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Does initial breastfeeding lead to lower blood cholesterol in adult life? A quantitative review of the evidence^1,2,3

¹ From the Division of Community Health Sciences, St George's, University of London, London, United Kingdom (CGO, PHW, SJK, DGC, ARR, and DPS); the Department of Social Medicine, University of Bristol, Bristol, United Kingdom (RMM and GDS); Public Health and Clinical Medicine, Umea University, Umea, Sweden (EB); the MRC National Survey of Health and Development, Department of Epidemiology and Public Health, Royal Free and University College Medical School, London, United Kingdom (SB and MEJW); the MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton, United Kingdom (CHF); the Department of Preventive Medicine, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, NY (JLF and JN); The George Institute, Sydney, Australia (RRH); the University Department of Paediatrics, Children's Hospital Zagreb, Zagreb, Croatia (SK); the Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, United Kingdom (CPL): the School of Clinical Medical Sciences, Newcastle University, and Sir James Spence Institute, Royal Victoria Infirmary, Newcastle-upon-Tyne, United Kingdom (MSP); the Department of Clinical Physiology, Turku University Central Hospital, Turku, Finland (OTR and IL); the Department of Medical Informatics, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands (ACR); and the Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand (SMW)

² Supported by the British Heart Foundation (project grant no. PG/04/072).

³ Reprints not available. Address correspondence to CG Owen, Division of Community Health Sciences, St George's, University of London, Cranmer Terrace, London SW17 ORE, United Kingdom. E-mail: cowen{at}sgul.ac.uk.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

 
Background: Earlier studies have suggested that infant feeding may program long-term changes in cholesterol metabolism.

Objective: We aimed to examine whether breastfeeding is associated with lower blood cholesterol concentrations in adulthood.

Design: The study consisted of a systematic review of published observational studies relating initial infant feeding status to blood cholesterol concentrations in adulthood (ie, aged >16 y). Data were available from 17 studies (17 498 subjects; 12 890 breastfed, 4608 formula-fed). Mean differences in total cholesterol concentrations (breastfed minus formula-fed) were pooled by using fixed-effect models. Effects of adjustment (for age at outcome, socioeconomic position, body mass index, and smoking status) and exclusion (of nonexclusive breast feeders) were examined.

Results: Mean total blood cholesterol was lower (P = 0.037) among those ever breastfed than among those fed formula milk (mean difference: –0.04 mmol/L; 95% CI: –0.08, 0.00 mmol/L). The difference in cholesterol between infant feeding groups was larger (P = 0.005) and more consistent in 7 studies that analyzed "exclusive" feeding patterns (–0.15 mmol/L; –0.23, –0.06 mmol/L) than in 10 studies that analyzed nonexclusive feeding patterns (–0.01 mmol/L; –0.06, 0.03 mmol/L). Adjustment for potential confounders including socioeconomic position, body mass index, and smoking status in adult life had minimal effect on these estimates.

Conclusions: Initial breastfeeding (particularly when exclusive) may be associated with lower blood cholesterol concentrations in later life. Moves to reduce the cholesterol content of formula feeds below those of breast milk should be treated with caution.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

 
Coronary heart disease (CHD) is the most common cause of death in Westernized societies, accounting for one-fifth of all mortality in the United Kingdom (1). Elevated concentrations of circulating blood cholesterol in adult life (total and LDL cholesterol in particular) are strong and reversible risk factors for CHD in adulthood (2, 3). Factors operating in adult life, including diet (particularly fat intake), are important influences on adult blood cholesterol concentrations (4-7). However, increasing evidence has suggested that early nutritional exposures, perhaps in the first weeks of postnatal life, may also modify cardiovascular risk, including blood cholesterol concentrations, in later life (8, 9). Our previous systematic review and meta-analysis showed that mean blood total cholesterol concentrations in breastfed subjects, compared with those in formula-fed subjects, were higher in infancy, similar in childhood, and lower in adult life (10). In agreement with earlier studies (11, 12), this finding led us to hypothesize that early exposure to the high cholesterol content of breast milk could affect long-term cholesterol metabolism (10). Although nutritional programming of cholesterol synthesis in later life is biologically plausible (13), there were several weaknesses in the data presented in our earlier review (10), which limited the strength of evidence for a causal association between breastfeeding and lower blood cholesterol concentrations in later life. First, the number of studies was small, with only 5 reports available for inclusion. Second, because almost all of the studies examining this association were observational, there was a possibility of confounding, particularly by familial and socioeconomic circumstances, which could not be taken into account with the published data available. Third, information on infant feeding practices was limited, partly because, in many cases, information was based on long-term recall and also because it was not always possible to distinguish exclusive breastfeeders or bottle feeders from mixed feeders. The inclusion of mixed-fed subjects in any comparison may dilute any potentially advantageous or harmful effects. We have therefore updated our review in an attempt to address these issues, using, insofar as possible, data provided by the authors of individual studies, to establish with greater precision the strength of the relation between infant feeding and blood cholesterol. We have focused entirely on total cholesterol, which is strongly associated with CHD risk (3), because considerably more data are available for this outcome than for LDL cholesterol. In our earlier review (10), the relations of infant feeding with both total and LDL cholesterol were extremely similar.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

 
Systematic review process
Eligible studies were those that collected data on initial infant feeding practices and measured concentrations of total blood cholesterol in adult life (defined as 16 y old). We searched MEDLINE (1950 to June 2007), EMBASE (1980 to June 2007), and Web of Science (1970 to June 2007) databases by using a combined text word and MESH and subject headings (for MEDLINE and EMBASE, respectively) search strategy (see Appendix A). The electronic search (conducted by SJK) was restricted to studies carried out in human subjects that were reported in English. In total, 1499 unduplicated references were found; a review of abstracts (conducted independently by CGO and SJK) showed that 21 (14-34) were relevant (Figure 1). Three publications were excluded: one study examined only the association between duration of breastfeeding and fasting plasma lipids at 17 y of age, and there was no formula-fed group for comparison (21); one examined the effect of nutritional supplementation in pregnant mothers, infants, and children on serum lipids in later life (18); and one was a review (22). Hence, 18 publications (representing 17 studies with 17 498 participants) were included in the review. (See Figure S1 under "Supplemental data" in the current online issue.) All were observational studies of either cross-sectional (with long-term recall of infant feeding practices) or longitudinal design.

View larger version (48K): [in this window] [in a new window]   FIGURE 1. Flow diagram showing the number of studies included in and excluded from the meta-analysis.

Table 1

Statistical analysis
Statistical analyses were carried out with the use of STATA/SE for WINDOWS software (version 9.2; StataCorp LP, College Station, TX). To carry out the meta-analyses, we used the mean difference in total cholesterol between those initially breastfed and those formula-fed and the SE of the difference from each study, with the adjustments listed 1–4 above. Heterogeneity in mean differences in total cholesterol between studies was examined by using chi-square tests. Fixed-effect models are reported throughout because they reflect only the random error within each study, and they are less affected by publication bias (whereas small studies tend to publish larger estimates). Funnel plots, Begg tests, and Egger tests (37-39) did not show any evidence of small study bias (P > 0.8 for all Begg and Egger tests). The effect among exclusive and nonexclusive feeders was compared by using meta-regression and sensitivity analysis. Because an a priori decision was made to consider studies with "pure" exposure, further analyses were carried out on a subgroup of studies that reported exclusive breastfeeding or formula feeding in early life. Separate analyses for males, females, and both sexes combined (additionally adjusted for sex) were conducted. The effect of study size, age groups at outcome measurement (comparing those aged 16–30 y with those aged 50 y), year of birth, the method of ascertainment of infant feeding status (whether contemporary or recalled over a period of 5 y) was examined by using meta-regression and sensitivity analysis. Meta-regression was also used to establish whether mean concentrations of total cholesterol in each study had any effect on mean differences between feeding groups. There were insufficient data to examine the effect of duration of breastfeeding.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

 
In total, we were able to extract mean differences in total cholesterol between those breastfed and formula-fed from all 17 eligible studies (representing 17 498 subjects); of these differences, 13 were based on the response of individual authors (11 703 subjects), whereas 4 were obtained from the published literature (Figure 1 and Table 1 for both). All but 4 studies reported using fasting concentrations of blood cholesterol; in those 4 studies (17, 27, 32, 35), fasting status was not imposed. Twelve studies were based in Northern Europe (including 8 in the United Kingdom), 1 in Eastern Europe, 2 in the United States, 1 in South America, and 1 in New Zealand. In 7 studies, it was possible to compare groups of subjects who were exclusive breastfeeders and bottle feeders. In the remaining 10 studies, the infant feeding groups were not completely exclusive, either because exclusivity of early feeding was unknown (4 studies), because the breastfeeding group included mixed feeders (5 studies), or because the bottle-feeding group included mixed feeders (1 study). Of the 17 estimates, 10 related breastfeeding to a lower mean concentration of total cholesterol in later life than was associated with formula feeding. There was evidence of marked heterogeneity between studies (² = 30, P = 0.02). In a fixed-effects model including all 17 studies, the breastfed subjects had marginally lower total cholesterol than did the formula-fed subjects (mean difference: –0.04 mmol/L; 95% CI: –0.08, 0.00 mmol/L; Figure 2); the pooled estimate from a random-effects model was similar (–0.05 mmol/L; 95% CI: –0.12, 0.02 mmol/L). The mean difference was unaffected by exclusion of one study with nearly one-half (45%) of the statistical weight (31) or after adjustment for age, current SEP, BMI, smoking status, or all (Table 1).

View larger version (32K): [in this window] [in a new window]   FIGURE 2. Mean (and 95% CI) differences in blood cholesterol between breastfed and bottle-fed participants in 17 studies (16 crude estimates, 1 adjusted for age). The box area of each study is proportional to the inverse of the variance, and the horizontal lines show the 95% CI. First author is listed on the y-axis; mean age is shown in ascending order; "M" refers to male-only studies. The pooled estimate based on a fixed-effects model is shown by a dashed vertical line and (95% CI).

Figure 3

Table 2

View larger version (24K): [in this window] [in a new window]   FIGURE 3. Mean (and 95% CI) differences in blood cholesterol between breastfed and bottle-fed participants in 7 studies that reported exclusive breastfeeding or bottle feeding in early life. The box area of each study is proportional to the inverse of the variance, and the horizontal lines show the 95% CI. The first author is listed on the y-axis, and mean age (y) is given in ascending order. The pooled estimate based on a fixed-effects model is shown by a dashed vertical line and (95% CI).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

 
This systematic review of 17 studies found a marginally lower mean concentration of total cholesterol in adult subjects who had been breastfed in infancy than in those who had been formula-fed. However, the reduction in cholesterol concentrations in adults who had been breastfed was more marked in a subgroup of studies in which comparisons were based on exclusive breastfeeding and formula-feeding groups in early life. This association among exclusive feeders was homogeneous across studies and sexes, and it did not appear to be influenced by small study or publication bias. The effect was not changed by systematic adjustment for confounders (eg, SEP or current smoking status) or by adjustment for BMI, which is a potential confounder but which could also be a mediating factor in the causal pathway between early feeding and cholesterol concentrations in later life.

A larger number of published studies relating infant feeding to adult cholesterol concentrations were available for the present review than had been available at the time of our previous review (17 compared with 5) (10). One of the major strengths of the present review is that data were obtained from all relevant studies identified; 13 studies (76%) provided additional analyses with systematic adjustment for potential confounders (including the 7 studies that reported exclusive feeding). It is reassuring that effect estimates were not materially altered by adjustment for confounders in adult life, but it remains possible that the observed differences in adult cholesterol may still be explained by residual confounding, because those initially breastfed may go on to have lifestyles different different from the lifestyles of those initially formula-fed. In particular, a formula-feeding group may be atypical in studies carried out at a time (ie, in the early part of the 20th century, when bottle feeds were predominantly cow-milk preparations) (15, 16, 24) or in cultures where breastfeeding was widespread (32). There was no evidence of any effect of year of birth (cohort) or geographical effects in this review (data not presented), although the statistical power of the analyses to examine these influences was limited. The only way of further examining the influence of confounding factors on this relation is to consider studies that randomly assign infants to be breastfed or formula-fed. However, experimental studies are generally impractical in this context, except in specific circumstances of preterm birth or randomized controlled trials of breastfeeding promotion (8, 41). Studies adopting these approaches, although they raise the possibility that breast milk is associated with lower LDL-cholesterol concentrations in adolescence (9), have yet to report on the effect of infant feeding on cardiovascular risk factors in adult life. Further follow-up of these study populations into adulthood may be of interest.

A limitation of the available information has been the small number of studies in which exclusively breastfed and bottle-fed subjects can be clearly defined. There is a paucity of studies in the world literature that identify persons who were exclusively fed in early life and that also collect data on the duration of exclusive feeding. In this review, only 7 (41%) of the 17 studies reported exclusive breastfeeding or formula feeding, and only 3 of those 7 studies (24, 33, 35, 40) could confirm that the median duration of breastfeeding in their subjects was 4 mo, which is a length of time akin to World Health Organization recommendations (36). Although the restriction of analysis to exclusive feeding groups resulted in the omission from analysis of more than half of the studies (10 of 17, 14 388 of 17 498 subjects), the effects observed were homogenous and based largely on contemporaneous ascertainment of exposure (either from birth records at the time of feeding or by maternal recall within 6 y after birth). The overall estimate from these studies (–0.15 mmol/L) was robust to adjustment and similar to the estimate published in our earlier review (–0.18 mmol/L), which was pooled from studies largely without adjustment for potential confounders [except 1 study that adjusted for body weight (26)]. This similarity in effect is not entirely surprising, because 4 studies used in the earlier review were included in the exclusive group (15, 16, 23, 25, 26, 35). However, in the present review, we were able to show that estimates of effect were largely unaltered by adjustment for potential confounders. Although there were insufficient data to explore the influence of the duration of feeding, exclusively breastfed persons are likely to represent a group who are breastfed for longer periods: ie, median breastfeeding durations of 4–9 mo were reported among the 3 studies with available data (24, 33, 35, 40). To further elucidate the influence of the duration and exclusivity of breastfeeding, more studies with detailed information on initial feeding—preferably recorded at the time of feeding—and with follow-up in adult life are needed. On the basis of the present review, it appears that such information is very limited.

The lower blood cholesterol concentrations observed in adult life in exclusively breastfed infants in the present review raise the possibility that exposure to breast milk [which is associated with a short-term increase in total cholesterol concentrations in infancy of 0.6 mmol/L (10)], may have long-term effects on blood cholesterol concentrations later in life (42). This possibility could be an example of nutritional programming (8, 10, 42). The composition of breast milk differs from that of formula milk in several respects. Breast milk has a higher cholesterol content, and breast milk, unlike formula milk, contains hormones (especially leptin and tri-iodothyronine), immunoglobulins, and nucleotides (17, 25). Early exposure to the high cholesterol content of breast milk could be important; enteral exposure to high cholesterol in infancy reduces the endogenous synthesis of cholesterol, probably by down-regulation of hepatic hydroxymethyl glutaryl coenzyme A reductase (13). However, other studies examining the effect of initial feeding on endogenous cholesterol fractional synthesis rates failed to show any long-term post-infancy imprinting effects (43). These results, however, provide no support for the possibility raised in animal studies that breastfeeding may program an adverse lipid profile (44, 45). A second possibility is that early exposure to breast milk has an effect on dietary behavior in later life (behavioral programming). Further investigation of the adult dietary patterns of breastfed and bottle-fed subjects would help to establish whether this possibility is an actuality.

If exclusive breastfeeding has a prevalence of 30% (46) and reduces blood cholesterol by 0.15 mmol/L, as much as 5% of all CHD cases could be avoided. On this basis, increases in rates of exclusive breastfeeding would have a discernible effect in reducing the burden of coronary disease, although the reduction in cholesterol associated with early breastfeeding would be small compared with that achievable by dietary means or pharmaceutical interventions in adult life (2, 4). There currently is, however, no consistent evidence from the small number of longitudinal studies that have examined this issue that breastfeeding results in a reduction in the risk of cardiovascular disease in later life (15, 47-49), although our results do suggest that moves to reduce cholesterol and saturated fat intake in infancy should be undertaken cautiously until the long-term effects on cholesterol metabolism are known (50). Although breastfeeding has modest effects on blood pressure (51) and adiposity (52, 53) in later life, it has numerous other health benefits, including protection against infectious disease morbidity (54) and mortality (55) in infancy and a lower risk of type 2 diabetes (56) and improved neural and psychosocial development in the longer term (57, 58). Hence, breastfeeding should be advocated, when possible, as the preferred method of feeding in early life.

	APPENDIX A

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX A REFERENCES

 
SEARCH STRATEGY USED
TEXT WORDS
Breast fed OR Breast feed OR Breast feeds OR Breast feeding OR Breast milk OR Bottle fed OR Bottle feed OR Bottle feeds OR Bottle feeding OR Infant feed OR Infant feeds OR Infant feeding OR Infant nutrition OR Formula fed OR Formula feed OR Formula feeds OR Formula feeding OR Infant diets OR Dried milk OR Early nutrition. AND Blood cholesterol OR Serum cholesterol OR Blood total cholesterol OR Serum total cholesterol OR Blood lipids OR Serum lipids OR Low density lipoprotein

MESH HEADINGS (MEDLINE)
Breast feeding/ OR Bottle feeding/ OR Milk, human/ OR Infant nutrition/ AND Cholesterol/ OR Cholesterol, LDL/ OR Lipids/ OR Lipoproteins/ OR Lipoproteins, LDL/ OR Lipoproteins/bl

SUBJECT HEADINGS (EMBASE)
Breast feeding/ OR Breast milk/ OR Bottle feeding/ OR Infant feeding/ OR Infant nutrition/ OR Artificial milk/ AND Cholesterol/ OR Cholesterol blood level/ OR Lipoprotein/ OR Lipoprotein blood level/ OR Low density lipoprotein cholesterol/ OR Lipid/ OR Lipid blood level/

WEB OF SCIENCE SEARCH STRATEGY
Breast fed OR Breast feed OR Breast feeds OR Breast feeding OR Breast milk OR Bottle fed OR Bottle feed OR Bottle feeds OR Bottle feeding OR Infant feed OR Infant feeds OR Infant feeding OR Infant nutrition OR Formula fed OR Formula feed OR Formula feeds OR Formula feeding OR Infant diet OR Dried milk OR Early nutrition AND Blood cholesterol OR Serum cholesterol OR Blood total cholesterol OR Serum total cholesterol OR Blood lipid OR Serum lipid OR Low density lipoprotein

	ACKNOWLEDGMENTS

 
The authors' responsibilities were as follows—PHW, CGO, and DGC: obtained funding and set up the EARLY Risk Exposures in Adult Disease (EARLY READ) collaboration; CGO, PHW, RMM, GDS, and DGC: contributed substantially to the conception and design of the study; CGO: sent the data requests, carried out the statistical analysis, and wrote the manuscript draft; SJK: carried out the literature search; EB, SB, MEJW, CHF, JLF, JN, RRH, SK, CPL, MSP, OTR, IL, JSV, ACR, ARR, DPS, and SMW: provided individual data or analyses for inclusion in the meta-analyses; and all authors: appraised the manuscript for intellectual content, had access to the data, and approved the final version of the manuscript. CGO will act as guarantor; the guarantor accepts full responsibility for the integrity of the work as a whole. None of the authors had a personal or financial conflict of interest.

	REFERENCES

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