University of Groningen. Lifestyle and reproduction Mutsaerts, Meike

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1 University of Groningen Lifestyle and reproduction Mutsaerts, Meike IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2015 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Mutsaerts, M. (2015). Lifestyle and reproduction [S.l.]: [S.n.] Copyright Other than for strictly personal use, 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), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 CHAPTER 9 SUMMARY AND GENERAL DISCUSSION

3 CH 9 The purpose of this thesis was to investigate the effect of modifiable lifestyle factors on fecundity, pregnancy complications and perinatal outcome, and the effect of lifestyle intervention aiming at weight loss in obese subfertile women on pregnancy chances, gestational complications and perinatal outcome. As our research focussed on the influence of lifestyle factors in a general and a subfertile population, this summary and general discussion is divided in two main parts. 1. Influence of lifestyle factors in a general population 1.1 Summary of the results In the first part of this thesis, the aim was to gain insight in the influence of maternal and paternal lifestyle factors on reproductive health in a general population. Knowledge of these influences is especially relevant for health care providers involved in preconception counselling in general populations of reproductive age. In chapter 2 our goal was to identify predictors of a couple s fecundity. For this purpose, we investigated the effect of several maternal and paternal lifestyle and socio-demographic factors on time to pregnancy (TTP) in 1924 parents of children participating in the GECKO (Groningen Expert Centre for Kids with Obesity) Drenthe study, a Dutch population-based birth cohort. Maternal non-modifiable factors including age, parity, menstrual cycle length, prior contraceptive use and educational level were identified as predictors of a couple s fecundity. Neither maternal nor paternal modifiable lifestyle factors, such as body mass index (BMI), smoking, alcohol use, and physical activity, had an independent influence on fecundity. The aim of chapter 3 was to investigate whether maternal and paternal lifestyle factors might influence the risk of hypertensive pregnancy complications, gestational diabetes (GDM), spontaneous preterm birth and small-for-gestational-age (SGA) infants. To investigate this, we analysed the data of 2264 parents of children participating in the GECKO Drenthe study. As expected, the study revealed that increased maternal pre-pregnancy BMI was associated with increased risk of hypertensive pregnancy complications, GDM and decreased risk of SGA, after adjustment for confounding by biological and sociodemographic factors. Maternal smoking during pregnancy was independently associated with increased risk of SGA. In contrast, paternal lifestyle factors did not have an independent effect on the investigated adverse pregnancy outcomes, although maternal and paternal lifestyle factors were positively correlated. In chapter 4 we investigated whether there was a dose-response relation between maternal pre-pregnancy BMI and risk of congenital anomalies. A case-control study was performed using data from EUROCAT (European Registration of Congenital Anomalies and Twins Northern Netherlands database), a Dutch population-based registry of congenital anomalies. We found a positive dose-response effect between maternal pre-pregnancy BMI and risk of neural tube defects (NTDs). No doseresponse relations could be identified between maternal pre-pregnancy BMI and other investigated birth defects. However, we did demonstrate an increased risk of a child affected by a respiratory anomaly in obese women, and an increased risk of the birth of a child with a congenital heart defect (CHD) in obese women who smoked. Class III obese women (BMI > 40 kg/m²) women were at a markedly increased risk of offspring affected by eye anomalies, clefts, digestive anomalies and urinary anomalies. 174

4 CH Reflection on the results of influence of lifestyle factors in fertile populations We showed that well-known non-modifiable maternal factors, such as age, parity and menstrual cycle length influenced fecundity, measured as TTP, in a fertile population (chapter 2). In contrast, modifiable maternal lifestyle factors such as body weight and smoking behaviour were not associated with fecundity, but were associated with increased risk of hypertensive pregnancy complications, GDM, and SGA and NTD-affected children (chapter 3 and 4). We could not demonstrate an effect of paternal factors on fecundity, on the investigated pregnancy complications or on pregnancy outcome after adjusting for maternal factors. We did demonstrate positive correlations between maternal and paternal lifestyle factors, implicating that unhealthy lifestyle is usually present in both partners of a couple. Preconception counselling aims to detect unhealthy lifestyle behaviour of a couple in order to optimise health and lifestyle prior to conception (1). In the general introduction, we outlined which known factors impact fecundity, pregnancy course and perinatal outcome. The results of our studies add evidence to the existing literature. However, our results should be interpreted with some caution. All three studies had a retrospective study design, and are therefore prone to recall bias, planning bias, selection bias, misclassification bias, and inclusion bias (2,3). The number of obese women, heavy drinkers and heavy smokers in the GECKO Drenthe cohort was relatively low, and could have been too small to detect a significant effect. Although we were able to investigate a variety of lifestyle and socio-demographic factors, other possibly relevant factors such as caffeine intake, diet or occupational exposures were not investigated. Taking the results and these limitations into account, we can conclude that couples of proven fertility, with a lifestyle characterised by moderate smoking and/or drinking are not expected to have a shorter TTP by optimising their lifestyle. Preconception counselling should specifically be aimed at women, because female factors such as overweight and smoking behaviour are well-known risk factors for pregnancy complications and poor neonatal outcome (4-11). The results demonstrated in chapter 3 and 4 are in concordance with these well-known associations. Women with overweight or obesity should be informed on their increased risk of a child affected by NTD. Obese women, specifically class III obese women, must be counselled on their possible increased risk of other major congenital anomalies such as respiratory anomalies, eye anomalies, clefts, digestive anomalies or urinary anomalies. Smoking cessation should be strongly encouraged in obese women, given their increased risk of a CHD-affected child. Possible pathophysiological explanations for the associations between maternal prepregnancy BMI and increased risk of these major congenital anomalies are not well known, but different body distribution of folate in obese women (12,13) or deficiency of other nutrients such as zinc, which are commonly seen in obese women (14), are supposed to be involved (15). Paternal factors did not have an independent effect on pregnancy complications and outcome. However, as unhealthy lifestyle is likely to be present in both partners of a couple (chapter 2 and 3), and given the fact that women are less likely to optimise their lifestyle if their partners continue their unhealthy lifestyle (16), both partners should actively be 175

5 CH 9 involved in preconception counselling in order to encourage them to optimise their lifestyle. Since we were only able to investigate a limited number of potential paternal risk factors, and given the fact that conclusive evidence on this topic is lacking, more research should be performed on the influence of paternal factors. In addition, the effectiveness of modifying female and male behaviour on perinatal outcome should be investigated. 1.3 Implications for clinical practice In the Netherlands, the guideline preconception care is used by general practitioners involved in preconception counselling (17). The guideline is extensive and informative, and the general practitioners are instructed to involve both partners of a couple in preconception counselling. Based on our results, the following recommendations for updating this guideline could be made: Couples of proven fertility, with a lifestyle characterised by moderate smoking and/ or drinking are not expected to have a shorter TTP if they optimise their lifestyle. Women with overweight and obesity, specifically women with a BMI 40 kg/m², should be counselled regarding their increased risk of offspring affected with NTD. They should also be counselled on their possible increased risk of other major congenital anomalies such as CHDs, eye anomalies, clefts, digestive anomalies or urinary anomalies. Obese women who smoke should be encouraged to stop smoking in order to reduce the risk of CHD in their offspring. Unhealthy lifestyle is likely to be present in both partners of a couple. As women are less likely to optimise their lifestyle if their partners continue their unhealthy lifestyle, their partners should be encouraged to modify their behaviour as well. 2. Influence of weight and weight reduction on reproduction in a subfertile population 2.1 Summary of the results The aim of the second part of the thesis was to assess the influence of overweight and obesity in subfertile women on fertility treatment, and the effectiveness of lifestyle intervention aiming at weight reduction prior to fertility treatment. In chapter 5 we performed a systematic review of the literature regarding the association between overweight and the occurrence of complications following assisted reproductive technology (ART), as well as pregnancy outcomes in terms of clinical pregnancy, ongoing pregnancy and live birth rates. Fourteen studies, including data of women, reported on the association between overweight and complications during or after ART. Six reported on ovarian hyperstimulation syndrome (OHSS), seven on multiple pregnancies and six on ectopic pregnancies. In none of the studies a positive association between overweight and ART complications was observed. The pooled odds ratios (ORs) for overweight versus normal weight for OHSS, multiple pregnancy and ectopic pregnancy were 1.0 (95% CI 0.77 to 1.3), 0.97 (0.91 to 1.04) and 0.96 (0.54 to 1.7) respectively. Twenty-seven studies, including women, reported on BMI and the success of ART. The pooled ORs for overweight versus normal-weight on live birth, ongoing and clinical pregnancy rates following ART were 0.90 (95% CI 0.82 to 1.0), 1.01 (0.75 to 1.4) and 0.94 (0.69 to 1.3), respectively. In chapter 6 we systematically reviewed the literature on the effect of lifestyle intervention 176

6 CH 9 programs (LIPs) in overweight and obese subfertile women. Fifteen studies were identified, of which ten reported drop-out rates (median drop-out rate 24% (range: 0-31%)). Four studies reported baseline characteristics of drop-outs, but predictors of drop-out could not be identified. Weight loss and pregnancy rates were lower in women who dropped out than in women who completed the LIPs. In chapter 7 the study protocol of the LIFEstyle study is described. The LIFEstyle study was a multicentre RCT in which the costs and effectiveness of a six-month LIP prior to fertility treatment versus immediate fertility treatment in obese subfertile women were investigated. The LIP aimed at 5-10% weight loss relative to the original body weight and consisted of the combination of an energy-restricted healthy diet, increase of physical activity and behavioural modification. After six months, in case no ongoing pregnancy had been achieved, these patients started with fertility treatment according to the Dutch fertility guidelines (18). In the immediate fertility treatment arm, fertility treatment was forthwith started, independent of the woman s BMI. The primary outcome was the vaginal birth of a healthy singleton born at term (19), secondary outcomes included live birth, ongoing and clinical pregnancy, miscarriage, mode of conception, fertility treatment cycles and complications, pregnancy complications, perinatal outcome, changes in body weight, quality of life and costs after a follow-up period of 24 months. Our study was registered in the Dutch Trial Registry (NTR 1530) and the protocol was published before data analyses (20). In chapter 8 the results of the LIFEstyle study are presented. We randomly allocated 290 women to lifestyle intervention (LIP arm) and 287 to immediate fertility treatment. In the LIP arm, 41 women (14%) quitted the LIP within 6 months due to spontaneous ongoing pregnancy, 63 (22%) discontinued the LIP for other reasons (drop-outs), and 186 women (64%) completed the LIP. Mean weight change in LIP completers and drop-outs was -4.4 kg (standard deviation (SD) 5.8). In the immediate fertility treatment arm, mean weight change in the same period in non-pregnant women was -1.1 kg (SD 4.3) (p < 0.001). Mean weight loss in women who completed the LIP (N=186) was 5.3 kg (SD 6.1), 80 of them (43%) lost 5% of their original body weight. In the intention-to-treat analysis, 76 (27%) women reached the primary outcome, which was the vaginal birth of a healthy singleton born at term, in the LIP arm, versus 100 (35%) in the immediate fertility treatment arm (RR 0.77, 95% CI 0.60 to 0.99) within the follow-up (FU) period of 24 months. Inclusion of data of pregnancies conceived within, but ended after FU, resulted in 90 (32%) versus 111 (39%) vaginal births of healthy singletons at term, leading to a RR of 0.82 (95% CI 0.65 to 1.02). The number of ongoing pregnancies was 150 (54%) and 167 (59%) respectively (RR 0.91, 95% CI 0.97 to 1.05) within FU. In the LIP arm, 73 ongoing pregnancies were conceived naturally (26%) versus 46 in the immediate fertility treatment arm (16%) (RR 1.6, 95% CI 1.2 to 2.2). Complications due to fertility treatment, pregnancy and perinatal outcome were comparable in both arms. The per-protocol analyses, in which drop-outs were excluded, revealed that women allocated to the LIP arm had comparable vaginal birth rates of healthy singletons at term (31% versus 35%) within the FU period of 24 months. Moreover, they received significantly less fertility treatment than women allocated to the immediate fertility treatment arm (69% versus 81% of women). 177

7 CH 9 Exploratory analysis revealed that, within the LIP arm, more weight loss was associated with higher live birth rates. Live birth rate in women who lost > 6.6% of their original body weight was 62%, while live birth rate in women who lost < 3.0% of their original body weight was 34% (p = 0.001). 2.2 Reflection on the results of influence of weight and weight reduction in a subfertile population From the systematic review performed on complications following ART in overweight women (chapter 5), we conclude that overweight women are not at increased risk of OHSS, multiple pregnancies or ectopic pregnancies. However, this conclusion should be interpreted with caution as data on the topic were scarce. Serious complications like infection, haemorrhage, thrombo-embolism or even mortality were not documented in relation to BMI. Recently, a consensus document was published in which it was recommended to systematically collect and report adverse events in clinical trials on fertility treatment (21). Given the results of our review, we can only underscore this recommendation. Overweight influences the efficacy of ART treatment negatively, with a reduction of 10% in live birth rates (chapter 5). Our results are confirmed by the review by Rittenberg et al. (2011), which was published in the same period as our study (22). They found a similar pooled OR (0.84, 95% CI 0.76 to 0.92) for live birth rates in overweight women compared with normal-weight women. Live birth rates in obese women were decreased as well, when compared to normal-weight women (0.80, 95% CI 0.71 to 0.90). LIPs are currently regarded as first choice treatment for women with obesity and subfertility (23,24), but only small studies have been conducted on the effect of LIPs on reproductive outcome in this patient population (25). Weight loss counteracts the negative effects of female obesity on reproductive health, in which hyperinsulinaemia, hyperandrogenism and accumulation of intra-abdominal fat play an important role (26-28). The insulin resistance leads to prolonged follicle growth or even follicle arrest (29), decreased oocyte quality (30) and putatively decreased endometrial receptivity (31). Weight loss in obese subfertile women is associated with a decrease in insulin resistance and free androgen levels, leading to resumption of ovulation in anovulatory women (32,33). The underlying mechanism of the positive effect of weight loss on reproductive outcome in ovulatory women is still unclear. Given the apparent benefits of weight reduction in obese subfertile women and the lack of large RCTs in which the effect of LIPs aimed at weight reduction has been investigated, we conducted a multicentre RCT in which a LIP prior to fertility treatment was compared with immediate fertility treatment in obese subfertile women (chapter 7 and 8). Although the study demonstrated that the scheduled LIP prior to fertility treatment was not superior to immediate fertility treatment in terms of vaginal births of healthy singletons at term within 24 months FU, it was superior in terms of spontaneously achieved ongoing pregnancies, which resulted in a decreased need for fertility treatment. Moreover, we estimated the effect of the LIP preceding fertility treatment in an extended FU period, by collecting data of all pregnancies conceived within the FU of 24 months, but ended after FU. This resulted in comparable cumulative vaginal birth rates of healthy singletons at term in both arms, and again higher spontaneous pregnancies in the LIP arm. This suggests that women 178

8 CH 9 participating in a LIP prior to fertility treatment have longer TTP, but decreased need for fertility treatment. Women who either completed the LIP prior to fertility treatment or conceived during the LIP had a similar vaginal birth rate of healthy singletons at term, and similar TTP, as women who immediately started with fertility treatment. In addition, they needed less fertility treatments. Mean weight loss in women who completed the LIP was 5.1% of the mean original body weight. We can only speculate whether a more intensive LIP might have been more effective in gaining more weight loss and higher live birth rates. Especially, because additional attendance for visits could have led to an increased drop-out rate. Moreover, a study of Clark et al. (1998) (34), in which the effect of a very intensive LIP in obese subfertile women was investigated, indeed showed more weight loss, but comparable live birth rates. This suggests that weight loss of approximately 5% is already effective in increasing live birth rates in this patient population. Drop-out rate of the LIP in the LIFEstyle study was comparable to drop-out rates in other LIPs for overweight and obese subfertile women (chapter 6). Adherence to a LIP is associated with increased weight loss, and is therefore crucial for a LIP to become successful (35). From the results of the LIFEstyle study and the review on drop-out rates in overweight and obese subfertile women (chapter 6), it is obvious that drop-out is detrimental for spontaneous pregnancy chances and live birth rates. Early identification of overweight and obese subfertile women prone for drop-out might increase adherence rates, for instance by adjustment of the LIP. Unfortunately, we have not been able to identify predictors for dropout so far (chapter 6). Women who dropped out of the LIP in the LIFEstyle study refrained more often from further fertility treatment. We can only speculate about the underlying reasons. It is conceivable that some women were ashamed of their incapacity to lose weight and therefore did not contact the fertility clinic for further treatment. Other reasons might be that women considered themselves ineligible for fertility treatment due to their weight or that clinics restricted fertility treatment to women below a certain BMI. Although we did not observe differences in complication rate due to fertility treatment, in pregnancy complications, and no differences in perinatal outcome in both arms of the LIFEstyle study, the study was not powered to detect significant differences in these secondary outcome measures. 2.3 Implications for clinical practice Recently, Koning et al. (2014) stated that obese women should be informed about the impact of their weight and encouraged to lose weight. However, if the woman is unable to do so, it is unjustifiable to withhold fertility treatment as long as other women who are at higher risk of complications are treated (e.g. women with advanced age or with diabetes type I) (36). One could disagree with the abovementioned argument, because age and diseases such as diabetes type I are non-modifiable factors and weight is a modifiable one, albeit a difficult modifiable lifestyle factor for many patients. Health care providers have the responsibility to inform couples in whom the woman is overweight or obese about the possible negative impact of increased body weight on spontaneous pregnancy chances, pregnancy chances following fertility treatment, 179

9 CH 9 increased miscarriage rates, increased risk of gestational complications, perinatal risks and the negative impact on long-term health of their future child. In addition, the benefits of weight loss (i.e. increase in spontaneous pregnancy chances, decreased need for fertility treatment and possible positive effect on pregnancy complications and perinatal outcome) should be emphasised. A structured LIP of at least six months aiming at weight reduction should be offered as a first choice to all overweight and obese subfertile women, in particular to women with a BMI 29. Realistic goals regarding the amount of expected weight loss should be set, and time the LIP takes and the importance of completing the LIP should be discussed prior to the start of the LIP. Ideally, the LIP itself should include procedures to actively approach women who drop-out, to prevent them from refraining from further treatment. Women should feel comfortable to inform the health care provider when they experience themselves to be incapable or unmotivated to complete the LIP. Women not completing the LIP should be invited to discuss motivational issues and further treatment options. If the health care provider is convinced that a woman seriously tried to lose weight, but is not capable to do so or to continue the LIP, and that further guidance of the woman will not result in additional weight loss, fertility treatment should be considered. In this respect, however, health care providers should still be aware of the increased anaestatic risk in (morbidly) obese women (37) as well as limited visualisation by ultrasound caused by increased fat deposition in the soft tissues of the pelvis. This might affect the complication rate and impair the effectiveness of fertility treatment. In morbidly obese women (BMI 40 kg/m2), bariatric surgery (BS) preceding fertility treatment could be an option. One could argue that fertility clinics have the responsibility to offer a LIP to women as part of their responsibility to provide the best available care, provided that a tariff for this service could be invoiced to the health care insurance companies. To maintain general health care affordable in The Netherlands, the LIP could also be provided in the primary care setting. Literature shows that clinical weight loss can be reached in LIP offered by primary care providers (38,39). Commercial programmes could provide the same service as well, but then the women must pay the LIP themselves. This might lead to a division in the healthcare for couples from lower income versus those with higher income, which in our opinion, is not justifiable. The time involved with following a LIP, which may be in excess of six months, might be a reason for women with advanced age to refuse to participate in a LIP. There is some evidence that, as patients reach the age of 36 years, the effect of age on IVF outcome appears to be stronger than BMI (40). Sub analyses in the LIFEstyle study will be performed in order to investigate the effect of the LIP in older women (up to 39 years). As these analyses have not been performed yet, recommendations on this topic will follow in future. Is there a place for bariatric surgery? BS has been suggested an option for morbidly obese women or women with a BMI 35 kg/m² and associated co-morbidity (41), incapable of losing a substantial amount of weight. BS is superior to LIPs in achieving and maintaining long-term substantial weight loss (42). Average weight loss after 1-2 years following BS is 20-32% of the original body weight (43). 180

10 CH 9 In a retrospective study of 110 obese subfertile women, 69 became pregnant after BS (44). The pregnancies proceeded without complications and ended in live births. In a systematic review and meta-analysis in which 5361 women who got pregnant after BS were included (45), it was demonstrated that those women had about half the risk of preeclampsia, GDM, and large-for-gestational age infants compared with obese women who did not undergo BS. On the contrary, following BS, women were at increased risk of SGA neonates or infants with a weight less than 2500 grams (RR 1.83, 95% CI 1.48 to 2.27), and preterm birth (1.28, 1.08 to 1.51). The benefits of BS should be balanced against the health consequences for women themselves and their neonates. Rates of complications associated with BS, such as bleeding, gastric stenosis, gastro-intestinal symptoms and nutritional and electrolyte abnormalities, range between 10 to 17%, and 7% of the patients need a reoperation (46). Mortality rates are low (0.08 to 0.35%). Postoperatively, women are recommended to delay pregnancy for 12 to 18 months (47) in order to obtain weight loss first, and not to conceive in a period of rapid weight loss. Maternal starvation may lead to poor foetal growth (42), and to long-term negative health effects for the neonates. For example, starvation during the Dutch famine in World War II had serious consequences for health later in life in children conceived during the period of maternal malnutrition (48), who were shown to be at increased risk of chronic diseases such as coronary heart disease and obstructive airway diseases. All these factors should be taken into account, including the fact that weight loss does not guarantee successful fertility treatment, before recommending morbidly obese women to undergo BS for the sake of subfertility. 181

11 CH 9 Recommendations for future research 1. Future studies should focus on the prevention of congenital anomalies in obese women, either by investigating the effect of losing weight prior to conception or by investigating the effect of increased intake of folic acid or other nutrients such as zinc on pregnancy outcome. 2. Generating sufficient evidence on the influence of paternal preconceptional risk factors is important to estimate the influence of paternal lifestyle on the health of future mothers and future children. In addition, the effects of modifying behaviour involved in unhealthy lifestyle of both partners prior to conception should be investigated. 3. Future studies should focus on predictors of drop-out in overweight and obese subfertile women participating in LIPs. This will enable the identification of patients prone for drop-out, who might benefit from extra support and monitoring in order to increase adherence rates, weight loss and spontaneous pregnancy chances. Moreover, implementation of a LIP preceding fertility treatment should include procedures to actively contact women who drop-out of a LIP in order to counsel them on further treatment options. 4. Clinical studies investigating the effectiveness of subfertility treatment should report complications due to the treatment, in resulting pregnancies, and during the neonatal period. 5. In overweight and obese subfertile women, patients preferences regarding participation in a LIP as first step of fertility treatment should be investigated. Using the data from the LIFEstyle study, the following additional analyses are planned: 1. A cost-effectiveness analysis of a LIP prior to fertility treatment versus immediate fertility treatment on pregnancy chances and reproductive outcomes. 2. A detailed analysis of the effectiveness of a LIP prior to fertility treatment versus immediate fertility treatment in anovulatory and ovulatory women. 3. An evaluation of quality of life of women participating in the LIFEstyle study. 4. The identification of baseline patient-related factors and intervention-related factors associated with drop-out and success of the LIP. 5. The effects of the LIP in women in different age and BMI categories. 6. Long-term follow-up of women who participated in the LIFEstyle study with respect to health and fertility. Influence of preconceptional weight loss on the health of their offspring. 182

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14 on IVF success appears age-related. Hum Reprod 2008 Aug;23(8): CBO guideline: Diagnostiek en Behandeling van Obesitas bij volwassenen en kinderen Sheiner E, Willis K, Yogev Y. Bariatric surgery: impact on pregnancy outcomes. Curr Diab Rep 2013 Feb;13(1): Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007 Aug 23;357(8): Musella M, Milone M, Bellini M, Sosa Fernandez LM, Leongito M, Milone F. Effect of bariatric surgery on obesity-related infertility. Surg Obes Relat Dis 2012 Jul-Aug;8(4): Galazis N, Docheva N, Simillis C, Nicolaides KH. Maternal and neonatal outcomes in women undergoing bariatric surgery: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2014 Oct;181: Chang SH, Stoll CR, Song J, Varela JE, Eagon CJ, Colditz GA. The effectiveness and risks of bariatric surgery: an updated systematic review and meta-analysis, JAMA Surg 2014 Mar;149(3): Kaska L, Kobiela J, Abacjew-Chmylko A, Chmylko L, Wojanowska-Pindel M, Kobiela P, et al. Nutrition and pregnancy after bariatric surgery. ISRN Obes 2013 Jan 30;2013: Roseboom T, de Rooij S, Painter R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev 2006 Aug;82(8):

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16 NEDERLANDSE SAMENVATTING

17 Wereldwijd vormen overgewicht (body mass index (BMI) kg/m²) en obesitas (BMI 30 kg/m²) een groot probleem voor de volksgezondheid. Overgewicht en obesitas leiden onder andere tot een verhoogd risico op hart- en vaatziekten, diabetes type II en bepaalde vormen van kanker. In Nederland heeft 24-39% van de vrouwen in de leeftijd van 20 tot 40 jaar overgewicht en 7 tot 11% heeft obesitas. Overgewicht en obesitas hebben niet alleen gevolgen voor de algemene gezondheid, maar ze kunnen ook leiden tot verminderde vruchtbaarheid (subfertiliteit), onder andere door het uitblijven van een eisprong (anovulatie). Vrouwen met overgewicht of obesitas die vruchtbaarheidsbehandelingen ondergaan, hebben meer medicatie nodig en ondergaan over het algemeen meer en ook langer durende behandelingen dan vrouwen met een normaal gewicht (BMI < 25 kg/m²). Bovendien zijn de zwangerschapskansen bij vruchtbaarheidsbehandelingen van vrouwen met overgewicht of obesitas verlaagd. Zwangere vrouwen met overgewicht of obesitas hebben een verhoogd risico op een miskraam. In geval van een doorgaande zwangerschap hebben zij meer kans op ernstige complicaties zoals hoge bloeddruk tijdens de zwangerschap, preëclampsie (zwangerschapsvergiftiging) en diabetes gravidarum (zwangerschapssuikerziekte). Bevallingen vinden vaker plaats door middel van een keizersnede. In geval van een vaginale bevalling zijn risico s op uitdrijvingsproblemen (o.a. schouderdystocie) en fluxus ( 1000 ml bloedverlies na de geboorte van het kind) verhoogd. Door het ongunstige milieu in de baarmoeder zijn de risico s op vroeggeboorte, een doodgeboren kind, een kind met congenitale afwijkingen zoals een neurale buis defect ( open ruggetje ) of een macrosoom kind (gewicht > p90 volgens de Nederlandse referentiecurven) verhoogd. Er zijn momenteel geen evidence-based behandelrichtlijnen voor subfertiele vrouwen met overgewicht of obesitas. Richtlijnen variëren tussen klinieken: in de ene kliniek wordt iedere vrouw behandeld, ongeacht de mate van overgewicht of obesitas, terwijl in andere klinieken BMI-grenzen gehanteerd worden die variëren tussen 30 en 40 kg/m² met het doel om de eerder genoemde complicaties te vermijden. Kleine studies in subfertiele vrouwen met overgewicht of obesitas laten zien dat een gewichtsverlies van 5 tot 10% van het oorspronkelijke gewicht leidt tot een toename van het aantal spontane zwangerschappen, een afname van het aantal vruchtbaarheidsbehandelingen, en mogelijk tot een afname van de zwangerschapscomplicaties en een verbetering van de zwangerschapsuitkomsten. Het is echter nooit in een grote gerandomiseerde studie onderzocht wat het effect is van een leefstijlinterventieprogramma (LIP) gericht op 5 tot 10% gewichtsverlies in deze patiëntenpopulatie. Niet alleen gewicht, maar ook andere leefstijlfactoren zoals roken, alcoholgebruik en lichaamsbeweging kunnen de vruchtbaarheid, zwangerschap en zwangerschapsuitkomsten beïnvloeden. Het onderzoek wat tot nu toe gedaan is, heeft zich echter vooral gericht op de invloed van de leefstijlfactoren van de vrouw, terwijl leefstijlfactoren van de man wellicht ook invloed kunnen hebben. 188

18 Doel van proefschrift In het eerste deel van dit proefschrift wordt het effect van verschillende leefstijlfactoren van zowel de vrouw als de man op de vruchtbaarheid, zwangerschapscomplicaties en -uitkomsten in een fertiele (normaal vruchtbare) populatie onderzocht (hoofdstuk 2 t/m 4). In het tweede deel van het proefschrift wordt onderzoek gedaan naar de invloed van overgewicht bij subfertiele (verminderd vruchtbare) vrouwen. De focus ligt op het effect van een LIP op zwangerschapskansen en -uitkomsten in subfertiele vrouwen met obesitas (hoofdstuk 5 t/m 8). Effect van leefstijlfactoren in fertiele populaties In hoofdstuk 2 hebben we de invloed van verschillende maternale (moeder) en paternale (vader) factoren op de tijd tot zwangerschap ( time to pregnancy (TTP), een veelgebruikte maat voor vruchtbaarheid) onderzocht. We hebben hiervoor data van de GECKO (Groningen Expertise Centrum voor Kinderen met Overgewicht) Drenthe studie, een groot Nederlands geboortecohort, gebruikt. Alle moeders én vaders van de kinderen die meededen aan de GECKO Drenthe-studie ontvingen een vragenlijst met daarin onder andere vragen over hun eigen geboortegewicht, leeftijd en gewicht op het moment dat de zwangerschap tot stand kwam, rookgedrag, alcoholgebruik, vitaminegebruik, mate van lichaamsbeweging, opleidingsniveau en netto inkomsten. De vrouwen werden ook gevraagd naar eerdere zwangerschappen, welke anticonceptie ze gebruikt hadden voorafgaande aan deze zwangerschap en de duur van de menstruele cyclus. Tenslotte werden beide ouders gevraagd of de huidige zwangerschap gepland was en zo ja, vanaf welke datum ze een actieve zwangerschapswens hadden. We analyseerden de resultaten van 1924 ouderparen en toonden aan dat, met name, maternale niet-beïnvloedbare factoren zoals een hogere leeftijd, nullipariteit (nooit eerder bevallen), langere menstruele cyclus en lager opleidingsniveau geassocieerd waren met een langere TTP. Maternale beïnvloedbare factoren (BMI, roken, alcoholgebruik, mate van lichaamsbeweging) noch paternale factoren hadden invloed op de TTP. Echter, weinig ouders hadden een zeer ongezonde leefstijl, zoals fors roken of fors alcoholgebruik. Het (waarschijnlijke negatieve) effect van deze leefstijlfactoren op TTP konden we hierdoor niet onderzoeken. Gebaseerd op onze uitkomsten hebben we geconcludeerd dat we niet verwachten dat fertiele paren met een gematigde leefstijl sneller zwanger raken als zij hun leefstijl zouden optimaliseren. In hoofdstuk 3 hebben we onderzocht wat de invloed was van maternale en paternale factoren op de kans op hypertensieve zwangerschapscomplicaties, diabetes gravidarum, spontane vroeggeboorte en een small-for-gestational-age (SGA) kind (kind met een geboortegewicht < p10 volgens de Nederlandse referentiecurven). Hiervoor hebben we opnieuw gebruik gemaakt van de GECKO Drenthe-studie en de vragenlijsten die de ouders hadden ingevuld. Voor deze studie analyseerden we de gegevens van 2264 ouderparen. We stelden vast dat een toegenomen maternale BMI voorafgaande aan de zwangerschap (preconceptioneel) geassocieerd was met een verhoogd risico op hypertensieve aandoeningen tijdens de zwangerschap en met een verhoogd risico op diabetes gravidarum. Een toegenomen maternale preconceptionele BMI was ook geassocieerd met een verlaagd 189

19 risico op een SGA-kind. Daarnaast hadden moeders die rookten tijdens de zwangerschap een verhoogd risico op een SGA-kind. Paternale factoren bleken niet geassocieerd met de onderzochte uitkomstmaten. Wel vonden we dat de leefstijl van de moeder gecorreleerd was aan de leefstijl van hun partner. Omdat vrouwen minder geneigd zijn om hun leefstijl aan te passen als hun partner dat niet ook doet, hebben we geconcludeerd dat preconceptiezorg voornamelijk gericht moet zijn op vrouwen, maar dat ook hun partners aangemoedigd moeten worden om hun leefstijl te verbeteren. Aangezien wij slechts een beperkt aantal paternale factoren onderzocht hebben, is meer onderzoek nodig naar de invloed van paternale factoren op zwangerschapscomplicaties en -uitkomsten. Ook is onderzoek naar het effect van preconceptionele gedragsaanpassing van beide partners noodzakelijk. Het doel van hoofdstuk 4 was om te onderzoeken of een toename in de maternale preconceptionele BMI geassocieerd was met een toe- of afname in de kans dat een kind een aangeboren afwijking had. We hebben voor dit doel een patiëntcontrole onderzoek verricht waarin we gebruikt maakten van data verkregen uit de EUROCAT (Europese Registratie van Congenitale Aandoeningen) database. In deze database worden alle kinderen en foetussen met congenitale afwijkingen geboren in Groningen, Friesland of Drenthe geregistreerd. Ouders van kinderen die zijn geregistreerd in de EUROCAT database ontvingen een uitgebreide lijst met vragen over onder andere hun gewicht en lengte voorafgaande aan de zwangerschap, chronische ziekten, inname van foliumzuur, medicijngebruik, werkzaamheden en opleidingsniveau. We analyseerden de gegevens van 4547 cases (kinderen of foetussen met een ernstige aangeboren afwijking, maar zónder een syndromale afwijking) en 1706 controles (kinderen of foetussen met een ernstige aangeboren afwijking, maar mét een syndromale afwijking). We vonden een dosisafhankelijke associatie tussen BMI en neurale buisdefecten: een toename van de maternale BMI was geassocieerd met een toename van de kans op een kind met een neuraal buisdefect. Tussen de maternale BMI en andere aangeboren afwijkingen (zoals hartafwijkingen of lipspleten) konden we deze associatie niet aantonen. Wel vonden we dat ziekelijk overgewicht van de moeder (BMI 40 kg/m²) geassocieerd was met een sterk verhoogd risico op een kind met een oogafwijking (odds ratio (OR) 7.08), een lipspleet (OR 7.99), een afwijking aan het spijsverteringsstelsel (OR 5.43) of een afwijking aan de urinewegen (OR 8.86). Mogelijk speelt een tekort van foliumzuur of andere voedingsstoffen zoals zink een rol bij het ontstaan van congenitale afwijkingen bij het kind van obese vrouwen. Het is belangrijk dat toekomstige studies zich richten op de preventie van aangeboren afwijkingen in (toekomstige) moeders met obesitas. Dit kan door het effect van preconceptioneel gewichtsverlies, of het effect van een hogere dosis foliumzuur, zink of andere voedingsstoffen, te evalueren. Effect van gewicht en gewichtsafname in een subfertiele populatie Om de invloed van overgewicht en obesitas op complicaties en op slagingskansen van in vitro fertilisatie (IVF)-behandelingen te onderzoeken, hebben we in hoofdstuk 5 een systematische review van beide onderwerpen uitgevoerd. We hebben 14 studies gevonden die rapporteerden over de relatie tussen overgewicht en complicaties ten gevolge van IVF-behandelingen bij, in totaal, vrouwen. In geen enkele studie werd een 190

20 verband aangetoond tussen BMI en het risico op een ovarieel hyperstimulatiesyndroom, buitenbaarmoederlijke zwangerschap of meerlingzwangerschap. We hebben 27 studies geïdentificeerd die rapporteerden over de invloed van BMI op zwangerschapskansen bij, in totaal, vrouwen. De resultaten toonden aan dat het aantal levendgeborenen na IVF significant lager was bij vrouwen met een BMI 25 kg/m² dan bij vrouwen met een BMI < 25 kg/m (OR 0.90 (95% betrouwbaarheidsinterval (BI) 0.82 tot 1.0). Gebaseerd op deze resultaten hebben we geconcludeerd dat er geen bewijs is dat overgewicht de risico s op complicaties van IVF-behandelingen verhoogd, maar dat er te weinig literatuur over dit onderwerp beschikbaar is om een eventuele associatie aan te tonen c.q. uit te sluiten. Vrouwen met overgewicht hebben na IVF echter wel 10% minder kans op een levendgeboren kind dan vrouwen met een normaal gewicht. In hoofdstuk 6 hebben we een systematische review verricht naar studies waarin het effect van een LIP voor subfertiele vrouwen met overgewicht en obesitas was onderzocht. Het doel van deze review was om te onderzoeken wat het gemiddelde drop-out (uitval) percentage was binnen deze LIPs. Vijftien studies bleken geschikt voor inclusie, waarvan in 10 studies het drop-out percentage werd gerapporteerd. Het mediane drop-out percentage was 24% (range: 0 tot 31%). In 4 studies was onderzocht of kenmerken van de vrouwen die deelnamen aan de LIPs konden voorspellen welke vrouwen voortijdig zouden stoppen met het LIP (drop-out gaan), maar in geen van deze studies kon een voorspellend kenmerk worden vastgesteld. Uit de review werd wel duidelijk dat drop-outs minder gewicht verliezen en lagere spontane zwangerschapskansen hebben dan vrouwen die een LIP afmaken. Hoofdstuk 7 beschrijft het protocol van de LIFEstyle-studie. De LIFEstyle-studie was een multicenter gerandomiseerde trial waarin de kosten en effecten van een gestructureerd LIP voorafgaande aan vruchtbaarheidsbehandelingen versus direct starten van vruchtbaarheidsbehandelingen in subfertiele vrouwen met obesitas zijn onderzocht. Vrouwen die lootten voor het LIP (LIP-arm, de ene arm van de studie) startten met het LIP gedurende een periode van maximaal zes maanden. Het LIP was gericht op een gewichtsverlies van 5 tot 10% van het oorspronkelijke gewicht en bestond uit de combinatie van een energiebeperkt gezond dieet, toename van de lichamelijke activiteit en gedragsverandering. Vooraf getrainde verpleegkundigen en coaches begeleidden de vrouwen tijdens het LIP. Wanneer vrouwen het LIP hadden afgerond en er nog geen doorgaande zwangerschap was ontstaan, startten zij met een vruchtbaarheidsbehandeling als daar een indicatie voor bestond (volgens de richtlijnen van de Nederlandse Vereniging voor Obstetrie en Gynaecologie (NVOG)), ongeacht de BMI. Vrouwen die lootten voor de andere arm van de studie (standaardzorg-arm), startten direct met vruchtbaarheidsbehandelingen volgens de richtlijnen van de NVOG, ongeacht de BMI. De belangrijkste uitkomstmaat was de vaginale geboorte van een gezond kind na een zwangerschapsduur van ten minste 37 weken (à terme). Andere eindpunten waren, onder andere, het percentage levendgeborenen, doorgaande en klinische zwangerschappen, miskramen, wijze waarop de zwangerschap was ontstaan, aantal vruchtbaarheidsbehandelingen en complicaties ten gevolge van deze behandelingen, zwangerschapscomplicaties, zwangerschapsuitkomsten, veranderingen in lichaamsgewicht, kwaliteit van leven en kosten. Dit alles binnen een follow-up periode van 24 maanden. De studie was geregistreerd in het Nederlandse Trial Register (NTR 1530) en 191