Inflammatory and metabolic markers in relation to outcome of in vitro fertilization in a cohort of predominantly overweight and obese women

Henrik Svensson, Snorri Einarsson, Daniel Olausson, Linda Kluge, Christina Bergh, Staffan Edén, Malin Lönn, Ann Thurin-Kjellberg, Henrik Svensson, Snorri Einarsson, Daniel Olausson, Linda Kluge, Christina Bergh, Staffan Edén, Malin Lönn, Ann Thurin-Kjellberg

Abstract

For overweight and obese women undergoing in vitro fertilization (IVF) the pregnancy and live birth rates are compromised while the underlying mechanisms and predictors are unclear. The aim was to explore the association between adipose tissue-related inflammatory and metabolic markers and the pregnancy and live birth outcome of IVF in a cohort of predominantly overweight and obese women. Serum samples, fulfilling standardizing criteria, were identified from 195 women having participated in either the control (n = 131) or intervention (n = 64) group of a randomized controlled trial (RCT), seeking to evaluate the effect of a weight reduction intervention on IVF outcome in obese women. Serum high-sensitivity C-reactive protein (hsCRP) and the adipokines leptin and adipocyte fatty acid-binding protein (AFABP) were analyzed for the whole cohort (n = 195) in samples collected shortly before IVF [at randomization (control group), after intervention (intervention group)]. Information on age, anthropometry [BMI, waist circumference, waist-to-height ratio (WHtR)], pregnancy and live birth rates after IVF, as well as the spontaneous pregnancy rate, was extracted or calculated from collected data. The women of the original intervention group were also characterized at randomization regarding all variables. Eight women [n = 3 original control group (2.3%), n = 5 original intervention group (7.8%)] conceived spontaneously before starting IVF. BMI category proportions in the cohort undergoing IVF (n = 187) were 1.6/20.1/78.3% (normal weight/overweight/obese). The pregnancy and live birth rates after IVF for the cohort were 35.8% (n = 67) and 24.6% (n = 46), respectively. Multivariable logistic regression revealed that none of the variables (age, hsCRP, leptin, AFABP, BMI, waist circumference, WHtR) were predictive factors of pregnancy or live birth after IVF. Women of the original intervention group displayed reductions in hsCRP, leptin, and anthropometric variables after intervention while AFABP was unchanged. In this cohort of predominantly overweight and obese women undergoing IVF, neither low-grade inflammation, in terms of hsCRP, other circulating inflammatory and metabolic markers released from adipose tissue (leptin, AFABP), nor anthropometric measures of adiposity or adipose tissue distribution (BMI, waist, WHtR) were identified as predictive factors of pregnancy or live birth rate.Trial registration: ClinicalTrials.gov number, NCT01566929. Trial registration date 30-03-2012, retrospectively registered.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
Flowchart of study design.
Figure 2
Figure 2
Correlation between change in serum leptin concentration (ng/mL) and change in serum AFABP concentration (ng/mL) during intervention (rho = − 0.530, p < 0.001, n = 46).

References

    1. van der Steeg JW, Steures P, Eijkemans MJ, Habbema JD, Hompes PG, Burggraaff JM, et al. Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women. Hum. Reprod. 2008;23(2):324–328. doi: 10.1093/humrep/dem371.
    1. Wise LA, Rothman KJ, Mikkelsen EM, Sorensen HT, Riis A, Hatch EE. An internet-based prospective study of body size and time-to-pregnancy. Hum. Reprod. 2010;25(1):253–264. doi: 10.1093/humrep/dep360.
    1. Metwally M, Ong KJ, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence. Fertil. Steril. 2008;90(3):714–726. doi: 10.1016/j.fertnstert.2007.07.1290.
    1. Zhou Y, Li H, Zhang Y, Zhang L, Liu J, Liu J. Association of maternal obesity in early pregnancy with adverse pregnancy outcomes: A Chinese prospective cohort analysis. Obesity (Silver Spring) 2019;27(6):1030–1036. doi: 10.1002/oby.22478.
    1. Dokras A, Baredziak L, Blaine J, Syrop C, VanVoorhis BJ, Sparks A. Obstetric outcomes after in vitro fertilization in obese and morbidly obese women. Obstet. Gynecol. 2006;108(1):61–69. doi: 10.1097/01.AOG.0000219768.08249.b6.
    1. Cnattingius S, Villamor E, Johansson S, Edstedt Bonamy AK, Persson M, Wikstrom AK, et al. Maternal obesity and risk of preterm delivery. JAMA J. Am. Med. Assoc. 2013;309(22):2362–2370. doi: 10.1001/jama.2013.6295.
    1. Johansson S, Villamor E, Altman M, Bonamy AK, Granath F, Cnattingius S. Maternal overweight and obesity in early pregnancy and risk of infant mortality: A population based cohort study in Sweden. BMJ. 2014;349:g6572. doi: 10.1136/bmj.g6572.
    1. Bellver J, Ayllon Y, Ferrando M, Melo M, Goyri E, Pellicer A, et al. Female obesity impairs in vitro fertilization outcome without affecting embryo quality. Fertil. Steril. 2010;93(2):447–454. doi: 10.1016/j.fertnstert.2008.12.032.
    1. Luke B, Brown MB, Missmer SA, Bukulmez O, Leach R, Stern JE, et al. The effect of increasing obesity on the response to and outcome of assisted reproductive technology: a national study. Fertil. Steril. 2011;96(4):820–825. doi: 10.1016/j.fertnstert.2011.07.1100.
    1. Rittenberg V, Seshadri S, Sunkara SK, Sobaleva S, Oteng-Ntim E, El-Toukhy T. Effect of body mass index on IVF treatment outcome: An updated systematic review and meta-analysis. Reprod. Biomed. Online. 2011;23(4):421–439. doi: 10.1016/j.rbmo.2011.06.018.
    1. Bellver J, Pellicer A, Garcia-Velasco JA, Ballesteros A, Remohi J, Meseguer M. Obesity reduces uterine receptivity: Clinical experience from 9,587 first cycles of ovum donation with normal weight donors. Fertil. Steril. 2013;100(4):1050–1058. doi: 10.1016/j.fertnstert.2013.06.001.
    1. Petersen GL, Schmidt L, Pinborg A, Kamper-Jorgensen M. The influence of female and male body mass index on live births after assisted reproductive technology treatment: A nationwide register-based cohort study. Fertil. Steril. 2013;99(6):1654–1662. doi: 10.1016/j.fertnstert.2013.01.092.
    1. Provost MP, Acharya KS, Acharya CR, Yeh JS, Steward RG, Eaton JL, et al. Pregnancy outcomes decline with increasing body mass index: Analysis of 239,127 fresh autologous in vitro fertilization cycles from the 2008–2010 Society for Assisted Reproductive Technology registry. Fertil. Steril. 2016;105(3):663–669. doi: 10.1016/j.fertnstert.2015.11.008.
    1. Sermondade N, Huberlant S, Bourhis-Lefebvre V, Arbo E, Gallot V, Colombani M, et al. Female obesity is negatively associated with live birth rate following IVF: A systematic review and meta-analysis. Hum. Reprod. Update. 2019;25(4):439–451. doi: 10.1093/humupd/dmz011.
    1. Einarsson S, Bergh C, Friberg B, Pinborg A, Klajnbard A, Karlstrom PO, et al. Weight reduction intervention for obese infertile women prior to IVF: A randomized controlled trial. Hum. Reprod. 2017;32(8):1621–1630. doi: 10.1093/humrep/dex235.
    1. Scherer PE. Adipose tissue: From lipid storage compartment to endocrine organ. Diabetes. 2006;55(6):1537–1545. doi: 10.2337/db06-0263.
    1. Bohler H, Jr, Mokshagundam S, Winters SJ. Adipose tissue and reproduction in women. Fertil. Steril. 2010;94(3):795–825. doi: 10.1016/j.fertnstert.2009.03.079.
    1. Svensson H, Oden B, Eden S, Lonn M. Adiponectin, chemerin, cytokines, and dipeptidyl peptidase 4 are released from human adipose tissue in a depot-dependent manner: An in vitro system including human serum albumin. BMC Endocr. Disord. 2014;14:7. doi: 10.1186/1472-6823-14-7.
    1. Unamuno X, Gomez-Ambrosi J, Rodriguez A, Becerril S, Fruhbeck G, Catalan V. Adipokine dysregulation and adipose tissue inflammation in human obesity. Eur. J. Clin. Investig. 2018;48(9):e12997. doi: 10.1111/eci.12997.
    1. Johnson AR, Milner JJ, Makowski L. The inflammation highway: Metabolism accelerates inflammatory traffic in obesity. Immunol. Rev. 2012;249(1):218–238. doi: 10.1111/j.1600-065X.2012.01151.x.
    1. Radin RG, Sjaarda LA, Silver RM, Nobles CJ, Mumford SL, Perkins NJ, et al. C-Reactive protein in relation to fecundability and anovulation among eumenorrheic women. Fertil. Steril. 2018;109(2):232–239. doi: 10.1016/j.fertnstert.2017.10.025.
    1. Bellver J, Martinez-Conejero JA, Labarta E, Alama P, Melo MA, Remohi J, et al. Endometrial gene expression in the window of implantation is altered in obese women especially in association with polycystic ovary syndrome. Fertil. Steril. 2011;95(7):2335–2341. doi: 10.1016/j.fertnstert.2011.03.021.
    1. Broughton DE, Moley KH. Obesity and female infertility: Potential mediators of obesity's impact. Fertil. Steril. 2017;107(4):840–847. doi: 10.1016/j.fertnstert.2017.01.017.
    1. Glenn T, Harris AL, Lindheim SR. Impact of obesity on male and female reproductive outcomes. Curr. Opin. Obstet. Gynecol. 2019;31(4):201–206. doi: 10.1097/GCO.0000000000000549.
    1. Fruhbeck G, Busetto L, Dicker D, Yumuk V, Goossens GH, Hebebrand J, et al. The ABCD of obesity: An EASO position statement on a diagnostic term with clinical and scientific implications. Obes. Facts. 2019;12(2):131–136. doi: 10.1159/000497124.
    1. Smith GI, Mittendorfer B, Klein S. Metabolically healthy obesity: Facts and fantasies. J. Clin. Investig. 2019;129(10):3978–3989. doi: 10.1172/JCI129186.
    1. Jernas M, Palming J, Sjoholm K, Jennische E, Svensson PA, Gabrielsson BG, et al. Separation of human adipocytes by size: Hypertrophic fat cells display distinct gene expression. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2006;20(9):1540–1542.
    1. Zaadstra BM, Seidell JC, Van Noord PA, te Velde ER, Habbema JD, Vrieswijk B, et al. Fat and female fecundity: Prospective study of effect of body fat distribution on conception rates. BMJ. 1993;306(6876):484–487. doi: 10.1136/bmj.306.6876.484.
    1. Wass P, Waldenstrom U, Rossner S, Hellberg D. An android body fat distribution in females impairs the pregnancy rate of in-vitro fertilization-embryo transfer. Hum. Reprod. 1997;12(9):2057–2060. doi: 10.1093/humrep/12.9.2057.
    1. Li MC, Minguez-Alarcon L, Arvizu M, Chiu YH, Ford JB, Williams PL, et al. Waist circumference in relation to outcomes of infertility treatment with assisted reproductive technologies. Am. J. Obstet. Gynecol. 2019;220(6):578. doi: 10.1016/j.ajog.2018.11.1105.
    1. Kahnberg A, Enskog A, Brannstrom M, Lundin K, Bergh C. Prediction of ovarian hyperstimulation syndrome in women undergoing in vitro fertilization. Acta Obst. Gynecol. Scand. 2009;88(12):1373–1381. doi: 10.3109/00016340903287482.
    1. Kim J, Patounakis G, Juneau C, Morin S, Neal S, Bergh P, et al. The appraisal of body content (ABC) trial: Increased male or female adiposity does not significantly impact in vitro fertilization laboratory or clinical outcomes. Fertil. Steril. 2021;116:444–452. doi: 10.1016/j.fertnstert.2020.12.037.
    1. Insogna IG, Lee MS, Reimers RM, Toth TL. Neutral effect of body mass index on implantation rate after frozen-thawed blastocyst transfer. Fertil. Steril. 2017;108(5):770–776. doi: 10.1016/j.fertnstert.2017.08.024.
    1. Prost E, Reignier A, Leperlier F, Caillet P, Barriere P, Freour T, et al. Female obesity does not impact live birth rate after frozen-thawed blastocyst transfer. Hum. Reprod. 2020;35(4):859–865. doi: 10.1093/humrep/deaa010.
    1. Timpson NJ, Nordestgaard BG, Harbord RM, Zacho J, Frayling TM, Tybjaerg-Hansen A, et al. C-reactive protein levels and body mass index: Elucidating direction of causation through reciprocal Mendelian randomization. Int. J. Obes. (Lond.) 2011;35(2):300–308. doi: 10.1038/ijo.2010.137.
    1. Brouillet S, Boursier G, Anav M, Du BouletDeLaBoissiere B, Gala A, Ferrieres-Hoa A, et al. C-reactive protein and ART outcomes: A systematic review. Hum. Reprod. Update. 2020;26(5):753–773. doi: 10.1093/humupd/dmaa012.
    1. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 2004;89(6):2548–2556. doi: 10.1210/jc.2004-0395.
    1. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, et al. Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat. Med. 1995;1(11):1155–1161. doi: 10.1038/nm1195-1155.
    1. Jafarpour S, Khosravi S, Janghorbani M, Mansourian M, Karimi R, Ghiasi MR, et al. Association of serum and follicular fluid leptin and in vitro fertilization/ICSI outcome: A systematic review and meta-analysis. J. Gynecol. Obstet. Hum. Reprod. 2021;50(6):101924. doi: 10.1016/j.jogoh.2020.101924.
    1. Llaneza-Suarez D, Llaneza P, Gonzalez C, De-La-Fuente P, Garcia-Ochoa C, Garrido P, et al. Assessment of follicular fluid leptin levels and insulin resistance as outcome predictors in women undergoing in vitro fertilization-intracytoplasmic sperm injection. Fertil. Steril. 2014;102(6):1619–1625. doi: 10.1016/j.fertnstert.2014.09.012.
    1. Merhi Z, Buyuk E, Berger DS, Zapantis A, Israel DD, Chua S, Jr, et al. Leptin suppresses anti-Mullerian hormone gene expression through the JAK2/STAT3 pathway in luteinized granulosa cells of women undergoing IVF. Hum. Reprod. 2013;28(6):1661–1669. doi: 10.1093/humrep/det072.
    1. Kralisch S, Fasshauer M. Adipocyte fatty acid binding protein: A novel adipokine involved in the pathogenesis of metabolic and vascular disease? Diabetologia. 2013;56(1):10–21. doi: 10.1007/s00125-012-2737-4.
    1. Furuhashi M. Fatty acid-binding protein 4 in cardiovascular and metabolic diseases. J. Atheroscler. Thromb. 2019;26(3):216–232. doi: 10.5551/jat.48710.
    1. Engl J, Ciardi C, Tatarczyk T, Kaser S, Laimer M, Laimer E, et al. A-FABP–A biomarker associated with the metabolic syndrome and/or an indicator of weight change? Obesity (Silver Spring) 2008;16(8):1838–1842. doi: 10.1038/oby.2008.273.
    1. Wang P, Zhu Q, Peng H, Du M, Dong M, Wang H. Fatty acid-binding protein 4 in endometrial epithelium is involved in embryonic implantation. Cell. Physiol. Biochem. 2017;41(2):501–509. doi: 10.1159/000456886.
    1. Christofolini J, Maria Christofolini D, Zaia V, Bianco B, Barbosa CP. Body fat distribution influences ART outcomes. Gynecol. Endocrinol. Off. J. Int. Soc. Gynecol. Endocrinol. 2020;36(1):40–43. doi: 10.1080/09513590.2019.1630609.
    1. Frank AP, de Souza Santos R, Palmer BF, Clegg DJ. Determinants of body fat distribution in humans may provide insight about obesity-related health risks. J. Lipid Res. 2019;60(10):1710–1719. doi: 10.1194/jlr.R086975.
    1. Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Investig. 2017;127(1):1–4. doi: 10.1172/JCI92035.
    1. Arner P, Ryden M. Fatty acids, obesity and insulin resistance. Obes. Facts. 2015;8(2):147–155. doi: 10.1159/000381224.
    1. Cai WY, Luo X, Song J, Ji D, Zhu J, Duan C, et al. Effect of hyperinsulinemia and insulin resistance on endocrine, metabolic, and reproductive outcomes in non-PCOS women undergoing assisted reproduction: A retrospective cohort study. Front. Med. (Lausanne) 2021;8:736320. doi: 10.3389/fmed.2021.736320.
    1. Chang EM, Han JE, Seok HH, Lee DR, Yoon TK, Lee WS. 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.) 2013;79(1):93–99. doi: 10.1111/cen.12099.
    1. Tian L, Shen H, Lu Q, Norman RJ, Wang J. Insulin resistance increases the risk of spontaneous abortion after assisted reproduction technology treatment. J. Clin. Endocrinol. Metab. 2007;92(4):1430–1433. doi: 10.1210/jc.2006-1123.
    1. Jungheim ES, Macones GA, Odem RR, Patterson BW, Moley KH. Elevated serum alpha-linolenic acid levels are associated with decreased chance of pregnancy after in vitro fertilization. Fertil. Steril. 2011;96(4):880–883. doi: 10.1016/j.fertnstert.2011.07.1115.
    1. Fertility treatments in Sweden. National Report 2020. (The National Quality Registry for Assisted Reproduction (Q-IVF) Sweden, 2020).

Source: PubMed

3
订阅