Nutritional supplements and mother’s milk composition: a systematic review of interventional studies

Background This study aims to systematically review the effects of maternal vitamin and/or mineral supplementation on the content of breast milk. Methods We systematically searched electronic databases including Medline via PubMed, Scopus and ISI Web of Science till May 24, 2018. The following terms were used systematically in all mentioned databases: (“human milk” OR “breast milk” OR “breast milk composition” OR “human breast milk composition” OR “composition breast milk” OR “mother milk” OR “human breast milk” OR “maternal milk”) AND (“vitamin a” OR “retinol” OR “retinal” OR “retinoic acid” OR “beta-carotene” OR “beta carotene” OR “ascorbic acid” OR “l-ascorbic acid” OR “l ascorbic acid” OR “vitamin c” OR “vitamin d” OR “cholecalciferol” OR “ergocalciferol” OR “calciferol” OR “vitamin e” OR “tocopherol” OR “tocotrienol” OR “alpha-tocopherol” OR “alpha tocopherol” OR “α-tocopherol” OR “α tocopherol” OR “vitamin k” OR “vitamin b” OR “vitamin b complex” OR “zinc” OR “iron” OR “copper” Or “selenium” OR “manganese” OR “magnesium”) and we searched Medline via Medical subject Headings (MeSH) terms. We searched Google Scholar for to increase the sensitivity of our search. The search was conducted on human studies, but it was not limited to the title and abstract. Methodological quality and risk of bias of included studies were evaluated by Jadad scale and Cochrane risk of bias tools, respectively. Results This review included papers on three minerals (zinc, iron, selenium) and 6 vitamins (vitamin A, B, D, C, E and K) in addition to multi-vitamin supplements. Although studies had different designs, e.g. not using random allocation and/or blinding, our findings suggest that maternal use of some dietary supplements, including vitamin A, D, vitamin B1, B2 and vitamin C might be reflected in human milk. Vitamin supplements had agreater effect on breast milk composition compared to minerals. Higher doses of supplements showed higher effects and they were reflected more in colostrum than in the mature milk. Conclusion Maternal dietary vitamin and/or mineral supplementation, particularly fat- soluble vitamins, vitamin B1, B2 and C might be reflected in the breast milk composition. No difference was found between mega dose and single dose administration of minerals.


Background
Human milk is known as the most convenient and available food source for infants in the first 6 months of life. Consuming breast milk should be continued until the end of the second year of an infant's life with suitable complementary foods. Human milk has a substantial effect on infant growth and development [1,2]. Consequently, study on the composition of human milk is of crucial importance.
Maternal breast milk composition usually depends on maternal nutrition [3,4], as has been indicated in previous studies [2][3][4][5]. A systematic review found that maternal dietary intake, particularly fatty acids, and some micronutrients, such as fat-soluble vitamins, vitamin B1 and C, was associated with micronutrient content in breast milk [2].
Micronutrients and vitamins are also very important factors for the development and growth of infants. Micronutrients and vitamins have a profound effect on the neural development of children, metabolic processes, development of soft tissues and muscles, transport of oxygen and synthesis of DNA. Micronutrients and vitamins also have anti-infectious effects and anti-oxidant effect, which is very important in infancy [3,4]. Lack of some of micronutrients and vitamins cause some diseases such as rickets and vitamin d, hemolytic anemia and also severe anemia with iron, hydrocephalus and vitamin B12, xerophthalmia and vitamin A and recurrent infectious diseases with vitamin A and E [6,7].
Many studies have been done on the composition of human milk and comparing human milk composition with infant formula. Unlike infant formula which has a standard and fixed composition, human milk composition varies due to factors such as maternal age, maternal parity, nutritional factors, behavioral factors, maternal hormones, environmental factors, infant sex, time of lactation and many other factors [8,9]. One of the biggest impacts on human milk composition is maternal nutritional status and diet. Many studies have investigated the effect of the amount and type of foods and supplements, such as micronutrients and vitamins that were consumed by mothers, and their effect on human milk. The results of these surveys were widely varied and occasionally contrasting. Maternal diet can influence her milk combination by different metabolic pathways that produce indirect effects and also some metabolic pathways regulate certain human milk combination directly through dietary intake [9][10][11].
In our recently published systematic review by on the effect of maternal diet on human milk composition [2], we found that the association for some elements were stronger including fatty acids and an attenuated association was found with fat soluble vitamins, vitamin B1, and vitamin C. The effects of maternal nutrition on breast milk composition are not the same in all components of macro-and micronutrients; therefore, the question is raised whether maternal supplement use can affect milk composition more than maternal diet.
Another study conducted on Nigerian mothers and their infants at birth and 6 month, showed that concentrations of fatty acids and vitamins such as vitamins A, C, and B6 reflected the respective dietary intakes of these nutrients in the maternal diet [12]. Conversely some other studies showed that the mineral content of human milk is generally considered less related to maternal dietary intakes [13][14][15].
Previous results on the effect of maternal micronutrients and vitamin intake on human milk are contradictory. Therefore, this study aims to systematically review the effects of maternal vitamin and/or mineral supplementation on breast milk content.

Methods
The review study was designed in accordance with the protocols of Systematic Review and Meta-Analysis (PRIS MA) [16]. The study protocol is registered in the PROS-PERO with identification number of CRD42020209008.

Literature search
We systematically searched the electronic databases including Medline via PubMed, Scopus and ISI Web of Science till May 24, 2018. The following key words were used systematically in all mentioned databases: ("human milk" OR "breast milk" OR "breast milk composition" OR "human breast milk composition" OR "composition breast milk" OR "mother milk" OR "human breast milk" OR "maternal milk") AND ("vitamin a" OR "retinol" OR "retinal" OR "retinoic acid" OR "beta-carotene" OR "beta carotene" OR "ascorbic acid" OR "l-ascorbic acid" OR "l ascorbic acid" OR "vitamin c" OR "vitamin d" OR "cholecalciferol" OR "ergocalciferol" OR "calciferol" OR "vitamin e" OR "tocopherol" OR "tocotrienol" OR "alphatocopherol" OR "alpha tocopherol" OR "α-tocopherol" OR "α tocopherol" OR "vitamin k" OR "vitamin b" OR "thiamin" OR "vitamin B1" OR "vitamin B12" OR "vitamin B6" OR "vitamin B7" OR "vitamin B3" OR "vitamin B2" OR "vitamin b complex" OR "thiamine" OR "riboflavin" OR "niacin" OR "pantothenic acid" OR "pyridoxine" OR "biotin" OR "folate" OR "cobalamin" OR "zinc" OR "iron" OR "copper" OR "selenium" OR "manganese" OR "magnesium"). Also, we searched Google scholar to increase the sensitivity of our search. The search was conducted on human studies, but it was not limited to title and abstract because our desired results or outcomes might have been considered a secondary aim of the studies and mentioned in the full text of articles. Limitations were applied to exclude conference papers, editorials, letters, commentary, short surveys, and notes. We did not consider any time limitation. Only English papers were used in the current review.

Hand searching
We checked the reference list of the published studies to increase the sensitivity and to identify more related studies.

Ethical consideration
Ethical approval was not required as this was a secondary study.

Data management
We used EndNote program (version 6) for managing and handling extracted references that were searched from databases. Duplicates were removed and entered into a duplicate library.

Selection criteria
Studies identified from the literature search were selected on the basis of the predefined selection criteria presented later:

Inclusion criteria
1-All interventional studies (randomized controlled trial, quasi experimental) 2-Studies that have studied the effect of any nutrient (macro or micro) and/or (?) supplements on human milk composition. 3-Studies assessing the composition of mother's milk.

Exclusion criteria
1. Conference papers, editorials, letters, commentary, short surveys, and notes 2. Animal studies 3. Laboratory studies 4. Studies that have studied the effect of any nutrient intake (macro or micro) and/or supplements on blood serum of mothers or infants (only the effect of nutritional supplements on milk composition were included). 5. Studies that used fortified foods, vegetables and/or fruits (oranges, carrots, etc.) rather than dietary supplements.

Assessment of study quality
For quality assessment we used Jadad scale for classification and ranking the methodological quality of eligible studies [17]. According to the study design such as randomization and blinding, each study was classified with a score ranging from 0 to 5, and studies with Jadad score above 3 were considered a high quality study.

Quality of included studies and risk of bias assessment
Quality assessment of each included study according to Jadad scale is demonstrated in the last column of Tables 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. Also, Figs. 1 and 2 show risk of bias item presented as a percentage and risk of bias item for each included study, respectively.

Risk of bias assessment
We assessed the quality of the included studies using the risk of bias assessment tools developed by the Cochrane Collaboration [1], covering the following six domains: sequence generation, allocation concealment, blinding, incomplete data, selective reporting, and other bias. Two reviewers independently conducted the risk of bias evaluation and resolved any disagreement by discussion with a third reviewer. The reviewers' judgment is categorized as 'Low risk', 'High risk' or 'Unclear risk' of bias. RevMan (version 5.3) software was used for graphical display of risk of bias of included studies.

Data extraction and abstraction
We retrieved 4046 unique references after removing duplicates (in the basic search 1971 articles were duplicates that were found and removed using EndNote, Fig. 3). Of them, 3034 were excluded on the basis of the title and abstract. For the remaining 1012 articles, the full text was retrieved and critically reviewed. After the selection process, 67 papers were included in this systematic review.
Two independent reviewers (MK and RS) screened the titles and abstracts of papers, which were identified by the literature search, for their potential relevance or assessed the full text for inclusion in the review. In the case of disagreement, the discrepancy was resolved in consultation with an expert investigator (RK).
Two reviewers abstracted the data independently (MK and RS). The required information that was extracted   Breast-milk βcarotene concentrations were higher in all women supplemented with βcarotene, but breast-milk retinol concentrations were higher only in women who received β -carotene + zinc. Zinc concentrations did not differ among groups in mothers and infants. Six months postpartum, plasma retinol concentrations were higher in the women who received zinc during pregnancy than in women who did not.

randomized controlled trial
To determine effect of continuous oral doses of b-Caroten on breast Milk composition.

Carotenoids b-Caroten isomers
In the experimental group, the mean maternal milk concentration of alltrans b-carotene significantly increased to seven times the baseline level by the end of the supplementation period. The maternal milk concentration of 9-cis bcarotene significantly increased to three times the baseline level by the end of the supplementation period.

2/5 Americas (AMRO)
Klevor [34] Women were randomly assigned to receive either the multiplemicronutrient supplement (MMN) providing 18 micronutrients, including 800 mg retinol equivalents of vitamin A, or the lipidbased nutrient supplement (LNS) with the same nutrients as the MMN group, plus 4 minerals and macronutrients, until 6 mo postpartum; a control group received iron and folic acid during pregnancy and a placebo (calcium tablet) during the first 6 months postpartum.
1320 women during pregnancy (≤20 wk. of gestation to delivery) and the first 6 mo postpartum.
A randomized, partially double-blind, controlled trial Assessing effect of daily supplementation with approximately the recommended daily intake of vitamin A in LNS or a multiplemicronutrient supplement (MMN) during pregnancy and the first 6 mo postpartum on breast milk retinol concentration at 6 mo postpartum.

Breast milk vitamin A
There were no significant differences in any of these outcomes among intervention groups and results did not change after controlling for significant covariates. We found no significant effect of daily lowdose vitamin A provided in LNS or MMN during pregnancy and the first 6 mo postpartum on breast milk retinol concentration at 6 mo postpartum.

5/5 Africa (AFRO)
Lietz [35] control group (n = 30), the sunflower oil group (n = 30), and the red palm oil group (n = 30)   from all eligible papers was as follows: data on first author's family name, year of publication, country of the study, type of supplement or food, characteristics of participants, type of study, aim, type of nutrients evaluated in the milk and the main findings of studies. Accordingly, because of the importance of the study areas, as shown in Tables 1, 2

Effect of mineral supplements on breast milk composition
In total, three minerals including zinc (3 papers), iron (4 papers) and selenium (6 papers) were reviewed. The summary of the effect of mineral supplements on breast milk content is presented in Tables 8, 9 and 10. Some findings are mentioned here, briefly.

Zinc
Two studies showed that zinc supplementation for lactating women positively influenced breast milk zinc levels [15,72] and maternal body stores [72]. However, another study found that the milk zinc level decreased significantly for all lactating women, and there was no significant difference in the rate of declining zinc levels between women who started supplementation during lactation and those who were not supplemented [71].

Iron
Most studies found that iron supplementation did not significantly change iron levels of milk [80][81][82]. However, iron supplementation increased the total iron ligands in breast milk, measured by total iron-binding capacity and increased the proportion of lactoferrin in total protein secreted [81]. Breast milk lactoferrin levels seemed to be higher among supplemented women [81].

Selenium
Most studies showed that selenium supplementation increased breast milk selenium levels [73,74,[76][77][78]; however, a recent study found that selenite supplementation was not related to a change of plasma or breast milk selenium concentrations [75].

Effect of vitamin supplements on breast milk composition
In total, six vitamins including vitamin A, B, D, C, E and K in addition to multi-vitamin supplements were reviewed. The summary about the effect of vitamin  supplements on breast milk content is presented in Tables 1, 2, 3, 4, 5, 6 and 7. Here, we mention some findings in brief.

Vitamin A
In total, 26 studies investigated the effect of vitamin A or its different supplementary forms including retinol, red palm oil (rich in pro-vitamin A), retinylpalmitate, βcarotene, and retinol palmitate on breast milk content. Vitamin A supplementation resulted in significantly increased retinol content, or α and β-carotene concentrations of breast milk in most studies [18-25, 27, 30, 31, 33, 35-39, 41, 42]. However, some studies found no association of vitamin A supplementation on breast milk composition [26,28,32,34,43].

Vitamin D
Vitamin D supplementation increased 25-hydroxy-D levels of breast milk [54-56, 58, 59], but in a recent study no significant incremental change was observed in 25 (OH) D levels of breast milk, however, change in 25 (OH) D levels in breast milk in the vitamin D supplemented group was significantly different from that of the placebo group [57].

Vitamin C
Vitamin C supplementation resulted in a significantly higher ascorbic acid level in human milk [53], however in another study there was no significant change in maternal milk after vitamin C supplementation [52].

Vitamin K
Vitamin K supplemented groups had significantly higher vitamin K (phylloqinone) milk concentrations in most studies [63,65,66].

Vitamin E
Breast milk α-tocopherol levels increased after supplementation in the intervention group [62,64,83], however, no significant time-dependent changes were observed in breast milk [61]. Maternal supplementation with 400 international units of RRR, α, tocopherol increased vitamin E concentrations of the colostrum and transitional milk [60,64,83] but not of the mature milk [83].

Multiple vitamins
Significant increases were observed in the retinol and αtocopherol levels of the colostrum among women who received vitamin A [68]. β-carotene supplementation did not significantly change the milk β-carotene  concentrations, other carotenoids, retinol or tocopherol [29,67] and retinol [67]. However, it is also reported that β-carotene supplementation might increase the mean β-carotene content of milk [67]. Another study showed that daily vitamin A and β-carotene supplementation during pregnancy and lactation resulted in increased retinol, β-carotene and α-carotene content of human milk at all time points during the first year postpartum [70]. However, supplementation with multivitamin (thiamin, riboflavin, vitamin B6, niacin, vitamin B12, vitamin C and E) was not associated with changes of β-carotene content, but it significantly decreased the γtocopherol levels of human milk at all times during lactation, and also reduced the retinol levels at delivery [70].

Previous systematic reviews
Based on our search in the mentioned databases, we found no comprehensive study quantifying the effects of dietary supplements including vitamins and minerals on breast milk composition. We found few systematic reviews on the effects of vitamin D [84], vitamin A [85], and vitamin K supplements on breast milk composition [86]. Additionally, two studies examined the effects of maternal nutrition and diet on breast milk composition, but not the effects of supplements on breast milk composition [2,13].

Risk of bias of the included studies
According to Fig. 1, we found that the most common bias was related to random sequence generation and blinding. Also, allocation concealment was the most unclear risk of bias. The least bias included attrition bias and reporting bias.

Discussion
This study systematically reviewed the effect of mineral and vitamin supplementation on breast milk composition. Different randomized controlled trials revealed the possible effect of maternal supplementation on breast milk content. Breast milk of healthy, well-nourished mothers contains almost all the necessary nutrients for an infant's growth and development. Association of maternal dietary supplements and milk composition might reflect the nutrient metabolism, since many ingredients of human milk are derived from maternal blood. In addition, understanding the effect of maternal nutrient supplementary intake on breast milk composition seems important, because almost all pregnant and lactating mothers receive supplements.
Previous studies have mostly focused on the effect of single vitamin or mineral supplementation on breast milk, while there is no comprehensive review on the effect of various vitamin and/or mineral supplementation during pregnancy and lactation and its impact on maternal milk composition.

Vitamin A supplementation and breast milk
Randomized controlled trials evaluating the effect of postpartum maternal vitamin A supplementation indicated a significant improvement in maternal serum retinol, breast milk retinol and vitamin A liver stores, after single dose of vitamin A supplementation.  Vitamin A supplementation might be given in different formulations including vitamin A, measured in retinol units (IU) of retinylpalmitate, water miscible formulation or β-carotene. Synthetic β-carotene supplements resulted in improved breast milk vitamin A content, compared with dietary intake of β-carotene [87]. There is controversy regarding the duration of vitamin A supplementation, possibly due to the different breast milk collection methods. It has been suggested that although vitamin A supplementation did not show any adverse side effects, but this might not apply for women and infants from well-nourished populations [87].
Type of interventions were different between studies, including maternal vitamin A supplementation (β-carotene or retinylpalmitate or water miscible formulation) alone or in combination with other micronutrients (iron, folic acid, vitamin E) in comparison with placebo, no intervention, other micro-nutrient or a low dose of vitamin A [87]. In addition, coexisting vitamin A, zinc and iron deficiencies are common nutritional problems and evidence suggests that zinc status affects some aspects of vitamin A metabolism such as absorption, transportation and its usage [87].
It has been suggested that the baseline vitamin A status of breast milk might affect the results of supplementation studies [87]. Continued exclusive breastfeeding for 6 months indicated a greater cumulative need for vitamin A compared to mothers who give only 1, 2 or 3 breastfeeds per day. In addition, the follow up pattern of subjects with initial normal or high values of vitamin A is different from those with already low values at starting time [87]. Moreover, some studies did not clarify the techniques used for maternal milk collection or which breast was used, and time of milk collection was also not considered. Some studies suggest that it was not possible to distinguish between full-breast sample collection and on-demand collection [87].
As vitamin A is fat-soluble and carried in lipid phase, the variability of fat content of milk needs to be considered. This might also result in sampling errors due to non-standardized collection methods. This error could also be explained by the content of the breast from which the sample collection occurred; fuller breast usually have lower fat content [87,88]. Moreover, fat content of milk which affects vitamin A concentrations is related to the time of day that samples are taken. Consistently, previous studies indicated greater agreement for lipid content in group and did not increase at all in the control group. Α-Tocopherol concentration of the transitional milk in the supplemented group was 35% higher compared with the control group.

Randomized clinical trial
To evaluate the effect of maternal supplementation with vitamin E on the concentration of α tocopherol in colostrums and its supply to the newborn.
a-tocopherol After supplementation, the mean concentration of -tocopherol in the mothers' colostrums was 1650.6 ± 968.7 and 2346.9 ± 1203.2 mg/dL in the CG and SG groups, respectively. However, the mean αtocopherol concentrations in supplemented women increased the concentration of αtocopherol secreted in colostrums by 61% (p < 0.001).

3/5 Americas (AMRO)
maternal milk collected between 6 AM and 8 AM of fasting women and greater variation in breast milk collected between 12 noon and 2 PM, and between 4 PM and 6 PM. This may explain differences between study findings without appropriate homogenization of procedures [89].

Vitamin D supplementation and breast milk
The vitamin D content of human milk is completely variable and might be affected by season, maternal dietary intake of vitamin D, and ethnicity. Most previous studies have demonstrated that maternal vitamin D supplementation increased vitamin D content of human milk [54-56, 58, 59], but a recent study found no significant changes in breast milk 25 (OH) D levels [57]. It seems that as mothers provided milk samples at different time points including months 1, 2, 3 and 4 of lactation, this could have affected the study results. Also, recent evidence has shown that there is a possibility of correlation between some minerals and levels of vitamin D [90][91][92].

Thiamin and riboflavin supplementation and breast milk
The main form of thiamin in milk is thiaminmonophosphate (TMP) with some free thiamin [93,94], while flavin adenine dinucleotide (FAD) is the main source of riboflavin, in addition to free riboflavin and few amounts of other flavin compounds [95]. However, little is known about mechanisms related to the transport of vitamins B1 and B2 to breast milk or possible alterations of vitamer uptake due to supplementation. Previous studies reported that maternal thiamin supplementation resulted in higher thiamin content of breast milk [96], however, it seems that thiamin is transferred into breast milk in limited amounts [96]. Previous research in the US indicated no effect of thiamin supplementation on breast milk

Vitamin K1
To test the influence of diet, mothers were given oral supplements of vitamin K I. Doses of 0.5-3 mg produced substantial rises in breast milk vitamin K I with peak levels between 12 and 24 h. In one mother in whom the milk sampling was standardized, a doseresponse relationship was observed.

Randomized clinical trial
To determine the effect of maternal supplementation with a megadose of retinyl palmitate in the immediate postpartum on atocopherol concentration in the colostrums.
Retinol, atocopherol A significant increase (P = 0.00) was observed in colostrums retinol in the supplemented group 24 h after administration of the retinyl palmitate capsule. A significant increase (P = 0.04) was also found in colostrums atocopherol concentration after vitamin A supplementation.
The amounts of phosphorylated vitamers might either decrease or not change over time, therefore possible phosphorylation of thiamin, hydrolysis of thiamin pyrophosphate (TPP) or secretion of thiamin   monophosphate (TMP) might be up-regulated in the early phase of lactation [47]. Among all vitamers of thiamin in human milk, only free thiamin levels increased during lactation which suggests an active transport of this vitamer to mammary glands. The major vitamer, TMP, might transport actively into the milk, but could also be found as a phosphorylation process of free thiamin or hydrolysis of TPP. Transportation, phosphorylation or hydrolysis processes might be up-regulated in the early stages of lactation. Riboflavin supplementation is associated with higher levels of vitamin B2 in maternal milk [44,96]. Free riboflavin is generally used in supplements, thus a greater increase in this vitamer is expected which suggests its efficient absorption and transport to breast milk, rather than conversion to its co-enzymatic forms prior to secretion. Supplementation might increase free riboflavin content of maternal milk, but not necessarily FAD levels, suggesting a favorable secretion of its free forms to breast milk [47]. More research is needed for a better understanding of mechanisms for vitamin secretion to maternal milk, factors associated with vitamer conversion in the mammary glands and the role of vitamers.

Vitamin C supplementation and breast milk
Little is known about the impact of increased intake of vitamin C on human milk. Previous reports demonstrated that increased intake of vitamin C in women with low maternal vitamin C content at baseline, might increase vitamin C levels of human milk [52,53,100]. In a previous study, a relatively high dose of vitamin C caused a modest response among European women compared to a 3-fold increase in mean human milk vitamin C levels of African women [53]. It has been suggested that there is an upper  To determine the factors that affect milk iron content at the second week of lactation and whether supplementation to lactating mother with iron might increase breast milk iron content between 2 weeks and 4 months postpartum.
Iron and zinc Iron supplementation to lactating nonanemic mothers did not change milk iron content and the decline in milk iron content and milk-toserum iron ratio. Milk iron content and milk-toserum iron ratio of iron could be regulated by active transport in cooperation with maternal iron status. Iron supplementation did not alter significantly iron and zinc levels in milk and the low iron to lactoferrin ratio was maintained, thus preserving the important functions of lactoferrin for the infant organism. However, iron supplementation increased total iron ligands in milk as measured by the total iron-binding capacity and increased the proportion of lactoferrin in total protein secreted. Also, lactoferrin levels tended (P = 0.059) to be higher in milk of the supplemented women.
2/5 Americas (AMRO) limit for ascorbic acid secreted by the mammary glands, possibly due to the saturation of the gland with vitamin C [52,100], however, the mechanism related to the regulation of ascorbic acid saturation and secretion by the glands are not completely understood. Differences between study findings suggest that there is significant variation in breast milk ascorbic acid content of individuals living in different regions. Moreover, milk samples were collected at different times, and the amount of milk expressed at each sampling varied. Lack of access to modern analytic techniques such as HPLC was another possible explanation; simple methods such as titration measures only reduced vitamin C (ascorbic acid) and not the total ascorbic acid. Based on previous studies, the dehydro-ascorbic acid level of human milk is lower than its reduced ascorbic content [53]. Dietary intake data was not collected in some studies, and urinary excretion of ascorbic acid was not monitored, as well [52,53,100].

Vitamin E supplementation and breast milk
Studies on the effect of maternal vitamin E supplementation on breast milk are scarce and inconclusive; some reported a correlation between supplementation and breast milk vitamin E levels and some did not [60,101,102]. Maternal supplementation with R, R, R, α-tocopherol increased vitamin E levels of colostrum and transitional milk, but not the vitamin E of mature milk [102]. The positive effect of vitamin E supplementation on colostrum and transitional milk might be explained by increased synthesis of fatty acids by the mammary gland in the first few days after childbirth [103], due to the role of vitamin E in lipid metabolism. The mechanisms responsible for vitamin E transfer into breast milk have not been completely clarified, but it seems that α-tocopherol reaches the milk via LDL receptors [102,104].
Previous studies indicated that vitamin E transportation to breast milk through independent and distinct mechanisms and limited by receptors, because maternal serum α-tocopherol content is not related to colostrum α-tocopherol levels [105]. Michaelis-Mentenkinetics is another hypothesis for α-tocopherol transfer to breast milk. This could transport vitamin E to the mammary gland regardless of its plasma levels [106,107].
Some limitations of previous studies are as follows; reduced number of initial participants, and loss to follow up for analysis of α-tocopherol in mature milk. In addition, different dietary habits might explain differences between study groups [102]. The results provide evidence on the importance of maternal vitamin E supplementation, especially among women with preterm infants, to meet infant vitamin E requirements and protect them against oxidative stress [102,108].
However, studies suggest that a single mega dose of 400 IU vitamin E seems not to be enough to increase vitamin E content of breast milk for a prolonged time [102].

Β-carotene supplementation and breast milk
Information is lacking regarding changes in milk carotenoid content of healthy, well-nourished women in the first month of lactation. Role of carotenoids in breast milk is not completely understood. It has been suggested that high levels of carotenoids transferred to infants during the first few days of lactation could correct abnormally low levels of β-carotene in neonates [109]. Other studies have indicated that βcarotene supplementation of lactating mothers could increase the β-carotene content of breast milk [67,110,111]. Lack of increase in milk β-carotene content suggests that transitional milk might be saturated with βcarotene. The higher milk lutein levels and subsequent decrease in plasma lutein, suggests that lutein metabolism might be changed in early lactation [29]. The lack of effect of β-carotene supplements on retinol, αtocopherol and other carotenoid levels of milk are consistent with previous reports [29,67].
Different results might be explained by different techniques used to measure carotenoid content; before development of HPLC, separation methods reported only total carotenoid content [29], while HPLC technique provided more details on each specific carotenoid level. Moreover, interpretation was limited to small sample size, lack of maternal dietary intake data or lack of milk fat content as a variable. It has also been suggested to consider milk fat variations in milk carotenoid analysis [29,33,67,112].

Limitation and strengths
Because of large heterogeneity between studies, we could not conduct a meta-analysis; however, this comprehensive review provides sufficient information on the effect of maternal vitamin and/or mineral supplementation breast milk composition.
Other underlying factors including significant individual variation in diet, role of dietary intake data and analysis, over and/or underestimation of dietary intake, milk sample collection method, different dose and forms of supplementations (natural vs. synthetic), different techniques for nutrient measurements, race and/or ethnicity, postpartum milk sampling, time of milk sampling, baseline nutrient level of breast milk, and duration of breastfeeding, might partly explained the large variation between studies. Maternal baseline nutritional status might be considered prior to supplementation. In addition, some methodological differences between studies, including not using random allocation and/or blinding as an important part of a clinical trial, might affect study results.

Limitations of the Jadad score
Considering three criteria (randomization, doubleblinding, and a description of dropouts), the Jadad scale, is a common tool used to summarize quality measures of randomized controlled trials (RCTs). However, the Jadad scale has its limitations [113,114]. First, the double blinding criterion is usually reported in around 10 to 20% of studies. Moreover, although the double blinding criterion accounts for 40% of the Jadad score, it is suggested that many trials involve devices, physical training, surgery, or other interventions e.g. exercise training for which double blinding is either impractical or impossible. In addition, the Jadad score does not Fig. 2 Risk of bias summary review: authors' judgements on each risk of bias item for each included study assess the appropriateness of the data analysis, or allocation concealment, or of intention to treat, among other glaring deficiencies [115,116].

Conclusion
In conclusion, studies with different designs, e.g. not using random allocation and/or blinding, found that maternal dietary vitamin and/or mineral supplementation, particularly fat soluble vitamins, vitamins B1, B2 and C were reflected in breast milk composition. Moreover, vitamin supplements had greater effects on the breast milk composition compared to minerals. Higher dose of supplements showed more effects, and they were reflected in colostrum more than in mature milk. No difference was found between amega dose and a single dose administration of minerals.