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Although high blood pressure before pregnancy is associated with a risk of gestational hypertension and preeclampsia, no convincing evidence has been produced to show that dietary salt

reduction helps in the prevention and treatment of hypertension during pregnancy. Thus the current guidelines do not recommend a sodium restriction during pregnancy to prevent gestational

hypertension and the development of preeclampsia. However, the long-term impact of hypertensive disorders of pregnancy for life-threatening diseases later in life is a critical issue.

Gestational hypertension could contribute to the risk of developing hypertension later in life, and recent studies have suggested that gestational hypertension and preeclampsia are linked to

cardiovascular complications. In this article, we provide an overview of the current perspectives on the salt intake of pregnant women and consider both the short-term influence and the

impact beyond the perinatal period.

High blood pressure before pregnancy is associated with a risk of gestational hypertension and preeclampsia,1, 2 and fertile women with chronic hypertension are encouraged to keep their

dietary sodium intake low to prevent their blood pressure from increasing.3 However, the current guidelines3, 4, 5, 6 do not recommend a sodium restriction during pregnancy to prevent

gestational hypertension and the development of preeclampsia. The World Health Organization Guideline Development Group dared to state that the group considered the avoidance of an

‘excessive’ dietary salt intake as a healthy dietary practice, whereas sodium restriction during pregnancy was not recommended for the purpose of preventing the development of preeclampsia

and its complications.4

Clinicians have long recommended the restriction of the dietary salt intake to prevent sodium and water retention, which can lead to the development of preeclampsia.7 Later (but still

decades ago), sodium restriction was considered a trigger of overt eclampsia among women with preeclampsia,8 and extra salt was considered essential for the health of pregnant women.9, 10

More recent studies have established long-term cardiovascular risk in women with a history of preeclampsia11, 12 and those with gestational hypertension.13 In the present article, we provide

an overview of the current issues on the salt intake of pregnant women and consider both the short-term influences and the impact beyond the perinatal period.

Sodium retention with an increase in the circulating plasma volume is observed during normal pregnancy,14, 15 whereas intravascular volume depletion may be associated with a relative sodium

deficiency among women with preeclampsia.9 Salt has been shown to cure eclampsia in a large percentage of cases, and it has been shown that the administration of salt to cure convulsions has

little risk of causing toxemia during pregnancy.10 In a study that included 2019 pregnant women, Robinson10 found that the prevalence of preeclampsia was approximately 2.6 times higher in

women who were advised to reduce their salt intake in comparison to those who were told to increase their salt intake (for example, by adding extra salt to their food at the table or eating

salty bacon or fish). The investigator further reported that all of the 20 women with preeclampsia who were treated with extra salt (16 of the patients took an extra 200–300 g sodium

chloride daily) improved in a dose-dependent manner (a larger dose was associated with a quicker and more complete recovery).10 The infusion of a stable plasma protein substitute produced a

transient 17/15 mm Hg reduction in the systolic/diastolic blood pressure of 9 pregnant women with hypertension.16 In 1970, Palomaki and Lindheimer8 reported that the restriction of dietary

sodium intake to 17 mEq (1 g) per day was associated with a worsening of the renal function in a preeclampsia patient, which was recovered with a sodium intake of 206 mEq (12 g) per day.

They stated that classic observations concerning the consistent benefits of avoiding salt during pregnancy may be misleading.8 On the contrary, a sodium overload of 3–6 g per day resulted in

lower blood pressure in a pregnant woman with chronic hypertension.9 In contrast to the non-pregnant state, increasing salt intake was shown to reduce blood pressure in pregnant women.17

Although the aldosterone level in normotensive pregnant women was spontaneously high, irrespective of the salt intake, the 24-h ambulatory blood pressure remained low despite high

aldosterone availability and a high-salt intake.17

The previous systematic review did not demonstrate any evidence of the benefits of a low-salt intake during pregnancy,18 and no significant difference was observed in the development of

preeclampsia between women with a low-salt intake and those with a normal salt intake during pregnancy (2 trials; relative risk, 1.11; 95% confidence intervals, 0.46–2.66). Furthermore, the

risk of the development of gestational hypertension did not differ to a statistically significant extent (1 trial; relative risk, 0.98; 95% confidence intervals, 0.49–1.94).18 Until

recently, no convincing evidence has been produced to suggest that dietary salt reduction helps in the prevention or treatment of hypertension during pregnancy.19, 20 Dietary salt

restriction during pregnancy is therefore not recommended by clinical guidelines in a number of countries.3, 4, 5, 6 Nevertheless, the National Institute for Health and Clinical Excellence

(NICE) Guideline Development Group stated that ‘this does not diminish the importance of an awareness of salt intake in a healthy lifestyle or of advising dietary salt reduction in chronic

hypertension’.3

The Yanomami (Yanomama or Yanomamo), which denotes a human being in their language, is considered to be a representative unacculturated population. Their sodium intake is extraordinarily

low—in the order of 1 mEq per day.21, 22 This population has been frequently referred to as having a low prevalence of hypertension or to be free from hypertension. The blood pressure values

of the Yanomami people increase from the first to second decade but do not systematically increase during the subsequent years of life.21 To compensate for low sodium intake, their plasma

renin activities and aldosterone excretions are extremely elevated; the aldosterone excretion of 11 Yanomami participants was reported to be 27.3–164.9 μg per day, which is markedly higher

than the upper limit of Caucasians (17.3 μg per day).21 Although the long-term effects of a low sodium intake on their health have not been evaluated, as the mean life expectancy of Yanomami

Indians is approximately 40 years,21, 23 investigators have inferred that maintaining a low blood pressure via a low sodium intake would prevent cardiovascular complications.

Similar to adults, the renin–angiotensin–aldosterone system (RAAS) of pregnant Yanomami women was shown to be markedly enhanced, which would contribute to maintaining their body’s sodium

balance.22 Mothers and infants in this culture appear healthy, with no evident disadvantage from their dietary pattern.22 However, we would like to mention an unusual custom of Yanomami

women: after giving birth, Yanomami women (at an average of 14 years of age) decide whether or not their child should live. If they decide that the child should not live, then the child’s

life is ended by the mothers themselves. Although this practice of infanticide by the Yanomami is of philosophical interest to us, we should be cautious in applying perspectives obtained

from the Yanomami to other acculturated populations.

Preeclampsia develops with increasing frequency as a pregnancy approaches term.20 Unfortunately, preeclampsia is not observed in mammalians other than humans and some primates because of

substantive differences in physiology; in particular, trophoblast invasion is very limited in mice, and the transformation of the uterine arteries depends on maternal factors.24 Attempts to

develop a useful animal model of preeclampsia25 will help to more fully elucidate the mechanism, prevention and treatment of preeclampsia in the future. Hitherto, the physiological mechanism

in normal and abnormal pregnancies has been investigated and is introduced in this review series.26, 27 We briefly overview the physiological aspects in relation to sodium during pregnancy.

A high-salt intake was shown to impair brachial artery flow-mediated dilatation, which was observed in the postprandial stage28 and after 1 week of salt loading.29 Low flow-mediated

dilatation was observed among women with preeclampsia and remained for 3 years postpartum,30 which suggested that the endothelial dysfunction precedes the onset of preeclampsia and remains

even after delivery.26, 30 Five days of salt loading in healthy adults reduced the plasma levels of nitrate and nitrite independent of the blood pressure response.31 The development of early

preeclampsia is associated with an altered nitric oxide metabolism and/or altered nitric oxide synthesis.32

Oxidative stress has a key role in the development of endothelial dysfunction.33 Savvidou et al.34 demonstrated that the endothelial function of pregnant women who developed preeclampsia was

impaired before the development of the clinical syndrome, and women with impaired placental perfusion (identified by a Doppler waveform) had significantly high plasma concentrations of

asymmetric dimethylarginine, which was partly associated with endothelial dysfunction.34 The mechanisms of endothelial dysfunction involve the release of soluble fms-like tyrosine kinase

(sFlt-1), which is also known as soluble vascular endothelial growth factor (VEGF) receptor-1 (sVEGFR-1).33 sFlt-1 is a circulating antiangiogenic protein and an endogenous inhibitor of VEGF

and enhances the endothelial dysfunction already established by oxidative stress, reactive oxygen species and damage.33 The levels of sFlt-1 increase in women with preeclampsia and disrupt

VEGF, which is established before the manifestation of the disorder.33 As Redman et al.35 discussed, angiogenic and antiangiogenic factors of placental origin may contribute to preeclampsia.

Furthermore, placental ischemia and reperfusion further contributes to oxidative damage, mainly through the conversion of xanthine dehydrogenase to xanthine oxidase,33 and subsequent

inflammation due to placental oxidation stress can lead to endothelial dysfunction. Sodium overload is reported to increase oxidative stress in various organs,36, 37 and it would also affect

oxidative stress in the placenta. It is noteworthy that low-dose aspirin is effective for preventing preeclampsia,38, 39 which may be because aspirin inhibits the production of superoxide

by neutrophils.40

Excess sodium chloride may affect the adaptive immune system via serum/glucocorticoid regulated kinase 1 signaling.41 Modest increases in the concentration of sodium chloride markedly

enhanced type 17 helper T (Th17) responses in vitro, as did a high-salt diet in vivo.42, 43 These high-salt conditions in the lymphoid tissues may be essential for an optimal adaptive immune

response during infection because the sodium concentrations in the interstitium and lymphoid tissues are 160–250 mmol l−1 when plasma sodium concentration is approximately 140 mmol l−1.44

In contrast, and probably to compensate for the activation of immune regulation,42, 43, 44 a high-salt diet would be linked to autoimmune diseases caused by a disturbance in immune

homeostasis (for example, rheumatoid arthritis and multiple sclerosis45) through the induction of Th17 cells.42 Interestingly, and different from the pro-inflammatory Th17 cells, Binger et

al.46 reported that a high-salt intake reduces non-inflammatory innate immune cell activation, including alternative activated M2 macrophages, which are induced by interleukin-4 and

interleukin-13. Based on these differential effects on immune cell activity, investigators hypothesize that sodium chloride may shift the overall balance of the immune system.45, 46 This

salt-regulatory concept can also be applied in normal pregnancy and to the changes observed in preeclampsia.47

A paradoxical hyperactivation of RAAS with an increase in the circulating plasma volume is observed among normal pregnant women,48, 49 and a blunt response of the blood vessels to

angiotensin II would support placentation. However, RAAS is suppressed with the reduction of the circulating plasma volume in women with preeclampsia.50 Therefore, enhanced vascular

reactivity to angiotensin II is observed. A reduction in the secretion and utilization of aldosterone leads to insufficient placental development. Furthermore, in women with hypertensive

disorders of pregnancy, increased sodium reabsorption at the ascending loop of Henle and the distal collecting duct in the kidney and the production of agonistic autoantibodies against

angiotensin II type 1 receptor may result in the suppression of renin. A higher urinary excretion of immunoreactive plasmin(ogen) and the plasmin-dependent activation of ENaC in urine were

also reported among women with preeclampsia.51 Mishra et al.40 reported that the vascular reactivity to angiotensin II was enhanced in the omental arteries of women with preeclampsia in

comparison to normal pregnant women; it was assumed that this could be attributed to the activation of reactive oxygen species. Sodium can mediate these pathways, and these mechanisms would

be linked to salt-sensitive hypertension, which is more frequently observed among women with metabolic disorders or obesity.52, 53 In addition, increased circulating soluble adhesion

molecule E-selection, von Willebrand factor, endothelin-1 and 24-h urinary albumin excretion levels were observed in individuals with salt-sensitive hypertension.54

High blood pressure and other cardiovascular risk factors before pregnancy are associated with a risk of gestational hypertension and preeclampsia.1, 2 Women with chronic hypertension are

also at risk of short-term postpartum complications, such as pulmonary edema and renal failure.55 Thus blood pressure in fertile women should be evaluated before conception, and if not, it

should be evaluated at the time of the first prenatal visit. Reducing or substituting the dietary sodium intake can reduce blood pressure, at least in the short term.23

The blood pressure of pregnant women is typically decreased during mid-pregnancy and steadily increases during the third trimester.56 This transient decrease in blood pressure can be

explained by the primary peripheral arterial vasodilation with relatively less arterial circulation, which occurs in the early stage of pregnancy57 and also leads to the enhancement of

cardiac output and secondary to afterload reduction, the stimulation of RAAS and vasopressin release and renal sodium and water retention with the expansion of the extracellular fluid and

plasma volume compartments.57 We clearly demonstrated such blood pressure trends among normal pregnant women based on self-measured home monitoring in the Babies and their Parents’

Longitudinal Observation in Suzuki Memorial Hospital in Intrauterine Period study.58 However, the Avon Longitudinal Study of Parents and Children study investigators reported that women who

developed gestational hypertension or preeclampsia had higher blood pressure from very early in pregnancy and that a reduction of the initial decline in systolic blood pressure occurred

during the second trimester.1 We can safely state that the reduction of mid-pregnancy blood pressure decline is associated with high-salt sensitivity because such pregnant women have been

reported to have a family history of hypertension,56 obesity in early pregnancy56 and gestational weight gain.56 Such disorders can be an early marker of hypertensive disorders,59

placenta-mediated diseases (including preeclampsia and fetal growth restriction)1, 60, 61 and preterm birth.61 Premenopausal women with a history of severe preeclampsia are comparably salt

sensitive,11 and salt sensitivity may be more likely among pregnant women without a typical mid-pregnancy alteration. Meanwhile, Veerbeek et al.62 inferred that the number and levels of

postpartum-modifiable cardiovascular risk factors differed between patients with early- and late-onset preeclampsia, and patients with other hypertensive disorders of pregnancy, women with

early-onset preeclampsia, showed an overall less favorable risk profile in comparison to those with late-onset preeclampsia. This was particularly reflected in their glucose and lipid

levels.62

Currently, chronic (preexisting) hypertension is defined as hypertension that presents either prepregnancy or that develops at 12.5 g of salt) is consumed per day but are not supportive for

reducing sodium intake in populations in which