International Journal of Obesity (2021) 45:296–307 https://doi.org/10.1038/s41366-020-0639-y ARTICLE Epidemiology and Population Health Less sedentary time is associated with a more favourable glucose- insulin axis in obese pregnant women—a secondary analysis of the DALI study Anna M. Dieberger 1 Gernot Desoye 1 Erwin Stolz2 David J. Hill3,4 Rosa Corcoy 5,6,7 David Simmons8 ● ● ● ● ● ● Jürgen Harreiter 9 Alexandra Kautzky-Willer 9 Fidelma Dunne10 Roland Devlieger11 ● ● ● ● Ewa Wender-Ozegowska12 Agnieszka Zawiejska12 Annunziata Lapolla13 Maria Grazia Dalfra13 ● ● ● ● Alessandra Bertolotto14 Sander Galjaard 15 Juan M. Adelantado5 Dorte Møller Jensen16,17,18 ● ● ● ● Lise-Lotte Andersen16,17,18 Mette Tanvig16,17,18 Peter Damm19,20 Elisabeth Reinhardt Mathiesen19,20 ● ● ● ● Frank J. Snoek21 Judith G. M. Jelsma22 Mireille N. M. van Poppel 23 ● ● Received: 16 March 2020 / Accepted: 3 July 2020 / Published online: 13 July 2020 © The Author(s) 2020. This article is published with open access 1234567890();,: 1234567890();,: Abstract Background/objectives Obese pregnant women are at high risk of developing gestational diabetes mellitus (GDM), which might be reduced by sufficient physical activity (PA) and reduced sedentary time (ST). We assessed whether PA and ST are longitudinally associated with the glucose-insulin axis in obese pregnant women. Subjects/methods In this secondary analysis of the DALI (vitamin D And Lifestyle Intervention for gestational diabetes mellitus prevention) study, pregnant women, <20 weeks gestation, with a pre-pregnancy body mass index (BMI) ≥ 29 kg/m2, without GDM on entry were included. Time spent in moderate-to-vigorous PA (MVPA) and ST were measured objectively with accelerometers at <20 weeks, 24–28 weeks and 35–37 weeks of gestation. Fasting glucose (mmol/l) and insulin (mU/l), insulin resistance (HOMA-IR) and first-phase and second-phase insulin release (Stumvoll first and second phase) were assessed at the same time. Linear mixed regression models were used to calculate between-participant differences and within-participant changes over time. Analyses were adjusted for gestational age, randomisation, pre-pregnancy BMI, education and age. MVPA, Insulin, HOMA-IR and Stumvoll first and second phase were log-transformed for analyses due to skewness. Results 232 women were included in the analysis. Concerning differences between participants, more ST was associated with higher fasting glucose (Estimate: 0.008; 95% CI: 0.002, 0.014), fasting insulin (0.011; 0.002, 0.019), HOMA-IR (0.012; 0.004, 0.021) and Stumvoll first and second phase (0.008; 0.001, 0.014 and 0.007; 0.001, 0.014). Participants with more MVPA had lower Stumvoll first and second phase (−0.137; −0.210, −0.064 and −0.133; −0.202, −0.063). Con- cerning changes over time, an increase in ST during gestation was associated with elevated Stumvoll first and second phase (0.006; 0.000, 0.011). Conclusions As the glucose-insulin axis is more strongly associated with ST than MVPA in our obese population, pregnant women could be advised to reduce ST in addition to increasing MVPA. Moreover, our findings suggest that behaviour change interventions aiming at GDM risk reduction should start in early or pre-pregnancy. Introduction Gestational diabetes mellitus (GDM), one of the most Supplementary information The online version of this article (https:// doi.org/10.1038/s41366-020-0639-y) contains supplementary common pregnancy complications, occurs in about 6.1% material, which is available to authorized users. (1.8–31.0%) of all pregnancies in Europe [1], with numbers growing steadily due to the continuous rise of obesity * Anna M. Dieberger among pregnant women [2]. GDM is associated with a anna.dieberger@medunigraz.at substantially elevated risk of adverse outcomes for mother Extended author information available on the last page of the article. and offspring including foetal overgrowth and increased Less sedentary time is associated with a more favourable glucose-insulin axis in obese pregnant. . . 297 caesarean section rates on the short term [3], and offspring In summary, the aim of this study is to investigate the obesity and development of type 2 diabetes in the mother on longitudinal relationship between objectively measured the long term [4]. physical activity levels and sedentary time and the glucose- Pre-conceptional obesity is the most important modifi- insulin axis in obese pregnant women. able risk factor for developing GDM [5]. However, this factor cannot be addressed in prenatal care, as most women first get in contact with a health care professional when Methods already pregnant. Therefore, other modifiable risk factors during pregnancy, such as physical activity and their asso- Participants ciation with GDM, need to be considered. Physical activity in pregnancy has been shown to This is a secondary analysis of the DALI study, a multi- improve glucose uptake and reduce circulating insulin centre randomised controlled trial. The DALI study was [6, 7]. In accordance with this, a meta-analysis showed that conducted between 2012–15 in nine European countries at physical activity before and in pregnancy was associated eleven different sites (Austria, Belgium, Denmark (Odense, with a significantly lower risk of developing GDM [8]. Copenhagen), Ireland, Italy (Padua, Pisa), Netherlands, However, most included studies measured physical activity Poland, Spain and United Kingdom) and was preceded by a before or in early pregnancy, not considering that on pilot study. The study was registered under trial registration average activity levels decrease with increasing gestation number ISRCTN70595832. Ethical approval was obtained [9, 10]. These longitudinal changes of physical activity from all local ethics committees and written informed levels over the course of pregnancy might influence the consent was signed by all participants prior to data collec- association with glucose and insulin. tion [16]. Furthermore, next to physical activity, too much seden- Pregnant women <20 weeks of gestation with a singleton tary behaviour has been identified as an independent risk pregnancy, aged ≥18 years with a pre-pregnancy body mass factor for type 2 diabetes, cardiovascular disease and pre- index (BMI) of ≥29 kg/m2 were asked to participate. All mature death outside of pregnancy [11–14]. However, the participants were screened for GDM before inclusion few studies assessing the relationship between sedentary (<20 weeks), following the criteria of the International behaviour and the glucose-insulin axis in pregnancy show Association of Diabetes in Pregnancy Study Groups inconsistent results [15], possibly due to heterogeneity in (IADPSG) [19] and were excluded if GDM was diagnosed. the definitions used and the measurement of sedentary Other exclusion criteria encompassed pre-existing diabetes, behaviour. Objective measurements of both sedentary chronic medical diseases, as well as abnormal calcium behaviour and physical activity at multiple time points in metabolism or calcium measurements in early pregnancy pregnancy are needed to gain more insight into how these for the vitamin D trial [16]. For this study, only participants two behaviours modify the glucose-insulin axis. with objectively measured physical activity levels measured The vitamin D And Lifestyle Intervention for gestational at least two out of three times were included to allow for diabetes mellitus prevention (DALI) study compared a longitudinal analyses. lifestyle intervention, including the promotion of physical Participants were randomised in the pilot trial to either a activity, to usual care as prevention for GDM [16]. While healthy eating (HE), a physical activity (PA) or a combined the interventions resulted in a reduction in sedentary time, (HE&PA) intervention, in the lifestyle trial to HE, PA or an increase in moderate-to-vigorous physical activity HE&PA intervention or a control group, and in the vitamin (MVPA) and a reduction in neonatal adiposity, these life- D trial, to vitamin D supplementation with and without a style changes did not result in improvement in glucose or HE&PA intervention or a placebo group with or without a insulin concentrations or insulin resistance [17, 18]. How- HE&PA intervention. For this paper, data were analysed ever, differences in MVPA and sedentary time between the within an observational setting, combining all randomised intervention groups were small. Therefore, analysing all participants from the pilot, lifestyle and vitamin D study participants as one cohort provides the opportunity to study into one cohort. a greater variation in activity levels. We hypothesise that reduced sedentary time and increased MVPA will improve Data collection the glucose-insulin axis. Previously reported improvements in physical activity and sedentary time in the DALI study Data collection took place at three time points in pregnancy were based on self-reported questionnaire data. For this (<20 weeks, 24–28 weeks and 35–37 weeks) and at secondary analysis, a sub-sample for which objectively delivery. At each time point, women who had not devel- measured accelerometer data are available, will be used to oped GDM undertook a standardised 75 g oral glucose study physical activity levels more accurately. tolerance test (OGTT) after a night of fasting, with blood 298 A. M. Dieberger et al. samples taken fasting and at 60 and 120 min after glucose measurement was only deemed valid if the daily wear time ingestion. The blood samples were centrifuged and separate was >480 min. For each time period three valid days had to aliquots (1000 µl or 250 µl) were placed in microrack tubes. be available. Then, the average number of minutes per day The samples were then stored at −20 °C or −80 °C until in sedentary (<100 counts/min), light (100–1951 counts/ further analysed at the central trial laboratory in Graz, min) and moderate-to-vigorous physical activity (MVPA) Austria. Glucose (mmol/l) was measured using the hex- (>1951 counts/min), were defined according to Freedson okinase method (DiaSys Diagnostic Systems, Holzheim, cut-off points [25]. Swimming time, as recorded in the Germany) with a lower limit of sensitivity of 0.1 mmol/l. activity diary, was added to minutes spent in MVPA Insulin (mU/l) was quantified by a sandwich-immunoassay [25, 26]. (ADVIA Centaur, Siemens Health Care Diagnostics Inc., Vienna, Austria) with an analytical sensitivity of 0.5 mU/l, Statistical analysis intra-assay coefficient of variation of 3.3% to 4.6%, and inter-assay coefficient of variation of 2.6% to 5.9%. All Sociodemographic characteristics of all included partici- assays were performed according to the instructions of the pants were presented by mean and standard deviation (SD), manufacturer. median and interquartile range (IQR) or count and propor- Development of GDM over the course of pregnancy was tion and were compared to those excluded due to missing assessed at 24–28 and 35–37 weeks, based on the IADPSG accelerometer data, using unpaired t-test or chi-square test. criteria: fasting venous plasma glucose ≥5.1 mmol/l and/or The outcome variables (fasting glucose, fasting insulin, 1 h glucose ≥10 mmol/l and/or 2 h glucose ≥8.5 mmol/l. HOMA-IR, Stumvoll first and second phase) and accel- Homeostatic Model Assessment for Insulin Resistance erometer variables (sedentary time, MVPA and wear time) (HOMA-IR) was calculated as (glucose0 × insulin0)/22.5 are presented separately for each time point. Differences [20] and has been validated in pregnancy [21]. As a measure between time points were tested by paired sample t-tests. of beta cell function, first and second-phase insulin release Variables that were not normally distributed were log- were calculated, according to Stumvoll et al., as follows transformed prior to analyses. [22]: Stumvoll first phase = 1194 + 4.724 × insulin0 –117 × The main analysis was performed using longitudinal glucose60 + 1.414 × insulin60; Stumvoll second phase = linear mixed regression models with a two-level structure 295 + 0.349 × insulin60 –25.72 × glucose60 + 1.107 × insu- with the observations (level 1) nested within the individuals lin0. Stumvoll first and second phase have not been validated (level 2), allowing for a random intercept and random slope in pregnancy. on level 2. All models were inspected for multicollinearity, Between the blood tests, anthropometric measurements normal distribution of the residuals and homoscedasticity to and questionnaire data were gathered. Maternal age, ethni- fulfil model prerequisites. If residuals were not normally city (Caucasian versus non-Caucasian), parity (multiparity distributed, variables were log-transformed using the natural versus nulliparity), marital status (with versus without logarithm function (ln). First, a simple model including only partner), employment (yes/no), smoking status (yes/no), the time variable (gestational age in weeks) as predictor was alcohol consumption (yes/no), and pre-pregnancy weight established, to see how the development over time could were assessed by questionnaire. Weight during pregnancy best be described (e.g., linear or quadratic). In the next step, was measured at the three defined time-points using cali- all other variables were added to the model. Sedentary time brated electronic scales (SECA Measure 888; 877). Mater- and MVPA were included in one model, to obtain inde- nal height was recorded on a stadiometer (SECA 206, pendent estimates. Both variables were converted before SECA, Birmingham, UK) during the first visit. Pre- analysis to units of 10 min per day and were adjusted for pregnancy BMI was calculated as pre-pregnancy weight accelerometer wear time. Light physical activity was not (kg) divided by the square of height (m2). Information on added in the model due to multicollinearity, as together with offspring sex was obtained from medical records. sedentary time and MVPA it makes up 100% of the mea- Physical activity was measured objectively by use of sured daily physical activity. Further, maternal age (years), accelerometers (ActiGraph GT1M, GT3X+ or Actitrainer; education, pre-pregnancy BMI (ln; kg/m2), randomisation Pensacola, Florida, USA) at <20 weeks, 24–28 weeks and group and country were included in the model. Offspring 35–37 weeks [23]. Participants were instructed to wear the sex, which is associated with maternal postprandial glucose accelerometers during waking hours for three days on an and risk of developing GDM [27], and severity of obesity elastic belt positioned over the right hip and to only remove were both considered as possible effect modifiers. There- the device while performing water-based activities such as fore, interactions between pre-pregnancy BMI/offspring sex swimming or showering. Time and reason of removal were and MVPA and sedentary time were added in additional recorded in an activity diary. Non-wear time was defined as models. Interactions with a p-value <0.10 were deemed periods with zero counts for at least 90 min [24]. A statistically significant. Less sedentary time is associated with a more favourable glucose-insulin axis in obese pregnant. . . 299 Fig. 1 Flow diagram of study participants included in main analysis and sensitivity analyses. BMI Body mass index, GDM gestational diabetes mellitus, OGTT oral glucose tolerance test. Mixed model analysis can be extended into a “hybrid” A two-tailed p-value of <0.05 was deemed significant for model, which produces separate estimates for within and all analyses. All analyses were performed in R: A language between effects (within-between random effects model) and environment for statistical computing (version 3.6.1) [28]. Within-person effects reflect effects of longitudinal [31]. Mixed model analyses were calculated using the lme4 changes in sedentary time or MVPA on changes in the package (version 1.1-21) [32]. Multiple imputation was outcome variables during gestation, i.e., representing performed using the mice package (version 3.6.0) [29]. changes within one individual over time. Between-person Plots were produced using the packages dotwhisker (ver- effects reflect associations between individuals’ average sion 0.5.0) [33] and ggplot2 (version 3.2.1) [34]. differences in sedentary time or MVPA and average glu- cose/insulin parameters, i.e., representing differences between different individuals, averaged over the whole time Results period. Participants with missing observations were inclu- ded on the assumption of “missing at random” (MAR). Study participants As sensitivity analyses, mixed regression models were repeated on several adjusted datasets. Firstly, we conducted Figure 1 shows the flow chart of participants throughout the a complete case analysis, that is, excluding all participants study. Of the original 740 women participating in the RCTs, with only two out of three accelerometer measurements. 232 had sufficient accelerometer measurements to be Secondly, as participants who developed GDM over the included in this secondary analysis. In Table 1 baseline course of pregnancy were not allowed to partake in further characteristics are compared between those included in the OGTTs, analyses were rerun with only those who did not analysis versus those who were excluded. The groups were develop GDM. Analyses were further repeated with a comparable, except for fewer Caucasian women and more categorised time variable, thus replacing gestational age in women who were working in the included group. weeks by the three time points (<20 weeks, 24–28 weeks, 35–37 weeks). Lastly, analyses were repeated after imput- Changes in sedentary time/MVPA and glucose/ ing missing data by multivariate imputation by chained insulin parameters over time equations, taking the two-level structure of the data into account [29], using the “transform then impute” approach Accelerometer data and blood parameters are presented [30] for variables derived from other variables. Twenty separately for each time point in Table 2. Accelerometer imputed datasets were created and models were estimated in wear time and time spent in MVPA significantly decreased each separate dataset and subsequently pooled. over the course of pregnancy, while daily minutes spent 300 A. M. Dieberger et al. sedentary remained constant. When expressed as percentage (24–28 weeks) from 69.7% to 71.5% but did not change of wear time, sedentary time increased significantly from further towards the end of pregnancy. Percentage of time the first time point (<20 weeks) towards mid-pregnancy spent in MVPA dropped significantly from mid to late pregnancy (4.0% to 3.7%). Table 1 Baseline characteristics comparing included and excluded Fasting glucose decreased slightly but significantly from participants. <20 weeks until 24–28 weeks. Postprandial glucose, fasting Included Excluded and postprandial insulin, insulin resistance, and Stumvoll (n = 232) (n = 507) first and second phase all increased significantly throughout the whole pregnancy (Table 2). Age, years (mean ± SD) 32.5 ± 5.2 31.8 ± 5.4 Pre-pregnancy BMI, kg/m2 32.5 (30.6–35.0) 32.9 (30.4–36.1) Longitudinal association between sedentary time/ (median (IQR)) MVPA and glucose/insulin parameters Parity, multiparous (n (%)) 120 (51.7) 252 (49.7) Ethnicity, Caucasian (n (%)) 189 (81.5) 450 (88.8)a Main results are presented in Table 3. The development of Education (n (%), total = 738) Stumvoll first and second phase over the course of preg- Low 27 (11.6) 63 (12.5) nancy can best be described quadratically, therefore gesta- Medium 75 (32.3) 159 (31.4) tional age has been added as a quadratic term for these two High 130 (56.0) 284 (56.1) analyses. Marital status, with partner (n 217 (93.5) 476 (94.1) Participants with on average more sedentary time had (%), total = 738) higher fasting glucose (Estimate: 0.008; 95% CI: 0.002, Occupational status, working 200 (86.2) 374 (73.8)a 0.014), increased ln fasting insulin (0.011; 0.002,0.019), (n (%)) increased ln HOMA-IR (0.012; 0.004, 0.021) and ln Smoking (n (%), total = 737) 33 (14.2) 89 (17.6) Stumvoll first and second phase (0.008; 0.001, 0.014 and Alcohol consumption (n (%), 12 (5.2) 32 (6.4) total = 731) 0.007; 0.001, 0.014), compared with those with less GDM diagnosis in pregnancy 74 (33.5) 138 (35.8) sedentary time (between participants effect). An increase in (n (%)) sedentary time throughout pregnancy (within participants Gestational weight gain at 8.0 ± 4.9 7.8 ± 4.8 effect) was associated with elevated ln Stumvoll first and 35–37 weeks, kg (mean ± SD) second phase (both 0.006; 0.000, 0.011), but not with other Offspring sex, female (n (%), 112 (49.3) 218 (49.4) outcomes. Participants with on average more time spent in total = 668) ln MVPA had lower ln Stumvoll first and second phase a represents a significant difference between included and excluded (−0.137; −0.210, −0.064 and −0.133; −0.202, −0.063) participants (p-value <0.05). (between participants effect), but changes in MVPA Table 2 Sedentary time (ST), moderate-to-vigorous physical activity (MVPA) and metabolic parameters at three time points in pregnancy. n T1 (<20 weeks) n T2 (24–28 weeks) n T3 (35–37 weeks) a Wear time, min/day (mean ± SD) 200 827.9 ± 87.6 196 802.5 ± 91.4 176 789.1 ± 96.7b Sedentary time, min/day (mean ± SD) 200 576.9 ± 99.6 196 575.3 ± 105.0 176 576.0 ± 94.7 Sedentary time, % of wear time (mean ± SD) 200 69.7 ± 9.5 196 71.5 ± 9.4a 176 73.0 ± 8.1 MVPA, min/day (median (IQR)) 200 38.1 (23.7–53.0) 196 34.0 (21.0–50.8)a 176 29.6 (15.7–41.9)b MVPA, % of wear time (median (IQR)) 200 4.5 (2.9–6.3) 196 4.0 (2.5–6.6) 176 3.7 (2.0–5.0)b Fasting glucose, mmol/l (mean ± SD) 232 4.7 ± 0.4 226 4.6 ± 0.4a 215 4.6 ± 0.4 1 h glucose, mmol/l (mean ± SD) 213 6.8 ± 1.4 223 7.5 ± 1.5a 194 8.0 ± 1.4b a 2 h glucose, mmol/l (mean ± SD) 213 5.8 ± 1.2 224 6.2 ± 1.3 194 6.6 ± 1.2b a Fasting insulin, mU/l (median (IQR)) 227 13.1 (9.3–17.5) 226 14.7 (11.0–18.6) 214 16.7 (12.7–23.1)b 1 h insulin, mU/l (median (IQR)) 209 78.5 (53.5–151.1) 219 127.1 (68.7–176.5)a 194 178.9 (120.5–236.5)b a 2 h insulin, mU/l (median (IQR)) 208 56.5 (38.6–86.2) 220 71.2 (46.7–122.5) 193 123.8 (67.4–185.8)b a HOMA-IR (median (IQR)) 227 2.7 (1.9–3.6) 224 3.0 (2.2–3.9) 213 3.4 (2.6–4.8)b Stumvoll first phase (median (IQR)) 206 1498.9 (1234.6–2035.4) 215 1820.2 (1353.7–2319.6) a 192 2592.5 (2031.7–3374.9)b Stumvoll second phase (median (IQR)) 206 385.0 (320.6–520.2) 215 468.8 (352.3–590.6)a 192 658.3 (522.0–846.5)b a represents a significant change between T1 and T2 (p-value < 0.05). b represents a significant change between T2 and T3 (p-value < 0.05). Less sedentary time is associated with a more favourable glucose-insulin axis in obese pregnant. . . 301 throughout pregnancy were not associated with Stumvoll Log transformed estimates can be interpreted as follows: when only the predictor variable is log-transformed, each 1% increase in the predictor variable increases the outcome variable by 1/100 coefficient. For example, a one-unit increase in ST (between) is associated with a 1.2% (EXP(0.012)–1) increase in HOMA-IR. If both predictor and outcome variable are log-transformed, every 1% increase in the predictor variable is associated with an increase in percentage of the outcome variable in the magnitude of the coefficient. For example, a 1% increase in MVPA (between) is −0.133*** (−0.202, −0.063) units of the estimate. For example, a 1% increase in MVPA (between) is associated with a 0.0005 mmol/l increase in fasting glucose. When only the outcome variable is log-transformed, the estimate needs to be exponentiated and subtracted by 1. A one unit increase in outcome variable can then be interpreted as a percentage change of the outcome variable in the magnitude of the Stumvoll second phasea first and second phase (within participants effect). MVPA was not significantly associated with other parameters. 0.016 (−0.026, 0.058) 0.006* (0.000, 0.011) 0.007* (0.001, 0.014) The results presented here imply that if two comparable Estimate (95% CI) Table 3 The longitudinal association between sedentary time (ST) and moderate-to-vigorous physical activity (MVPA) in pregnancy and metabolic parameters in obese women. participants differ only in sedentary time (e.g., participant A is on average 60 min per day more sedentary than partici- 226 (513) pant B throughout her pregnancy), participant A would have 0.048 mmol/l higher glucose levels, 6.8% higher fasting insulin, 7.5% higher HOMA-IR, 4.9% higher All analyses adjusted for gestational age, accelerometer wear time, maternal age, education, pre-pregnancy BMI, randomisation group, country, ST or MVPA. Stumvoll first phase and 4.3% higher Stumvoll second −0.137*** (−0.210, −0.064) phase throughout pregnancy. If participant A increased her sedentary behaviour over 0.018 (−0.026, 0.061) 0.006* (0.000, 0.011) 0.008* (0.001, 0.014) the course of pregnancy by 60 min, her Stumvoll first and Stumvoll first phasea Estimate (95% CI) second phase would increase by 3.6% each. If participant A on average spent 10% more time in 226 (513) MVPA throughout her pregnancy compared to participant B (e.g., 44 min compared to 40 min per day), participant A would have 1.3% lower Stumvoll first phase and 1.3% lower Stumvoll second phase. −0.001 (−0.010, 0.007) −0.022 (−0.110, 0.065) 0.012** (0.004, 0.021) 0.042 (−0.028, 0.113) Effect modification Estimate (95% CI) When testing for effect modification by offspring sex, a HOMA-IRa 232 (554) statistically significant association was found between off- spring sex and sedentary time. Other interactions were not significant. When stratifying results by offspring sex (Sup- plementary table 1), most significant associations were −0.002 (−0.010, 0.006) −0.034 (−0.116, 0.048) driven by women pregnant with male offspring. In partici- 0.037 (−0.028, 0.102) Fasting insulina, mU/l 0.011* (0.002, 0.019) pants pregnant with girls, there was a positive association Estimate (95% CI) between sedentary time (between participants) and fasting glucose, and a negative association between sedentary time 232 (555) (within participants) and fasting insulin and HOMA-IR. When testing for effect modification by pre-pregnancy BMI, there was a significant positive interaction with fast- Natural log transformed values were used in the regression analyses. ing insulin and Stumvoll first and second phase. When Fasting glucose, mmol/l 0.008** (0.002, 0.014) 0.019 (−0.035, 0.073) 0.052 (−0.011, 0.115) stratifying results by median maternal BMI (<32.5 kg/m2 0.001 (-0.006, 0.007) associated with a −0.133% change in Stumvoll second phase. and ≥32.5 kg/m2), results indicated a stronger association Estimate (95% CI) between sedentary time and insulin secretion in the higher BMI group (results not shown). 232 (563) Sensitivity analyses In Figure 2 results of the main analysis and the sensitivity Sedentary time (between), 10 min/day *p < 0.05; **p < 0.01; ***p < 0.001. Sedentary time (within), 10 min/day analyses are displayed graphically. Estimates and statis- tical significance of the sensitivity analyses in those MVPA (between)a, 10 min/day MVPA (within)a, 10 min/day without GDM and with the time variable categorised were similar to the main analysis. When analysing only com- plete cases participants, estimates were similar, but several associations were no longer statistically significant. After n (observations) imputation, estimates again were similar but only the relationship between sedentary time (between-partici- pants) and fasting glucose and insulin resistance remained statistically significant. a 302 A. M. Dieberger et al. Fig. 2 Graphical presentation Sedentary time (within) of results of main analysis and 0.01 sensitivity analyses showing coefficient estimates and 95% 0.00 confidence intervals. GDM −0.01 gestational diabetes mellitus, HOMA-IR Homeostatic model assessment for insulin Sedentary time (between) resistance, MVPA moderate-to- vigorous physical activity. 0.02 Coefficient Estimates 0.01 0.00 Main analysis (n = 232) MVPA (within) Complete cases (n = 108) No GDM cases (n = 144) 0.10 Time as categorical (n = 232) Multiple imputation (n = 232) 0.05 0.00 −0.05 −0.10 MVPA (between) 0.1 0.0 −0.1 −0.2 os e ln) (ln ) (ln ) (ln ) uc n( se l uli − IR a se n gG Ins MA ph p ha sti t ing HO fi rst nd Fa s oll co Fa mv se oll Stu mv Stu Discussion changes can all be attributed to physiological metabolic adaptations during pregnancy [1]. We also found a sig- In this study we have shown that overweight and obese nificant reduction in MVPA over time, which has been pregnant women with less sedentary time have more shown by other studies [35–37]. Time spent sedentary favourable glucose and insulin levels, insulin sensitivity and increased significantly during pregnancy, albeit only when insulin secretion compared to women with more sedentary adjusted for accelerometer wear time. While Di Fabio et al. time. A reduction in sedentary time over the course of also found a trend in increasing sedentary time with pregnancy is associated with decreased insulin secretion increasing gestation [37], others did not find any changes without a concurrent increase in glucose. This implies that [35, 38, 39]. next to promoting physical activity, reducing sedentary time should be encouraged in pregnancy. Our data also suggest Sedentary time and MVPA and glucose/insulin that, as changes in behaviour throughout pregnancy have parameters limited influence on maternal metabolism, interventions should target early pregnancy or pre-pregnancy. We found Our findings of a positive relationship between sedentary sex-differences, indicating that these associations were time (between estimate) and fasting glucose and insulin, more pronounced in women pregnant with male offspring. insulin resistance and secretion are partly in line with the results of Wagnild et al., who found a significant association Development of glucose/insulin parameters and between objectively measured sedentary time and fasting sedentary time/MVPA over time and post-load glucose in those without GDM [40]. How- ever, in the cross-sectional study of Gradmark et al. [41] Our data showed a slight decrease in fasting glucose over and the longitudinal study of Nayak et al. [38], no asso- the course of pregnancy, while fasting insulin, postprandial ciations between objectively measured sedentary time and glucose and insulin, insulin resistance and secretion all either glucose or insulin sensitivity were found. Both stu- increased progressively throughout pregnancy. These dies comprised a relatively small sample size and therefore Less sedentary time is associated with a more favourable glucose-insulin axis in obese pregnant. . . 303 might have been underpowered to detect weak yet statisti- offspring. It has been shown that women pregnant with cally significant associations. male offspring have poorer beta cell function and an We found a statistically significant positive association increased risk of GDM, indicating foetal influence on the between MVPA and insulin secretion (between estimate). maternal metabolism [27, 45]. This supports the idea of While outside of pregnancy very low values of insulin lifestyle variables being associated differently with the secretion are associated with reduced beta cell function, we maternal glucose-insulin axis, depending on foetal sex. think that in our study the reduction of Stumvoll first and second phase reflects a reduced need of insulin due to better Strengths and weaknesses insulin sensitivity and can therefore be seen as beneficial. This is endorsed by the fact that women in our study with A weakness of this study is its observational design, which GDM compared to those without had higher levels of precludes us from studying causal effects. However, ana- insulin secretion (data not shown). lysing the original RCT groups together as one cohort Other relationships with MVPA were not significant. allowed us to firstly, pick up small, possibly relevant dif- This could be due to the participants in this study being ferences between individual participants that would be lost overweight or obese, who might not provide enough var- when comparing groups. Secondly, it allowed us to apply a iation in MVPA to detect significant relationships. longitudinal statistical method which incorporates repeated We found that differences in activity behaviour between measurements over time into one analysis and produces women were more strongly associated with the glucose- separate estimates for changes in sedentary behaviour and insulin axis than changes in activity behaviour within a MVPA within individual participants over time (within woman over time. We cannot preclude that unmeasured participants effect), as well as estimates that compare dif- confounding (e.g., by dietary factors) might have influenced ferent participants with each other (between participants the between-participant estimates more than the within- effect) [28]. participant estimates. Another explanation for our findings Another weakness is the reduction in sample size could be that our first measurement, which occurred at on compared to the original study (n = 740 versus n = 232). average 15 weeks of gestation, might be too late to have an However, while reducing the number of included partici- impact on the glucose-insulin axis within the remaining pants, it enabled us to study physical activity and seden- weeks of pregnancy. These findings are in line with a meta- tary behaviour in an objective way. The objective analysis that found significant associations between physi- measurement of physical activity is especially important in cal activity in early or pre-pregnancy and reduced odds of our study of obese women, as individuals with higher GDM, with the highest reduction in odds with physical body fat less accurately self-report physical activity than activity performed before pregnancy [42]. This is further lean participants [46]. corroborated by a review of Song et al. [43], that showed The objective measurement of physical activity with that only lifestyle interventions starting before 15 weeks of accelerometers is preferable to self-reported questionnaire gestation are effective in the reduction of GDM risk. This data, which are subject to recall bias and are less robust could also explain the lack of effect of our intervention on when measuring light to moderate activity [47]. This metabolic outcomes. Overall, this suggests that changes in accurate distinction between light physical activity and behaviour should take place before 15 weeks of gestation, sedentary behaviour is essential. The time spent sedentary thus in early pregnancy or even before pregnancy. and in light physical activity and MVPA make up a per- As our study only includes women with a BMI ≥ 29 kg/ son’s total day. For example, a reduction in sedentary time m2, results cannot be generalised to the general pregnant automatically results in an increase in MVPA or light population. However, as the worldwide prevalence of obe- physical activity. This is especially important in our study sity in women is predicted to surpass 21% by 2025 [44], it as we showed that reducing sedentary behaviour coinciding is essential to research how to reduce pregnancy compli- with unchanged MVPA, which consequently results in cations in this high-risk population. Nevertheless, associa- increased light physical activity, is associated with tions likely differ for obese and non-obese women. Even improved glucose and insulin parameters. within our obese cohort, we found significant interactions Light physical activity comprises exercises such as between sedentary time and pre-pregnancy BMI, indicating stretching or light weight training but mostly consists of stronger associations with increasing BMI. However, a non-exercise activities such as standing, light housework, larger sample size would be needed to stratify and look into walking or shopping. Non-exercise activities induce energy specific BMI sub-groups separately. expenditure, defined as non-exercise activity thermogenesis We also found significant interactions between sedentary (NEAT) [48]. NEAT accounts for the majority of a person’s behaviour and foetal sex. The stratified results showed that daily variable energy expenditure [48] and can therefore most results were driven by women pregnant with male play an important role in body weight regulation outside of 304 A. M. Dieberger et al. pregnancy [49]. Our results support the notion that Data availability increased light physical activity and consequently increased NEAT also has positive effects in pregnancy. Data are available from the corresponding author on rea- A strength of our study is the analysis of sedentary sonable request. behaviour independently of MVPA and vice versa. Adjusting analyses for both sedentary behaviour and Acknowledgements We thank all participants, coaches, research midwives/nurses and health professionals who collaborated in the MVPA is essential to tease apart the effect of reducing recruitment. sedentary behaviour from increasing MVPA, as it has been shown that individuals with increased sedentary time have a Funding The project described has received funding from the European higher risk of adverse health outcomes, even when Community’s 7th Framework Program (FP7/2007–2013) under grant achieving recommended physical activity levels [15]. agreement no 242187. In the Netherlands, additional funding was pro- vided by the Netherlands Organisation for Health Research and The sensitivity analyses, which were performed to test Development (ZonMw) (Grant no. 200310013). In Poland, additional the robustness of the results, also strengthen our study. The funding was obtained from Polish Ministry of Science (Grant no. 2203/ sensitivity analyses with gestational age as categorical 7. PR/2011/2). In Denmark, additional funding was provided by Odense variable and only participants without GDM showed results University Free Research Fund. In the UK, the DALI team acknowl- edges the support received from the NIHR Clinical Research Network: and significances very similar to the original analysis. The Eastern, especially the local diabetes clinical and research teams based in complete case and multiple imputation analyses showed Cambridge. In Spain, additional funding was provided by CAIBER similar albeit mostly non-significant estimates. This could 1527-B-226. The funders had no role in any aspect of the study beyond be due to the wider confidence intervals in those two ana- funding. This work was supported by the Austrian Science Fund FWF (DOC 31-B26) and the Medical University Graz through the PhD lyses, caused by the reduced sample size in the complete Programme Inflammatory Disorders in Pregnancy (DP-iDP). Open case analysis (n = 144 versus n = 232) and by the added access funding provided by the Austrian Science Fund FWF. random error in the multiple imputation model. Author contributions Conceptualisation: AMD, MNMvP; methodol- Practical implications ogy: AMD, ES, MNMvP; formal analysis, visualisation, writing–original draft: AMD; supervision: MNMvP; investigation, resources: all authors except AMD and ES; writing–review and edit- Our results imply that reducing sedentary behaviour in ing: all authors. obese pregnant women might be more relevant for meta- bolic health than increasing physical activity. It would Compliance with ethical standards also be beneficial for neonatal outcomes, since we pre- viously found that a reduction of neonatal adiposity was Conflict of interest The authors declare that they have no conflict of mediated by a reduction of sedentary time [18]. In the interest. general population, recent public health guidelines have Publisher’s note Springer Nature remains neutral with regard to also stressed the importance of reducing sedentary time in jurisdictional claims in published maps and institutional affiliations. addition to physical activity [50]. Specific guidelines in pregnancy on sedentary behaviour might further help Open Access This article is licensed under a Creative Commons health care providers, especially since they often struggle Attribution 4.0 International License, which permits use, sharing, with giving advice on physical activity [51]. Furthermore, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the focussing on changing sedentary behaviour might also be source, provide a link to the Creative Commons license, and indicate if easier for obese women than increasing physical activity changes were made. The images or other third party material in this levels alone. article are included in the article’s Creative Commons license, unless Future intervention studies, focussing on reducing indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended sedentary behaviour by encouraging light physical activity use is not permitted by statutory regulation or exceeds the permitted and breaking up sitting time, are needed. Those studies use, you will need to obtain permission directly from the copyright should also include leaner women to compare effects holder. 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Adelantado5 Dorte Møller Jensen16,17,18 ● ● ● ● Lise-Lotte Andersen16,17,18 Mette Tanvig16,17,18 Peter Damm19,20 Elisabeth Reinhardt Mathiesen19,20 ● ● ● ● Frank J. Snoek21 Judith G. M. Jelsma22 Mireille N. M. van Poppel 23 ● ● 1 7 Department of Obstetrics and Gynaecology, Medical University of CIBER Bioengineering, Biomaterials and Nanotechnology, Graz, Graz, Austria Instituto de Salud Carlos III, Madrid, Spain 2 8 Institute of Social Medicine and Epidemiology, Medical Macarthur Clinical School, Western Sydney University, University of Graz, Graz, Austria Sydney, Australia 3 9 Recherche en Santé Lawson SA, Bronschhofen, Switzerland Gender Medicine Unit, Division of Endocrinology and 4 Metabolism, Department of Medicine III, Medical University of Lawson Health Research Institute, London, ON N6C 2R5, Canada Vienna, Vienna, Austria 5 Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, 10 Galway Diabetes Research Centre and College of Medicine Barcelona, Spain Nursing and Health Sciences, National University of Ireland, 6 Galway, Ireland Department of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain Less sedentary time is associated with a more favourable glucose-insulin axis in obese pregnant. . . 307 11 18 KU Leuven Department of Development and Regeneration: Department of Clinical Research, Faculty of Health Sciences, Pregnancy, Fetus and Neonate, Gynaecology and Obstetrics, University of Southern Denmark, Odense, Denmark University Hospitals Leuven, Leuven, Belgium 19 Center for Pregnant Women with Diabetes, Departments of 12 Division of Reproduction, Poznan University of Medical Endocrinology and Obstetrics, Rigshospitalet, Sciences, Poznan, Poland Copenhagen, Denmark 13 20 Universita Degli Studi di Padova, Padua, Italy Department of Clinical Medicine, Faculty of Health and Medical 14 Sciences, University of Copenhagen, Copenhagen, Denmark Azienda Ospedaliero Universitaria Pisana, Pisa, Italy 21 15 Department of Medical Psychology, Amsterdam University Department of Obstetrics and Gynaecology, Division of Obstetrics Medical Centres, Vrije Universiteit Amsterdam, Amsterdam and Prenatal Medicine, Erasmus MC, University Medical Centre Public Health Research Institute, Amsterdam, the Netherlands Rotterdam, Rotterdam, the Netherlands 22 16 Department of Public and Occupational Health, Amsterdam Public Steno Diabetes Center Odense, Odense University Hospital, Health research institute, Amsterdam UMC, Vrije Universiteit Odense, Denmark Amsterdam, Amsterdam, the Netherlands 17 Department of Gynaecology and Obstetrics, Odense University 23 Institute of Sport Science, University of Graz, Graz, Austria Hospital, Odense, Denmark