Advertisement

Cholesterol at ages 6, 12 and 24 months: Tracking and associations with diet and maternal cholesterol in the Infant Cholesterol Study

  • Linn K.L. Øyri
    Affiliations
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, PO Box 1046, Blindern, 0317, Oslo, Norway
    Search for articles by this author
  • Martin P. Bogsrud
    Affiliations
    Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital Ullevål, PO Box 4956, Nydalen, 0424, Oslo, Norway

    Norwegian National Advisory Unit on Familial Hypercholesterolemia, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital Aker, PO Box 4959, Nydalen, 0424, Oslo, Norway
    Search for articles by this author
  • Anne Lene Kristiansen
    Affiliations
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, PO Box 1046, Blindern, 0317, Oslo, Norway

    Faculty of Humanities, Sports and Educational Science, Department of Sports, Physical Education and Outdoor Studies, University of South-Eastern Norway, PO Box 235, 3603, Kongsberg, Norway
    Search for articles by this author
  • Jannicke B. Myhre
    Affiliations
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, PO Box 1046, Blindern, 0317, Oslo, Norway
    Search for articles by this author
  • Helene Astrup
    Affiliations
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, PO Box 1046, Blindern, 0317, Oslo, Norway

    National Centre for Suicide Research and Prevention, Institute of Clinical Medicine, University of Oslo, PO Box 1171, Blindern, 0318, Oslo, Norway
    Search for articles by this author
  • Kjetil Retterstøl
    Affiliations
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, PO Box 1046, Blindern, 0317, Oslo, Norway

    The Lipid Clinic, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital Aker, PO Box 4959, Nydalen, 0424, Oslo, Norway
    Search for articles by this author
  • Hilde K. Brekke
    Affiliations
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, PO Box 1046, Blindern, 0317, Oslo, Norway
    Search for articles by this author
  • Jeanine E. Roeters van Lennep
    Affiliations
    Department of Internal Medicine, Erasmus University Medical Center, Erasmus MC, Dr Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands
    Search for articles by this author
  • Lene F. Andersen
    Affiliations
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, PO Box 1046, Blindern, 0317, Oslo, Norway
    Search for articles by this author
  • Kirsten B. Holven
    Correspondence
    Corresponding author. P.O. box 1046, Blindern, 0317, Oslo, Norway.
    Affiliations
    Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, PO Box 1046, Blindern, 0317, Oslo, Norway

    Norwegian National Advisory Unit on Familial Hypercholesterolemia, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital Aker, PO Box 4959, Nydalen, 0424, Oslo, Norway
    Search for articles by this author
Open AccessPublished:May 05, 2021DOI:https://doi.org/10.1016/j.atherosclerosis.2021.04.017

      Highlights

      • Increased lifelong cholesterol (TC) exposure increases the risk of atherosclerosis.
      • TC showed a wide range in offspring aged 6, 12 and 24 months.
      • There was significant tracking of offspring TC from 6 to 12 months of age.
      • Maternal and offspring TC were positively associated.
      • Breastfeeding and TC were positively associated at age 6 and 12, but not 24 months.

      Abstract

      Background and aims

      There are indications for tracking of circulating total cholesterol concentration (TC) from childhood to later in life. An increased lifelong TC exposure increases the risk of developing atherosclerosis, however little is known about the determinants of TC early in life. We aimed to describe TC in Norwegian offspring aged 6, 12 and 24 months, and to explore if maternal TC, breastfeeding and offspring diet are associated with offspring TC.

      Methods

      In this cross-sectional study, mothers of offspring aged 6 (n = 629), 12 (n = 258) and 24 (n = 263) months completed a questionnaire of the offspring's diet and took home-based dried blood spot samples from themselves and their offspring. The mothers and offspring participating at age 12 months also participated at age 6 months of the offspring.

      Results

      Offspring TC showed a wide range in all three age groups. Twenty one percent of the offspring had TC ≥ 5.1 mmol/l. There was significant tracking of offspring TC from 6 to 12 months of age (r = 0.42, p < 0.001). Maternal and offspring TC was positively associated in all age groups (0.20 ≤ β ≤ 0.40, p < 0.001 for all). Breastfeeding was positively associated with offspring TC at ages 6 and 12 months (0.05 ≤ β ≤ 0.26, 0.001 ≤ p ≤ 0.03), but not at age 24 months.

      Conclusions

      The wide range in TC and probable tracking of TC from infancy to later in life highlights the importance of early identification of children with elevated TC who can benefit from preventive measures.

      Keywords

      1. Introduction

      Atherosclerosis is a progressive disease involving retention of lipids and an inflammatory response in the arterial wall [
      • Borén J.
      • Chapman M.J.
      • Krauss R.M.
      • Packard C.J.
      • Bentzon J.F.
      • Binder C.J.
      • et al.
      Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.
      ]. It may begin as early as in childhood [
      • Berenson G.S.
      • Srinivasan S.R.
      • Bao W.
      • Newman 3rd, W.P.
      • Tracy R.E.
      • Wattigney W.A.
      Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study.
      ,
      • Napoli C.
      • Glass C.K.
      • Witztum J.L.
      • Deutsch R.
      • D'Armiento F.P.
      • Palinski W.
      Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: fate of Early Lesions in Children (FELIC) study.
      ]. Both the circulating concentration of total cholesterol (TC) [
      • Peters S.A.
      • Singhateh Y.
      • Mackay D.
      • Huxley R.R.
      • Woodward M.
      Total cholesterol as a risk factor for coronary heart disease and stroke in women compared with men: a systematic review and meta-analysis.
      ] and low-density lipoprotein cholesterol [
      • Borén J.
      • Chapman M.J.
      • Krauss R.M.
      • Packard C.J.
      • Bentzon J.F.
      • Binder C.J.
      • et al.
      Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.
      ] are well-known risk factors for atherosclerosis. We have previously shown that TC is 1.4 mmol/l in newborns [
      • Øyri L.K.L.
      • Bogsrud M.P.
      • Christensen J.J.
      • Ulven S.M.
      • Brantsæter A.L.
      • Retterstøl K.
      • et al.
      Novel associations between parental and newborn cord blood metabolic profiles in the Norwegian Mother, Father and Child Cohort Study.
      ] and three times as high in infants around one year of age [
      • Oyri L.K.L.
      • Bogsrud M.P.
      • Kristiansen A.L.
      • Myhre J.B.
      • Retterstol K.
      • Brekke H.K.
      • et al.
      Infant cholesterol and glycated haemoglobin concentrations vary widely-Associations with breastfeeding, infant diet and maternal biomarkers.
      ]. Furthermore evidence for tracking of TC from childhood to adulthood has been observed in multiple studies [
      • Juhola J.
      • Magnussen C.G.
      • Viikari J.S.
      • Kahonen M.
      • Hutri-Kahonen N.
      • Jula A.
      • et al.
      Tracking of serum lipid levels, blood pressure, and body mass index from childhood to adulthood: the Cardiovascular Risk in Young Finns Study.
      ,
      • Webber L.S.
      • Srinivasan S.R.
      • Wattigney W.A.
      • Berenson G.S.
      Tracking of serum lipids and lipoproteins from childhood to adulthood. The Bogalusa Heart Study.
      ]. This suggests that infant TC can provide a glimpse into the future of an individual's lifelong cholesterol exposure [
      • Ference B.A.
      • Graham I.
      • Tokgozoglu L.
      • Catapano A.L.
      Impact of lipids on cardiovascular health: JACC health promotion series.
      ]. Thus, it is of public health relevance to first elucidate the determinants of TC in early life, and secondly to identify children who might benefit from preventive measures. Previous studies have shown positive associations between the concentration of maternal cholesterol before or in early pregnancy and offspring cholesterol in childhood or adulthood [
      • Daraki V.
      • Georgiou V.
      • Papavasiliou S.
      • Chalkiadaki G.
      • Karahaliou M.
      • Koinaki S.
      • et al.
      Metabolic profile in early pregnancy is associated with offspring adiposity at 4 years of age: the Rhea pregnancy cohort Crete, Greece.
      ,
      • Christensen J.J.
      • Retterstol K.
      • Godang K.
      • Roland M.C.
      • Qvigstad E.
      • Bollerslev J.
      • et al.
      LDL cholesterol in early pregnancy and offspring cardiovascular disease risk factors.
      ,
      • Mendelson M.M.
      • Lyass A.
      • O'Donnell C.J.
      • D'Agostino R.B.
      • Sr
      • Levy D.
      Association of maternal prepregnancy dyslipidemia with adult offspring dyslipidemia in excess of anthropometric, lifestyle, and genetic factors in the framingham heart study.
      ]. In adults, a diet consisting of a higher ratio of polyunsaturated fatty acids (PUFA) to saturated fatty acids (SFA) is associated with lower TC and is protective against cardiovascular disease (CVD) [
      • Mozaffarian D.
      • Micha R.
      • Wallace S.
      Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials.
      ]. There are some studies indicating that both a higher ratio of dietary PUFA to SFA and breastfeeding during infancy are associated with lower TC in adult life [
      • Laitinen T.T.
      • Nuotio J.
      • Juonala M.
      • Niinikoski H.
      • Rovio S.
      • Viikari J.S.A.
      • et al.
      Success in achieving the targets of the 20-year infancy-onset dietary intervention: association with insulin sensitivity and serum lipids.
      ,
      • Owen C.G.
      • Whincup P.H.
      • Odoki K.
      • Gilg J.A.
      • Cook D.G.
      Infant feeding and blood cholesterol: a study in adolescents and a systematic review.
      ]. In the present Infant Cholesterol Study, we aimed to describe TC in Norwegian offspring aged 6, 12 and 24 months, and to explore if maternal TC, breastfeeding and offspring diet are associated with offspring TC.

      2. Patients and methods

      The Infant Cholesterol Study had both a prospective cohort design (“population 1”) and a cross-sectional design (“population 2”). In “population 1”, 2099 mothers of offspring aged 6 months participating in the nationwide dietary survey among infants in Norway “Spedkost 3” [
      • Myhre J.B.
      • Andersen L.F.
      • Kristiansen A.L.
      "Spedkost 3. Landsomfattende undersøkelse av kostholdet blant spedbarn i Norge, 6 måneder" [Spedkost 3. Nationwide dietary survey among infants in Norway, age 6 months].
      ] were invited to participate in the Infant Cholesterol Study (Supplementary Fig. 1). The mothers who provided blood samples in “population 1” were invited to participate for a second time six months later when the offspring were 12 months of age. In “population 2”, 1349 mothers of offspring participating in the nationwide dietary survey among 2-year-olds in Norway “Småbarnskost 3” [
      • Astrup H.
      • Myhre J.B.
      • Andersen L.F.
      • Kristiansen A.L.
      Småbarnskost 3. Landsomfattende Undersøkelse Av Kostholdet Blant 2-åringer I Norge". [Småbarnskost 3. Nationwide Dietary Survey Among 2-Year-Olds in Norway]. Rapport 2020.
      ] were invited to participate in the Infant Cholesterol Study. In the “Spedkost 3” and the “Småbarnskost 3” dietary studies, a nationwide selection was drawn from the Norwegian National Registry. Only offspring of mothers born in Norway, Sweden, or Denmark were invited. Recruitment and data collection in the two studies were performed at the University of Oslo, Norway, from September 2018 to June 2019.

      2.1 Dietary questionnaires

      Offspring diet during the preceding 14 days was assessed by semi-quantitative food frequency questionnaires (FFQs) containing 44–50 questions. The FFQs and the results of the “Spedkost 3” and the “Småbarnskost 3” dietary studies have been published previously [
      • Myhre J.B.
      • Andersen L.F.
      • Kristiansen A.L.
      "Spedkost 3. Landsomfattende undersøkelse av kostholdet blant spedbarn i Norge, 6 måneder" [Spedkost 3. Nationwide dietary survey among infants in Norway, age 6 months].
      ,
      • Astrup H.
      • Myhre J.B.
      • Andersen L.F.
      • Kristiansen A.L.
      Småbarnskost 3. Landsomfattende Undersøkelse Av Kostholdet Blant 2-åringer I Norge". [Småbarnskost 3. Nationwide Dietary Survey Among 2-Year-Olds in Norway]. Rapport 2020.
      ,
      • Paulsen M.M.
      • Myhre J.B.
      • Andersen L.F.
      • Kristiansen A.L.
      "Spedkost 3. Landsomfattende undersøkelse av kostholdet blant spedbarn i Norge, 12 måneder" [Spedkost 3. Nationwide dietary survey among infants in Norway, age 12 months].
      ]. The FFQ for offspring aged 6 months contained questions regarding breastfeeding frequency, formula feeding and supplementary feeding. Absolute intake of nutrients could not be calculated as portion sizes were mostly not assessed. The FFQs for offspring aged 12 and 24 months included use of approximately 200 foods, and were used to calculate average daily intake of energy and nutrients, using the “Kostberegningssystem” (KBS) version 7.3 and the food database AE18 developed at the University of Oslo, Norway. At age 12 and 24 months, breastfeeding status (yes/no), but not the quantity of breastmilk given, was assessed and could therefore not be included in the calculation of energy and nutrients. All three FFQs included questions about the offspring's sex, body weight and length, and maternal age, education and smoking status. Breastfeeding frequency (at 6 months of age) and status (yes/no, at 12 months of age) were also assessed at the time of blood sampling in “population 1”, and these data are used in the presentation of the breastfeeding results at 6 and 12 months of age.

      2.2 Dried blood spot samples

      As part of the Infant Cholesterol Study (Supplementary Fig. 1), the subjects received a “dried blood spot” (DBS) kit by mail, allowing home-based blood sampling from the fingertips of both mother and offspring at ages 6, 12 and 24 months. Capillary blood drops were placed on DBS cards, which were dried at room temperature for 2–4 h, placed in a sealed aluminum bag and returned by mail. The DBS cards were frozen (−80°) within 10 days after blood sampling. A maximum of three months passed between completion of the FFQ and blood sampling. TC (primary endpoint) was measured at an accredited medical laboratory (Vitas AS, Oslo, Norway). We have previously found a strong correlation between TC from venous blood samples analyzed by the DBS method and routine laboratory methods at accredited medical laboratories (r = 0.94, p < 0.001) [
      • Oyri L.K.L.
      • Bogsrud M.P.
      • Kristiansen A.L.
      • Myhre J.B.
      • Retterstol K.
      • Brekke H.K.
      • et al.
      Infant cholesterol and glycated haemoglobin concentrations vary widely-Associations with breastfeeding, infant diet and maternal biomarkers.
      ]. The American College of Cardiology and American Heart Association has defined TC ≥ 5.1 mmol/l as abnormal among children [
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • Beam C.
      • Birtcher K.K.
      • Blumenthal R.S.
      • et al.
      AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines.
      ].

      2.3 Ethics

      The Infant Cholesterol Study was approved by the Regional Committees for Medical and Health Research Ethics southeast region of Norway (no. 2017/980), and mothers and fathers with parental responsibility provided written informed consent. The “Spedkost 3” and “Småbarnskost 3” dietary studies were approved by the Norwegian Centre for Research Data (ref. 58855 and 60537), and parents provided written informed consent. All the studies were conducted according to the principles of the Declaration of Helsinki.

      2.4 Statistics

      Data are presented as mean (standard deviation [SD]) for continuous variables and frequency (%) for categorical variables. Kernel density plots are used to visualize the distribution of TC in the three age groups. Change in TC was calculated in offspring and mothers participating at both age 6 and 12 months. Tracking of TC from 6 to 12 months of age was assessed by Pearson's correlation coefficient. Univariable and multivariable linear regression analyses with offspring TC as outcome were stratified by age groups. Maternal TC, maternal higher education (yes vs no), offspring sex (girls vs boys) and offspring weight/length were included in the regression analyses in all age groups. Additionally, breastfeeding (frequency/day) was included in the model with offspring aged 6 months, and breastfeeding status (yes vs no) was included in the models with offspring aged 12 months and 24 months. The exposures were selected based on previous knowledge and directed acyclic graphs. Univariable linear regression analyses were also used to explore the association between offspring dietary intake of fat and TC. The residuals were examined to check model assumptions. Regression results are presented in a table as univariable and multivariable regression (β) coefficients with 95% confidence intervals (CIs) and p-values. A selection of the correlation and multivariable regression results are presented in scatter plots and box plots. p-values <0.05 were considered significant. The statistical analyses were performed in R version 3.6.1 with RStudio IDE version 1.3.1073 [
      • R Core Team
      R: A Language and Environment for Statistical Computing.
      ].

      3. Results

      3.1 Characteristics

      Of the 2099 invited mothers in “population 1”, 629 (30%) mother-offspring pairs provided blood samples at age 6 months of the offspring, and of these 258 (41%) provided blood samples again at age 12 months of the offspring. Of the 1349 invited mothers in “population 2”, 263 (19%) mother-offspring pairs provided blood samples at age 24 months of the offspring (Supplementary Figure 1). The blood samples were drawn mean (SD, min-max) 42 (21, 4–98) days after the FFQs were completed. In “population 1” and “population 2”, the mean age of the mothers was 32 and 33 years, and 77% and 78% had higher education, respectively (Table 1). One percent of the mothers were regular/daily smokers. BMI was mean 24.9 kg/m2 in the mothers in “population 2”. Age, education and smoking prevalence were similar as in mothers participating only in the dietary studies (“Spedkost 3” and “Småbarnskost 3”) (Supplementary Table 1). The offspring's weight and length for age were between the 50th and the 75th percentiles [
      ].
      Table 1Subject characteristics.
      Population 1Population 2
      6 months12 months24 months
      OffspringMothersOffspringMothersOffspringMothers
      n629629258258263263
      Age, years, mean (SD)32 (4)32 (4)33 (5)
      Female, n (%)273 (43.4)110 (42.6)128 (48.7)
      Body weight, kg, mean (SD)8.0 (1.0)9.9 (1.1)12.8 (1.4)70.2 (13.3)
      Length, cm, mean (SD)68.0 (2.5)76.1 (2.8)87.8 (3.7)168.0 (5.9)
      Weight/Length, kg/m, mean (SD)11.8 (1.2)12.9 (1.2)14.6 (1.3)
      Breastfeedinga, n (%)489 (77.7)100 (38.8)26 (10.0)
      Higher education, n (%)481 (76.5)207 (80.2)205 (77.9)
      Regular smokers, n (%)8 (1.3)3 (1.2)3 (1.1)
      TC, mmol/la, mean (SD)4.2 (0.9)4.9 (0.9)4.4 (0.8)4.9 (0.9)4.9 (0.9)5.0 (0.9)
      SD, standard deviation; TC, circulating concentration of total cholesterol. aTC was measured mean 42 days after completion of the dietary questionnaire. In population 1, breastfeeding status was measured simultaneously to TC.

      3.2 Maternal and offspring TC

      The mean (SD) offspring TC was 4.2 (0.9), 4.4 (0.8), and 4.9 (0.9) mmol/l at age 6, 12 and 24 months, respectively (Table 1). There were wide ranges in offspring TC in all three age groups (min-max: 1.7–8.4 mmol/l) (Fig. 1). TC was ≥5.1 mmol/l in 186 (21%) offspring and >6 mmol/l in 40 (5%) offspring. The distribution of maternal TC was similar in the three age groups (Supplementary Figure 2). Changes in TC from 6 to 12 months of age ranged between −2.3 and 3.3 mmol/l in the offspring and −3.4 to 3.4 mmol/l in the mothers (n = 258). Offspring and maternal TC showed significant tracking from 6 to 12 months of age (r = 0.42 and r = 0.51, p < 0.001 for both, Fig. 2 and Supplementary Figure 3). Maternal and offspring TC were positively associated in all age groups (multivariable 0.20 ≤ β ≤ 0.40, p < 0.001 for all), after adjustment for maternal education, offspring sex, offspring body weight/length, and breastfeeding (Fig. 3 and Supplementary Table 2). Changes in maternal and offspring TC from 6 to 12 months of age were also positively associated (multivariable β = 0.27, p < 0.001, data not shown).
      Fig. 1
      Fig. 1Density plot of distributions of offspring TC at ages 6, 12 and 24 months.
      TC, circulating concentration of total cholesterol.
      Fig. 2
      Fig. 2Tracking of offspring TC from age 6–12 months (n = 258).
      Results are presented as Pearson's correlation coefficient (r) and p-value. TC, circulating concentration of total cholesterol.
      Fig. 3
      Fig. 3Associations between maternal and offspring TC.
      Results are presented as multivariable regression coefficients (β) and p-values, after adjustment for maternal education, offspring sex, offspring body weight/length, and breastfeeding. TC, circulating concentration of total cholesterol.

      3.3 Breastfeeding and offspring TC

      The prevalence of any (partial or exclusive) breastfeeding was 78% at age 6 months, 39% at age 12 months and 10% at age 24 months (Table 1). The prevalence of exclusive breastfeeding was 9% at age 6 months (data not shown). Breastfeeding frequency at age 6 months and offspring TC were positively associated (multivariable β = 0.05, p < 0.001, Fig. 4A and Supplementary Table 2). Offspring who were breastfed at age 12 months had significantly higher TC than offspring who were not breastfed at this age (multivariable β = 0.26, p = 0.03, Fig. 4B and Supplementary Table 2). There was no significant difference in TC between offspring who were breastfed compared to not breastfed at age 24 months (multivariable β = −0.12, p = 0.50, Fig. 4C and Supplementary Table 2).
      Fig. 4
      Fig. 4Associations between breastfeeding and offspring TC at ages 6 (A), 12 (B) and 24 (C) months.
      Results are presented as multivariable regression coefficients (β) and p-values, after adjustment for maternal TC, maternal education, offspring sex, and offspring body weight/length. TC, circulating concentration of total cholesterol.

      3.4 Offspring diet and TC

      Dietary intake of macronutrients was calculated at ages 12 months and 24 months (Supplementary Figure 4). The mean (SD) intake of energy was 4.5 (1.5) MJ at age 12 months and 5.4 (1.5) MJ at age 24 months. At ages 12 and 24 months, 113 (44%) and 225 (86%) got ≥ 10% of energy from SFA in the diet. We found no significant associations between offspring dietary intake of SFA, monounsaturated fatty acids, PUFA or cholesterol and TC at age 12 months and 24 months (univariable 0.11 ≤ p ≤ 0.91, Supplementary Table 2). The results were similar when excluding infants who were breastfed (data not shown). Thus, dietary intake of fat was not included in the multivariable analyses.

      4. Discussion

      We found a positive association between maternal and offspring TC in all age groups, and between breastfeeding and TC in offspring aged 6 and 12 months, but not in offspring aged 24 months. Offspring TC showed a wide range, and we found significant tracking of TC from 6 to 12 months of age. The current study, together with our previous work [
      • Øyri L.K.L.
      • Bogsrud M.P.
      • Christensen J.J.
      • Ulven S.M.
      • Brantsæter A.L.
      • Retterstøl K.
      • et al.
      Novel associations between parental and newborn cord blood metabolic profiles in the Norwegian Mother, Father and Child Cohort Study.
      ], indicates large inter-individual differences in the cholesterol exposure during the first two years of life.
      TC increases with age and the largest increase in TC through life occurs before adulthood [
      • Ference B.A.
      • Graham I.
      • Tokgozoglu L.
      • Catapano A.L.
      Impact of lipids on cardiovascular health: JACC health promotion series.
      ]. Mean offspring TC observed in the present study is a bit higher than German paediatric references [
      • Dathan-Stumpf A.
      • Vogel M.
      • Hiemisch A.
      • Thiery J.
      • Burkhardt R.
      • Kratzsch J.
      • et al.
      Pediatric reference data of serum lipids and prevalence of dyslipidemia: results from a population-based cohort in Germany.
      ]. Mean maternal TC is similar to TC measured in average Norwegian women between 30 and 39 years [
      ]. As many as 21% of the offspring in the current study had abnormal TC [
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • Beam C.
      • Birtcher K.K.
      • Blumenthal R.S.
      • et al.
      AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines.
      ]. Large inter-individual differences in TC appear to be present from infancy throughout life [
      • Dathan-Stumpf A.
      • Vogel M.
      • Hiemisch A.
      • Thiery J.
      • Burkhardt R.
      • Kratzsch J.
      • et al.
      Pediatric reference data of serum lipids and prevalence of dyslipidemia: results from a population-based cohort in Germany.
      ,
      • Balder J.W.
      • de Vries J.K.
      • Nolte I.M.
      • Lansberg P.J.
      • Kuivenhoven J.A.
      • Kamphuisen P.W.
      Lipid and lipoprotein reference values from 133,450 Dutch Lifelines participants: age- and gender-specific baseline lipid values and percentiles.
      ,
      • Balder J.W.
      • Lansberg P.J.
      • Hof M.H.
      • Wiegman A.
      • Hutten B.A.
      • Kuivenhoven J.A.
      Pediatric lipid reference values in the general population: the Dutch lifelines cohort study.
      ]. Our finding of tracking of TC during infancy is important as others have shown tracking of TC from infancy to childhood [
      • Ohlund I.
      • Hernell O.
      • Hornell A.
      • Lind T.
      Serum lipid and apolipoprotein levels in 4-year-old children are associated with parental levels and track over time.
      ] and from childhood to adulthood [
      • Juhola J.
      • Magnussen C.G.
      • Viikari J.S.
      • Kahonen M.
      • Hutri-Kahonen N.
      • Jula A.
      • et al.
      Tracking of serum lipid levels, blood pressure, and body mass index from childhood to adulthood: the Cardiovascular Risk in Young Finns Study.
      ,
      • Webber L.S.
      • Srinivasan S.R.
      • Wattigney W.A.
      • Berenson G.S.
      Tracking of serum lipids and lipoproteins from childhood to adulthood. The Bogalusa Heart Study.
      ], thus affecting the lifelong cholesterol exposure [
      • Ference B.A.
      • Graham I.
      • Tokgozoglu L.
      • Catapano A.L.
      Impact of lipids on cardiovascular health: JACC health promotion series.
      ]. Furthermore, atherosclerosis begins already in childhood [
      • Berenson G.S.
      • Srinivasan S.R.
      • Bao W.
      • Newman 3rd, W.P.
      • Tracy R.E.
      • Wattigney W.A.
      Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study.
      ,
      • Napoli C.
      • Glass C.K.
      • Witztum J.L.
      • Deutsch R.
      • D'Armiento F.P.
      • Palinski W.
      Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: fate of Early Lesions in Children (FELIC) study.
      ], and a 1 mmol/l reduction in low-density lipoprotein cholesterol over 30–40 years may half the risk of developing atherosclerotic CVD [
      • Ference B.A.
      • Ginsberg H.N.
      • Graham I.
      • Ray K.K.
      • Packard C.J.
      • Bruckert E.
      • et al.
      Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
      ]. Hence, early identification of children with elevated TC is important to facilitate preventive measures such as dietary adjustments.
      In agreement with the current study, a relation between maternal and offspring TC has previously been found in infancy [
      • Routi T.
      • Ronnemaa T.
      • Jokinen E.
      • Viikari J.
      • Niinikoski H.
      • Leino A.
      • et al.
      Correlation of toddlers' serum lipoprotein(a) concentration with parental values and grandparents' coronary heart disease: the STRIP baby study.
      ], childhood [
      • Daraki V.
      • Georgiou V.
      • Papavasiliou S.
      • Chalkiadaki G.
      • Karahaliou M.
      • Koinaki S.
      • et al.
      Metabolic profile in early pregnancy is associated with offspring adiposity at 4 years of age: the Rhea pregnancy cohort Crete, Greece.
      ,
      • Christensen J.J.
      • Retterstol K.
      • Godang K.
      • Roland M.C.
      • Qvigstad E.
      • Bollerslev J.
      • et al.
      LDL cholesterol in early pregnancy and offspring cardiovascular disease risk factors.
      ,
      • Ohlund I.
      • Hernell O.
      • Hornell A.
      • Lind T.
      Serum lipid and apolipoprotein levels in 4-year-old children are associated with parental levels and track over time.
      ] and adult life [
      • Mendelson M.M.
      • Lyass A.
      • O'Donnell C.J.
      • D'Agostino R.B.
      • Sr
      • Levy D.
      Association of maternal prepregnancy dyslipidemia with adult offspring dyslipidemia in excess of anthropometric, lifestyle, and genetic factors in the framingham heart study.
      ]. In the present study, a 20% increase in maternal TC corresponded to about 5–10% increase in offspring TC in all age groups. The mother-offspring TC associations can be attributed to genetics [
      • Tikkanen E.
      • Tuovinen T.
      • Widén E.
      • Lehtimäki T.
      • Viikari J.
      • Kähönen M.
      • et al.
      Association of known loci with lipid levels among children and prediction of dyslipidemia in adults.
      ], epigenetics [
      • Ordovas J.M.
      • Smith C.E.
      Epigenetics and cardiovascular disease.
      ], and shared lifestyle. The results were similar before and after adjustment for breastfeeding. About 20% of the variance in TC in young children can be explained by known single nucleotide polymorphisms [
      • Tikkanen E.
      • Tuovinen T.
      • Widén E.
      • Lehtimäki T.
      • Viikari J.
      • Kähönen M.
      • et al.
      Association of known loci with lipid levels among children and prediction of dyslipidemia in adults.
      ]. Moreover, maternal TC might alter the epigenetic pattern of the offspring, affecting their susceptibility to hypercholesterolemia and CVD [
      • Ordovas J.M.
      • Smith C.E.
      Epigenetics and cardiovascular disease.
      ]. A cholesterol-lowering diet during pregnancy has been shown to lower maternal TC [
      • Khoury J.
      • Henriksen T.
      • Christophersen B.
      • Tonstad S.
      Effect of a cholesterol-lowering diet on maternal, cord, and neonatal lipids, and pregnancy outcome: a randomized clinical trial.
      ]. Thus, identifying and treating women with gestational hypercholesterolemia might provide short- and long term benefits for both mother and offspring. However, there is no consensus regarding the definition of gestational hypercholesterolemia as TC naturally rises during pregnancy [
      • Wang Q.
      • Wurtz P.
      • Auro K.
      • Makinen V.P.
      • Kangas A.J.
      • Soininen P.
      • et al.
      Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence.
      ]. TC > 7.2 mmol/l has been suggested as a cut-off for gestational supraphysiological hypercholesterolemia [
      • Cantin C.
      • Fuenzalida B.
      • Leiva A.
      Maternal hypercholesterolemia during pregnancy: potential modulation of cholesterol transport through the human placenta and lipoprotein profile in maternal and neonatal circulation.
      ].
      Offspring who were breastfed had 0.3 mmol/l higher TC than offspring who were not breastfed at age 12 months in the current study. Others have found similar associations in infancy [
      • Owen C.G.
      • Whincup P.H.
      • Odoki K.
      • Gilg J.A.
      • Cook D.G.
      Infant feeding and blood cholesterol: a study in adolescents and a systematic review.
      ,
      • Harit D.
      • Faridi M.M.
      • Aggarwal A.
      • Sharma S.B.
      Lipid profile of term infants on exclusive breastfeeding and mixed feeding: a comparative study.
      ], but inverse associations in adult life [
      • Owen C.G.
      • Whincup P.H.
      • Odoki K.
      • Gilg J.A.
      • Cook D.G.
      Infant feeding and blood cholesterol: a study in adolescents and a systematic review.
      ]. The TC increasing effect has been suggested to persist only as long as breastfeeding is continued [
      • Jooste P.L.
      • Rossouw L.J.
      • Steenkamp H.J.
      • Rossouw J.E.
      • Swanepoel A.S.
      • Charlton D.O.
      Effect of breast feeding on the plasma cholesterol and growth of infants.
      ]. We found no difference in TC between offspring aged 24 months who were breastfed compared to not breastfed, however, few offspring aged 24 months were breastfed. The lipid quality and quantity in breastmilk vary greatly, however, infant formulas commonly used in Norway are within the normal ranges of breastmilk [
      • Delplanque B.
      • Gibson R.
      • Koletzko B.
      • Lapillonne A.
      • Strandvik B.
      Lipid quality in infant nutrition: current knowledge and future opportunities.
      ,
      • Matvaretabellen
      Mattilsynet.
      ]. The most likely reason for the increased TC associated with breastfeeding is that breastmilk contains more cholesterol than infant formulas [
      • Owen C.G.
      • Whincup P.H.
      • Odoki K.
      • Gilg J.A.
      • Cook D.G.
      Infant feeding and blood cholesterol: a study in adolescents and a systematic review.
      ,
      • Delplanque B.
      • Gibson R.
      • Koletzko B.
      • Lapillonne A.
      • Strandvik B.
      Lipid quality in infant nutrition: current knowledge and future opportunities.
      ]. Maternal dietary fat quality has a market effect on the lipid composition of breastmilk [
      • Delplanque B.
      • Gibson R.
      • Koletzko B.
      • Lapillonne A.
      • Strandvik B.
      Lipid quality in infant nutrition: current knowledge and future opportunities.
      ,
      • Innis S.M.
      Impact of maternal diet on human milk composition and neurological development of infants.
      ], but whether this affects offspring TC should be further explored. Nutritional programming has been suggested as an explanatory mechanism for the beneficial effect of breastfeeding on adult TC [
      • Owen C.G.
      • Whincup P.H.
      • Odoki K.
      • Gilg J.A.
      • Cook D.G.
      Infant feeding and blood cholesterol: a study in adolescents and a systematic review.
      ]. However, there is insufficient evidence regarding the association between breastfeeding and later CVD [
      • Hörnell A.
      • Lagström H.
      • Lande B.
      • Thorsdottir I.
      Breastfeeding, introduction of other foods and effects on health: a systematic literature review for the 5th Nordic Nutrition Recommendations.
      ].
      In the present study, a large proportion of the offspring got more SFA from the diet than recommended [
      • Nordic Council of M.
      Nordic Nutrition Recommendations 2012.
      ]. However, intake of SFA and PUFA showed a small range which might explain the non-significant associations with offspring TC. A higher ratio of dietary PUFA to SFA from 6 to 12 months of age has previously been associated with lower TC at 12 months of age in a cohort study [
      • Ohlund I.
      • Hornell A.
      • Lind T.
      • Hernell O.
      Dietary fat in infancy should be more focused on quality than on quantity.
      ] and a randomized controlled trial [
      • Lapinleimu H.
      • Viikari J.
      • Jokinen E.
      • Salo P.
      • Routi T.
      • Leino A.
      • et al.
      Prospective randomised trial in 1062 infants of diet low in saturated fat and cholesterol.
      ]. In the latter study, the cholesterol-lowering effect persisted until 20 years of age [
      • Laitinen T.T.
      • Nuotio J.
      • Juonala M.
      • Niinikoski H.
      • Rovio S.
      • Viikari J.S.A.
      • et al.
      Success in achieving the targets of the 20-year infancy-onset dietary intervention: association with insulin sensitivity and serum lipids.
      ]. Replacing dietary SFA with PUFA is safe and recommended in children from two years of age throughout life [
      • Mozaffarian D.
      • Micha R.
      • Wallace S.
      Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials.
      ,
      • Grundy S.M.
      • Stone N.J.
      • Bailey A.L.
      • Beam C.
      • Birtcher K.K.
      • Blumenthal R.S.
      • et al.
      AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines.
      ,
      • Gidding S.S.
      • Dennison B.A.
      • Birch L.L.
      • Daniels S.R.
      • Gillman M.W.
      • Lichtenstein A.H.
      • et al.
      Dietary recommendations for children and adolescents: a guide for practitioners: consensus statement from the American Heart Association.
      ].
      Limitations of our study are that one cannot exclude recall bias in the completion of the FFQs. The FFQ for offspring at 12 months of age has been shown to overestimate energy intake and absolute nutrient intake in a validation study [
      • Andersen L.F.
      • Lande B.
      • Arsky G.H.
      • Trygg K.
      Validation of a semi-quantitative food-frequency questionnaire used among 12-month-old Norwegian infants.
      ], thus we chose to include intake of nutrients in percentage of energy in the regression analyses. Of the sample drawn from the Norwegian National Registry, the dietary studies included 73% at 6 months [
      • Myhre J.B.
      • Andersen L.F.
      • Kristiansen A.L.
      "Spedkost 3. Landsomfattende undersøkelse av kostholdet blant spedbarn i Norge, 6 måneder" [Spedkost 3. Nationwide dietary survey among infants in Norway, age 6 months].
      ], 66% at 12 months [
      • Paulsen M.M.
      • Myhre J.B.
      • Andersen L.F.
      • Kristiansen A.L.
      "Spedkost 3. Landsomfattende undersøkelse av kostholdet blant spedbarn i Norge, 12 måneder" [Spedkost 3. Nationwide dietary survey among infants in Norway, age 12 months].
      ] and 47% at 24 months of age [
      • Astrup H.
      • Myhre J.B.
      • Andersen L.F.
      • Kristiansen A.L.
      Småbarnskost 3. Landsomfattende Undersøkelse Av Kostholdet Blant 2-åringer I Norge". [Småbarnskost 3. Nationwide Dietary Survey Among 2-Year-Olds in Norway]. Rapport 2020.
      ], while the Infant Cholesterol Study only included 21% at 6 months, 9% at 12 months and 9% at 24 months of age, making selection bias possible. The mothers in the current study gave birth at a similar age as average Norwegian women [
      ], but a higher proportion had higher education (77–80% vs 60%) [
      ] and fewer were smokers (1% vs 5%) [
      ] compared to average Norwegian women in their age range. Thus, our selection is probably healthier than the average. Other epidemiological studies also find higher participation rate among non-smoking subjects with higher education [
      • Galea S.
      • Tracy M.
      Participation rates in epidemiologic studies.
      ]. As the study focused on cholesterol, conditions such as hypercholesterolemia or heart disease in the family may also have motivated participation. Due to the high prevalence of breastfeeding, intake of nutrients was not assessed in offspring aged 6 months. The logistics of the study did not allow simultaneous completion of the FFQ and blood sampling. Thus, the offspring's anthropometrics and diet may have changed between completion of the FFQ and blood sampling. Strengths in the study are the use of simple, resource effective and non-invasive techniques to collect both dietary data and TC from a large number of subjects. The current study adds novel information about TC in Norwegian infants and toddlers and how it is related to breastfeeding, diet and maternal TC.

      4.1 Conclusions

      In the current study we found a positive association between maternal and offspring TC in all age groups, and between breastfeeding and TC in offspring aged 6 and 12 months, but not in offspring aged 24 months. Thus, maternal TC and breastfeeding are probable determinants of offspring TC in early life. The wide ranges in TC and probable tracking of TC from infancy to later in life, highlight the importance of early identification of children with elevated TC who can benefit from preventive measures. Further studies should explore if a dietary intervention early in life may lower the lifelong cholesterol exposure and incidence of premature CVD. Moreover, routine measurement of TC during childhood at least once should be considered.

      Financial support

      The study was supported by the University of Oslo , the National Advisory Unit on Familial Hypercholesterolemia , Oslo University Hospital , the Throne Holst Foundation for Nutrition Research , the Blix Foundation for the Promotion of Medical Research , Eckbos Legate, and the Freia Corporation Medical Fund, Norway . The external funders had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

      Author contributions

      Conceived and designed the study: LKLØ, ALK, MPB, KBH. Collected the data: LKLØ, MPB, ALK, JBM, HA, LFA, KBH. Performed the analyses: LKLØ. Drafted the paper: LKLØ, MPB, KBH. All authors (LKLØ, MPB, ALK, JBM, HA, KR, HKB, JRVL, LFA, KBH) contributed to the interpretation of the data and critically reviewed the paper. LKLØ, MPB, and KBH hold primary responsibility for the content.

      Declaration of competing interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: During the past five years, MPB reports grants and personal fees from Amgen, grants and personal fees from Sanofi, personal fees from MSD, personal fees from Boehringer Ingelheim, grants and personal fees from Mills AS, and grants from Kaneka, none of which are related to the content of this manuscript. KR reports personal fees from Amgen, personal fees from Mills AS, personal fees from The Norwegian Medical Association, personal fees from The Norwegian Directorate of Health, personal fees from Sanofi, personal fees from Takeda, personal fees from Chiesi, personal fees from Bayer, and personal fees from MSD, none of which are related to the content of this manuscript. JRVL has received research grants from Amryt, which are not related to the content of this manuscript. KBH has received research grants or honoraria from Mills AS, Tine SA, Olympic Seafood, Amgen, Sanofi, and Pronova, none of which are related to the content of this manuscript. LKLØ, ALK, JBM, HA, HKB, and LFA declare no conflicts of interest.

      Acknowledgements

      The authors would like to acknowledge all participants for their contribution.

      Appendix A. Supplementary data

      The following is the supplementary data to this article:

      References

        • Borén J.
        • Chapman M.J.
        • Krauss R.M.
        • Packard C.J.
        • Bentzon J.F.
        • Binder C.J.
        • et al.
        Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.
        Eur. Heart J. 2020; 41: 2313-2330
        • Berenson G.S.
        • Srinivasan S.R.
        • Bao W.
        • Newman 3rd, W.P.
        • Tracy R.E.
        • Wattigney W.A.
        Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study.
        N. Engl. J. Med. 1998; 338: 1650-1656
        • Napoli C.
        • Glass C.K.
        • Witztum J.L.
        • Deutsch R.
        • D'Armiento F.P.
        • Palinski W.
        Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: fate of Early Lesions in Children (FELIC) study.
        Lancet (London, England). 1999; 354: 1234-1241
        • Peters S.A.
        • Singhateh Y.
        • Mackay D.
        • Huxley R.R.
        • Woodward M.
        Total cholesterol as a risk factor for coronary heart disease and stroke in women compared with men: a systematic review and meta-analysis.
        Atherosclerosis. 2016; 248: 123-131
        • Øyri L.K.L.
        • Bogsrud M.P.
        • Christensen J.J.
        • Ulven S.M.
        • Brantsæter A.L.
        • Retterstøl K.
        • et al.
        Novel associations between parental and newborn cord blood metabolic profiles in the Norwegian Mother, Father and Child Cohort Study.
        BMC Med. 2021; 19: 91
        • Oyri L.K.L.
        • Bogsrud M.P.
        • Kristiansen A.L.
        • Myhre J.B.
        • Retterstol K.
        • Brekke H.K.
        • et al.
        Infant cholesterol and glycated haemoglobin concentrations vary widely-Associations with breastfeeding, infant diet and maternal biomarkers.
        Acta Paediatr. 2019; (00): 1-7
        • Juhola J.
        • Magnussen C.G.
        • Viikari J.S.
        • Kahonen M.
        • Hutri-Kahonen N.
        • Jula A.
        • et al.
        Tracking of serum lipid levels, blood pressure, and body mass index from childhood to adulthood: the Cardiovascular Risk in Young Finns Study.
        J. Pediatr. 2011; 159: 584-590
        • Webber L.S.
        • Srinivasan S.R.
        • Wattigney W.A.
        • Berenson G.S.
        Tracking of serum lipids and lipoproteins from childhood to adulthood. The Bogalusa Heart Study.
        Am. J. Epidemiol. 1991; 133: 884-899
        • Ference B.A.
        • Graham I.
        • Tokgozoglu L.
        • Catapano A.L.
        Impact of lipids on cardiovascular health: JACC health promotion series.
        J. Am. Coll. Cardiol. 2018; 72: 1141-1156
        • Daraki V.
        • Georgiou V.
        • Papavasiliou S.
        • Chalkiadaki G.
        • Karahaliou M.
        • Koinaki S.
        • et al.
        Metabolic profile in early pregnancy is associated with offspring adiposity at 4 years of age: the Rhea pregnancy cohort Crete, Greece.
        PloS One. 2015; 10e0126327
        • Christensen J.J.
        • Retterstol K.
        • Godang K.
        • Roland M.C.
        • Qvigstad E.
        • Bollerslev J.
        • et al.
        LDL cholesterol in early pregnancy and offspring cardiovascular disease risk factors.
        J. Clin. Lipidol. 2016; 10 (e7): 1369-1378
        • Mendelson M.M.
        • Lyass A.
        • O'Donnell C.J.
        • D'Agostino R.B.
        • Sr
        • Levy D.
        Association of maternal prepregnancy dyslipidemia with adult offspring dyslipidemia in excess of anthropometric, lifestyle, and genetic factors in the framingham heart study.
        JAMA Cardiol. 2016; 1: 26-35
        • Mozaffarian D.
        • Micha R.
        • Wallace S.
        Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials.
        PLoS Med. 2010; 7e1000252
        • Laitinen T.T.
        • Nuotio J.
        • Juonala M.
        • Niinikoski H.
        • Rovio S.
        • Viikari J.S.A.
        • et al.
        Success in achieving the targets of the 20-year infancy-onset dietary intervention: association with insulin sensitivity and serum lipids.
        Diabetes Care. 2018; 41: 2236-2244
        • Owen C.G.
        • Whincup P.H.
        • Odoki K.
        • Gilg J.A.
        • Cook D.G.
        Infant feeding and blood cholesterol: a study in adolescents and a systematic review.
        Pediatrics. 2002; 110: 597-608
        • Myhre J.B.
        • Andersen L.F.
        • Kristiansen A.L.
        "Spedkost 3. Landsomfattende undersøkelse av kostholdet blant spedbarn i Norge, 6 måneder" [Spedkost 3. Nationwide dietary survey among infants in Norway, age 6 months].
        Rapport. 2020; (Oslo: Folkehelseinstituttet og Universitetet i Oslo): 2020
        • Astrup H.
        • Myhre J.B.
        • Andersen L.F.
        • Kristiansen A.L.
        Småbarnskost 3. Landsomfattende Undersøkelse Av Kostholdet Blant 2-åringer I Norge". [Småbarnskost 3. Nationwide Dietary Survey Among 2-Year-Olds in Norway]. Rapport 2020.
        Folkehelseinstituttet og Universitetet i Oslo, Oslo2020
        • Paulsen M.M.
        • Myhre J.B.
        • Andersen L.F.
        • Kristiansen A.L.
        "Spedkost 3. Landsomfattende undersøkelse av kostholdet blant spedbarn i Norge, 12 måneder" [Spedkost 3. Nationwide dietary survey among infants in Norway, age 12 months].
        Rapport. 2020; (Oslo: Folkehelseinstituttet og Universitetet i Oslo, 2020)
        • Grundy S.M.
        • Stone N.J.
        • Bailey A.L.
        • Beam C.
        • Birtcher K.K.
        • Blumenthal R.S.
        • et al.
        AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines.
        Circulation. 2018; 139 (2019): e1082-e1143
        • R Core Team
        R: A Language and Environment for Statistical Computing.
        R Foundation for Statistical Computing, Vienna, Austria2019 ([Available from:)
      1. Child Growth Standards: World Health Organization. 2021 ([Available from:)
        • Dathan-Stumpf A.
        • Vogel M.
        • Hiemisch A.
        • Thiery J.
        • Burkhardt R.
        • Kratzsch J.
        • et al.
        Pediatric reference data of serum lipids and prevalence of dyslipidemia: results from a population-based cohort in Germany.
        Clin. Biochem. 2016; 49: 740-749
      2. Indicators for Non-communicable Diseases. Total Cholesterol Level (Indicator 17). Norwegian Institute of Public Health, 2021 ([Available from: https://www.fhi.no/en/op/Indicators-for-NCD/cholesterol/kolesterolniva-indikator-17/)
        • Balder J.W.
        • de Vries J.K.
        • Nolte I.M.
        • Lansberg P.J.
        • Kuivenhoven J.A.
        • Kamphuisen P.W.
        Lipid and lipoprotein reference values from 133,450 Dutch Lifelines participants: age- and gender-specific baseline lipid values and percentiles.
        J. Clin. Lipidol. 2017; 11 (e6): 1055-1064
        • Balder J.W.
        • Lansberg P.J.
        • Hof M.H.
        • Wiegman A.
        • Hutten B.A.
        • Kuivenhoven J.A.
        Pediatric lipid reference values in the general population: the Dutch lifelines cohort study.
        J. Clin. Lipidol. 2018; 12: 1208-1216
        • Ohlund I.
        • Hernell O.
        • Hornell A.
        • Lind T.
        Serum lipid and apolipoprotein levels in 4-year-old children are associated with parental levels and track over time.
        Eur. J. Clin. Nutr. 2011; 65: 463-469
        • Ference B.A.
        • Ginsberg H.N.
        • Graham I.
        • Ray K.K.
        • Packard C.J.
        • Bruckert E.
        • et al.
        Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
        Eur. Heart J. 2017;
        • Routi T.
        • Ronnemaa T.
        • Jokinen E.
        • Viikari J.
        • Niinikoski H.
        • Leino A.
        • et al.
        Correlation of toddlers' serum lipoprotein(a) concentration with parental values and grandparents' coronary heart disease: the STRIP baby study.
        Acta paediatrica (Oslo, Norway. 1992; 85 (1996): 407-412
        • Tikkanen E.
        • Tuovinen T.
        • Widén E.
        • Lehtimäki T.
        • Viikari J.
        • Kähönen M.
        • et al.
        Association of known loci with lipid levels among children and prediction of dyslipidemia in adults.
        Circ Cardiovasc Genet. 2011; 4: 673-680
        • Ordovas J.M.
        • Smith C.E.
        Epigenetics and cardiovascular disease.
        Nat. Rev. Cardiol. 2010; 7: 510-519
        • Khoury J.
        • Henriksen T.
        • Christophersen B.
        • Tonstad S.
        Effect of a cholesterol-lowering diet on maternal, cord, and neonatal lipids, and pregnancy outcome: a randomized clinical trial.
        Am. J. Obstet. Gynecol. 2005; 193: 1292-1301
        • Wang Q.
        • Wurtz P.
        • Auro K.
        • Makinen V.P.
        • Kangas A.J.
        • Soininen P.
        • et al.
        Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence.
        BMC Med. 2016; 14: 205
        • Cantin C.
        • Fuenzalida B.
        • Leiva A.
        Maternal hypercholesterolemia during pregnancy: potential modulation of cholesterol transport through the human placenta and lipoprotein profile in maternal and neonatal circulation.
        Placenta. 2020; 94: 26-33
        • Harit D.
        • Faridi M.M.
        • Aggarwal A.
        • Sharma S.B.
        Lipid profile of term infants on exclusive breastfeeding and mixed feeding: a comparative study.
        Eur. J. Clin. Nutr. 2008; 62: 203-209
        • Jooste P.L.
        • Rossouw L.J.
        • Steenkamp H.J.
        • Rossouw J.E.
        • Swanepoel A.S.
        • Charlton D.O.
        Effect of breast feeding on the plasma cholesterol and growth of infants.
        J. Pediatr. Gastroenterol. Nutr. 1991; 13: 139-142
        • Delplanque B.
        • Gibson R.
        • Koletzko B.
        • Lapillonne A.
        • Strandvik B.
        Lipid quality in infant nutrition: current knowledge and future opportunities.
        J. Pediatr. Gastroenterol. Nutr. 2015; 61: 8-17
        • Matvaretabellen
        Mattilsynet.
        ([cited 16.10]. Available from:)
        • Innis S.M.
        Impact of maternal diet on human milk composition and neurological development of infants.
        Am. J. Clin. Nutr. 2014; 99 (734s-41s.)
        • Hörnell A.
        • Lagström H.
        • Lande B.
        • Thorsdottir I.
        Breastfeeding, introduction of other foods and effects on health: a systematic literature review for the 5th Nordic Nutrition Recommendations.
        Food Nutr. Res. 2013; 57
        • Nordic Council of M.
        Nordic Nutrition Recommendations 2012.
        Nordic Council of Ministers, 2014
        • Ohlund I.
        • Hornell A.
        • Lind T.
        • Hernell O.
        Dietary fat in infancy should be more focused on quality than on quantity.
        Eur. J. Clin. Nutr. 2008; 62: 1058-1064
        • Lapinleimu H.
        • Viikari J.
        • Jokinen E.
        • Salo P.
        • Routi T.
        • Leino A.
        • et al.
        Prospective randomised trial in 1062 infants of diet low in saturated fat and cholesterol.
        Lancet (London, England). 1995; 345: 471-476
        • Gidding S.S.
        • Dennison B.A.
        • Birch L.L.
        • Daniels S.R.
        • Gillman M.W.
        • Lichtenstein A.H.
        • et al.
        Dietary recommendations for children and adolescents: a guide for practitioners: consensus statement from the American Heart Association.
        Circulation. 2005; 112: 2061-2075
        • Andersen L.F.
        • Lande B.
        • Arsky G.H.
        • Trygg K.
        Validation of a semi-quantitative food-frequency questionnaire used among 12-month-old Norwegian infants.
        Eur. J. Clin. Nutr. 2003; 57: 881-888
      3. Mean Age of Parents at All Birth, by Contents and Year (05530): Statistics Norway. 2019 ([Available from:)
      4. Educational Attainment of the Population: Statistics Norway. 2020 ([Available from:)
      5. Percentage Daily Smokers and Occasional Smokers, by Sex and Age (05307): Statistics Norway. 2020 ([Available from: https://www.ssb.no/statbank/table/05307/)
        • Galea S.
        • Tracy M.
        Participation rates in epidemiologic studies.
        Ann. Epidemiol. 2007; 17: 643-653