Optimal nutrition in lactating women and its effect on later health of offspring: A systematic review of current evidence and recommendations (EarlyNutrition project)

ABSTRACT Background: EarlyNutrition (www.project-earlynutrition.eu) is an international research consortium investigating the effects of early nutrition on metabolic programming. Objective: To summarize current evidence and standards, recommendations, guidelines, and regulations on nutrition or supplements in lactating women with emphasis placed on long-term health effects in offspring, including cardiovascular disease, hypertension, overweight/obesity, metabolic syndrome, diabetes, or glucose intolerance. Methods: Medline, Embase, selected databases and websites were searched for documents published between 2010 and 2015. Results: Thirteen documents met the inclusion criteria. Effects of maternal long-chain polyunsaturated fatty acid (LC-PUFA) supplementation on overweight/obesity or hypertension in offspring were assessed in 10 studies. One study described the effect of maternal vitamin D supplementation on overweight/obesity, and the remaining 2 studies assessed the effects of maternal probiotic/synbiotic supplementation during lactation on overweight/obesity or metabolic syndrome in their infants. Forty-one documents contained dietary recommendations on various macro- and micronutrients for lactating women, but without consideration of our long-term health outcomes in infants. Conclusion: Literature on nutrition of lactating women and its effect on their infants' later health with respect to metabolic programming outcomes appeared to be scarce, and focused mostly on supplementation of LC-PUFA's. No recent guidelines or recommendations were available, highlighting the significant research gaps regarding this topic.


Introduction
Both fetal and early postnatal life are periods of rapid growth and development during which imbalanced nutrition might result in metabolic or body composition alterations (Gluckman and Hanson, 2008). Emerging evidence specifically suggests that increased risk of overweight or obesity later in life is programmed by nutrition during early life (Barker, 2004;McMillen and Robinson, 2005;Gluckman and Hanson, 2008). This relation is thought to be multifactorial and is likely to be U-shaped, with increased risks of adverse health outcomes both for early-life undernutrition as well as overnutrition (Gluckman and Hanson, 2008). Obesity in children is associated with adolescent and adult onset of noncommunicable diseases, such as type 2 diabetes mellitus, cardiovascular disease and hypertension (Barouki et al., 2012;Agostoni et al., 2013).
Given the well-known short-and long-term advantages of breastfeeding for infant and maternal health (vanRossum et al., 2005;Agostoni et al., 2009), leading health authorities such as the World Health Organization (WHO), the American Academy of Pediatrics (AAP) and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) highly recommend breastfeeding as the preferred source of postnatal nutrition. In the context of the fetal-infant programming hypothesis, maternal diet during lactation is thought to contribute to desirable long-term health advantages in children (Rush, 2001;Luoto et al., 2010) including the quality of growth in later life.
EarlyNutrition (www.project-earlynutrition.eu) is an international research project, sponsored by the European Union 7th Framework Programme (Koletzko et al., 2014b). The project's objectives include providing evidence of the effects of early nutrition on metabolic programming and their consequent health impacts. This project brings together an international consortium of experts in various research fields. The aim is to form a multilateral partnership for the enhancement of knowledge on early nutrition and metabolic programming and its impact on obesity and the risk of related disorders in adulthood.
The primary objective of the current systematic review, prepared as part of the EarlyNutrition project, was to summarize current evidence from systematic reviews and randomized controlled trials (RCTs) and standards, recommendations, guidelines, and regulations on nutrition in lactating women with emphasis on EarlyNutrition project outcomes. These include the effects on later health of the offspring with respect to adiposity overweight or obesity, cardiovascular disease, hypertension, metabolic syndrome, diabetes, or glucose intolerance. The secondary objective was to identify potential research gaps, as this will enable to develop research agendas.

Search strategy
Bibliographic databases, i.e. Ovid MEDLINE, EMBASE (both http://ovid.com), Cochrane Central Register of Controlled Trials (CENTRAL), and several selected guideline databases or websites of relevant professional organizations that may have produced guidelines were searched in May 2015 (Table 1). In addition, references were obtained by consultation of experts in the field (partners of the EarlyNutrition project). Searches in EMBASE and MEDLINE combined groups of key-words related to our target population, different nutrition components, and the type of preferred documents or study design. The detailed search strategy is provided in Table 2. All other databases, if possible, were searched with a combination of the phrases (infant Ã or child Ã ) AND (lactat Ã OR breastfe Ã OR or systematic Ã ) adj3 (bibliographic Ã or review Ã or literature)) or (meta-analy Ã or metaanaly Ã or "research synthesis" or ((information or data) adj3 synthesis) or (data adj2 extract Ã ))).ti,ab. or ((cochrane adj3 trial Ã ) or "web of science").ab. or "cochrane database of systematic reviews".jn. or ((review adj5 (rationale or evidence)).ti,ab. and review.pt.) or meta-analysis as topic/ or Meta-Analysis.pt. 32. ("clinical trial" or "clinical trial, phase i" or "clinical trial, phase ii" or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or "multicenter study" or "randomized controlled trial").pt. or double-blind method/ or clinical trials as topic/ or clinical trials, phase i as topic/ or clinical trials, phase ii as topic/ or clinical trials, phase iii as topic/ or clinical trials, phase iv as topic/ or controlled clinical trials as topic/ or randomized controlled trials as topic/ or early termination of clinical trials as topic/ or multicenter studies as topic/ or ((randomi?ed adj7 trial Ã ) or (controlled adj3 trial Ã ) or (clinical adj2 trial Ã ) or ((single or doubl Ã or tripl Ã or treb Ã ) and (blind Ã or mask Ã ))).ti,ab. 33. 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 34. 19 and 33 35. limit 34 to yr D "2010 -Current" "breast milk") AND (nutrition OR diet). Alternatively, they were simply hand searched.
Searches were limited to human studies published in the last five years (2010 and onwards), and restricted to English-language publications.

Selection of documents
Studies and documents were eligible for inclusion if they were relating to diet and nutrition for lactating women. In addition the documents had to consider the effect of this dietary exposure/ intervention on EarlyNutrition health outcomes in the offspring, i.e. adiposity, overweight or obesity, cardiovascular disease, hypertension, metabolic syndrome, diabetes, or glucose intolerance.
We excluded documents focusing exclusively on prevention or treatment of a particular disease, such as allergic diseases or iron deficiency anemia that were not related to the outcomes mentioned above, or that focused on the period of pregnancy only. In addition, scientific documents other than randomized controlled trials, systematic reviews and meta-analysis, and documents dedicated to a local community, without national or international outreach were excluded.
Two authors (MDW and either SK, PCE or JCL) searched the provided sources and screened titles, abstracts and then full-text reports for inclusion independently. The total list of titles was additionally screened by BB. Any discrepancies were resolved through discussion or by consultation with an expert in the field.

Data extraction process
For each eligible study MDW, SK, PCE, and JCL independently extracted the following data: general information (title, author, year of publication, type of document: scientific trial or guideline, recommendation or consensus statement), document characteristics (scientific trial: design, participants characteristics, intervention and control regimens), the impact on defined health outcomes, and authors' suggestions for further research. Other documents: report type, target population, brief recommendation, the impact on defined health outcomes, the level of evidence (if stated by the authors), and authors' suggestions for further research. Inconsistencies were checked and resolved through discussion.
We did not perform any formal methodological assessment of the included documents' quality, and we did not attempt to evaluate the level of evidence of each recommendation if not done so by the authors.

Determining research gaps
Research gaps, associated with EarlyNutrition outcomes, were extracted from the identified documents if recognized by the authors of the documents.

Results
Selection of documents Figure 1 shows a detailed description of the study selection process. The search strategy yielded 4218 documents, 3902 of which were excluded based on title or abstract. Full text evaluation of the remaining 316 records identified 13 documents that met our selection criteria. None of these were guidelines or clinical protocols.
The effect of maternal fatty acid supplementation was assessed in 10 of the included studies, 1 study described the effect of Vitamin D supplementation and the remaining 2 assessed the effects of maternal probiotics/synbiotic supplementation during lactation. An outline of all included studies is provided in Table 3.
Forty-one of the excluded documents did contain dietary recommendations on various macro-and micronutrients for lactating women (Table 4), but without consideration of our EarlyNutrition outcomes.
The seven systematic reviews enclosed a total of 10 publications (describing outcomes of five randomized trials), including the three RCTs we identified. The remaining seven publications were published before the year 2010, and were therefore not individually identified by our search (Helland et al., 2001;Ulbak et al., 2004;Jensen et al., 2005;Lauritzen et al., 2005;Lucia Bergmann et al., 2007;Helland et al., 2008;Asserhoj et al., 2009). Their results were however included in the current review, since the previous reviews were based upon them (Table 4).
The (updated) Cochrane review was the most recently published document and included all 10 publications. The remaining systematic reviews included part, but not all, of the publications (Table 3).
The effects of LC-PUFA supplementation exclusively during lactation was described in 1 systematic review, whereas two others additionally included supplementation during both pregnancy and lactation. The remaining four reviews also included supplementation only during pregnancy. Since this subject did not fall within the scope of the current review, we did not recite results exclusively on this topic.
Doses of n-3 LCPUFA in the described intervention groups ranged from 200 mg docosahexaenoic acid (DHA) to 1183 mg DHA plus 803 mg eicosapentaenoic acid (EPA) (with a total of 2494 mg n-3 LC-PUFA), and were derived from fish oil or algal oils.
Intervention periods extended from 15, 18, or 21 weeks of pregnancy to 3 or 4 months after delivery or exclusively during the first 4 months postpartum.
All included reviews came to the same conclusion that evidence on the potential relationship between maternal n-3 LC-PUFA intake and infant growth or later body composition was inconclusive. Supplementation with LC-PUFA did not seem to exert a clear and consistent short-or long-term benefit in offspring, and any transient early differences disappeared in subsequent assessments.
The EarlyNutrition outcome "hypertension" was assessed in two of the publications based on the same RCT (Ulbak et al., 2004;Asserhoj et al., 2009). At 2.5 years of age no difference in either systolic or diastolic blood pressure (SBP and DBP) between groups was observed. At seven years of age, children in the LC-PUFA supplemented group had a higher unadjusted mean SBP and mean arterial pressure (MAP). After adjustment for covariates SBP did not differ between the randomized groups anymore. Due to an interaction between intervention and sex (p D 0.027 for DBP and p D 0.026 for MAP), adjusted ANOVA was performed separately for the two sexes. Among boys, both DBP and MAP differed between the randomized groups, but blood pressure of girls did not.

Vitamin D supplementation during lactation
The one publication on vitamin D intake during lactation referred to the EarlyNutrition outcome overweight/obesity, and was a prospective, double blinded, randomized controlled trial of vitamin D supplementation during lactation in both mother and infant (Czech-Kowalska et al., 2014).
Examined outcomes in the infants were weight, length, head circumference, and body composition (fat mass) by dual-energy X-ray absorptiometry (DXA) measurements at three time points: three weeks after delivery (baseline visit), and three and six months after delivery. The maternal intervention group received 1200 IU/d of cholecalciferol, the control group 400 IU/d. All breastfed infants received 400 IU/d. No significant differences in body composition and bone mass as examined by DXA were found between the intervention groups at any time point. However, serum hydroxy-vitamin D status (25(OH)D) was significantly higher in the 1200 IU/d group although the recommended level (>20 ng/mL by the Institute of Medicine (IOM) or >30 ng/mL (Holick et al., 2011;Pludowski et al., 2013b;Pludowski et al., 2013a) was still not reached in many women. This might have been due to the low baseline levels at study entry (65% of postpartum vitamin D deficiency) Reasons: -not in English -not on our outcomes Figure 1. Flowchart of study selection process. 1 No access to this database outside Great-Britain. 2 Duplicates within one database or at one website were identified and excluded from the number of screened records, duplicates between databases or websites were not.    Adequate intake for lactating women is approximately 700 mL/day higher.

Australian dietary guidelines 2013
Minimum recommended intake for lactating women are > 7 serves/day of vegetables 2 serves/day of fruit 8 1 = 2 serves/day of grain/cereal (2 slices of bread D 2 serves.) 2 1 = 2 serves/day for milk, yoghurt, cheese and/or alternatives 2 1 = 2 serves/day for lean meats and poultry, fish, eggs, tofu, nuts and seeds, and legumes/beans For women who are lactating, not drinking alcohol is the safest option.

WHO 2013
Women in the postnatal period need to maintain a balanced diet. Counseling for maternal and newborn health care Iron and folic acid supplementation should also continue for 3 months after birth.
A handbook for building skills Women who are breastfeeding require additional food and should drink sufficientclean water. Australia and New Zealand, Early-Life Nutrition, Working Party 2014 Typically, a breastfeeding woman needs an additional 2,000-2,100kj per day over the recommended daily intake for women. The energy intake of a breastfeeding woman would be at least 20% fatany less may affect the fat content of your milk. Nurturing future health through nutrition Ensure an adequate intake of iodine (150mg daily) and other important vitamins and minerals.
In case of a vegan, vegetarian, or other restrictive diet, there may be a greater risk for nutrient deficiencies. Consideration of seeing a dietitian to ensure the diet is nutritionally balanced to meet the needs of breastfeeding is needed.

EFSA 2012
For lactation a protein intake of 19 g/day during the first six months, and 13 g/day after six months is recommended.

Scientific Opinion on Dietary
Reference Values for protein EFSA 2012 Available data are insufficient to establish an upper limit for n-3 LC-PUFA (individually or combined) for any population group. Scientific Opinion on the Tolerable Upper Intake Level of EPA, DHA and DPA1

EFSA 2010
The Panel proposes to set an adequate intake of 250 mg for eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) for adults based on cardiovascular considerations. To this intake 100 to 200 mg of preformed DHA should be added during lactation to compensate for oxidative losses of maternal dietary DHA and accumulation of DHA in body fat of the infant.

Dietary Guidelines for Americans 2010
For lactating women consuming 8-12 ounces/week of seafood from a variety of seafood types is associated with improved infant health outcomes, such as visual and cognitive development. Lactating women should limit white (albacore) tuna to 6 ounces/week and should not eat tilefish, shark, swordfish, and king mackerel, due to their high methyl mercury content. Lactating women should be very cautious about drinking alcohol, if they choose to drink at all.

NGC 2010
Women who are breastfeeding should consume 8 to 12 ounces of seafood per week from a variety of seafood types. Due to their high methyl mercury content, lactating women should limit white (albacore) tuna to 6 ounces per week and should not eat the following four types of fish: tilefish, shark, swordfish, and king mackerel. NGC-8567 They should maintain appropriate calorie balance to maintain weight during breastfeeding.

MICRONUTRIENTS: GENERAL ADVICE SACN 2011
There are increased requirements for a number of nutrients for lactation.
Early-Life Nutrition Report These include referent nutrient intakes set for the provision of energy (for different stages of lactation), protein, folate, vitamin A, vitamin D, vitamin C, B vitamins (thiamin, riboflavin, niacin, vitamin B12) and also for a number of minerals (calcium, phosphorus, magnesium, zinc, copper and selenium) [Department of Health, 1991]. Current advice is that all of these intakes can be achieved through a varied and balanced diet, apart from vitamin D, which requires a 10 mg daily supplement for the duration of breastfeeding in order to ensure the requirement is met.

WHO 2013
Recommended composition of multiple micronutrient supplements for lactating women, designed to provide the daily recommended intake of each nutrient ( Lactating women should be given this supplement providing one reference nutrition intake (RNI) of micronutrients daily, whether they receive fortified rations or not. Iron and folic acid supplements, when already provided, should be continued.

CALCIUM EFSA 2012
The upper limit for calcium for all adults, including lactating women is 2,500 mg. This upper limit was based on different long-term intervention studies in which a total daily intake of 2,500 mg of calcium/day from all sources (diet and supplements) was tolerated without adverse effects. Scientific Opinion on the Tolerable Upper Intake Level of calcium (Continued on next page)

WHO 2011
Vitamin A supplementation in postpartum women is not recommended for the prevention of maternal and infant morbidity and mortality.

EFSA 2015
Vitamin A population reference intakes for women are 650 mg retinol equivalent/day.

Scientific Opinion on Dietary
Reference Values for vitamin A For lactation, additional vitamin A requirements of 1300 mg retinol equivalent/day are recommended, related to transfer of retinol into breast milk.

VITAMIN C EFSA 2013
Lactating women secrete vitamin C via breast milk. Vitamin C concentration in human milk reflects maternal vitamin C intake more than the infants' requirement (WHO/FAO, 2004). The Panel notes that mean vitamin C concentration of human milk from healthy mothers not taking vitamin C supplements is in the range of 35-90 mg/L.

Scientific Opinion on Dietary
Reference Values for vitamin C For lactating women 60 mg/day in addition to the population reference intake of 95 mg/day of non-lactating women are proposed.

VITAMIN D EFSA 2012
The upper limit of vitamin D for all adults, including lactating women is 100 mg/day.

Scientific Opinion on the Tolerable Upper Intake Level of vitamin D NICE 2014
Population groups at higher risk of having a low vitamin D status including all breastfeeding women, particularly teenagers and young women, are currently advised to take a supplement that meets 100% of the reference nutrient intake for their age group. This is 10 mg/day (400 IU) for adults.

NICE guidelines [PH56]
NICE public health guidance 11, 2014 In 1991, Committee on Medical Aspects of Food and Nutrition Policy set a reference nutrient intake (RNI) of 10 mg of vitamin D per day for all pregnant and breastfeeding women.

Maternal and child nutrition
In 2007, the Scientific Advisory Committee on Nutrition confirmed that these recommendations should remain unchanged.

Public Health England 2014
Lactating women should take a vitamin D supplement (10 mg/day) to ensure they get enough vitamin D. Vitamin D: for healthcare professionals and the public NGC 2011 Midwives should offer every woman information and advice on the benefits of taking a vitamin D supplement (10 mg/day) while breastfeeding. NGC-6418 They should explain that it will increase both the mother's and her baby's vitamin D stores and reduce the baby's risk of developing rickets.

SIGN 2010
It is recommended that breastfeeding mothers take a supplement containing 10 mg vitamin D.

Management of obesity IoM 2011
There is no evidence that calcium requirements are different for lactating females compared with non-lactating counterparts, since post-lactation maternal bone mineral is restored without consistent evidence that higher calcium intake is required. The estimated average requirement for calcium for non-lactating women and adolescents are applicable, which are 800 mg/day and 1,100 mg/day respectively.
(Continued on next page) which highly depends on the maternal diet before birth and to sun exposure.

Probiotic and synbiotic supplementation during lactation
Two publications of RCTs referring to probiotic or synbiotic (both pre-and probiotic) supplementation in lactating mothers, assessing the EarlyNutrition outcomes overweight/obesity and metabolic syndrome were identified. (Aaltonen et al., 2011;Ostadrahimi et al., 2013). In the first RCT, by Aaltonen et al. 256 pregnant women in Finland were randomized to receive dietary counseling C a probiotic supplement, dietary counseling C placebo, or no counseling C placebo, starting in the first trimester until six months after delivery. Anthropometrics of the offspring were measured at three study visits (first trimester, third trimester, and six months postdelivery). In addition, infants' breastfeeding status was recorded and their metabolic status was evaluated, by serum 32-33 split proinsulin. This is a novel marker of adverse metabolic status in infancy, and has previously been shown to be a well-characterized predictor for insulin resistance in adults and older children (Mykkanen et al., 1997). The authors found that the infants' risk of high 32-33 split proinsulin concentration was significantly lower in the dietary counseling C probiotics and

REFERENCE RECOMMENDATION
Increased maternal vitamin D intakes increase maternal serum 25OHD levels, with no effect on the neonatal serum 25OHD levels of breastfed infants unless the maternal intake of vitamin D is extremely high (i.e., 4,000 to 6,400 IU/day). Observational studies report no relationship between maternal serum 25OHD levels and bone mass density. There is no evidence that lactating adolescents require any more vitamin D or higher serum 25OHD levels than non-lactating adolescents. The estimated average requirement is thus 400 IU/day of vitamin D for lactating women and adolescents. Available data do not indicate a basis for deriving upper limits for calcium and vitamin D for lactating women that are different from those for their non-lactating counterparts (2,500 mg/day calcium and 4,000 IU (100 mg)/day vitamin D)

Dietary Reference Intakes for Calcium and Vitamin
Oberhelman et al. 2013 Either single dose (150000IU) or daily maternal cholecalciferol (5000IU) can provide breast milk concentrations that result in vitamin D sufficiency in their infants. PMID 3923377 Larger trials demonstrating the safety of cholecalciferol supplementation in lactating mothers need to be conducted before universally adopting this strategy for preventing infant vitamin D deficiency.

VITAMIN K eMedicine.com 2014
The adequate intake for vitamin K for lactating women is 90 mcg/day. These recommendations only fulfill the requirement for coagulation function. Vitamin K Deficiency (Treatment)

SODIUM WHO 2012
WHO recommends a reduction in sodium intake to reduce blood pressure and risk of cardiovascular disease, stroke and coronary heart disease in adults to <2 g/day sodium (5 g/day salt) in adults (strong recommendation).

Sodium intake for adults and children
This recommendation applies to all individuals, with or without hypertension, including lactating women.

ZINC EFSA 2014
The population reference intake for zinc for adult women is 7.5-12.7 mg/day. This is derived from zinc requirement of individuals with a body weight at the 97.5th percentile for reference weights for women.

Scientific Opinion on Dietary
Reference Values for zinc During lactation, zinc requirements are an additional 2.9 mg/day, related to transfer into breast milk.

OTHER EFSA 2014
Adequate intake for adults: 40 mg/day. For lactating women, an additional 5 mg/day, is recommended to compensate for biotin losses through breast milk. Mean concentrations of biotin in mature human milk measured by microbiological assays typically range between about 4 and 6 mg/L.

EFSA 2014
The Panel concludes that no average requirement and no population reference intake for chromium can be defined, that there is no evidence of beneficial effects associated with chromium intake in healthy subjects, and that the setting of an adequate intake for chromium is also not appropriate Scientific Opinion on Dietary Reference Values for chromium

EFSA 2013
The adequate intake of fluoride from all sources (including non-dietary sources for both children and adults, including lactating women is 0.05 mg/kg/day.

Scientific Opinion on Dietary
Reference Values for fluoride EFSA 2013 The adequate intake of manganese for all adults, including lactating women is 3 mg/day.

Scientific Opinion on Dietary
Reference Values for manganese EFSA 2013 The adequate intake of molybdenum for all adults, including lactating women is 65 mg/day.

Scientific Opinion on Dietary
Reference Values for molybdenum EFSA 2014 The average requirement for niacin for all adults, including lactating women is 1.3 mg NE/MJ (5.5 mg NE/1 000 kcal, which is adopted by the Scientific Committee for Food.

Scientific Opinion on Dietary
Reference Values for niacin EFSA 2014 The adequate intake for lactating women is 7 mg/day, to compensate for pantothenic acid losses through breast milk.

Scientific Opinion on Dietary
Reference Values for pantothenic acid EFSA 2014 An adequate intake of 70 mg/day for adults was set. Based on an average amount of selenium secreted in breast milk of 12 mg/day and an absorption efficiency of 70% from usual diets, an additional selenium intake of 15 mg/day was considered to replace these losses. Thus, an adequate intake of 85 mg/day is proposed for lactating women.

Scientific Opinion on Dietary
Reference Values for selenium dietary counseling C placebo groups, compared to the control group. In a multivariate analysis, the independent effect of dietary counseling on the infants' 32-33 split proinsulin was still statistically significant (with breastfeeding and mother's glucose level at 6 months, and weight gain during pregnancy). However, there was no effect of the probiotic supplementation in this population. The second trial, by Ostradahimi et al. in 2013, was conducted in lactating mothers and their exclusively breastfed infants in Iran. The authors examined the effect of a synbiotic supplement on infant weight and growth (synbiotic: n D 40, placebo, n D 40). They found that the administration of synbiotics may prevent weight loss in undernourished lactating mothers, enhance breastfeeding duration and infant weight gain.

Research gaps
Research gaps as identified and described by the authors of the 13 included studies were summarized in Table 6. All included systematic reviews on maternal LC-PUFA supplementation pointed out that there was a wide variation in interventions, outcome parameters and follow-up periods between trials and that most trials were prone to methodological limitations. In addition, identified research gaps comprised a lack of control for nutritional status and intakes at baseline, as well as for genetic variation. The latter was based on the identification of polymorphisms in the fatty acid desaturase (FADS) gene cluster (Glaser et al., 2011;Lattka et al., 2011). This gene plays a role in the conversion of n-3 LC-PUFA's from their precursors, and it was demonstrated that pregnant and lactating women with the less common genotypes of the FADS gene cluster had very low conversion rates Lattka et al., 2011;Steer et al., 2013).
For vitamin D supplementation, the authors stated that taking into account previous studies, vitamin D supplementation seems to be a more effective source for supplementation than additional input from diet and endogenous skin synthesis in many contemporary industrialized populations with changing lifestyles (sun exposure, obesity, unhealthy diet). Yet, they feel that more studies are needed in various settings, specifically addressing infants' long-term outcomes.
The identified research gap for studies on pro-and synbiotic supplementation was the need for targeted studies to evaluate the independent effect of synbiotic supplementation in lactating mothers on infants' health outcomes.

Discussion
The EarlyNutrition project was designed to answer clinically important questions and to help in building foundations of future evidence-based recommendations. To our knowledge, this is the first systematic review assessing the effect of nutrition of lactating women on their infants' later health with respect to adiposity, overweight or obesity, cardiovascular disease, hypertension, metabolic syndrome, diabetes, or glucose intolerance. Literature on this topic appeared to be scarce, and focused mostly on the supplementation of LC-PUFA's. In the past five years, no guidelines or recommendations on nutrition in breastfeeding women relating to our defined effects on their offsprings' health were published.
The lack of literature and guidelines was unsuspected, since the programming hypothesis of early-life nutrition now is a pertinent topic. The hypothesis proposes that overweight or obesity, impaired glucose metabolism, and heightened blood pressure are modulated by environmental cues that originate in developmental plasticity, including nutritional aspects (Barker, 2004).
In both developed and less developed countries, excess body weight is now a major health problem; more than 20% of children and adolescents in Europe and more than 30% in the United States suffer from overweight or obesity (www.IASO. org). Becoming obese earlier in life clearly amplifies certain health risks such as type 2 diabetes. Based on the fetal-infant programming hypothesis it has been suggested that attempts to prevent obesity should start during early life. Alteration of early exposure to certain nutrients via maternal diet during lactation is such an attempt. However, our current review showed that (human) evidence for the effectiveness of this is so far scarce and limited to interventions with LC-PUFAs, vitamin D and probiotics/synbiotics. Acquisition of fat cells early in life appears to be an irreversible process, and early exposure to n-3 LC-PUFA's is suggested to have the potential to limit adipose tissue deposition, mainly by limiting the production of prostacyclin which has been shown to enhance adipogenesis. A deficiency in vitamin D during breastfeeding has been shown to be associated with a range of negative health outcomes in mother and child, such as cardiovascular disease, hypertension and diabetes (Pludowski et al., 2013a). Finally, research in animals and humans has shown that probiotics have an effect on the host energy metabolism by altering the gut microbiota. The combination of probiotics and prebiotics, referred to as synbiotics, may affect the host by improving the survival and the implementation of live bacterial strains in the gastrointestinal tract, thus exerting potentiated positive health effects. Our results showed that there is little evidence to support a favorable programming effect by maternal n-3 LC-PUFA or vitamin D supplementation during lactation. One small trial suggested that there might be a possible positive effect of maternal probiotic/synbiotic supplementation on infants' weight gain and body composition. Yet, much more evidence is needed to support these findings and to formulate evidence-based recommendations.
A major part of the documents excluded from this review focused on nutrition in lactating women, and some of them did include recommendations (Table 4). However, most of these recommended intakes were extrapolated from known losses of nutrients in milk, sometimes with adjustment for bioavailability, and not on possible health effects for the infants. Studies analyzing those losses also emerged from our literature search. Although these studies did not fall within the scope of our review, they can be considered crucial early stages for the documents that we were searching for, since effects of nutrients on health of offspring can only be expected if certain levels in breastmilk will be reached. Research on the extent to which the nutrient composition of human milk can be affected by maternal status and intake is on the other hand scarce (Allen, 2012). In the past, nutrients have been categorized into 2 groups during lactation. Poor maternal status of group I nutrients (thiamin, riboflavin, vitamin B-6, vitamin B-12, choline, retinol, vitamin A, vitamin D, selenium and Iodine) results in low concentrations of these nutrients in breast milk whereby the infant becomes depleted, whereas group II nutrients (folate, calcium, Iron, copper, and zinc) in breast milk are relatively unaffected by maternal intake or status; the mother gradually becomes more depleted when intake is less than the amount secreted in milk, but milk concentrations are maintained (Allen, 2012). Future research focusing on supplementation of group I nutrients in lactating women is therefore to be expected to show the clearest results on infants' health.
The major strength of the current review is the extensive search strategy. Limitations were the restriction to Englishlanguage publications leading to the possibility that eligible documents in other languages may have been omitted, and the restriction on year of publication. To ensure that we included the latest and most up-to-date documents we only considered documents published from 2010 onwards, in order to be consistent with other systematic reviews performed as part of the EarlyNutrition project. It is therefore possible that we have not included some potentially relevant documents. On the other hand, as systematic reviews were included, with studies originating more than 5 years ago, we are quite confident that the important studies are included. Another limitation is that we did not set out to critically appraise the documents that we identified, in terms of their quality, nor did we directly assess any of the information that the documents and conclusions were based upon.

Conclusions
This systematic review of current literature and recommendations on nutrition of lactating women and its effects on later health outcomes in their offspring showed that current evidence is scarce and many aspects of nutrition need further elucidation. This review can form a foundation for further research based on gaps provided by the authors of included documents and identified during the process of this review. -Pilot study in the field, therefore further studies (in undernourished mothers) are needed Synbiotic supplementation in lactating women Aaltonen et al.

Funding
-Independent effect of maternal probiotic supplementation during lactation on infants' 32-33 high split proinsulin Maternal dietary counseling, probiotic supplementation during pregnancy and lactation Rodriquez et al.
-Mechanisms on the potential relationship between maternal n-3 LC-PUFA intake and infant growth or later body composition n-3 LC-PUFA supplementation in lactating women Muhlhauser et al.
-Sufficiently powered studies, with appropriate controls, adequate blinding of participants and investigators, and high retention rates. -Mechanisms underlying long-term benefits of early nutritional interventions n-3 LC-PUFA supplementation in lactating women.