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Supplementary material

Polyunsaturated fatty acid levels at birth and child-to-adult growth: results from

the MEFAB cohort

Nikos Stratakis, Marij Gielen, Katerina Margetaki, Roger Godschalk, Inge van der Wurff, Sven Rouschop, Abdalla Ibrahim, Eva Antoniou, Leda Chatzi, Renate de Groot, Maurice Zeegers

Table of Contents

Text A: Modelling of height and BMI trajectories.................................................................................2

Table A2. Distribution of observed and predicted sex-specific height and BMI values at specific time points............................................................................................................................................ 3

Table S1. Comparison of subject characteristics in MEFAB between those included and not included in the analysis............................................................................................................................4

Table S2. Distribution of length/height and body mass index measurements from 6 months till 23 years of age in MEFAB males and females included in the analysis..............5

Table S3. Correlation coefficients among height measurements from 6 months till 23 years of age in males and females from the MEFAB birth cohort.................................................6

Table S4. Correlation coefficients among body mass index measurements from 6 months till 23 years of age in males and females from the MEFAB birth cohort...................7

Table S5. Associations of secondary cord blood PUFAs of interest with height from 6 months till 23 years of age in males and females from the MEFAB birth cohort...................8

Table S6. Associations of secondary cord blood PUFAs of interest with BMI from 6 months till 23 years of age in males and females from the MEFAB birth cohort...................9

Table S7. Associations of cord blood PUFAs with height from 6 months till 23 years of age in males and females from the MEFAB birth cohort after further adjusting for gestational age................................................................................................................................................... 10

Table S8. Associations of cord blood phospholipid PUFAs with from 6 months till ΒΜΙ23 years of age in males and females from the MEFAB birth cohort after further adjusting for gestational age.......................................................................................................................11

Table S9. Associations of cord blood PUFAs with at 23 years of age in men and ΒΜΙwomen from the MEFAB birth cohort after further adjustment for fish oil supplementation, alcohol intake, and educational level assessed at the age of outcome assessment.......................................................................................................................................................... 12

Figure S1. Directed acyclic graph for the association of fatty acid status at birth with postnatal growth.............................................................................................................................................. 13


Text A: Modelling of height and BMI trajectories

Growth follows a complex non-linear pattern. This non-linearity can be incorporated into multi-level models (two levels: measurement occasion and individual) by including non-linear age functions to find the best-fitting average growth trajectory in the study population. Such models allow for individual variation in growth curves, and can easily handle unbalanced data with different numbers of repeated measures per child [1]. Moreover, these models allow for change in scale and variance of the growth measures over time [2]. We modelled height and BMI growth trajectories from birth to 23 years of age. As age must be strictly positive when using fractional polynomials, a constant of 0.001 was added to age. A series of models for height (in cm) and BMI (in kg/m2) were run in which age was raised to a large number of combinations of powers out of the following: -2, -1, -0.5, 0 (log function), 0.5, 1, 2, or 3 in order to find a function of age that best describes each trajectory [3]. All models were stratified by sex. We used the −2 log likelihood statistic and Bayesian Information Criterion (BIC) to select the model with the lowest deviance.The best-fitting fractional polynomial model for each growth measure was fitted with an unstructured variance-covariance matrix for the random effects [1], and had the following form for male and female participants:

BMIi , j=(β¿¿0+ui , 0+εi , j)+(β¿¿1+ui ,1)age i , j0.5+(β¿¿2)agei , j

0.5 log (agei , j )+(β¿¿3+ui ,2)age i , j3 ¿¿¿¿

Height i , j=(β ¿¿0+ui , 0+εi , j)+(β ¿¿1+ui ,1)agei , j+(β ¿¿2)agei , j0.5+(β ¿¿3+ui ,2)agei , j

3 ¿¿¿¿

where β0 β1, β2, β3 denote the fixed effects, ui , 0, ui , 1, ui , 2 denote the random effects, and ε i , j denotes the error term with i = 1,. . .n and j = 1,. . .ni (n: number of subjects; ni: number of measurements of individual i).

The tables A1 and A2 show that there were high levels of agreement between observed growth measurements and those predicted by the models.

Table A1. Agreement levels between observed and predicted measurements

Males FemalesHeight BMI Height BMI

rhocDifference Difference Difference Difference

Mean (SD) rhoc Mean (SD) rhoc Mean (SD) rhoc Mean (SD)0.99 0.00 (1.56) 0.94 0.00 (0.83) 0.99 0.00 (1.70) 0.95 0.00 (0.89)

rhoc, concordance correlation coefficient. Difference represents the average difference between observed and predicted values.

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Table A2. Distribution of observed and predicted sex-specific height and BMI values at specific time points

MEFABBoys Girls

Actual Predicted Actual PredictedMean (SD) Mean (SD) Mean (SD) Mean (SD)

Height (cm)6±2 months 67.6 (2.7) 67.9 (2.3) 65.3 (2.7) 66.0 (2.0)24±6 months 88.8 (3.6) 88.1 (2.9) 87.6 (3.7) 86.8 (2.8)48±6 months 105.5 (4.1) 106.0 (3.7) 103.9 (4.7) 104.4 (4.0)84±6 months 127.2 (5.0) 127.9 (5.3) 125.5 (5.8) 126.3 (5.8)144±12 months 154.0 (7.6) 153.9 (7.1) 154.8 (10.9) 153.9 (10.6)277±12 months 181.6 (7.2) 181.7 (6.9) 166.2 (8.1) 166.7 (8.1)

BMI (kg/m2)6±2 months 17.0 (1.3) 17.1 (0.7) 16.6 (1.3) 16.6 (0.8)24±6 months 16.3 (1.2) 16.4 (0.8) 16.1 (1.4) 16.2 (1.0)48±6 months 15.6 (1.2) 15.7 (0.9) 15.7 (1.4) 15.8 (1.2)84±6 months 15.4 (1.7) 15.6 (1.4) 15.6 (1.6) 15.8 (1.4)144±12 months 17.8 (2.5) 17.1 (1.2) 18.0 (2.2) 17.4 (2.1)277±12 months 23.0 (4.3) 23.2 (3.9) 22.4 (3.2) 22.6 (2.8)

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Table S1. Comparison of subject characteristics in MEFAB between those included and not included in the analysis Subjects not included

(n=953)Subjects included

(n=250)P for differenceMean (SD) or n (%) Mean (SD) or n (%)

Parental characteristicsMaternal age at birth (years) 29.1 (4.3) 30.2 (4.0) <0.001Maternal BMI at study entry (kg/m2) 24.2 (4.3) 23.5 (3.7) 0.02Gestational weight gain (kg) 11.7 (4.6) 11.1 (4.0) 0.08Maternal smoking in pregnancy (yes, %) 236 (26.3) 56 (22.4) 0.21Alcohol intake in pregnancy (yes, %) 29 (3.1) 12 (4.8) 0.19Parity (primiparous, %) 693 (76.2) 176 (70.4) 0.06Area-based socioeconomic status at birth (high, %)* 268 (38.4) 78 (35.1) 0.08

Child characteristicsSex (female, %) 423 (44.8) 113 (45.2) 0.91Birth weight (gr) 3272 (519) 3303 (479) 0.39Gestational age (weeks) 39.9 (1.7) 39.9 (1.6) 0.95Cord blood n-3 PUFA levels (wt %) 6.9 (1.6) 6.8 (1.6) 0.57Cord blood n-6 PUFA levels (wt %) 32.1 (1.7) 32.2 (1.7) 0.55

Values are means (SD) or absolute numbers (percentages). P values for difference were estimated using Student’s t test for continuous variables and Pearson's 2 test for categorical variables. PUFA, polyunsaturated fatty acid; wt %, weight percentage of total fatty acids χpresent in the chromatogram.* Area-based socio-economic status at birth was determined based on the postal code of the place of residence [4].

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Table S2. Distribution of length/height and body mass index measurements from 6 months till 23 years of age in MEFAB males (n=137) and females (n=113) included in the analysis

Height (cm) BMI (kg/m2)Males Females Males Females

n Mean (SD) n Mean (SD) n Mean (SD) n Mean (SD)Mean age (SD), years0.5 (0.7) 126 67.6 (2.6) 94 65.5 (3.0) 126 17.0 (1.3) 94 16.6 (1.3)2.0 (0.2) 124 88.7 (3.5) 100 87.2 (5.0) 123 16.3 (1.2) 99 16.3 (1.9)4.1 (0.3) 119 105.8 (4.6) 98 104.2 (5.1) 119 15.6 (1.2) 98 15.7 (1.4)7.3 (0.3) 137 127.2 (4.9) 113 126.1 (5.8) 137 15.5 (1.7) 113 15.8 (1.7)12.8 (1.1) 51 159.3 (10.5) 33 158.6 (9.4) 51 18.5 (2.5) 33 19.1 (2.4)23.8 (1.1) 45 182.2 (8.2) 59 167.0 (8.0) 45 23.2 (3.8) 59 23.3 (3.8)

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Table S3. Correlation coefficients among height measurements from 6 months till 23 years of age in males (n=137) and females (n=113) from the MEFAB birth cohort

Age 6 months 1 year 2 years 3 years 4 years 8 years 12 years 23 yearsMales

6 months 1.001 year 0.59 1.00

P-value <0.0012 years 0.39 0.56 1.00

P-value <0.001 <0.0013 years 0.50 0.65 0.73 1.00

P-value <0.001 <0.001 <0.0014 years 0.38 0.60 0.66 0.84 1.00

P-value <0.001 <0.001 <0.001 <0.0018 years 0.34 0.51 0.62 0.78 0.79 1.00

P-value <0.001 <0.001 <0.001 <0.001 <0.00112 years -0.02 0.18 0.27 0.42 0.28 0.68 1.00

P-value 0.91 0.25 0.08 0.005 0.06 <0.00123 years 0.31 0.26 0.56 0.75 0.74 0.79 0.52 1.00

P-value 0.05 0.10 <0.001 <0.001 <0.001 <0.001 0.01

Females6 months 1.001 year 0.67 1.00

P-value <0.0012 years 0.55 0.67 1.00

P-value <0.001 <0.0013 years 0.56 0.69 0.64 1.00

P-value <0.001 <0.001 <0.0014 years 0.54 0.66 0.59 0.81 1.00

P-value <0.001 <0.001 <0.001 <0.0018 years 0.50 0.56 0.54 0.82 0.78 1.00

P-value <0.001 <0.001 <0.001 <0.001 <0.00112 years 0.52 0.34 0.59 0.63 0.33 0.80 1.00

P-value 0.01 0.06 <0.001 <0.001 0.06 <0.00123 years 0.56 0.64 0.38 0.81 0.79 0.77 0.83 1.00

P-value <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

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Table S4. Correlation coefficients among body mass index measurements from 6 months till 23 years of age in males (n=137) and females (n=113) from the MEFAB birth cohort

Age 6 months 1 year 2 years 3 years 4 years 8 years 12 years 23 yearsMales

6 months 1.001 year 0.50 1.00

P-value <0.0012 years 0.34 0.62 1.00

P-value <0.001 <0.0013 years 0.25 0.57 0.67 1.00

P-value 0.01 <0.001 <0.0014 years 0.18 0.45 0.55 0.65 1.00

P-value 0.06 <0.001 <0.001 <0.0018 years 0.16 0.39 0.63 0.56 0.71 1.00

P-value 0.07 <0.001 <0.001 <0.001 <0.00112 years -0.01 0.06 0.42 0.36 0.49 0.81 1.00

P-value 0.96 0.71 0.005 0.02 <0.001 <0.00123 years -0.27 0.09 0.34 0.18 0.34 0.44 0.51 1.00

P-value 0.09 0.60 0.03 0.29 0.03 0.003 0.01

Females6 months 1.001 year 0.76 1.00

P-value <0.0012 years 0.65 0.68 1.00

P-value <0.001 <0.0013 years 0.65 0.74 0.38 1.00

P-value <0.001 <0.001 <0.0014 years 0.50 0.65 0.39 0.91 1.00

P-value <0.001 <0.001 <0.001 <0.0018 years 0.34 0.47 0.31 0.78 0.78 1.00

P-value <0.001 <0.001 <0.001 <0.001 <0.00112 years 0.19 0.30 0.42 0.51 0.55 0.70 1.00

P-value 0.34 0.10 0.02 0.007 0.001 <0.00123 years -0.03 0.14 0.04 0.38 0.45 0.66 0.50 1.00

P-value 0.82 0.33 0.79 0.007 0.002 <0.001 0.02

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Table S5. Associations of secondary cord blood PUFAs of interest with height from 6 months till 23 years of age in males (n=137) and females (n=113) from the MEFAB birth cohort

Height (cm) 6 months 2 years 4 years 7 years 12 years 23 years

(95% CI)β (95% CI)β (95% CI)β (95% CI)β (95% CI)β (95% CI)βMales

DPA n-3 0.56 (0.20, 0.92)** 0.30 (-0.14, 0.73) 0.23 (-0.35, 0.82) 0.30 (-0.55, 1.16) 0.55 (-0.69, 1.79) 0.77 (-0.97, 2.51)GLA n-6 -0.64 (-1.01, -0.26)** -0.64 (-1.10, -0.19)** -0.62 (-1.24, 0.01) -0.56 (-1.49, 0.37) -0.49 (-1.85, 0.88) -0.67 (-2.50, 1.16)DGLA n-6 0.04 (-0.33, 0.40) -0.04 (-0.47, 0.40) -0.26 (-0.85, 0.34) -0.62 (-1.49, 0.26) -1.05 (-2.35, 0.24) -0.03 (-2.07, 2.01)Osbond acid n-6 0.34 (-0.01, 0.69) 0.31 (-0.11, 0.72) 0.47 (-0.10, 1.04) 0.82 (-0.02, 1.66) 1.38 (0.14, 2.62)* 1.43 (-0.36, 3.23)

FemalesDPA n-3 0.22 (-0.16, 0.60) 0.00 (-0.51, 0.51) -0.14 (-0.86, 0.59) -0.22 (-1.29, 0.85) -0.14 (-1.68, 1.04) 1.00 (-0.84, 2.83)GLA n-6 -0.12 (-0.51, 0.27) -0.09 (-0.60, 0.43) 0.01 (-0.72, 0.74) 0.18 (-0.89, 1.25) 0.49 (-1.04, 2.03) 1.14 (-0.54, 2.83)DGLA n-6 -0.20 (-0.58, 0.19) 0.01 (-0.51, 0.52) 0.21 (-0.51, 0.94) 0.45 (-0.62, 1.51) 0.62 (-0.93, 2.17) -0.49 (-2.34, 1.36)Osbond acid n-6 0.17 (-0.23, 0.56) 0.30 (-0.23, 0.82) 0.38 (-0.35, 1.12) 0.45 (-0.63, 1.54) 0.51 (-1.06, 2.08) 0.56 (-1.18, 2.30)

coefficients and their 95% CIs were calculated using mixed effects linear regression models adjusted for child age terms (ageβ 0.5, age, age3), maternal age at birth, maternal BMI at study entry, gestational weight gain, maternal alcohol intake in pregnancy, maternal smoking in pregnancy, parity, parental education, breastfeeding status, and cross-products of each PUFA exposure with the child age terms. Effect estimates correspond to a standard deviation score (SDS) increase in PUFAs. DGLA, dihomo- -linolenic acid γ(C20:3n-6); DPA, docosapentaenoic acid (C22:5n-3); GLA, -Linolenic acid (C18:3n-6); Osbond acid, C22:5n-6; PUFA, polyunsaturated fatty acid.γ* p <0.05; ** p <0.01

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Table S6. Associations of secondary cord blood PUFAs of interest with BMI from 6 months till 23 years of age in males (n=137) and females (n=113) from the MEFAB birth cohort

BMI (kg/m2) 6 months 2 years 4 years 7 years 12 years 23 years


DPA n-3 -0.09 (-0.27, 0.08) -0.08 (-0.25, 0.09) -0.02 (-0.21, 0.18) 0.08 (-0.17, 0.33) 0.24 (-0.16, 0.64) 0.57 (-0.32, 1.46)GLA n-6 0.03 (-0.16, 0.22) 0.07 (-0.11, 0.25) 0.09 (-0.12, 0.29) 0.07 (-0.21, 0.35) -0.02 (-0.46, 0.42) -0.34 (-1.34, 0.65)DGLA n-6 0.02 (-0.15, 0.19) 0.07 (-0.09, 0.24) 0.16 (-0.03, 0.35) 0.25 (0.00, 0.51) 0.34 (-0.09, 0.76) 0.34 (-0.69, 1.37)Osbond acid n-6 -0.08 (-0.24, 0.09) 0.01 (-0.15, 0.17) 0.09 (-0.09, 0.28) 0.13 (-0.11, 0.38) 0.07 (-0.34, 0.48) -0.38 (-1.34, 0.58)

FemalesDPA n-3 0.04 (-0.17, 0.24) -0.03 (-0.24, 0.18) -0.08 (-0.32, 0.15) -0.13 (-0.41, 0.16) -0.14 (-0.53, 0.26) -0.03 (-0.87, 0.82)GLA n-6 0.11 (-0.10, 0.32) -0.02 (-0.23, 0.20) -0.11 (-0.35, 0.13) -0.21 (-0.49, 0.08) -0.32 (-0.71, 0.07) -0.49 (-1.30, 0.32)DGLA n-6 -0.04 (-0.25, 0.17) -0.03 (-0.25, 0.18) 0.05 (-0.19, 0.30) 0.19 (-0.11, 0.48) 0.36 (-0.04, 0.77) 0.61 (-0.24, 1.47)Osbond acid n-6 0.05 (-0.16, 0.26) 0.03 (-0.19, 0.24) 0.00 (-0.24, 0.24) -0.07 (-0.36, 0.23) -0.24 (-0.64, 0.16) -0.77 (-1.59, 0.05)

coefficients and their 95% CIs were calculated using mixed effects linear regression models adjusted for child age terms β (age0.5, age0.5log[age], age), maternal age at birth, maternal BMI at study entry, gestational weight gain, maternal alcohol intake in pregnancy, maternal smoking in pregnancy, parity, parental education, breastfeeding status, and cross-products of each PUFA exposure with the child age terms. Effect estimates correspond to a standard deviation score (SDS) increase in PUFAs. DGLA, dihomo- -linolenic acid (C20:3n-6); DPA, docosapentaenoic acid (C22:5n-3); GLA, -Linolenic acid (C18:3n-6); Osbond acid, C22:5n-6; PUFA, γ γpolyunsaturated fatty acid.

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Table S7. Associations of cord blood PUFAs with height from 6 months till 23 years of age in males (n=137) and females (n=113) from the MEFAB birth cohort after further adjusting for gestational age

Height (cm) 6 months 2 years 4 years 7 years 12 years 23 years


ALA -0.10 (-0.30, 0.10) -0.17 (-0.43, 0.08) -0.26 (-0.62, 0.10) -0.39 (-0.93, 0.16) -0.63 (-1.45, 0.19) -1.48 (-3.35, 0.39)EPA+DHA 0.05 (-0.35, 0.45) -0.16 (-0.65, 0.32) -0.15 (-0.79, 0.50) 0.05 (-0.88, 0.98) 0.40 (-0.93, 1.74) -0.04 (-1.97, 1.89)Total n-3 PUFAs 0.05 (-0.35, 0.45) -0.19 (-0.68, 0.29) -0.20 (-0.84, 0.44) -0.03 (-0.95, 0.90) 0.31 (-1.03, 1.64) -0.08 (-1.99, 1.82)LA 0.16 (-0.26, 0.58) 0.33 (-0.19, 0.85) 0.15 (-0.55, 0.86) -0.29 (-1.32, 0.74) -0.91 (-2.41, 0.60) 0.73 (-1.48, 2.95)AA 0.07 (-0.32, 0.45) 0.24 (-0.24, 0.72) 0.34 (-0.33, 1.00) 0.36 (-0.62, 1.35) 0.19 (-1.24, 1.63) -1.34 (-3.28, 0.60)Total n-6 PUFAs 0.23 (-0.12, 0.58) 0.45 (0.00, 0.90) 0.35 (-0.28, 0.97) -0.02 (-0.94, 0.91) -0.68 (-2.03, 0.67) -0.71 (-2.72, 1.30)Total n-3:n-6 ratio -0.01 (-0.41, 0.40) -0.28 (-0.77, 0.20) -0.28 (-0.93, 0.37) -0.06 (-0.99, 0.87) 0.36 (-0.98, 1.71) -0.01 (-1.96, 1.95)

FemalesALA -0.38 (-0.90, 0.14) -0.70 (-1.42, 0.01) -0.86 (-1.89, 0.16) -0.89 (-2.40, 0.62) -0.61 (-2.79, 1.57) 1.32 (-1.03, 3.67)EPA+DHA 0.15 (-0.25, 0.55) -0.09 (-0.63, 0.44) -0.34 (-1.09, 0.40) -0.63 (-1.72, 0.45) -0.89 (-2.45, 0.67) 0.04 (-1.82, 1.89)Total n-3 PUFAs 0.12 (-0.28, 0.52) -0.12 (-0.66, 0.41) -0.36 (-1.10, 0.38) -0.62 (-1.70, 0.45) -0.82 (-2.38, 0.73) 0.25 (-1.60, 2.09)LA -0.51 (-1.05, 0.02) -0.43 (-1.16, 0.30) -0.24 (-1.27, 0.79) 0.05 (-1.46, 1.57) 0.41 (-1.77, 2.59) -0.24 (-2.75, 2.27)AA -0.32 (-0.74, 0.10) -0.35 (-0.92, 0.23) -0.48 (-1.31, 0.34) -0.73 (-1.95, 0.49) -1.07 (-2.83, 0.70) -0.78 (-2.90, 1.34)Total n-6 PUFAs -0.60 (-0.99, -0.20)* -0.44 (-1.00, 0.12) -0.31 (-1.12, 0.49) -0.19 (-1.39, 1.00) -0.14 (-1.88, 1.60) -0.88 (-2.79, 1.03)Total n-3:n-6 ratio 0.23 (-0.17, 0.63) -0.01 (-0.55, 0.52) -0.24 (-0.99, 0.50) -0.49 (-1.58, 0.59) -0.67 (-2.23, 0.89) 0.46 (-1.40, 2.32)

coefficients and their 95% CIs were calculated using mixed effects linear regression models adjusted for child age terms (ageβ 0.5, age, age3), maternal age at birth, maternal BMI at study entry, gestational weight gain, maternal alcohol intake in pregnancy, maternal smoking in pregnancy, gestational age, parity, parental education, breastfeeding status, and cross-products of each PUFA exposure with the child age terms. Effect estimates correspond to a standard deviation score (SDS) increase in PUFAs and to a unit increase in the total n-3:n-6 ratio. AA, arachidonic acid (C20:4n-6); ALA, a-linolenic acid (C18:3n-3); DHA, docosahexaenoic acid (C22:6n-3); EPA, eicosapentaenoic acid (C20:5n-3); LA, linoleic acid (C18:2n-6); PUFA, polyunsaturated fatty acid; total n-3 (n-6) PUFAs, the sum of n-3 (n-6) PUFAs present in the chromatogram.* p <0.01

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Table S8. Associations of cord blood phospholipid PUFAs with from 6 months till 23 years of age in males (n=137) and females (n=113) from the MEFAB birth cohortΒΜΙ after further adjusting for gestational age

BMI (kg/m2) 6 months 2 years 4 years 7 years 12 years 23 years


ALA 0.02 (-0.09, 0.12) 0.03 (-0.07, 0.13) 0.04 (-0.08, 0.16) 0.02 (-0.14, 0.18) -0.03 (-0.34, 0.28) -0.24 (-1.11, 0.63)EPA+DHA -0.18 (-0.37, 0.02) -0.16 (-0.35, 0.03) -0.11 (-0.32, 0.11) -0.01 (-0.28, 0.27) 0.20 (-0.24, 0.63) 0.70 (-0.28, 1.67)Total n-3 PUFAs -0.17 (-0.37, 0.02) -0.16 (-0.35, 0.03) -0.10 (-0.32, 0.11) 0.00 (-0.28, 0.28) 0.20 (-0.23, 0.63) 0.69 (-0.28, 1.66)LA 0.18 (-0.02, 0.39) 0.19 (-0.01, 0.40) 0.15 (-0.08, 0.39) 0.09 (-0.21, 0.40) 0.02 (-0.48, 0.52) -0.06 (-1.22, 1.11)AA -0.05 (-0.23, 0.14) -0.11 (-0.30, 0.07) -0.19 (-0.41, 0.02) -0.25 (-0.54, 0.04) -0.23 (-0.69, 0.23) 0.10 (-0.95, 1.15)Total n-6 PUFAs 0.06 (-0.11, 0.24) 0.06 (-0.11, 0.24) 0.04 (-0.16, 0.25) 0.04 (-0.24, 0.31) 0.09 (-0.36, 0.53) 0.34 (-0.70, 1.39)Total n-3:n-6 ratio -0.17 (-0.37, 0.02) -0.16 (-0.35, 0.03) -0.10 (-0.32, 0.11) -0.01 (-0.29, 0.27) 0.17 (-0.27, 0.60) 0.57 (-0.41, 1.55)

FemalesALA -0.22 (-0.50, 0.06) -0.12 (-0.42, 0.18) -0.02 (-0.36, 0.32) 0.04 (-0.37, 0.45) 0.01 (-0.55, 0.57) -0.41 (-1.52, 0.69)EPA+DHA -0.17 (-0.38, 0.04) -0.18 (-0.40, 0.05) -0.18 (-0.43, 0.07) -0.17 (-0.47, 0.13) -0.13 (-0.55, 0.28) -0.01 (-0.90, 0.88)Total n-3 PUFAs -0.17 (-0.38, 0.04) -0.18 (-0.40, 0.04) -0.19 (-0.44, 0.06) -0.18 (-0.48, 0.12) -0.16 (-0.57, 0.26) -0.06 (-0.94, 0.83)LA 0.04 (-0.25, 0.33) 0.15 (-0.15, 0.45) 0.21 (-0.13, 0.56) 0.26 (-0.16, 0.67) 0.28 (-0.29, 0.85) 0.25 (-0.96, 1.45)AA -0.16 (-0.38, 0.07) -0.19 (-0.43, 0.04) -0.23 (-0.50, 0.04) -0.22 (-0.55, 0.12) -0.10 (-0.57, 0.37) 0.40 (-0.63, 1.43)Total n-6 PUFAs -0.15 (-0.37, 0.07) -0.12 (-0.35, 0.11) -0.07 (-0.34, 0.20) 0.02 (-0.31, 0.35) 0.19 (-0.26, 0.63) 0.58 (-0.33, 1.50)Total n-3:n-6 ratio -0.12 (-0.33, 0.10) -0.13 (-0.36, 0.09) -0.15 (-0.40, 0.10) -0.17 (-0.47, 0.13) -0.18 (-0.60, 0.23) -0.19 (-1.09, 0.71)

coefficients and their 95% CIs were calculated using mixed effects linear regression models adjusted for child age terms (ageβ 0.5, age0.5log[age], age), maternal age at birth, maternal BMI at study entry, gestational weight gain, maternal alcohol intake in pregnancy, maternal smoking in pregnancy, gestational age, parity, parental education, breastfeeding status, and cross-products of each PUFA exposure with the child age terms. Effect estimates correspond to a standard deviation score (SDS) increase in PUFAs and to a unit increase in the total n-3:n-6 ratio. AA, arachidonic acid (C20:4n-6); ALA, a-linolenic acid (C18:3n-3); DHA, docosahexaenoic acid (C22:6n-3); EPA, eicosapentaenoic acid (C20:5n-3); LA, linoleic acid (C18:2n-6); PUFA, polyunsaturated fatty acid; total n-3 (n-6) PUFAs, the sum of n-3 (n-6) PUFAs present in the chromatogram.

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Table S9. Associations of cord blood PUFAs with at 23 years of age inΒΜΙ men (n=81) and women (n=117) from the MEFAB birth cohort after further adjustment for fish oil supplementation, alcohol intake, and educational level assessed at the age of outcome assessment

BMI (kg/m2)Men Women

(95% CI)β (95% CI)βALA -0.54 (-1.61, 0.53) 0.02 (-0.64, 0.69)EPA+DHA -0.03 (-0.85, 0.78) 0.54 (-0.28, 1.37)Total n-3 PUFAs -0.10 (-0.90, 0.71) 0.52 (-0.30, 1.33)LA -0.09 (-1.07, 0.89) 0.58 (-0.45, 1.61)AA 0.33 (-0.47, 1.13) 0.18 (-0.67, 1.02)Total n-6 PUFAs -0.03 (-0.85, 0.79) 0.35 (-0.47, 1.16)Total n-3:n-6 ratio -0.06 (-0.85, 0.74) 0.39 (-0.42, 1.21)

coefficients and their 95% CIs were calculated using linear regression βmodels adjusted for maternal BMI at study entry, gestational weight gain, maternal smoking during pregnancy, maternal age at birth, parity, parental education, breastfeeding, age, fish oil supplementation, alcohol intake, and educational level. Effect estimates correspond to a standard deviation score (SDS) increase in PUFAs and to a unit increase in the total n-3:n-6 ratio. AA, arachidonic acid (C20:4n-6); ALA, a-linolenic acid (C18:3n-3); DHA, docosahexaenoic acid (C22:6n-3); EPA, eicosapentaenoic acid (C20:5n-3); LA, linoleic acid (C18:2n-6); PUFA, polyunsaturated fatty acid; total n-3 (n-6) PUFAs, the sum of n-3 (n-6) PUFAs present in the chromatogram.

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Figure S1. Directed acyclic graph for the association of fatty acid status at birth with postnatal growth.

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References

1. W. Johnson, N. Balakrishna, P.L. Griffiths, Modeling physical growth using mixed effects models, Am J Phys Anthropol 150 (2013) 58-67.2. L. Graversen, L.D. Howe, T.I. Sorensen, U. Sovio, L. Hohwu, K. Tilling, J. Laitinen, A. Taanila, A. Pouta, M.R. Jarvelin, C. Obel, Body mass index trajectories from 2 to 18 years - exploring differences between European cohorts, Pediatr Obes 12 (2017) 102-109.3. P. Royston, E.M. Wright, A method for estimating age-specific reference intervals (“normal ranges”) based on fractional polynomials and exponential transformation, J R Statist Soc 161 (1998) 79-101.4. J. Veldwijk, S. Scholtens, G. Hornstra, W.J. Bemelmans, Body mass index and cognitive ability of young children, Obes Facts 4 (2011) 264-269.

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