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Long chain polyunsaturated fatty acid supplementation in infant formula and blood pressure in later childhood: follow up of a randomised controlled trial

J S Forsyth, consultant paediatrician ^a, P Willatts, senior lecturer ^b, C Agostoni, professor ^c, J Bissenden, consultant paediatrician ^d, P Casaer, professor ^e, G Boehm, director, infant nutrition research ^f. 

^a Tayside Institute of Child Health, University of Dundee, Dundee DD1 9SY, ^b Department of Psychology, University of Dundee, ^c Department of Paediatrics, University of Milan, Milan, Italy, ^d Department of Paediatrics, City Hospital, Birmingham B18 7QH, ^e Department of Paediatrics, University of Leuven, Leuven, Belgium, ^f Numico Research, Friedrichsdorf, Germany

Correspondence to: J S Forsyth j.stewart.forsyth{at}tuht.scot.nhs.uk

	Abstract

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Objective: To determine whether supplementation of infant formula milk with long chain polyunsaturated fatty acids (LCPUFAs) influences blood pressure in later childhood.
Design: Follow up of a multicentre, randomised controlled trial.
Setting: Four study centres in Europe.
Participants: 147 formula fed children, with a reference group of 88 breastfed children.
Intervention: In the original trial newborn infants were randomised to be fed with a formula supplemented with LCPUFAs (n=111) or a formula without LCPUFAs but otherwise nutritionally similar (n=126). In the present follow up study the blood pressure of the children at age 6 years was measured.
Main outcome measures: Systolic, diastolic, and mean blood pressure.
Results: 71 children in the LCPUFA supplementation group (64% of the original group) and 76 children in the non-supplementation group (60%) were enrolled into the follow up study. The LCPUFA group had significantly lower mean blood pressure (mean difference 3.0 mm Hg (95% confidence interval 5.4 mm Hg to 0.5 mm Hg)) and diastolic blood pressure (mean difference 3.6 mm Hg (6.5 mm Hg to 0.6 mm Hg)) than the non-supplementation group. The diastolic pressure of the breastfed children (n=88 (63%)) was significantly lower than that of the non-supplemented formula group but did not differ from the LCPUFA formula group.
Conclusions: Dietary supplementation with LCPUFAs during infancy is associated with lower blood pressure in later childhood. Blood pressure tends to track from childhood into adult life, so early exposure to dietary LCPUFAs may reduce cardiovascular risk in adulthood.

What is already known on this topic Breast milk contains long chain polyunsaturated fatty acids, and breastfed children have lower blood pressure than children fed with formula milk Blood pressure differences in childhood are known to carry through into adulthood Dietary omega 3 fatty acid supplementation can lower blood pressure in adults with hypertension What this paper adds Supplementation with long chain polyunsaturated fatty acids in infancy results in lower blood pressure later in childhood

	Introduction

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Recent reports have linked breast feeding in infancy to lower blood pressure during childhood.^1-3 The mechanisms underlying this relation are unclear. Breast milk contains a wide range of substancestrophic substances, hormones, and specific nutrientsthat are not included in formulas and that may influence blood pressure.

Considerable interest has been shown recently in the role of long chain polyunsaturated fatty acids (LCPUFAs), which are in breast milk but are not routinely available in formula milks.⁴ During the first weeks of life preterm infants and some term infants may not be able to synthesise enough LCPUFAs to meet demand, and therefore infants fed with formula without supplementation may be relatively deficient in LCPUFAs, compared with breastfed infants. These fatty acids are preferentially incorporated into neural cell membranes but are also incorporated into other cell membranes, including vascular endothelium. ^{5 6} Several studies have reported lower blood pressure in adults whose diet was supplemented with omega 3 fatty acids, but no published studies have looked at the effect of LCPUFA supplementation on blood pressure in children. ^{7 8}

In an earlier tolerance study of LCPUFA supplementation and its effect on cognitive development we randomly assigned newborn infants to be fed with a formula containing LCPUFAs or to a formula without LCPUFAs but otherwise nutritionally similar. ^{9 10} We therefore had the opportunity to further investigate the randomised groups to determine the relation of LCPUFA supplementation in infancy to blood pressure in later childhood.

	Methods

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In 1992 six European centres took part in a multicentre, randomised controlled trial of a new infant formula that was supplemented with docosahexaenoic acid and arachidonic acid.⁶ Four of the centres that contributed to this original study agreed to take part in the present follow up study. Each centre had a cohort of 6 year old children who as infants had been randomised to be fed one of the trial formulas and a reference group of breastfed children.

The children had all been born between 37 and 42 weeks gestation and weighed between 2500 g and 4000 g at birth. Immediately after birth the infants were assigned to a formula supplemented with LCPUFAs or a formula without supplementation (see bmj.com for the composition of the formulas). The LCPUFA source was egg yolk, with approximately 70% of LCPUFAs being esters of phospholipids. All the children were fed the trial formula during the first four months of life.

In the present follow up study the children and their families were invited to attend a clinic or laboratory in the relevant study centre. During the visits, which took place between April 1998 and March 2000, a demographic and clinical questionnaire was completed and the child's blood pressure measured. Throughout both studies research assistants and parents or guardians were blind to the formula each child had received.

	Results

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Nearly two thirds (235/376) of the participants in the original tolerance and safety study were recruited to the present study. Compared with the children in the randomised groups who took part in the follow up study, the children who did not take part had a lower birth weight, length, and mid-arm circumference. The mean age of the children at the time of blood pressure assessment was 70.1 months (SD 3.5 months). There were no demographic or anthropometrical differences between the two randomised groups (table 1).

As expected, there were social differences between the formula fed children and the reference group of breastfed children: children who were breast fed had more siblings, fewer smokers in the family, older parents, and fathers who were more educated (see bmj.com).

Six children declined to have their blood pressure measured, and in 10 children technical difficulties resulted in unreliable data. The final analysis was on 219 children (65 in the LCPUFA group, 71 in the non-LCPUFA group, and 83 breastfed children).

Diastolic blood pressure was significantly lower in the LCPUFA group than in the non-LCPUFA group (table 2). Systolic blood pressure was also lower, but not significantly. However, mean blood pressure was significantly lower in the LCPUFA group than in the non-LCPUFA group. The blood pressure of the breastfed children was 92.5 mm Hg systolic (SD 9.7 mm Hg) and 57.5 mm Hg diastolic (SD 8.5 mm Hg). The diastolic pressure of breastfed children was significantly lower than that of the non-LCPUFA group (mean difference 3.4 mm Hg (95% confidence interval 6.8 mm Hg to 0.01 mm Hg; P=0.02)) but did not differ from that of the LCPUFA group.

	Discussion

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Limitations of the study
Nearly two thirds of the original group took part in the present study of blood pressure. Social characteristics of the children who did not take part in the follow up study did not differ from those of the participants, but mean weight, length, and mid-arm circumference at birth were all lower in the children who did not participate. The impact of these anthropometrical differences on our results is uncertain. However, it has been shown that the amount of stored LCPUFAs at birth is directly related to birth weight¹¹; it could therefore be postulated that the effect of LCPUFA supplementation in lowering blood pressure might have been more marked among the children who did not take part in the present study.

Mechanisms of action
The mechanisms underlying the relation of LCPUFAs to blood pressure remain uncertain. Several studies of adults with hypertension have shown that an increased dietary intake of omega 3 fatty acids is associated with lower blood pressure.⁷ A double blind, placebo controlled trial showed that docosahexaenoic acid but not eicosapentaenoic acid lowered ambulatory blood pressure in overweight men.⁸ The authors of this trial reported in another study of the same cohort that docosahexaenoic acid enhanced dilatory responses to sodium nitroprusside and attenuated constrictor responses to noradrenaline.¹² These data are supported by animal studies. ^{13 14}

Implications
Our results support an association between early nutritional intervention and health benefits in later life. Whether the influence of LCPUFAs on blood pressure would have been stronger with a longer period of supplementation is uncertain. A recent animal study noted higher blood pressure in adult rats that were deficient in omega 3 fatty acids in the perinatal period, and this increase in blood pressure was not prevented by later repletion with fatty acids.¹⁵

Blood pressure is known to track from childhood into adult life, and deviations from normal blood pressure during childhood are amplified in later life.¹⁶ Our findings are therefore relevant to public health strategies aimed at improving the long term health of the population. It has previously been reported that lowering a population's diastolic blood pressure by even a few millimetres can significantly reduce hypertension, coronary heart disease, and stroke. ^{17 18} These benefits can be achieved by simple dietary measures early in life.

	Acknowledgments

We thank the original investigators in Leuven (E Eggermont) and Milan (M Giovannini) for their contributions. M Smith and A Elliot (Dundee), A McNaughton (Birmingham), H Daniels and M Huybens (Leuven), and L Gianni (Milan) undertook the assessments.

Contributors: See bmj.com

	Footnotes

Funding: Research grant from Milupa (Friedrichsdorf, Germany).

Competing interests: JSF, PW, CA, and JB have received research support from Milupa and other milk formula companies and honorariums for lecturing at conferences that were partly or wholly sponsored by these companies.

Ethical approval: All centres obtained ethical approval from the relevant authorities.

This is an abridged version; the full version is on bmj.com

	References

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1.	Wilson AC, Forsyth JS, Greene SA, Irvine L, Hau C, Howie PW. Relation of infant diet to childhood health: seven year follow up of cohort in Dundee infant feeding study. BMJ 1998; 316: 21-25[Abstract/Free Full Text].
2.	Taittonen L, Nuutinen M, Turtinen J, Uhari M. Prenatal and postnatal factors in predicting later blood pressure among children: cardiovascular risk in young Finns. Pediatr Res 1996; 40: 627-632[Web of Science][Medline].
3.	Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials. Lancet 2001; 357: 413-419[CrossRef][Web of Science][Medline].
4.	Koletzko B, Agostoni C, Carlson SE, Clandinin T, Hornstra G, Neuringer M, et al. Long chain polyunsaturated fatty acids (LC-PUFA) and perinatal development. Acta Paediatr 2001; 90: 460-464[Web of Science][Medline].
5.	Cunnane SC, Francescutti V, Brenna JT, Crawford MA. Breast-fed infants achieve a higher rate of brain and whole body docosahexaenoate accumulation than formula-fed infants not consuming dietary docosahexaenoate. Lipids 2000; 35: 105-111[CrossRef][Web of Science][Medline].
6.	Engler MM, Engler MB, Kroetz DL, Boswell KD, Neeley E, Krassner SM. The effects of a diet rich in docosahexaenoic acid on organ and vascular fatty acid composition in spontaneously hypertensive rats. Prostaglandins Leukot Essent Fatty Acids 1999; 61: 289-295[CrossRef][Web of Science][Medline].
7.	Mori TA, Beilin LJ. Long-chain omega 3 fatty acids, blood lipids and cardiovascular risk reduction. Curr Opin Lipidol 2001; 12: 11-17[CrossRef][Web of Science][Medline].
8.	Mori TA, Bao DQ, Burke V, Puddey IB, Beilin LJ. Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans. Hypertension 1999; 34: 253-260[Abstract/Free Full Text].
9.	Willatts P, Forsyth JS, DiModugno MK, Varma S, Colvin M. Effect of long-chain polyunsaturated fatty acids in infant formula on problem solving at 10 months. Lancet 1998; 352: 688-691[CrossRef][Web of Science][Medline].
10.	Forsyth JS, Varma S, Colvin M. A randomised controlled study of the effect of long chain polyunsaturated fatty acid supplementation on stool hardness during formula feeding. Arch Dis Child 1999; 81: 253-256[Abstract/Free Full Text].
11.	Clandinin MT, Chappell JE, Heim T, Swyer PR, Chance GW. Fatty acid utilization in perinatal de novo synthesis of tissues. Early Hum Dev 1981; 5: 355-366[CrossRef][Web of Science][Medline].
12.	Mori TA, Watts GF, Burke V, Hilme E, Puddey IB, Beilin LJ. Differential effects of eicosapentaenoic acid on vascular reactivity of the forearm microcirculation in hyperlipaemic, overweight men. Circulation 2000; 102: 1264-1269[Abstract/Free Full Text].
13.	Rousseau D, Helies-Toussaint C, Raederstorff D, Moreau Grynberg A. Dietary n-3 polyunsaturated fatty acids affect the development of renovascular hypertension in rats. Mol Cell Biochem 2001; 225: 109-119[CrossRef][Web of Science][Medline].
14.	Engler MB, Engler MM. Docosahexaenoic acid-induced vasorelaxation in hypertensive rats: mechanisms of action. Biol Res Nurs 2000; 2: 85-95[Abstract/Free Full Text].
15.	Weisinger HS, Armitage JA, Sinclair AJ, Vingrys AJ, Burns PL, Weisinger RS. Perinatal omega-3 fatty acid deficiency affects blood pressure in later life. Nat Med 2001; 7: 258-259[CrossRef][Web of Science][Medline].
16.	Whincup PH, Cook D, Papacosta O, Walker M. Birth weight and blood pressure: cross sectional and longitudinal relations in childhood. BMJ 1995; 311: 773-776[Abstract/Free Full Text].
17.	Cook NR, Cohen J, Herbert PR, Taylor JO, Hennekens CH. Implications of small reductions in diastolic blood pressure for primary prevention. Arch Intern Med 1995; 155: 701-709[Abstract/Free Full Text].
18.	Rose G. The strategy of preventive medicine. Oxford: Oxford University Press, 1992.

(Accepted 7 March 2003)