1. Severe resetting of the osmostat
2. Syndrome of inappropriate antidiuretic hormone (SIADH)
(a) Nausea vomiting
(b) Pain
(c) Medications
3. Nephrogenic syndrome of inappropriate antidiuresis (NSIAD)
4. Addison’s disease
5. Sheehan’s syndrome
6. Pseudo-Bartter’s syndrome
(a) Anorexia, laxative abuse, chloride-deficient diet
7. Secondary Bartter’s syndrome
(a) Loop diuretic abuse, prostaglandin infusion
8. Oxytocin administration
9. Hypotonic IVF resuscitation
10. Psychogenic polydipsia
Implications for Mother and Fetus
Though effects of hyponatremia on maternal health are well known, the fetal implications of hyponatremia are less well established. Not surprisingly, fetal serum sodium is reflective of the mother’s serum sodium [9]. Prolonged fetal exposure to hypoosmolality can induce the fetal kidneys to excrete large amounts of water resulting in polyhydramnios [9, 11, 12].
Treatment
In the peripartum period, it is important to administer IV fluids and oxytocin conservatively particularly in patients who were hyponatremic prior to pregnancy to prevent iatrogenic worsening of hyponatremia.
Though there is no ideal target sodium, if a pregnant patient is symptomatic, correction of the sodium at a rate of 0.5–1 meq/L/h until symptoms resolve can be considered. No more than a correction of 6–8 mEq/L in 24 hours should occur as it increases the risk of central pontine myelinolysis [2]. In hyponatremia related to SIADH, hypertonic saline infusion of 1.5% or 3% sodium chloride can be used. If hypertonic saline is required, monitoring in an intensive care unit, and coordination with a nephrologist, is recommended. Water restriction is not recommended in pregnant patients as it can be detrimental to organ perfusion and the fetus [8]. Other medications used to treat SIADH in nonpregnant patients such as demeclocycline and vaptans are contraindicated in pregnancy. Diuretics such as furosemide are listed as category C medications and can lead to oligohydramnios and a decrease in breast milk production if used postpartum [9]. If hyponatremia is worsening, not responding to treatment or related to preeclampsia, induction of labor may be appropriate [9].
Conclusion
Physiologic hyponatremia of pregnancy is typically without side effects or significant impact on the developing fetus. However it does require close monitoring and coordination of care between nephrologists and obstetricians if serum sodium is <130 meq/dL or if symptoms occur. Clinically significant hyponatremia in pregnancy is rare and poorly researched, and if severe, it has important implications for both maternal and fetal outcomes.
If a patient has preexisting hyponatremia prior to pregnancy, closer monitoring and/or investigation may be warranted given the tendency for hyponatremia to worsen during pregnancy. There are no studies supporting an ideal target sodium in pregnancy. However, given that the low end of normal physiologic sodium in pregnancy is around 130 meq/L, it can be considered a safe minimum target.
Potassium Regulation in Pregnancy
During pregnancy there is an increase in total body potassium concentration. This is largely attributable to progesterone-related antikaliuresis. At the same time, there is a counterregulatory increase in renal tubular excretion of cations such as potassium and magnesium [13]. Increased renin-angiotensin activation (RAAS) during pregnancy may contribute [13]. The measured serum potassium in pregnancy tends to be similar to normal values in nonpregnant patients.
The increased activation of the RAAS system in pregnancy is primarily due to hormonally related systemic vasodilation. Blood pressure typically decreases by 10 mmHg despite increased intravascular volume. In addition to juxtaglomerular cells, renin is also released from the ovaries and the endometrial decidua [14]. Placental estrogen stimulates increased angiotensinogen synthesis from the liver [14]. RAAS activation causes the increased aldosterone secretion that is typical of pregnancy. Aldosterone levels can be two to three times the upper limit of normal during pregnancy [15]. This results in increased urinary excretion of potassium and sodium reabsorption via stimulation of distal tubular sodium potassium exchange [16]. Counterbalancing aldosterone-mediated kaliuresis is progesterone-mediated antikaliuresis. The net effect results in an increase in total body potassium of 320 meq by the end of pregnancy [14, 16].
Pathologies in Potassium Balance in Pregnancy
The differential diagnosis of hypokalemia in pregnancy is similar to those who are not pregnant. Primary hyperaldosteronism, though rare, is estimated to be the cause of hypertension in pregnancy in up to 10% of cases [17, 18]. Differentiating primary hyperaldosteronism from the physiologic increases in aldosterone seen in normal pregnancy may be difficult. Renin can be helpful in establishing the diagnosis. Serum renin levels are usually elevated during pregnancy. However in primary hyperaldosteronism, serum renin levels are normal or suppressed. Hypokalemia is a helpful finding in support of the diagnosis [19, 20]. Diagnosis of primary hyperaldosteronism is important as it is associated with increased risks of maternal and fetal complications, including low birth weight [19]. If primary hyperaldosteronism is diagnosed prior to conception and attributed to a unilateral adrenal adenoma, the treatment is adrenalectomy prior to pregnancy. Aggressive antihypertensive regimens and potassium repletion are the treatment of choice for primary hyperaldosteronism diagnosed during pregnancy [20]. Mineralocorticoid receptor antagonists such as spironolactone are first-line drugs in primary hyperaldosteronism in the nonpregnant patient. Spironolactone is an FDA category C drug, and studies have shown it may cause undervirilization in male infants [20]. Eplerenone, an FDA category B drug, has less placental crossing and less antiandrogenic effects than spironolactone [18, 19]. Eplerenone has been used successfully during pregnancy in four documented cases [15]. If hypertension secondary to hypersecreting adrenal adenoma is refractory to treatment during pregnancy, adrenalectomy may be considered in the first and second trimester [17].
In a review published in the New England Journal of Medicine, two pregnant patients (and one menopausal woman) with genetic mutations causing aldosterone secreting tumors were found to have increased gonadal receptor luteinizing hormone-chorionic gonadotropin receptors (LH-CGR) and gonadotropin-releasing hormone receptors (GNRHR) [19]. In addition to hypertension and hypokalemia, increased levels of human chorionic gonadotropin, luteinizing hormone, and gonadotropin-releasing hormone led to the diagnosis [19].
Special care needs to be taken in pregnant patients with distal renal tubular acidosis (dRTA). The disease may worsen during pregnancy [21]. Typically these patients have chronic hypokalemia, a non-anion gap metabolic acidosis, urinary pH >6.5 with elevated urinary potassium, and absence of glycosuria and phosphaturia [21]. Severe acute metabolic acidosis in pregnancy can impair fetal circulation [21]. It is suggested that the worsening acidosis in chronic RTA during pregnancy can also impair fetal growth and development [21]. These patients require aggressive monitoring and increasing doses of oral bicarbonate and potassium supplementation [21]. Treatment with daily supplementation of potassium citrate can normalize both the hypokalemia and the metabolic acidosis of distal RTA [22]. Typically as long as hypokalemia is corrected in order to maintain normal muscle function, a vaginal birth is achievable. If the birth occurs during uncontrolled hypokalemia, ability to push during delivery may be impaired. Neonates in this setting may suffer episodes of flaccid paralysis and respiratory distress and may also have difficulties with feeding [23].
Severe hyperventilation of pregnancy has been shown to cause a chronic respiratory alkalosis and rarely, concomitant hypokalemia caused by transcellular shifts. During systemic alkalosis, hydrogen ions exit the cell to maintain acid-base balance, with potassium entering cells to maintain charge balance, resulting in low serum potassium levels. This hypokalemia tends to be mild and asymptomatic. There has been one case report of flaccid weakness of the upper and lower extremities in a pregnant patient with acute on chronic respiratory alkalosis in which other causes of hypokalemia were ruled out [24].
Liddle’s syndrome is an autosomal dominant condition presenting with hyporeninemic hypoaldosteronism, hypertension, and hypokalemia secondary to a gain of function mutation of the renal tubular epithelial sodium channel (ENaC) [25]. The main concern for a pregnant Liddle’s patient is uncontrolled hypertension which can worsen during pregnancy and cause adverse neonatal and maternal outcomes [25]. In addition, the preexisting hypertension renders an increased susceptibility to preeclampsia [25]. A case report from Italy successfully managed hypertension in a pregnant woman with Liddle’s syndrome by using amiloride and hydrochlorothiazide. Amiloride directly antagonizes the ENaC channel, preventing further renal potassium losses. The dose suggested by the authors of this case report is 15 mg daily. It is an FDA category B drug in pregnancy. It is important to note that amiloride has also been used successfully in pregnancy in patients with Bartter’s syndrome and secondary hyperaldosteronism and in Gitelman’s syndrome [25].
Gitelman’s syndrome is an autosomal recessive salt-wasting nephropathy associated with hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis, hyperreninemia, hyperaldosteronism, and hypotension [26]. Patients typically present with symptoms of fatigue, weakness, and in severe cases paralysis. This is typically a diagnosis already known prior to pregnancy, and as long as electrolytes are aggressively monitored and repleted throughout pregnancy, it generally confers a good prognosis for both mother and fetus [26].
Hypokalemic paralysis poses a threat to both mother and fetus. Undiagnosed severe hypokalemia can lead to respiratory failure and even death [21]. Hypokalemic myopathy typically presents with numbness or weakness of the extremities and is seen in patients with serum K < 2.5 meq/L. Severe cases may require ventilatory support [23]. Pregnant patients may be predisposed to develop hypokalemia-induced rhabdomyolysis. Normally, potassium is released from contracting muscle cells into the interstitial fluid around adjoining dilated arterioles. This mediates potassium-induced increase in muscular blood flow. However in hypokalemia, decreased potassium release into the interstitium leads to diminished hyperemia, muscle ischemia, and injury [21, 22].
There are case reports of both thyrotoxicosis and RTAs in pregnancy causing hypokalemic paralysis and/or rhabdomyolysis [21, 27]. Acquired syndromes such as betamethasone or pica-associated hypokalemic rhabdomyolysis have been reported as well [23]. Pica involving clay ingestion has been documented in several case reports as a cause of hypokalemia in pregnancy [28]. It is hypothesized that clay binds potassium in the gut causing severe but reversible hypokalemic myopathy.
Conclusion
Though total body potassium increases in pregnancy, serum potassium levels tend to be normal. The differential diagnoses of hypokalemia during pregnancy are similar to those in nonpregnant patients.
Magnesium Regulation in Pregnancy
Magnesium requirements increase during pregnancy, and most pregnant women following regular diets do not meet this increased demand [29]. Magnesium deficiency during pregnancy has both maternal and fetal health repercussions [29]. Pregnant women should be counseled to increase their intake of magnesium-rich foods such as nuts, seeds, beans, and dark leafy greens [29].
Several prospective studies have suggested a neuroprotective effect of magnesium sulfate administration in preterm babies [30–33]. Magnesium sulfate is thought to decrease fetal brain nitric oxide-related inflammation of white matter, thereby preventing brain injury [30–33]. In vitro studies suggest it also protects against free radical oxidative damage [34].
Magnesium is a well-known treatment for preeclampsia as it helps prevent eclamptic seizures and tocolysis in preterm labor [34]. While its exact mechanism of action remains unclear, several reports have found statistically significantly lower magnesium levels in patients with severe preeclampsia compared to patients with mild preeclampsia and normal pregnancies [35]. There have also been case reports and case control studies showing high plasma-magnesium concentrations in women with preeclampsia. However in these cases, the hypermagnesemia is thought to be related to impaired renal function [36, 37]. It is suggested that perhaps the characteristic vasoconstriction of preeclampsia results in loss of plasma into the extravascular space, thereby leading to higher concentration of serum magnesium and overall hemoconcentration [36].
Compared to normal pregnancies, preeclamptic mothers have higher levels of lipid peroxidation in their red blood cells, myometrium, and syncytiotrophoblast plasma membranes [34]. Magnesium sulfate (MgSO4) has been shown to reduce lipid peroxidation of red blood cell membranes, thereby reducing the red blood cell membrane osmotic fragility known to occur during preeclampsia [34]. MgSO4 administration in preeclamptic women has a vasodilatory effect and is thought to improve placental and fetal perfusion [34]. MgSO4 may interact with calcium channels of vascular smooth muscle and endothelial cells, decreasing systemic blood pressure and cerebral artery perfusion pressure and may have endothelial cell protective effects as well [34, 38–40].
A recent study suggested MgSO4 administration in combination with the calcium channel blocker nifedipine in patients with preeclampsia resulted in significant reductions in circulating proinflammatory IL-6 levels that are known to increase during preeclampsia [40]. This study suggests that MgSO4 administration reduced both the production of and response to IL-6 by endothelial cells, possibly interrupting the inflammatory feedback loop in preeclampsia [40]. Nifedipine is thought to reverse nitric oxide (NO)-related endothelial cell activation. It has been demonstrated that the effects of MgSO4 are NO independent [40]. This study therefore suggests that nifedipine and MgSO4 may both reduce endothelial cell activation in preeclampsia by independent and complimentary mechanisms [40].
Despite the noted benefits, it’s important to recognize there is a dose-related toxicity of magnesium sulfate both to mother and baby. Excessive magnesium can cause maternal hypotension, respiratory depression, and decreased urine output [41]. In the fetus, magnesium toxicity increases risk of still birth, early neonatal death, birth asphyxia, bradycardia, hypotonia, hyporeflexia, gastrointestinal hypomotility, and meconium plug syndrome [41]. One has to be particularly careful when administering magnesium in patients with acute kidney injury or advanced renal disease because of reduced renal excretion resulting in rapid rise of serum magnesium.
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