Context Early childhood introduction of nutritional habits aimed at atherosclerosis
prevention is compatible with normal growth, but its effect on neurological
development is unknown.
Objective To analyze how parental counseling aimed at keeping children's diets
low in saturated fat and cholesterol influences neurodevelopment during the
first 5 years of life.
Design Randomized controlled trial conducted between February 1990 and November
1996.
Setting Outpatient clinic of a university department in Turku, Finland.
Participants A total of 1062 seven-month-old infants and their parents, recruited
at well-baby clinics between 1990 and 1992. At age 5 years, 496 children still
living in the city of Turku were available to participate in neurodevelopmental
testing.
Intervention Participants were randomly assigned to receive individualized counseling
aimed at limiting the child's fat intake to 30% to 35% of daily energy, with
a saturated:monounsaturated:polyunsaturated fatty acid ratio of 1:1:1 and
a cholesterol intake of less than 200 mg/d (n = 540) or usual health education
(control group, n = 522).
Main Outcome Measures Nutrient intake, serum lipid concentrations, and neurological development
at 5 years, among children in the intervention vs control groups.
Results Absolute and relative intakes of fat, saturated fatty acids, and cholesterol
among children in the intervention group were markedly less than the respective
values of control children. Mean (SD) percentages of daily energy at age 5
years for the intervention vs control groups were as follows: for total fat,
30.6% (4.5%) vs 33.4% (4.4%) (P<.001); and for
saturated fat, 11.7% (2.3%) vs 14.5% (2.4%) (P<.001).
Mean intakes of cholesterol were 164.2 mg (60.1 mg) and 192.5 mg (71.9 mg)
(P<.001) for the intervention and control groups,
respectively. Serum cholesterol concentrations were continuously 3% to 5%
lower in children in the intervention group than in children in the control
group. At age 5 years, mean (SD) serum cholesterol concentration of the intervention
group was 4.27 (0.63) mmol/L (165 [24] mg/dL) and of the control group, 4.41
(0.74) mmol/L (170 [29] mg/dL) (P = .04). Neurological
development of children in the intervention group was at least as good as
that of children in the control group. Relative risks for children in the
intervention group to fail tests of speech and language skills, gross motor
functioning plus perception, and visual motor skills were 0.95 (90% confidence
interval [CI], 0.60-1.49), 0.95 (90% CI, 0.58-1.55), and 0.65 (90% CI, 0.39-1.08),
respectively (P = .85, .86, and .16, respectively,
vs control children).
Conclusion Our data indicate that repeated child-targeted dietary counseling of
parents during the first 5 years of a child's life lessens age-associated
increases in children's serum cholesterol and is compatible with normal neurological
development.
Increased serum cholesterol and low-density lipoprotein cholesterol
(LDL-C) concentrations are closely associated with aortic fatty streaks in
pediatric autopsies,1,2 suggesting
that children with high serum cholesterol values are predisposed to atherosclerosis
and coronary heart disease (CHD) later in life. The high prevalence of early
vascular changes is well documented in the Pathobiological Determinants of
Atherosclerosis in Youth study,3 which found
that all 15- to 19-year-old Americans have fatty streaks in the aorta, about
half had lesions in the right coronary artery, and that the prevalence of
coronary fatty streaks increases to 75% before age 35 years. In the Bogalusa
Heart Study,4 50% of children whose serum LDL-C
concentration was above the 75th percentile of the study population when first
measured still had high values 12 years later. Furthermore, elevated serum
cholesterol values in early adult life are associated with cardiovascular
disease risk a quarter of a century later.5
Coronary heart disease is clearly an end point in a lifelong process.
Modification of dietary fat intake beginning in early childhood might
diminish CHD risk in a population,6,7
but such interventions have been hampered by concerns about possible long-term
effects on growth and development.8,9
While results from the Dietary Intervention Study in Children10
suggest that a low–saturated fat, low-cholesterol diet decreases serum
LDL-C concentration in children with hyperlipemia without effects on growth
and psychosocial health, and cohort studies indicate that differences in fat
consumption do not affect growth,11,12
prospective randomized studies are needed to prove the safety of early interventions.
We showed in the prospective randomized Special Turku Coronary Risk
Factor Intervention Project (STRIP)13 that
serum cholesterol concentration increased only slightly in children in the
intervention group who were exposed to a low–saturated fat, low-cholesterol
diet after age 7 months, whereas a greater increase in cholesterol values
was seen in control children during the first 3 years of life.14
Furthermore, the intervention did not influence growth.15,16
In the current phase of the project, we evaluated the effects of a diet low
in saturated fat and cholesterol on children's neurological development at
age 5 years.
The STRIP project is a randomized trial aimed at decreasing exposure
to known environmental atherosclerosis risk factors. As previously described,13,14 the nurses at the well-baby clinics
in the city of Turku recruited families to the project at the regular 5-month
visit of the infants. After obtaining informed consent from the parents, 7-month-old
infants were allocated into an intervention group or a control group by random
numbers. The families in the intervention and control groups met a pediatrician
and a dietitian at 1- to 3-month and 4- to 6-month intervals, respectively;
after age 2 years, the visits in both groups were at 6-month intervals. The
parents and personnel of community-run or private day care centers recorded
the child's food consumption in a 3-day record at ages 8, 13, and 18 months,
and in a 4-day record twice a year thereafter, always including 1 weekend
day. The records were analyzed with Micro-Nutrica program (Research and Development
Unit of the Social Insurance Institution, Turku, Finland; version 2.5),17 using the Food and Nutrient Database of the Social
Insurance Institution, Turku.18 Venous blood
samples were drawn for serum lipid measurement at ages 7, 13, and 24 months
and yearly thereafter. A pediatrician examined the child at each visit.
Infants were recruited to the study between February 1990 and June 1992.
All 5-year-old children had been evaluated by November 1996.
The study was approved by the Joint Commission on Ethics of Turku University
and Turku University Central Hospital.
Families in the intervention group received individualized counseling
aimed at maintaining the child's fat intake at 30% to 35% of daily energy,
saturated:monounsaturated:polyunsaturated fatty acid (PUFA) ratio of 1:1:1,
and cholesterol intake of less than 200 mg/d. In practice, families were advised
to continue breastfeeding as long as the mother felt it feasible or to use
formula as the milk source until the infant reached age 12 months and skim
milk, 0.5 to 0.6 L/d, thereafter. Parents were taught to add 2 or 3 teaspoonfuls
of soft margarine or vegetable oil, mainly low–erucic acid rapeseed
oil, to the daily food of the 12- to 24-month-old children to maintain fat
intake.
Control families received the health education given to all Finnish
families at the well-baby clinics. They were advised to continue breastfeeding
or to use formula until the infant reached age 12 months, but cows' milk containing
at least 1.9% fat (1.5% after May 1995) was recommended thereafter. No advice
concerning dietary fat was given.
In both groups, at least partial breastfeeding continued for a mean
(SD) of 5 (4) months, and solid foods were introduced at age 3 to 5 months.
All children were weaned by age 13 months. Because accurate measurement of
breast-milk consumption was impossible in a trial this large, the intake analysis
at age 8 months comprised data on the formula-fed infants only.
Before age 5 years, nonfasting blood samples were drawn for measurement
of serum cholesterol and high-density lipoprotein cholesterol (HDL-C) concentrations.14 Therefore, non–HDL-C (total cholesterol minus
HDL-C) values were used because serum triglyceride values19
were not available for calculation of LDL-C values. At age 5 years, fasting
blood samples were drawn for the first time, allowing calculation of LDL-C
values using the formula of Friedewald et al.20
Only 1 venipuncture attempt was made and was successful in 87.5% of children.
Analyses were done in the laboratory of the Research and Development Unit
of the Social Insurance Institution in Turku.
Analysis of Children's Neurological Development
At age 5 years, neurological development of children living in Turku
was assessed using a collection of developmental screening tests. Although
similar screening tests are used in all communities around Turku, the testing
was restricted to the city because the tests were validated there, the well-baby
clinic nurses were uniformly trained to use the tests, and performance could
be continuously monitored and further assessed by an independent team. The
test collection comprised tests of speech and language skills,21
gross motor functioning and perception,22-24
and visual motor skills.25,26
The speech and language test, validated for children speaking Finnish,21 formed the largest part of the testing. The 7 items
studied (sentence formation; speech comprehension; oromotor function; auditory
serial memory; sentence repetition and kinesthetic skills; serial naming and
articulation; and ability to count from 1 to 5, name colors, and follow instructions)
covered both expressive and receptive abilities. Voice, fluency of speech,
and hearing were evaluated. Items were assessed as pass, fail, or refuse.
A child failed the test if he or she failed or refused to perform in 3 different
tasks or if the voice, hearing, or fluency of speech were abnormal.
Gross motor functioning and perception were tested using parts of the
Test of Motor Impairment,22 the Miller Assessment
for Preschoolers,23 and the Southern California
Sensory Integration Tests.24 A total of 6 items
(jumping on 1 foot, cross steps, throwing and catching a ball, block designs,
finger localization, and imitation of postures) were assessed with the terms
pass, fail, or refuse. A child failed the test if he or she failed or refused
to perform in 1 of the tasks.
Parts of the Bender Gestalt Test (forms A1, A2, 3, 6.1, and 6.2)25 and the Goodenough Draw-a-Man Test26
were used in testing visual motor skills and eye-hand coordination. A child
failed the test if he or she made 3 errors in copying the forms of the Bender
Gestalt Test. In addition, a child failed if he or she made 2 errors in copying
the forms and had 2 of the following characteristics: failed the speech and
language skills tests or the gross motor functioning and perception tests;
was unable to draw a man as expected for children at age 5 years; or behaved
in a clearly abnormal manner during the testing, such as evidencing lack of
concentration, restlessness, poor motivation, and contact difficulties. In
the data analysis, the tests of the visual motor skills were combined with
behavioral characteristics because these 2 parts of the test together efficiently
determine whether a child is avoiding a task by demonstrating abnormal behavior.
The nurses who performed the testing were blinded to whether the child
belonged to the intervention or control group.
Representativeness of the Study Children
Recruitment was performed at well-baby clinics, visited regularly by
more than 98% of Finnish families, representing equally all socioeconomic
classes. All 1880 eligible families received information about the long-term
trial; 1054 families with 1062 children (56.5% of the eligible children at
that age) decided to participate (Figure 1). At age 5 years, 764 children (72% of the original study cohort)
were still participating in the trial. Of the children, 522 lived within the
city boundaries of Turku and 496 (95% of Turku residents; 65% of the available
5-year cohort) were included in the neurodevelopmental analysis.
Reasons for nonparticipation in the trial or later discontinuation were
evaluated. After recruitment, a random sample of 442 families who did not
participate in the study was contacted and asked for the reasons for nonparticipation
via a mailed questionnaire. The most common reasons were situational (difficulties
in arranging visits to the Cardiorespiratory Research Unit) or attitudinal
(eg, no changes wanted in child's diet and lifestyle). The socioeconomic (parent
education and family size) and health belief characteristics (attitudes toward
food and dietary counseling and locus of control) of the participating and
a randomly selected group of 417 nonparticipating families also were analyzed.
No major differences in the measured parameters were found between the 2 groups.
Finally, reasons for discontinuing trial participation were evaluated. The
most common reason was moving to a remote location. Other reasons were frequent
contacts with other physicians because of the child's recurrent infections,
the child being afraid of blood draws, lack of time, or the family's unwillingness
to keep food diaries.
We also compared the mean heights, weights, and serum cholesterol concentrations
of the children who remained in the study at age 5 years with the same measurements
for the entire initial study cohort when all the children were aged 7 months.
All values studied were similar in the 2 groups. Children who were still participating
in the trial at age 5 years but who had moved out of Turku (n = 242) or whose
parents refused permission to use developmental data (15 intervention and
11 control families) did not differ from the children who were tested. Proportions
of children in the intervention and control groups and of boys and girls did
not differ between those continuing and discontinuing participation, and the
longitudinal data on serum lipid concentrations in these 2 groups showed no
difference over time. The 26 children whose parents refused permission to
use developmental test data had shown no abnormal symptoms or signs during
the 4 years of clinical follow-up by the study pediatrician.
Results are shown as means (SD) with 95% confidence intervals (CIs)
for the mean. A 2-sample t test was used in comparison
of dietary intake data, serum cholesterol values, serum LDL-C values, and
serum triglyceride concentrations of the intervention and control children.
Because of the skewed distribution of serum triglyceride concentrations, we
used values that were log-transformed for the statistical analysis, and the
CIs are not presented. Longitudinal data of serum lipid concentrations were
analyzed using the random coefficients' regression model as if the data had
a normal distribution. No major deviation from normality was found when testing
with normal probability plots. Longitudinal data analysis was used to evaluate
linear trends in serum lipid values of children between ages 13 and 60 months
in the series and to analyze differences between the regression lines of the
intervention and control children.27
Because the aim of the study was to show that children in the intervention
group performed at least as well as the control children in the testing of
children's neurological development (ie, were not inferior to the control
children [noninferiority]),28 relative risk
(RR) of failing (intervention vs control) was used as a measure for group
differences. The interpretation of RR is RR = 1, probabilities of failure
are equal; RR<1, probability of failure in the intervention group is less
than in the control group; and RR>1, probability of failure in the intervention
group is greater than in the control group. Adjusted RRs of failing the developmental
screening tests were estimated using the Mantel-Haenszel method29
stratified by sex because of the markedly better outcome of girls in the testing.
The statistical test for the null hypothesis of inferiority vs the alternative
hypothesis of noninferiority is the 1-sided test at 5% level for the hypothesis:
H0: RR>RR0 and H1: RR<RR0,
where RR0 is the stated noninferiority limit. The 1-sided test
procedure at the 5% level is equal to calculating a 90% 2-sided CI. Noninferiority
was accepted when the upper limit of a 90% CI was less than the stated noninferiority
limit RR0. The noninferiority limit for RR0 was set
at 1.5 because the proportion of failures in the 3 major areas studied in
a normal population is approximately 10%21
so that an increase of 5% is considered insignificant. We have noted noninferiority
and noninferiority of borderline significance and presented 90% CIs where
appropriate. Differences were considered significant at P<.05. Analysis was done with SAS, version 6.12.30
The sample size of 496 children had 60% power to show noninferiority at the
5% level when the true population proportions of failures are 10% in both
target populations.
At age 8 months, when only data of formula-fed infants were included,
children in intervention and control groups had similar intakes of energy;
energy nutrients; and saturated, monounsaturated, and PUFAs (Table 1). Daily energy intake of children in the intervention group
was continuously somewhat lower than that of the control children thereafter.
The absolute and relative intakes of fat, saturated fatty acids, and
cholesterol at 13 months and later were consistently lower in the intervention
group than in the control group (Table 1). Fat provided a surprisingly small proportion of energy in the
diet of children in the intervention as well as of the control group at ages
8 and 13 months, but the proportion increased rapidly with age so that at
age 5 years the mean fat (saturated fat) intake of children in the intervention
group was 30.6% (11.7%) of energy and that of children in the control group
33.4% (14.5%) of energy. After age 8 months, children in the intervention
group had constantly higher intake of PUFAs than children in the control group,
and the polyunsaturated:saturated fat ratio in their diet was consistently
higher than that in the diet of the control group (P<.001
for both values). The absolute and relative intakes of linoleic and linolenic
acid in the intervention group after age 8 months were also consistently higher
than the intake values in the control group.
At age 7 months, serum lipid and lipoprotein values of children in the
intervention and control groups were similar (Figure 2).
Random coefficient regression analysis, used for evaluation of the influence
of the intervention on serum cholesterol concentration, showed a difference
in linear trends for the period of follow-up from age 13 to 60 months (P = .003). The regression lines differed at every age of
measurement, and the mean serum cholesterol values were continuously 3% to
5% lower in the intervention group than in the control group (Figure 2). Similarly, the slopes of the regression models for serum
non–HDL-C values of the intervention and control children differed during
the follow-up (P = .01).
Serum HDL-C values were, in general, slightly lower in the intervention
group than in the control group. The intervention and control groups showed
a difference in linear trends (P = .03). The regression
lines differed during the first 3 years of life but not at later ages. Linear
trends of the HDL-C to total cholesterol ratios of the intervention and control
groups were similar for the entire study period (P
= .95 and .82 for difference in the intercepts and slopes, respectively).
At age 5 years, mean (SD) serum cholesterol concentrations of the intervention
group were 4.27 (0.63) mmol/L (165 [24] mg/dL) and of the control group, 4.41
(0.74) mmol/L (170 [29] mg/dL) (95% CI, −0.27 to −0.01 mmol/L
[−10.4 to −0.4 mg/dL]; P = .04). The
mean (SD) serum LDL-C concentration of the intervention group was lower than
that of the control group (2.75 [0.57] mmol/L [106 {22} mg/dL] vs 2.88 [0.64]
mmol/L; [111 {25} mg/dL]; 95% CI, −0.24 to −0.02 mmol/L [−9
to −1 mg/dL]; P = .03) (95% CI is for difference
between the mean values for children in the intervention and control groups).
The intervention group had 4.5% lower mean LDL-C values than the control group.
The mean serum triglyceride value of the intervention group was slightly higher
(0.68 [0.22] mmol/L [60 {19} mg/dL]) than that of the control group (0.64
[0.21] mmol/L [57 {19} mg/dL]; P = .04).
Neurological and Neuropsychological Development
The proportion of children who failed the individual tests ranged from
0.4% to 35.9%, but when the results were combined to cover the 3 major areas
studied, the percentages of failures in the 3 major areas were quite uniform
(Figure 3).
The intervention group managed at least as well as the control group
in the tests of speech and language skills, gross motor functioning and perception,
and visual motor development (Table 2)
(RRs of children in the intervention group to fail were <1 in every major
area studied). The noninferiority of children in the intervention group vs
those in the control group was shown in the tests of speech and language skills
and visual motor skills (upper 90% confidence limits, 1.49 and 1.08, respectively),
and the noninferiority of borderline significance was shown in the testing
of gross motor functioning and perception (upper 90% confidence limit, 1.55).
Only 4 children (1.6%) in the intervention group and 5 control children (2.1%)
refused to participate in all of the main tests.
This study shows that in a randomized, controlled trial in which a low-saturated-fat,
low-cholesterol diet was recommended by individualized dietary counseling,
intake of saturated fatty acids was markedly reduced, age-related increase
in serum cholesterol concentrations was diminished, and the neurological development
of children in the intervention group was at least as good as that of children
in the control group, with no specific areas of developmental dysfunction.
Despite current recommendations that intake of fat by adults and children
older than 2 years should be less than 30% of energy, that of saturated fatty
acids less than 10% of energy, and that of cholesterol less than 300 mg/d,31-33 the ability to hold
intakes to such low levels during childhood has been questioned.8
Furthermore, the safety of fat-modified diets in young children has raised
much concern, including fears of disturbing normal growth and neurological
development.9 Growth has been affected in a
few children who received extremely restricted, energy-deficient, unsupervised
diets,8,9 but this contrasts with
the findings of this study and of others where the diet provides adequate
amounts of energy and essential nutrients. All such studies show that relative
intake of fat and growth are not associated.11,12,15,16
The fears of neurological dysfunction in children exposed early to fat-modified
diets are based on the rapid development of the central nervous system during
the first years of life. Because 75% of brain growth is completed by age 3
years,34 the ability of the brain to recover
from early nutritional deficiencies is limited. Severe malnutrition in the
first year of life, even if corrected later, is associated with intelligence
deficiencies at ages 11 to 18 years.35 Endogenous
synthesis of cholesterol in humans fulfills the requirements of membrane synthesis
and hormone production, and no dietary cholesterol is actually needed. The
only essential components in dietary fats are 2 PUFAs, the linoleic and α-linolenic
acids, that are the precursors of n-3 and n-6 long-chain PUFAs present prominently in neural membranes in the
central nervous system and that are important for cognitive development and
visual function.36 Premature, and also possibly
young term infants, may require long-chain PUFAs during the first few months
of life. If the diet provides an adequate supply of calories, vitamins, essential
fatty acids, and other nutrients, there are no theoretical reasons why modification
of dietary fat quality might be detrimental to a child's development. Children
receiving the intervention in our study consumed more PUFAs than control children,
including essential linoleic and linolenic acids.
Normal growth of the children in this STRIP study15,16
and in other studies where children have been consuming diets similar to that
recommended here show that moderately decreased fat intake has little impact
on growth.10-12
However, neurological development of children has previously been evaluated
in only 1 long-term intervention study,6 in
which 51 three-year-old children who had received a low–saturated fat,
low-cholesterol diet from birth failed in a screening test as rarely as their
420 controls. Unfortunately, no details of the test results are given, and
the true composition of the diet used by the children was not analyzed. In
the Dietary Intervention Study in Children,10
which recruited 663 eight- to ten-year-old children with hyperlipidemia, a
psychological assessment revealed no differences between adolescents in the
intervention and control groups except that adolescents in the intervention
group had less depression at the end of the 3-year follow-up than the control
adolescents.
Minor neurodevelopmental deficits are difficult to recognize during
the first few years of life, but at age 5 years appropriate analysis is possible,
and the test results correlate well with later academic skills and neurological
performance.37 Children in STRIP were examined
by experienced, specially trained nurses, and, combined with pediatrician's
examination, the results of the testing should be reliable. However, it is
still possible that families of children with developmental difficulties may
be overrepresented among those families who have discontinued participation
in the trial or refused permission to use the developmental data. Because
the number of the dropouts and the socioeconomic status of the families were
similar in the intervention and control groups, such bias in the outcome is
unlikely.
Although the test collection used in our study covers the most important
aspects of a child's development, several details in performance that might
be detectable using more extensive neuropsychological testing may remain unrecognized.
However, in a trial this large, a more detailed testing of the children was
impossible because of the limited resources available. Because the RR of failure
of children in the intervention group was less than 1.0 in all 3 major areas
studied, the appearance of serious adverse effects of such dietary intervention
later in life is unlikely.
Whether the original sample of children represents the Finnish population
is a difficult question to answer, although comparison of the nonparticipating
and participating families revealed no significant differences. Recruiting
a more representative cohort in such a long-term intervention study would
be difficult. The proportion of families remaining in the study for more than
4 years is reasonable. Furthermore, the socioeconomic characteristics and
health beliefs of the families in the 5-year cohort and in the original study
cohort were quite similar, suggesting that the 496 children included in the
final analysis probably represent the original study cohort reasonably well.
The strongest long-term effect of dietary fat modification in children
on serum cholesterol concentration shows that the value remained 6% lower
among 3-year-old children in the intervention group than among control children
if a low-saturated-fat, low-cholesterol diet is consumed from birth.6 In another study, a school-based intervention, the
net mean change in serum cholesterol concentration ranged from 2.9% to 5.1%
during the 5-year follow-up,7 whereas in the
studies concerning hypercholesterolemic children, the decreases in serum LDL-C
values were even greater.38,39
In the intervention group of our study, the 3.2% mean difference in serum
cholesterol concentration and 4.5% mean difference in LDL-C concentrations
are within the same range as was seen in previous studies in normocholesterolemic
children. A low-fat diet reduces serum HDL-C concentration as well as serum
LDL-C concentration. However, although serum HDL-C values of children receiving
the intervention in this trial were slightly lower during the first 2.5 years
of follow-up, the ratio of HDL-C to total cholesterol for the intervention
and control groups was similar for the entire study period. Assuming that
the earlier the age at which serum cholesterol values are decreased, the greater
the decrease in incidence of CHD later in life,40
a 3% to 5% permanent reduction in serum cholesterol concentration starting
in early childhood may considerably influence the incidence of CHD in adulthood
without adverse effects on neurological development.
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