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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 trialVaccination News Home Page Scandals subscribe Vaccination NewsLetter http://bmj.com/cgi/content/full/326/7396/953
PapersLong chain polyunsaturated fatty acid supplementation in infant formula and blood pressure in later childhood: follow up of a randomised controlled trialJ S Forsyth 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@tuht.scot.nhs.uk
Objective: To determine whether supplementation of infant
formula milk with long chain polyunsaturated fatty acids (LCPUFAs)
influences blood pressure in later childhood.
Recent reports have linked breast feeding in infancy to lower blood pressure during childhood. Two longitudinal observational studies of term infants showed that children who were breast fed for at least three months had lower systolic and diastolic blood pressures in later childhood and adolescence than children who were formula fed. This difference remained after adjustment for known confounding variables. 1 2 A study involving preterm infants who had been randomised to be fed with banked breast milk had lower systolic and diastolic blood pressures at the age of 15 years than children who were fed term or preterm formula.3 The mechanisms underlying the relation between breast feeding in infancy and
blood pressure during childhood are unclear. The study involving
preterm infants found no difference in blood pressure of infants who
were fed a term formula and infants who were fed a preterm formula
that contained additional protein, energy, and minerals, including
sodium.3 Breast milk contains a wide
range of substances Considerable interest has been shown recently in the role of long chain polyunsaturated fatty acids (LCPUFAs), as these fatty acids 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. As these fatty acids are preferentially incorporated into neural cell membranes, studies have predominantly focused on the influence of fatty acids on visual and cognitive development. 5 6 However, it is also known that LCPUFAs are incorporated into other cell membranes, including vascular endothelium. 7 8 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. 9 10 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. 6
11 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.
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 tolerance and safety study agreed to take part in the present follow up study. Each centre (Dundee and Birmingham in the United Kingdom, Leuven in Belgium, and Milan in Italy) 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. Each centre obtained consent from the parent or guardian of the child. The figure shows the numbers of children who participated in the original trial and the follow up study.
The children had all been born between 37 and 42 weeks' gestation and weighed between 2500 g and 4000 g at birth. A computer generated randomisation table was used to assign the infants immediately after birth to a formula supplemented with LCPUFAs or a formula without supplementation. Permutated blocks of six were used, so that after every sixth infant the two groups were numerically balanced. Randomisation was stratified to ensure sex matching. Table 1 shows the composition of the formulas. The LCPUFA source was egg yolk, with approximately 70% of LCPUFAs being esters of phospholipids.
Each of the children was fed the trial formula during the first four months of life. Each month the children's weight, length, head circumference, subscapular skinfold thickness, and mid-arm circumference were measured. Other factors relating to safety and tolerance were also recorded. 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. Psychological assessments were also done (data not included). Blood pressure was measured while the child was sitting on a chair with the right arm held in the horizontal position. In all centres staff used an automated blood pressure monitor (OMRON 711 Automatic IS, Omron Healthcare, Hamburg, Germany) with a child cuff (type 40S, 15-22 cm). Systolic, diastolic, and mean blood pressures were recorded as the average of three readings. Throughout both studies research assistants and parents or guardians were blind to the formula each child had received. Previous studies have shown the standard deviation of childhood blood
pressure measurements to be 8 mm Hg, and so we calculated that a
sample size of 63 children in each group was needed to detect a
difference of 4 mm Hg with a power of 80% at the 0.05 level of
significance. We used Student's t test to compare normally
distributed variables.
Nearly two thirds (235/376) of the participants in the original tolerance and safety study were recruited to the present study (table 2). The figure shows the reasons for non-enrolment in the present study. Compared with the children from the randomised groups who took part in the follow up study, the children who did not take part had a lower birth weight (mean (SD) 3108 g (411 g) v 3292 g (397 g); P=0.001), length (49.8 cm (2.0 cm) v 50.5 cm (2.6 cm); P=0.04), and mid-arm circumference (10.1 cm (0.9 cm) v 10.5 cm (1.0 cm); P=0.007).
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 at the time of the follow up (table 3). 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 (table 4).
Six children declined to have their blood pressure measured. In 10 children technical difficulties resulted in unreliable data being obtained, and attempts to repeat the measurements were unsuccessful. 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 5). 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
Blood pressure at age 6 years was lower in children who as infants had been fed with a formula supplemented with LCPUFAs than in children who were fed a formula without LCPUFAs. Blood pressure in the reference group of breastfed children was similar to that in the supplemented formula group, but a direct comparison of the two groups is not possible because of confounding variables (including milk composition, age and education of fathers, and family history of smoking). Strengths and limitations of the study
Mechanisms of action
Implications Blood pressure is known to track from childhood into adult life, and deviations from normal blood pressure during childhood are amplified in later life.18 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. 19 20 These benefits can be achieved by simple dietary measures early in life.
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: JSF and PW designed the study, analysed the data, and contributed to the writing of the paper. JB, PC, and CA discussed the study design, supervised the study in Birmingham, Leuven, and Milan, respectively, and edited the paper. GB was involved in the initial implementation and monitoring of the study.
Funding: Research grant from Milupa (Friedrichsdorf, Germany). Competing interests: JSF, PW, and CA have received research support from Milupa and other milk formula companies and honorariums for speaking at and attending conferences that were partly or wholly sponsored by these companies. Ethical approval: All centres obtained ethical approval from the relevant
authorities.
(Accepted 7 March 2003) © 2003 BMJ
Publishing Group Ltd
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Abstract 
Introduction
3.0 mm Hg
(95% confidence interval 
trophic substances, hormones, and specific
nutrients
