{"paper_id":"617ebb91-7278-4872-849e-7f922367812c","body_text":"1 \n \nA randomised controlled trial of preconception lifestyle intervention on maternal \nand offspring health in people with increased risk of gestational diabetes: study \nprotocol for the BEFORE THE BEGINNING trial  \nSujan MAJ 1,2, Skarstad HS 1, Rosvold G 1, Fougner SL 3,4, Nyrnes SA 1,5, Iversen AC 3,6, \nFollestad T3,7, Salvesen KÅ2,3, Moholdt T1,2,*   \n1Department of Circulation and Medical Imaging, Norwegian University of Science and \nTechnology, Trondheim, Norway \n2Department of Women’s Health, St. Olavs Hospital, Trondheim University Hospital, \nTrondheim, Norway  \n3Department of Clinical and Molecular Medicine, Norwegian University of Science and \nTechnology, Trondheim, Norway  \n4Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, \nTrondheim, Norway  \n5Children’s clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway \n6Centre of Molecular Inflammation Research, Norwegian University of Science and \nTechnology, Trondheim, Norway  \n7Clinical Research Unit Central Norway, St. Olavs Hospital, Trondheim Norway \n*Corresponding author  \nPostal address: NTNU, Faculty of Medicine and Health Sciences, Department of Circulation \nand Medical Imaging, Postbox 8905, 7491 Trondheim, Norway \n \nE-mail addresses: MAJS: md.a.j.sujan@ntnu.no\n, HSS: hanna.s.skarstad@ntnu.no , GR: \nguro.rosvold@ntnu.no, SLF: stine.fougner@ntnu.no, SAN: siri.a.nyrnes@ntnu.no, ACI: ann-\ncharlotte.iversen@ntnu.no, TF: turid.follestad@ntnu.no , KÅS: pepe.salvesen@ntnu.no , TM: \ntrine.moholdt@ntnu.no \n \nWord count: 4199  \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n2 \n \nAbstract \nIntroduction: Gestational diabetes mellitus (GDM) is associated with increased risk for type \n2 diabetes in the mother and cardiometabolic diseases in the child. The preconception period \nis an optimal window to adapt the lifestyle for improved outcomes for both mother and child. \nOur aim is to determine the effect of a lifestyle intervention, initiated before and continued \nthroughout pregnancy, on maternal glucose tolerance and other maternal and infant \ncardiometabolic outcomes. \nMethods and analysis:  This ongoing randomised controlled trial has included 167 females \naged 18-39 years old at increased risk for GDM who are contemplating pregnancy. The \nparticipants were randomly allocated 1:1 to an intervention or control group. The intervention \nconsists of exercise (volume is set by a heart rate-based app and corresponds to \n≥  1 hour of \nweekly exercise at ≥  80% of individual heart rate maximum), and time-restricted eating (≤  10 \nhours/day window of energy intake). The primary outcome measure is glucose tolerance in \ngestational week 28. Maternal and offspring outcomes are measured before and during \npregnancy, at delivery, and at 6-8 weeks postpartum. Primary and secondary continuous \noutcome measures will be compared between groups based on the “intention to treat” \nprinciple using linear mixed models. \nEthics and dissemination: The Regional Committees for Medical and Health Research \nEthics in Norway has approved the study (REK 143756). The anonymised results will be \nsubmitted for publication and posted in a publicly accessible database of clinical study \nresults. \n \nAbstract word count: 236 \n \nTrial registration number: Clinical trial gov NCT04585581. \n \nKeywords: insulin resistance, time-restricted eating, aerobic exercise, glycaemic control, diet \n \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n3 \n \nStrengths and limitations of this study \n• The intervention starts before and continues throughout pregnancy to make it easier \nfor the participants to adopt an active lifestyle before pregnancy. \n• This study includes individuals at high risk of GDM from multiple ethnic \nbackgrounds, which improves the generalisability of the findings. \n• The effects of the intervention on the cardiac function and body composition of the \noffspring will be comprehensively evaluated. \n• Due to the difficulty of blinding investigators and participants to behavioural \ninterventions, investigators will not be blinded for outcome assessments. \n• Due to the long duration of the intervention, adherence to lifestyle modifications may \nbe difficult for some participants despite regular monitoring and motivational support. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n4 \n \nIntroduction \nThe global prevalence of gestational diabetes mellitus (GDM), i.e., high plasma glucose first \nidentified during pregnancy, continues to increase. Both environmental and genetic factors \ncontribute to the development of GDM, and up to 14 % of live births are negatively impacted \nby this condition.(1) GDM typically occurs because of pancreatic β -cell dysfunction with pre-\nexisting insulin resistance and increases the risk for type 2 diabetes and cardiovascular \ndisease in the mother.(2, 3) Maternal obesity and hyperglycaemia affect the offspring through \nthe egg cell quality, intrauterine environment, and foetal organ development. These metabolic \nconditions eventually increase the risk for cardiac dysfunction at birth, and early onset \ndiabetes, obesity, and cardiovascular diseases later in life.(4-9) Higher maternal blood \nglucose concentration, even below the diagnostic criteria for GDM, is associated with \nincreased birth weight, elevated levels of cord-blood C-peptide, childhood obesity, and \nelevated blood pressure, independent of maternal body mass index (BMI).(10-12) Besides the \ninheritable risk factors, epigenetic modifications in utero, low-grade inflammation, and \nmodifications of the gut microbiome can also negatively affect the cardiometabolic health of \nthe offspring.(4) \nLifestyle interventions, including dietary changes, increased physical activity, and \nself-monitoring of blood glucose, are the first-line choice for GDM management.(13) \nHowever, many pregnant individuals fail to adhere to the recommendations for diet and \nexercise training(14, 15) and there is inconclusive evidence for clinically meaningful effects \nof diet-exercise interventions on pregnancy outcomes for the mother or child.(5, 16-18) \nSeveral recent randomised controlled trials (RCTs) and reviews conclude that pre-pregnancy \nlifestyle interventions are urgently needed to improve maternal health and increase the \nlikelihood of adherence to a healthy lifestyle during pregnancy.(19-23) Alternative diet-\nexercise strategies, such as time-restricted eating (TRE) and high-intensity interval training \n(HIIT), have shown promising results on improving metabolic health among reproductive-\naged females.(24-26) TRE is a safe and feasible intervention in individuals with overweight, \nobesity, prediabetes, and type 2 diabetes.(27) It has been shown to improve glucose tolerance, \nand insulin sensitivity, and reduce appetite, hunger, HbA1c, and total body and fat mass in \nthis population.(28-36) While data on the effects of TRE in pregnancy are scarce, \nobservational data suggest that longer maternal night-fasting intervals are associated with \ndecreased fasting glucose.(37) The safety of HIIT is not yet established during pregnancy, but \nrecent publications indicate that HIIT is safe, with higher enjoyment and improved adherence \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n5 \n \nthan continuous moderate-intensity training,(38) and may provide cardiometabolic benefits \nfor both mothers and their offspring.(39-41)  \nPre-pregnancy patterns of physical activity and exercise are important determinants of \nexercise during pregnancy,(42) and pre-pregnancy inception of healthy dietary habits is \nassociated with a lower risk of GDM.(43-45) So far, there is limited evidence on the \neffectiveness of implementing both dietary and exercise-based lifestyle interventions before \npregnancy. It is highly relevant to find feasible and effective pre-pregnancy lifestyle \ninterventions which can reduce maternal hyperglycaemia and its related negative \nconsequences for mother and child.  \nThe primary hypothesis for the BEFORE THE BEGINNING (BTB) trial is that the \nparticipants allocated to the intervention group (time-restricted eating and exercise) will have \nimproved maternal glucose tolerance in gestational week 28, compared with participants in \nthe control group. We will also determine the effect of the intervention on secondary \ncardiometabolic outcomes in both the mothers and their newborns. \nAims \nThe primary aim of BEFORE THE BEGINNING \n• To determine the effect of a lifestyle intervention, commenced preconception and \ncontinuing throughout pregnancy, on maternal glucose tolerance in pregnancy. \nSecondary aims of BEFORE THE BEGINNING \n• To evaluate the effect of the intervention on insulin sensitivity, blood glucose, \ncirculating lipids, body composition, cardiorespiratory fitness, systemic inflammation, \nand blood pressure in the mothers. \n• To evaluate the effect of the intervention on cardiac function, body composition, and \nsystemic inflammation in the newborns. \n• To evaluate the adherence to the interventions, and their effects on sleep quality, \nappetite and hunger, physical activity, and dietary intake. \nMethods \nDesign and study setting \nThis is an ongoing single-centre RCT with two parallel groups: an intervention group and a \ncontrol group, undertaken at the Norwegian University of Science and Technology (NTNU) \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n6 \n \nin Trondheim, Norway, in collaboration with the St. Olav’s Hospital, Trondheim, Norway. \nSPIRIT reporting guidelines were used in reporting this study protocol.(46) \nRecruitment and participants \nThe trial was announced through social media, hospital and university webpages, local stores, \nand public places. Additionally, potential participants were identified through the National \nPopulation Register, and we regularly sent out electronic invitations to females aged 20-35 \nyears in Trondheim and the surrounding area to participate in the trial. The invitation \nprompted them to visit the study website, which contains a short description of the trial and \nallows potential participants to self-screen for eligibility before further screening by \ntelephone. The first participant was included on 25\nth September 2020 and the last participant \nwas included on 28th April 2023. \n \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n7 \n \nBox 1 shows the inclusion and exclusion criteria for participation in the \nstudy.\n \nRandomisation and allocation \nAfter screening and assessments at baseline, the participants were randomly allocated (1:1) to \nthe intervention or a standard care control group, after stratifying for GDM in a previous \npregnancy (yes/no). At the first visit, the study procedures, equipment, and applications were \nset up and explained to the participants. \nBox 1: Inclusion and exclusion criteria \n \nInclusion criteria  \n• Female \n Age: 18-39 years old \n Contemplating pregnancy within the next six months \n Understands oral and written Norwegian or English \n At least one of the following criteria must apply: \n Body mass index ≥  25 < 40 kg/m\n2\n, \n Gestational diabetes in a previous pregnancy,  \n Close relative with diabetes (either parents, siblings, or children with \ndiabetes),  \n Fasting plasma glucose > 5.3 mmol/L,  \n Previous newborn > 4.5 kg, or \n Non-European ethnicity (with one or both parents originating from an area \noutside Europe). \nExclusion criteria \n On-going pregnancy \n Trying to conceive \n≥  6 cycles at study entry \n Known diabetes (type 1 or 2) \n Shift work that includes night shifts > 2 days per week \n Previous hyperemesis \n Known cardiovascular diseases \n High-intensity exercise > 2 times per week in the last 3 months \n Habitual eating window ≤  12 hours \n Bariatric surgery \n Any other reason which according to the researchers makes the potential participant \nineligible \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n8 \n \nWe used a computer random number generator (WebCRF3) developed and administered at \nThe Clinical Research Unit (Klinforsk), NTNU/St. Olav’s Hospital, Trondheim, Norway to \nrandomly allocate participants using various block sizes.  \nIntervention \nThe intervention starts before pregnancy and continues throughout pregnancy and consists of \na combination of TRE and exercise. Participants are counselled to change their daily time- \nwindow of energy intake to \n≤  10 hours, ending no later than 19:00 hours, for minimum 5 \ndays per week throughout the intervention. The remaining 2 days are “days off” when they \ncan consume food ad libitum if they wish. Apart from current recommendations about \npreconception/pregnancy nutrition, we give no advice regarding food choices, nor do we \nencourage a reduced total energy intake. \nWe use the Personal Activity Intelligence (PAI) score, a science-backed activity \nmetric based on heart rate (HR)(47, 48) to prescribe exercise. Since PAI is HR-based, high-\nintensity exercise gives substantially higher PAI scores than low-to-moderate-intensity \nexercise. The goal for the participants in the intervention group is to earn and maintain \n≥  100 \nPAI per week, which can be reached by minimum 1 hour of weekly exercise at ≥  80% of HR \nmaximum. One week after the baseline visit, we invite the participants for a supervised \nintroductory exercise session and provide a brochure with exercise options (e.g., treadmill \nwalking/running, cycling).  We invite the participants for a second session 2 weeks after the \nintroductory session. The participants can choose their mode of exercise. Once pregnant, we \nadvise the participants to either do short work-bouts at high intensity with low-to-moderate \nintensity periods in-between, or longer work periods up to 85% of heart rate maximum. We \ncontact the participants not reaching 100 PAI to offer additional supervised exercise sessions, \nand they can also ask for extra support and supervised exercise sessions if they want to. \nParticipants in the control group receive standard care and are asked to continue with \ntheir habitual physical activity and dietary habits. We contact these participants once every 8 \nweeks to support adherence to registrations and monitoring. \nExperimental procedures and outcome measures \nThe study period spans from baseline assessments in the pre-pregnancy period to 6-8 weeks \nafter delivery (Figure 1). Participants who do not become pregnant within 6 months after \ninclusion in the trial (changed from 12 months from December 2022, see below under \nmodifications to the protocol after trial commencement) are excluded. For participants who \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n9 \n \nexperience spontaneous abortions, we add the number of weeks that the participant was \npregnant plus 4 weeks to their time in the trial before exclusion pre-pregnancy. \nAssessments of the participants are performed twice during preconception (at baseline \nbefore randomisation, and after 8 weeks), and twice during pregnancy (in gestational weeks \n12 and 28). Outcomes in the newborns are assessed within 72 hours after delivery and at age \n6-8 weeks (Figure 2). All participants receive a brochure from the Norwegian Health \nDirectorate with the current recommendations for physical activity, diet, and folic acid, and \niodine supplements. The participants are invited to ultrasound examinations in gestational \nweeks 12, 19, and 32. \nPrimary outcome measure \nThe primary outcome measure is plasma glucose concentration obtained 2 hours after a 75 g \noral glucose tolerance test (OGTT) in gestational week 28. After an overnight fast (\n≥  10 \nhours) and no exercise for ≥  24 hours, the participants consume 75 g of glucose (Glucosepro, \nFinnamedical, Finland) diluted in 250 mL water within 5 minutes. Using an indwelling \ncatheter, we collect venous blood before the OGTT, with subsequent collections at 30, 60, 90, \nand 120 minutes after ingestion of glucose. \nSecondary outcome measures  \nSecondary maternal and neonatal outcome measures (Figure 2) are described below.  \nBlood sampling and biochemistry \nFrom all visits, fasting blood lipids, plasma glucose, and HbA1c are measured immediately \nafter sampling, at St. Olav’s Hospital, following local standardised procedures. Additional \nfasting plasma, serum, full blood, and urine are stored in a biobank at -80°C for later \nanalyses. GDM is recorded at Visit 3 and 4, according to the WHO 2013 criteria (fasting \nplasma glucose 5.1-6.9 mmol/L and/or 2-hour plasma glucose 8.5-11.0 mmol/L after 75 g \nOGTT).(49) At the event of a GDM diagnosis, the participant and their general practitioner \nare informed for further evaluation and management. Insulin sensitivity will be calculated \nusing homeostasis model assessment of insulin resistance (HOMA-IR)(50) and pancreatic \nbeta cell function using HOMA-\nβ .(50) At visit 3 and 4, the area under the curve (AUC) and \nincremental AUC (iAUC) from glucose and insulin concentrations will be calculated from \nvenous blood sampling every 30 minutes during the 2-hour OGTT. Insulin Sensitivity Index, \nISI\n0,120,(51) insulinogenic index during the first 30 minutes of the 2-hour OGTT,(52) and beta \ncell function (AUCins/AUCglu) will be estimated.(53) \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n10 \n \nContinuous glucose monitoring  \nThe participants wear a continuous glucose monitor (CGM, FreeStyle Libre 1, Abbott \nDiabetes Care, Norway) for 14 days at baseline (7 days pre-intervention followed by the first \n7 days of intervention/control), and for 14 days starting at 8 weeks from baseline. From these \nmeasurements, we will determine 24-hour glycaemic control, 3-hour postprandial glucose \nlevels (AUC) for the first meal of the day, and nocturnal glycaemic control. The screens of \nthe CGM readers are taped over to avoid lifestyle changes based on the participants’ glucose \nlevels. We also plan to explore other CGM data that can predict glycaemic control during \npregnancy, using machine learning.  \nHeight, weight, body composition, BMI, and waist circumference \nHeight is measured with the participants standing without shoes using a standard stadiometer. \nWeight and body composition are estimated in the morning after overnight fasting using \nbioelectrical impedance analysis (Inbody 720, Biospace CO, Korea), with participants \nwearing light clothes and standing barefoot. BMI is calculated as weight in kilograms divided \nby the square value of height in metres (kg/m\n2). To account for the increase in fat-free mass \nhydration as pregnancy progresses, we will use a regression equation that estimates fat-free \nmass density as a function of gestational age.(54) Waist circumference is measured using a \nmeasuring tape at the level of the belly button with the participant standing. \nCardiorespiratory fitness \nWe measure peak oxygen uptake (VO\n2peak) using indirect calorimetry (Metalyzer II, Cortex, \nGermany), using an individualised treadmill protocol in which the participants walk or run \nuntil volitional exhaustion. The test starts after a 10-minute warm-up. The speed or \ninclination is increased every 1 – 2 minutes, by 0.5 – 1.0 km/hour or 1% – 2%. VO 2peak is \ndetermined as the average of the three highest consecutive 10 seconds measured and will be \nreported as both absolute (L/min) and relative (mL/min/kg) values. We record HR throughout \nthe exercise tests and use the peak HR recorded during the test as an estimate of the HR \nmaximum.(55) \nBlood pressure and resting heart rate \nWe use an automatic blood pressure device (Welch Allyn, Germany) to measure blood \npressure (diastolic and systolic, in mmHg) and resting HR (beats per minute, bpm) on the \nparticipants’ left arm after they have rested in a seated position for 15 minutes. We will report \nthe average of three measurements taken at 1-minute intervals. \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n11 \n \nPhysical activity, diet, and sleep \nWe use activity monitors to estimate physical activity levels, energy expenditure, and sleep \nduration. All participants wear Sensewear Armbands (BodyMedia, Pennsylvania, USA) for \n14 days at baseline (7 days pre-intervention followed by the first 7 days of \nintervention/control), and the participants in the intervention group wear Amazfit GTS \n(Huami, China) smartwatches throughout the intervention. The smartwatch is connected to \nthe Zepp app and shares PAI data with the research team via the Memento app. Participants \nregister their diet in an online food diary (Fatsecret app) and record the time of first and last \nenergy intake in the project handbook for 4 days (3 weekdays and 1 weekend day) every 8 \nweeks. They also complete questionnaires about physical activity, sleep quality, and \npsychological well-being every 8 weeks throughout the study period. We use the following \nquestionnaires: 1) International Physical Activity Questionnaire,(56) 2) Pittsburgh Sleep \nQuality Index,(57) and 3) Psychological General Well-Being Index.(58) At baseline, the \nparticipants fill in the Horne-Östberg Morningsness-Eveningness Questionnaire.(59) We \nrecord medication and supplements, early miscarriages, abortions, and time to pregnancy and \nlive birth. Additionally, expectant fathers are asked to complete questionnaires at baseline \nand every 8 weeks throughout the trial, including questions regarding their body weight, \nheight, physical activity, and diet. These data will be used as co-variates in later analyses. \nNeonatal and other outcomes \nWe obtain standard clinical neonatal outcomes from hospital birth records. Midwives at St. \nOlav’s Hospital collect umbilical cord blood immediately after birth, prior to the delivery of \nthe placenta. Placental tissues are collected from 1) around the base of the umbilical cord on \nthe foetal side, 2) the periphery on the maternal side (full-thickness tissue), 3) the centre of \nthe maternal side, also for storage in RNAlater solution (Invitrogen, Thermofisher scientific, \nLithuania) and 4% formaldehyde solution, and 4) the periphery on the maternal side. The \nsamples are put in 1.8 mL cryotubes and snap-frozen immediately in liquid nitrogen, before \nstorage at -80°C for later analyses. The samples in RNAlater solution are stored at 4°C \novernight, followed by storage at -80°C for later analyses. The samples in 4% formaldehyde \nsolution are stored under a fume hood at room temperature for 48 hours before histology slide \npreparation in collaboration with the CMIC Histology Lab at NTNU. \nWithin 72 hours of birth, and at age 6-8 weeks, body composition of the newborn is \nestimated using bioimpedance (BioScan touch i8-nano, Maltron, UK). Additionally, an \nexperienced paediatric cardiologist examines cardiac morphology, structure, and function in \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n12 \n \nthe newborn, using a Vivid E95 scanner (GE Vingmed Ultrasound, Horten, Norway) and a \nGE  6s, and M5s phased-array transducers (GE Healthcare, Milwaukee, WI). A full clinical \nechocardiography including conventional echocardiographic parameters as well as study \nimages with a focus on measurement of systolic and diastolic myocardial function is \nperformed. The scanner is equipped with research software enabling high frame rate \nechocardiography to study cardiac flow and tissue properties as described previously.(60-62) \nA corresponding group of neonates (N = 30), from mothers with no known increased risk of \nGDM and BMI in the normal range (18.6-24.9 kg/m\n2) will be used for comparison. \nAdherence  \nWe record adherence to TRE as the average daily time-window for energy intake for 4 days \nevery 8 weeks. Additionally, we categorise participants as adherent if they report a ≤  10-hour \ntime-window for energy intake on ≥ 2 of these 4 days. Adherence to exercise is recorded as \nthe number of PAI points the participants get per rolling 7 days. To ensure compliance and \nmaintain adherence, we send text messages to all participants as reminders to complete \nquestionnaires and dietary reporting. We also announce friendly competitions such as “Who \ncan keep 100 weekly PAI points or more for a whole month?” in a Facebook group for the \nparticipants. The data are only accessible to the researchers and a gift card is awarded to the \nwinners. \nModifications to the protocol after trial commencement \nSince June 2021, we invite the participants to participate in a follow-up study after delivery in \nwhich we collect infant faecal samples (immediately after birth, at 6 weeks, and 6 months), \nmaternal faecal samples (at 6 weeks and 6 months), and breast milk (at 6 weeks and 6 \nmonths). These samples are stored at -80°C for later analyses. Additionally, we started to \noffer supervised exercise training sessions to the participants in the intervention group. From \nNovember 2022, we started sending invitations using eFORSK (electronic form-based data \ncollection, developed by Central Norway Regional Health Authority) and added ‘Bariatric \nsurgery’ to the exclusion criteria.  ‘Any other reason which according to the researchers \nmakes the potential participant ineligible’ to undergo either or both interventions (e.g., \ntraumatic foot injury, anorexia/bulimia, etc.) was also added to the exclusion criteria in \nNovember 2022. From December 2022, we removed ‘Planned assisted fertilisation with \nfemale factor reason’ from the exclusion criteria. In addition, we changed the maximum time \nbefore pregnancy from 12 months to 6 months to allow for the trial to be terminated in time \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n13 \n \nfor us to analyse the data within the project period. In March 2023, the required number of \ntotal participants was reduced from 260 to 200 based on the revised calculation as described \nin the sample size calculation, with additional specification of stopping before 200 if we had \nsufficient pregnant participants for the primary outcome measure. In June 2023, we changed \nfrom Amazfit GTS to Polar Ignite 2 (Polar, Finland) smartwatch and from Zepp and \nMemento to Polar Flow and Mia app. \nSample size calculation \nThe primary outcome of this study is glucose tolerance (after a 2-hour OGTT) in gestational \nweek 28. The HAPO study results(63) indicate strong, continuous associations of maternal \nglucose levels, even below the diagnostic level of GDM with adverse maternal and offspring \noutcomes. Based on the increasing risk of adverse maternal and offspring outcomes across 2-\nhour plasma glucose categories with a change of ~1 mmol/L, we consider a difference of 1 \nmmol/L in 2-hour plasma glucose after OGTT between the intervention and control group as \nclinically relevant. We also used the observed standard deviation (1 SD = 1.3 mmol/L) in 2-\nhour plasma glucose after OGTT in the HAPO study for the sample size calculations. \nCalculation of the sample size for a two-sided t-test to detect a difference of 1 mmol/L \nbetween the groups, using an SD of 1.3 mmol/L, a power of 0.90, and a significance level of \n0.05, yields 37 participants in each group in gestational week 28. To allow for an expected \nexclusion from the study due to not conceiving within the study period (~50%)(64) yielding \n74 per group, further drop-out during the study period (10-20%), yielding 93 per group, and \nto increase statistical power for secondary analyses, we initially wanted to include 260 \nparticipants in the trial. \nHowever, we terminated the inclusion of new participants at 167 participants since we \nhad reached 47 participants in each group who were pregnant in gestational week 12. With \nthis number of participants, we foresee that we will have at least 37 participants in each group \nin gestational week 28, allowing for up to 20% dropout during pregnancy. We expect more \nparticipants who are already included to become pregnant in the upcoming period, which will \nincrease the number of pregnant participants. \nStatistical analyses \nThe primary analysis will be done according to the ‘intention to treat’ principle, using all \nobtained data irrespective of participant adherence to the intervention and completeness of \noutcome measures. We plan to use linear mixed models (LMMs) to compare primary and \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n14 \n \nsecondary continuous outcome measures between groups, with time and group x time \ninteractions as fixed effects variables, and subject as random factor.(65) Since no systematic \nbaseline differences between the groups are expected in RCTs, means at baseline will be \nconstrained to be equal in the LMMs. We will report estimates with corresponding 95% \nconfidence intervals and p-values for differences between the intervention group and the \ncontrol group. We will check the normality of residuals by visual inspection of QQ-plots and \nbootstrapping, transformations or non-parametric methods will be used in cases of non-\nnormal model residuals. For the primary outcome measure, we will consider a p-value < 0.05 \nas statistically significant. For the secondary outcome measures, p-values < 0.01 will be \nconsidered statistically significant, due to multiple comparisons, and these analyses will be \nexplorative. We will also perform per-protocol analyses: Participants with an average of \n≥  75 \nPAI per rolling week and adherence to TRE (as per definition above) during the \npreconception period will be included in the per-protocol analyses for all outcome measures. \nWe will report additional results from all participants who were included in the trial, from the \npreconception period, irrespective of whether they became pregnant or not during the study \nperiod. \nBlinding \nThe study is not blinded as it is difficult to blind participants and treatment providers to \nbehavioural intervention. However, baseline assessments are undertaken before \nrandomisation. \nMonitoring \nWe do not expect any adverse effects in this study. If pregnant women are worried about \nfoetal safety during exercise, we have experienced personnel available in the research group \nto monitor foetal heart rate during exercise sessions. The investigators are responsible for the \ndocumentation of any adverse or serious adverse events in the Case Report Form and the \nSerious Adverse Events Report Form, respectively. Participants are advised to contact the \ninvestigators if they have any unusual symptoms. All serious adverse events will be reported \nto the sponsor (NTNU) within 24 hours after the investigators have been informed of the \nevent. \nPatient and public involvement \nWe have involved users in the planning of the study and will continue involving them in the \nimplementation and dissemination. In the planning phase, we arranged a 1-hour digital \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n15 \n \nworkshop with users (reproductive-aged females with overweight/obesity), where we \nencouraged the audience to ask questions and give us feedback about relevant topics or issues \nrelated to participation. Regarding the challenges of long-term adherence, we use these \nfeedbacks to find ways to incorporate exercise training and TRE into daily life. \nEthics and dissemination \nThe Regional Committees for Medical and Health Research Ethics in Norway approved the \nstudy (REK, reference number 143756). The comparative analysis of the neonatal \nechocardiography data from this study with a corresponding group of neonates from mothers \nwith normal BMI and no increased risk of GDM is also approved (REK reference number \n67584). The work is conducted according to the Declaration of Helsinki and the ICMJE \nRecommendations for authorship. The participants sign an informed written consent before \nparticipating in the study and can at any time withdraw from the study without further \nexplanation. Study specific ID numbers are used as participants’ identification. We ensure \ndata quality by double data entry into an electronic CRF and treat the collected data following \nthe General Data Protection Regulation. All protocol modifications are reported to REK. \nUpon completion of the study and finalization of the study report, we will submit the results \nfor publication and/or in a publicly accessible database of clinical study results after \nanonymizing the data. \nDiscussion \nBased on a thorough literature search, the BTB study will be the first RCT to investigate the \ncombined effects of TRE and exercise training, initiated before and continued throughout \npregnancy, on cardiometabolic parameters in people at risk of GDM and their infants. We \nhypothesise that the combination of these two lifestyle interventions will induce an additive \nand clinically relevant improvement in maternal glucose tolerance, and potentially also in our \nsecondary outcome measures in mothers and infants. As such, the initiation of lifestyle \nmodification before pregnancy will provide a better platform for improved adherence and \nhealth outcomes, potentially breaking the intergenerational cycle of cardiometabolic \ndisorders, and thereby reducing the risk of diabetes for future generations. \nSo far, there is limited data on the combination of TRE and exercise training in \nhumans. Haganes and colleagues reported that the combination of TRE and HIIT in females \nwith a BMI of ≥  27 kg/m\n2 for 7 weeks significantly reduced HbA1c compared with a no-\nintervention control group and lead to greater losses in body weight, fat mass, and visceral fat \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n16 \n \narea compared with either intervention alone.(26) Since the duration of the intervention is \nmuch longer in the BTB trial, there may be lower adherence to one or both intervention \nstrategies. The possible reasons for lower adherence are that the participants may lack \nmotivation for such a long time, find the intervention program boring and/or difficult, or \ndevelop physical symptoms that may hinder the participant to adhere to the intervention \n(especially during pregnancy). Combining motivational human interaction with digital \ninterventions can increase engagement and the effectiveness of behaviour change \ninterventions.(66) To improve adherence throughout the study period, we offer an \nindividualised exercise regimen and provide encouragement, support, and monitor the \nparticipants regularly, both in person and over the phone. \nThe incidence and risk of obesity, insulin resistance, and GDM persists through \ngenerations.(67) To disrupt this intergenerational cycle, it is urgently necessary to develop \nand implement effective and practical lifestyle intervention strategies which can improve the \ncardiometabolic health outcomes of both mother and offspring. If the preconception lifestyle \ninterventions implemented in this study lead to favourable outcomes and prove to be feasible \nand effective, it can pave the way for novel interventions that can be adopted in clinical \npractice during the preconception period, especially among those who are at risk of \ndeveloping GDM. \nAuthor contributions \nMAJS drafted the manuscript. TM, SAN, KÅS, ACI, TF, and SLF conceived and contributed \nto the design of the study and the plan for analyses. GR, MAJS, and HSS coordinate the \nstudy, perform measurements on test days, monitor participants, and supervise the exercise \ntraining. SAN performs the echocardiogram on the newborns. All authors provided feedback \nand approved the final manuscript. \nAcknowledgments \nThe authors wish to thank all the participants for their contribution. We also thank the other \nmembers of the research team, Elisabeth Axe and Hilde Lund, who contributed to the \nexecution of the BEFORE THE BEGINNING Study. The equipment and lab facilities for \ncardiorespiratory fitness testing is provided by NeXt Move, Norwegian University of Science \nand Technology (NTNU), and the clinical measurements are obtained at the Clinical \nResearch Facility, St. Olavs Hospital. We would also like to thank the midwives at the \nWomen and Children's Centre, St. Olavs Hospital for the collection of samples related to \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n17 \n \nbirth. eFORSK, a stand-alone form-based information and communications technology \nsolution for electronic collection of data, developed by Central Norway Regional Health \nAuthority is used for sending invitations to the study. \nFunding \nThe trial is funded by the Novo Nordisk Foundation (NNF19SA058975), The Liaison \nCommittee for education, research, and innovation in Central Norway, and The Joint \nResearch Committee between St. Olav’s Hospital and the Faculty of Medicine and Health \nSciences, NTNU (FFU). The ultrasound part of the project is also funded by the Centre for \nInnovative Ultrasound Solutions (CIUS), a large research and innovation project led by \nNTNU. The sponsors have no role in study design, data collection, analysis, and publication \nof results. \nCompeting interests \nThe authors declare that they have no competing interests. \n \n \n \n \n \n \n \n \n \n \n \n \nReferences \n1. Inte rna tiona l Di a be te s  Fede r a tio n. I DF Diabe te s A tla s, 1 0th edn .  Bru ssel s, Be l gium: 2021. \nAva ilable  a t: ht tp s : // w ww. diab et es atla s . org \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint \n\n18 \n \n2. Pl ows  JF, Stan l ey JL , B ake r  P N, Re ynold s CM, Vic ker s MH . The  Pa thoph y s i ology  o f G e s t ation a l  \nDiabe te s M ell it u s . Int J Mol  Sci . 2018;1 9 ( 11):3342.  \n3. 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Pe rso nal  Activi t y  \nIntell ig enc e ( PA I ) ,  S eden tary Beha vio r a nd Ca rdiova s c ular  Ri s k  F ac tor  Clu s t e r i ng  -  the  HU NT  Study .  \nProg C a r d iova sc Di s . 201 7;60(1 ):89-95 .  \n49. World Hea l th O. Di ag no s tic  c r i teria  an d cla ssific a tion o f hypergl yca emia firs t de t e c ted i n  \npregna ncy.  Ge neva:  W orld Hea lth O rga ni z a t i on ; 2013  2013.  Cont r a ct N o.: WH O / N MH/MN D/ 13 . 2.  \n50. Matt hew s D R , Ho s ke r  J P, Rud e n s k i AS,  Naylor BA, Tre ac her DF, Tu rner  RC . Home o s ta si s  \nmodel  a s se ssmen t: in s ul in r e si st a nc e a nd β-c el l func tion from f a s ting  pla s ma  gl ucose a nd i n s uli n  \nco ncentr ation s in ma n . Diab eto log ia. 19 8 5;28(7) :412 - 9 .  \n51. Gut t M, Davi s CL, Spi t ze r S B, Llabre M M, Kumar M, Czarn eck i EM, e t  al . Va lid ation of the  \ninsulin sen si tivity  index  (ISI (0,12 0) ) :  co mpa r is on w ith othe r mea sure s.  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H um  Re pr od. \n2013 ;28(5) :1398-40 5.  \n6 5 .  J  T ,  L  B ,  T  H ,  J  R ,  M  W ,  M  H .  D i f f e r e n t  w a y s  t o  e s t i m a t e  t r e a t m e n t  e f f e c t s  i n  r a n d o m i s e d  \nco nt roll ed tr i als . C ont emp Cli n Trial s C o mmun.  2018;10 :80-5 .  \n66. Bark er  M, D ombrow ski SU, Colbour n  T, Fal l CHD, Kriz n ik NM, L awrenc e  W T,  e t  al . \nInte rventio n  stra tegie s to improve  nu t riti on a nd he al t h b e havio urs b efo re co nception . L anc e t  \n(Lon don, Eng land ). 20 18;391 (101 32):185 3-64 .  \n67. Ma R C W , Po pkin BM. I nte r g ene rati on al  diabe te s and ob e s i t y — A cyc le t o b reak ? PL O S  \nMedic ine . 2 017;14(10 ):e 1002415 .  \n \n \n \n \n \n \n \nFIGURE LEGENDS \n \nFigure 1. Consort flow diagram of the BEFORE THE BEGINNING trial  \n(Ongoing study: status 25.09.2020 – 17.07.2023) \n \n* If the participants are not pregnant within 12 months of inclusion, they are excluded from \nthe study. From December 2022, the time-window for exclusion if not pregnant was reduced \nfrom 12 to 6 months.  \n \nFigure 2. Overview of time-points for assessments in the trial. \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted July 23, 2023. ; https://doi.org/10.1101/2023.07.18.23292734doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}