Human milk fatty acid profile across lactational stages after term and preterm delivery: A pooled data analysis

Prostaglandins, Leukotrienes and Essential Fatty Acids xxx (xxxx) xxxx

Contents lists available at ScienceDirect

Prostaglandins, Leukotrienes and Essential Fatty Acids journal homepage: www.elsevier.com/locate/plefa

Human milk fatty acid profile across lactational stages after term and preterm delivery: A pooled data analysis L.M. Florisa, B. Stahla,b, , M. Abrahamse-Berkevelda, I.C. Tellera ⁎

a b

Danone Nutricia Research, Utrecht, 3584 CT, the Netherlands Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, the Netherlands

ARTICLE INFO

ABSTRACT

Keywords: Human milk Fatty acids Term Preterm Lactational stages Pooled data

Background: Lipids in human milk (HM) provide the majority of energy for developing infants, as well as crucial essential fatty acids (FA). The FA composition of HM is highly variable and influenced by multiple factors. We sought to increase understanding of the variation in HMFA profiles and their development over the course of lactation, and after term and preterm delivery, using a pooled data analysis. Objective: To review the literature and perform a pooled data analysis to qualitatively describe an extensive FA profile (36 FAs) in term and preterm colostrum, transitional - and mature milk up to 60 days postpartum. Design: A Medline search was conducted for HMFA profile data following term or preterm delivery. The search was confined to English language papers published between January 1980 and August 2018. Studies reporting original data, extensive FA profiles in HM from healthy mothers were included. Weighted least squares (WLS) means were calculated from the pooled data using random or fixed effect models. Results: Our pooled data analysis included data from 55 studies worldwide, for a total of 4374 term milk samples and 1017 preterm milk samples, providing WLS means for 36 FAs. Patterns in both term and preterm milk were apparent throughout lactation for some FAs: The most abundant FAs (palmitic, linoleic and oleic acid) remained stable over time, whereas several long-chain polyunsaturated FAs (including ARA and DHA) seemed to decrease and short- and medium-chain FAs increased over time. Conclusions: High heterogeneity between individual studies was observed for the reported levels of some FAs, whereas other FAs were remarkably consistent between studies. Our pooled data suggests that specific FA categories fluctuate according to distinct patterns over the course of lactation; many of these patterns are comparable between term and preterm milk.

1. Introduction Early life is a critical period for the growth and development of the infant's organs and tissues [1, 2]. Nutrition plays a key role in this period of rapid development, i.e. the programming of long-term health determines an individuals’ resilience to the development of communicable and non-communicable diseases in later life [3–5]. Human milk (HM) is the optimal source of nutrition for any infant and it is recommended to be the sole source of nutrition for the first six months of life and continued up to 2 years of life [6]. Lipids are a substantial part of HM, providing around 50% of the energy to the infant, as well as essential fatty acids (FA) and fat-soluble

vitamins [7]. The HMFA profile is diverse with over 200 FA types in varying isoforms and concentrations [8]. FAs are integral parts of cell membranes, can act as signalling molecules, modulators of immune response, and contribute to a favourable microenvironment for the gastrointestinal microbiota [9]. Best investigated are long-chain polyunsaturated FAs (LCPUFA) and their metabolites which regulate pain signalling pathways, inflammation, thrombosis, and vasoconstriction [10]. The dietary intake of certain LCPUFAs has been related to an improved neurocognitive development and growth in infants, especially in preterm infants who have little reserves of body fat and are at risk for neurocognitive impairment [11, 12]. However, for many HMFAs, the contribution to physiological function and development of

Abbreviations: ALA, α-Linolenic acid (C18:3 n−3); ARA, Arachidonic acid (C20:4 n−6); DGLA, Dihomo-gamma-linolenic acid (C20:3 n−6); DPA, Docosapentaenoic acid (C22:5 n−3); EFSA, European Food Safety Authority; FA, Fatty acid; GLA, Gamma-linolenic acid (C18:3 n−6); HM, Human milk; LA, Linoleic acid (C18:2 n−6); LCPUFA, Long-chain polyunsaturated fatty acids; MCFA, Medium-chain fatty acids; PP, Postpartum; SCFA, Short-chain fatty acids; WLS, Weighted least squares (means) ⁎ Corresponding author at: Danone Nutricia Research, PO box 80141, 3508 TC Utrecht, the Netherlands. E-mail address: [email protected] (B. Stahl). https://doi.org/10.1016/j.plefa.2019.102023 Received 19 June 2019; Received in revised form 18 September 2019; Accepted 15 October 2019 0952-3278/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

Please cite this article as: L.M. Floris, et al., Prostaglandins, Leukotrienes and Essential Fatty Acids, https://doi.org/10.1016/j.plefa.2019.102023

Prostaglandins, Leukotrienes and Essential Fatty Acids xxx (xxxx) xxxx

L.M. Floris, et al.

the infant is unknown. HM composition is variable, which is driven by many factors, including the duration of a feed, climate, ethnicity, stage of lactation, and maternal diet and lifestyle [7, 13–17]. Although it is not firmly established whether HM composition differs by gestational age [18], deviations for docosahexaenoic acid (DHA; C22:6 n−3), as an example, have been observed in preterm compared to term HM [19]. Whether FA composition varies with lactational stages, as shown for other nutrients, is controversial with some [20–23] but not all [24] publications demonstrating changes over time. A number of individual studies has investigated HMFA composition at specific stages or in particular populations [25–30]. Although pooled data analyses exist for selected HMFAs [19, 31], macronutrients [32] and amino acids [33], a consolidated HMFA profile based on multiple worldwide studies and reflective of term and preterm milk over the course of lactation is not available yet. Such a consolidation is useful as reference composition, e.g. for comparison of individual study outcomes. With our current pooled data analysis, we generated an extensive and qualitative overview of the 36 predominant FAs in term and preterm HM in three lactational stages up to 60 days applying sophisticated statistical models. 2. Materials and methods

short-chain FAs (SCFA) with a chain length of < C6, medium-chain FAs (MCFA) in the range of C6–C12 and long-chain FAs ≥ C18 and/or (ii) based on saturation status, possibly in combination with chain length, such as saturated FAs (SFA) which are FAs without double-bond, monounsaturated FAs (MUFA) with one double-bond, polyunsaturated FAs (PUFA) with more than one double bond. Data extraction was limited to ≤60 days PP. Data from intervention or milk fortification studies were extracted for (non-fortified) baseline samples and/or those from a control group that did not receive an intervention nor were provided a placebo that could affect the HMFA profile. If it was not clear which FA derivate was reported (e.g. identified as “18:1" only and lacking positioning of the double-bond) and the double-bond could have multiple locations, then data were excluded from analysis. When the number of mothers but not the number of samples were reported, one milk sample per mother was assumed. If multiple samples within one lactational stage were collected for one study, the means and SD for each FA were pooled per lactational stage before further analysis as described in detail in the Supplementary material and according to Higgins et al. [41]. If studies presented their (non-normally distributed) data as difference between min-max of IQR instead of the actual min and max values defining the IQR, data were not extracted since they could not be standardized according to our methods as described.

2.1. Literature search, inclusion and exclusion criteria

2.3. Data standardization

In August 2018, a Medline search was conducted to obtain publications in English more recent than 1980 comprising term and/or preterm HMFA analyses. The time limit was applied since HMFA composition has changed substantially in the last 40 years, possibly due to changes in the food chain and maternal dietary habits [34, 35]. Additional inclusion criteria were: Healthy mothers, presence of a 24 h milk sample or a single sample and when data of at least 12 HMFAs were reported in g/100 g FA (% of total FAs). Data should be presented as mean or median, and standard error of the mean (SEM), standard deviation (SD), range, 95% confidence interval (CI) and/or interquartile range (IQR; min - max), Exclusion criteria were: Donor HM because of its additional processing, milk sample collection later than 60 days postpartum (PP), usage of packed gas chromatography columns in FA analytical methodology as it could overestimate DHA and ARA values [31], unidentified type or lactational stage, pooled samples from multiple mothers or lactational stages, mismatch of lactational stage definition (>2 days), insufficient sample size (n = 1), maternal dietary restriction studies, or non-original data or reviews. We chose not to exclude by timing of sampling within one breastfeeding session as the FA profile in foremilk and hindmilk has been shown to be comparable, despite total fat content being higher in the hindmilk [36, 37].

When data was reported as mean ± SEM, mean (95% CI) or as median (IQR), we standardized to the same units (mean ± SD) for further analysis according to Hozo et al. [42] and as described in further detail in the Supplementary material. 2.4. Statistical analyses Data analyses were performed using the statistical software RStudio (version 1.1.383, 2009–17) [43], the Metafor package, and by choosing the corresponding “rma.uni” function, which has been validated [44]. For each FA in term and preterm milk, and per lactational stage, the weighted least squares (WLS) means and SEM were calculated. Weighting of data was based on heterogeneity and sampling variances. Fixed effects models were used when k (i.e. number of studies) was ≤5 and random effects models in case k was >5. When a study presented data on a FA as “not traceable” or “not detected” it was treated as a mean content of 0.001% in the pooled data analysis. Meta-analysis of the data across the different lactational stages was explored but found to be statistically inadvisable due to multiple testing issues and thus not performed in this paper. Meta-analysis for milk types (term vs. preterm milk) was also not feasible because of data paucity. Choosing the pooled data analysis approach offered the opportunity to include all studies that reported on either term or preterm milk or both, resulting in more data for this analysis and WLS mean estimates that are reflective of worldwide HMFA profiles.

2.2. Data extraction HMFA profile data were extracted and assigned to one of three lactational stages defined as colostrum (0–≤5 days PP), transitional (6–≤15 days PP), or mature milk (16–≤60 days PP) [38]. Some assumptions had to be applied to allocate the extracted data: We categorised the data from Roy et al. [39] as “transitional milk” because, although they sampled milk between 5 and 20 days PP, they did not specify the average days PP. The same was true for the data of Golfetto et al. [40]: Here samples were collected between 4 and 7 days PP and the author's classification of transitional milk was applied in the current analysis. Definitions for preterm and term birth were used as in the original publication, generally defined as birth <37 weeks and ≥37–≤42 weeks of gestation, respectively. For the purpose of description, we defined the following FA categories (i) based on chain length including

3. Results 3.1. Data description The literature search resulted in a total of 2172 records. Several studies were excluded for being a review or not including original data. The secondary literature from these papers [28, 31, 45-53] was retrieved and examined in full-text to assess validity according to our inclusion and exclusion criteria. Finally, 55 studies were included in the pooled data analysis (Fig. 1). Of these studies, 50 analysed term milk (4374 samples at 105 time points [31 colostrum, 25 transitional milk, 49 mature milk]), and 13 studies analysed preterm milk (1017 samples at 38 time points [8 colostrum, 15 transitional milk, 15 mature milk]), providing data on in total 36 individual FAs. 2

Prostaglandins, Leukotrienes and Essential Fatty Acids xxx (xxxx) xxxx

L.M. Floris, et al.

Fig. 1. Flow diagram of the study selection process and reasons for exclusion. FA Fatty acid(s), PP postpartum.

volatile FA methyl esters [54, 55]. Only two studies reported on caproic acid (C6:0) in preterm milk and indicate that this FA is lowest in mature milk. The opposite pattern is observed in term milk, with slightly more data available showing that low contents are present in colostrum and transitional milk, with a substantial increase in mature milk. Similarly, few studies reported on caprylic acid (C8:0) in preterm milk and capric acid (C10:0) in preterm colostrum. Both FAs seem to be almost absent in preterm colostrum and steadily rising in transitional and mature milk. Based on more data, a rising pattern is also observed in term milk for both caprylic and capric acid with contents almost doubling in transitional milk and remaining stable thereafter. Lauric acid (C12:0) is the most abundant MCFA, contributing to the total term and preterm HMFA profile with 3.86 ± 0.71% and 3.16 ± 0.38% in colostrum, respectively, almost doubling in transitional and remaining stable thereafter in mature milk.

Table 1 provides an overview of the included studies for both term and preterm milk across the three lactational stages with the majority being from Europe and Asia, mostly represented by Spanish, Swedish, and Chinese data, respectively. By illustrating the lowest and highest mean contents of the three most abundant HMFAs in mature preterm and term milk (Fig. 2), the interstudy variation becomes apparent. The complete overview with all 55 included studies are available for the 30 most reported FAs in Supplementary Figure 1–30. Of the three example FAs in Fig. 2, the highest interstudy variability is observed for oleic (C18:1 n−9) and linoleic (LA; C18:2 n−6) acid, whereas palmitic acid (C16:0) contents show to be relatively constant among individual studies. For all three FAs contents largely overlap between term and preterm milk (Fig. 2, Supplementary Figure 5, 14, 18). 3.2. Pooled data analysis The WLS means and SEM that were generated by pooled data analyses are shown for each of the 36 predominant FAs in term (Table 2) and preterm milk (Table 3). A broad range of HMFAs from all FA categories, i.e. from SCFAs to LCPUFAs, are included in the dataset. As an illustration, Fig. 3 shows the FA categories and diversity of individual FAs in term mature HM.

3.2.2. Saturated and monounsaturated FA SFAs and MUFAs are the largest FA categories in HM, each category contributing just over one-third of the total fat content of HM. During the three stages of lactation in both term and preterm milk, the WLS means of the most abundant SFAs palmitic (C16:0), stearic (C18:0) and myristic (C14:0) acid remain stable. A similar pattern is observed for arachidic acid (C20:0) in term milk, however for preterm milk it shows an increase in mature milk reaching comparable levels to mature term milk. Most MUFAs, including the most abundant HMFA oleic acid (C18:1 n−9), remain stable over the course of lactation. Exceptions are gondoic (C20:1 n−9), erucic (C22:1 n−9) and nervonic (C24:1 n−9) acid which all three decrease over time.

3.2.1. Short- and medium-chain FA SCFAs and most MCFAs contribute relatively little to the overall fat content of HM, and especially SCFAs are seldomly reported in the included studies. Only one of the included studies reported SCFA butyric acid (C4:0) in term HM, possibly because in other studies analytical methods to measure HMFAs may not adapted to measure these highly 3

Prostaglandins, Leukotrienes and Essential Fatty Acids xxx (xxxx) xxxx

L.M. Floris, et al.

Table 1 Overview of studies included in pooled data analysis sorted by publication date. Term milk was generally defined as ≥37–≤42 weeks gestation and preterm milk as <37 weeks gestation by the studies. The N indicates samples, not maternal donors. Reporting unit indicates the degree of conversion to be applied for standardization before pooled data analysis. Author and year

Country

Term milk

Preterm milk

Gestational age (weeks)

N

Gestational age (weeks)

N

Reporting unit

Lactation duration (days)

Stage classification

2x C M C, M M 2x T, M 2x M T, M C, T & 2xM

Uhari et al. 1985 [78] Innis et al. 1990 [79] Martin et al. 1993 [80] van Beusekom et al. 1993 [81] Luukkainen et al. 1994 [22] Jørgensen et al. 1996 [82] Huisman et al. 1996 [83]

Finland Canada France Dominica Finland Sweden The Netherlands

“Term” – 39.7 ± 1.7 “Term” >37 37–42 37-42

30 – 48 7 25 33 198

– 29.4 ± 1.4 – – 25–33 – –

– 9 – – 32 – –

Mean Mean Mean Mean Mean Mean Mean

Genzel-Boroviczeny et al. 1997 [36] Innis et al. 1997 [84]

Germany

39.91 ± 0.64

146

28.63 ± 3.72

68

Mean ± SEM

3, 4–5 ∼19 5, 30 20–22 7, 14, 28 30, 60 14.4 ± 3.5, 42.1 ± 2.7 5, 10, 20, 30

United States and Canada China Spain and Panama France Canada China Mauritania and France Slovenia: 3 regions Italy Sweden Japan Italy Cuba Spain Australia Spain Brazil USA Spain Brazil Spain Korea China Germany: 4 populations Portugal Canada China: 2 regions Sweden Korea Spain

37-41

55

–

–

Mean ± SD

14

T

“Term” “Term”

22 48

– 33–36

– 18

Mean ± SEM Mean ± SD

22–47 1–5, 6–15, 16–35

M C, T & M

37 – 42 37–41 “Term” 38–40

30 103 18 28

– – – –

– – – –

Mean Mean Mean Mean

5, 42 60 30 5, 42

C, M M M C, M

“Term”

41

–

–

Mean ± SEM

3

C

37–42 40.1 ± 0.3 37–40 “Term” 40.4 ± 1.53 39.33 ± 0.97 “Term” 37–42 “Term” 39.5 ± 1.3 39.65 ± 0.94 37–47 38–42 “Term” 39.6 ± 1.1 “Term”

95 19 20 102 52 120 138 6 77 81 66 31 10 12 45 769

– – – – – – – – – – – – – – – –

– – – – – – – – – – – – – – – –

Mean ± SD Mean ± SEM Mean ± SD Mean [95% CI] Mean ± SD Mean ± SD Mean ± SEM Mean ± SEM Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Median (range]

1 1, 28 1–7 1, 4–7, 14–28 60 ∼3, 11, 24 30, 60 20–25 15 ± 1 11.2 ± 5.8 1–5, 6–15, 15–30 22.7 1–5, 15–30 4–7 5, 42 42

C C, M C C, T, M M C, T & M 2x M M T T C, T & M M C, M T C and M M

39.1 ± 1.3 37–42 ∼39–40 – 39.1 ± 1.06 38–40

93 60 102 – 26 23

– – – 24–36 31.7 ± 3.07 <37

– – – 39 244 20

Mean Mean Mean Mean Mean Mean

7, 28, 56 28 5 6–10 7, 14, 28, 42, 56 2–4, 8–12, 28–32

T & 2x M M C T 2xT & 3x M C, T, M

Italy Brazil Tanzania India: 2 regions Singapore

“no complications” 39.7 ± 1.06 ∼39 “Term” “Term”

120 20 83 135 50

– 32.25 ± 2.83 ∼32 – –

– 20 50 – –

Mean ± SD Mean ± SD Median (range] Mean ± SEM Mean ± SD

0–5, 6–15, >15 2–4, 16 2–5, 6–15, 16–56 7–20 28

C, T, M C&M C, T & M T M

Taiwan Sweden

39.1 ± 1.2 39.6 ± 1.2

42 49

– –

– –

Mean ± SD Mean ± SEM

42 3, 10, 30

M C, T, M

Poland

40–41

136

–

–

Mean ± SD

17–30

M

China: 3 regions Sudan USA Israel Israel

39.4–40.1 “Term” – – 39 ± 1.2

125 63 – – 20

– – ≤30 34.5–35.1 31 ± 2.9

– – 129 108 63

Median (IQR] Mean ± SD Mean ± SD Mean ± SD Mean ± SD

C, T, M T, M M C, 2x T C & 2xT

The Netherlands Spain Sweden China

“Term” “Term” – 37–39

50 5 – 309

– – <28 –

– – 139 –

Mean ± SD Individual values Median (IQR] Mean ± SD

3–5, 14, 28 6–10, 25–30 20.9 ± 10.4 <3, 7, 14 4–5, 10–11, 14–15 30, 60 30–60 7, ∼45 1–5, 6–15, >15

Lee-Kim et al. 1998 [85] Rueda et al. 1998 [86] Maurage et al. 1998 [87] Innis et al. 1999 [88] Xiang et al. 1999 [89] Pugo-Gunsam et al. 1999 [90] Fidler et al. 2000 [91] Marangoni et al. 2000 [92] Xiang et al. 2000 [93] Wang et al. 2000 [94] Scopesi et al. 2001 [95] Krasevec et al. 2002 [96] López-López et al. 2002 [97] Mitoulas et al. 2003 [98] Sala-Vila et al. 2004 [99] Da Cunha et al. 2005 [100] Mosley et al. 2005 [101] Sala-Vila et al. 2005 [102] Patin et al. 2006 [103] Sala-Vila et al. 2006 [104] Golfetto et al. 2007 [40] Peng et al. 2007 [105] Szabó et al. 2007 [106] Ribeiro et al. 2008 [107] Tijerina- Sáenz et al. 2009 [108] Peng et al. 2009 [109] Sabel et al. 2009 [110] Jang et al. 2011 [76] Molto-Puigmarti et al. 2011 [23] Haddad et al. 2012 [111] Berenhauser et al. 2012 [77] Kuipers et al. 2012 [26] Roy et al. 2012 [39] Cruz-Hernandez et al. 2013 [112] Huang et al. 2013 [61] Storck Lindholdm et al. 2013 [113] Szlagatys‐Sidorkiewicz et al. 2013 [114] Urwin et al. 2013 [63] Nyuar et al. 2013 [115] Berseth et al. 2014 [116] Lubetzky et al. 2016 [117] Granot et al. 2016 [75] Van de Heijning et al. 2017 [24] Barreiro et al. 2018 [118] Nilsson et al. 2018 [119] Qi et al. 2018 [62]

± SD ± SEM ± SD ± SD [95% CI] ± SD ± SD

± ± ± ±

± ± ± ± ± ±

SD SEM SEM SEM

SD SEM SD SD SD SD

C = colostrum (0 - ≤5 days postpartum (PP)), T = transitional milk (6 - ≤15 days PP), M = mature milk (16 - ≤60 days PP).

4

2x M M T, M C, T, M

Prostaglandins, Leukotrienes and Essential Fatty Acids xxx (xxxx) xxxx

L.M. Floris, et al.

Fig. 2. The extent of interstudy variation for linoleic, oleic and palmitic acid, as shown by the three studies reporting the highest and lowest mean levels in both term and preterm mature milk (16–≤60 days postpartum (PP)). Supplementary Figures 5, 14, 18 show the complete variation profile of all individual studies. The interstudy variation is high for linoleic and oleic acid with 7.9–30.6% and 18.4–52.5% of total fatty acids (FA), respectively. This is in contrast to palmitic acid whose levels have been reported in the range between 15.4–31.0% total FAs with relatively tight error bars.

3.2.3. Trans-FA Trans-FAs naturally occur in ruminant fat or dairy products or are formed by hydrogenation of vegetable oils; trans-FAs translate into HM from maternal dietary intake [56–58]. Although several studies reported on trans-FA contents for term milk, much less data has been reported for preterm milk, resulting in a low number of studies per time point, especially for rumenic acid (trans-C18:2 n−6). In term milk, elaidic acid (trans-C18:1 n−9) is present in noteworthy amounts, with WLS means highest in colostrum and decreasing thereafter in transitional and mature milk. In contrast, the little data available for rumenic acid (trans-C18:2 n−6) in term milk point towards a low overall content, seemingly dipping even further in transitional milk. Vaccenic acid (C18:1 n−7) is the predominant trans-FAs in

HM and our data indicate that contents remain relatively stable throughout lactation in both term and preterm milk. 3.2.4. LCPUFA LCPUFAs are a significant fraction (15–20%) of the total FA profile, with n−6 PUFAs, and more specifically LA (C18:2 n−6), the most abundant compared to n−3 PUFAs (Fig. 3). Almost all LCPUFA WLS means, including arachidonic acid (ARA; C20:4 n−6), decrease roughly by half over the course of lactation in both term and preterm milk. DHA (C22:6 n−3) and docosapentaenoic acid (DPA; C22:5 n−3) WLS means decrease steadily over all lactational stages in term milk, while in preterm milk the amounts stay high longer. Four exceptions can be observed: Gamma-linoleic acid (GLA; C18:3 5

Prostaglandins, Leukotrienes and Essential Fatty Acids xxx (xxxx) xxxx

L.M. Floris, et al.

Table 2 Weighted least squares mean contents of fatty acids (FA) in term human milk across lactational stages in g/100 g FA (%). Colostrum k C4:0 C6:0 C8:0 C10:0 C12:0 C14:0 C16:0 C17:0 C18:0 C20:0 C22:0 C24:0 C26:0 C14:1 n−5 C16:1 n−7 C17:1 n−7 C18:1 n−7 C18:1 n−9 trans-C18:1 n−9 C20:1 n−9 C22:1 n−9 C24:1 n−9 C18:2 n−6 trans-C18:2 n−6 C18:3 n−6 C20:2 n−6 C20:3 n−6 C20:4 n−6 C22:4 n−6 C22:5 n−6 C18:3 n−3 C18:4 n−3 C20:3 n−3 C20:5 n−3 C22:5 n−3 C22:6 n−3

0 2 8 10 16 21 23 9 23 14 11 10 0 9 16 7 4 22 4 13 9 12 24 1 18 18 23 24 13 8 22 4 7 21 15 24

N 133 289 320 641 857 919 315 919 601 546 501 427 702 280 164 817 198 470 374 502 943 40 832 801 933 943 484 341 897 108 289 866 629 943

Mean ± SEM

Transitional milk k N

Mean ± SEM

Mature milk k N

Mean ± SEM

NR 0.06 0.13 0.77 3.16 5.66 24.9 0.33 6.40 0.22 0.16 0.18 NR 0.18 2.05 0.19 2.69 35.3 1.95 0.88 0.22 0.28 14.4 0.16 0.09 0.89 0.60 0.77 0.34 0.17 0.82 0.22 0.11 0.10 0.30 0.51

1 5 12 14 16 19 21 9 21 12 11 12 1 7 17 5 5 20 5 12 11 9 21 2 12 15 19 21 15 10 19 3 6 18 17 20

0.01 0.03 0.25 1.38 5.98 7.04 22.6 0.30 6.39 0.26 0.21 0.15 0.01 0.22 2.22 0.14 1.98 32.2 1.13 0.60 0.21 0.27 14.1 0.02 0.14 0.58 0.49 0.65 0.22 0.11 0.95 0.06 0.18 0.14 0.22 0.46

0 8 17 26 31 35 37 15 37 23 18 20 0 14 28 9 15 34 9 24 20 20 38 4 27 28 34 38 22 15 36 5 13 32 27 38

NR 0.14 0.25 1.61 6.14 6.80 22.2 0.31 6.46 0.23 0.10 0.08 NR 0.20 2.30 0.19 1.87 32.9 1.16 0.45 0.11 0.07 15.0 0.12 0.17 0.38 0.41 0.48 0.10 0.08 0.97 0.10 0.06 0.09 0.15 0.31

± 0.00 ± 0.06 ± 0.27 ± 0.38 ± 0.30 ± 0.62 ± 0.02 ± 0.24 ± 0.03 ± 0.04 ± 0.03 ± 0.05 ± 0.15 ± 0.02 ± 0.07 ± 0.64 ± 0.02 ± 0.07 ± 0.02 ± 0.04 ± 0.91 ± 0.03 ± 0.02 ± 0.07 ± 0.04 ± 0.04 ± 0.05 ± 0.04 ± 0.08 ± 0.01 ± 0.02 ± 0.02 ± 0.03 ± 0.04

81 314 672 733 913 979 1034 546 1034 618 578 594 81 417 866 237 101 935 300 553 513 415 1034 71 689 808 876 1034 722 410 1001 261 455 901 865 957

± 0.00 ± 0.00 ± 0.06 ± 0.19 ± 0.57 ± 0.48 ± 0.73 ± 0.02 ± 0.32 ± 0.06 ± 0.07 ± 0.04 ± 0.00 ± 0.03 ± 0.22 ± 0.00 ± 0.04 ± 1.02 ± 0.02 ± 0.05 ± 0.07 ± 0.12 ± 0.70 ± 0.00 ± 0.04 ± 0.05 ± 0.03 ± 0.04 ± 0.03 ± 0.02 ± 0.11 ± 0.00 ± 0.08 ± 0.03 ± 0.03 ± 0.06

496 755 1959 2176 2278 2373 689 2373 1745 1634 1700 559 2065 443 1489 2216 1267 1768 1697 1532 2397 1009 2122 2053 2263 2397 1767 676 2362 122 1376 1451 1266 2397

± 0.05 ± 0.05 ± 0.16 ± 0.38 ± 0.34 ± 0.47 ± 0.02 ± 0.18 ± 0.03 ± 0.01 ± 0.01 ± 0.02 ± 0.10 ± 0.01 ± 0.22 ± 0.72 ± 0.27 ± 0.03 ± 0.01 ± 0.01 ± 0.74 ± 0.00 ± 0.03 ± 0.03 ± 0.02 ± 0.03 ± 0.01 ± 0.02 ± 0.06 ± 0.00 ± 0.01 ± 0.01 ± 0.01 ± 0.03

Colostrum = 0–≤ 5 days postpartum (PP); transitional milk = 6–≤15 days PP; mature milk = 16–≤60 days PP. k = number of studies; N = number of samples; NR = not reported by any of the studies.

n−6) contents double after colostrum and continue to show a steady rise between transitional and mature milk. LA (C18:2 n−6), eicosapentaenoic (EPA; C20:5 n−3) and α-linolenic (ALA; C18:3 n−3) acid WLS means remain relatively stable at all time points.

66, 67], since a substantial body of evidence has shown physiological relevance for the growth and development of the infant (as reviewed by [68]). The current study shows that WLS means of a number of FAs, of which palmitic acid (C16:0) and the essential FAs LA (C18:2 n−6) and ALA (C18:3 n−3) amongst others, remain relatively stable over time. For the essential FAs this could be explained by their source being predominantly maternal body fat tissue depots (70%) and only 30% originating from the variable maternal diet [69]. Some of the other observed temporal changes in FA contents may be reflective of adaptations in the milk production process in the mammary gland, due to an altered hormonal environment or the maturation of the mammary gland [36, 70, 71]. As an example, several MCFAs seem to increase with duration of lactation for both term and preterm milk, the increase seemingly greater in the latter. It could be hypothesized that MCFA contents increase with maturation of the mammary gland as MCFAs are only synthesized de novo in the mammary gland and, as shown by others, known to increase over the course of lactation [69, 71]. Furthermore, LCPUFAs are known to play an important role in the development and function of the immune system [9, 72, 73]; correspondingly almost all LCPUFAs are highest in colostrum, except for LA, ALA and GLA. When comparing the interstudy variation of the three predominant HMFAs in mature milk, palmitic acid (C16:0) demonstrated remarkable consistency, varying by about 16% between studies, in contrast to LA and oleic acid (C18:1 n−9) that vary by 23% and 34%, respectively, between studies. This leaves room for the hypothesis that palmitic acid may be genetically regulated more strongly than oleic acid and LA,

4. Discussion and conclusions Our study is the first to provide a reference FA profile of HM by pooled data analysis from 55 studies. It generates an extensive and qualitative overview of the complex and diverse FA profiles in term and preterm HM over the course of lactation. Our WLS means confirm findings of previous papers that applied statistical methods which do not take weighting or population variation into account, and finally reporting either FA ranges or focussing on selected individual HMFAs [31, 59]. This conformity is most likely explained by a partial overlap of included studies. In addition, most of our WLS means are in line with reference values given by the European Food Safety Authority (EFSA) [60]. A noteworthy exception being ARA (C20:4 n−6) with a value of only 0.48% in mature term HM in the current study vs. the range of 0.7 – 1.1% reported by EFSA. Even the individual average contents of the included studies are consistently below the range reported by EFSA, with exception of three out of 38 studies [61-63]. This discrepancy seems to exemplify the value of a pooled data approach combining 38 studies to generate a representative ARA reference value in contrast to a single study selection as a base for the EFSA range [60, 64]. This is of interest to notice as the European Union legislation for infant and follow-on formula [65] no longer considers ARA mandatory, a decision that has been widely contested [9, 6

Prostaglandins, Leukotrienes and Essential Fatty Acids xxx (xxxx) xxxx

L.M. Floris, et al.

Table 3 Weighted least squares mean contents of fatty acids (FA) in preterm human milk across lactational stages in g/100 g FA (%).

C4:0 C6:0 C8:0 C10:0 C12:0 C14:0 C16:0 C17:0 C18:0 C20:0 C22:0 C24:0 C26:0 C14:1 n−5 C16:1 n−7 C17:1 n−7 C18:1 n−7 C18:1 n−9 trans-C18:1 n−9 C20:1 n−9 C22:1 n−9 C24:1 n−9 C18:2 n−6 trans-C18:2 n−6 C18:3 n−6 C20:2 n−6 C20:3 n−6 C20:4 n−6 C22:4 n−6 C22:5 n−6 C18:3 n−3 C18:4 n−3 C20:3 n−3 C20:5 n−3 C22:5 n−3 C22:6 n−3

Colostrum k N

Mean ± SEM

Transitional milk k N

Mean ± SEM

Mature milk k N

Mean ± SEM

0 1 3 5 6 6 7 2 7 4 3 4 0 2 4 1 3 7 2 4 4 2 7 1 5 4 6 7 3 3 6 0 3 6 3 7

NR 0.11 0.03 0.09 3.86 6.49 23.3 0.31 6.17 0.17 0.08 0.20 NR 0.12 1.72 0.16 2.37 32.1 0.39 0.66 0.16 0.29 15.0 0.10 0.07 0.92 0.75 0.79 0.46 0.16 0.89 NR 0.11 0.08 0.32 0.57

0 1 3 6 8 9 10 3 10 5 5 6 0 4 8 1 4 10 1 5 6 5 10 1 8 5 10 10 5 4 8 2 4 8 7 8

NR 0.16 0.10 1.35 6.62 8.58 22.5 0.26 6.46 0.15 0.06 0.13 NR 0.22 2.30 0.15 2.58 32.4 0.26 0.50 0.12 0.14 12.5 0.15 0.11 0.29 0.51 0.61 0.22 0.05 0.86 0.02 0.08 0.13 0.30 0.57

0 2 4 6 8 9 10 4 10 6 5 6 0 4 7 1 4 10 2 7 6 5 10 0 6 5 8 10 7 6 9 3 4 9 8 10

NR 0.07 0.16 1.63 6.91 8.21 21.6 0.26 6.63 0.25 0.07 0.06 NR 0.21 2.23 0.17 2.15 34.2 0.35 0.44 0.08 0.04 13.3 NR 0.16 0.24 0.45 0.53 0.15 0.07 0.99 0.02 0.06 0.12 0.20 0.40

14 55 91 101 101 120 26 120 74 64 70 50 61 20 40 120 30 50 70 26 120 30 96 61 110 120 40 40 114 70 101 40 120

± 0.01 ± 0.00 ± 0.00 ± 0.71 ± 0.70 ± 0.81 ± 0.01 ± 0.37 ± 0.01 ± 0.00 ± 0.01 ± 0.01 ± 0.06 ± 0.01 ± 0.06 ± 1.55 ± 0.02 ± 0.02 ± 0.00 ± 0.01 ± 1.28 ± 0.01 ± 0.00 ± 0.03 ± 0.06 ± 0.11 ± 0.02 ± 0.01 ± 0.20 ± ± ± ±

0.01 0.02 0.02 0.14

23 85 324 441 464 483 104 483 354 354 360 331 386 20 127 483 20 282 360 298 483 78 437 169 483 483 282 127 399 233 294 386 344 366

± 0.01 ± 0.01 ± 0.32 ± 0.91 ± 0.63 ± 1.00 ± 0.01 ± 0.47 ± 0.00 ± 0.00 ± 0.03 ± 0.00 ± 0.24 ± 0.01 ± 0.04 ± 1.89 ± 0.03 ± 0.01 ± 0.02 ± 0.00 ± 1.11 ± 0.01 ± 0.02 ± 0.01 ± 0.04 ± 0.07 ± 0.00 ± 0.00 ± 0.16 ± 0.00 ± 0.00 ± 0.03 ± 0.06 ± 0.10

142 171 266 337 346 376 216 376 322 312 312 299 327 20 94 376 30 328 318 305 376 335 229 357 376 327 238 370 279 309 346 336 376

± 0.00 ± 0.00 ± 0.48 ± 1.19 ± 0.82 ± 0.70 ± 0.00 ± 0.43 ± 0.05 ± 0.00 ± 0.00 ± 0.00 ± 0.26 ± 0.01 ± 0.03 ± 2.46 ± 0.04 ± 0.06 ± 0.00 ± 0.00 ± 1.05 ± ± ± ± ± ± ± ± ± ± ± ±

0.05 0.00 0.05 0.05 0.02 0.02 0.14 0.00 0.00 0.04 0.04 0.09

Colostrum = 0–≤ 5 days postpartum (PP); transitional milk = 6–≤15 days PP; mature milk = 16–≤60 days PP. k = number of studies; N = number of samples; NR = not reported by any of the studies.

similar to the reports of genetic control securing ARA levels in HM versus the much more dietary origin of DHA [17, 74]. Although the approach of the current study did not allow for statistical comparison between FA profiles of term and preterm HM, we did observe that, with a few exceptions, patterns were largely comparable across lactational stages for WLS means in term and preterm milk. In contrast to Bokor et al. [19], who summarized five studies on specific FAs in term and preterm HM and found that DHA was significantly higher in preterm milk than term milk in some individual studies and time points, the current study did not confirm differences in mean DHA levels of the same magnitude, possibly because a greater number of studies was included in our analyses. Since DHA in HM is known to be strongly influenced by maternal diet [31], alternative explanations may be region-specific differences in maternal diet between the included term and preterm studies, which confound the direct comparison of values. This may also explain the slower decline in DHA contents from transitional to mature preterm milk, since a higher proportion of the studies reporting on transitional preterm milk are from regions with a known high fish or marine food intake [26, 75, 76]. In line with our observations for (some of the) MCFAs, several studies directly comparing FA profiles of term and preterm milk found higher amounts in preterm milk, especially in early milk (i.e. colostrum or transitional milk) [23, 26, 36, 76], others found lower contents [77]. The data paucity particularly in early milk after preterm birth for these MCFAs emphasize once more the importance of research in HMFA composition across gestational ages and lactational stages. The use of a large dataset combining HM studies from different

regions around the world is considered as one of the strengths of this study. In addition, we are the first to present pooled data mean concentrations of an extensive FA profile in both term and preterm HM, acknowledging the three successive stages of lactation, enabling for both temporal changes as well as changes related to gestational age to be observed. Limitations were the exclusion of non-English publications and subsequent potential selection bias, possibly overlooking different maternal dietary patterns and resulting in HMFA composition differences [14]. While statistical weighting reduces impact of outliers, it may diminish estimation accuracy for specific FAs with high variance and/or heterogeneity. Given the limited data available for specific FAs at certain time points for preterm HM, caution should be taken whenever comparing these WLS means to values in the current study or in other studies. The aim of the current study was to give a qualitative synopsis of (relevant) published literature in our effort to describe HMFA composition across lactational stages. Our analyses were not restricted to those studies with longitudinal sampling across (all) lactational stages only, but we chose to include as much data as possible instead to gain accuracy of the WLS mean estimates. This approach, also including studies reported HMFA data for single lactational stages, prohibited us from performing repeated measures analyses which could have more adequately addressed changes over time. Hence, future studies on development of HMFA profiles after term and/or preterm delivery should ideally be designed longitudinally with samples collected across different lactational stages within each study to appropriately evaluate any differences in HMFA profiles specifically related to gestational age or lactational stages. By applying solid statistical models, we were successful in 7

Prostaglandins, Leukotrienes and Essential Fatty Acids xxx (xxxx) xxxx

L.M. Floris, et al.

Fig. 3. Diversity of fatty acid (FA) categories and individual FA in term mature human milk after pooled data analysis of worldwide milk samples. The figure highlights the distribution per FA category and particular FAs predominantly contributing to the total HMFA fraction. The overall contribution of LCPUFAs is relatively low compared to the other FA categories and mainly comes from linoleic acid (C18:2 n−6). MCFA = (saturated) medium-chain FA (C6–C12); SFA = saturated FA (FA without double-bond); MUFA = monounsaturated FA (one double-bond); LCPUFA = long-chain polyunsaturated FA (≥C18 and more than one doublebond).

abundant FAs (palmitic, linoleic and oleic acid) remained stable over time, whereas several LCPUFAs seemed to decrease and short- and medium-chain FAs increased. Many of these patterns were comparable between term and preterm milk.

generating a global representative HMFA profile, ranging from SCFAs to LCFAs, still acknowledging the high variation in HM. Our data also show the development of the FA profile from the first days up to 2 months and covers both term and preterm milk. With these data, we address a scientific gap to gain a better understanding of HM and we provide a reference that can be used in comparisons with the FA composition of individuals or specific populations. Our analysis clearly shows that HM has a very diverse FA profile and contains many FA species for which we do not yet know the individual or synergetic physiological effects in the breastfed infant. Changes during lactation may provide first insights indicating FA functionality, but clearly more longitudinal studies (especially in a preterm setting) are required to confirm these findings. Future research is needed to elucidate the effects of individual FAs, FA categories and metabolites on the growth and development of infants. Given the relevance of dietary FAs in early life, we need to better understand the specific contribution of HMFAs for later health outcomes irrespective or dependent of gestational maturity.

CRediT authorship contribution statement L.M. Floris: Methodology, Formal analysis, Visualization, Writing original draft, Writing - review & editing. B. Stahl: Writing - review & editing. M. Abrahamse-Berkeveld: Visualization, Writing - review & editing. I.C. Teller: Conceptualization, Methodology, Writing - review & editing. Declaration of Competing Interest At the time of writing all authors were employees of Danone Nutricia Research.

5. Summary

Acknowledgments

This pooled data analysis describes mean levels of an extensive human milk (HM) fatty acid (FA) profile to increase our understanding of its variation and development across lactational stages after term and preterm delivery. A Medline search was conducted on HMFA data following term or preterm delivery. The search was confined to English language with a time limitation from January 1980 until August 2018. Studies providing original data on extensive HMFA profiles from healthy mothers were included. Weighted least squares means were calculated using random or fixed effect models. We included 55 studies worldwide (5391 samples). High interstudy variation was observed for some FAs, whereas others were remarkably constant. Apparent patterns emerged throughout lactation: The most

We thank Catherine Matthews for development of the literature search strategy; Katerina Papadimitropoulou for assisting with the statistical analysis; and Silvia Ringler and Bert van de Heijning for reviewing the manuscript. Funding source declaration This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Data described in the manuscript can be made available upon request to [email protected]. 8

Prostaglandins, Leukotrienes and Essential Fatty Acids xxx (xxxx) xxxx

L.M. Floris, et al.

Supplementary materials

breast milk worldwide, Am. J. Clin. Nutr. 85 (2007) 1457–1464. [32] D.A. Gidrewicz, T.R. Fenton, A systematic review and meta-analysis of the nutrient content of preterm and term breast milk, BMC Pediatr. 14 (2014) 216. [33] Z. Zhang, A.S. Adelman, D. Rai, J. Boettcher, B. Lonnerdal, Amino acid profiles in term and preterm human milk through lactation: a systematic review, Nutrients 5 (2013) 4800–4821. [34] G. Ailhaud, F. Massiera, P. Weill, P. Legrand, J.M. Alessandri, P. Guesnet, Temporal changes in dietary fats: role of n-6 polyunsaturated fatty acids in excessive adipose tissue development and relationship to obesity, Prog. Lipid Res. 45 (2006) 203–236. [35] T.L. Blasbalg, J.R. Hibbeln, C.E. Ramsden, S.F. Majchrzak, R.R. Rawlings, Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century, Am. J. Clin. Nutr. 93 (2011) 950–962. [36] O. Genzel-Boroviczeny, J. Wahle, B. Koletzko, Fatty acid composition of human milk during the 1st month after term and preterm delivery, Eur. J. Pediatr. 156 (1997) 142–147. [37] H. Demmelmair, B. Koletzko, Lipids in human milk, Best Pract. Res. Clin. Endocrinol. Metab. 32 (2018) 57–68. [38] B. Koletzko, M. Rodriguez-Palmero, H. Demmelmair, N. Fidler, R. Jensen, T. Sauerwald, Physiological aspects of human milk lipids, Early Hum. Dev. 65 (Suppl) (2001) S3–S18. [39] S. Roy, P. Dhar, S. Ghosh, Comparative evaluation of essential fatty acid composition of mothers' milk of some urban and suburban regions of West Bengal, India, Int. J. Food Sci. Nutr. 63 (2012) 895–901. [40] I. Golfetto, R. McGready, K. Ghebremeskel, et al., Fatty acid composition of milk of refugee Karen and urban Korean mothers. Is the level of DHA in breast milk of Western women compromised by high intake of saturated fat and linoleic acid? Nutr. Health 18 (2007) 319–332. [41] J.P. Higgins, S. Green, Cochrane Handbook For Systematic Reviews of Interventions, version 5.1.0, John Wiley & Sons, 2011. [42] S.P. Hozo, B. Djulbegovic, I. Hozo, Estimating the mean and variance from the median, range, and the size of a sample, BMC Med. Res. Methodol. 5 (2005) 13. [43] R. Core Team, R: a Language and Environment For Statistical Computing, R Foundation for Statistical Computing, Vienna, Austria, 2017. [44] W. Viechtbauer, Conducting meta-analyses in R with the metafor package, J. Stat. Softw. 36 (2010) 1–48. [45] Y. Fu, X. Liu, B. Zhou, A.C. Jiang, L. Chai, An updated review of worldwide levels of docosahexaenoic and arachidonic acid in human breast milk by region, Public Health Nutr. 19 (2016) 2675–2687. [46] Y.N.V. do Amaral, D. Marano, L.M.L. da Silva, A.C.L.D. Guimarães, M.E.L. Moreira, Are there changes in the fatty acid profile of breast milk with supplementation of omega-3 sources? A systematic review, Rev. Bras. Ginicol. Obstet. 39 (2017) 128–141. [47] N.T. Waidyatillake, S.C. Dharmage, K.J. Allen, et al., Association of breast milk fatty acids with allergic disease outcomes - a systematic review, Allergy 73 (2018) 295–312. [48] P. Dominguez-Salas, S.E. Moore, M.S. Baker, et al., Maternal nutrition at conception modulates DNA methylation of human metastable epialleles, Nat. Commun. 5 (2014) 3746. [49] T. Yang, L. Zhang, W. Bao, S. Rong, Nutritional composition of breast milk in Chinese women: a systematic review, Asia Pac. J. Clin. Nutr. 27 (2018) 491–502. [50] R.G. Jensen, The lipids in human milk, Prog. Lipid Res. 35 (1996) 53–92. [51] R.G. Jensen, S. Patton, The effect of maternal diets on the mean melting points of human milk fatty acid, Lipids 35 (2000) 1159–1161. [52] E.N. Smit, I.A. Martini, H. Mulder, E.R. Boersma, F.A.J. Muskiet, Estimated biological variation of the mature human milk fatty acid composition, Prostaglandins Leukot Essent Fatty Acids 66 (2002) 549–555. [53] S.M. Innis, Human milk and formula fatty acids, J. Pediatr. 120 (1992) S56–S61. [54] M. Primec, D. Mičetić-Turk, T. Langerholc, Analysis of short-chain fatty acids in human feces: a scoping review, Anal. Biochem. 526 (2017) 9–21. [55] J.T. Brenna, M. Plourde, K.D. Stark, P.J. Jones, Y.-.H. Lin, Best practices for the design, laboratory analysis, and reporting of trials involving fatty acids, Am. J. Clin. Nutr. 108 (2018) 211–227. [56] J.E. Chappell, M.T. Clandinin, C. Kearney-Volpe, Trans fatty acids in human milk lipids: influence of maternal diet and weight loss, Am. J. Clin. Nutr. 42 (1985) 49–56. [57] R. Friesen, S.M. Innis, Trans fatty acids in human milk in Canada declined with the introduction of trans fat food labeling, J Nutr 136 (2006) 2558–2561. [58] L. Rist, A. Mueller, C. Barthel, et al., Influence of organic diet on the amount of conjugated linoleic acids in breast milk of lactating women in the Netherlands, Br. J. Nutr. 97 (2007) 735–743. [59] B. Delplanque, R. Gibson, B. Koletzko, A. Lapillonne, B. Strandvik, Lipid quality in infant nutrition: current knowledge and future opportunities, J. Pediatr. Gastroenterol. Nutr. 61 (2015) 8–17. [60] European Food Safety Authority (EFSA), Scientific opinion on the essential composition of infant and follow-on formulae, EFSA J. 12 (2014) 3760. [61] H.-.L. Huang, Ll-T. Chuang, H.-.H. Li, C.-.P. Lin, R.H. Glew, Docosahexaenoic acid in maternal and neonatal plasma phospholipids and milk lipids of Taiwanese women in Kinmen: fatty acid composition of maternal blood, neonatal blood and breast milk, Lipids Health Dis. 12 (2013) 27. [62] C. Qi, J. Sun, Y. Xia, et al., Fatty acid profile and the sn-2 position distribution in triacylglycerols of breast milk during different lactation stages, J. Agric. Food Chem. 66 (2018) 3118–3126. [63] H.J. Urwin, J. Zhang, Y. Gao, et al., Immune factors and fatty acid composition in human milk from river/lake, coastal and inland regions of China, Br. J. Nutr. 109 (2013) 1949–1961. [64] A. Antonakou, K.P. Skenderi, A. Chiou, C.A. Anastasiou, C. Bakoula, A.-.L. Matalas, Breast milk fat concentration and fatty acid pattern during the first six months in exclusively breastfeeding Greek women, Eur. J. Nutr. 52 (2012) 963–973. [65] Commission Delegated Regulation (EU) 2016/128, Off. J. Eur. Commun., Brussels,

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.plefa.2019.102023. References [1] A. Singhal, The role of infant nutrition in the global epidemic of non-communicable disease, Proc. Nutr. Soc. 75 (2016) 162–168. [2] B. Koletzko, B. Brands, L. Poston, K. Godfrey, H. Demmelmair, Early nutrition programming of long-term health, Proc. Nutr. Soc. 71 (2012) 371–378. [3] B. Hanley, J. Dijane, M. Fewtrell, et al., Metabolic imprinting, programming and epigenetics - a review of present priorities and future opportunities, Br. J. Nutr. 104 (Suppl 1) (2010) S1–25. [4] P.D. Gluckman, M.A. Hanson, C. Cooper, K.L. Thornburg, Effect of in utero and early-life conditions on adult health and disease, N. Engl. J. Med. 359 (2008) 61–73. [5] W.H. Dietz, Critical periods in childhood for the development of obesity, Am. J. Clin. Nutr. 59 (1994) 955–959. [6] World Health Organisation (WHO), Global Strategy For Infant and Young Child Feeding, World Health Organisation, Geneva, 2003. [7] R.G. Jensen, Handbook of Milk Composition, Academic Press, San Diego, CA, USA, 1995. [8] N.J. Andreas, B. Kampmann, K.M. Le-Doare, Human breast milk: a review on its composition and bioactivity, Early Hum. Dev. 91 (2015) 629–635. [9] B. Koletzko, Human milk lipids, Ann. Nutr. Metab. 69 (Suppl 2) (2016) 28–40. [10] R. Uauy, P. Mena, Long-chain polyunsaturated fatty acids supplementation in preterm infants, Curr. Opin. Pediatr. (2015). [11] B. Koletzko, B. Pointdexter, R. Uauy, Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines, in: B. Koletzko (Ed.), World Review of Nutrition and Dietetics, Karger, Basel, Switzerland, 2014XII + 314. [12] S.M. Innis, Dietary (n-3) fatty acids and brain development, J. Nutr. 137 (2007) 855–859. [13] S.M. Innis, Human milk: maternal dietary lipids and infant development, Proc. Nutr. Soc. 66 (2007) 397–404. [14] R. Yuhas, K. Pramuk, E.L. Lien, Human milk fatty acid composition from nine countries varies most in DHA, Lipids 41 (2006) 851–858. [15] F. Bravi, F. Wiens, A. Decarli, A. Dal Pont, C. Agostoni, M. Ferraroni, Impact of maternal nutrition on breast-milk composition: a systematic review, Am. J. Clin. Nutr. 104 (2016) 646–662. [16] L.G. Smithers, M. Markrides, R.A. Gibson, Human milk fatty acids from lactating mothers of preterm infants: a study revealing wide intra- and inter-individual variation, Prostaglandins Leukot Essent Fatty Acids 83 (2010) 9–13. [17] L. Xie, S.M. Innis, Genetic variants of the FADS1 FADS2 gene cluster are associated with altered (n-6) and (n-3) essential fatty acids in plasma and erythrocyte phospholipids in women during pregnancy and in breast milk during lactation, J. Nutr. 138 (2008) 2222–2228. [18] J. Maly, I. Burianova, V. Vitkova, E. Ticha, M. Navratilova, E. Cermakova, Preterm human milk macronutrient concentration is independent of gestational age at birth, Arch. Dis. Child Fetal. Neonatal. Ed. 104 (2019) F50–F56. [19] S. Bokor, B. Koletzko, T. Decsi, Systematic review of fatty acid composition of human milk from mothers of preterm compared to full-term infants, Ann. Nutr. Metab. 51 (2007) 550–556. [20] J. Jiang, K. Wu, Z. Yu, et al., Changes in fatty acid composition of human milk over lactation stages and relationship with dietary intake in Chinese women, Food Funct. 7 (2016) 3154–3162. [21] É. Szabó, G. Boehm, C. Beermann, et al., Fatty acid profile comparisons in human milk sampled from the same mothers at the sixth week and the sixth month of lactation, J. Pediatr. Gastroenterol. Nutr. 50 (2010) 316–320. [22] P. Luukkainen, M.K. Salo, T. Nikkari, Changes in the fatty acid composition of preterm and term human milk from 1 week to 6 months of lactation, J. Pediatr. Gastroenterol. Nutr. 18 (1994) 355–360. [23] C. Molto-Puigmarti, A.I. Castellote, X. Carbonell-Estrany, M.C. Lopez-Sabater, Differences in fat content and fatty acid proportions among colostrum, transitional, and mature milk from women delivering very preterm, preterm, and term infants, Clin. Nutr. 30 (2011) 116–123. [24] B.J.M. van de Heijning, B. Stahl, M.W. Schaart, E.M. van der Beek, E.H.H.M. Rings, M.L. Mearin, Fatty acid and amino acid content and composition of human milk in the course of lactation, Adv. Pediatr. Res. 4 (2017) 2–15. [25] B. Koletzko, M. Mrotzek, H.J. Bremer, Fatty acid composition of mature human milk in Germany, Am. J. Clin. Nutr. 47 (1988) 954–959. [26] R.S. Kuipers, M.F. Luxwolda, D.A. Dijck-Brouwer, F.A. Muskiet, Fatty acid compositions of preterm and term colostrum, transitional and mature milks in a subSaharan population with high fish intakes, Prostaglandins Leukot Essent Fatty Acids 86 (2012) 201–207. [27] H. Kumar, E. du Toit, A. Kulkarni, et al., Distinct patterns in human milk microbiota and fatty acid profiles across specific geographic locations, Front. Microbiol. 7 (2016) 1619. [28] S.-.Y. Li, X.-.L. Dong, W.-S.V. Wong, Y.-.X. Su, M.-.S. Wong, Long-chain polyunsaturated fatty acid concentrations in breast milk from Chinese mothers: comparison with other regions, Int. J. Child. Health Nutr. 4 (2015) 230–239. [29] R. Lubetzky, G. Zaidenberg-Israeli, F.B. Mimouni, et al., Human milk fatty acids profile changes during prolonged lactation: a cross-sectional study, Isr. Med. Assoc. J. 14 (2012) 7–10. [30] O. Saphier, J. Blumenfeld, T. Silberstein, T. Tzor, A. Burg, Fatty acid composition of breastmilk of Israeli mothers, Indian Pediatr. 50 (2013) 1044–1046. [31] J.T. Brenna, B. Varamini, R.G. Jensen, D.A. Diersen-Schade, J.A. Boettcher, L.M. Arterburn, Docosahexaenoic and arachidonic acid concentrations in human

9

Prostaglandins, Leukotrienes and Essential Fatty Acids xxx (xxxx) xxxx

L.M. Floris, et al. 2015. [66] J.T. Brenna, Arachidonic acid needed in infant formula when docosahexaenoic acid is present, Nutr. Rev. 74 (2016) 329–336. [67] M.A. Crawford, Y. Wang, S. Forsyth, J.T. Brenna, The European Food Safety Authority recommendation for polyunsaturated fatty acid composition of infant formula overrules breast milk, puts infants at risk, and should be revised, Prostaglandins Leukot Essent Fatty Acids 102-103 (2015) 1–3. [68] K.B. Hadley, A.S. Ryan, S. Forsyth, S. Gautier, N. Salem, The essentiality of arachidonic acid in infant development, Nutrients 8 (2016) 216. [69] R.S. Kuipers, M.F. Luxwolda, D.A. Dijck-Brouwer, F.A. Muskiet, Differences in preterm and term milk fatty acid compositions may be caused by the different hormonal milieu of early parturition, Prostaglandins Leukot Essent Fatty Acids 85 (2011) 369–379. [70] M.C. Neville, T.B. McFadden, I. Forsyth, Hormonal regulation of mammary differentiation and milk secretion, J. Mammary Gland Biol. Neoplasia 7 (2002) 49–66. [71] M.C. Neville, M.F. Picciano, Regulation of milk lipid secretion and composition, Annu. Rev. Nutr. 17 (1997) 159–184. [72] K. Laitinen, U. Hoppu, M. Hämäläinen, K. Linderborg, E. Moilanen, E. Isolauri, Breast milk fatty acids may link innate and adaptive immune regulation: analysis of soluble CD14, prostaglandin E2, and fatty acids, Pediatr. Res. 59 (2006) 723–727. [73] L.S. Harbige, Fatty acids, the immune response, and autoimmunity: a question of n−6 essentiality and the balance between n-6 and n-3, Lipids 38 (2003) 323–341. [74] J.T. Brenna, S.E. Carlson, Docosahexaenoic acid and human brain development: evidence that a dietary supply is needed for optimal development, J. Hum. Evol. 77 (2014) 99–106. [75] E. Granot, K. Ishay-Gigi, L. Malaach, O. Flidel-Rimon, Is there a difference in breast milk fatty acid composition of mothers of preterm and term infants? J. Matern. Fetal Neonatal. Med. 29 (2016) 832–835. [76] S.H. Jang, B.S. Lee, J.H. Park, et al., Serial changes of fatty acids in preterm breast milk of Korean women, J. Hum. Lact. 27 (2011) 279–285. [77] A.C. Berenhauser, A.C. Pinheiro do Prado, R.C. da Silva, L.A. Gioielli, J.M. Block, Fatty acid composition in preterm and term breast milk, Int. J. Food Sci. Nutr. 63 (2012) 318–325. [78] M. Uhari, A. Alkku, T. Nikkari, E. Timonen, Neonatal jaundice and fatty acid composition of the maternal diet, Acta Paediatr. 74 (1985) 867–873. [79] S.M. Innis, K.D. Foote, M.J. MacKinnon, D.J. King, Plasma and red blood cell fatty acids of low-birth-weight infants fed their mother's expressed breast milk or preterm-infant formula, Am. J. Clin. Nutr. 51 (1990) 994–1000. [80] J. Martin, P. Bougnoux, A. Fignon, et al., Dependence of human milk essential fatty acids on adipose stores during lactation, Am. J. Clin. Nutr. 58 (1993) 653–659. [81] C.M. Van Beusekom, H. Nijeboer, C.N. van der Veere, et al., Indicators of long chain polyunsaturated fatty acid status of exclusively breastfed infants at delivery and after 20–22 days, Early Hum. Dev. 32 (1993) 207–218. [82] M.H. Jørgensen, O. Hernell, P. Lund, G. Hølmer, K.F. Michaelsen, Visual acuity and erythrocyte docosahexaenoic acid status in breast-fed and formula-fed term infants during the first four months of life, Lipids 31 (1996) 99–105. [83] M. Huisman, C.M. van Beusekom, C.I. Lanting, H.J. Nijeboer, F.A. Muskiet, E.R. Boersma, Triglycerides, fatty acids, sterols, mono- and disaccharides and sugar alcohols in human milk and current types of infant formula milk, Eur. J. Clin. Nutr 50 (1996) 255–260. [84] S.M. Innis, S.S. Akrabawi, D.A. Diersen-Schade, M.V. Dobson, D.G. Guy, Visual acuity and blood lipids in term infants fed human milk or formulae, Lipids 32 (1997) 63–72. [85] Y.C. Lee-Kim, T. Park, E.J. Chung, et al., Relationship between fatty acid compositions and taurine concentration in breast milk from Chinese rural mothers, Asia Pac. J. Clin. Nutr. 7 (1998) 77–83. [86] R. Rueda, M. Ramírez, J.L. García-Salmerón, J. Maldonado, A. Gil, Gestational age and origin of human milk influence total lipid and fatty acid contents, Ann. Nutr. Metab. 42 (1998) 12–22. [87] C. Maurage, P. Guesnet, M. Pinault, et al., Effect of two types of fish oil supplementation on plasma and erythrocyte phospholipids in formula-fed term infants, Neonatology 74 (1998) 416–429. [88] S.M. Innis, D.J. King, Trans fatty acids in human milk are inversely associated with concentrations of essential all-cis n-6 and n-3 fatty acids and determine trans, but not n-6 and n-3, fatty acids in plasma lipids of breast-fed infants, Am. J. Clin. Nutr. 70 (1999) 383–390. [89] M. Xiang, S. Lei, T. Li, R. Zetterström, Composition of long chain polyunsaturated fatty acids in human milk and growth of young infants in rural areas of northern China, Acta Paediatr. 88 (1999) 126–131. [90] P. Pugo-Gunsam, P. Guesnet, A.H. Subratty, D.A. Rajcoomar, C. Maurage, C. Couet, Fatty acid composition of white adipose tissue and breast milk of Mauritian and French mothers and erythrocyte phospholipids of their full-term breast-fed infants, Br. J. Nutr. 82 (1999) 263–271. [91] N. Fidler, K. Salobir, V. Stibilj, Fatty acid composition of human milk in different regions of Slovenia, Ann. Nutr. Metab. 44 (2000) 187–193. [92] F. Marangoni, C. Agostoni, A.M. Lammard, M. Giovannini, C. Galli, E. Riva, Polyunsaturated fatty acid concentrations in human hindmilk are stable throughout 12-months of lactation and provide a sustained intake to the infant during exclusive breastfeeding: an Italian study, Br. J. Nutr. 84 (2000) 103–109. [93] M. Xiang, G. Alfvén, M. Blennow, M. Trygg, R. Zetterström, Long-chain polyunsaturated fatty acids in human milk and brain growth during early infancy, Acta Paediatr. 89 (2000) 142–147.

[94] L. Wang, Y. Shimizu, S. Kaneko, et al., Comparison of the fatty acid composition of total lipids and phospholipids in breast milk from Japanese women, Pediat. Int. 42 (2000) 14–20. [95] F. Scopesi, S. Ciangherotti, P.B. Lantieri, et al., Maternal dietary PUFAs intake and human milk content relationships during the first month of lactation, Clin. Nutr. 20 (2001) 393–397. [96] J.M. Krasevec, P.J. Jones, A. Cabrera-Hernandez, D.L. Mayer, W.E. Connor, Maternal and infant essential fatty acid status in Havana, Cuba, Am. J. Clin. Nutr. 76 (2002) 834–844. [97] A. López-López, M.C. López-Sabater, C. Campoy-Folgoso, M. Rivero-Urgell, A.I. Castellote-Bargalló, Fatty acid and sn-2 fatty acid composition in human milk from Granada (Spain) and in infant formulas, Eur. J. Clin. Nutr. 56 (2002) 1242–1254. [98] L.R. Mitoulas, L.C. Gurrin, D.A. Doherty, J.L. Sherriff, P.E. Hartmann, Infant intake of fatty acids from human milk over the first year of lactation, Br. J. Nutr. 90 (2003) 979–986. [99] A. Sala-Vila, A.I. Castellote, C. Campoy, M. Rivero, M.A. Rodriguez-Palmero, M.C. López-Sabater, The source of long-chain Pufa in formula supplements does not affect the fatty acid composition of plasma lipids in full-term infants, J. Nutr. 134 (2004) 868–873. [100] J. da Cunha, T.H. Macedo da Costa, M.K. Ito, Influences of maternal dietary intake and suckling on breast milk lipid and fatty acid composition in low-income women from Brasilia, Brazil, Early Hum. Dev. 81 (2005) 303–311. [101] E.E. Mosley, A.L. Wright, M.K. McGuire, M.A. McGuire, Trans fatty acids in milk produced by women in the United States, Am. J. Clin. Nutr. 82 (2005) 1292–1297. [102] A. Sala-Vila, A.I. Castellote, M. Rodriguez-Palmero, C. Campoy, M.C. LópezSabater, Lipid composition in human breast milk from Granada (Spain): changes during lactation, Nutrition 21 (2005) 467–473. [103] R.V. Patin, M.R. Vítolo, M.A. Valverde, P.O. Carvalho, G.M. Pastore, F.A. Lopez, The influence of sardine consumption on the omega-3 fatty acid content of mature human milk, J. Pediatr. 82 (2006) 63–69. [104] A. Sala-Vila, C. Campoy, A. Castellote, et al., Influence of dietary source of docosahexaenoic and arachidonic acids on their incorporation into membrane phospholipids of red blood cells in term infants, Prostaglandins Leukot Essent Fatty Acids 74 (2006) 143–148. [105] Y.M. Peng, T.Y. Zhang, Q. Wang, R. Zetterström, B. Strandvik, Fatty acid composition in breast milk and serum phospholipids of healthy term Chinese infants during first 6 weeks of life, Acta Paediatr. 96 (2007) 1640–1645. [106] É. Szabó, G. Boehm, C. Beermann, M. Weyermann, H. Brenner, D. Rothenbacher, T. Decsi, Trans octadecenoic acid and trans octadecadienoic acid are inversely related to long-chain polyunsaturates in human milk: results of a large birth cohort study, Am. J. Clin. Nutr. 85 (2007) 1320–1326. [107] M. Ribeiro, V. Balcao, H. Guimaraes, et al., Fatty acid profile of human milk of Portuguese lactating women: prospective study from the 1st to the 16th week of lactation, Ann. Nutr. Metab. 53 (2008) 50–56. [108] A. Tijerina‐Sáenz, S. Innis, D. Kitts, Antioxidant capacity of human milk and its association with vitamins A and E and fatty acid composition, Acta Paediatr. 98 (2009) 1793–1798. [109] Y. Peng, T. Zhou, Q. Wang, et al., Fatty acid composition of diet, cord blood and breast milk in Chinese mothers with different dietary habits, Prostaglandins Leukot Essent Fatty Acids 81 (2009) 325–330. [110] K.G. Sabel, C. Lundqvist-Persson, E. Bona, M. Petzold, B. Strandvik, Fatty acid patterns early after premature birth, simultaneously analysed in mothers' food, breast milk and serum phospholipids of mothers and infants, Lipids Health Dis. 8 (2009) 20. [111] I. Haddad, M. Mozzon, N.G. Frega, Trends in fatty acids positional distribution in human colostrum, transitional, and mature milk, Eur. Food Res. Technol. 235 (2012) 325–332. [112] C. Cruz-Hernandez, S. Goeuriot, F. Giuffrida, S.K. Thakkar, F. Destaillats, Direct quantification of fatty acids in human milk by gas chromatography, J. Chromatogr. 1284 (2013) 174–179. [113] E. Storck Lindholm, B. Strandvik, D. Altman, A. Möller, C. Palme Kilander, Different fatty acid pattern in breast milk of obese compared to normal-weight mothers, Prostaglandins Leukot Essent Fatty Acids 88 (2013) 211–217. [114] A. Szlagatys‐Sidorkiewicz, D. Martysiak‐Żurowska, G. Krzykowski, M. Zagierski, B. Kamińska, Maternal smoking modulates fatty acid profile of breast milk, Acta Paediatr. 102 (2013) e353–e359. [115] K.B. Nyuar, Y. Min, M. Dawood, S. Abukashawa, A. Daak, K. Ghebremeskel, Regular consumption of Nile river fish could ameliorate the low milk DHA of Southern Sudanese women living in Khartoum city area, Prostaglandins Leukot Essent Fatty Acids 89 (2013) 65–69. [116] C.L. Berseth, C.L. Harris, J.L. Wampler, D.R. Hoffman, D.A. Diersen-Schade, Liquid human milk fortifier significantly improves docosahexaenoic and arachidonic acid status in preterm infants, Prostaglandins Leukot Essent Fatty Acids 91 (2014) 97–103. [117] R. Lubetzky, N. Argov-Argaman, F.B. Mimouni, et al., Fatty acids composition of human milk fed to small for gestational age infants, J. Matern. Fetal. Med. 29 (2016) 3041–3044. [118] R. Barreiro, P. Regal, O. López-Racamonde, A. Cepeda, C.A. Fente, Comparison of the fatty acid profile of Spanish infant formulas and Galician women breast milk, J. Physiol. Biochem. 74 (2018) 127–138. [119] A.K. Nilsson, C. Löfqvist, S. Najm, et al., Long‐chain polyunsaturated fatty acids decline rapidly in milk from mothers delivering extremely preterm indicating the need for supplementation, Acta Paediatr. 107 (2018) 1020–1027.

10