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Background Despite increasing use of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII, insulin pumps) in type 1 diabetes (T1D) in pregnancy, achieving recommended pregnancy glycaemic targets (3.5–7.8 mmol/L or 63–140 mg/dL) remains challenging. Consequently, the risk of adverse pregnancy outcomes remains high. Outside pregnancy, hybrid closed-loop (HCL) insulin delivery systems have led to a paradigm shift in the management of T1D, with 12% higher time in glucose target range (TIR) compared to conventional CSII. However, most commercially available HCL systems are currently not approved for use in pregnancy. This study aims to evaluate the efficacy, safety and cost-effectiveness of the MiniMed™ 780G HCL system (Medtronic) in T1D in pregnancy. Methods In this international, open-label, randomized controlled trial (RCT), we will compare the MiniMed™ 780G HCL system to standard of care (SoC) in T1D in pregnancy. Women aged 18–45 years with T1D diagnosis of at least one year, HbA1c ≤ 86 mmol/mol (≤ 10%), and confirmed singleton pregnancy up to 11 weeks 6 days will be eligible. After providing written informed consent, all participants will wear a similar CGM system (Guardian™ 3 or Guardian™ 4 CGM) during a 10-day run-in phase. After the run-in phase, participants will be randomised 1:1 to 780G HCL (intervention) or SoC [control, continuation of current T1D treatment with multiple daily injections (MDI) or CSII and any type of CGM] stratified according to centre, baseline HbA1c (< 53 vs. ≥ 53 mmol/mol or < 7 vs. ≥ 7%), and method of insulin delivery (MDI or CSII). The primary outcome will be the time spent within the pregnancy glucose target range, as measured by the CGM at four time points in pregnancy: 14–17, 20–23, 26–29, and 33–36 weeks. Prespecified secondary outcomes will be overnight TIR, time below range (TBR: <3.5 mmol/L or < 63 mg/dL), and overnight TBR. Other outcomes will be exploratory. The planned sample size is 92 participants. The study will end after postpartum discharge from hospital. Analyses will be performed according to intention-to-treat as well as per protocol. Discussion This large RCT will evaluate a widely used commercially available HCL system in T1D in pregnancy. Recruitment began in January 2021 and was completed in October 2022. Study completion is expected in May 2023. Trial registration ClinicalTrials.gov: NCT04520971. Registration date: August 20, 2020. https://clinicaltrials.gov/ct2/show/NCT04520971

BackgroundImproving 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.MethodsSix 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.ResultsSixty 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.ConclusionsChildren 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 registrationLIFEstyle 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).

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. 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. 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).

This study aimed to investigate the association between hyperemesis gravidarum (HG) severity and early enteral tube feeding on cardiometabolic markers in offspring cord blood. We included women admitted for HG, who participated in the MOTHER randomised controlled trial (RCT) and observational cohort. The MOTHER RCT showed that early enteral tube feeding in addition to standard care did not affect symptoms/birth outcomes. Among RCT and cohort participants, we assessed how HG severity affected lipid, c-peptide, glucose and free thyroxine cord blood levels. HG severity measures were severity of vomiting at inclusion and 3 weeks after inclusion, pregnancy weight gain and 24-h energy intake at inclusion, readmissions and duration of hospital admissions. Cord blood measures were also compared between RCT participants allocated to enteral tube feeding and those receiving standard care. Between 2013-2016, 215 women were included: 115 RCT and 100 cohort participants. Eighty-one cord blood samples were available. Univariable not multivariable regression analysis showed that lower maternal weight gain was associated with higher cord blood glucose levels (β: –0·08, 95% CI –0·16, –0·00). Lower maternal weight gain was associated with higher Apo-B cord blood levels in multivariable regression analysis (β: –0·01, 95% CI –0·02, –0·01). No associations were found between other HG severity measures or allocation to enteral tube feeding and cord blood cardiometabolic markers. In conclusion, while lower maternal weight gain was associated with higher Apo-B cord blood levels, no other HG severity measures were linked with cord blood cardiometabolic markers, nor were these markers affected by enteral tube feeding.

STUDY QUESTION Do mental health and sexual function differ between women with or without polycystic ovary syndrome (PCOS) with comparable BMI and fertility characteristics? SUMMARY ANSWER Women with PCOS have a poorer mental quality of life than women without PCOS, but there were no differences in symptoms of depression, anxiety, physical quality of life or sexual function. WHAT IS KNOWN ALREADY Various studies suggest that women with PCOS have poorer mental health, such as higher symptoms of anxiety and depression with a lower quality of life, and have an impaired sexual function compared to women without PCOS. However, in most studies, BMI and infertility status differ between women with and without PCOS, which may hamper comparability. STUDY DESIGN, SIZE, DURATION This study is a cross-sectional analysis of a 5-year follow-up of a randomized controlled trial (RCT) among women with obesity and a history of infertility. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants in this follow-up study of an RCT were women with obesity and infertility randomized to a lifestyle intervention followed by infertility treatment or prompt infertility treatment (control), stratified by ovulatory status and trial centre. In total, 173 (30.0%) women of the 577 women randomized in the initial trial participated in this follow-up study, with a mean follow-up of 5.5 years (range 3.7–7.0 years); of these women 73 had been diagnosed with PCOS and 100 did not have PCOS. Participants completed questionnaires on symptoms of anxiety and depression (Hospital Anxiety and Depression scale (HADS)), quality of life (36-item Short Form Health Survey (SF-36)) and sexual function (McCoy Female Sexuality Questionnaire (MFSQ)). We also compared quality of life subscale scores in women with and without PCOS and compared them to an age-matched Dutch reference population with average BMI. Effect sizes were calculated to assess the differences. MAIN RESULTS AND THE ROLE OF CHANCE Symptoms of anxiety and depression, physical quality of life and sexual function did not differ significantly between obese women with and without PCOS. However, women with PCOS had a worse mental quality of life summary component score (−3.60 [95% CI −6.72 to −0.56]), mainly due to a lower score on the subscale ‘role limitations due to emotional problems’ (−12.41 [95% CI −22.78 to −2.28]), compared to women without PCOS. However, compared to an age-matched Dutch reference population, the obese infertile women with and without PCOS both scored lower on almost all physical and mental quality of life subscales. LIMITATIONS, REASONS FOR CAUTION These are secondary analyses of the follow-up study of the RCT. No power analysis was performed for the outcomes included in this analysis and, as our study had a relatively small sample size, the null findings could be based on insufficient power to detect small differences between the groups. Our study population had a high mean BMI (average total group 34.5 [SD ± 5.1]); therefore, our results may only be generalizable to women with obesity. WIDER IMPLICATIONS OF THE FINDINGS Our results indicate that PCOS status is associated with impaired mental quality of life. Anxiety and depression, physical quality of life and sexual function in obese infertile women with PCOS seem more related to the obesity than the PCOS status. STUDY FUNDING/COMPETING INTEREST(S) The initial study and follow-up were supported by grants from: ZonMw (50-50110-96-518), the Dutch Heart Foundation (2013T085) and the European Commission (633595). The Department of Obstetrics and Gynaecology of the UMCG received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands, outside the submitted work. A.H. reports consultancy for Ferring pharmaceuticals. B.W.J.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.J.M. reports consultancy for ObsEva, Merck Merck KGaA, iGenomix and Guerbet. All other authors declare no competing interests. TRIAL REGISTRATION NUMBER The initial trial was registered on 16 November 2008 in the Dutch trial register; clinical trial registry number NTR1530.

IntroductionThe use of low-dose aspirin by pregnant women to prevent preterm pre-eclampsia is gradually increasing. The administration of aspirin during pregnancy improves perinatal outcome, which could translate into improved child outcome in the long term. However, antenatal exposure to aspirin could have adverse effects on child development that may manifest later in life. The aim of this follow-up study is to assess the long-term effects of antenatal exposure to low-dose aspirin compared with placebo on survival, (neuro)development, behaviour and general health at 4 years corrected age.Methods and analysisThis is a follow-up study of the Dutch double-blind randomised controlled APRIL trial which assessed the effectiveness of treatment with aspirin (80 mg daily) compared with placebo for the prevention of preterm birth in women with a previous spontaneous preterm birth. Treatment was initiated before 16 weeks of gestation and continued until 36 weeks or birth. We aim to follow-up all 379 children born to women who participated in the APRIL trial and survived the neonatal period, at the corrected age of 4 years. The main outcomes are (neuro)development as assessed by the Ages and Stages Questionnaire, and behaviour as assessed by the Strength and Difficulties Questionnaire. Additional outcomes include mortality, growth and general health from birth up to 4 years, and a composite outcome including mortality, abnormal (neuro)development and problem behaviour. Analyses will be performed by intention-to-treat using a superiority design.Ethics and disseminationInstitutional Review Board approval was obtained from the Medical Research Ethics Committee from Amsterdam Medical Center (no. W20 289#20.325). The results will be published in a peer-reviewed journal and presented at conferences.Trial registration numberThe APRIL trial (NTR5675, NL5553; EudraCT number 2015-003220-31) and the APRIL follow-up study (NL8950) are registered in the Dutch trial register. The study is funded by the Amsterdam Reproduction & Development research institute.

Aims/hypothesis People who were small at birth have an increased risk of type 2 diabetes in later life. People who were in utero during the Dutch famine had decreased glucose tolerance and raised insulin concentrations at age 50. We aimed to evaluate whether prenatal famine exposure leads to more rapid progression of impaired glucose/insulin homeostasis with increasing age. Methods We performed an OGTT in 702 men and women at age 50 and in 699 men and women at age 58, all born as term singletons immediately before, during or after the 1944-1945 Dutch famine. Results People who had been exposed to famine in utero had significantly higher 120-min glucose concentrations at age 58 compared with people who had not been exposed to famine (difference=0.4 mmol/l, 95% CI 0.1 to 0.7, adjusted for sex and BMI). Glucose tolerance deteriorated between the age of 50 and 58. The unadjusted 120-min glucose concentrations rose by 0.2 mmol/l (95% CI 0.0 to 0.4), while 120-min insulin concentrations had increased by 64 pmol/l (95% CI 48 to 82). There were no differences in the rates of glucose and insulin level increase between the famine-exposed group and the unexposed group (p=0.28 for the difference in increase in glucose concentrations and p=0.09 for insulin concentrations). Conclusions/interpretation Although we confirmed that undernutrition during gestation is linked to decreased glucose tolerance, the effect does not seem to become more pronounced at age 58 as compared with age 50.

IntroductionWomen, 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 analysisObese 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 disseminationThe 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 numberThe original LIFEstyle study is registered at The Netherlands Trial Registry (number 1530).

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.

Introduction/BackgroundThe International Network of Cancer, Infertility and Pregnancy was launched in order to register women of reproductive age with a cancer diagnosis. Over the years, the project has expanded with currently 2653 cases registered by 114 centres and an annual registration rate of 150 patients. The expected rising numbers of cancer diagnosis during pregnancy as a result of an increased age at first childbirth and the possibility of early cancer detection by the non-invasive prenatal testing calls for an ongoing evaluation of clinical practice. Moreover, women might become pregnant while exposed to new target therapies that are being introduced into oncological practice.MethodologyThe INCIP database consists of a secured on-line registration tool. Oncological, obstetric and neonatal data are registered by members. Annual scientific meetings give updates on the ongoing research projects.ResultsMost patients were registered in Belgium, the Netherlands, Italy and USA and one third of participating centres are non-European. Currently 2059 patients with a cancer diagnosis or treatment during pregnancy are registered, 395 women that received fertility preservation and 199 patients with a postnatal cancer diagnosis (figure 1). Breast cancer, lymphoma and cervical cancer are the most frequent registered cancer types and the majority of patients (67%) received antenatal cancer treatment (figure 2). Most women delivered a live born baby (88%), however 47% delivered preterm and 80% of preterm deliveries were medically induced. One-fifth of neonates (21%) were small for gestational age. Congenital malformations were reported in 3% of live births.Abstract – Figure 1Registered cases by INCIPAbstract – Figure 2Management of cancer during pregnancy according to trimester of diagnosisConclusionCancer occurring in women endangers obstetrical and neonatal outcome and potentially future fertility. The INCIP registry is open for further collection of data since for such a relatively rare situation, only a large scale project will provide better insights on maternal and foetal risks assessment, which is essential for optimal patient counselling and care.DisclosureThe INCIP network would not be able to operate without the ongoing support of ESGO. Furthermore the project is supported by the Research Foundation—Flanders (FWO) in Belgium (grant no G070514N) and the European Union’s Horizon 2020 research and innovation program under grant agreement No 647047. There are no conflicting interests to declare.