Discriminatory Value of Steroid Hormones on Polycystic Ovary Syndrome and Clustering of Hyperandrogenism and Metabolic Factors.

OBJECTIVE: We determined (1) if 11-oxygenated androgens better identify polycystic ovary syndrome (PCOS) diagnosis in women with obesity compared to total or free testosterone (T) and free androgen index; (2) how biochemical hyperandrogenism and metabolic factors cluster in a cohort of women with infertility and obesity. METHODS: Women with obesity and PCOS comprised the study group (N = 132). Ovulatory women with obesity and idiopathic, tubal or male factor infertility were the control group (N = 83). Steroid hormones were measured by means of liquid chromatography tandem mass spectrometry. Receiver operating characteristic curves and principal component analysis were used. RESULTS: Women with obesity and PCOS had higher 11-ketotestosterone (11 KT) (1.22 nmol/L [0.84; 1.65] vs 1.05 [0.78; 1.35], P = .04) compared to controls, but not 11ß-hydroxyandrostenedione 4.30 [2.87; 5.92] vs 4.06 [3.22; 5.73], P = .44). 11-ketotestosterone (area under the curve: 0.59) did not better discriminate PCOS in women with obesity compared to: total T (0.84), free T (0.91), and free androgen index (0.85). We identified 4 principal components (PCs) in the PCOS group (72.1% explained variance): (1) insulin resistance status; (2) blood pressure; (3) obesity; (4) androgen status and 4 PCs in the control group (68.7% explained variance) with variables representing metabolism being dispersed in component 2, 3, and 4. CONCLUSIONS: Eleven-oxygenated androgens do not aid in the diagnosis of PCOS in women with obesity. Insulin resistance is the strongest PC in the PCOS group. There is no major dominant characteristic that defines obese non-PCOS women.

Quantum Sensing of Free Radicals in Primary Human Granulosa Cells with Nanoscale Resolution.

Cumulus granulosa cells (cGCs) and mural granulosa cells (mGCs), although derived from the same precursors, are anatomically and functionally heterogeneous. They are critical for female fertility by supporting oocyte competence and follicular development. There are various techniques used to investigate the role of free radicals in mGCs and cCGs. Yet, temporospatial resolution remains a challenge. We used a quantum sensing approach to study free radical generation at nanoscale in cGCs and mGCs isolated from women undergoing oocyte retrieval during in vitro fertilization (IVF). Cells were incubated with bare fluorescent nanodiamonds (FNDs) or mitochondria targeted FNDs to detect free radicals in the cytoplasm and mitochondria. After inducing oxidative stress with menadione, we continued to detect free radical generation for 30 min. We observed an increase in free radical generation in cGCs and mGCs from 10 min on. Although cytoplasmic and mitochondrial free radical levels are indistinguishable in the physiological state in both cGCs and mGCs, the free radical changes measured in mitochondria were significantly larger in both cell types, suggesting mitochondria are sites of free radical generation. Furthermore, we observed later occurrence and a smaller percentage of cytoplasmic free radical change in cGCs, indicating that cGCs may be more resistant to oxidative stress.

Women of reproductive age living in the North of the Netherlands: Lifelines Reproductive Origins of Adult Health and Disease (Lifelines-ROAHD) cohort.

PURPOSE: The Lifelines Reproductive Origins of Adult Health and Disease (Lifelines-ROAHD) cohort provides a uniquely detailed dataset allowing investigations of determinants of reproductive health as well as the influence of reproductive events on future health and disease of mother and child(ren). Lifelines-ROAHD cohort is embedded in the population-based Lifelines cohort study. PARTICIPANTS: In total, 5412 women of reproductive age (20-45 years) were included in the Lifelines-ROAHD cohort, in the period 2017-2018. FINDINGS TO DATE: In the population, 45.6% of the women indicated that they had a natural menstrual cycle. In total, 908 women (16.8%) consulted a healthcare provider for infertility; subsequently diagnosed fertility problems were anovulation (24.4%), male partner infertility problems (22.5%) or unexplained infertility (22.2%). Women underwent various consecutive assisted reproductive treatments, for example, ovulation induction (19.8%) or in vitro fertilisation (5.4%). In total, 2808 women experienced 6158 pregnancies and 5068 births. Adverse pregnancy outcomes were miscarriage (14.3%), ectopic pregnancy (0.9%) or termination of pregnancy or medical abortion (2.0 %). The modes of delivery were vaginal births (74.9%), instrumental vaginal births (11.9%), elective caesarean section (3.9%) and emergency caesarean section (9.3%). Birth outcomes were born alive at term (93.6%), born alive (very) pre-term (5.8%), stillbirth (0.316%) and neonatal death (0.197%). Additional data about 2660 most recent pregnancies showed that 19.9% of the women had irregular working hours. One year postpartum, women indicated adverse physical health issues in one or more domains, range 0.5%-12.5%. They also indicated adverse psychological health issues in one or more domains, range 0.7%-1.6%, and 1.6% experienced diminished sexual health. FUTURE PLANS: Due to the embedding of Lifelines-ROAHD cohort in the original Lifelines cohort, the women will be longitudinally followed. Additionally, we aim to collect data with a second online questionnaire aiming to complete women's reproductive histories, by collecting data about potential first and subsequent pregnancies conceived after the date of completion of baseline Lifelines-ROAHD cohort.

Live birth is not the only relevant outcome in research assessing assisted reproductive technology.

In assisted reproductive technology (ART) research, live birth has been generally accepted as an important outcome, if not the most important one. However, it has been reported inconsistently in the literature and solely focusing on live birth can lead to misinterpretation of research findings. In this review, we provide an overview on the definitions of live birth, including various denominators and numerators use. We present a series of real clinical examples in ART research to demonstrate the impact of variations in live birth on research findings and the importance of other outcomes, including multiple pregnancy, pregnancy loss, time to pregnancy leading to live birth, other short and long term maternal and offspring health outcomes and cost effectiveness measures. We suggest that outcome choices in ART research should be tailored for the research questions. A holistic outcome assessment beyond live birth would provide a full picture to address research questions in ART in terms of effectiveness and safety, and thus facilitate evidence-based decision making.

A preconception lifestyle intervention in women with obesity and cardiovascular health in their children.

BACKGROUND: Maternal obesity during pregnancy is associated with poorer cardiovascular health (CVH) in children. A strategy to improve CVH in children could be to address preconception maternal obesity by means of a lifestyle intervention. We determined if a preconception lifestyle intervention in women with obesity improved offspring's CVH, assessed by magnetic resonance imaging (MRI). METHODS: We invited children born to women who participated in a randomised controlled trial assessing the effect of a preconception lifestyle intervention in women with obesity. We assessed cardiac structure, function and geometric shape, pulse wave velocity and abdominal fat tissue by MRI. RESULTS: We included 49 of 243 (20.2%) eligible children, 24 girls (49%) girls, mean age 7.1 (0.8) years. Left ventricular ejection fraction was higher in children in the intervention group as compared to children in the control group (63.0% SD 6.18 vs. 58.8% SD 5.77, p = 0.02). Shape analysis showed that intervention was associated with less regional thickening of the interventricular septum and less sphericity. There were no differences in the other outcomes of interest. CONCLUSION: A preconception lifestyle intervention in women with obesity led to a higher ejection fraction and an altered cardiac shape in their offspring, which might suggest a better CVH. IMPACT: A preconception lifestyle intervention in women with obesity results in a higher ejection fraction and an altered cardiac shape that may signify better cardiovascular health (CVH) in their children. This is the first experimental human evidence suggesting an effect of a preconception lifestyle intervention in women with obesity on MRI-derived indicators of CVH in their children. Improving maternal preconception health might prevent some of the detrimental consequences of maternal obesity on CVH in their children.

Dietary and/or physical activity interventions in women with overweight or obesity prior to fertility treatment: protocol for a systematic review and individual participant data meta-analysis.

INTRODUCTION: Dietary and/or physical activity interventions are often recommended for women with overweight or obesity as the first step prior to fertility treatment. However, randomised controlled trials (RCTs) so far have shown inconsistent results. Therefore, we propose this individual participant data meta-analysis (IPDMA) to evaluate the effectiveness and safety of dietary and/or physical activity interventions in women with infertility and overweight or obesity on reproductive, maternal and perinatal outcomes and to explore if there are subgroup(s) of women who benefit from each specific intervention or their combination (treatment-covariate interactions). METHODS AND ANALYSIS: We will include RCTs with dietary and/or physical activity interventions as core interventions prior to fertility treatment in women with infertility and overweight or obesity. The primary outcome will be live birth. We will search MEDLINE, Embase, Cochrane Central Register of Controlled Trials and trial registries to identify eligible studies. We will approach authors of eligible trials to contribute individual participant data (IPD). We will perform risk of bias assessments according to the Risk of Bias 2 tool and a random-effects IPDMA. We will then explore treatment-covariate interactions for important participant-level characteristics. ETHICS AND DISSEMINATION: Formal ethical approval for the project (Venus-IPD) was exempted by the medical ethics committee of the University Medical Center Groningen (METc code: 2021/563, date: 17 November 2021). Data transfer agreement will be obtained from each participating institute/hospital. Outcomes will be disseminated internationally through the collaborative group, conference presentations and peer-reviewed publication. PROSPERO REGISTRATION NUMBER: CRD42021266201.

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.

Which factors play a role in the decision of mothers to participate in child follow-up examinations after participation in an RCT?: a semi-quantitative study.

OBJECTIVES: To determine which factors contribute to the decision of mothers to participate with their child in follow-up (FU) examinations after participation in a randomised controlled trial (RCT) prior to conception. DESIGN: A cross-sectional survey, including Likert-scale items. Comparisons will be made between respondents who participated in all FU rounds of data collection and those who did not participate in any FU round with their child. PARTICIPANTS: Women who participated in an RCT investigating the effect of a preconception lifestyle intervention (LIFEstyle study: Netherlands Trial Register: NTR1530) were invited to participate with their child in three FU data collections when the child had a mean age of 4.2 years, 4.6 years and 6.5 years, respectively. FU rounds included a health questionnaire, physical examination and cardiac assessment, successively. RESULTS: Sixty-seven respondents were included, of whom 7 (10%) did not participate in any FU round and 24 (36%) participated in all FU rounds. Women who participated with their child in all 3 FU data collection rounds felt more involved in the FU research (95.8%) and agreed more often that the FU was introduced well (91.7%) as compared with women that did not participate in any FU data collection round with their child (14.3% and 28.6%, respectively). Participants of FU rounds more often agreed that participation felt like a health check for their child as compared with non-participants. In addition, participants of the physical examination and cardiac assessment more often let their decision to participate depend fully on their child, as compared with non-participants (39.4% vs 17.7% and 52.5% vs 24%, respectively). CONCLUSIONS: To increase participation rates in future FU studies of children after maternal participation in an RCT, we suggest to involve women in the design of the FU study, to emphasise possible perceived benefits of participation and to encourage women to actively involve their child in the decision of participation.

Local and Systemic Oxidative Stress Biomarkers for Male Infertility: The ORION Study.

Infertility problems occur in around 10% of all couples worldwide, with male-factor infertility as the sole contributor in 20-30% of these cases. Oxidative stress (OS) is suggested to be associated with the pathophysiology of male infertility. In spermatozoa, OS can lead to damage to the cell membrane, resulting in disruption of DNA integrity and a decrease in motility. Established biomarkers for OS include free thiols and malondialdehyde (MDA), both representing different components of the reactive species interactome (RSI). This exploratory study aimed to investigate seminal plasma-free thiol and MDA levels in relation to semen parameters as defined by the World Health Organization (WHO) to determine if these markers are adequate to define local OS status. Furthermore, this study investigated if there is a relation between systemic and local OS status by comparing seminal concentrations of free thiol (R-SH, sulfhydryl groups, representing the extracellular redox status) and MDA (lipid peroxidation product) levels to those measured in serum. Free thiol and MDA measurements in both serum and semen plasma were performed in 50 males (18-55 y) of couples seeking fertility treatment. A significant positive correlation was found between seminal plasma-free thiol levels and sperm concentration and progressive motility (r = 0.383, p = 0.008 and r = 0.333, p = 0.022, respectively). In addition, a significant positive correlation was found between MDA levels in seminal plasma and sperm concentration (r = 0.314, p = 0.031). This study supports that seminal plasma-free thiols may be promising as local OS biomarkers. No associations were observed between local and systemic OS biomarker concentrations.

Preconception lifestyle intervention in women with obesity and echocardiographic indices of cardiovascular health in their children.

BACKGROUND: Improving maternal lifestyle before conception may prevent the adverse effects of maternal obesity on their children's future cardiovascular disease (CVD) risk. In the current study, we examined whether a preconception lifestyle intervention in women with obesity could alter echocardiographic indices of cardiovascular health in their children. METHODS: Six years after a randomized controlled trial comparing the effects of a 6-month preconception lifestyle intervention in women with obesity and infertility prior to fertility care to prompt fertility care, 315 of the 341 children conceived within 24 months after randomization were eligible for this study. The intervention was aimed at weight loss (≥5% or until BMI < 29 kg/m2). Children underwent echocardiographic assessment of cardiac structure and function, conducted by a single pediatric cardiologist, blinded to group allocation. Results were adjusted for multiple variables including body surface area, age, and sex in linear regression analyses. RESULTS: Sixty children (32 girls, 53%) were included, mean age 6.5 years (SD 1.09). Twenty-four children (40%) were born to mothers in the intervention group. Children of mothers from the intervention group had a lower end-diastolic interventricular septum thickness (-0.88 Z-score, 95%CI -1.18 to -0.58), a lower left ventricle mass index (-8.56 g/m2, 95%CI -13.09 to -4.03), and higher peak systolic and early diastolic annular velocity of the left ventricle (1.43 cm/s 95%CI 0.65 to 2.20 and 2.39 cm/s 95%CI 0.68 to 4.11, respectively) compared to children of mothers from the control group. CONCLUSIONS: Children of women with obesity, who underwent a preconception lifestyle intervention, had improved cardiac structure and function; a thinner interventricular septum, lower left ventricle mass, and improved systolic and diastolic tissue Doppler velocities. Despite its high attrition rates, our study provides the first experimental human evidence suggesting that preconception lifestyle interventions may present a method of reducing CVD risk in the next generation. CLINICAL TRIAL REGISTRATION: LIFEstyle study: Netherlands Trial Register: NTR1530 ( https://www.trialregister.nl/trial/1461 ). This follow-up study was approved by the medical ethics committee of the University Medical Centre Groningen (METC code: 2008/284).

Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Women positive for thyroid peroxidase antibodies (TPO-Ab) have a higher risk of recurrent pregnancy loss. Evidence on whether levothyroxine treatment improves pregnancy outcomes in women who are TPO-Ab positive women with recurrent pregnancy loss is scarce. The aim of this study was to determine if levothyroxine increases live birth rates in women who were TPO-Ab positive with recurrent pregnancy loss and normal thyroid function. METHODS: The T4LIFE trial was an international, double-blind, placebo-controlled, phase 3 study done in 13 secondary and tertiary hospitals in the Netherlands, one tertiary hospital in Belgium, and one tertiary hospital in Denmark. Women (18-42 years) who were TPO-Ab positive, had two or more pregnancy losses, and had a thyroid stimulating hormone (TSH) concentration within the institutional reference range were eligible for inclusion. Women were excluded if they had antiphospholipid syndrome (lupus anticoagulant, anticardiolipin IgG or IgM antibodies, or ß2-glycoprotein-I IgG or IgM antibodies), other autoimmune diseases, thyroid disease, previous enrolment in this trial, or contraindications for levothyroxine use. Before conception, women were randomly assigned (1:1) to receive either levothyroxine or placebo orally once daily. The daily dose of levothyroxine was based on preconception TSH concentration and ranged from 0·5-1·0 µg/kg bodyweight. Levothyroxine or placebo was continued until the end of pregnancy. The primary outcome was live birth, defined as the birth of a living child beyond 24 weeks of gestation measured in the intention-to-treat population. The trial was registered within the Netherlands Trial Register, NTR3364 and with EudraCT, 2011-001820-39. RESULTS: Between Jan 1, 2013, and Sept 19, 2019, 187 women were included in the study: 94 (50%) were assigned to the levothyroxine group and 93 (50%) were assigned to the placebo group. The trial was prematurely stopped when 187 (78%) of the 240 predefined patients had been included because of slow recruitment. 47 (50%) women in the levothyroxine group and 45 (48%) women in the placebo group had live births (risk ratio 1·03 [95% CI 0·77 to 1·38]; absolute risk difference 1·6% [95% CI -12·7 to 15·9]). Seven (7%) women in the levothyroxine group and seven (8%) in the placebo group reported adverse events, none of them were directly related to the study procedure. INTERPRETATION: Compared with placebo, levothyroxine treatment did not result in higher live birth rates in euthyroid women with recurrent pregnancy loss who were positive for TPO-Ab. On the basis of our findings, we do not advise routine use of levothyroxine in women who are TPO-Ab positive with recurrent pregnancy loss and normal thyroid function. FUNDING: Dutch Organization for Health Research and Development, Fonds NutsOhra, Dutch Patient Organization of Thyroid Disorders, the Jan Dekkerstichting and Dr Ludgardine Bouwmanstichting, and a personal donation through the Dutch Patient Organization of Thyroid Disorders.

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.

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.

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.

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).

Lifestyle intervention prior to IVF does not improve embryo utilization rate and cumulative live birth rate in women with obesity: a nested cohort study.

STUDY QUESTION: Does lifestyle intervention consisting of an energy-restricted diet, enhancement of physical activity and motivational counseling prior to IVF improve embryo utilization rate (EUR) and cumulative live birth rate (CLBR) in women with obesity? SUMMARY ANSWER: A 6-month lifestyle intervention preceding IVF improved neither EUR nor CLBR in women with obesity in the first IVF treatment cycle where at least one oocyte was retrieved. WHAT IS KNOWN ALREADY: A randomized controlled trial (RCT) evaluating the efficacy of a low caloric liquid formula diet (LCD) preceding IVF in women with obesity was unable to demonstrate an effect of LCD on embryo quality and live birth rate: in this study, only one fresh embryo transfer (ET) or, in case of freeze-all strategy, the first transfer with frozen-thawed embryos was reported. We hypothesized that any effect on embryo quality of a lifestyle intervention in women with obesity undergoing IVF treatment is better revealed by EUR and CLBR after transfer of all fresh and frozen-thawed embryos. STUDY DESIGN SIZE DURATION: This is a nested cohort study within an RCT, the LIFEstyle study. The original study examined whether a 6-month lifestyle intervention prior to infertility treatment in women with obesity improved live birth rate, compared to prompt infertility treatment within 24 months after randomization. In the original study between 2009 and 2012, 577 (three women withdrew informed consent) women with obesity and infertility were assigned to a lifestyle intervention followed by infertility treatment (n = 289) or to prompt infertility treatment (n = 285). PARTICIPANTS/MATERIALS SETTING METHODS: Only participants from the LIFEstyle study who received IVF treatment were eligible for the current analysis. In total, 137 participants (n = 58 in the intervention group and n = 79 in the control group) started the first cycle. In 25 participants, the first cycle was cancelled prior to oocyte retrieval mostly due to poor response. Sixteen participants started a second or third consecutive cycle. The first cycle with successful oocyte retrieval was used for this analysis, resulting in analysis of 51 participants in the intervention group and 72 participants in the control group. Considering differences in embryo scoring methods and ET day strategy between IVF centers, we used EUR as a proxy for embryo quality. EUR was defined as the proportion of inseminated/injected oocytes per cycle that was transferred or cryopreserved as an embryo. Analysis was performed per cycle and per oocyte/embryo. CLBR was defined as the percentage of participants with at least one live birth from the first fresh and subsequent frozen-thawed ET(s). In addition, we calculated the Z-score for singleton neonatal birthweight and compared these outcomes between the two groups. MAIN RESULTS AND THE ROLE OF CHANCE: The overall mean age was 31.6 years and the mean BMI was 35.4 ± 3.2 kg/m2 in the intervention group, and 34.9 ± 2.9 kg/m2 in the control group. The weight change at 6 months was in favor of the intervention group (mean difference in kg vs the control group: -3.14, 95% CI: -5.73 to -0.56). The median (Q25; Q75) number of oocytes retrieved was 4.00 (2.00; 8.00) in the intervention group versus 6.00 (4.00; 9.75) in the control group, and was not significantly different, as was the number of oocytes inseminated/injected (4.00 [2.00; 8.00] vs 6.00 [3.00; 8.75]), normal fertilized embryos (2.00 [0.50; 5.00] vs 3.00 [1.00; 5.00]) and the number of cryopreserved embryos (2.00 [1.25; 4.75] vs 2.00 [1.00; 4.00]). The median (Q25; Q75) EUR was 33.3% (12.5%; 60.0%) in the intervention group and 33.3% (16.7%; 50.0%) in the control group in the per cycle analysis (adjusted B: 2.7%, 95% CI: -8.6% to 14.0%). In the per oocyte/embryo analysis, in total, 280 oocytes were injected or inseminated in the intervention group, 113 were utilized (transferred or cryopreserved, EUR = 40.4%); in the control group, EUR was 30.8% (142/461). The lifestyle intervention did not significantly improve EUR (adjusted odds ratio [OR]: 1.36, 95% CI: 0.94-1.98) in the per oocyte/embryo analysis, taking into account the interdependency of the oocytes per participant. CLBR was not significantly different between the intervention group and the control group after adjusting for type of infertility (male factor and unexplained) and smoking (27.5% vs 22.2%, adjusted OR: 1.03, 95% CI: 0.43-2.47). Singleton neonatal birthweight and Z-score were not significantly different between the two groups. LIMITATIONS REASONS FOR CAUTION: This study is a nested cohort study within an RCT, and no power calculation was performed. The randomization was not stratified for indicated treatment, and although we corrected our analyses for baseline differences, there may be residual confounding. The limited absolute weight loss and the short duration of the lifestyle intervention might be insufficient to affect EUR and CLBR. WIDER IMPLICATIONS OF THE FINDINGS: Our data do not support the hypothesis of a beneficial short-term effect of lifestyle intervention on EUR and CLBR after IVF in women with obesity, although more studies are needed as there may be a potential clinically relevant effect on EUR. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50-50110-96-518). A.H. has received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet, has been a member of the ObsEva advisory board and holds Stock options for ObsEva. B.W.J.M. has received research funding from Guerbet, Ferring and Merck. F.J.M.B. reports personal fees from membership of the external advisory board for Merck Serono and a research support grant from Merck Serono, outside the submitted work. TRIAL REGISTRATION NUMBER: The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530). https://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1530.

The Effects of a Preconception Lifestyle Intervention on Childhood Cardiometabolic Health-Follow-Up of a Randomized Controlled Trial.

Maternal obesity is associated with adverse metabolic outcomes in her offspring, from the earliest stages of development leading to obesity and poorer cardiometabolic health in her offspring. We investigated whether an effective preconception lifestyle intervention in obese women affected cardiometabolic health of their offspring. We randomly allocated 577 infertile women with obesity to a 6-month lifestyle intervention, or to prompt infertility management. Of the 305 eligible children, despite intensive efforts, 17 in the intervention and 29 in the control group were available for follow-up at age 3-6 years. We compared the child's Body Mass Index (BMI) Z score, waist and hip circumference, body-fat percentage, blood pressure Z scores, pulse wave velocity and serum lipids, glucose and insulin concentrations. Between the intervention and control groups, the mean (±SD) offspring BMI Z score (0.69 (±1.17) vs. 0.62 (±1.04)) and systolic and diastolic blood pressure Z scores (0.45 (±0.65) vs. 0.54 (±0.57); 0.91 (±0.66) vs. 0.96 (±0.57)) were similar, although elevated compared to the norm population. We also did not detect any differences between the groups in the other outcomes. In this study, we could not detect effects of a preconception lifestyle intervention in obese infertile women on the cardiometabolic health of their offspring. Low follow-up rates, perhaps due to the children's age or the subject matter, combined with selection bias abating contrast in periconceptional weight between participating mothers, hampered the detection of potential effects. Future studies that account for these factors are needed to confirm whether a preconception lifestyle intervention may improve the cardiometabolic health of children of obese mothers.

The long-term costs and effects of tubal flushing with oil-based versus water-based contrast during hysterosalpingography.

RESEARCH QUESTION: What are the long-term costs and effects of oil- versus water-based contrast in infertile women undergoing hysterosalpingography (HSG)? DESIGN: This economic evaluation of a long-term follow-up of a multicentre randomized controlled trial involved 1119 infertile women randomized to HSG with oil- (n = 557) or water-based contrast (n = 562) in the Netherlands. RESULTS: In the oil-based contrast group, 39.8% of women needed no other treatment, 34.6% underwent intrauterine insemination (IUI) and 25.6% had IVF/intracytoplasmic sperm injection (ICSI) in the 5 years following HSG. In the water-based contrast group, 35.0% of women had no other treatment, 34.2% had IUI and 30.8% had IVF/ICSI in the 5 years following HSG (P = 0.113). After 5 years of follow-up, HSG using oil-based contrast resulted in equivalent costs (mean cost difference -€144; 95% confidence interval [CI] -€579 to +€290; P = 0.515) for a 5% increase in the cumulative ongoing pregnancy rate compared with HSG using water-based contrast (80% compared with 75%, Relative Risk (RR) 1.07; 95% CI 1.00-1.14). Similarly, HSG with oil-based contrast resulted in equivalent costs (mean cost difference -€50; 95% CI -€576 to +€475; P = 0.850) for a 7.5% increase in the cumulative live birth rate compared with HSG with water-based contrast (74.8% compared with 67.3%, RR 1.11; 95% CI 1.03-1.20), making it the dominant strategy. Scenario analyses suggest that the oil-based contrast medium is the dominant strategy up to a price difference of €300. CONCLUSION: Over a 5-year follow-up, HSG with an oil-based contrast was associated with a 5% increase in ongoing pregnancy rate, a 7.5% increase in live birth rate and similar costs to HSG with water-based contrast.

A lifestyle intervention randomized controlled trial in obese women with infertility improved body composition among those who experienced childhood adversity.

Previous research indicates that tailoring lifestyle interventions to participant characteristics optimizes intervention effectiveness. Our objective was to assess whether the effects of a preconception lifestyle intervention in obese infertile women depended on women's exposure to adversity in childhood. A follow-up of a preconception lifestyle intervention randomized controlled trial (the LIFEstyle study) was conducted in the Netherlands among 577 infertile women (age 18-39 years) with a body mass index (BMI) ≥29 kg/m2 at time of randomization; N = 110 (19%) consented to the follow-up assessment, 6 years later. A 6-month preconception lifestyle intervention aimed weight loss through improving diet and increasing physical activity. The control group received care as usual. Outcome measures included weight, BMI, waist and hip circumference, body fat percentage, blood pressure and metabolic syndrome. The potential moderator, childhood adversity, was assessed with the Life Events Checklist-5 questionnaire. Among the 110 women in our follow-up study, n = 65 (59%) reported no childhood adverse events, n = 28 (25.5%) reported 1 type of childhood adverse events and n = 17 (15.5%) reported ≥2 types of childhood adverse events. Regression models showed significant interactions between childhood adversity and effects of lifestyle intervention at the 6-year follow-up. Among women who experienced childhood adversity, the intervention significantly reduced weight (-10.0 [95% CI -18.5 to -1.5] kg, p = 0.02), BMI (-3.2 [-6.1 to -0.2] kg/m2 , p = 0.04) and body fat percentage (-4.5 [95% CI -7.2 to -1.9] p < 0.01). Among women without childhood adversity, the intervention did not affect these outcomes (2.7 [-3.9 to 9.4] kg, p = 0.42), (0.9 [-1.4 to 3.3] kg/m2 , p = 0.42) and (1.7 [95% CI -0.3 to 3.7] p = 0.10), respectively. Having a history of childhood adversity modified the effect of a preconception lifestyle intervention on women's body composition. If replicated, it may be important to consider childhood adversity as a determinant of lifestyle intervention effectiveness.