Dietary Intake of Sodium during Infancy and the Cardiovascular Consequences Later in Life: A Scoping Review

The relation between events in early life and health conditions in later life has been extensively studied, indicating that environmental factors in early life have thorough effects on vulnerability on disease later in life [1]. One of its leading principles is the Developmental Origins of Health and Disease-Hypothesis, often referred to as “The Barker Hypothesis” [2]. The Barker Hypothesis proposes that early developmental adverse influences, for example, poor fetal and postnatal nutrition, are implicated to adaptations that program future propensity to permanent negative health outcomes in physiology and metabolism, such as cardiovascular diseases, obesity, and diabetes [3].

In recent years, the consumption of sodium in adults has been thoroughly investigated and there has been convincing body of evidence from epidemiological, clinical, and experimental studies demonstrating that high sodium intake in adulthood has profound negative health effects, especially cardiovascular diseases, such as high blood pressure (BP) and stroke [4-6]. The mechanistic pathways by which sodium leads to arterial alterations and increase of BP are thought to mature from conception until adulthood and are primarily studied in animals models [7]. In humans, sodium intake after birth was evaluated in several studies, which conclude that the majority of infants ingest excessive amounts of sodium in early life [8-11]. According to these studies, sodium consumption in infants is often higher than recommended values by different national and international guidelines, resulting in approximately 4–8 times higher sodium consumption [8-11].

Altogether, high sodium intake may have a negative influence on health in later life, and the consequences of high sodium intake in early infancy are not well understood. The aim of this study was to perform a scoping review of the literature on the association between sodium intake in the first 6 months after birth and cardiovascular health outcomes later in life.

We searched the literature regarding sodium intake in the first 6 months after birth. We included all original articles as well as review articles based on either human or animal studies, published between January 1980 and April 2019. As the mechanistic pathways of high sodium intake are mainly studied in animal studies, we decided to include both human and animal studies. In addition, articles published before 1980 were excluded because lead was used in drinking water pipes before this date, affecting the levels of minerals in drinking water, which may influence the outcomes. We explicitly searched for articles focusing on the relation between sodium intake in infancy and cardiovascular health outcome in later life. For our search, we defined in later life as in adolescence or adulthood. The following databases were used to obtain the literature: Medline, Embase, and CAB Abstract and the following search strings were used: “(sodium intake OR salt intake OR sodium consumption OR salt consumption OR NaCl intake OR NaCl consumption NOT parenteral) AND (diabetes OR non-communicable disease OR cardiovascular disease* OR renal or kidney OR metabolic syndrome* OR insulin OR lifespan OR hypertension OR coronary heart disease) AND (baby OR babies OR infant* OR newborn* OR neonate* OR pediatric* OR paediatric* OR toddler*).”

The literature search in the databases was conducted by a clinical librarian on April 25, 2019 and contained 2,475 records after duplicates were removed. To ensure that all relevant articles were included, we hand-searched bibliographies of all included articles and used the “similar articles” function in PubMed. We identified 4 more records by hand searching. Two authors (N.E.E. and F.J.) independently reviewed all records and 2,364 articles were excluded based on reviewing the title and abstract (Fig. 1). Of the remaining 115 articles, 25 articles met the inclusion criteria for our scoping review. There were 2 duplicated cohorts, both in 2 articles. We included all 4 articles because the articles respectively described 2 different outcomes in one cohort [12, 13] and 2 similar outcomes at different time points [14, 15]. Finally, 25 articles were included in the scoping review. Any differences were resolved by reaching agreement through discussion. If agreement was not achieved, differences in opinion were solved through discussion with a third author (R.M.E.). There was one article written in French; a native speaker translated this article.

The different articles were divided into 2 categories: human and animal studies. The first category was then subdivided into full-term born and preterm born infants and/or low birth weight infants because preterm birth and/or low birth weight is a confounder for cardiovascular health outcome (40). We extracted the following information of each study: (1) author and year of publication; (2) country of publication and/or investigation; (3) study aim; and (4) study outcome. In addition, of the human studies, we extracted the study design, sample size and method of sodium intake assessment, whereas of the animal studies we extracted the study design, animal species, sample size, and method of Na intake assessment. Two studies [16, 17] described results of children age 4 months to 8 years. In this case, we only used the results until the age of 6 months.

We identified 25 studies: 18 human studies and 7 animal studies. Furthermore, 11 were review studies, 8 were randomized controlled trials, 5 prospective cohort studies, and 1 retrospective cohort study (Tables 1-4).

At birth, infants show an aversion or indifference to salty solutions in contrast to plain water [18-21]. According to Liem [21], the preference for salty taste develops because of repeated exposure to salty foods [21].

A relation was found between early salt intake and salt acceptance and/or preference in adulthood [17-19, 22, 23]. For example, Stein et al. [19] found that infants on an early high sodium diet (7.82 g/L NaCl) at 2 months were more likely to accept salt at 6 months than the low sodium group (3.91 g/L NaCl). Similarly, Schwartz et al. [17] found that the development of salt acceptance and preference starts between 3 and 6 months, and can predict salt intake of adults. The most sensitive period for infants’ salt acceptance and preference is between 2 and 6 months of age [22, 23]. In addition, Lava et al. [24] described that reduced salt intake benefits children and further they described specific risk groups with an even higher prevalence of salt sensitivity and therefore an increased risk of developing high BP, including overweight, preterm, and/or small for gestational age and African American children.

Besides taste imprinting, early dietary sodium intake seems to affect later BP. To determine the effect of sodium intake on BP, infants were randomized either to a low (0.05–0.32 g/L) or a normal (0.52–1.76 g/L) sodium diet during the first 6 months of life [25]. Systolic BP was significant lower in the low-sodium group (114.1 mm Hg) compared to the normal-sodium group (116.1 Hg) and total sodium intake over 6 months was 3 times lower in the low-sodium group [25]. At the 15-year follow-up, Geleijnse et al. [15] found that the low-sodium group had lower systolic and diastolic BP (3.6 and 2.2 mm Hg respectively) than in the normal-sodium group. Interestingly, differences in BP between low- and normal-sodium groups were significantly larger than any reported effects of low-salt diets in adults. This suggests that sodium in infancy plays a more important role than salt reduction in adults, as well as that sodium intake during infancy may be a key factor for later BP [26, 27]. As 44% of sodium consumption in infants has been reported to be via tap water, BP in infants receiving milk formula prepared with low-sodium mineral water (32 mg/L) or high-sodium tap water (196 mg/L) or breast milk was evaluated [28]. Milk formula prepared with high-sodium tap water results in saltier milk (382 mg/L) compared to low-sodium mineral water (218 mg/L) or breast milk (161 mg/L) [28]. After adjustment for age, sex and energy intake and sodium intake at 4 months was positively associated with systolic BP at 7 years (p = 0.02) [29]. One study found no significant effect of dietary sodium on BP [16]. Geleijnse and Grobbee [14] suggested that high levels of sodium may cause early kidney damage. More specific, as high levels of sodium intake during early kidney development may cause abnormal sodium handling and increased salt sensitivity, BP elevations may occur. According to the study, the kallikrein system plays an important role in the early kidney development and its maturation is affected by sodium intake [14]. Three mechanisms for the relation between sodium intake and BP have been proposed: (1) high sodium intake result in an expansion of extracellular fluid volume. (2) Sodium has a direct influence on peripheral vascular resistance [25] and (3) salt taste responses relate to BP regulation and therefore becomes a risk factor for later high BP [30].

Only one study reported on sodium intake and later health outcomes in preterm born infants but follow-up was only performed up to 18 months [31]. Lucas et al. [31] randomized preterm born infants to diets with different amounts of sodium in infancy and measured BP at the age of 18 months. The results did not show a difference in BP between the 2 groups.

All animal studies included for this review were performed in rats. We found that high sodium intake in the first week of life was associated with adverse health outcomes in later life in several animal experiments [12, 13, 32-36], whereas high sodium intake after this period was not, suggesting that the timing of taste exposure is important. In line with this, the results of Moreira et al. [33] indicate that an overload of sodium intake during the postnatal period permanently alters the excretion patterns and spontaneous sodium intake patterns in adulthood. Furthermore, sodium intake during postnatal period promotes salty food preferences in adulthood [33]. In addition, BP increases due to salt supplementation during suckling and BP of high-salt-diet offspring is higher [35]. Postnatal salt intake suppresses the postnatal rise in renal kallikrein gene expression, confirming that sodium intake is important during the maturation of renal kallikrein synthesis [32]. Additionally, angiotensin II receptors may be up regulated due to high dietary salt [13].

Our scoping review suggests that high sodium intake in infancy may have adverse outcomes on cardiovascular health in later life [25]. Infants seem to be less capable to excrete high levels of sodium and there appears to be a direct association between dietary sodium intake and hypertension later in life [37, 38].

We decided to review both the direct as well as indirect consequences of salt intake in early life on cardiovascular health later in life. With the increasing survival of this specific target group, more preterm born infants reach adulthood. There is an association between preterm birth and later systolic BP (mean follow-up range 6–30 years) [39]; therefore, it would be important to determine the association between early sodium intake levels and cardiovascular outcome in adolescence and adulthood.

This may indicate that the effect of sodium intake in early life has different outcomes in preterm born infants’ later life. Unfortunately, only one study focused on preterm born infants [31]. The authors found no negative effect of early high sodium intake in the preterm born infants on BP later in life. However, the follow-up period was only 18 months and the relationship between high sodium intake in preterm-infancy and cardiovascular diseases later in life was not examined in this study. Furthermore, Singhal et al. [40] stated that in preterm born infants, other factors besides high sodium intake in the first weeks of life, may lead to an increase in BP. These factors may also address the indirect relation between sodium intake in early life and cardiovascular consequences later in life. For example, a higher sodium intake in early infancy, for example, due to high concentrations of sodium in drinking water, is associated with high intake of sodium during adolescence and early adulthood as well. Therefore, we cannot discriminate between the impact of increased sodium intake early in life compared with higher sodium intake later in life on BP in adolescence and adulthood.

A limitation of this study includes the diversity of the articles. Of the 25 included studies, 44% were review studies and as expected most of the randomized controlled trials were performed in animals. There were only a few randomized controlled trial studies that met our inclusion criteria. Given the relevance and importance of this relation, we decided for our scoping review to include both original and review articles of human as well as animal studies. It should be taken into consideration that animal studies and their results may not in all aspects reflect the human situation. Another limitation is that other factors, for example, protein intake in early life may impact later cardiovascular outcome. Higher protein intake early in life is associated with higher growth and increased for overweight and obesity [41], which in turn increases risk of cardiovascular problems later in life [42]. In future studies, differences other than only sodium intake should be taken into account when evaluating the effect of sodium intake on later cardiovascular outcome.

Because we performed a complete search with both search strings and hand search methods in different databases, we were able to identify all of the relevant articles and make a clear overview of the existing literature on this topic.

Our scoping review provides evidence that higher intake of sodium in the first 6 months after birth may have adverse cardiovascular health outcomes later in life. A clear gap in the literature is the lack of sufficient evidence of cut-off levels of sodium intake in infancy. As only limited studies are performed on this relation, it is recommended to conduct more well-designed studies with sufficient follow-up to determine more precisely the effect of sodium intake in infancy on cardiovascular outcome in adulthood and define cut-off levels of sodium intake in infancy.

To avoid excessive sodium intake in the first 6 months of life, the total salt intake from food and drink products should be limited and the addition of salt during preparation should be avoided [8, 43, 44].

The findings of this scoping review, including the recommendations for further research, are important for health organizations. As cardiovascular disease, including high BP, is one of the major causes of death, prevention through adequate, but not excessive, intake of sodium in the first 6 months of life is crucial for later health.

The authors declare that they have no competing interests. In addition, Emmerik has written this manuscript independently of her work for the ministry of Health, Welfare and Sport.

There are no funding sources to declare.

N.E.E. and F.J. participated in designing the study, reviewed all abstracts and articles, interpreted study results, coordinated and drafted the manuscript, revised and approved final manuscript. R.M.E. participated in designing the study, took part as the third reviewer, reviewed and approved final manuscript. All authors read and approved the final manuscript.

N.E.E. and F.J. contributed equally to this work.