Preconception Lifestyle and Cardiovascular Health in the Offspring of Overweight and Obese Women.

Women's lifestyle has important implications for the development and health of their offspring. Yet little is known about the association between women's preconception dietary intake and physical activity with cardiovascular health of the offspring. We therefore examined this association in a group of Dutch women with overweight or obesity (BMI ≥ 29 kg/m2) and infertility, who participated in a 6-month randomized preconception lifestyle intervention trial, and their offspring (n = 46). Preconception dietary intake and physical activity were assessed during the 6-month intervention using a food frequency questionnaire and the Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH), respectively. Offspring cardiovascular health (i.e., BMI, waist:height ratio, systolic and diastolic blood pressure, fat and fat free mass, and pulse wave velocity) was measured at age 3-6 years. Multivariable linear regression analyses were used to examine the associations between preconception lifestyle and offspring cardiovascular health. Higher preconception vegetable intake (per 10 g/day) was associated with lower offspring diastolic blood pressure (Z-score: -0.05 (-0.08; -0.01); p = 0.007) and higher preconception fruit intake (per 10 g/day) was associated with lower offspring pulse wave velocity (-0.05 m/s (-0.10; -0.01); p = 0.03). Against our expectations, higher preconception intake of sugary drinks was associated with a higher offspring fat free mass (0.54 kg (0.01; 1.07); p = 0.045). To conclude, preconception dietary intake is associated with offspring health.

Effects of maternal lifestyle interventions on child neurobehavioral development: Follow-up of randomized controlled trials.

Obesity is a major public health problem. Children of women who were obese before or during pregnancy are at increased risk for neurobehavioral developmental problems. Whether a maternal lifestyle intervention conducted before and during pregnancy in obese women affects child neurobehavioral development is unknown. This study reports on the follow-up of a subsample of two randomized controlled trials, the Finnish RADIEL (n = 216) and Dutch LIFEstyle (n = 305) trial. Women with a pre-pregnancy BMI ≥29 kg/m2 wishing to conceive or who were already pregnant (<20 weeks) were allocated to a lifestyle intervention or to care as usual. Child neurodevelopment was measured with the Ages and Stages Questionnaire and child behavioral problems were measured with the Childhood Behavior Checklist (RADIEL) or the Strengths and Difficulties Questionnaire (LIFEstyle) at age 3-6 years. We used linear and binary logistic regression analyses to assess the effects of the lifestyle interventions on children's neurobehavioral developmental scores. Follow-up data was available from 161(38%) RADIEL and 96(32%) LIFEstyle children. Child neurodevelopmental scores did not differ significantly between children in the intervention and the control group (RADIEL:median = 275 vs. 280; LIFEstyle:median = 270 vs 267). Child behavioral problem scores did not differ significantly between children in the intervention and the control group (RADIEL:median = 22 vs. 21; LIFEstyle:median = 8 vs. 8). We did not observe considerable effects of the lifestyle interventions before or during pregnancy in obese women on child neurobehavioral development. With our sample sizes, we were not able to detect subtle differences in neurobehavioral development however.

Child outcomes after placement of a cervical pessary in women with a multiple pregnancy: A 4-year follow-up of the ProTWIN trial.

INTRODUCTION: The ProTWIN trial previously showed no beneficial effect of treatment with a cervical pessary vs usual care to prevent preterm birth in women with a multiple pregnancy. However, in women with a midtrimester short cervix (<38 mm), pessary did reduce the composite outcome of neonatal morbidity and mortality. This follow-up study evaluates the long-term outcomes of all children born to mothers who participated in the ProTWIN trial at 4 years of age. MATERIAL AND METHODS: Parents received the Ages and Stages Questionnaire, Strength and Difficulties Questionnaire and a health questionnaire. All questionnaires were reported separately and as a combined outcome (abnormal child outcome). A linear mixed effects model was used to adjust for correlated data in twins and correction for confounders was performed. In exploratory analysis, a composite outcome of death or survival with abnormal child outcome was used by combining extrapolated data on child outcome with survival data. All data were analyzed for the total group and the subgroup of women with midtrimester short cervix. RESULTS: Of the original 813 women of the ProTWIN trial, we approached 579, of whom 258 participated (45%) in follow-up. We received questionnaires of 514 children (281 pessary vs 233 control), with 119 children in the subgroup of women with midtrimester short cervix. An abnormal child outcome was found in 23% in the pessary group vs 16% in the control group (odds ratio 1.58; 95% confidence interval 0.94-2.65). In exploratory analysis with extrapolated data on child outcome (n = 815), no difference in abnormal child outcome was seen between the pessary and control group. In the subgroup of women with a short cervix (n = 268), this composite outcome indicated a favorable outcome for children born to mothers with pessary. CONCLUSIONS: In women with a multiple pregnancy, the use of a cervical pessary did not improve development, behavior or physical outcomes of the surviving children at age 4.

The link between maternal obesity and offspring neurobehavior: A systematic review of animal experiments.

Maternal obesity in pregnancy is associated with neurobehavioral problems in the offspring. Establishing causality has been challenging in existing human studies, due to confounding by genetic and postnatal environment. Animal experiments can improve our understanding of this association. This systematic review examined the effects of maternal obesity in pregnancy on offspring neurobehavior in animal models. We included 26 studies (1047 offspring animals). Meta-analyses showed that offspring of obese mothers displayed higher levels of locomotor activity (standardized mean difference (SMD) 0.34 [0.10; 0.58]) and anxiety behavior (SMD 0.47 [0.16; 0.79]) than offspring of lean mothers, but similar memory abilities (SMD -0.06 [-0.52; 0.39]). Meta-analysis of learning abilities was not sensible due to heterogeneity. Although the evidence was heterogeneous and the quality of the included studies generally unclear, this systematic review of animal studies indicates an effect of maternal obesity on increased offspring locomotor activity and anxiety, but not on offspring memory performance. These findings may be important from a public health perspective since obesity is rapidly increasing worldwide, and warrant further research.

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 ).

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).

The association between pre-pregnancy overweight/obesity and offspring's behavioral problems and executive functioning.

The prevalence of obesity among women of childbearing age has been rising dramatically over the last decades. Pre-pregnancy obesity may have negative neurodevelopmental consequences for the offspring. The present study examined the association of maternal pre-pregnancy overweight and obesity with child behavior problems and executive functioning at age 5 years. Data of 4094 mother-child pairs of the Amsterdam Born Children and their Development birth cohort study was used. Child behavioral problems were assessed with the maternal and teacher version of the Strengths and Difficulties Questionnaire. Two executive functioning constructs, inhibitory control and cognitive flexibility, were measured with the Response Organization Objects task of the Amsterdam Neuropsychological Tasks test battery. Increased maternal pre-pregnancy BMI was associated with an increase in children's behavioral problems (OR total behavioral problems reported by mothers pre-pregnancy obesity versus normal weight: 1.78 [95% CI 1.17 to 2.69] and reported by teachers for pre-pregnancy overweight versus normal weight: 1.32 [1.00 to 1.74]). Maternal pre-pregnancy obesity was associated with an increase in peer relationship problems reported by teachers (OR: 1.77 [1.18 to 2.64]). It was also associated with a small decrease in cognitive flexibility (increased Reaction Time in ms: B = 67.59 [5.88 to 129.30] and Within Subject Standard Deviation in ms: B = 76.46 [32.00 to 120.92]), but not with inhibitory control. Cognitive flexibility did not mediate the association between maternal pre-pregnancy BMI and children's behavioral problems.

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).

Women, their Offspring and iMproving lifestyle for Better cardiovascular health of both (WOMB project): a protocol of the follow-up of a multicentre randomised controlled trial.

INTRODUCTION: Women, their Offspring and iMproving lifestyle for Better cardiovascular health of both (WOMB) project is the follow-up of the LIFEstyle study, a randomised controlled trial in obese infertile women, and investigates the effects of a preconception lifestyle intervention on later health of women (WOMB women) and their children (WOMB kids). METHODS AND ANALYSIS: Obese infertile women, aged between 18 and 39 years, were recruited in 23 Dutch fertility clinics between June 2009 and June 2012. The 284 women allocated to the intervention group received a 6-month structured lifestyle programme. The 280 women in the control group received infertility care as usual. 4 to 7 years after inclusion in the trial, all women (n=564) and children conceived during the trial (24 months after randomisation) (n=305 singletons and age 3-5 years) will be approached to participate in this follow-up study (starting in 2015). The main focus of outcome will be cardiovascular health, but the dataset comprises a wide range of physical and mental health measures, diet and physical activity measures, child growth and development measures, biological samples and genetic and epigenetic information. The follow-up assessment consists of three stages that take place between 2016 and 2018, and includes (online) questionnaires, accelerometry and physical and behavioural measurements in a mobile research vehicle. A subsample of 100 women and 100 children are planned for cardiac ultrasound measurements. ETHICS AND DISSEMINATION: The protocol of this follow-up study is approved by the local medical ethics committee (University Medical Centre Groningen). Study findings of the WOMB project will be widely disseminated to the scientific community, healthcare professionals, policy makers, future parents and general public. TRIAL REGISTRATION NUMBER: The original LIFEstyle study is registered at The Netherlands Trial Registry (number 1530).

Influence of prenatal maternal stress, maternal plasma cortisol and cortisol in the amniotic fluid on birth outcomes and child temperament at 3 months.

This prospective, longitudinal study aimed to investigate relationships between indicators of maternal prenatal stress, infant birth outcomes and early temperament. We examined the pattern of associations and postulated pathways between physiological (cortisol plasma concentrations) and self-report indices (stress, anxiety) of maternal prenatal stress, cortisol in the amniotic fluid, birth outcomes and infant temperament at 3 months. The sample consisted of 158 women undergoing amniocentesis in the 2nd trimester of pregnancy. Questionnaire measures of maternal stress and anxiety were found to be unrelated to cortisol in plasma or amniotic fluid. Maternal cortisol was related to amniotic cortisol, which in turn was associated with lower birth weight. Birth weight predicted infant fear and distress to limitation at 3 months old. We found trend-like indirect effects of amniotic fluid on infant distress to limitation and fear via birth weight. This is one of the few studies to simultaneously assess the role of maternal and amniotic fluid cortisol on birth outcomes and infant emotional development. The results suggest that foetal cortisol may be an important predictor of infant outcomes and shed light on the mechanisms through which prenatal maternal stress affects infant psychological health.

Differential effects of prenatal testosterone on lateralization of handedness and language.

OBJECTIVE: Handedness is the most noticeable functional expression of cerebral lateralization in humans. However, its developmental process and plasticity remain elusive. It has been postulated that prenatal testosterone (pT) has an effect on human lateralization development. In the present study we examined the relationship between pT and handedness and compared the outcome to previously published data on language lateralization in the same children. METHOD: pT was assessed from amniotic fluid of healthy pregnant women using radioimmunoassay. Strength and direction of handedness of the children (n = 65 [31 girls, 34 boys], mean age [years]: 6.43, range: 5.97-7.53) was assessed based on hand choice during performance of age appropriate tasks. Regression procedures and the Olkin & Siotani Z-statistic were used. RESULTS: Results demonstrate that higher pT exposure was related to a decrease in strength of handedness (R² = .11, p = .01). The analysis shows that pT has quite stronger explanatory power than sex by itself, although there may be an additional effect of sex independent from pT. In a subgroup of these children we recently reported that higher levels of pT are related to increased left hemisphere dominance for language. Analyses show that pT is differentially related to handedness and language lateralization in these children (Z > 2.75, p < .003). CONCLUSIONS: Results imply a differential effect of pT on language lateralization and handedness. This may be explained by differential sensitivity of different areas of the corpus callosum or hemispheres for androgens, fuelling the ongoing debate about the relationship between prenatal exposure to testosterone and lateralization of brain and behavior.

Prenatal sex hormones (maternal and amniotic fluid) and gender-related play behavior in 13-month-old Infants.

Testosterone, estradiol, and progesterone levels were measured in the second trimester of pregnancy in maternal serum and amniotic fluid, and related to direct observations of gender-related play behavior in 63 male and 63 female offspring at age 13 months. During a structured play session, sex differences in toy preference were found: boys played more with masculine toys than girls (d = .53) and girls played more with feminine toys than boys (d = .35). Normal within-sex variation in prenatal testosterone and estradiol levels was not significantly related to preference for masculine or feminine toys. For progesterone, an unexpected significant positive relationship was found in boys between the level in amniotic fluid and masculine toy preference. The mechanism explaining this relationship is presently not clear, and the finding may be a spurious one. The results of this study may indicate that a hormonal basis for the development of sex-typed toy preferences may manifest itself only after toddlerhood. It may also be that the effect size of this relationship is so small that it should be investigated with more sensitive measures or in larger populations.

Prenatal sex hormone effects on child and adult sex-typed behavior: methods and findings.

There is now good evidence that human sex-typed behavior is influenced by sex hormones that are present during prenatal development, confirming studies in other mammalian species. Most of the evidence comes from clinical populations, in which prenatal hormone exposure is atypical for a person's sex, but there is increasing evidence from the normal population for the importance of prenatal hormones. In this paper, we briefly review the evidence, focusing attention on the methods used to study behavioral effects of prenatal hormones. We discuss the promises and pitfalls of various types of studies, including those using clinical populations (concentrating on those most commonly studied, congenital adrenal hyperplasia, androgen insensitivity syndrome, ablatio penis, and cloacal exstrophy), direct measures of hormones in the general population (assayed through umbilical cord blood, amniotic fluid, and maternal serum during pregnancy), and indirect measures of hormones in the general population (inferred from intrauterine position and biomarkers such as otoacoustic emissions, finger length ratios, and dermatoglyphic asymmetries). We conclude with suggestions for interpreting and conducting studies of the behavioral effects of prenatal hormones.

Relationships between sex hormones assessed in amniotic fluid, and maternal and umbilical cord serum: what is the best source of information to investigate the effects of fetal hormonal exposure?

Levels of testosterone (T) (total and free), androstenedione (A4), dehydroepiandrosterone sulphate (DHEAS), sex hormone-binding globulin (SHBG), and estradiol (E2) were measured by radioimmunoassay (RIA) in 156 normal pregnancies (77 male and 79 female fetuses). Samples were obtained from amniotic fluid, 2nd and 3rd trimester maternal serum, and umbilical cord serum at birth. During the critical period of brain differentiation, at the beginning of the second trimester of pregnancy, sex differences in T and A4 were found in amniotic fluid and not in maternal serum. This finding adds to the fact that mostly low and nonsignificant correlations were found for the different androgenic hormones between levels assessed in amniotic fluid and maternal plasma at this particular and very sensitive period of fetal brain development. On the other hand, high correlations were found for the same hormones between the samples of maternal serum in the 2nd and the 3rd trimester. Our data show that, of all available sources, amniotic fluid seems to be the best candidate to investigate the effects of early fetal androgen exposure.