Pre-eclampsia complicated by severe hyponatraemia

Abstract

A 41-year-old woman was diagnosed with pre-eclampsia at 35 weeks gestation. She was treated with antihypertensives but, unfortunately, her condition became complicated by severe hyponatraemia. Her sodium levels rapidly dropped to 125 mmol/L. The cause for the hyponatraemia was the syndrome of inappropriate antidiuretic hormone secretion. She was initially managed with fluid restriction, but an emergency caesarean section was necessary in view of fetal distress. Her sodium levels returned to normal within 48 hours of delivery.

Pre-eclampsia is rarely associated with hyponatraemia. A low maternal sodium level further increases the mother’s risk for seizures during this state. Additionally, the fetal sodium rapidly equilibrates to the mother’s and may result in fetal tachycardia, jaundice and polyhdraminios. All these factors may necessitate an emergency fetal delivery.

Background

Pregnancy is a state of physiological changes to the body’s salt and water balance. The normal serum sodium level decreases by 5 mmol/L to term. Pre-eclampsia is a well-recognised complication of pregnancy. Hyponatraemia may infrequently develop during pre-eclampsia. It might be challenging to find the cause for the low sodium levels but it is vital to do so as it will influence the acute and long-term prognosis of both the mother and the fetus.

Case presentation

A 40-year-old woman known to suffer from type 1 diabetes on insulin pump therapy presented with newly diagnosed hypertension at 32 weeks gestation. This was her third pregnancy. Her obstetric history was significant for pre-eclampsia in the previous pregnancy.

Treatment with labetalol 100 mg bd (twice daily) was initiated but she was admitted at 34 weeks due to uncontrolled hypertension. Serum sodium level on admission was 134 mmol/L (135–145 mmol/L). Labetalol was increased to 200 mg three times a day and she was discharged after 4 days with a sodium level of 129 mmol/L.

She was readmitted at 35 weeks with pre-eclampsia as evidenced by severe headaches, persistent hypertension (blood pressure up to 186/92 mm Hg), a high uric acid (400 μmol/L), low platelet count (91×10⁹/L) and proteinuria (1557.1 mg/24 hours). Her sodium had rapidly dropped to 125 mmol/L in just 1 week. Renal function was normal with a creatinine level of 53 μmol/L and estimated glomeurlar filtration rate (eGFR) 117 mL/min/1.73 m². Liver function tests were normal with an alanine aminotransferase (ALT) 13 U/L, alkaline phosphatase (ALP) 73 U/L gamma glutamyl transferase (GGT) 11 U/L and bilirubin 5.6 μmol/L. Labetalol was increased to 300 mg three times a day.

A decision to induce labour at the earliest was taken in view of pre-eclampsia and low sodium levels. Dexamethasone injection was given twice 12 hours apart pre-delivery. Investigations for low sodium at this stage showed a urine sodium of 38 mmol/L, urine osmolality of 267 mOsm/kg and serum osmolality of 269 mOsm/kg. The patient was euvolaemic with normal thyroid function (table 1). She was diagnosed with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the context of pre-eclampsia.

Table 1.

Investigations pre-delivery and post-delivery

	Pre-delivery	Third trimester range16	48-hour post-delivery	Non-pregnant range
Serum sodium	125	130–148 mmol/L	134	135–145 mmol/L
Serum osmolality	269	278–280 mOsm/kg		282–300 mOsm/kg
Urine sodium	38	54–190 mmol/L
Urine osmolality	267	238–1034 mOsm/kg		50–1200 mOsm/kg
Serum potassium	4.98	3.3–5.1 mmol/L	5	3.5–5.1 mmol/L
Urea	4	1.07–3.9 mmol/L	3.7	1.7–8.3 mmol/L
Creatinine	53	35–79 umol/L	55	45–84 umol/L
eGFR	117 ml/min/1.73 m2		112 ml/min/1.73 m2
Bilirubin	5.6	1.7–18 mmol/L	<2.5	0–21 mmol/L
Serum alkaline phosphatase	73	38–229 U/L	90	40–104 U/L
Alanine aminotransferase	13	2–25 U/L	31	5–33 U/L
Gamma-glutamyl transferase	11	3–26 U/L	15	5–36 U/L
Uric acid	400	184–374 μmol/L	313	142.8–339.2 μmol/L
Thyroid stimulating hormone	2.446	0.38–4.04 μIU/mL		0.3-3 μIU/mL
Free thyroxine	12.8	6.4–10.3 pmol/L		11–18 pmol/L
Haemoglobin (g/L)	11.7	9.5–15.0	11.1	12–15
Platelets (×109/L)	91	146–429	147	132–349
INR	0.98	0.80–0.94	1.08	0.84–1.04
Urine protein	1557.1 mg/24 hours	46–185 mg/24 hours	759.9	1–150 mg/24 hours

eGFR, estimated Glomerular filtration rate; INR, International normalised ratio.

The mother was not allowed any oral intake. Intravenous fluids consisting of 10% dextrose at 166 mL/hour were started as her blood glucose level was less than 4 mmol/L. Her subcutaneous insulin pump was switched off and short acting insulin was administered intravenously via an infusion pump. Unfortunately, signs of fetal distress appeared on cardiotocographic monitoring after a few hours. A decision to deliver the fetus via a caesarean section was taken. A female infant was delivered with an Apgar score of 9 and sodium level of 127 mmol/L.

The mother’s intravenous fluids were changed to 5% dextrose in 0.9% normal saline at 44 mL/hour as her blood sugar increased. Five hundred millilitres oxytocin diluted in Hartmann’s fluid were administered intravenously post-delivery. Intravenous fluids were stopped as soon as she was able to tolerate oral intake. Her oral fluid intake was initially restricted to 1.25 L/day on the first day post-delivery and then to 2 L/day on the second day as her sodium levels improved.

Her sodium levels gradually improved from 125 mmol/L to 134 mmol/L within 48 hours of delivery (figure 1). Proteinuria decreased to 759.9 mg/24 hours, while platelet count (147×10⁹/L) and uric acid (313 μmol/L) normalised. She was no longer fluid restricted as from the third day post-delivery. Both mother and child were discharged 1 week after delivery.

Figure 1.

Changes in sodium level from admission date till day 3 post-delivery. The dotted red line indicates the lower level of accepted sodium post-delivery.

Differential diagnosis

Hyponatraemia may be categorised into hypovolaemic, euvolaemic or hypervolaemic hyponatraemia depending on the patient’s fluid status.¹ The differential diagnosis of a euvolaemic hyponatraemia in pre-eclampsia includes primary polydyspisa, low salt intake, renal failure, glucocorticoid deficiency and hypothyroidism. Urine sodium is >20 mmol/L in these cases.

Our patient did not drink excessively and had adequate salt intake. Her renal function remained normal. Unfortunately, she was given dexamethasone injections prior to labour and thus we do not have a baseline cortisol level prior to steroid administration. A baseline cortisol level prior to pregnancy was normal at 521 nmol/L. Also, if hypocortisolaemia was the cause of the low sodium, this would have corrected post-glucocorticoid administration which did not occur in this case.

She fulfilled the criteria for SIADH as she had low serum osmolality (<275 mOsm/kg), inappropriately high urine osmolality (>100 mOsm/kg) and urine sodium >30 mmol/L in the setting of euvolaemia and normal thyroid function.² The diagnosis of SIADH can only be reached after ruling out other possible causes of euvolaemic hypoosmolar hyponatraemia.

Other causes for hyponatraemia in pre-eclampsia include dilutional hyponatraemia and nephrotic syndrome. However, we excluded these as possible causes in our case as they are both states of fluid overlad and the urine sodium would be less than 10mmol/L.¹ Hyponatraemia with hypervolaemia occurs in heart, renal or liver failure or when excess intravenous fluids are administered.

Treatment

Our patient needed fluid restriction and an emergency caesarean section both of which led to complete resolution of the hyponatraemia.

Outcome and follow-up

Both mother and baby remained well and were both discharged a few days after delivery.

Discussion

There are important physiological changes of salt and water balance that occur during pregnancy. The serum sodium levels decreases by 5 mmol/L and the serum osmolality drops by 10 mOsm/kg to term. Osmotic ADH secretion occurs at a lower serum osmolality and the thirst centre is stimulated at a lower osmolality in pregnancy.³ The mechanism that causes this phenomenon is not known but a fetal–placental unit is necessary for this to occur.⁴

Human chorionic gonadotropin, oxytocin and relaxin are three major pregnancy hormones that increase total body water more than sodium and thus bring about a decrease in serum osmolality.⁵ Relaxin increases ADH secretion and fluid intake in pregnancy.⁶

Oxytocin has a similar structure to ADH and leads to water reabsorption in the kidneys. Plasma oxytocin levels rise during pregnancy and during the first and second stage of labour to stimulate uterine contractions. Administration of oxytocin during labour may lead to hyponatraemia. The fluid which is used to dilute oxytocin also affects the degree of hyponatraemia. Oxytocin diluted in 5% dextrose causes hyponatraemia more frequently than when it is diluted in normal saline or Hartmann’s fluid.⁷ Our patient received 500 mL of oxytocin, which was diluted in Hartmann’s fluid after delivery. This is the standard post-delivery dose and is unlikely to contribute to hyponatraemia.³

A decrease in blood pressure occurs as early as the sixth week of pregnancy. This results in a decrease in effective circulatory volume which triggers the non-osmotic release of ADH and stimulates the sympathetic nervous system and the renin angiotensin system to ensure adequate organ perfusion.⁸ Nausea and vomiting or pain during labour can also trigger ADH release. Low sodium intake, polydipsia or excess intravenous fluids may all worsen the hyponatraemia.¹

Pre-eclampsia is a hypertensive disorder of pregnancy with multisystem involvement. Diagnostic criteria include new onset hypertension (systolic: ≥140 mm Hg or diastolic: ≥90 mm Hg) after 20 weeks gestation and proteinuria exceeding 300 mg/24 hours or a protein/creatinine ratio ≥0.3 mg/dL. In the absence of proteinuria, pre-eclampsia can also be diagnosed if new onset hypertension is associated with one or more of the following; thrombocytopenia (platelets <100×10⁹/L), renal insufficiency (serum creatinine >1.1 mg/dL or a doubling of serum creatinine in the absence of other renal disease), impaired liver function (liver transaminases twice the normal range), pulmonary oedema and cerebral or visual disturbances (eg, photopsia and/or scotomata, severe headache and altered mental status).⁹

Pre-eclampsia is rarely associated with hyponatraemia. It is still debatable why only a few patients with pre-eclampsia develop hyponatraemia. Razavi et al noted that 31 out of 332 pregnancies (9.7%) with pre-eclampsia suffered hyponatraemia—defined as a sodium level of <130 mmol/L.¹⁰ A recent systematic review of 56 published cases reports of pre-eclampsia-associated hyponatraemia reported that 59% had hypervolaemia and 41% had SIADH-associated hyponatraemia.¹¹

The major causes for the hyponatraemia in pre-eclampsia were SIADH or hypervolaemia. High ADH was described in one patient by Sutton et al in 1993 and persistent excretion of ADH after a water loading test postpartum was confirmed by Hayslett et al in 1998. Hyponatraemia was also diagnosed in pre-eclampsia associated with nephrotic syndrome. It is difficult to differentiate intrinsic renal disease from pre-eclampsia and a diagnosis can only be achieved a few weeks after delivery.⁶

The exact mechanism of SIADH in pre-eclampsia is not well understood. Although water and electrolytes are abundant in pre-eclampsia, they are mainly located in the interstitium. Thus, pre-eclampsia is defined as a state of low effective circulatory volume. It is hypothesised that the non-osmotic release of ADH combined with the increased renal sensitivity to ADH leads to hyponatraemia.¹² Another mechanism states that due to pre-eclampsia, the damaged placenta releases less vasopressinase, thus resulting in increased levels of ADH.⁶ Premature contractions and preterm labour may stimulate ADH and oxytocin release under the influence of ovarian steroids. These are usually secreted in a pulsatile manner. Alteration of these pulsations may lead to hyponatraemia.¹³

Symptoms of severe hyponatraemia may overlap with symptoms of pre-eclampsia with severe features. These include nausea, lethargy, headache and malaise and in severe cases seizures, coma and cardiac arrest. Hyponatraemia may be considered a marker of severe pre-eclampsia.¹¹

There are no guidelines on the management of pre-eclampsia-associated hyponatraemia. Treatment is based on the severity of symptoms. Fluid restriction is the initial treatment and may be needed for up to 48 hours post-delivery.¹³ This usually leads to resolution of hyponatraemia within 24–72 hours.¹⁴ Demeclocycline and vaptans are contraindicated in pregnancy.¹³ Oral salt supplements may be used.¹³

Hypertonic saline may be administered in severe symptomatic hyponatraemia if clinically indicated following the recommendations in the hyponatraemia guidelines issued by the Society for Endocrinology.¹⁵ Hypertonic saline was successfully used by Jhaveri et al.¹² Hypertonic saline was also administered in a case reported by Anglim et al⁵

Severe hyponatraemia in the context of pre-eclampsia may be an indication for urgent delivery as it may lead to maternal and fetal complications. It further increases the risk for maternal seizures. The fetal sodium rapidly equilibrates with the mothers’ sodium. A fetal sodium is <130 mmol/L and can lead to polyhydramnios, fetal jaundice, respiratory distress and seizures.¹³ Risks for hyponatraemia in pre-eclampsia is higher in twin pregnancies,⁶ older maternal age¹⁴ and severe pre-eclampsia.¹⁰

Learning points.

• Syndrome of inappropriate anti diuretic hormone (ADH) secretion is a rare complication of pre-eclampsia.

• Hyponatraemia may be an indicator of severe pre-eclampsia.

• Hyponatraemia may be a reason for urgent caesarean section in pre-eclampsia.