenital malformations: cohort study.,” BMJ, vol. 350, p. h1035, 2015.

[27] M. M. Costantine and K. Cleary, “Pravastatin for the prevention of preeclampsia in high-risk pregnant women.,” Obstet. Gynecol., vol. 121, no. 2 Pt 1, pp. 349–53, 2013.

[28] University of Birmingham, “The StAmP Trial: A Proof of Principle, Double-Blind, Randomised Placebo-Controlled, Multi Centre Trial of pravaStatin to Ameliorate Early Onset Pre-eclampsia,” 2013. [Online]. Available: . [Accessed: 15-Feb-2016].