Received: 16 October 2019 Accepted: 5 February 2020 DOI: 10.1111/ijpo.12628 ORIGINAL RESEARCH Temporal relationships between maternal metabolic parameters with neonatal adiposity in women with obesity differ by neonatal sex: Secondary analysis of the DALI study Rodrigo A. Lima1 | Gernot Desoye2 | David Simmons3,4 | Roland Devlieger5 | Sander Galjaard5,6 | Rosa Corcoy7 | Juan M. Adelantado7,8 | Fidelma Dunne9 | Jürgen Harreiter10 | Alexandra Kautzky-Willer10 | Peter Damm11 | Elisabeth R. Mathiesen11 | Dorte M. Jensen12,13,14 | Lise-Lotte Andersen13,14 | Mette Tanvig13,14 | Annunziata Lapolla15 | Maria G. Dalfra15 | Alessandra Bertolotto16 | Ewa Wender-Ozegowska17 | Agnieszka Zawiejska17 | David J. Hill18 | Frank J. Snoek19 | Judith G. M. Jelsma20 | Mireille N. M. van Poppel1,20 1 Institute of Sport Science, University of Graz, Graz, Austria 2 Department of Obstetrics and Gynecology, Medizinische Universitaet Graz, Graz, Austria 3 Western Sydney University, Campbelltown, New South Wales, Australia 4 The Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK 5 KU Leuven Department of Development and Regeneration: Pregnancy, Fetus and Neonate, Gynaecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium 6 Department of Obstetrics and Gynaecology, Division of Obstetrics and Prenatal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands 7 Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 8 CIBER Bioengineering, Biomaterials and Nanotechnology, Instituto de Salud Carlos III, Zaragoza, Spain 9 Galway Diabetes Research Centre and College of Medicine Nursing and Health Sciences, National University of Ireland, Galway, Ireland 10 Gender Medicine Unit, Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria 11 Center for Pregnant Women with Diabetes, Department of Endocrinology and Obstetrics, Rigshospitalet, Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 12 Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark 13 Department of Gynecology and Obstetrics, Odense University Hospital, Odense, Denmark 14 Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark 15 Universita Degli Studi di Padova, Padua, Italy 16 Azienda Ospedaliero Universitaria – Pisa, Pisa, Italy 17 , Poland Medical Faculty I, Poznan University of Medical Sciences, Poznan 18 Recherche en Santé Lawson SA, Bronschhofen, Switzerland 19 Department of Medical Psychology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands 20 Department of Public and Occupational Health, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Public Health research institute, Amsterdam, The Netherlands Abbreviations: BMI, body mass index; DALI, vitamin D and lifestyle intervention for gestational diabetes mellitus prevention: an European multicentre randomized trial; GDM, gestational diabetes; HAPO, hyperglycemia and adverse pregnancy outcome; HOMA-IR, HOMA-index of insulin resistance. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation Pediatric Obesity. 2020;15:e12628. wileyonlinelibrary.com/journal/ijpo 1 of 11 https://doi.org/10.1111/ijpo.12628 20476310, 2020, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijpo.12628 by Readcube (Labtiva Inc.), Wiley Online Library on [27/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2 of 11 LIMA ET AL. Correspondence Rodrigo A. Lima, Institute of Sport Science, Summary University of Graz, Mozartgasse 14, 8010 Objectives: To investigate the importance of time in pregnancy and neonatal sex on Graz, Austria. Email: rodrigoantlima@gmail.com the association between maternal metabolic parameters and neonatal sum of skinfolds. Funding information CAIBER, Grant/Award Number: 1527-B-226; Methods: This was a longitudinal, secondary analysis of the vitamin D and lifestyle Odense University Free Research Fund; Polish intervention for gestational diabetes mellitus study, conducted in nine European Ministry of Science, Grant/Award Numbers: 2203/7, PR/2011/2; Seventh Framework countries during 2012 to 2015. Pregnant women with a pre-pregnancy body mass Programme, Grant/Award Number: 242187; index (BMI) of ≥29 kg/m2 were invited to participate. We measured 14 maternal ZonMw, Grant/Award Number: 200310013 metabolic parameters at three times during pregnancy: <20 weeks, 24 to 28 weeks, and 35 to 37 weeks of gestation. The sum of four skinfolds assessed within 2 days after birth was the measure of neonatal adiposity. Results: In total, 458 mother-infant pairs (50.2% female infants) were included. Insulin resistance (fasting insulin and HOMA-index of insulin resistance) in early pregnancy was an important predictor for boys' sum of skinfolds, in addition to fasting glucose and maternal adiposity (leptin, BMI and neck circumference) throughout pregnancy. In girls, maternal lipids (triglycerides and fatty acids) in the first half of pregnancy were important predictors of sum of skinfolds, as well as fasting glucose in the second half of pregnancy. Conclusions: Associations between maternal metabolic parameters and neonatal adiposity vary between different periods during pregnancy. This time-dependency is different between sexes, suggesting different growth strategies. KEYWORDS foetal growth, foetal programming, maternal health, metabolic syndrome, neonatal body composition, pregnancy 1 | I N T RO DU CT I O N increased in women with obesity and/or gestational diabetes (GDM) already at 20 weeks of gestation or even before9,10; maternal insulin Globally, in 2017 an estimated 38 million children under 5 years of resistance in the first half of pregnancy is related to neonatal fat age presented either overweight or obesity. This is a major public percentage,7 and fasting glucose in the first trimester with the risk 1 health concern. Hence, strategies have to be developed to reduce of a large-for-gestational age baby.11 Although these studies suggest this burden and prevent childhood obesity. This requires a thorough an influence of the early pregnancy period, surprisingly little is identification and understanding of the underlying determinants. known about temporal relations between maternal metabolic mea- Maternal obesity in pregnancy is linked with the development of sures and neonatal fat accrual.12 2-5 neonatal and childhood adiposity. Although there is much interest Female neonates are known to be more insulin resistant,13,14 in the relationship between maternal obesity and childhood adiposity, which might explain why males are more affected by in utero expo- maternal metabolic factors driving the increase in offspring adiposity sure to gestational diabetes.9 Therefore, it is mandatory to assess have not been fully understood. temporal relations of maternal metabolism with neonatal adiposity in The Hyperglycemia and Adverse Pregnancy Outcome study a sex-dependent manner. showed a continuous positive relationship of maternal glucose in In this study, we investigated the association between maternal the second trimester with measures of neonatal body fat.6 Findings health measures at different times during pregnancy and neonatal from the Healthy Start Study support this and, in addition, showed sum of skinfolds in a sex-specific manner. We hypothesized that: temporal changes in the association of glucose and neonatal fat, (a) associations between maternal metabolic parameters and neonatal with stronger associations in the second half of pregnancy com- adiposity differ at different time points, and (b) these temporal differ- pared to early pregnancy.7,8 However, other studies clearly indicate ences are sex-specific. We tested these hypotheses in 458 mother- that the influence of maternal phenotype on foetal growth can infant pairs in the vitamin D and lifestyle intervention for gestational already be demonstrated in the early pregnancy period: foetal diabetes mellitus (DALI) study, a pan-European study originally abdominal circumference, as proxy for foetal overgrowth, is designed for the prevention of gestational diabetes.15 20476310, 2020, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijpo.12628 by Readcube (Labtiva Inc.), Wiley Online Library on [27/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License LIMA ET AL. 3 of 11 2 | METHODS (SECA 888 and 877, SECA, UK) at baseline (<20 weeks), 24 to 28 weeks, and at 35 to 37 weeks of gestation. BMI was calculated as 2.1 | Design and participants weight in kilogram divided by the square of height in metres. Gesta- tional weight gain was defined as the change in objectively measured This is a longitudinal, secondary analysis of the DALI study, which was a weight from pre-pregnancy to <20, <20 to 24-28 weeks and from multicentre parallel randomized trial conducted in nine European countries 24-28 to 35-37 weeks. Neck circumference was obtained in a stand- (Austria, Belgium, Denmark, Ireland, Italy, Netherlands, Poland, Spain and ing relaxed upright position between mid-cervical spine and mid- United Kingdom) during 2012 to 2015. The study was prospectively regis- anterior neck, to within 1 mm.19 tered as a randomized clinical trial (RCT) with the primary aim to prevent After fasting for 10 hours, blood was collected and mothers con- gestational diabetes mellitus on November 21, 2011 (ISRCTN70595832). sumed a 250 mL 75 g glucose drink (within a period of 5 minutes). Local ethics committee approval and written informed consent of all Further blood collections took place after 60 and 120 minutes. All the women was obtained. Pregnant women with a pre-pregnancy body mass samples were centrifuged and separated aliquots of plasma (1000 μL index (BMI) of ≥29 kg/m2, <20 weeks of gestation, a singleton pregnancy or 250 μL) placed in microrack tubes and stored at −20 C or −80 C in and aged ≥18 years were invited to participate.16 Exclusion criteria the central trial laboratory, prior to analysis, in Graz, Austria. The 17,18 included diagnosis with early gestational diabetes mellitus, pre- maternal concentrations of plasma fasting glucose, fasting insulin, tri- existing diabetes, and chronic medical conditions. glycerides, free fatty acids and leptin were quantified. For insulin and leptin commercially available Enzyme-Linked Immuno Sorbent Assays were used. In the samples taken 60 and 120 minutes after glucose 2.2 | Design and procedures load, only glucose (1-hour glucose and 2-hour glucose) and insulin (1-hour insulin and 2-hour insulin) were assessed. Fasting insulin resis- The study was originally designed as an RCT with the following tance was derived from homeostasis model assessment (HOMA-index groups, pre-stratified for site: (a) healthy eating; (b) physical activity; of insulin resistance – HOMA-IR).20 Insulin secretion after glucose (c) healthy eating + physical activity; (d) healthy eating + physical load were calculated with the Stumvoll first phase and Stumvoll sec- activity + vitamin D; (e) healthy eating + physical activity + placebo; ond phase validated equations.21 (f) vitamin D; (g) placebo, (h) control. Staff involved with measure- ments, but not participants, were blinded to the lifestyle intervention. Both staff and participants were blinded to vitamin D intervention. 2.3.3 | Covariates For the purpose of this analysis, the data were analyzed as a longitudi- nal cohort. Maternal measurements took place at baseline Information on possible covariates was collected in the baseline ques- (<20 weeks), at 24 to 28 and at 35 to 37 weeks of gestation. Since tionnaire or from medical files: national site(s) of recruitment, maternal 16 methodology has been extensively described elsewhere, only vari- age, gestational age during pregnancy (<20, 24 to 28 and 35 to ables of interest will be detailed in this manuscript. 37 weeks), maternal ethnicity (European or non-European descent), maternal education (low, medium and high), smoking status at 35 to 37 weeks of gestation (yes/no), pre-pregnancy BMI and gestational 2.3 | Measurements age at birth. 2.3.1 | Neonatal outcome 2.4 | Statistical analyses Triceps, subscapular, supra-iliac and quadriceps skinfolds were mea- sured within 48 hours of birth with a Harpenden skinfold calliper All analyses were performed in STATA version 13 for windows (Baty, UK), and the values summed to obtain the primary neonatal (StataCorp LP, College Station, Texas) and a 5% type I error rate outcome measure, the sum of skinfolds. Each skinfold measurement was used for the analyses. We have 80% statistical power to was measured twice and if a difference of more than 0.2 mm was reg- detect associations with small effect sizes (f2 = 0.04) considering istered, a third measurement was performed and the average of the the number of participants evaluated (n = 458) and the number of three was taken. The neonatal age at the measurement was the time exposures and confounding variables in each of our models. between birth and measurements, which was registered in hours. Skewed variables were log-transformed before analyses (fasting insulin, 1-hour insulin, 2-hour insulin, HOMA-IR, Stumvoll first phase, Stumvoll second phase, triglycerides, leptin and BMI). Inde- 2.3.2 | Maternal metabolic and adiposity pendent t tests were performed to evaluate descriptive differences parameters in the mother's metabolic and adiposity parameters for each preg- nancy period in relation to their child's sex (results shown in Maternal height was determined at baseline with a stadiometer (SECA Table 1). Independent t tests also evaluated sex-differences in neo- 206; SECA, UK). Women were weighed on calibrated electronic scales natal skinfolds. 4 of 11 TABLE 1 Mean and SD of the mothers' variables included in the main analyses for different gestational time and stratified by sex <20 weeks 24-28 weeks 35-37 weeks Boys Girls Boys Girls Boys Girls Maternal parameters Mean SD Mean SD P Mean SD Mean SD P Mean SD Mean SD P Fasting glucose (mmol/L) 4.58 0.38 4.61 0.36 .39 4.54 0.40 4.61 0.43 .07 4.47 0.45 4.56 0.43 .05 1-h glucose (mmol/L) 6.60 1.38 6.80 1.47 .15 7.56 1.70 7.77 1.60 .19 7.93 1.55 8.12 1.45 .25 2-h glucose (mmol/L) 5.72 1.11 5.81 1.18 .45 6.17 1.25 6.15 1.27 .87 6.44 1.25 6.49 1.12 .70 Fasting insulin (μU/mL) 12.69 1.03 13.12 1.03 .46 13.98 1.03 15.46 1.03 .02 17.05 1.04 17.97 1.04 .37 1-h insulin (μU/mL) 85.48 1.05 84.98 1.05 .93 112.62 1.04 124.58 1.04 .09 157.47 1.05 166.11 1.05 .43 2-h insulin (μU/mL) 60.87 1.05 53.62 1.06 .43 72.44 1.05 76.22 1.05 .47 107.99 1.06 110.62 1.06 .75 HOMA-IR ([μU/mL]*[mmol/L]) 2.57 1.03 2.68 1.03 .40 2.84 1.03 3.15 1.03 .03 3.31 1.04 3.62 1.05 .16 Stumvoll first phase (pmol/L) 1639.26 1.02 1616.57 1.02 .68 1740.14 1.02 1872.26 1.03 .04 2556.15 1.03 2676.00 1.03 .31 Stumvoll second phase (pmol/L) 421.81 1.02 416.57 1.02 .70 449.52 1.02 482.72 1.02 .03 650.25 1.03 680.23 1.03 .30 Triglycerides (mmol/L) 1.23 1.02 1.26 1.02 .48 1.76 1.02 1.70 1.02 .25 2.21 1.03 2.13 1.03 .33 Fatty acids (mmol/L) 0.63 0.23 0.64 0.21 .48 0.59 0.23 0.58 0.19 .37 0.59 0.23 0.61 0.21 .40 Leptin (pg/mL) 33.63 1.03 34.16 1.03 .74 32.59 1.03 34.29 1.04 .30 32.07 1.04 33.02 1.04 .59 Neck circumference (cm) 36.18 2.06 36.21 2.17 .89 36.29 2.12 36.28 2.23 .98 36.53 2.17 36.60 2.22 .74 BMI (kg/m2) 34.13 1.01 34.17 1.01 .91 35.63 1.01 35.64 1.01 .97 36.88 1.01 36.96 1.01 .84 Gestational weight gain (kg) 2.02 3.92 1.84 4.48 .64 4.06 3.28 3.92 2.74 .63 3.82 2.78 3.76 2.82 .82 Note: P value from independent t test; Fasting insulin, 1-hour insulin, 2-hour insulin, HOMA-IR, Stumvoll first phase, Stumvoll second phase, triglycerides, leptin and BMI were log-transformed for the analyses, but the values in the table were exponentiated for clarity. Abbreviation: BMI, body mass index. LIMA ET AL. 20476310, 2020, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijpo.12628 by Readcube (Labtiva Inc.), Wiley Online Library on [27/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 20476310, 2020, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijpo.12628 by Readcube (Labtiva Inc.), Wiley Online Library on [27/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License LIMA ET AL. 5 of 11 We conducted principal component factor analyses for each mea- 2.5 | Supplementary analysis surement time during pregnancy to group the exposures with shared variances in the same factor. All components from the mother's health Multiple linear multilevel analyses tested the association between profile were included in the factor analyses: fasting glucose, 1-hour each of the maternal measurements during pregnancy and neonatal glucose, 2-hour glucose, fasting insulin, 1-hour insulin, 2-hour insulin, sum of skinfolds (see Table S2). Sex-effects were estimated by inclu- HOMA-IR, Stumvoll first phase, Stumvoll second phase, triglycerides, sion of an interaction term between the exposures and sex. All ana- free fatty acids, leptin, neck circumference, BMI and gestational lyses were adjusted for intervention group, site of recruitment, weight gain. Independent of the pregnancy period, the scree plot maternal ethnicity, education, BMI (except when BMI was the expo- determined that four factors were relevant to be estimated. Thus, four sure), age, smoking status, gestational age during pregnancy (<20, factors were estimated for each time during pregnancy by the follow- 24 to 28 and 35 to 37 weeks), gestational age at birth (weeks) and ing criteria: neonatal age at measurement (hours post birth). The cluster structure of data was also taken into account with individuals nested into the 1. Independent of the time during pregnancy, each factor should be site of recruitment. We used robust correction for estimating the composed of the same variables; standard errors and used the Bonferroni adjustment for multiple test- 2. Each factor was composed of variables with high loading factors ing. Analyses with triglycerides and fatty acids as exposures were fur- (≥0.4) in at least two measuring points after varimax rotation of ther adjusted for HOMA-IR. the correlation matrix; 3. Components with high loading factors (≥0.4) in more than one fac- tor were only included in the factor with the highest loading 3 | RE SU LT S factor; 4. Factors were estimated using the linear regression prediction In total, 458 mother-infant pairs (50.2% female infants) were included score. in the study. On average, the mothers were 32.1 (±5.3) years of age and their infants were measured 19.9 (±30.5) hours after birth. Mothers At all three time points during pregnancy, factor 1 was composed gave birth after 39.7 (±1.4) weeks of gestation, and most mothers per- of fasting insulin and HOMA-IR (representing insulin resistance); fac- ceived themselves as of European descent (84.6%) and did not smoke tor 2 was composed of 1-hour insulin, 2-hour insulin, Stumvoll first during pregnancy (85.6%). More than half of the mothers (57.6%) phase and Stumvoll second phase (representing insulin response); fac- reported high educational level, whereas 32.0% reported medium edu- tor 3 was constituted of 1-hour glucose and 2-hour glucose (rep- cational level. Neonatal boys exhibited lower sum of skinfolds com- resenting glucose tolerance), and, factor 4 was composed of leptin, pared to girls (Mean sum of skinfoldsboys = 20.3 mm [±5.2]; Mean sum BMI and neck circumference (representing maternal adiposity). of skinfoldsgirls = 21.5 mm [±5.4]; P = .02). Table S1 presents the cumulative variance of each factor in the three periods of gestation. Fasting glucose, triglycerides, free fatty acids and gestational weight gain did not have a high loading factor for any of 3.1 | Maternal metabolic parameters at three time the factors, nor did they built a separate factor, and were not included points in any of the factors. Thus, they were analyzed as single exposures in relation to neonatal sum of skinfolds. Table 1 describes the unadjusted sex-differences in the mothers' The association of each resulting factor from the mother's health metabolic profile for each gestational time. In the first measurement profile with neonatal sum of skinfolds was assessed using linear multi- prior to 20 weeks of gestation, no differences were observed in level analyses, adjusted for intervention group, site of recruitment, maternal metabolic measurements between mothers of boys and gestational age during pregnancy, gestational age at birth, neonatal girls. At 24 to 28 weeks of gestation, mothers of girls had higher age at measurement, maternal ethnicity, maternal education, BMI fasting insulin, HOMA-IR and Stumvoll first and second phases com- (except in factor 4 since BMI was part of this factor), maternal age, pared to mothers of boys. At 35 to 37 weeks of gestation, mothers smoking status and the cluster structure. Sex-effects were estimated of girls had higher fasting glucose compared to those of boys by inclusion of an interaction term between the factor and sex. We (Table 1). used robust correction for estimating the standard errors and esti- mated P-values using the Bonferroni adjustment for multiple testing. The association between the mother's health profile not included in 3.2 | Associations of maternal metabolic any of the factors (fasting glucose, triglycerides, free fatty acids and parameters with neonatal adiposity gestational weight gain) and neonatal sum of skinfolds was evaluated following the same procedure abovementioned. Note that we tested Associations of the four factors, and fasting glucose, triglycerides, the same analysis replacing BMI for gestational weight gain as a con- fatty acids and gestational weight gain at the three time points with founder. The conclusions were similar, so we only present the results neonatal adiposity are described in Table 2. Factor 1 (fasting insulin with BMI adjustment. and HOMA-IR) at <20 weeks of gestation was associated with boys' 20476310, 2020, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijpo.12628 by Readcube (Labtiva Inc.), Wiley Online Library on [27/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 11 LIMA ET AL. sum of skinfolds, and with girls' sum of skinfolds at 35 to 37 weeks of that associations of metabolic parameters with neonatal adiposity gestation. Factor 2 (1-hour insulin, 2-hour insulin, Stumvoll first phase, change between different time-periods and differ between sexes. We Stumvoll second phase) was associated with boys' sum of skinfolds at demonstrate a complex pattern of metabolic metabolism and its asso- 35 to 37 weeks of gestation, and no association was found of this fac- ciation with neonatal fat measured as sum of skinfolds, as illustrated tor with girls' sum of skinfolds. Factor 3 (1-hour glucose and 2-hour in Figure 2. In summary, insulin resistance in early pregnancy is an glucose) at 35 to 37 weeks of gestation was associated with boys' important predictor for boys' sum of skinfolds, in addition to fasting sum of skinfolds and at 24 to 28 and 35 to 37 weeks of gestation with glucose throughout pregnancy. In girls, maternal lipids in the first half girls' sum of skinfolds. Finally, factor 4 (leptin, BMI and neck circum- of pregnancy period play a role for sum of skinfolds, as well as fasting ference) was associated with boys' sum of skinfolds in all pregnancy glucose in the second half of pregnancy. periods, but not with girls' sum of skinfolds (Figure 1). In both sexes, the early pregnancy period is relevant for neonatal Fasting glucose at <20, 24 to 28 and 35 to 37 weeks of gestation adiposity, although for different metabolic parameters (ie, insulin was associated with boys' sum of skinfolds, and at 24 to 28 and 35 to resistance in boys and lipid levels in girls). Although a later interven- 37 weeks of gestation with girls' sum of skinfolds. Triglycerides at tion was effective in reducing neonatal adiposity,22 our data suggest <20 weeks were positively associated with the sum of skinfolds in that ideally maternal metabolism shall be normalized already early in girls, and 35 to 37 weeks with sum of skinfolds of boys. Fatty acids pregnancy to reduce the risk of neonatal adiposity. Hence, interven- were associated with sum of skinfolds in girls at <20 and 24 to tions beginning prior to or in very early pregnancy might be even 28 weeks. Gestational weight gain at <20 weeks was positively asso- more effective than those initiated later, and achieved a 9% reduction ciated with boys' sum of skinfolds (Table 2). Table S2 describes the in neonatal fat.22 Our results also indicate that both types of nutrients, associations of maternal parameters that were included in the factors glucose and lipids, are related to neonatal adiposity, although associa- with neonatal adiposity. tions are time- and sex-dependent. This argues for future time- and sex-specific studies to delineate metabolic pathways between mater- nal adiposity, insulin resistance, the different nutrients and neonatal 4 | DISCUSSION adiposity. The physiological pathways influencing neonatal adiposity origi- The main aim of the present study was to identify the effect of some nate from maternal insulin resistance, which is higher with increasing maternal metabolism on neonatal skinfolds at different times in preg- maternal BMI. Indeed, in the Healthy Start Study7 maternal insulin nancy in a sex-dependent manner. Results confirmed our hypotheses resistance in the first half of pregnancy was an independent predictor T A B L E 2 Multilevel regression coefficients of the association between maternal health profile components and child's sum of skinfolds (mm) by sex in three periods of gestation Boys Girls <20 weeks 24-28 weeks 35-37 weeks <20 weeks 24-28 weeks 35-37 weeks Maternal parameters β P β P β P β P β P β P Factor 1 1.091 .006 .130 .713 .445 .103 .536 .094 .339 .372 .347 .044 Fasting insulin and HOMA-IR Factor 2 .458 .163 .305 .256 .673 .009 .389 .228 .449 .215 .208 .521 1-h and 2-h insulin, and Stumvoll first and second phases Factor 3 .384 .362 −.241 .617 1.083 .022 .529 .280 1.387 .012 1.520 .020 1-h and 2-h glucose Factor 4 1.136 .004 1.114 .008 1.342 .008 .349 .196 .505 .100 .596 .152 Leptin, BMI and neck circumference Fasting glucose (mmol/L) 1.792 <.001 1.406 .011 2.085 .019 −.045 .968 2.475 .008 1.361 .035 Triglycerides (log) 1.428 .423 .235 .854 2.740 .005 2.005 .031 1.907 .119 1.395 .235 Fatty acids (mmol/L) 1.555 .152 .462 .787 1.179 .544 3.886 <.001 4.942 .011 −1.678 .203 Gestational weight gain (kg) .197 .033 −.003 .975 .059 .645 .021 .646 .125 .345 .010 .526 Note: Adjusted for intervention group, site of recruitment, maternal ethnicity, education, BMI (except when BMI was the exposure), age and smoking status, gestational age during pregnancy (weeks), gestational age at birth (weeks) and neonatal age at measurement (hours), and cluster structure (individuals nested in site of measurement). Besides the aforementioned adjustments, HOMA-index was also an adjustment when triglycerides and fatty acids were the exposures. P values are Bonferroni adjusted. Abbreviation: BMI, body mass index. 20476310, 2020, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijpo.12628 by Readcube (Labtiva Inc.), Wiley Online Library on [27/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License LIMA ET AL. 7 of 11 (A)2.0 Boys Girls (B) 1.4 Boys Girls Factor 2 - One-hour Insulin; Two-hour Insulin; Stumvoll 1st phase; Stumvoll 2nd phase Factor 1 - Fasting Insulin and HOMA-IR 1.2 1.5 1.0 1.09 0.8 1.0 0.67 0.6 β (95% CI) β (95% CI) 0.46 0.45 0.54 0.5 0.45 0.4 0.34 0.39 0.35 0.31 0.2 0.21 0.13 0.0 0.0 -0.2 -0.5 -0.4 -1.0 <20 weeks 24-28 weeks 35-37 weeks -0.6 <20 weeks 24-28 weeks 35-37 weeks (C) Boys Girls (D) Boys Girls 3.0 2.5 Factor 3 - One-hour Glucose; Two-hour Glucose 2.5 Factor 4 - Leptin; BMI; Neck circumference 2.0 2.0 1.5 1.39 1.52 1.5 1.34 β (95% CI) β (95% CI) 1.0 1.08 1.14 1.11 1.0 0.5 0.53 0.38 0.51 0.60 0.0 0.5 -0.24 0.35 -0.5 0.0 -1.0 -1.5 -0.5 <20 weeks 24-28 weeks 35-37 weeks <20 weeks 24-28 weeks 35-37 weeks F I G U R E 1 Multilevel regression coefficients of the association between (A) factor 1 (fasting insulin and HOMA-index); (B) factor 2 (1-hour insulin, 2-hour insulin, Stumvoll phase 1 and Stumvoll phase 2); (C) factor 3 (1-hour glucose and 2-hour glucose) and (D) factor 4 (leptin, BMI and neck circumference) and neonatal sum of skinfolds (mm) by sex in three periods of gestation. Adjusted intervention group, site of recruitment, gestational age during pregnancy, gestational age at birth, neonatal age at measurement, maternal ethnicity, maternal education, body mass index (BMI), except in the factor 4 since BMI was part of this factor, maternal age, smoking status and cluster structure (individuals nested in site of measurement) of neonatal adiposity. This is in principle in line with our findings of various populations,7,24-26 the role of fasting glucose for neonatal adi- insulin resistance (represented by factor 1) in early pregnancy playing posity in women with obesity is a novel finding to the best of our a role, but in our study, this was limited to boys only. Later in preg- knowledge. Maternal fasting glucose was a driver of fat accretion nancy, the positive association of insulin resistance with neonatal adi- throughout pregnancy in boys and mainly in later pregnancy in girls. posity was found in both boys and girls. The strong determining role The sex difference in early pregnancy might explain why the Healthy of early insulin resistance for neonatal adiposity is not without prece- Start Study7 only found an association of fasting glucose after dent and extends to the pre-pregnancy period, in which insulin resis- 20 weeks of gestation, but not before, with neonatal adiposity. The tance had the strongest association with neonatal fat mass, more so reasons for the sex-difference in the timing of the association of than insulin resistance in late pregnancy.23 However, neither of those fasting glucose with neonatal fat remain speculative. The glucose steal previous studies tested for sex differences in this association or, spe- phenomenon posits foetal hyperinsulinemia, the main driver of fat cifically, in pregnant women with obesity. Two studies that analyzed accretion, as the result of maternal hyperglycemia from early on.27 A 24,25 boys and girls separately found associations of insulin resistance sex-difference in the timing of the glucose steal may be one explana- late in pregnancy with measures of adiposity in girls, but not in boys, tion for our findings, but this remains to be studied. which is not fully in line with our findings. The different finding might Interestingly, independent of maternal insulin sensitivity, lipids in be explained by differences in maternal BMI or the participants' level the first half of the pregnancy period were associated with sum of of glucose tolerance, since those other studies were not limited to skinfolds in girls. In boys, only triglycerides at 35 to 37 weeks were women with obesity without GDM at baseline, as in our study related with neonatal skinfolds. This sex interaction in the association 24,25 sample. of lipids with neonatal skinfolds might explain the lack of association The pathway from insulin resistance to neonatal adiposity might in previous studies not distinguishing between sexes.7,19,20 To compli- 8 be through one of the nutrients glucose or lipids. Although found in cate matters further, the association of maternal lipids with neonatal 20476310, 2020, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijpo.12628 by Readcube (Labtiva Inc.), Wiley Online Library on [27/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 11 LIMA ET AL. Insulin resistance Boys skinfolds Glycaemia Lipids Higher Importance Medium Importance Weak or No Importance <20 weeks 24-28 weeks 35-37 weeks Pregnancy period Insulin resistance Girls skinfolds Glycaemia Lipids Higher Importance Medium Importance Weak or No Importance <20 weeks 24-28 weeks 35-37 weeks Pregnancy period FIGURE 2 Summarized visualization of the degree of importance of some maternal parameters in relation to neonatal sum of skinfolds by sex adiposity might also depend on maternal metabolic status and/or is a powerful method for establishing causal exposure-outcome rela- 7 weight. Crume et al observed that maternal triglycerides, in middle to tions. The present results call for using this method in a sex-specific late pregnancy, were associated with neonatal fat mass only in women manner, and at the same time distinguishing between women with with obesity before pregnancy. In a study including women with a different weight status. Moreover, neonatal fat percentage is the rele- normal glucose metabolism and those with gestational diabetes, vant offspring outcome more sensitive to in utero influences, and maternal lipids, triglycerides and free fatty acids in late pregnancy hence, more variable than birth weight. were positively associated with neonatal fat mass only in women with While analysis of the insulin secretory response (factor 2) did not gestational diabetes, but not in women with normal glycaemia.28 This result in a clear picture, glucose tolerance (factor 3) at the end of preg- complex interaction between maternal phenotype, neonatal sex and nancy was related to neonatal adiposity for boys and girls. Conflicting maternal lipid profile could be a reason why in a Mendelian randomi- results have been found on the association of glucose tolerance with zation approach no causal effect of maternal triglyceride concentra- neonatal adiposity. Most,7,25,30 but not all,23 studies reported positive 29 tions on offspring birth weight was found. Mendelian randomization associations. None of those assessed sex differences, and importantly, 20476310, 2020, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijpo.12628 by Readcube (Labtiva Inc.), Wiley Online Library on [27/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License LIMA ET AL. 9 of 11 only one study evaluated exclusively pregnant women with obesity. prevalence of pregnant women with obesity is alarming,44 studying Thus, more information is needed to draw any conclusions on the role the consequences of maternal obesity is of public health relevance. A of insulin secretory response or glucose tolerance for neonatal strength of our study is the measurements of maternal metabolic adiposity. parameters at three time points in pregnancy. Without this elaborate Maternal adiposity, mostly assessed by the pre-pregnancy BMI, approach, identification of time-dependent effects had not been has been related with neonatal adiposity in numerous possible. 4,5,25,31-33 34 studies, although one reported no association. We found DALI study was designed to evaluate the effects of different maternal adiposity to be associated with neonatal adiposity in boys interventions on preventing gestational diabetes in pregnant women throughout pregnancy, but no association was found in girls. with obesity. Although we adjusted the analyses for the various inter- Although, when analyzed individually, maternal BMI in the second half ventions, we cannot fully exclude a minor influence on the results. of pregnancy period was associated with the girls' adiposity. Different While more direct measures of neonatal adiposity by for example, air from many of the previously mentioned studies, we only had women displacement plethysmography, would have been preferred, we with obesity in our sample, which might have precluded finding strong recently reported an association of sum of skinfolds with cord blood associations with maternal adiposity. Reports on sex differences in leptin in this cohort,22 supporting the validity of the skinfold measures the association of maternal adiposity and neonatal adiposity are con- as proxy for neonatal adiposity. flicting: Some find associations only in boys,35 but other studies only in girls.36,37 Prior studies in pregnant women with diabetes have reported an interaction of foetal sex with a number of maternal vari- 5 | CONC LU SION ables in the prediction of large or small-for-gestational age new-borns but results are not comparable since the outcome variable was not Our results show time-dependent associations of maternal metabolic new-born adiposity and maternal variables did not include lipids or parameters with neonatal adiposity. Importantly, and a novel key insulin sensitivity.38 result, we demonstrate that this time-dependence varies between sexes. Thus, the study highlights the urgent need for inclusion of neo- natal sex in all analyses, not as confounder, but as major determinant 4.1 | Sex and time differences and modifying factor. This has been recommended previously.45,46 The present study can inform future studies to include larger sample Conceptually, male and female foetuses follow different growth strat- sizes, because of the sex differences, but also measurements of egies in utero.39,40 Mechanisms are not well understood, but male maternal metabolism at more than one time point during pregnancy. embryos have more rapid cell divisions compared to females,41 which could lead to a more rapid growth.39,40 Their higher growth rate might AC KNOW LEDG EME NT S explain why male foetuses are also more responsive to changes in The authors would like to thank all participants for their time on par- nutrient supply.39,40 In addition, the peak growth velocity of males ticipating in this study. The project described received funding from seems to be later in pregnancy compared to female foetuses.39 These the European Union seventh framework (FP7/2007-2013) under different growth strategies might result in differences in nutritional Grant Agreement no. 242187. In the Netherlands, additional funding needs, at different times in pregnancy. The results of our study pro- was provided by the Netherlands Organisation for Health Research vide strong evidence to support this concept. However, more system- and Development (ZonMw; grant 200310013). In Poland, additional atic assessments of time- and sex-dependent associations of maternal funding was obtained from Polish Ministry of Science (grants 2203/7, metabolism with neonatal adiposity are needed in future studies. PR/2011/2). In Denmark, additional funding was provided by Odense 42,43 Although foetal fat is mostly accumulated late in pregnancy, University Free Research Fund. In the United Kingdom, the DALI team our data highlight that also the early pregnancy period is important for acknowledges the support received from the NIHR Clinical Research neonatal adiposity. This finding is in line with other studies, showing Network: Eastern, especially the local diabetes clinical and research that maternal metabolism that led to gestational diabetes diagnosis teams based in Cambridge. In Spain, additional funding was provided later in pregnancy, had an influence on foetal abdominal circumfer- by CAIBER 1527-B-226. The funders had no role in any aspect of the ence already at 17 weeks of pregnancy, with a more pronounced study beyond funding. effect in males.9 Also maternal obesity was related to accelerated growth at 20 weeks of gestation,10 without sex differences studied. CONFLIC T OF INT ER E ST No conflict of interest was declared. 4.2 | Strengths and limitations AUTHOR CONTRIBU TIONS R.L. designed this study, conducted the statistical analysis, contributed The European representativeness of our study sample with trials sites to the interpretation of the results and drafted the manuscript. spread over Europe is a strength, but the restriction to women with G.D. and M.v.P. designed this study, contributed to the interpretation obesity can be seen as a limitation of our study. However, since the of the results and drafted the manuscript. All authors, except R.L., 20476310, 2020, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ijpo.12628 by Readcube (Labtiva Inc.), Wiley Online Library on [27/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 10 of 11 LIMA ET AL. made substantial contribution to the conception of the DALI study 15. Simmons D, Jelsma JGM, Galjaard S, et al. Results from a European and acquisition of data. All authors revised the manuscript and con- multicenter randomized trial of physical activity and/or healthy eating to reduce the risk of gestational diabetes mellitus: the DALI lifestyle tributed to the content. All authors approved the final manuscript as pilot. Diabetes Care. 2015;38(9):1650-1656. https://doi.org/10.2337/ submitted and agree to be accountable for all aspects of the work. dc15-0360. 16. Jelsma JGM, van Poppel MNM, Galjaard S, et al. DALI: vitamin D and ORCID lifestyle intervention for gestational diabetes mellitus (GDM) preven- tion: an European multicentre, randomised trial—study protocol. 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