Published online June 1, 2007
PEDIATRICS Vol. 119 No. 6 June 2007, pp. 1152-1158 (doi:10.1542/peds.2006-2706)
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Endothelial Function in Newborn Infants Is Related to Folate Levels and Birth Weight

Helena Martin, MD, PhDa, Bo Lindblad, MD, PhDb and Mikael Norman, MD, PhDc

a Department of Woman and Child Health
b Division of International Health, Department of Public Health Sciences
c Department of Clinical Science, Intervention, and Technology, Karolinska Institute, Stockholm, Sweden


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Low maternal folate levels during pregnancy correlate with low birth weight, a perinatal risk factor for later cardiovascular disease. We studied relationships between red blood cell folate levels, birth weight, and vascular endothelial function (a key factor in the early pathophysiologic processes of heart disease) in newborn infants.

METHODS. We included 82 infants (30 low birth weight) and their mothers. A laser Doppler technique was used to measure skin perfusion during transdermal iontophoresis of acetylcholine (an endothelium-dependent vasodilator). Red blood cell folate, vitamin B12, and homocysteine levels were determined.

RESULTS. The perfusion response to acetylcholine was lower in low birth weight infants than in normal birth weight control subjects (mean: 35 vs 76 perfusion units). The neonatal acetylcholine response correlated with red blood cell folate levels in both infants and their mothers. The folate levels of low birth weight and control infants did not differ significantly (mean: 1603 vs 1795 nmol/L), but mothers of low birth weight infants had lower folate levels than did mothers of control infants (mean: 805 vs 1109 nmol/L). In multivariate analysis, low birth weight and red blood cell folate levels contributed independently to endothelial function in newborn infants. The levels of vitamin B12 and homocysteine were similar in the 2 groups and did not correlate with endothelial function.

CONCLUSION. The data presented here provide the first evidence for a relationship between folate levels and vascular endothelial function in newborn infants.

Key Words: birth weight • intrauterine growth restriction and hypoxia • endothelial function • cardiovascular disease • folate metabolism

Abbreviations: LBW—low birth weight • NBW—normal birth weight • RBC—red blood cell • LD—laser Doppler • PU—perfusion unit

Dysfunction of the vascular endothelium precedes formation of atheromatous plaques and is linked to metabolic and sympathetic abnormalities.1,2 The degree of endothelial dysfunction is related to the severity and prognosis of heart disease.3–5 Evaluation of endothelial function thus permits assessment of cardiovascular risk in healthy subjects and study of pathogenetic mechanisms. Already as newborn infants, subjects with low birth weight (LBW) show an impairment in endothelium-dependent vasodilation.6,7 Endothelial dysfunction also characterizes LBW children and adults.8–10 At present, the causes of endothelial damage to human fetuses are not known. Experimental data show that nutritional imbalances in pregnancy cause lasting endothelial dysfunction in the offspring.11

Low folate and high homocysteine levels, in combination or independently, have been shown to be risk factors for endothelial dysfunction and cardiovascular disease.12,13 Their metabolism is inversely correlated. The molecular mechanisms proposed include oxidative inactivation and reduced synthesis of the endothelium-derived vasodilator nitric oxide (Fig 1).12,13 During pregnancy, low folate and high homocysteine levels are associated with maternal vascular complications, for example, spontaneous abortion, preeclampsia, and placental abruption.14,15 More recently, low folate and high homocysteine levels were found to be associated with LBW.16–18 The associations with lower birth weight cannot be attributed to folate-related genetic polymorphisms alone19 or blocked placental transport and binding of folate20 but are ascribed mainly to deficient dietary intakes. In randomized trials, high but not low doses of folic acid during pregnancy reduced the prevalence of LBW.21


Figure 1
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  		FIGURE 1 Mechanisms of dietary folate effects. Dietary folate may enhance endothelium-dependent vasodilation through (1) DNA methylation and upregulated expression of mRNA for endothelial nitric oxide synthase,26 (2) decreased levels of intracellular homocysteine, a nitric oxide scavenger,12,13 and (3) a direct antioxidant effect of folate, which increases the bioavailability of nitric oxide released from the endothelium.12,13 TH folate indicates tetrahydrofolate; eNOS, endothelial nitric oxide synthase. (Modified with permission from Lindblad B, Zaman S, Malik A, et al. Acta Obstet Gynecol Scand. 2005;84:1056.)

 
We measured endothelium-dependent vasodilation in LBW and normal birth weight (NBW) infants born at term and their mothers. We hypothesized that impairment in vascular endothelial function would be associated with low folate/high homocysteine levels. Because vitamin B12 deficiency in pregnancy may cause the accumulation in tissue of homocysteine and lower birth weight,22 the levels of vitamin B12 were also determined.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Subjects
We studied 82 newborn infants and their mothers, for a total of 164 subjects (Table 1). Parental informed consent was obtained, and the study was approved by the regional ethics committee of Karolinska Institute.


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  		TABLE 1. Characteristics of Study Groups

 
All mothers were healthy nonsmokers who used no medications or special diets. Subjects with manifest (blood pressure of >140/90 mm Hg) or borderline (diastolic blood pressure of >85 mm Hg) hypertension before pregnancy or with insulin-dependent diabetes mellitus or glucose intolerance during the index pregnancy were excluded, as were multiple pregnancies and infants with congenital infections, chromosomal disorders, malformations, or neonatal asphyxia. Gestational age was determined through ultrasonography, and only infants born after 35 weeks of gestation were included.

Using these criteria, we identified 41 consecutive cases of LBW infants born at Danderyd Hospital in Stockholm between September 2003 and September 2004. LBW was defined as a birth weight less than the mean – 2 SD (ie, below the gender-specific 2.5th percentile for gestational age), according to Swedish reference data for normal fetal growth.23 Among the eligible infants, 9 were lost because of lack of investigator time and 2 because their parents declined to participate in the study. Thirty case subjects and 52 NBW control subjects were included. The birth weights of the 2 groups did not overlap (Table 1).

In the LBW group, prenatal fetometry using ultrasonography showed impaired growth for 16 of 30 fetuses. An obstetrical decision to deliver through cesarean section was made for 12 of 30 in the LBW group. The NBW control group was matched with respect to postnatal and gestational ages, gender, and mode of delivery.

Of women delivering a LBW infant, 3 had gestational hypertension and 4 had preeclampsia (gestational hypertension plus proteinuria of >1+). No mother who delivered a NBW infant had hypertension during pregnancy.

All infants were breastfed by their mothers in the maternity ward. Extra formula was provided to a larger proportion of LBW infants (11 of 30 infants), compared with NBW infants (7 of 52 infants; P < .05). On the day of examination, all infants had plasma glucose and hematocrit levels within the reference ranges (Table 1). Parents were interviewed concerning a family history of diabetes mellitus, myocardial infarction, stroke, hypertension, or hyperlipidemia among first-degree relatives.

Vascular Studies
Endothelial function was determined once, 3 to 4 days after delivery. The investigation was performed within 1 hour after feeding of the infants, while they were sleeping in the prone position. Mothers did not eat or drink for 2 hours before measurements. During the study, they sat comfortably in chairs, resting their forearms and hands on armrests at heart level.

A laser Doppler (LD) instrument (Periflux 4001; Perimed, Stockholm, Sweden) and a micropharmacology system were used to measure skin perfusion before and after transdermal delivery of acetylcholine, an endothelium-dependent vasodilator. The LD signal is proportional to the number and velocity of moving blood cells in the illuminated superficial skin microvessels and is expressed in perfusion units (PUs) of output voltage (1 PU = 10 mV). The combined drug-delivery and LD probe was fixed to the dorsal aspect of the hand with double-adhesive tape. The temperature of the LD probe facing the skin was standardized to 32°C. To study endothelium-dependent vasodilation, basal skin perfusion was recorded for 2 minutes, after which 2% acetylcholine chloride (Sigma-Aldrich, Steinheim, Germany) was transferred across the skin through iontophoresis (anodal current of 0.1 mA for 20 s, repeated 5 times at 60-s intervals). Basal perfusion and changes in response to acetylcholine were measured as the area under the curve. Details of the methods have been discussed elsewhere.6 Because of movement artifacts in infants, successful LD recordings were obtained for 78 of 82 subjects.

Biochemical Analyses
Blood samples were drawn from mothers and infants after vascular measurements. Plasma was separated within 30 minutes and stored at –20°C until analysis. Red blood cell (RBC) folate and vitamin B12 levels were determined with fluoroimmunoassays and plasma homocysteine levels with a fluorescence-polarization immunoassay.24,25 Maternal blood sampling and analyses were complete for all subjects. For healthy newborn infants, repeated blood sampling was not approved by the ethics committee. Because the metabolic screening program had first priority, sufficient sampling volumes and successful analyses of RBC folate and plasma homocysteine levels were obtained for 54 of 82 newborn infants.

Statistical Analyses
Values are means ± SEMs or numbers of subjects and proportions. Student's t test, analysis of variance, or the {chi}2 test was used to compare groups of data. Correlation coefficients were calculated and regression analyses were performed to evaluate contributions to differences in endothelial function (outcome). In these calculations, birth weight, levels of folate, homocysteine, and vitamin B12, family history of cardiovascular disease, gestational hypertension, mode of delivery, and neonatal hematocrit levels were included as covariates. Initially, group comparisons or linear regressions were performed for each covariate one by one. Covariates with P < .20 were entered into a multivariate regression model. Assessments of perfusion responses to acetylcholine provocations in the 2 groups were made by using 2-factor analysis of variance for repeated measurements. We planned to include at least 30 case subjects and 30 control subjects, to detect a group difference in endothelium-dependent vasodilation of 0.7 SD at a significance level of .05 and power of 0.80.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Folate, Homocysteine, and Vitamin B12 Levels
The RBC folate levels in LBW and NBW infants were not significantly different (ie, 1603 ± 87 vs 1795 ± 73 nmol/L; P = .11). Mothers of LBW infants had lower RBC folate levels (805 ± 63 nmol/L) than did mothers of NBW infants (1109 ± 86 nmol/L; P = .02). We found no differences in plasma homocysteine levels between LBW and NBW infants (6.5 ± 0.4 vs 6.9 ± 0.3 µmol/L; P = .48) or between their mothers (9.7 ± 0.6 vs 9.1 ± 0.4 µmol/L; P = .40).

The vitamin B12 concentrations were 386 ± 36 pmol/L for LBW infants and 362 ± 72 pmol/L for NBW infants (P = .92). Maternal vitamin B12 levels were 222 ± 18 pmol/L for mothers of LBW infants and 191 ± 14 pmol/L for mothers of NBW infants (P = .20). There were significant correlations between folate levels in maternal and neonatal blood (r = 0.47; P < .001), between maternal and neonatal plasma homocysteine levels (r = 0.59; P < .0001), and between maternal and neonatal vitamin B12 levels (r = 0.79; P < .0001).

Endothelial Function and Birth Weight
Basal skin perfusion was 14 ± 0.7 PUs in LBW infants and 14 ± 0.8 PUs in NBW infants (P = .56). Acetylcholine-induced, endothelium-dependent vasodilation was significantly lower in LBW infants than in NBW infants. Peak perfusion induced by acetylcholine was 35 ± 3 PUs in LBW infants and 76 ± 5 PUs in NBW infants (P < .001) (Fig 2).


Figure 2
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  		FIGURE 2 Skin perfusion responses to acetylcholine (an endothelium-dependent vasodilator) in LBW and NBW newborn infants (right) and their mothers (left).

 
Mothers of LBW infants had lower basal skin perfusion (9.0 ± 1 PUs) than did mothers of NBW infants (12 ± 0.6 PUs; P = .002). Acetylcholine-induced, endothelium-dependent, peak perfusion was lower (with borderline significance) in mothers of LBW infants (94 ± 9 PUs) than in mothers of NBW infants (116 ± 8 PUs; P = .07) (Fig 2).

Endothelial Function in Relation to Folate Levels
In newborn infants, basal skin perfusion showed no correlation with the results of blood analyses. Endothelium-dependent, peak perfusion correlated with neonatal (r = 0.43; P = .003) and maternal (r = 0.36; P = .004) RBC folate levels (Fig 3). We found no associations between endothelial function and plasma homocysteine and vitamin B12 levels. In mothers, basal skin perfusion correlated with RBC folate levels (r = 0.25; P < .05). No associations between maternal endothelial function and RBC folate, plasma homocysteine, and vitamin B12 levels were noted.


Figure 3
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  		FIGURE 3 Neonatal skin perfusion responses to acetylcholine (an endothelium-dependent vasodilator) in relation to neonatal RBC folate levels (r = 0.43; P = .003).

 
Endothelial Function in Relation to Other Covariates
Endothelial function did not differ in infants with (20 of 82 infants) or without a positive family history of cardiovascular disease (P = .28). All infants of mothers with a history of gestational hypertension or preeclampsia (7 of 82 infants) were in the LBW group and had lower endothelium-dependent peak perfusion levels, compared with infants of mothers without such a history (P = .02). Within the LBW group, endothelium-dependent peak perfusion did not differ in infants with or without a history of gestational hypertension or preeclampsia (P = .48). Endothelial function did not correlate significantly with mode of delivery (P = .08), but an inverse correlation between neonatal hematocrit levels and endothelium-dependent peak perfusion was found (r = –0.30; P < .05). Maternal endothelial function did not correlate with a family history of cardiovascular disease or gestational hypertension.

Multivariate Analysis of Endothelial Function
Multivariate analysis with infant endothelial function as outcome and birth weight, gestational hypertension, mode of delivery, and infant RBC folate and hematocrit levels as independent risk factors showed that both LBW (P < .001) and RBC folate levels (P < .05) contributed independently to endothelium-dependent peak perfusion. Taken together, these risk factors could explain 41% of the estimated variance in neonatal endothelial function (R2 = 0.41; P < .001). Gestational hypertension (P = .40), mode of delivery (P = .18), and neonatal hematocrit levels (P = .88) did not contribute to neonatal endothelium-dependent peak perfusion.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This is the first human study demonstrating a relationship between low maternal/neonatal folate levels and microvascular endothelial dysfunction in newborn infants. The observation is important. First, it provides insight into intrauterine mechanisms that can adversely affect the developing human vascular system. Second, neonatal endothelial damage may extend long after the perinatal period,8–10 ultimately affecting the risk of cardiovascular disease in adult life. Finally, trials with folate supplementation, at least at high doses, in pregnancy have shown a reduced risk of LBW21 and, as indicated by animal data, folate supplementation during pregnancy may abolish vascular endothelial dysfunction in the offspring.26

One of the earliest signs of susceptibility to atherosclerosis is endothelial dysfunction, which precedes structural vascular lesions by decades. We and others previously found impaired endothelium-dependent vasodilation in infants, children, and young adults born small at term.6–10 Because systemic endothelial dysfunction in peripheral and coronary arteries is related to cardiovascular end points,3–5 these findings may facilitate understanding of the epidemiologic associations between LBW and heart disease. Although the causal pathway in early human life is still unclear, findings in animals show that permanent vascular endothelial dysfunction ensues in the adult offspring of diet-challenged pregnancies.11

Mothers of LBW infants showed lower basal skin perfusion and a trend toward lower endothelium-dependent peak perfusion responses. Therefore, the mothers of LBW infants showed signs of a blunted endothelial response similar to that of their infants. Accordingly, contributions from a common genetic pathway for endothelial dysfunction in LBW infants cannot be excluded.

Besides LBW, this study indicates low folate levels as a risk factor for endothelial dysfunction. Preterm infants do not show impaired endothelial function.7,27,28 This may indicate that the third trimester is a particularly sensitive period for adverse vascular effects. Therefore, adequate folate levels may be important throughout pregnancy until term and not only during the periconceptional period for prevention of neural tube defects.

The possibility of deficient placental transfer of folate as a cause of fetal vascular damage is contradicted by our findings. In agreement with previous data on a concentration gradient across the placenta,20 we and others previously found that folate levels in the offspring exceeded those in the mother.17,18,29

All infants in our study were breastfed. To prevent hypoglycemia, LBW infants more often received extra formula in the first days after birth. Therefore, the possibility that LBW infants had higher postnatal folate intake cannot be excluded. However, because mothers of LBW infants showed lower folate levels, their breast milk likely contained less folate. In addition, RBC folate levels are not influenced by daily fluctuations in intake but reflect more-long-term bioavailability.

For almost all mothers and infants in our study, the folate levels were within the reference range defined by our chemistry laboratory (RBC folate levels of 350–1500 nmol/L). This could mean that not only folate-deficient pregnant women are at risk for adverse vascular effects on their fetuses. In fact, we found that the differences in neonatal endothelial function were related to physiologic variations in maternal folate levels, which can be much larger than those reported here.30

The molecular mechanisms through which low folate levels could acutely affect endothelial function include oxidative inactivation and reduced synthesis of the endothelium-derived vasodilator nitric oxide (Fig 1).12,13 These effects are reversible once folate levels are increased. Because endothelial function was measured only a few days after birth, maternal folate levels could still have been relevant to infant vascular function. Low folate levels have also been found to relate to hyperhomocysteinemia, which may add to endothelial dysfunction.12,13 However, our results do not indicate that the association between folate levels and endothelial function in newborn infants is mediated via high homocysteine levels.

Although previous cross-sectional studies indicated that endothelial dysfunction in LBW subjects persists throughout childhood and beyond,8–10 it is possible that the presently found association between low folate levels and endothelial dysfunction may be transient. Questions regarding if and how folate levels in early life can have long-lasting effects on the vascular system remain to be clarified. There is a need for longitudinal studies beyond the neonatal period to determine the relevance of our findings to cardiovascular disease in adulthood. In addition, the role of folate in DNA methylation, with genomic imprinting and epigenetic activation or silencing of genes, could be one target for future mechanistic research. In a rat model, endothelial nitric oxide synthase mRNA levels were found to be decreased in adult offspring of protein-restricted dams. Folate supplementation for the protein-restricted pregnant rats increased endothelial nitric oxide synthase expression in the adult offspring (Fig 1).26

In Sweden, grain products are not enriched with folic acid. After folic acid fortification of grains was implemented in the United States and Canada in 1998, stroke mortality rates have been observed to decrease.31 Although secondary prevention with folic acid and vitamin B12 supplementation for middle-aged cardiovascular patients failed to lower the risk of recurrent disease,32,33 the impact of folate supplementation during pregnancy may be different.

In previous studies of LBW infants and children, we demonstrated that vasodilation independent of the endothelium was unaffected.6,8 Given the short periods of quiet sleep for newborn infants, which offer a limited opportunity for vascular measurements, only tests of endothelial function were performed in this study.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Our findings suggest a relationship between low maternal folate levels in late pregnancy and vascular endothelial dysfunction in the newborn infants, independent of LBW. Low maternal folate levels may be a preventable perinatal contribution to cardiovascular disease in the offspring. Studies of maternal, placental, and fetal outcomes after folate and vitamin B12 supplementation throughout pregnancy are warranted. Longitudinal follow-up studies of subjects born to mothers participating in previous or coming trials of macronutrient and micronutrient interventions during pregnancy would also be helpful. Taken together, such efforts should contribute to useful, evidence-based, perinatal strategies for prevention of adult disease and improvements in public health.


   ACKNOWLEDGMENTS
 
This study was supported by grants from the Swedish Research Council (project 71P-14158 and project 348-2002-6975), Swedish Heart Lung Foundation, Karolinska Institute Research Foundations, and Sällskapet Barnavård, Karolinska University Hospital.

We thank Jessica Schiött, research nurse, for help with the study.


   FOOTNOTES
 
Accepted Jan 18, 2007.

Address correspondence to Helena Martin, MD, PhD, Department of Pediatrics, Astrid Lindgren Children Hospital, Q6:00, Karolinska Hospital Solna, S-17176 Stockholm, Sweden. E-mail: helena.martin{at}ki.se

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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