UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
Lifestyle interventions for obese women before and during pregnancy: The
effect on pregnancy outcomes
Ruifrok, A.E.
Publication date
2014
Document Version
Final published version
Link to publication
Citation for published version (APA):
Ruifrok, A. E. (2014). Lifestyle interventions for obese women before and during pregnancy:
The effect on pregnancy outcomes.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.
Anneloes E. Ruifrok
LIFESTYLE INTERVENTIONS FOR OBESE
WOMEN BEFORE AND DURING
PREGNANCY
Ruifrok, Anneloes E.
Lifestyle Interventions for Obese Women before and during Pregnancy: The Effect on Pregnancy Outcomes
Proefschrift Amsterdam ISBN: 978-90-5335-854-2 © Copyright 2014 A.E. Ruifrok
All rights are reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without permission of the author.
Financial support for the printing of this thesis was kindly provided by the Graduate School AMC, Medical Dynamics, BMA B.V., and Goodlife Fertility.
Cover: RJ.G. Ruifrok i.c.w. A.E. Ruifrok Lay-out: RJ.G. Ruifrok (Grafixed) Printed by: Ridderprint B.V.
LIFESTYLE INTERVENTIONS FOR
OBESE WOMEN BEFORE AND
DURING PREGNANCY
THE EFFECT ON PREGNANCY OUTCOMES
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctor
aan de Universiteit van Amsterdam
op gezag van de Rector Magnificus
prof. dr. D.C. van den Boom
ten overstaan van een door het college
voor promoties ingestelde commissie,
in het openbaar te verdedigen
in de Agnietenkapel op
dinsdag 20 mei 2014, te 10:00 uur
door
Anneloes Elisabeth Ruifrok
geboren te Groningen
Promotor Prof. dr. B.W.J. Mol Prof. dr. C.J.M. de Groot Copromotor Dr. M.N.M. van Poppel Overige leden
Prof. dr. M. Wieringa-de Waard Prof. dr. J.A.M. van der Post Prof. dr. W. van Mechelen Prof. dr. R. Devlieger Dr. M.J.M. Serlie Dr. T.G.M. Vrijkotte
Paranimfen
Elsemieke G. Ruifrok Willem-Peter T. Ruifrok
Content
Chapter 1: General introduction 8
Chapter 2: Subfertiliteit bij vrouwen met overgewicht 18 Nederlands Tijdschrift voor Geneeskunde, 2006
Chapter 3: Insulin sensitizing drugs for weight loss in women of reproductive age who are overweight or obese:
Systematic review and meta-analysis 30
Human Reproduction Update, 2009 Chapter 4: Association between weight gain during
pregnancy and pregnancy outcomes after dietary and lifestyle interventions: A meta-analysis 52 American Journal of Perinatology, 2013
Chapter 5: The relationship of objectively measured physical activity and sedentary behaviour with gestational
weight gain and birth weight 72
Submitted
Chapter 6: Economic consequences of lifestyle and dietary interventions in pregnant women who are
overweight or obese: A budget impact analysis 84 Submitted
Chapter 7: Does body mass index influence sick leave before,
during and after pregnancy? 100
Submitted
Chapter 8: Study protocol: Differential effects of diet and physical activity based interventions in pregnancy on maternal and foetal outcomes: Individual patient data (IPD) meta-analysis and health economic
evaluation 114
Chapter 9: Global alignment, coordination and collaboration in perinatal research: the Global Obstetrics
Network (GONet) initiative 136
American Journal of Perinatology, 2013
Chapter 10: Summary and general discussion 146 Chapter 11: Summary in Dutch (Nederlandse Samenvatting) 162
Dankwoord 170
General introduction
...
CHAPTER
General introduction
10
Background
The increasing prevalence of obesity worldwide has forced the World Health Organization (WHO) to regard this as one of the priorities for reducing the ‘Global burden of disease’.1
In addition to long-term health consequences, the rising prevalence of obesity in women worldwide has implications for their reproductive outcome, and affects their chances of pregnancy. Also, the result of pregnancy may be adversely affected by obesity.
Obesity is associated with menstrual disorders and anovulation2-4 but
fertility is also decreased in women with regular menstrual cycles who are overweight.5;6 Furthermore, women, who are overweight or obese while
undergoing assisted reproduction, have lower pregnancy rates and higher miscarriage rates.7-9 During pregnancy, obesity leads to a significant
increase in pregnancy complications10;11 and difficulties during labour.12
Infants are at greater risk of congenital abnormalities13;14 and intrauterine
demise15;16 contributing to an increase in perinatal morbidity and mortality.
Not only pre-pregnancy obesity is related to adverse outcomes. Also excessive weight gain during pregnancy is associated with an increased risk of obstetrical, maternal and foetal complications, postpartum maternal weight retention, and also with an increased risk of obesity in the offspring.17-28
Excessive gestational weight gain and the associated postpartum weight retention contribute to the prevalence of women who are overweight or obese and increase the long-term risk of body weight-associated diseases, which impose a great pressure on health care.28-31
The Institute of Medicine (IOM) guidance in the US provides recommended weight gain ranges in pregnancy for normal, overweight and obese women based on observational data.32 In the absence of
validation of these recommendations in large interventional trials, the benefits of adhering to these weight gain guidelines during pregnancy are unclear. The economic evaluation commissioned by NICE acknowledged this limitation and considered that the assumed effects of weight changes on pregnancy outcomes were subject to strong assumptions.33 Currently,
the National Institute for Health and Clinical Excellence in the United Kingdom34 does not recommend specific weight gain targets in pregnancy
in the absence of robust data validated in interventional trials. Therefore, there is a clear need for establishing the relationship between gestational weight gain and pregnancy outcomes from randomised intervention trials.
11
1
Results of Recent Trials
Pre-pregnancy InterventionsNorman et al.35 showed in their review that reducing the pre-pregnancy
weight in overweight or obese women with infertility increases the chances of both spontaneous conception and conception after ovulation induction and assisted reproduction. Weight loss achieved by a lifestyle programme – a combination of diet and physical activity – leads to an increase in spontaneous pregnancies and pregnancies after fertility treatment.36 An
RCT of Hoeger et al.37 showed that in obese women with polycystic ovary
syndrome (PCOS), not the type of treatment (metformin versus lifestyle programme versus placebo), but the amount of weight reduction was the most important factor for the resumption of ovulation. These trials show that weight loss in infertile obese women should be considered as the first treatment.
In view of the low success rate of lifestyle interventions in achieving weight loss and even lower success rate for maintaining this weight loss, drug therapy for obesity in conjunction with the continuation of lifestyle changes could be an asset in the treatment of women with infertility.
Although insulin sensitising drugs are not considered anti-obesity drugs, evidence indicates that metformin therapy might contribute to weight loss.38;39 If metformin treatment does contribute to weight loss, treatment
of women of reproductive age with obesity and infertility could improve the chances of conception.
According to a randomised controlled trial (RCT), the combination of a lifestyle modification programme with drug therapy achieves more weight loss than a lifestyle programme alone.40
Interventions during Pregnancy
Many trials have been conducted evaluating the effect of different lifestyle interventions on gestational weight gain (GWG) and adverse pregnancy outcomes, which were recently reviewed and combined in a meta-analysis.41
Dietary and lifestyle interventions in pregnancy have been shown to significantly reduce gestational weight gain, and lead to reduced risk of pregnancy complications such as pre-eclampsia, gestational diabetes mellitus, gestational hypertension and preterm delivery without any reported adverse effects.42 In a subgroup analysis, a stronger effect was
observed in obese and overweight women. Dietary interventions seem to be more effective than physical activity.42 However, it must be noted
that the compliance with the interventions was either not assessed or insufficient in some trials. Furthermore, the relationship between GWG and pregnancy complications was not investigated.
Impact on Society
Worldwide working women of childbearing age are a vital part of the working population. Given the association between obesity and
12
pregnancy complications and obesity and sick leave in general,43-46 one
might expect that obese pregnant women would have an increased risk for sick leave. However, to date, the relationship between body mass index and sick leave in pregnant women has not been investigated.
Pre-pregnancy maternal obesity, and excessive weight gain in pregnancy impose an increasing pressure on health care resources,31;47;48
due to increase chance of pregnancy complications.
A reduction of the number of maternal and neonatal complications, for instance by decreasing GWG, might result in a decrease in health care cost during and after pregnancy. Previous meta-analysis already reported positive effects of lifestyle interventions in pregnancy on maternal and neonatal health.42 A reduction of the number of maternal and neonatal
complications, might result in a decrease in health care cost during pregnancy.
Little is known about the effect of GWG and pregnancy complications. Also the budget impact of lifestyle intervention is not yet clear. The potential economic consequences of providing a lifestyle intervention for overweight and obese women in pregnancy could be helpful to stimulate policymakers to advocate implementation of lifestyle interventions in pregnancy.
Aim of the Thesis
The aim of this thesis was to assess effects of weight-reduction interventions before, and lifestyle interventions during pregnancy on pregnancy related outcomes and gestational weight gain. In addition, we aimed to estimate costs to society associated with obesity and weight gain in pregnancy, in terms of monetary costs and in terms of sick leave.
Outline of this Thesis
Obesity is associated with a decreased fertility and an increased rate of complications during pregnancy. Chapter 2 shows an overview of the possible effects of obesity on fertility and pregnancy complications in women of reproductive age. In chapter 3 of this thesis we assessed the effects of insulin sensitising drugs on weight loss compared to diet or a lifestyle programme in overweight and obese women of reproductive age.
Lifestyle interventions in obese pregnant women reduce adverse maternal outcomes of pregnancy. However, the association between differences in gestational weight gain due to interventions and the actual reduction in complications is unknown. In chapter 4, the association between gestational weight gain and pregnancy complications was assessed. The relationship between sedentary behaviour and weight (gain) has been found in women and adolescent girls outside of pregnancy.49;50
13
1
During pregnancy, women in the United States spent more than half of the monitored day in sedentary behaviour.51 However, whether the amount
of time spent sedentary influences gestational weight gain or birth weight is currently unknown.
In chapter 5, the relationship of physical activity and sedentary behaviour in pregnancy with gestational weight gain and birth weight was determined.
Being overweight or obese during pregnancy and excessive weight gain increase the chance of complications, including among others maternal death, miscarriage, pre-eclampsia, gestational diabetes mellitus, postpartum haemorrhage.12;52 This imposes a great pressure on health
care.31;47;48 In chapter 6 we evaluated the budget impact of decreasing
the risk of pregnancy complications through lifestyle interventions.
In many cost-effectiveness analyses of interventions in pregnancy, only short term effects on health care consumption and associated costs were evaluated. However, sick leave associated with obesity and/or pregnancy complications might have a great impact on costs for society. To date, the relationship between body mass index and sick leave of pregnant women has not been investigated. In chapter 7 we assessed the relationship between BMI and sick leave before, and during pregnancy and one year postpartum.
Most meta-analyses are based on aggregated average outcomes per study, thereby limiting the statistical precision of the meta-analysis. Also, due to the aggregated data there is heterogeneity within and between the studies. An individual patient data (IPD) meta-analysis would overcome this problem. This approach provides adequate power to generate valid, reliable answers and to create models for decision analytic modelling for health economic evaluation.
We therefore plan an IPD meta-analysis to evaluate the differential effects of diet and physical activity based interventions on maternal and foetal outcomes. Chapter 8 describes the protocol for this IPD meta-analysis, which is conducted in international collaboration.
IPD meta-analyses and large clinical studies provide information and insight that are used to develop clinical guidelines. Many researchers have therefore initiated multicentre studies. In some situations, the activities of these groups have led to networks, through which multiple trials have been executed over a longer period of time. The Global Obstetrics Network (GONet) was formed to link the different types of networks. The expectation is that this will lead to better studies and more efficient use of resources. Chapter 9 explains the need of international collaboration and the mission, goals and structure of GONet.
14
References
1. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000;894: i-xii, 1-253.
2. Green BB, Weiss NS, Daling JR. Risk of ovulatory infertility in relation to body weight. Fertil Steril 1988;50:721-6.
3. Grodstein F, Goldman MB, Cramer DW. Body mass index and ovulatory infertility. Epidemiology 1994;5:247-50.
4. Lake JK, Power C, Cole TJ. Women’s reproductive health: the role of body mass index in early and adult life. Int J Obes Relat Metab Disord 1997;21:432-438.
5. Jensen TK, Scheike T, Keiding N, Schaumburg I, Grandjean P. Fecundability in relation to body mass and menstrual cycle patterns. Epidemiology 1999;10:422-8.
6. Van der Steeg JW, Steures P, Eijkemans MJ, Habbema JD, Hompes PG, Burggraaff JM, Oosterhuis GJ, Bossuyt PM, van der Veen F, Mol BW. Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women. Hum Reprod 2008;23:324-328.
7. Wang JX, Davies M, Norman RJ. Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study. BMJ 2000;321:1320-1. 8. Lintsen AM, Pasker-de Jong PC, Boer EJ de, Burger CW, Jansen CA, Braat DD,
et al. Effects of subfertility cause, smoking and body weight on the success rate of IVF. Hum Reprod 2005;20:1867-75.
9. Maheshwari A, Stofberg L, Bhattacharya S. Effect of overweight and obesity on assisted reproductive technology a systematic review. Hum Reprod Update 2007;13:433-444.
10. Cedergren MI. Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstet Gynecol 2004;103:219-224.
11. Weiss JL, Malone FD, Emig D, Ball RH, Nyberg DA, Comstock CH, Saade G, Eddleman K, Carter SM, Craigo SD et al. Obesity, obstetric complications and cesarean delivery rate: a population-based screening study. Am J Obstet Gynecol 2004;190:1091-1097.
12. Sebire NJ, Jolly M, Harris JP, Wadsworth J, Joffe M, Beard RW, et al. Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord 2001;25: 1175-82.
13. Waller DK, Mills JL, Simpson JL, Cunningham GC, Conley MR, Lassman MR, Rhoads GG. Are obese women at higher risk for producing malformed offspring? Am J Obstet Gynecol 1994;170:541-548.
14. Werler MM, Louik C, Shapiro S, Mitchell AA. Prepregnant weight in relation to risk of neural tube defects. J Am Med Assoc 1996;275: 1089-1092.
15. Stephansson O, Dickman PW, Johansson A, Cnattingius S. Maternal weight, pregnancy weight gain, and the risk of antepartum stillbirth. Am J Obstet Gynecol 2001;184:463-469.
16. Nohr EA, Bech BH, Davies MJ, Frydenberg M, Henriksen TB, Olsen J. Prepregnancy obesity and fetal death: a study within the Danish National Birth Cohort. Obstet Gynecol 2005;106:250-259.
17. Cedergren MI. Optimal gestational weight gain for body mass index categories. Obstet Gynecol 2007;110(4):759-764.
18. DeVader SR, Neeley HL, Myles TD, Leet TL. Evaluation of gestational weight gain guidelines for women with normal prepregnancy body mass index. Obstet Gynecol 2007;110(4):745-751.
19. Dietz PM, Callaghan WM, Cogswell ME, Morrow B, Ferre C, Schieve LA. Combined effects of prepregnancy body mass index and weight gain during
15
1
pregnancy on the risk of preterm delivery. Epidemiology 2006;17(2):170–177. 20. Hedderson MM, Gunderson EP, Ferrara A. Gestational weight gain and risk of
gestational diabetes mellitus. Obstet Gynecol 2010;115(3):597-604.
21. Olson CM. Achieving a healthy weight gain during pregnancy. Annu Rev Nutr 2008;28:411-423.
22. Rasmussen T, Stene LC, Samuelsen SO, et al. Maternal BMI before pregnancy, maternal weight gain during pregnancy, and risk of persistent positivity for multiple diabetes-associated autoantibodies in children with the high-risk HLA genotype: the MIDIA study. Diabetes Care 2009;32(10):1904-1906.
23. Siega-Riz AM, Siega-Riz AM, Laraia B. The implications of maternal overweight and obesity on the course of pregnancy and birth outcomes. Matern Child Health J 2006;10(5, Suppl): S153-S156.
24. Thorsdottir I, Torfadottir JE, Birgisdottir BE, Geirsson RT. Weight gain in women of normal weight before pregnancy: complications in pregnancy or delivery and birth outcome. Obstet Gynecol 2002;99(5 Pt 1):799-806.
25. Zhang X, Decker A, Platt RW, Kramer MS. How big is too big? The perinatal consequences of fetal macrosomia. Am J Obstet Gynecol 2008;198(5):e1–e6. 26. Oken E, Taveras EM, Kleinman KP, Rich-Edwards JW, Gillman MW. Gestational
weight gain and child adiposity at age 3 years. Am J Obstet Gynecol 2007;196(4):e1-e8.
27. Sharma AJ, Cogswell ME, Grummer Strawn LM. The association between pregnancy weight gain and childhood overweight is modified by mother’s pre pregnancy BMI [abstract]. Pediatr Res 2005;58:1038.
28. US Department of Health and Human Services. Healthy Eating and Physical Activity across your Life Span: Fit for Two: Tips for Pregnancy. NIDDK Weight Control Information Network. NIH Publication No. 02-5130. 2002.
29. Linné Y, Dye L, Barkeling B, Rössner S. Long-term weight development in women: a 15-year follow-up of the effects of pregnancy. Obes Res 2004;12(7):1166-1178.
30. Rooney BL, Schauberger CW. Excess pregnancy weight gain and long-term obesity: one decade later. Obstet Gynecol 2002;100(2): 245-252.
31. Galtier-Dereure F, Boegner C, Bringer J. Obesity and pregnancy: complications and cost. Am J Clin Nutr 2000;71(5, Suppl): 1242S-1248S.
32. Rasmussen KM, Yatkine AL, editors. Weight gain during pregnancy: re-examining the guidelines. Committee to Reexamine Institute of Medicine Pregnancy Weight Guidelines 2009.
33. Madan J, Chilcott J. Weight Management in Pregnancy: Economic Modelling. ScHARR Public Health Collaborating Centre 2012.
34. NICE public health guidance 27. Dietary interventions and physical activity interventions for weight management before, during and after pregnancy. National Institute for Health and Clinical Excellence 2010.
35. Norman RJ, Noakes M, Wu R, Davies MJ, Moran L, Wang JX. Improving reproductive performance in overweight/obese women with effective weight management. Hum Reprod Update 2004;10:267-80.
36. Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 1998;13:1502-1505.
37. Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril. 2004;82(2):421-9.
16
EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
39. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551-566.
40. Wadden TA, Berkowitz RI, Womble LG, Sarwer DB, Phelan S, Cato RK, Hesson LA, Osei SY, Kaplan R, Stunkard AJ. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med 2005;353:2111-2120.
41. Thangaratinam S, Rogozińska E, Jolly K, Glinkowski S, Duda W, Borowiack E, Roseboom T, Tomlinson J, Walczak J, Kunz R, Mol BW, Coomarasamy A, Khan KS. Interventions to reduce or prevent obesity in pregnant women: a systematic review. Health Technol Assess 2012;16(31):iii-iv, 1-191.
42. Thangaratinam S, Rogozinska E, Jolly K, Glinkowski S, Roseboom T, Tomlinson JW, Kunz R, Mol BW, Coomarasamy A, Khan KS. Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis of randomised evidence. BMJ 2012;344:e2088.
43. Neovius K, Johansson K, Kark M, Neovius M. Obesity status and sick-leave: a systematic review. Obes Rev 2009;10:17-27.
44. Neovius K, Neovius M, Kark M, Rasmussen F. Association between obesity status and sick-leave in Swedish men: nationwide cohort study. Eur J Public Health 2010;22:112-6.
45. Harvey SB, Glozier N, Carlton O, Mykletun A, Henderson M, Hotopf M, et al. Obesity and sickness absence: results from the CHAP study. Occupational Med 2010;60:362-8.
46. Van Duijvenbode DC, Hoozemans MJ, van Poppel MN, Proper KI. The relationship between overweight and obesity, and sick-leave: a systematic review. Int J Obes 2009;33:807-16.
47. UK: National Audit Office. Tackling obesity in England. Stationery Office, 2001. 48. Heslehurst N, Rankin J, Wilkinson JR, Summerbell CD. A nationally representative
study of maternal obesity in England, UK: trends in incidence and demographic inequalities in 619 323 births, 1989-2007. Int J Obes (Lond) 2010; 34:420-428. 49. Hu FB, Li TY, Colditz GA, Willett WC et al. Television watching and other
sedentary behaviors in relation to risk of obesity and type 2 diabetes mellitus in women. JAMA 2003;289(14):1785-1791.
50. Costigan SA, Barnett L, Plotnikoff RC et al. The Health Indicators Associated With Screen-Based Sedentary Behavior Among Adolescent Girls: A Systematic Review. J Adolesc Health 2013;52(4):382-392.
51. Evenson KR, Wen F. Prevalence and correlates of objectively measured physical activity and sedentary behavior among US pregnant women. Prev Med 2011; 53(1-2):39-43.
52. Cnattingius S, Bergström R, Lipworth L, Kramer MS. Prepregnancy weight and the risk of adverse pregnancy outcomes. N Engl J Med 1998;338(3):147-52.
Subfertiliteit bij vrouwen met
overgewicht
...
W.K.H. Kuchenbecker A.E. Ruifrok J.H.T. Bolster M.J. Heineman A. HoekNederlands Tijdschrift voor Geneeskunde 2006;150(45):2479-83
HOOFDSTUK
Subfertiliteit bij vrouwen met
overgewicht
...
W.K.H. Kuchenbecker A.E. Ruifrok J.H.T. Bolster M.J. Heineman A. HoekNederlands Tijdschrift voor Geneeskunde 2006;150(45):2479-83
20
Samenvatting
Wereldwijd en ook in Nederland neemt de prevalentie van overgewicht sterk toe. Naast langetermijneffecten voor de gezondheid heeft overgewicht als gevolg dat er bij vrouwen in de fertiele levensfase meer reproductieve stoornissen optreden.
Vrouwen met overgewicht zijn minder vruchtbaar dan vrouwen met een normaal gewicht. Bij overgewicht is de kans op een spontane zwangerschap kleiner, evenals de kans op zwangerschap bij ovulatie-inductie of bij toepassing van ondersteunende voortplantingstechnieken. De kans op een levendgeborene is kleiner ten gevolge van een verhoogd risico op een miskraam. Ook wordt de uitkomst van een zwangerschap nadelig beïnvloed door complicaties die met overgewicht samenhangen.
Een gewichtsverlies van 5-15% bij subfertiele vrouwen met overgewicht leidt tot een toename van de kans op spontane zwangerschappen en zwangerschappen na fertiliteitsbehandeling; dit gewichtsverlies is te bereiken door een caloriearm dieet, meer beweging en een verandering van het gedragspatroon.
21
2
Introductie
De toenemende prevalentie van overgewicht wereldwijd heeft de Wereldgezondheidsorganisatie genoodzaakt dit probleem aan te merken als een van de prioriteiten in de ‘global burden of disease’.1
Ook in Nederland neemt de prevalentie van overgewicht toe. Volgens de gegevens van het Centraal Bureau voor de Statistiek had in 2005 van de vrouwen met een leeftijd van 25-44 jaar 31,6% overgewicht en 8,5% obesitas (er is overgewicht bij een ‘body mass index’ (BMI) van 25-29,9 kg/m2 en er is ernstig overgewicht ofwel obesitas bij een BMI ≥30 kg/
m2)
(www.cbs.nl/nl-NL/menu/themas/mens-maatschappij/gezondheid-welzijn/cijfers/default.htm).
Naast langetermijneffecten voor de gezondheid heeft overgewicht bij vrouwen in de fertiele levensfase een negatieve invloed op de kans op een zwangerschap. Ook de uitkomst van de zwangerschap kan nadelig worden beïnvloed door overgewicht. In dit artikel geven wij inzicht in de gevolgen van overgewicht voor de fertiliteit van vrouwen en wij bespreken de consequenties van overgewicht voor zwangerschap en bevalling.
Pathofysiologische Mechanismen van Subfertiliteit bij Vrouwen in Samenhang met Overgewicht
Over het algemeen hebben vrouwen met overgewicht een regelmatige menstruele cyclus zonder aanwijzingen voor verstoringen van sekshormoonsynthese en -metabolisme. De meningen over het mechanisme dat leidt tot subfertiliteit bij vrouwen met een ovulatoire cyclus en overgewicht lopen uiteen; de genoemde oorzaken variëren van subtiele ovulatiestoornissen tot implantatiestoornissen.2
De duidelijkste oorzaak van subfertiliteit bij overgewicht is anovulatie. Algemeen wordt aangenomen dat hyperinsulinemie ten gevolge van de insulineresistentie die met overgewicht samenhangt, hierbij een centrale rol speelt.3 Insuline stimuleert de productie van androgenen via zijn
eigen receptoren en via activering van receptoren van insulineachtige groeifactor 1 (IGF-1) op de stromale cellen en thecacellen in het ovarium. Hyperinsulinemie vermindert de productie van sekshormoonbindende globuline (SHBG) door de lever. De verlaagde SHBG-spiegels en de toegenomen androgeensynthese leiden tot functionele hyperandrogenemie. Het versterkte androgeenmicromilieu rondom de zich ontwikkelende follikels en het synergistische effect van hyperinsulinemie en een verhoogde waarde van luteïniserend hormoon (LH) leiden tot stilstand van de folliculaire ontwikkeling, met als gevolg anovulatie. Toegenomen aromatisatie van androgenen tot oestrogenen in het vetweefsel leidt tot continu verhoogde oestrogeenspiegels die middels terugkoppeling naar de hypothalamus bijdragen tot afwijkingen van de pulsgenerator van gonadotrofine-‘releasing’ hormoon (GnRH), met als gevolg anovulatie.
Centrale vetdistributie gaat gepaard met hyperinsulinemie; het gaat daarbij voornamelijk om het viscerale abdominale vet. Vrije vetzuren van
22
het viscerale abdominale vet bereiken de lever via het portale veneuze systeem en leiden tot verminderde afbraak van insuline in de lever. Hyperinsulinemie en hyperandrogenemie dragen tevens bij tot accumulatie van visceraal abdominaal vet. Hyperinsulinemie, hyperandrogenemie en het viscerale abdominale vet hebben dus een potentiërend effect op elkaar. Op basis van de huidige kennis is dit het centrale mechanisme dat leidt tot de toename van de kans op onvruchtbaarheid ten gevolge van anovulatie bij obese vrouwen met centrale vetdistributie en met voornamelijk viscerale vetaccumulatie.
Het polycysteus-ovariumsyndroom (PCOS) is de meest voorkomende oorzaak van anovulatie. Insulineresistentie en viscerale vetaccumulatie bij PCOS spelen de belangrijkste rol in het ontstaan van anovulatie. Bij 65% van de PCOS-patiënten draagt overgewicht bij tot de pathofysiologische mechanismen van anovulatie.3
Spontane Conceptie en Anovulatoire Subfertiliteit
Uit de ‘British birth cohort study’ is onder meer gebleken dat een verhoogde BMI op 23-jarige leeftijd samenhangt met een toegenomen kans op het uitblijven van een zwangerschap tot op de leeftijd van 33 jaar (relatief risico (RR): 0,67; 95% betrouwbaarheidsinterval (BI): 0,52 - 0,87).4
Uit patiënt-controleonderzoeken en cohortonderzoeken blijkt dat overgewicht leidt tot anovulatoire subfertiliteit.5-7 Een prospectief, genest
patiënt-controleonderzoek binnen de ‘Nurses health study’ toonde aan dat bij een BMI >24 kg/m2 de kans op anovulatoire subfertiliteit is
toegenomen (RR: 1,3; 95% BI: 1,2 - 1,6) en bij een BMI >32 kg/m2 nog meer
(RR: 2,7; 95% BI: 2,0 - 3,7).5 In overeenstemming hiermee is in een onderzoek
onder 1880 subfertiele vrouwen gebleken dat reeds bij een BMI >27 kg/m2
de kans op anovulatoire subfertiliteit toeneemt (RR: 3,1; 95% BI: 2,2 - 4,4).6
Ook vrouwen met overgewicht en ovulatoire cycli hebben een verminderde kans op conceptie.8 Ondanks een regelmatige menstruele
cyclus is de tijdsduur vóór het optreden van een zwangerschap langer bij vrouwen met een BMI >25 kg/m2 dan bij vrouwen met een normaal
lichaamsgewicht (BMI: 19-25 kg/m2). Bij 500 vrouwen die kunstmatige
inseminatie met donorsemen ondergingen (91% van de vrouwen had een spontane cyclus) hing de afname van de kans op een conceptie meer samen met de vetaccumulatie op de taille dan met een verhoogde BMI.9
Ovulatie-inductie bij Vrouwen met Anovulatoire Subfertiliteit
Bij vrouwen met chronische anovulatie en subfertiliteit is ovulatie-inductie geïndiceerd om een zwangerschap mogelijk te maken. Clomifeencitraat, een relatieve oestrogeenreceptorblokker, is veelal het middel van eerste keus bij vrouwen met chronische anovulatie.10 De meeste studies met
betrekking tot ovulatie-inductie bij deze patiënten tonen aan dat er met een toename van de BMI hogere clomifeencitraatdoseringen noodzakelijk zijn voor een goed resultaat.11;12 De kans op succesvolle ovulatie-inductie
neemt af met toename van de BMI.13
23
2
zwangerschap optreedt, wordt overgegaan op ovulatie-inductie middels gonadotrofinen. Bij vrouwen met overgewicht zijn hogere doseringen gonadotrofinen nodig voor het slagen van de behandeling. Er bestaat bij deze groep vrouwen geen verband tussen de BMI en de kans op zwangerschap na succesvolle ovulatie-inductie.14
Ovariële Hyperstimulatie en Intra-uteriene Inseminatie
Bij langdurige onbegrepen subfertiliteit of bij subfertiliteit op basis van een geringe mannelijke factor (gedefinieerd als ‘volume van ejaculaat (in ml) × dichtheid (in aantal spermatozoa per ml) × percentage beweeglijke zaadcellen per ejaculaat >10 miljoen’) kan men de kans op een zwangerschap vergroten door het toepassen van ovariële hyperstimulatie (waarbij meerdere follikels tot ontwikkeling komen) in combinatie met intra-uteriene inseminatie.15 Uit de bestaande literatuur is geen eenduidige
conclusie te trekken betreffende de invloed van overgewicht op de kans op een zwangerschap bij deze behandeling.2;16 Bij 1144 vrouwen die ovariële
hyperstimulatie (met behulp van clomifeencitraat of gonadotrofinen) en donorinseminatie ondergingen, bleek de kans op zwangerschap kleiner te zijn naarmate de BMI hoger was.16 Uit data van 4509 voltooide cycli
na ovariële hyperstimulatie in combinatie met intra-uteriene inseminatie constateerde men dat de cumulatieve zwangerschapskans in de groepen met overgewicht en obesitas respectievelijk 30 en 50% groter was dan in de groep vrouwen met een normaal gewicht.2 De auteurs stelden
dat door ovariële hyperstimulatie een onderliggend ovulatieprobleem bij deze obese patiënten werd opgeheven, waardoor zonder verdere beperking bevruchting en implantatie konden plaatsvinden.2 Er zijn geen
data te vinden over het percentage meerlingzwangerschappen in deze patiëntencategorie.
Ondersteunende Voortplantingstechnieken
Na falen van ovariële hyperstimulatie of intra-uteriene inseminatie of bij ernstige mannelijke subfertiliteit (gedefinieerd als ‘volume × dichtheid × percentage beweeglijke zaadcellen per ejaculaat ≤10 miljoen’) wordt overgegaan op ondersteunende voortplantingstechnieken (in-vitrofertilisatie (ivf) en bij ernstige sperma-afwijkingen ook intracytoplasmatische sperma-injectie (ICSI)).
Oudere publicaties laten geen effect zien van overgewicht op de zwangerschapskans na ondersteunende voortplantingstechnieken.17;18
Recentere studies, met grotere patiëntenaantallen, laten wel een progressieve afname zien van de kans op zwangerschap met toename van de BMI.19-21
Er is een positieve correlatie waargenomen tussen de BMI en de totale duur van gecontroleerde ovariële hyperstimulatie en tussen de BMI en het totale aantal gebruikte ampullen gonadotrofinen. Er is een negatieve correlatie waargenomen tussen de BMI en het aantal oöcyten verkregen bij de follikelpunctie. Overgewicht heeft geen effect op het percentage bevruchte oöcyten na ondersteunende voortplantingstechnieken en op
24
de kwaliteit van de ontstane embryo’s.19
In een retrospectief onderzoek van 3586 vrouwen die ondersteunende voortplantingstechnieken (ivf, ICSI) ondergingen, werd er met toename van de BMI een lineaire afname van de kans op zwangerschap gezien met een oddsratio (OR) van 0,81 (95% BI: 0,68 - 0,97) bij overgewicht en een OR van 0,50 (95% BI: 0,32 - 0,77) bij ernstig overgewicht.21 In een Nederlands
retrospectief onderzoek bij 8457 vrouwen die hun eerste ivf-behandeling ondergingen, hing een BMI >27 kg/m2 samen met een afname van de kans
op een levendgeborene met 33%.20 Vooral bij vrouwen met onverklaarde
subfertiliteit was deze kans afgenomen, maar ook bij subfertiliteit door een tubaire of een mannelijke factor was de kans op een levendgeborene kleiner.
Risico op Miskraam
Vrouwen met overgewicht en subfertiliteit hebben een grotere kans op een miskraam na spontane conceptie.22 Ook zwangerschappen op basis
van ovulatie-inductie bij vrouwen met overgewicht eindigen vaker met een miskraam.23 Vrouwen met het PCOS hebben eveneens een kleinere
kans op een levendgeborene vanwege het verhoogde risico op een miskraam.24 Ook bij zwangerschappen die ontstaan zijn na toepassing van
ondersteunende voortplantingstechnieken gaat een toename van de BMI gepaard met een lineaire toename van de kans op een miskraam.25
Zwangerschapsziekten en -complicaties
Zwangeren met overgewicht hebben een toegenomen kans op diabetes gravidarum, hypertensieve ziekten (pre-eclampsie en zwangerschapshypertensie) en foetale macrosomie.26;27 De foetus
heeft een grotere kans op congenitale afwijkingen28;29 en intra-uteriene
vruchtdood.30;31 Bij zwangeren met overgewicht wordt de baring vaker
ingeleid. Er vinden bij hen meer kunstverlossingen plaats, de kans op schouderdystocie en geboortetrauma is groter, de apgar scores zijn lager en het percentage keizersneden is driemaal zo hoog als bij zwangeren zonder overgewicht.27;32 De keizersneden zijn lastiger uit te voeren en
postoperatief worden vaker wondcomplicaties en diepe veneuze trombose waargenomen.33 Overgewicht bij zwangeren gaat dus
gepaard met een toegenomen perinatale morbiditeit en sterfte, en met een toegenomen maternale morbiditeit.
Interventie gericht op Gewichtsverlies
Gezien de consequenties van overgewicht bij vrouwen met subfertiliteit doet zich de vraag voor of gewichtsverlies de kans op zwangerschap en de kans op een levendgeborene vergroot. Uit een uitgebreide review blijkt dat gewichtsverlies niet alleen de kans op spontane zwangerschappen vergroot, maar ook de kans op zwangerschappen na toepassing van ovulatie-inductie en ondersteunende voortplantingstechnieken.34 Bij
vrouwen met anovulatie vergroot 5-15% gewichtsverlies de kans op spontane ovulaties en dientengevolge de kans op zwangerschap.35-38
25
2
Afname van de insulineresistentie, daling van de hyperandrogenemie en stijging van de SHBG-waarde zijn de cruciale fysiologische mechanismen waardoor na gewichtsverlies weer ovulaties optreden. Bij PCOS-patiënten met overgewicht is vooral verlies van centraal vet noodzakelijk voor herstel van spontane ovulatie.39
Uit een observationeel onderzoek blijkt dat gewichtsverlies door middel van een lifestyleprogramma – bestaand uit een caloriearm dieet en meer beweging, gefaciliteerd door begeleiding van individu en groep – leidt tot een toename van spontane zwangerschappen en van zwangerschappen na fertiliteitsbehandeling, hetgeen resulteert in een aanzienlijke kostenbesparing.40
Behandeling van PCOS-patiënten met metformine vergroot de kans op spontane ovulatie, vooral door een vermindering van de insulineresistentie.41 Randomisatie van obese patiënten met PCOS in een
groep met metforminebehandeling, een groep met placebo of een groep met een lifestyleprogramma liet zien dat niet de aard van de behandeling, maar de mate van gewichtsverlies bepalend is voor herstel van spontane ovulatie.42 Een dubbelblind, placebogecontroleerd onderzoek van obese
PCOS-patiënten toonde dat gewichtsverlies door implementatie van een lifestyleprogramma leidt tot herstel van de normale menstruele cyclus en de ovulatie; metforminebehandeling bleek geen meerwaarde te hebben.43
Farmacotherapie middels sibutramine of orlistat leidt tot statistisch significant meer gewichtsverlies en tot een betere handhaving van het verlaagde gewicht dan dieet alleen.44 Met het oog op de veiligheid
van de ongeboren vrucht kan het gebruik van deze twee middelen voor gewichtsverlies bij subfertiele vrouwen niet worden aanbevolen. Bij zwangerschappen na bariatrische chirurgie wegens morbide obesitas is in oudere literatuur een verhoogd risico voor de foetus op congenitale afwijkingen, intra-uteriene groeiretardatie en partus praematurus beschreven.45 Zwangerschappen die ontstaan waren
na laparoscopische plaatsing van een verstelbare maagband, met suppletie van cyanocobalamine (vitamine B12) en foliumzuur tijdens de graviditeit, hadden volgens recentere literatuur dezelfde uitkomsten als zwangerschappen van controlepatiënten die dezelfde BMI hadden en geen operatie ondergingen.46 Het voordeel van de verstelbare maagband
is dat de mate van restrictie van de maag kan worden aangepast tijdens de zwangerschap.
Conclusie
Vrouwen met overgewicht hebben een verminderde kans op een spontane zwangerschap en op een zwangerschap na fertiliteitsbehandeling. Verder is de kans op een levendgeborene kleiner ten gevolge van een verhoogd risico op een miskraam. Gewichtsverlies is noodzakelijk om de kans op zwangerschap te vergroten en het risico op zwangerschapsgerelateerde complicaties te beperken. Gewichtsverlies
26
vergroot tevens de kans op ovulatie-inductie en zwangerschappen op basis van ondersteunende voortplantingstechnieken en verbetert de kans op een levendgeborene door afname van het miskraamrisico. In het kader van gerichte interventie bij subfertiliteit in samenhang met obesitas bestaat er behoefte aan grotere gerandomiseerde onderzoeken naar de effectiviteit en kosteneffectiviteit van diverse interventies die gericht zijn op gewichtsverlies, zoals lifestyleverandering, medicamenteuze behandeling en bariatrische chirurgie.
27
2
Referenties
1. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000;894: i-xii, 1-253.
2. Wang JX, Warnes GW, Davies MJ, Norman RJ. Overweight infertile patients have a higher fecundity than normal-weight women undergoing controlled ovarian hyperstimulation with intrauterine insemination. Fertil Steril. 2004;81:1710-2. 3. Pasquali R, Pelusi C, Genghini S, Cacciari M, Gambineri A. Obesity and
reproductive disorders in women. Hum Reprod Update. 2003;9:359-72.
4. Lake JK, Power C, Cole TJ. Women’s reproductive health: the role of body mass index in early and adult life. Int J Obes Relat Metab Disord. 1997;21:432-8. 5. Rich-Edwards JW, Goldman MB, Willett WC, Hunter DJ, Stampfer MJ, Colditz
GA, et al. Adolescent body mass index and infertility caused by ovulatory disorder. Am J Obstet Gynecol. 1994;171:171-7.
6. Grodstein F, Goldman MB, Cramer DW. Body mass index and ovu latory infertility. Epidemiology. 1994;5:247-50.
7. Green BB, Weiss NS, Daling JR. Risk of ovulatory infertility in relation to body weight. Fertil Steril. 1988;50:721-6.
8. Jensen TK, Scheike T, Keiding N, Schaumburg I, Grandjean P. Fecundability in relation to body mass and menstrual cycle patterns. Epidemiology. 1999;10:422-8.
9. 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;306:484-7.
10. Beck JI, Boothroyd C, Proctor M, Farquhar C, Hughes E. Oral antioestrogens and medical adjuncts for subfertility associated with anovulation [Cochrane review]. Cochrane Database Syst Rev. 2005;(1):CD002249.
11. Dickey RP, Taylor SN, Curole DN, Rye PH, Lu PY, Pyrzak R. Relationship of clomiphene dose and patient weight to successful treatment. Hum Reprod. 1997;12:449-53.
12. Lobo RA, Gysler M, March CM, Goebelsmann U, Mishell jr DR. Clinical and laboratory predictors of clomiphene response. Fertil Steril. 1982;37:168-74. 13. Imani B, Eijkemans MJ, Velde ER te, Habbema JD, Fauser BC. Predictors of
patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab. 1998;83:2361-5.
14. McClure N, McQuinn B, McDonald J, Kovacs GT, Healy DL, Burger HG. Body weight, body mass index, and age: predictors of menotropin dose and cycle outcome in polycystic ovarian syndrome? Fertil Steril. 1992;58:622-4.
15. Hughes EG. The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Hum Reprod. 1997;12:1865-72.
16. Koloszar S, Daru J, Kereszturi A, Zavaczki Z, Szollosi J, Pal A. Effect of female body weight on efficiency of donor AI. Arch Androl. 2002;48:323-7.
17. Lashen H, Ledger W, Bernal AL, Barlow D. Extremes of body mass do not adversely affect the outcome of superovulation and in-vitro fertilisation. Hum Reprod. 1999;14:712-5.
18. Lewis CG, Warnes GM, Wang XJ, Matthews CD. Failure of body mass index or body weight to influence markedly the response to ovarian hyperstimulation in normal cycling women. Fertil Steril. 1990;53:1097-9.
19. Fedorcsak P, Dale PO, Storeng R, Ertzeid G, Bjercke S, Oldereid N, et al. Impact of overweight and underweight on assisted reproduction treatment. Hum Reprod. 2004;19:2523-8.
28
20. Lintsen AM, Pasker-de Jong PC, Boer EJ de, Burger CW, Jansen CA, Braat DD, et al. Effects of subfertility cause, smoking and body weight on the success rate of IVF. Hum Reprod. 2005;20:1867-75.
21. Wang JX, Davies M, Norman RJ. Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study. BMJ. 2000;321:1320-1. 22. Lashen H, Fear K, Sturdee DW. Obesity is associated with increased risk of first
trimester and recurrent miscarriage: matched casecontrol study. Hum Reprod. 2004;19:1644-6.
23. Hamilton-Fairley D, Kiddy D, Watson H, Paterson C, Franks S. Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotrophin. Br J Obstet Gynaecol. 1992;99:128-31.
24. Al-Azemi M, Omu FE, Omu AE. The effect of obesity on the outcome of infertility management in women with polycystic ovary syndrome. Arch Gynecol Obstet. 2004;270:205-10.
25. Wang JX, Davies MJ, Norman RJ. Obesity increases the risk of spontaneous abortion during infertility treatment. Obes Res. 2002;10:551-4.
26. Weiss JL, Malone FD, Emig D, Ball RH, Nyberg DA, Comstock CH, et al. Obesity, obstetric complications and cesarean delivery rate – a population-based screening study. Am J Obstet Gynecol. 2004;190:1091-7.
27. Cedergren MI. Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstet Gynecol. 2004;103:219-24.
28. Waller DK, Mills JL, Simpson JL, Cunningham GC, Conley MR, Lassman MR, et al. Are obese women at higher risk for producing malformed offspring? Am J Obstet Gynecol. 1994;170:541-8.
29. Werler MM, Louik C, Shapiro S, Mitchell AA. Prepregnant weight in relation to risk of neural tube defects. JAMA. 1996;275:1089-92.
30. Stephansson O, Dickman PW, Johansson A, Cnattingius S. Maternal weight, pregnancy weight gain, and the risk of antepartum stillbirth. Am J Obstet Gynecol. 2001;184:463-9.
31. Nohr EA, Bech BH, Davies MJ, Frydenberg M, Henriksen TB, Olsen J. Prepregnancy obesity and fetal death: a study within the Danish National Birth Cohort. Obstet Gynecol. 2005;106:250-9.
32. Sebire NJ, Jolly M, Harris JP, Wadsworth J, Joffe M, Beard RW, et al. Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord. 2001;25:1175-82.
33. Perlow JH, Morgan MA. Massive maternal obesity and perioperative cesarean morbidity. Am J Obstet Gynecol. 1994;170:560-5.
34. Norman RJ, Noakes M, Wu R, Davies MJ, Moran L, Wang JX. Im proving reproductive performance in overweight/obese women with effective weight management. Hum Reprod Update. 2004;10:267-80.
35. Clark AM, Ledger W, Galletly C, Tomlinson L, Blaney F, Wang X, et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod. 1995;10:2705-12.
36. Hollmann M, Runnebaum B, Gerhard I. Effects of weight loss on the hormonal profile in obese, infertile women. Hum Reprod. 1996;11:1884-91.
37. Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol (Oxf ). 1992;36:105-11.
38. Moran LJ, Noakes M, Clifton PM, Tomlinson L, Galletly C, Norman RJ. Dietary composition in restoring reproductive and metabolic physiology in overweight
29
2
women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:812-9.
39. Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab. 1999;84:1470-4.
40. Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod. 1998;13:1502-5.
41. Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome [Cochrane review]. Cochrane Database Syst Rev. 2003;(3):CD003053.
42. Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril. 2004;82:421-9.
43. Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Hum Reprod. 2006;21:80-9.
44. Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int J Obes Relat Metab Disord. 2003;27:1437-46.
45. Knudsen LB, Kallen B. Intestinal bypass operation and pregnancy outcome. Acta Obstet Gynecol Scand. 1986;65:831-4.
46. Dixon JB, Dixon ME, O’Brien PE. Birth outcomes in obese women after laparoscopic adjustable gastric banding. Obstet Gynecol. 2005;106(5 Pt 1):965-72.
Insulin sensitizing drugs for weight
loss in women of reproductive
age who are overweight or obese:
Systematic review and meta-analysis
...
A.E. Ruifrok W.K.H. Kuchenbecker A. Hoek P. Middleton R.J. NormanHuman Reproduction Update 2009;15(1):57-68
CHAPTER
3
Insulin sensitizing drugs for weight
loss in women of reproductive
age who are overweight or obese:
Systematic review and meta-analysis
...
A.E. Ruifrok W.K.H. Kuchenbecker A. Hoek P. Middleton R.J. NormanHuman Reproduction Update 2009;15(1):57-68
32
Abstract
ObjectiveWomen of reproductive age, who are overweight or obese, are prone to infertility. Weight loss in these women leads to increased fecundity, higher chances of conception after infertility treatment and improved pregnancy outcome. In spite of the advantages, most patients have difficulty in losing weight and often regain lost weight over time. This review assesses whether treatment with insulin sensitising drugs contributes to weight loss, compared with diet or a lifestyle modification programme.
Methods
After a systematic search of the literature, only randomised controlled trials (RCTs), investigating the effect of insulin sensitising drugs on weight loss compared with placebo and diet and/or a lifestyle modification programme, were included. Subjects were restricted to women of reproductive age. The main outcome measure was change in body mass index (BMI).
Results
Only 14 trials, unintentionally all but two on women with polycystic ovary syndrome (PCOS) only, were included in the analysis. Treatment with metformin showed a statistically significant decrease in BMI compared with placebo (weighted mean difference, 20.68; 95% CI 21.13 to 20.24). There was some indication of greater effect with high-dose metformin (>1500 mg/day) and longer duration of therapy (>8 weeks). Limitations were power, low use of intention-to-treat analysis and heterogeneity of the studies.
Conclusion
A structured lifestyle modification programme to achieve weight loss should still be the first line treatment in obese women with or without PCOS. Adequately powered RCTs are required to confirm the findings of this review and to assess whether the addition of high-dose metformin therapy to a structured lifestyle modification programme might contribute to more weight loss.
33
3
Introduction
The rising prevalence of obesity in women worldwide has implications for their reproductive outcome. Obesity is associated with menstrual disorders and anovulation (Hartz et al., 1979; Green et al., 1988; Grodstein et al., 1994; Lake et al., 1997) but fertility is also decreased in women with regular menstrual cycles who are overweight (Jensen et al., 1999; van der Steeg et al., 2008). Furthermore, women, who are overweight or obese while undergoing assisted reproduction, have lower pregnancy rates and higher miscarriage rates (Wang et al., 2000; Lintsen et al., 2005; Maheshwari et al., 2007). During pregnancy, obesity leads to a significant increase in pregnancy complications (Cedergren, 2004; Weiss et al., 2004) and difficulties during labour (Sebire et al., 2001). Infants are at greater risk of congenital abnormalities (Waller et al., 1994; Werler et al., 1996) and intrauterine demise (Stephansson et al., 2001; Nohr et al., 2005) contributing to an increase in perinatal morbidity and mortality.
Obesity is characterised by insulin resistance and consequent hyperinsulinaemia. Hyperinsulinaemia contributes to anovulatory infertility by increased ovarian androgen secretion (Poretsky, 1991; Dunaif, 1997). In women with polycystic ovary syndrome (PCOS), insulin enhances intraovarian steroidogenesis by interacting with luteinising hormone (LH) leading to inappropriate advancement of granulosa cell differentiation and arrest of follicle growth (Franks et al., 1996; Willis et al., 1996).
The cornerstone of the treatment of obesity should be based on lifestyle changes by diet, exercise and behavioural modification (NIH, 1998). In obese women with anovulatory infertility, weight loss leads to spontaneous ovulation and improves the chances of spontaneous conception (Kiddy et al., 1992; Guzick et al., 1994; Clark et al., 1995; Hollmann et al., 1996). In obese women with PCOS, a minimum of 5% loss of abdominal fat is essential for the resumption of spontaneous ovulation (Huber-Buchholz et al., 1999). An intensive lifestyle modification programme improves the chances of spontaneous conception and conception during fertility treatment (Clark et al., 1998). Pre-pregnancy weight loss can reduce the incidence of gestational diabetes (Glazer et al., 2004).
In view of the low success rate in achieving weight loss and even lower success rate for maintaining this weight loss, drug therapy for obesity in conjunction with the continuation of lifestyle changes is advised according to obesity guidelines (NIH, 1998). According to a randomised controlled trial (RCT), the combination of a lifestyle modification programme with drug therapy, achieves more weight loss than a lifestyle programme alone (Wadden et al., 2005). Orlistat and sibutramine, two approved anti-obesity drugs, should, however, not be used in women who anticipate conception because of lack of safety data on their use during early pregnancy.
Insulin sensitising drugs are not considered anti-obesity drugs even though some evidence indicates that metformin therapy might contribute to weight loss (Knowler et al., 2002). A systematic review confirming the effectiveness of metformin for ovulation induction in women with PCOS,
34
could not demonstrate that metformin contributes to weight loss (Lord et al., 2003). Another review on the same topic did, however, demonstrate a contribution of metformin to weight loss (Harborne et al., 2003). A recent RCT comparing three ovulation induction modalities (metformin and placebo, metformin and clomiphene, clomiphene and placebo) in women with PCOS also showed more weight loss in women treated with metformin (Legro et al., 2007).
If metformin treatment does contribute to weight loss, treatment of women of reproductive age with obesity and infertility could improve the chances of conception. Data on the safety of metformin use in the first trimester are re-assuring (Gilbert et al., 2006; Lilja and Mathiesen, 2006).
The objective of this review was to assess whether treatment of women, of reproductive age who are overweight or obese, with insulin sensitising agents contributes to weight loss in comparison to placebo and diet and/ or a lifestyle modification programme.
Materials and Methods
The following clinical comparisons were assessed: (i) The effectiveness of insulin sensitising drugs for losing weight compared with placebo, with or without a diet/lifestyle programme. (ii) The side-effects and drop-out rate reported by women taking these drugs. (iii) The most effective insulin sensitising drug for losing weight, compared with each other, with or without a diet/lifestyle modification programme.
Data sources
Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EmBASE were searched up to and including August 2007. Only RCTs were included.
Main keywords used for this search were body weight, BMI, obesity, RCT, diet, insulin sensitising drugs and weight loss (see Appendix 1 for the full list of keywords).
Hand-searching was performed on the references used in the included studies and relevant review articles were meticulously searched for related articles. Authors were contacted for missing data or questions regarding the methodology.
Study selection
Titles and abstracts identified through the search strategies were independently screened by two reviewers (A. Ruifrok, W. Kuchenbecker). Articles were discarded if they did not meet the inclusion criteria. Full text articles were obtained of studies for potential inclusion. Independent review of the trials was undertaken by the same two reviewers to assess the quality and characteristics of the studies. Differences in opinion between the reviewers on selected articles were settled by consensus.
The subjects were women of reproductive age who are overweight (Body mass index (BMI) 25-29.9 kg/m2)) or obese (BMI ≥30 kg/m2) according
35
3
to accepted diagnostic criteria (NIH, 1998) and who were deemed eligible for weight loss measures. Studies that included pre-pubertal and postmenopausal women were excluded.
Main intervention
Treatment with insulin sensitising drugs: metformin, pioglitazone, rosiglitazone or d-chiro-inositol. Treatment with metformin was assessed in two subanalyses according to the daily dosage of ≤1500 or >1500 mg. This dosage cut-off for metformin was used because most initial studies used the dosage of 500 mg tablets three times daily (low dose) and later studies using 1000 mg two times daily or 850 mg tablets two to three times daily (high dose).
Comparison interventions
One or more of the following: placebo only or placebo with diet advice or a lifestyle modification programme. The primary outcome measure was change in BMI in kilogram per square metre. Secondary outcomes were drop-out rates and side-effects caused by the drugs.
Data synthesis and analysis
The effect was measured as weighted mean difference (WMD) and 95% confidence intervals (CI), using RevMan for the analysis. Data from the 14 trials were stratified over two main interventions, and subanalyses were performed on four co-interventions while still maintaining adequate numbers of patients for analysis.
For statistical analysis, standard deviations (SDs) were required. Hence, for all trials, in which 95% CI or standard error of the means (SEM) were given, these values were converted into SDs. In two trials (Fleming et al., 2002; Kjotrod et al., 2004) more expanded calculations were needed to derive the SDs.
Quality assessment
Trial quality was assessed on minimisation of selection bias, performance bias, attrition bias and detection bias. Assessment of the quality of allocation concealment was graded in four categories: adequate (A), unclear (B), inadequate (C) or not given (D). Other trial characteristics assessed were differences in baseline values, non-compliance, standardised outcome measures, drop-out rate, the extent of losses to follow-up, side-effects, blinding methods and whether analysis was by intention to treat.
In the statistical analysis, the WMD was used to express the effect of each continuous outcome. Heterogeneity in the data was noted and cautiously explored using certain characteristics of the study, particularly assessments of quality. In order to examine the stability of the results in relation to a number of factors, sensitivity analyses were performed. These analyses included quality of allocation concealment, blinding, treatment length over eight weeks, high or low dose of metformin, inclusion BMI and ethnicity.
36
Results
Search resultsThe search strategy revealed 31 trials eligible for inclusion in this review. After studying these publications, 17 trials were excluded (see separate reference list in Appendix 2) and the data of the remaining 14 trials were analysed. See Table 1 of included studies for full details of the 14 included trials (extended version of Table I hosted on website of Human Reproduction Update).
The 14 included studies randomised 649 women with 20 subjects in the smallest trials (Pasquali et al., 2000; Gambineri et al., 2004) and 143 in the largest trial (Tang et al., 2006).
Eleven of these trials were stated to be double-blind and two single-blind. One did not state the blinding method (Mitkov et al., 2006).
In three trials, randomisation was performed by centre (Nestler and Jakubowicz, 1996; Kjotrod et al., 2004; Tang et al., 2006) and in three trials the randomisation was computer generated (Vandermolen et al., 2001; Fleming et al., 2002; Yarali et al., 2002).
Pasquali et al. (2000) packaged drug and placebo and labelled according to subject number. Then randomisation was performed in blocks of four.
One trial stated that it ‘randomly placed’ its subjects (Gambineri et al., 2004), two trials numbered the participants sequentially (Jakubowicz et al., 2001; Kocak et al., 2002). However, Kocak et al., (2002), randomised patients by order of admission, resulting in a quasi-randomised study. Two studies used random number tables (Kilicdag et al., 2005; Ortega-Gonzalez et al., 2005) and two (Crave et al., 1995; Mitkov et al., 2006) did not state the method of randomisation.
In four studies, a power calculation was performed (Fleming et al., 2002; Kjotrod et al., 2004; Kilicdag et al., 2005; Tang et al., 2006), while the other nine did not mention a sample size calculation. In three trials, an analysis by intention-to-treat was stated to have been performed (Vandermolen et al., 2001; Fleming et al., 2002; Kjotrod et al., 2004).
The analysis of metformin versus thiazolidinediones was included even though these three trials tested two different thiazolidinediones: rosiglitazone and pioglitazone.
The analysis comparing the duration of trials was included as the effectiveness of the drugs involved might be correlated with the duration of its use.
Five trials were included in the ‘duration ≤ 8 weeks’ arm (Nestler and Jakubowicz, 1996; Jakubowicz et al., 2001; Vandermolen et al., 2001; Kocak et al., 2002; Yarali et al., 2002), lasting 35 days to 7–8 weeks. Six trials were included in the ‘duration >8 weeks’ arm (Crave et al., 1995; Pasquali et al., 2000; Fleming et al., 2002; Gambineri et al., 2004; Kjotrod et al., 2004; Tang et al., 2006), lasting from 16 weeks to 6 months.
The criteria for diet or no-diet were not very strict. When mention was made of diet or lifestyle adaptations, the trial was coded as diet,
37
3
even if compliance to diet was not assessed. In seven of the included studies, no mention was made of a diet (Nestler and Jakubowicz, 1996; Jakubowicz, 2001; Vandermolen et al., 2001; Kocak et al., 2002; Yarali et al., 2002; Kilicdag et al., 2005; Mitkov et al., 2006). In two trials (Gambineri et al., 2004; Ortega-Gonzalez et al., 2005), the women were instructed not to modify their usual eating or exercise patterns during the study period, these trials were coded as ‘no diet’.
In the other five trials, diet as co-intervention was implemented with a variety of criteria (Crave et al., 1995; Pasquali et al., 2000; Gambineri et al., 2004; Kjotrod et al., 2004; Tang et al., 2006). Pasquali et al. (2000) and Gambineri et al. (2004) placed the women on a standardised hypo caloric diet (1200–1400 kCal daily) for the first month, and continuing dietary treatment for the rest of the study period. Crave et al. (1995) placed the women on a low fat low caloric diet (1500 kCal daily with 30% fat). Kjotrod et al. (2004) mentioned diet and lifestyle modification without specifying the intervention. The patients in the trial of Tang et al. (2006) received standardised dietary advice from a research dietician aiming for a calorie reduction of 500 kCal per day.
In one of the 12 trials, clomiphene citrate (CC) was used as a co-intervention (Vandermolen et al., 2001). In this trial, all participants received CC for the first 5 days of the first cycle. With ovulation, the CC dose did not change, but with persistent anovulation, the dosage of CC was increased by 50 mg/day for the next cycle.
All studies used for this review were fully published in peer reviewed journals. Ten of the included trials were single centre studies (Crave et al., 1995; Pasquali et al., 2000; Jakubowicz et al., 2001; Fleming et al., 2002; Kocak et al., 2002; Kjotrod et al., 2004; Gambineri et al., 2004; Kilicdag et al., 2005; Ortega-Gonzalez et al., 2005; Mitkov et al., 2006) and four trials were multicentre (Nestler and Jakubowicz, 1996; Vandermolen et al., 2001; Yarali et al., 2002; Tang et al., 2006).
Unintentionally all studies, except two (Crave et al., 1995; Pasquali et al., 2000), were found to be on women with PCOS. The diagnostic criteria for PCOS broadly followed the National Institute of Health consensus criteria (anovulation and hyperandrogenemia with exclusion of other endocrinopathies) or the diagnostic criteria of the Rotterdam consensus meeting (Rotterdam criteria, 2004). The following criteria were used to define overweight/obesity: in three trials all women required a BMI >28 kg/m2 (Gambineri et al., 2004; Kjotrod et al., 2004; Mitkov et al., 2006) and
in one trial (Nestler and Jakubowicz, 1996) all participants required a BMI ≥27.5 kg/m2. The remaining trials (Crave et al., 1995; Pasquali et al., 2000;
Jakubowicz et al., 2001; Fleming et al., 2002; Kocak et al., 2002; Yarali et al., 2002; Kilicdag et al., 2005; Mitkov et al., 2006; Tang et al., 2006) did not specify their criteria; seven of these trials had an average BMI at baseline >28 kg/m2 in both treatment arms and in three (Crave et al., 1995; Kilicdag
et al., 2005; Mitkov et al., 2006) the average BMI in both treatment arms at baseline was >25 kg/m2.
