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.

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).

Sexual function and pelvic floor activity in women: the role of traumatic events and PTSD symptoms.

BACKGROUND: Traumatic sexual experiences can negatively affect sexual functioning and increase pelvic floor activity in women, especially when post-traumatic stress disorder (PTSD) is developed. However, little is known about the effect of other types of interpersonal and non-interpersonal, traumatic experiences on sexual function and pelvic floor overactivity. OBJECTIVE: The aim of this study was to examine the effects of lifetime traumatic experiences and subsequent PTSD symptoms on sexual function and pelvic floor activity and to investigate whether the effects differ for interpersonal and non-interpersonal trauma. METHODS: Women (N=82) with obesity and a history of infertility, participating in a follow-up study of an RCT investigating a lifestyle intervention programme, completed questionnaires on lifetime exposure to traumatic events (LEC-5), PTSD symptoms (PC-PTSD-5), sexual function (MFSQ) and pelvic floor activity (AOPFS-SV). RESULTS: A large majority of women (85%) reported exposure to at least one traumatic event during their lifetime. Sexual function and pelvic floor activity did not differ between women who experienced non-interpersonal or interpersonal (including sexual) trauma and those who did not experience traumatic events during their lifetime. Women who had developed PTSD symptoms, however, did have higher pelvic floor activity, but sexual function was not affected. Women with a positive screen for PTSD had the highest pelvic floor activity score, and individual PTSD symptoms nightmares and hypervigilance were associated with significantly higher pelvic floor activity scores. CONCLUSION: Trauma exposure is associated with pelvic floor overactivity in women with a positive screen for PTSD, such that pelvic floor overactivity is more severe with greater PTSD severity. These findings suggest that the development of PTSD after interpersonal trauma is pivotal in this association. Sexual function was unrelated to trauma exposure and pelvic floor function, perhaps related to the fact that the interpersonal trauma events reported in this study were mainly non-sexual.

Antecedentes: Las experiencias sexuales traumáticas pueden comprometer negativamente el funcionamiento sexual e incrementar la actividad del piso pélvico en mujeres, especialmente cuando se desarrolla un trastorno de estrés postraumático (TEPT). Sin embargo, se sabe poco sobre los efectos de otros tipos de experiencias traumáticas, interpersonales y no interpersonales, en la función sexual y la hiperactividad del piso pélvico.Objetivo: El propósito de este estudio fue evaluar los efectos de las experiencias traumáticas a lo largo de la vida, con síntomas del TEPT subsecuentes, en la función sexual y la actividad del piso pélvico e investigar si los efectos difieren entre trauma interpersonal y no interpersonal.Métodos: Un grupo (N=82) de mujeres con obesidad y antecedente de infertilidad que estaba participando de un estudio clínico longitudinal aleatorizado (RCT) sobre un programa de intervención sobre estilos de vida, respondió un cuestionario sobre exposición a eventos traumáticos a lo largo de la vida (LEC-5, por sus siglas en inglés), síntomas del TEPT (PC-PTSD-5, por sus siglas en inglés), función sexual (MFSQ, por sus siglas en inglés) y actividad del piso pélvico (AOPFS-SV, por sus siglas en inglés).Resultados: Una gran mayoría de las mujeres (85%) reportó exposición a al menos un evento traumático a lo largo de la vida. No hubo diferencia de la función sexual y la actividad del piso pélvico entre las mujeres que experimentaron trauma no interpersonal, entre las mujeres que experimentaron trauma interpersonal (incluyendo el sexual), y entre aquellas que no experimentaron eventos traumáticos a lo largo de su vida. Sin embargo, en las mujeres que desarrollaron síntomas del TEPT se encontró mayor actividad del piso pélvico, pero sin comprometer la función sexual. Las mujeres con un puntaje significativo para el TEPT presentaban los puntajes más altos en actividad del piso pélvico, y síntomas puntuales del TEPT como pesadillas e hipervigilancia se asociaron a puntajes de actividad del piso pélvico más altas.Conclusión: La exposición a trauma se asocia con hiperactividad del piso pélvico en mujeres con puntajes significativos para el TEPT, y tal hiperactividad del piso pélvico es más severa a mayor severidad del TEPT. Estos hallazgos sugieren que el desarrollo del TEPT luego del trauma interpersonal es un aspecto clave en esta asociación. La función sexual no estaba relacionada con la exposición al trauma o a la función del piso pélvico, quizá relacionado al hecho que los eventos reportados como eventos traumáticos interpersonales eran principalmente no sexuales.

The effects of a pre-conception lifestyle intervention in women with obesity and infertility on perceived stress, mood symptoms, sleep and quality of life.

BACKGROUND: Obesity is an increasing problem worldwide and is associated with serious health risks. Obesity not only reduces physical health, but can also negatively affect levels of perceived stress, mood symptoms, sleep quality and quality of life (QoL), which may lead to further weight gain. We have previously shown that a pre-conception lifestyle intervention reduced weight and improved physical QoL in the short term. In the current study, we assessed the effects of this intervention in women with obesity and infertility on perceived stress, mood symptoms, sleep quality and QoL five years after randomization. METHODS AND FINDINGS: We followed women who participated in the LIFEstyle study. This is a multi-center randomized controlled trial comparing a six-month lifestyle intervention to improve diet and increase physical activity followed by infertility treatment, versus prompt infertility treatment. Participants were 577 women with infertility between 18 and 39 years of age with a body mass index (BMI) ≥ 29 kg/m2. For the current study we measured perceived stress, mood symptoms, sleep quality and QoL in 178 women five years after randomization. T-tests and linear regression models were used to assess differences between the intervention and control groups. Five years after randomization, no differences were observed for perceived stress, mood symptoms, sleep quality and QoL between the intervention (n = 84) and control groups (n = 94). There was selective participation: women who did not participate in the follow-up had lower baseline mental QoL, and benefitted more from the intervention in terms of improved physical QoL during the original LIFEstyle intervention. CONCLUSIONS: We found no evidence that a pre-conception lifestyle intervention improved female well-being five years after randomization.

Long-term effects of a preconception lifestyle intervention on cardiometabolic health of overweight and obese women.

BACKGROUND: The global prevalence of obesity in women keeps increasing. The preconception period may be a window of opportunity to improve lifestyle, reduce obesity and improve cardiometabolic health. This study assessed the effect of a preconception lifestyle intervention on long-term cardiometabolic health in two randomized controlled trials (RCTs). METHODS: Participants of the LIFEstyle and RADIEL preconception lifestyle intervention studies with a baseline body mass index (BMI) ≥29 kg/m2 were eligible for this follow-up study. Both studies randomized between a lifestyle intervention targeting physical activity, diet and behaviour modification or usual care. We assessed cardiometabolic health 6 years after randomization. RESULTS: In the LIFEstyle study (n = 111) and RADIEL study (n = 39), no statistically significant differences between the intervention and control groups were found for body composition, blood pressure, arterial stiffness, fasting glucose, homeostasis model assessment of insulin resistance, HbA1c, lipids and high sensitive C-reactive protein levels 6 years after randomization. Participants of the LIFEstyle study who successfully lost ≥5% bodyweight or reached a BMI <29 kg/m2 during the intervention (n = 22, [44%]) had lower weight (-8.1 kg; 99% CI [-16.6 to -0.9]), BMI (-3.3 kg/m2; [-6.5 to -0.8]), waist circumference (-8.2 cm; [-15.3 to -1.3]), fasting glucose (-0.5 mmol/L; [-1.1 to -0.0]), HbA1c (-4.1 mmol/mol; [-9.1 to -0.8]), and higher HDL-C (0.3 mmol/L; [0.1-0.5]) compared with controls. CONCLUSION: We found no evidence of improved cardiometabolic health 6 years after a preconception lifestyle intervention among overweight and obese women in two RCTs. Women who successfully lost weight during the intervention had better cardiometabolic health 6 years later, emphasizing the potential of successful preconception lifestyle improvement.

A lifestyle intervention improves sexual function of women with obesity and infertility: A 5 year follow-up of a RCT.

BACKGROUND: Obesity and infertility are associated with poorer sexual function. We have previously shown that a lifestyle intervention in women with obesity and infertility reduced weight and improved cardiometabolic health and quality of life, which may positively affect sexual function. We now report on sexual function 5 years after randomization. METHODS AND FINDINGS: In total 577 women, between 18-39 years of age, with infertility and a BMI ≥29 kg/m2 were randomized to a six-month lifestyle intervention targeting physical activity, diet and behavior modification or prompt infertility care as usual. Intercourse frequency and sexual function were assessed with the McCoy Female Sexuality Questionnaire (MFSQ), 5.4±0.8 years after randomization. 550 women could be approached for the follow-up study, of whom 84 women in the intervention and 93 in the control group completed the MFSQ. Results were adjusted for duration of infertility, polycystic ovary syndrome and whether women were attempting to conceive. The intervention group more often reported having had intercourse in the past 4 weeks compared to the control group (aOR: 2.3 95% CI 0.96 to 5.72). Among women reporting intercourse in the past 4 weeks, the intervention group (n = 75) had intercourse more frequently (6.6±5.8 vs. 4.9±4.0 times; 95% CI 0.10 to 3.40) and had higher scores for vaginal lubrication (16.5±3.0 vs. 15.4±3.5; 95% CI 0.15 to 2.32) and total 'sexual function' score (96.5±14.2 vs. 91.4±12.8; 95% CI 0.84 to 9.35) compared to the control group (n = 72). Sexual interest, satisfaction, orgasm and sex partner scores did not differ statistically between the groups. The intervention effect on sexual function was for 21% mediated by the change in moderate to vigorous physical activity. CONCLUSION: A six-month lifestyle intervention in women with obesity and infertility led to more frequent intercourse, better vaginal lubrication and overall sexual function 5 years after the intervention. (Trial Registration: NTR1530).

Long-Term Effects of Oral Antidiabetic Drugs During Pregnancy on Offspring: A Systematic Review and Meta-analysis of Follow-up Studies of RCTs.

INTRODUCTION: Antidiabetic drugs (OADs) are increasingly prescribed to treat hyperglycaemia during pregnancy in women with gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS), even though long-term effects on offspring are unknown. This systematic review summarises the evidence of follow-up studies of randomised controlled trials (RCTs) reporting on long-term effects of prenatal exposure to OADs on offspring. METHODS: The MEDLINE, EMBASE and CENTRAL databases were searched from inception to April 2018 for the concepts antidiabetic agents and prenatal exposure (or pregnancy and offspring/child) in combination with an RCT search filter. RCTs evaluating post-neonatal health effects in offspring and comparing maternal treatment with an OAD with no treatment, placebo, an alternative OAD or insulin during pregnancy were eligible for inclusion. Two independent researchers selected, extracted and assessed the data. Meta-analyses were performed using a random effects model and the Cochrane Collaboration's risk of bias tool was used for quality assessment. RESULTS: Ten studies were included, with a maximal follow-up duration of 9 years, comprising 778 children of mothers with GDM or PCOS who were randomised to either metformin or insulin/placebo during pregnancy. Meta-analysis showed that children prenatally exposed to metformin were heavier compared to controls (standardised mean difference (SMD) 0.26 [95% CI 0.11-0.41]), but not taller (SMD 0.10 [95% CI -0.14-0.33]). Additionally, offspring body mass index (BMI) z scores did not differ according to metformin exposure (mean difference 0.30 [95% CI -0.01-0.61]). Individual small studies reported that prenatal exposure to metformin was associated with greater mid-upper arm, head and waist circumferences, biceps skinfolds, waist-to-height ratio, more arm fat, higher fasting glucose, ferritin and lower LDL cholesterol in offspring. CONCLUSION: Prenatal exposure to metformin is associated with increased offspring weight, but not with height or BMI. Larger follow-up studies are needed to confirm and look into the implications of these findings. Plain language summary available for this article.

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).

Dyscholesterolemia Protects Against Ischemia-Induced Ventricular Arrhythmias.

BACKGROUND: Hypercholesterolemia protects against ventricular fibrillation in patients with myocardial infarction. We hypothesize that hypercholesterolemia protects against ischemia-induced reentrant arrhythmias because of altered ion channel function. METHODS AND RESULTS: ECGs were measured in low-density lipoprotein receptor knockout (LDLr(-/-)), apolipoprotein A1 knockout (ApoA1(-/-)), and wild-type (WT) mice. Action potentials, calcium handling, and ion currents were recorded in ventricular myocytes. Gene expression was determined by quantitative polymerase chain reaction and Western blot. In isolated perfused hearts, regional ischemia was induced and arrhythmia inducibility was tested. Serum low-density lipoprotein (LDL) cholesterol was higher in LDLr(-/-) mice than in WT mice (2.6 versus 0.4 mmol/L), and high-density lipoprotein cholesterol was significantly lower in ApoA1(-/-) mice than in WT mice (0.3 versus 1.8 mmol/L). LDLr(-/-) and ApoA1(-/-) myocytes contained more cholesterol than WT (34.4±2.8 and 36.5±2.4 versus 25.5±0.4 µmol/g protein). The major potassium currents were not different in LDLr(-/-) and ApoA1(-/-) compared with WT mice. The L-type calcium current (I(Ca)), however, was larger in LDLr(-/-) and ApoA1(-/-) than in WT (12.1±0.7 and 12.8±0.8 versus 9.4±1.1 pA/pF). Calcium transient amplitude and fractional sarcoplasmic reticulum calcium release were larger and action potential and QTc duration longer in LDLr(-/-) and ApoA1(-/-) than in WT mice (action potential duration at 90% of repolarization: 102±4 and 106±3 versus 84±3.1 ms; QTc: 50.9±1.3 and 52.8±0.8 versus 43.5±1.2 ms). During ischemia, ventricular tachycardia/ventricular fibrillation inducibility was larger in WT than in LDLr(-/-) and ApoA1(-/-) hearts. Expression of sodium channel and Ca-handling genes were not significantly different between groups. CONCLUSIONS: Dyscholesterolemia is associated with action potential prolongation because of increased I(Ca) and reduces occurrence of reentrant arrhythmias during ischemia.