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* Center for Advanced Food Studies, Department of Human Nutrition, the Royal Veterinary and Agricultural University, Frederiksberg, Denmark and Department of Nephrology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark
2 To whom correspondence should be addressed. E-mail: ll{at}kvl.dk.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • fish oil • blood pressure • breast milk • children • heart rate variability
The hemodynamic effect of (n-3) PUFA has become of general public health interest because studies indicated that intake of (n-3) long-chain (
20 carbon) PUFA (LC-PUFA),3 in particular, affects several cardiovascular disease risk markers, including blood pressure (BP) and heart rate (HR) (1–8) and may also improve mortality in coronary artery disease patients (9,10). The (n-3) PUFA are also regarded of importance in infancy for optimal brain development (11). The long- and short-term effects of (n-3) LC-PUFA intake on health in infancy and childhood are less well investigated.
Hypertension is uncommon in childhood (12), but BP may track from early childhood to adulthood (13), and some nutritional programming may occur. Perinatal maternal (n-3) PUFA deficiency was found to have a long-term BP-raising effect in the offspring of rats (14). A follow-up study of a randomized, controlled trial, in which human infants were randomly assigned to formulas with or without LC-PUFA, also demonstrated a long-term beneficial effect of early LC-PUFA supplementation on BP (15). Breast-fed children had a diastolic BP similar to that of the LC-PUFA–supplemented group, but significantly lower than that of the unsupplemented group in the study (15). Breast-fed children also were found to have lower BP later in childhood compared with bottle-fed children in 2 observational studies (16,17).
The homeostatic processes involved in the regulation of BP are complex and involve local factors as well as the autonomic nervous system. (n-3) PUFA are incorporated as docosahexaenoic acid (DHA) in the cell membranes of all tissues, including the vascular endothelium and the nervous system, with uniquely high levels in the latter (18,19). The autonomic nervous system is also involved in the control of heart rate variability (HRV) and in the control of arterial compliance. Early intake of (n-3) PUFA was shown to affect the accretion of DHA in the central nervous system (11). In contrast to most infant formulas (n-3) LC-PUFA are present in breast milk (20). The concentration of (n-3) LC-PUFA in breast milk depends on the maternal diet, specifically the intake of marine oils (21–23). Fish oil supplementation effectively increases (n-3) LC-PUFA in breast milk and infant tissues (11). Little is known about the importance of breast milk (n-3) LC-PUFA content on the vascular risk markers, BP, pulse wave velocity (PVW), HR, and HRV in childhood.
In the present study, we investigated the long-term hemodynamic effect of maternal fish oil supplementation during the first 4 mo of lactation. The trial focused on the influence of (n-3) LC-PUFA on visual and cognitive development (24). In the present follow-up study, we assessed the effects of early (n-3) LC-PUFA intake on cardiovascular risk markers in the children at 2.5 y of age. The short-term effects of the dietary (n-3) PUFA intake of the children were also investigated.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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A diagram of the trial profile with focus on the present follow-up study is presented (Fig. 1). The participants were recruited from the Danish National Birth Cohort (DNBC) (25) as previously described (24). Briefly, healthy pregnant women with term singleton deliveries were selected on the basis of their fish intake. Women with fish intake below the population median [<0.4 g (n-3) LC-PUFA/d] were randomly assigned to receive either a daily 4.5 g supplement of fish oil (FO, Dry (n-3) 5:25/12:18 from BASF Health and Nutrition) or olive oil (OO) during the first 4 mo after delivery. Women with a high fish intake (HFI), corresponding to >75th percentile [>0.82 g (n-3) LC-PUFA/d], were included as a reference group. Of the 150 mothers who completed the initial 4-mo study period, 107 complied with the criterion for exclusive breast-feeding during the intervention. Those who did not conform were not excluded, but the degree of breast-feeding during the 4-mo intervention period was estimated from the intake of other foods related to the standard energy requirement. The degree of breast-feeding tended to be lower (P = 0.057) in the FO group than in the OO group (Table 1). Birth weight, duration of breast-feeding, and compliance did not differ between the intervention groups (Table 1). This was a double-blind study throughout y 1 of the child's life.
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RBC fatty acid analysis. RBC fatty acid composition was assessed at 4 mo and at 2.5 y of age. Infant blood samples (0.5 mL) were obtained in EDTA-conditioned tubes by heel-prick. At the end of the follow-up visit, 1-mL blood samples were collected in heparin-conditioned tubes from the 2.5-y-old children by venipuncture. RBC were isolated and processed as previously described (24). The lipids were extracted by the procedure of Folch (26), and the fatty acid composition was determined by GLC as previously described (27). Data are given as the percentage of each fatty acid relative to the total area of fatty acid peaks in the chromatogram (FA%). Successful RBC fatty acid measurements were available for 77 and 88 children at 4 mo and 2.5 y, respectively.
Diet. The habitual diet of the children was recorded at 2.5 y of age by the parents for 7 consecutive days, using a coded dietary questionnaire adapted from the questionnaire used in the Danish National Food Surveys (28) as previously described (29). The intake of nutrients was calculated using the GIES computer program (version 0.9, the Danish Institute for Food and Veterinary Research).
Blood pressure.
BP and HRBP were measured at 2.5 y of age with an automatic device during cuff inflation (model 506N; Criticare Systems). The measurement was performed shortly after arrival and again later with 
1 h between measurements. The second measurement was performed after 30 min of rest, and this single measurement was used in the data analysis. BP and HRBP were measured successfully in 82 and 81 of the children, respectively. Reasons for missing BP-data included irritated or restless children. The mean maximum outdoor temperature during the week of the examination was controlled for in the statistical analysis of BP because previous studies reported that BP is affected by this variable (30,31). Outdoor temperatures were obtained from the Danish Meteorological Institute.
Pulse wave velocity. PWV was measured between the aorta and arteria radialis by a noninvasive optical method for assessment of arterial stiffness. Due to their age, the measurement was performed with the children in a seated position. A belt with electrodes on each side of the heart was placed around the chest. The pulse in the wrist was registered with an infrared transducer. The position of the transducer was adjusted until a clear pulse curve with a sharp rise was achieved. The pulse curve and electrocardiogram were sampled for 20 s by the program "Pulse," version 4.0 (MRC Environmental Epidemiology Unit). The transit time was calculated by the analysis program "Pulse Analysis Program," version 97.1.1.1 (MRC Environmental Epidemiology Unit) as the time from the R-peak in the electrocardiograms to the beginning of the pulse curve in the wrist. The identification of the R-peak and the beginning of the pulse curve was checked by visual inspection; in a few cases, it was necessary to identify these manually. The distance between the heart, as measured from the suprasternal notch, and the transducer was determined to the nearest 0.5 cm by a tape measure. PWV was then calculated as the distance divided by the transit time. Single measurements were obtained. Measurements were successful in 69 of the children. Missing PWV data were due to the unwillingness of the children to co-operate.
Heart rate variability.
Electrocardiograms were recorded continuously for 0.5 h by a 2-channel tape recorder (Tracker Reynolds, Reynolds Medical), while the child was watching a video. The signal was derived from 4 electrodes placed according to the instruction manual on the chest after preparation of the skin. Before each recording, the equipment was calibrated for accurate time assessment. All recordings were analyzed with commercially available software from Diagnostics Monitoring. The following time-domain HRV variables were analyzed: the mean of all normal RR intervals during the recording (RR), the mean of the SD of all normal RR intervals in 5-min segments of the recording (SDNNi), the SD of the mean of RR intervals measured in successive 5-min intervals (SDANN), the percentage of successive RR interval differences 50 ms (pNN50), and the square root of the mean of the sum of the squares of the differences between adjacent intervals (RMSSD). QRS complexes with abnormal morphology were excluded from the HRV analysis. HRV data were successfully assessed in 84 children on the basis of 1720 ± 866 normal beats. HRHRV was also assessed from the recordings in 90 of the children. Thus, HR was measured in 2 ways, from the BP and the HRV measurements. HRBP correlated significantly with HRHRV (Pearson correlation = 0.697, n = 73, P 
0.001). The HR-value from the HRV measurements is considered to be the most accurate because it is recorded over a longer time period. In addition, the SD was slightly lower for the HR of the HRV recordings, resulting in a higher power to detect differences. This measure is given throughout, but statistical analysis was performed on both measures. These analyses had similar results, except when stated.
Statistical analysis.
Results are expressed as means ± SD. All data were analyzed using SPSS software (version 12.0; SPSS). Group comparisons (FO vs. OO, sex, or included vs. excluded) were carried out by Student's t test or the Mann-Whitney U-test for nonparametric variables. Bivariate correlations between variables (e.g., diet and hemodynamic parameters) were examined by Pearson's correlation coefficient or by Spearman's 
. Correlations including BP were adjusted for temperature by linear regression analysis. Dependent variables (i.e., BP, HR, HRV, and PWV) were analyzed by multiple linear regression analysis using General Linear Models with group (FO, OO) and sex as fixed factors including a group x sex interaction term. The degree of breast-feeding was included as a covariate because it may influence the effect of the intervention. If the interaction term had a significant effect in the analysis, ANOVA was performed for each sex separately. Outdoor temperature was included as a confounder in all multiple analyses of BP, and BP was included as a covariate in the analysis of PWV. The significance level was set to 0.05. With 60 children in the randomized groups, the study was powered to show a difference of 0.7 x SD in the measured outcome variables with a power of 80.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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0.001). The (n-3) PUFA levels in the RBC did not differ between infants in the 2 groups at 2.5 y [Table 1, see (32)]. The (n-3) PUFA intakes of the 2.5-y-old children were lower in the OO group than in the FO group (P = 0.037) (Table 1). Hemodynamic variables did not differ between the FO- and OO groups at 2.5 y (Table 2). There were no significant bivariate correlations between RBC (n-3) LC-PUFA at 4 mo and BP variables, PVW, HR, or HRV measures at 2.5 y in children of the 2 randomized groups (data not shown). Boys and girls did not differ in the BP variables or PWV and HRV measures, but the HRHRV was lower in boys (P = 0.033), and HRBP tended to be lower in boys (P = 0.069, data not shown).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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6 mm Hg, when the children were 6 y old (15). However, the present study showed that fish oil supplementation of the mothers during the first 4 mo of lactation was not associated with lower BP of their 2.5-y-old offspring. Most of the children in the present study were exclusively breast-fed during the intervention, and the content of (n-3) LC-PUFA in the breast milk of unsupplemented mothers may have been sufficient to secure optimal BP regulation. Forsyth et al. (15) found that the BP of children fed LC-PUFA–supplemented infant formula milk was comparable to that of breast-fed children. This indicates that the LC-PUFA intake of breast-fed children is optimal with respect to BP. We found, however, that the dietary intake of (n-3) PUFA of breast-fed children at the time of the follow-up visit at 2.5 y correlated with mean arterial pressure, indicating a short-term advantageous effect similar to that observed in adults (1,33,34). A similar favorable effect of (n-3) PUFA intake was also observed on systolic BP in a controlled study of 9- to 12-mo-old infants (35). PWV and most measures of HRV were not affected in the children 2 y after the intervention, although significant group differences were detected in heart rhythm (HR, RR, and SDANN), when the analyses were performed separately in the sexes. SDANN was the only HRV variable that was affected by fish oil supplementation during lactation, but in girls only. SDANN is a low-frequency HRV component, which expresses variations in HR between the 5-min intervals and thus expresses the long-term HRV. This is expected to be unaffected by a transient change in mood or attention, such as may occur when watching a video; therefore it may reflect a favorable shift in the sympathovagal balance toward parasympathetic activity. High parasympathetic activity was shown to be associated with low BP, low HR, and high HRV (36,37) and thus with a low cardiovascular risk.
It was demonstrated previously that early diet affects HR in a study that compared the 18-h HR of breast-fed and formula-fed infants at 1 and 4 mo of age, and found lower HR in breast-fed infants (38). Furthermore, a long-term effect of early nutrition was also observed on arterial stiffness because the PWV of 10-y-old children was shown to be positively associated with the duration of breast-feeding (39). Apart from these studies, to the best of our knowledge, the effect of diet or nutritional programming on these outcomes in children has not been investigated.
The present study had power to show differences of 0.7 x SD in the hemodynamic variables. With the observed SD, this corresponds to a decrease in HR and BP variables in the fish oil–supplemented group of 6–7 bpm and 8 mm Hg, respectively. Supplementation with (n-3) LC-PUFA or higher intake of fish in healthy and hypertensive adults was shown to result in a reduction in systolic BP and diastolic BP of 2–6 and 1.5–2 mm Hg, respectively, and a reduction of 2–4 bpm in 24-h HR (1,4,33,34). The long-term effects on BP in 6-y-old children who were supplemented with LC-PUFA–enriched formula during infancy were of similar magnitude (15). There was no indication of any effect of fish oil supplementation on BP variables. The variation in BP measurements is high in small children compared with adults and older children; hence, larger differences between groups are required in small children. Furthermore, the power was impaired by the relatively low participation in the follow-up study. Only 65% agreed to participate in the follow-up visit.
The observed difference in HR for girls and boys was 7 and 5 bpm, respectively. The power of the subsex comparisons is theoretically lower, but the mean differences were larger and the SD were reduced in the subgroups compared with the entire groups. The effects on HR and HRV were most pronounced in girls and in the direction expected from short-term effects in adults, i.e., lower HR and higher HRV after fish oil supplementation (3,4,34). The effects on HR in boys were less clear and in the opposite direction. The significant effects are contradictory and may be caused by random observations in both groups. However, physiological differences between sexes may exist. A study in rats administered various ratios of the dietary (n-6):(n-3) fatty acids during the perinatal period showed a sex-specific long-term effect on systolic BP in adults rat (40). Thus, we cannot exclude that a difference between the sexes can occur in humans but the presence of sex-specific differences has to be confirmed by further studies. Overall we did not find any conclusive long-term effect of maternal fish oil supplementation during lactation on HR and HRV variables.
Compared with the reported values for HRV indices of normal children in early childhood, the HRV measures in this study were lower, except for RR (41–43). This may be due to the shorter recording periods because 24-h recording was applied in those studies. The BP values were slightly higher compared with the reported values for children at that age (12,44). However, BP was measured with other types of equipment in those studies, which makes it difficult to compare the results (45).
Some of the infants in the randomized groups were not exclusively breast-fed throughout the intervention period, which may have reduced the effect of the intervention. In addition, the degree of breast-feeding was not equally distributed, with a trend toward a lower degree of breast-feeding in the FO group. Lower breast-feeding would be expected to reduce the (n-3) LC-PUFA supply of the infant, and thus possible (n-3) LC-PUFA–induced benefits in the FO groups. Furthermore, the level of habitual dietary intake of fish may also influence the effect of the maternal supplementation. In Denmark, the intake of (n-3) LC-PUFA from fish in the population is relatively high compared with other European countries (46), especially the intake of very fatty fish (47). It is possible that fish oil supplementation would have resulted in larger effects in a population with a low habitual fish intake. The (n-3) PUFA intake of the young Danish children examined, however, appears not to be high. The levels of (n-3) LC-PUFA in RBC at 2.5 y of age are in agreement with a low intake of (n-3) PUFA (5.53 ± 1.07% DHA compared with 8.01 ± 1.21% in the mothers). This may explain why we could observe an association between (n-3) PUFA intake and BP in these healthy children. A BP-reducing effect of (n-3) PUFA in adults was shown only after supplementation with large doses of fish oil and appears to be most prominent in hypertensive or older subjects (1). The results of the present and our previously published study (35) may possibly be due to the poor (n-3) PUFA status of the subjects.
These results indicated that a high dietary intake of (n-3) PUFA occurring in childhood is associated with a favorable effect on the BP. No consistent long-term effects after fish oil supplementation in lactating mothers were observed. Lower HR and BP are associated with a lower risk of coronary heart disease in adults, but the long-term effect of a lower BP in young children is not known. There is some degree of tracking of BP from y 1 of life (13), but it is uncertain whether this is also the case for effects caused by early diet in young children. Infant diet was shown to have long-term effects on BP, in both term (15) and preterm infants (48), but it is unknown whether the diet during y 3 of life can also have a programming effect. Further research is warranted before conclusions are made concerning how (n-3) PUFA intake during infancy and early childhood affect long-term health.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BP, blood pressure; DHA, docosahexaenoic acid; DNBC, Danish National Birth Cohort; EPA, eicosapentaenoic acid; FA%, percentage of fatty acids relative to all identified fatty acids in sample; FO, fish oil; HFI, high fish intake; HR, heart rate; HRV, heart rate variability; LC-PUFA, long-chain (20 carbon) PUFA; MAP, mean arterial pressure; OO, olive oil; pNN50, percentage of successive RR interval differences 50 ms; PWV, pulse wave velocity; RMSSD, square root of the mean of the sum of the squares of the differences between adjacent intervals; RR, mean time of RR intervals; SDANN, SD of the mean of RR intervals measured in successive 5-min intervals; SDNNi, SD of all normal RR intervals in 5-min segments of the recording.
Manuscript received 1 December 2005. Initial review completed 25 January 2006. Revision accepted 9 March 2006.
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