Postpartum severe hyponatremia in preterm birth and mature newborns: Dangers for mother and child?

Introduction: Sodium is the ion with the highest extracellular concentration and thus also determines the osmolality in the extracellular space. The lower the serum sodium, the more serious the dilemma. Case Series: Case 1: A eutrophic female was born at 37+3 weeks gestation, birth by vacuum extraction, birth weight 2570-gram, umbilical cord blood gas analysis performed in delivery showed severe hyponatremia (sodium 122 mmol/L). Case 2: A eutrophic male was born at 40+4 weeks gestation, spontaneous labor, birth weight 3230-gram, suspicion of cerebral seizure, postpartum hyponatremia, perinatal metabolic acidosis, respiratory failure, and hypoxic ischemic encephalopathy. Case 3: A eutrophic male was born at 38+4 weeks gestation, spontaneous birth, birth weight 2895-gram, postpartum severe hyponatremia, suspicion of cerebral seizure, cyanosis attacks. Case 4: A preterm female was born at 31+1 weeks gestation, birth weight 1195-gram, sodium 125 mmol/L, potassium 6.3 mmol/L with respiratory disorder. Conclusion: We recommend a quick diagnosis and stop the factors that cause hyponatremia. Laboratory Felix Sierra1, Steffen Kunzmann2, Niki Mouzakiti1, Nafisa Sabarai1, Franz Bahlmann1 Affiliations: 1Department of Obstetrics and Gynecology, Center for Ultrasound and Prenatal Medicine, Buergerhospital and Clementine Children’s Hospital, Frankfurt am Main, Germany; 2Department of Neonatology and Pediatric Intensive Care, Buergerhospital and Clementine Children’s Hospital, Frankfurt am Main, Germany. Corresponding Author: Felix Sierra, Department of Obstetrics and Gynecology, Center for Ultrasound and Prenatal Medicine, Buergerhospital and Clementine Children’s Hospital, Frankfurt am Main, Germany; Email: sierrafelix303@gmail. com Received: 10 November 2020 Accepted: 28 January 2021 Published: 22 February 2021 S RIES PEER REVIEWED | OPEN A CE S tests, history, and physical examination could reduce hyponatremia to ensure adequate treatment.


INTRODUCTION
Sodium is the ion with the highest extracellular concentration and thus also determines the osmolality in the extracellular space. The lower the serum sodium, the more serious the dilemma.
Although the laboratory definition may be slightly higher. Hyponatremia, defined as serum sodium concentration below 135 mmol/L, is a commonly electrolyte abnormality encountered in hospitalized patients. Hyponatremia is a clinical complication of a wide variety of diseases, surgical procedure, pregnancies, and drug treatments. Hyponatremia is primarily a disorder of water balance, with a relative excess of body water compared to total body sodium and potassium content [1,2].
During pregnancy, hyponatremia can be caused by various mechanisms. An osmotic phenomenon is one of the physiologic changes that occur during pregnancy. Normal pregnancy is a state marked by avid sodium retention and plasma volume expansion. Increased epithelial sodium channel activity in pregnancy may mediate these changes.
Prevention of sodium retention was associated with a decrease in maternal blood pressure and body weight, as well as fetal growth restriction. Taken together, these findings emphasize the importance of increased sodium channel activity during pregnancy in maintaining the pregnancy-mediated changes in sodium balance, volume status, and blood pressure. The reabsorption of water in the kidney is controlled by vasopressin, which in turn regulated by plasma osmolality. Vasopressin is eliminated due to increased osmolality, causing water retention that will restore osmolality [3,4].
Reduction of plasma osmolality by ≤10 mOsm/kg occurs in early pregnancy mainly because of a decrease in plasma sodium by ≤5 mmol/L. By 11+6 weeks of gestation, the plasma osmolality remains low until after delivery.
On day of admission, serum sodium (mmol/L), osmolality in serum (mOsm/kg), sodium in urine, and osmolality in urine should be performed [5].
Changes in plasma sodium concentration are therefore a reflection of abnormal water balance, rather than the dysregulation of sodium intake and excretion. The neonatal electrolyte disorders account for 10% of seizures at the newborn, 25% ill newborns developed a mild hyponatremia, and 1% a moderate hyponatremia [6,7]. The water content of the body depends on age. In the first year of life there is a rapid and later slower decrease in body water. The total body fluid in preterm infants is 80% of body mass in the 28th week of pregnancy, decreases to 70-75% in term infants, 65-70% in infants, 60% in children, adolescents, and adults [8][9][10][11].
Postnatally there is an adaptation of the newborn, which proceeds according to a characteristic pattern. The prediuretic phase comprises the first two days of life. The newborn loses fluid mainly through the "perspiratio insensibilis" (release of water through the breath and skin). In this phase, the amount of urine is minimal and independent of the amount of fluid applied. This transepidermal loss of fluid is particularly high in premature babies. Increased water loss is also caused by sweating, fever, hyperventilation, or tachypnea [10,11]. The kidneys play an increasingly important role in fluid regulation. The urine production is adjusted to the amount of fluid administered. The influence of the skin on the fluid balance decreases through the stratum corneum (34 weeks of pregnancy), whereby the fluid balance in this phase is mainly regulated by the kidneys [11]. The physiologically induced weight loss after birth is also due to the loss of sodium and water through the kidneys and thus a loss of extracellular fluid [11,12]. The weight loss in premature babies is up to 15%, in term babies around 10% [13,14]. However, this is not seen as dehydration, but as a physiological adaptation to extrauterine life. Furthermore, the pulmonary vascular resistance drops postnatally, which increases the left atrial venous return. This results in a stretching of the atrial muscles, which in turn leads to the release of the "atrial natriuretic peptide" (ANP). Diuresis, natriuresis, and weight loss are the results [13,15].

Diagnosis
A eutrophic female was born at 37+3 weeks gestation, birth by vacuum extraction, birth weight 2570-gram, umbilical cord blood gas analysis performed in delivery showed severe hyponatremia (sodium 122 mmol/L). Her arterial pH was 7.2, body temperature 36.2°C, breathing rate 27/min, heart rate 117/min, blood pressure 71/46 mmHg, and left dacryocystocele. The newborn was transferred to Neonatal Intensive Care Unit (NICU) due to the hyponatremia.
The skull ultrasound showed no evidence of past or recent bleeding, no calcification, no evidence of a liquor circulation disorder and Doppler of the anterior cerebral artery was normal. The ultrasound showed normal bilateral kidneys. Figures 1 and 2 show the electrolyte and saturation changes for seven days.

Diagnosis
A eutrophic male was born at 40+4 weeks gestation, spontaneous labor, birth weight 3230-gram, suspicion of cerebral seizure, postpartum hyponatremia, perinatal metabolic acidosis, respiratory failure, and hypoxic ischemic encephalopathy.
Good postnatal adaptation, APGAR score 9/10/10, arterial pH 7.21. The newborn was given to the mother for bonding, after 1 hour we found a livid apneic and bradycardic newborn (20-30/min). Rapid heart rate increases with bagging, and we decided on endotracheal intubation.
The umbilical cord blood gas analysis performed in delivery room showed hyponatremia (sodium 127 mmol/L), arterial pH 6.88, BE-25, lactate 14. The newborn was transferred to NICU, blood gas analysis performed showed hyponatremia, arterial pH 7.13, BE-19, lactate 16. The mother's sodium was 126 mmol/L.
The skull ultrasound showed a cerebral edema stage II, end-systolic and end-diastolic flow velocities increased, diffuse echogenicity increased in parenchyma.
After 7 hours there was a decrease in oxygen saturation of up to 20% and a generalized increase in tone. Despite the substitution, we assessed the result as a seizure with renewed hyponatremia. Due to hypothermia, the newborn was reintubated and sedated.
The hypotension was supported with norepinephrine, the newborn was extubated successfully without additional oxygen requirement.
Due to the withdrawal symptoms, dexmedetomidine was administered after extubation therapy and therapy with ampicillin and gentamicin was carried out for 5 days which led to the control of cerebral edema stage II. The newborn was transferred to the Children's Hospital in good general condition. Figure 3 shows sodium, lactate, and saturation changes for nine days.

Maternal characteristics
A 41-year-old mother, gravida 1, para 1, blood group A rhesus positive, pre-existing arterial hypertension, insulin resistant diabetes, obesity, and hypothyroidism, spontaneous birth in skull position, and pulpy amniotic fluid.
In the NICU, we observed seizures with staring gaze, changes in skin color, a drop in oxygen saturation and breathing difficulties. The amplitude-integrated electroencephalogram (aEEG) showed no evidence of focal or generalized convulsive activity. The severe hyponatremia was normalized by sodium substitution. In the further course the electrolytes were normal. The mother also had hyponatremia of 131 mmol/L, potassium value was 3.9 mmol/L at the time of delivery. We assume syndrome of inappropriate antidiuretic hormone (SIADH) symptoms were highly likely during childbirth. Figure 4 shows changes of potassium and lactate for thirteen days. Figure 5 shows the course of sodium, chloride concentration (mmol/L), saturation (%), and arterial pH blood gas analysis (mmHg) for 13 days.

Maternal characteristics
A 24-year-old mother, gravida 1, para 1, blood group A rhesus positive, conditions after rupture of membranes, spontaneous birth in skull position.
Neonatal echocardiogram revealed a muscular ventricle septum defect (VSD) with left-right shunt as well as atrium septum defect (ASD II) with left-right shunt, retrograde flow in the descending aorta with Vmax 162 cm/s and slight pleural effusion. The metabolic screening showed an abnormal finding of 17-hydroxyprogesterone (OH) progesterone, which is the biochemical marker for diagnosing Adrenogenital syndrome (AGS).

Maternal characteristics
A 38-year-old mother, gravida 1, para 1, blood group A rhesus positive, HBsAg negative, cytomegalovirus (CMV) positive, inpatient admission due to suspected gestosis. As develops hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, so decision for caesarean section was taken.
The maternal osmolality in serum was 277 mOsm/kg at day 3, 265 mOsm/kg at day 6, total protein in urine was 498 mg/24 h and sodium in urine was 53 mmol/L. The placenta showed a chorangiosis type I. Figure 6 shows maternal and neonatal serum sodium concentration (mmol/L) for 13 days and Figure 7 shows maternal and neonatal serum calcium concentration (mmol/L) for 8 days.

DISCUSSION
The risks and dangers of maternal hyponatremia in pregnancy and during labor have previously been recognized [16][17][18]. Maternal hyponatremia can also be reflected in the fetus and may increase the incidence of respiratory distress and hyperbilirubinemia in hyponatremic neonate [19,20]. Acute hyponatremia in our cases reflected maternal pre-delivery hyponatremia and the neonate reflected those of mother. Administration of oxytocin with glucose infusion causes in neonate hyponatremia, and the same with excessive oral water intake during labor and other medications [21][22][23]. Sodium-active drugs use like diuretics, angiotensin converting enzyme (ACE) inhibitors, and selective serotonin reuptake inhibitors (SSRIs) could be provoking a maternal hyponatremia [19,24]. Diagnostic difficulties during labor are obvious as initial symptoms of hyponatremic encephalopathy are nonspecific and may easily be confused with symptoms of pre-eclampsia [17]. The symptoms of lower sodium levels can occur during pregnancy and a reduction in brain size [25]. Although the importance of this reduction remains to be explained, it could be due to an intracellular adaptation to pregnancy.
When life threatening symptoms (vomiting, irritability, headache, nausea, brain edema, and coma) occur, therapy must aim at quick restitution of serum sodium and osmolality [26].
Severe hyponatremic can cause encephalopathy, respiratory failure, and death [20,27]. Hyponatremia is a rare complication of preeclampsia. The pathogenesis of the severe hyponatremia in our case is not fully understood as most women with preeclampsia do not develop hyponatremia. It is hypothesized that the non-osmotic stimulation of vasopressin in the setting of a hypervolemic state with low effective circulating plasma volume is the main mechanism of hyponatremia. Previous case reports have described hyponatremia with pre-eclampsia with and without nephrotic syndrome [28,29].   A fall in serum osmolality suppresses the release of antidiuretic hormone, allowing excretion of the excess water in dilute urine [11].
We know that higher fluid administration during labor may cause significant hyponatremia in women.
Oral fluid intake during labor should be documented to avoid intravenous administration of hypotonic solutions [30,31].
We know that the common clinical problem of hyponatremia is frequently developed in hospitalized patients [32]. Although morbidity varies widely in severity, serious complications can arise from the disorder itself as well as from errors in management [30]. The manifestation of hyponatremia is largely related to dysfunction of the central nervous system, and it is more conspicuous when the decrease in the serum sodium concentration is large or rapid [33]. Massive fluid intake during labor can cause hyponatremia due to sodium loss through sweating and fluid retention [34].
Complications of severe or rapidly evolving hyponatremia include seizures, coma, permanent brain damage, respiratory arrest, brain-stem herniation, and death. These complications often occur with excessive water retention in patients who are essentially euvolemic [27].
The management of hypotonic, hypertonic hyponatremia requires balancing the risks of hypotonicity, and hypertonicity against those of therapy. The presence of symptoms and their severity largely determine the pace of correction [35]. At patients with symptomatic hyponatremia and concentrated urine osmolality (≥ 200 mOsm/kg of water) and clinical euvolemia or hypervolemia require infusion of hypertonic saline.
Algorithm for the management and therapy of hypotonic hyponatremia bevor and during pregnancy.

CONCLUSION
The therapeutic options for treating hyponatremia have recently expanded. Clinicians should be familiar with the diagnosis and management of various forms of hyponatremia, and the therapeutic approach should primarily be based on the severity of the symptoms. Laboratory assessment should include plasma osmolality, urine osmolality, and urine sodium. Additionally, we recommend tests of thyroid and adrenal function which may also be necessary. All these tests are required for the differential diagnosis of hyponatremia. For clinical practice, it should be noted that if a sudden increase in urine output to >100 ml/h signals of rapid rise in serum sodium concentration. If vasopressin activity is suddenly suppressed, as happens when intravascular volume is restored in hypovolemia, free water clearance can dramatically increase, resulting in serum sodium concentration rising more rapidly than expected. We recommend prompt diagnostic assessment, and stop if would be possible, medications and other factors that can contribute to or provoke hyponatremia. The cause of cases of hyponatremia can be deduced from the history, physical examination, and basic laboratory tests. In addition, the etiology of hyponatremia must be systematically determined to ensure adequate treatment.

Author Contributions
Felix Sierra -Conception of the work, Design of the work, Acquisition of data, Analysis of data, Interpretation of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Steffen Kunzmann -Acquisition of data, Analysis of data, Interpretation of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Niki Mouzakiti -Analysis of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Nafisa Sabarai -Analysis of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved Franz Bahlmann -Analysis of data, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

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