Preconception insulin resistance and neonatal birth weight in women with obesity: role of bile acids.

RESEARCH QUESTION: Does maternal preconception insulin resistance affect neonatal birth weight among women with obesity? Is insulin resistance associated with circulating bile acids? Do bile acids influence the association between maternal preconception insulin resistance and neonatal birth weight? DESIGN: An exploratory post-hoc analysis of the LIFEstyle randomized controlled trial comparing lifestyle intervention with conventional infertility treatment in women with a BMI of ≥29 kg/m2. Fasting blood samples were collected at randomization and after 3 and 6 months in 469 women. Insulin resistance was quantified using the homeostasis model assessment of insulin resistance (HOMA-IR). Bile acid sub-species were determined by liquid chromatography with tandem mass spectrometry. Singletons were included (n = 238). Birth weight Z-scores were adjusted for age, offspring gender and parity. Multilevel analysis and linear regressions were used. RESULTS: A total of 913 pairs of simultaneous preconception HOMA-IR (median [Q25; Q75]: 2.96 [2.07; 4.16]) and total bile acid measurements (1.79 [1.10; 2.94]) µmol/l were taken. Preconception HOMA-IR was positively associated with total bile acids (adjusted B 0.15; 95% CI 0.09 to 0.22; P < 0.001) and all bile acid sub-species. At the last measurement before pregnancy, HOMA-IR (2.71 [1.91; 3.74]) was positively related to birth weight Z-score (mean ± SD 0.4 ± 1.1; adjusted B 0.08; 95% CI 0.01 to 0.14; P = 0.03). None of the preconception bile acids measured were associated with birth weight. CONCLUSION: Maternal preconception insulin resistance is an important determinant of neonatal birth weight in women with obesity, whereas preconception bile acids are not.

Randomized Trial of a Lifestyle Program in Obese Infertile Women.

BACKGROUND: Small lifestyle-intervention studies suggest that modest weight loss increases the chance of conception and may improve perinatal outcomes, but large randomized, controlled trials are lacking. METHODS: We randomly assigned infertile women with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 29 or higher to a 6-month lifestyle intervention preceding treatment for infertility or to prompt treatment for infertility. The primary outcome was the vaginal birth of a healthy singleton at term within 24 months after randomization. RESULTS: We assigned women who did not conceive naturally to one of two treatment strategies: 290 women were assigned to a 6-month lifestyle-intervention program preceding 18 months of infertility treatment (intervention group) and 287 were assigned to prompt infertility treatment for 24 months (control group). A total of 3 women withdrew consent, so 289 women in the intervention group and 285 women in the control group were included in the analysis. The discontinuation rate in the intervention group was 21.8%. In intention-to-treat analyses, the mean weight loss was 4.4 kg in the intervention group and 1.1 kg in the control group (P<0.001). The primary outcome occurred in 27.1% of the women in the intervention group and 35.2% of those in the control group (rate ratio in the intervention group, 0.77; 95% confidence interval, 0.60 to 0.99). CONCLUSIONS: In obese infertile women, a lifestyle intervention preceding infertility treatment, as compared with prompt infertility treatment, did not result in higher rates of a vaginal birth of a healthy singleton at term within 24 months after randomization. (Funded by the Netherlands Organization for Health Research and Development; Netherlands Trial Register number, NTR1530.).

Determinants of successful lifestyle change during a 6-month preconception lifestyle intervention in women with obesity and infertility.

PURPOSE: To identify demographic, (bio)physical, behavioral, and psychological determinants of successful lifestyle change and program completion by performing a secondary analysis of the intervention arm of a randomized-controlled trial, investigating a preconception lifestyle intervention. METHODS: The 6-month lifestyle intervention consisted of dietary counseling, physical activity, and behavioral modification, and was aimed at 5-10% weight loss. We operationalized successful lifestyle change as successful weight loss (≥ 5% weight/BMI ≤ 29 kg/m2), weight loss in kilograms, a reduction in energy intake, and an increase in physical activity during the intervention program. We performed logistic and mixed-effect regression analyses to identify baseline factors that were associated with successful change or program completion. RESULTS: Women with higher external eating behavior scores had higher odds of successful weight loss (OR 1.10, 95% CI 1.05-1.16). Women with the previous dietetic support lost 0.94 kg less during the intervention period (95% CI 0.01-1.87 kg). Women with higher self-efficacy reduced energy intake more than women with lower self-efficacy (p < 0.01). Women with an older partner had an increased energy intake (6 kcal/year older, 95% CI 3-13). A high stage of change towards physical activity was associated with a higher number of daily steps (p = 0.03). A high stage of change towards weight loss was associated with completion of the intervention (p = 0.04). CONCLUSIONS: Determinants of lifestyle change and program completion were: higher external eating behavior, not having received previous dietetic support, high stage of change. This knowledge can be used to identify women likely to benefit from lifestyle interventions and develop new interventions for women requiring alternative support. TRIAL REGISTRATION: The LIFEstyle study was registered at the Dutch trial registry (NTR 1530; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1530 ).

Effects of preconception weight loss after lifestyle intervention on fertility outcomes and pregnancy complications.

It is well documented that obesity decreases natural fertility among men and women as well as pregnancy chances after conventional infertility and assisted reproductive technology (ART)-based treatments. Moreover, pregnancy complications are increased in women with overweight and obesity. General guidelines on the treatment of obesity recommend lifestyle intervention, including diet and exercise as the first-line treatment, coupled with or without medical treatments, such as weight loss medication or bariatric surgery, to reduce complications of obesity in adults. In the context of infertility in various countries and infertility clinics, there is a body mass index limit for public refund of infertility treatment of women with obesity. In this respect, it is important to investigate the evidence of effects of lifestyle intervention preceding infertility treatment on reproductive outcomes. The combined results of 15 randomized controlled trials (RCTs) of the effectiveness of preconception lifestyle intervention on reproductive outcomes documented in the latest systemic review and meta-analysis, together with the most recent RCT performed in 2022 are discussed. The current evidence suggests that greater weight loss and increase in clinical pregnancy, live birth, and natural conception rates after lifestyle intervention compared with no intervention were observed, but it seems no beneficial effect of lifestyle intervention preceding ART was observed on these parameters. With respect to potential harm of lifestyle intervention, there is no significant increased risk of early pregnancy loss, although the most recent RCT (not included in the systematic review and meta-analysis) showed a trend toward an increased risk. Complications during pregnancy, such as early pregnancy loss and maternal as well as fetal and neonatal complications, are underreported in most studies and need further analysis in an individual participant data meta-analysis. Limitations of the studies as well as future perspectives and challenges in this field of research will be highlighted.

Dietary Intake, Eating Behavior, Physical Activity, and Quality of Life in Infertile Women with PCOS and Obesity Compared with Non-PCOS Obese Controls.

To personalize lifestyle advice for women with polycystic ovary syndrome (PCOS) and obesity, detailed information regarding dietary intake, eating behavior, physical activity levels, and quality of life (QoL) may be useful. We aimed to investigate in a post-hoc cross-sectional analysis within a large multicenter randomized controlled trial in women with infertility whether there are significant differences in dietary intake (vegetables, fruits, sugary drinks, alcoholic beverages, savory snacks, and sweet snacks); eating behavior (emotional eating, external eating, and restricted eating); physical activity; and QoL between women with PCOS and obesity and non-PCOS obese controls. Participants were asked to complete the food frequency questionnaire (FFQ), the Dutch Eating Behavior Questionnaire (DEBQ), the Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH), and the 36-item Short Form Health Survey (SF-36) at study entry (PCOS: n = 170; non-PCOS: n = 321, mean BMI: 36). Linear and binary (multinomial) logistic regressions were used, and the analyses were adjusted for age, waist-hip circumference ratio, and homeostasis model assessment of insulin resistance (HOMA-IR). No statistically significant differences in dietary intake or physical activity were observed between the two groups. The overall score of emotional eating was 34.6 ± 11.2 in the PCOS group and 34.1 ± 11.3 in the non-PCOS group (p = 0.11). QoL scores (physical and mental) did not differ between PCOS and non-PCOS women. These findings suggest that infertile women with PCOS and obesity and infertile non-PCOS obese controls do not have different dietary habits and have similar mental and physical QoL.

Effectiveness of a 6-Month Lifestyle Intervention on Diet, Physical Activity, Quality of Life, and Markers of Cardiometabolic Health in Women with PCOS and Obesity and Non-PCOS Obese Controls: One Size Fits All?

Little is known about the difference in effectiveness of lifestyle intervention between women with PCOS and non-PCOS women. In a post hoc longitudinal analysis of a randomized, controlled trial, we aimed to investigate whether infertile women with PCOS and obesity (N = 87) responded differently to a 6-month lifestyle intervention program than infertile non-PCOS obese controls (N = 172). We evaluated several aspects of the intervention such as changes in diet, physical activity, and dropout rate, as well as the effect on weight, quality of life (QoL), and cardiometabolic outcomes. Multilevel analyses were used, and analyses were adjusted for baseline characteristics such as age, education, and smoking. Although BMI in both groups significantly decreased at 3 months and 6 months, there were no significant differences between the groups at 3 months (adjusted B: -0.3, 95% CI: -0.9 to 0.3, p = 0.35) and 6 months (adjusted B: 0.5, 95% CI: -0.4 to 1.4, p = 0.29). Women with PCOS and non-PCOS women had similar compliance with the lifestyle intervention in terms of actual change in diet and physical activity. Mental QoL scores were not different at either 3 or 6 months. Physical QoL scores were lower in women with PCOS compared with non-PCOS women at 3 months (adjusted B: -2.4, 95% CI: -4.8 to -0.06, p = 0.045) but not at 6 months. Cardiometabolic parameters did not differ between the groups. Our results showed that infertile women with PCOS and obesity and non-PCOS obese controls responded largely similarly to our lifestyle intervention and achieved the same level of improvement in markers of cardiometabolic health.

The Effect of Lifestyle Intervention on Systemic Oxidative Stress in Women with Obesity and Infertility: A Post-Hoc Analysis of a Randomized Controlled Trial.

We aimed to study whether lifestyle intervention could reduce systemic oxidative stress (OS) and the association between OS and cardiometabolic outcomes in women with obesity and infertility. From 2009 to 2012, infertile women with a BMI ≥ 29 kg/m2 were randomly assigned to a six-month lifestyle intervention followed by infertility treatment (N = 289) or to prompt infertility treatment (N = 285). Fasting serum free thiols (FT) concentrations were determined by colorimetry at baseline, at three and six months after randomization. Generalized estimating equations and restricted cubic spline regressions were used to estimate mean differences in serum FT levels between groups and to explore associations between serum FT levels and cardiometabolic outcomes. Baseline serum FT levels did not differ between the two groups (N = 203 in the intervention group vs N = 226 in the control group, 222.1 ± 48.0 µM vs 229.9 ± 47.8 µM, p = 0.09). Body weight decreased by 3.70 kg in the intervention group compared with the control group at six months (95% confidence interval [CI]: -7.61 to 0.21, p = 0.06). No differences in serum FT levels were observed between groups at either three months (N = 142 vs N = 150, mean differences: -1.03 µM, 95% CI: -8.37 to 6.32, p = 0.78) or six months (N = 104 vs N = 96, mean differences: 2.19 µM, 95% CI: -5.90 to 10.28, p = 0.60). In a pooled analysis of all available measurements, triglycerides (crude B: 5.29, 95% CI: 1.08 to 9.50, p = 0.01), insulin (crude B: 0.62, 95% CI: 0.26 to 0.98, p = 0.001), and homeostasis model assessment of insulin resistance (crude B: 2.50, 95% CI: 1.16 to 3.38, p < 0.001) were positively associated with serum FT levels. High-sensitivity C-reactive protein (hs-CRP) was negatively associated with serum FT levels (crude B: -0.60, 95% CI: -1.11 to -0.10, p = 0.02). The change in hs-CRP during the lifestyle intervention was strongly and inversely associated with serum FT levels (crude B: -0.41, 95% CI: -0.70 to -0.13, p = 0.005). No significant deviations from linear associations were observed between serum FT and hs-CRP. We do not observe an improvement in systemic OS in women with obesity and infertility with modest weight loss. There were potential associations between OS and biomarkers of cardiometabolic health. Trial registration: This trial was registered on 16 November 2008 at the Dutch trial register (NTR1530).

Effects of a preconception lifestyle intervention in obese infertile women on diet and physical activity; A secondary analysis of a randomized controlled trial.

BACKGROUND: Lifestyle changes are notoriously difficult. Since women who intend to become pregnant are more susceptible to lifestyle advice, interventions during this time window might be more effective than interventions during any other period in life. We here report the effects of the first large preconception lifestyle intervention RCT on diet and physical activity in obese infertile women. METHODS: In total, 577 women were randomized between a six-month lifestyle intervention program (intervention group; N = 290) or prompt infertility treatment (control group; N = 287). Self-reported dietary behaviors and physical activity were assessed at baseline, three, six and twelve months after randomization. Mixed models were used to analyze differences between groups. RESULTS: Compared to the control group, the intervention group reduced their intake of sugary drinks at three months (-0.5 glasses/day [95% C.I. = -0.9;-0.2]), of savory snacks at three (-2.4 handful/week [-3.4;-1.4]) and at six months (-1.4 handful/week [-2.6;-0.2]), and of sweet snacks at three (-2.2 portion/week [-3.3;-1.0]) and twelve months after randomization (-1.9 portion/week [-3.5;-0.4]). Also, the intervention group was more moderate to vigorous physically active at three months after randomization compared to the control group (169.0 minutes/week [6.0; 332.1]). CONCLUSION: Our study showed that obese infertile women who followed a six-month preconception lifestyle intervention program decreased their intake of high caloric snacks and beverages, and increased their physical activity. These changes in lifestyle may not only improve women's health but their offspring's health too.

Effect of a lifestyle intervention in obese infertile women on cardiometabolic health and quality of life: A randomized controlled trial.

BACKGROUND: The prevalence of obesity, an important cardiometabolic risk factor, is rising in women. Lifestyle improvements are the first step in treatment of obesity, but the success depends on factors like timing and motivation. Women are especially receptive to advice about lifestyle before and during pregnancy. Therefore, we hypothesize that the pre-pregnancy period provides the perfect window of opportunity to improve cardiometabolic health and quality of life of obese infertile women, by means of a lifestyle intervention. METHODS AND FINDINGS: Between 2009-2012, 577 infertile women between 18 and 39 years of age, with a Body Mass Index of ≥ 29 kg/m2, were randomized to a six month lifestyle intervention preceding infertility treatment, or to direct infertility treatment. The goal of the intervention was 5-10% weight loss or a BMI < 29 kg/m2. Cardiometabolic outcomes included weight, waist- and hip circumference, body mass index, systolic and diastolic blood pressure, fasting glucose and insulin, HOMA-IR, hs-CRP, lipids and metabolic syndrome. All outcomes were measured by research nurses at randomization, 3 and 6 months. Self-reported quality of life was also measured at 12 months. Three participants withdrew their informed consent, and 63 participants discontinued the intervention program. Intention to treat analysis was conducted. Mixed effects regression models analyses were performed. Results are displayed as estimated mean differences between intervention and control group. Weight (-3.1 kg 95% CI: -4.0 to -2.2 kg; P < .001), waist circumference (-2.4 cm 95% CI: -3.6 to -1.1 cm; P < .001), hip circumference (-3.0 95% CI: -4.2 to -1.9 cm; P < .001), BMI (-1.2 kg/m2 95% CI: -1.5 to -0.8 kg/m2; P < .001), systolic blood pressure (-2.8 mmHg 95% CI: -5.0 to -0.7 mmHg; P = .01) and HOMA-IR (-0.5 95% CI: -0.8 to -0.1; P = .01) were lower in the intervention group compared to controls. Hs-CRP and lipids did not differ between groups. The odds ratio for metabolic syndrome in the intervention group was 0.53 (95% CI: 0.33 to 0.85; P < .01) compared to controls. Physical QoL scores were higher in the lifestyle intervention group (2.2 95% CI: 0.9 to 3.5; P = .001) while mental QoL scores did not differ. CONCLUSIONS: In obese infertile women, a lifestyle intervention prior to infertility treatment improves cardiometabolic health and self-reported physical quality of life (LIFEstyle study: Netherlands Trial Register: NTR1530).

Association between periconceptional weight loss and maternal and neonatal outcomes in obese infertile women.

BACKGROUND: Obesity in women of reproductive age has deleterious effects on reproductive and offspring health. In this study, we aimed to evaluate the association between the magnitude of periconceptional body-mass index (BMI) change and maternal and neonatal outcomes in obese infertile women who participated in the LIFEstyle study. The LIFEstyle study was a randomized controlled trial, evaluating if a six-month lifestyle intervention program prior to infertility treatment in obese infertile women improved birth rates, compared to prompt infertility treatment. METHODS AND FINDINGS: This is an exploratory post hoc analysis of the LIFEstyle study. We recorded periconceptional BMI change in women with an ongoing pregnancy, pooling data of all women, regardless of randomization arm. Periconceptional BMI change was calculated using weight at randomization and the periconceptional weight (measured in kilograms 12 weeks before or after conception and expressed as BMI change in units BMI (kg/m2)). Subsequently, women were categorized into quartiles according to the magnitude of their periconceptional change in BMI. The odds of maternal and neonatal outcomes were calculated using logistic regression analysis, comparing women in each of the first three weight change quartiles separately, and combined, to women in the fourth quartile. The fourth quartile was chosen as reference group, since these women had the least weight loss. We adjusted for periconceptional BMI, nulliparity and smoking status. In addition, we performed a subgroup analysis for singleton pregnancies. In the LIFEstyle study, 321 obese infertile women achieved an ongoing pregnancy which was conceived within 24 months after randomization. Periconceptional BMI change was available in 244 of these women (76%). Median BMI at randomization was 35.9 kg/m2. Women in the first quartile (Q1) had a periconceptional BMI change of <-2.1 kg/m2, women in the second quartile (Q2) -2.1 to -0.9 kg/m2, women in the third quartile (Q3) -0.9 to 0.1 kg/m2 and women in the fourth quartile (Q4) gained ≥0.1 kg/m2. There were no significant differences between women in the quartiles regarding rates of excessive gestational weight gain (in term pregnancies), gestational diabetes, preterm birth, induction of labor, spontaneous vaginal birth and Caesarean section. Compared to women in Q4, the adjusted odds ratios, aOR, and 95% confidence interval for a hypertensive complication were; 0.55 (0.22-1.42) for women in Q1, 0.30 (0.12-0.78) for women in Q2, 0.39 (0.16-0.96) for women in Q3 and 0.39 (0.19-0.82) for women in Q1 to Q3 combined. In the subgroup analysis, investigating singleton pregnancies only, the statistically significant decreased rate of a hypertensive complication remained in women in Q2 (aOR 0.27, 95% CI 0.10-0.72) and Q3 (aOR 0.39, 95%CI 0.16-0.98) and when comparing women in Q1 to Q3 together to women in Q4 (aOR 0.38, 95%CI 0.18-0.80). Furthermore, there was a significantly decreased aOR (95%CI) of preterm birth in women in Q2 (0.24, 0.06-0.98) and when combining women in Q1 to Q3 (0.37, 0.14-0.97) compared to women in Q4. CONCLUSIONS: These results suggest that a periconceptional decrease in BMI in obese infertile women could lead to a decrease of the rates of hypertensive pregnancy complications and preterm birth. The results are limited by the exploratory nature of the analyses and further evidence is necessary to provide more definitive conclusions.