Polyuria in pregnancy

INTRODUCTION — 

Urinary frequency in pregnancy is common and caused by hormonal and anatomic changes to the urinary tract. Urinary frequency that is accompanied by polyuria (urine output that exceeds 3 L per 24 hours) can be due to primary polydipsia or to a pathologic process caused by arginine vasopressin (AVP) deficiency, AVP resistance, or increased degradation of AVP, leading to an impaired ability to concentrate the urine [1]. These disorders related to AVP affect approximately 4 in 100,000 pregnancies [2]. Recognition and management of these disorders is important because water restriction (as often occurs during labor and delivery) can result in hypernatremia, which can have serious neurologic consequences for the mother.

This topic will discuss the clinical presentation, evaluation, diagnosis, and management of AVP disorders in pregnant patients. Related topics on polyuria and AVP disorders are presented separately:

●(See "Evaluation of patients with polyuria".)

●(See "Urine output in arginine vasopressin disorders (diabetes insipidus)".)

●(See "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation".)

●(See "Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation".)

●(See "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Treatment".)

●(See "Arginine vasopressin deficiency (central diabetes insipidus): Treatment".)

Much of the data used to guide the approach to patients with polyuria in pregnancy are derived from case reports and small case series. The paucity of data precludes definitive conclusions on evaluation and management of such patients.

DEFINITION — 

Polyuria is defined as abnormal urine output that exceeds 3 liters per 24 hours [3]. By contrast, changes in lower urinary tract function during pregnancy result in increased frequency of urination without increased urine output.

Polyuria and polydipsia can be caused by primary polydipsia or by a disorder related to arginine vasopressin (AVP). AVP disorders result from loss of urine concentrating ability by the kidneys, either because of deficiency of the antidiuretic hormone arginine vasopressin (AVP-D) or to resistance of the kidneys to the hormone (AVP-R). These disorders may be due to central causes (eg, head trauma, pituitary adenoma, hypophysitis [inflammation of the pituitary]) that produce AVP deficiency, nephrogenic causes (eg, gene mutations, lithium toxicity) that produce AVP resistance, or increased metabolic clearance of AVP (also known as transient AVP-D of pregnancy) (table 1) [4]. In all cases, the result is impaired renal water reabsorption, leading to production of a large volume of dilute urine. Urine osmolality and urine specific gravity are low.

Both AVP-D and AVP-R are discussed in more detail separately. (See "Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation" and "Arginine vasopressin deficiency (central diabetes insipidus): Treatment" and "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation" and "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Treatment".)

PATHOPHYSIOLOGY

AVP and vasopressinase in pregnancy — Arginine vasopressin (AVP) increases renal water reabsorption and decreases urine output. This effect is mediated by activation of the V2 vasopressin receptor in the renal collecting tubules, resulting in enhanced renal water reabsorption and the formation of concentrated urine. Most AVP disorders are caused by either inadequate AVP production (ie, AVP-D) or renal resistance to AVP (ie, AVP-R). (See "Urine output in arginine vasopressin disorders (diabetes insipidus)", section on 'Determinants of urine output'.)

Between the eighth gestational week and midpregnancy, the metabolic clearance of AVP increases four- to sixfold because of an increase in vasopressinase (also known as oxytocinase), which is produced by the placenta and degrades circulating, endogenously secreted AVP. Vasopressinase activity peaks in the third trimester, remains high during labor and delivery, and then falls to undetectable levels two to four weeks postpartum. In most pregnant patients, plasma concentrations of AVP remain in the normal range, despite increased metabolic clearance, because of a compensatory increase in AVP production and release by the hypothalamus and posterior pituitary gland. As a result, most patients do not become polyuric.

Transient AVP deficiency of pregnancy — Transient AVP-D of pregnancy is caused by an amplification of the normal pregnancy-related increase in vasopressinase activity (table 1).

Patients with preeclampsia; hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome; and acute fatty liver of pregnancy are at increased risk for transient AVP-D of pregnancy [5]. The mechanism in these cases is decreased degradation of vasopressinase due to hepatic dysfunction [6,7]. Patients with multiple gestations, because of a larger placental volume, have higher circulating levels of vasopressinase and thus are more likely to experience polyuria, particularly if there is coexistent hepatic dysfunction. These conditions are discussed in detail separately. (See "Preeclampsia: Clinical features and diagnosis", section on 'Oliguria' and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)" and "Acute fatty liver of pregnancy".)

Transient AVP resistance of pregnancy — Transient AVP-R of pregnancy has been reported rarely [8,9]. The mechanism is uncertain, but spontaneous resolution occurs after delivery.

Exacerbation of a preexisting AVP disorder — Some pregnant patients have AVP-D or AVP-R that was present (although sometimes subclinically) prior to pregnancy (table 1) [6,8,10]. Such patients typically describe polyuria and polydipsia prior to pregnancy, with worsening of symptoms during pregnancy due to placental vasopressinase. In these cases, polyuria tends to recur with every pregnancy. (See 'Prognosis' below.)

Acute AVP deficiency — Pituitary infarction (ie, pituitary apoplexy) following postpartum hemorrhage is a rare cause of acute AVP-D in the early postpartum period [11]. Other signs and symptoms of hypopituitarism are also typically present, such as failure of lactation, hypotension (adrenal insufficiency), and hypothyroidism. This is discussed in detail separately. (See "Causes of hypopituitarism", section on 'Pituitary infarction (Sheehan syndrome)'.)

CLINICAL PRESENTATION — 

The typical presenting features of AVP disorders are polydipsia and polyuria; these symptoms can be difficult to distinguish from urinary frequency of normal pregnancy [4,6,8,12-17]. However, patients generally report thirst and increased urinary output that are far greater than those normally seen in pregnancy. While AVP resistance and AVP deficiency can present at any point in pregnancy, transient AVP deficiency of pregnancy is most common in the third trimester (table 1).

DIAGNOSTIC EVALUATION AND DIAGNOSIS — 

Evaluation for an arginine vasopressin deficiency (AVP-D) or arginine vasopressin resistance (AVP-R) disorder should be considered in any patient reporting excessive thirst or excessive urine output.

Confirmation of polyuria — Evaluation begins with a 24-hour urine collection to measure urine volume. As polyuria is defined as urine output >3 liters per 24 hours, if urine output is <3 liters per 24 hours, the patient can be reassured their symptoms reflect normal pregnancy physiology.

If polyuria is present, measurement of plasma glucose and sodium concentrations is also performed. The most common cause of polyuria is poorly controlled diabetes mellitus, which is typically apparent clinically. Further evaluation for a cause of polyuria is unnecessary in such patients unless their symptoms persist despite adequate control of hyperglycemia. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'Symptomatic hyperglycemia'.)

Polyuria with a normal serum sodium — Because of the effects of plasma tonicity on thirst, most patients with an AVP disorder replace their urinary water losses with increased oral water intake and maintain a normal serum sodium. Patients with polyuria due to primary polydipsia excrete a dilute urine and also usually maintain a normal serum sodium. Thus, the serum sodium is typically normal in pregnant patients with polyuria.

Confirm the presence of a water diuresis — Polyuria caused by an AVP disorder or primary polydipsia represents a water diuresis. The presence of a water diuresis is confirmed by measuring the urine osmolality on the 24-hour urine sample:

●Urine osmolality <300 mOsmol/kg – These patients have a water diuresis; subsequent evaluation is appropriate to determine if they have an AVP disorder. (See 'Subsequent evaluation in patients with a water diuresis' below.)

●Urine osmolality 300 to 600 mOsmol/kg – Polyuric patients with urine osmolality that is intermediate (300 to 600 mOsmol/kg) may have either a water or a solute (ie, osmotic) diuresis. For such patients, total daily osmolar output (ie, urine osmolality multiplied by 24-hour urine volume) is calculated:

•If the total daily osmolar output is <1000 mOsmol, the patient has a water diuresis. (See 'Subsequent evaluation in patients with a water diuresis' below.)

•If the total daily osmolar output is >1000 mOsmol, then the patient has a solute diuresis. (See "Etiology and evaluation of hypernatremia in adults", section on 'Osmotic diuresis'.)

●Urine osmolality >600 mOsmol/kg – These patients have a solute diuresis. Patients with a solute diuresis do not have an AVP disorder. Such patients are managed according to their underlying etiology (eg, poorly controlled diabetes mellitus). This is discussed separately. (See "Etiology and evaluation of hypernatremia in adults", section on 'Osmotic diuresis'.)

Subsequent evaluation in patients with a water diuresis — In nonpregnant polyuric patients with a water diuresis and a normal serum sodium, the traditional confirmatory test is a water restriction test with assessment of urinary response to desmopressin (DDAVP). (See "Evaluation of patients with polyuria", section on 'Patients with a normal serum sodium'.)

However, water restriction is generally avoided in pregnancy, as dehydration can result in uteroplacental insufficiency [15]. Thus, our approach to the evaluation of those with a water diuresis is as follows:

●For pregnant patients with an intact thirst mechanism and unrestricted access to water, diagnostic evaluation can be deferred until postpartum, if polyuria does not resolve. (See 'Prognosis' below.)

For such patients, access to water should be ensured and the serum sodium concentration should be monitored. In ambulatory patients with normal serum sodium and stable polyuria, serum sodium can be monitored intermittently (eg, every four to eight weeks). By contrast, in the peripartum period, serum sodium is measured more frequently (eg, once daily). The frequency and duration of serum sodium monitoring are determined clinically based on the severity of the AVP disorder (eg, higher urine output indicates greater risk for hypernatremia, necessitating more frequent monitoring) and whether the patient has an intact thirst mechanism and free access to water (patients without access to water are at higher risk for hypernatremia due to unreplaced urinary free water losses).

●For pregnant patients without intact thirst or for whom access to water is restricted, we proceed with diagnostic evaluation by administering an empiric trial of desmopressin. The typical dose of desmopressin is 10 mcg by nasal insufflation or 2 to 4 mcg subcutaneously or intravenously.

Since desmopressin is resistant to degradation by vasopressinase, polyuria in transient AVP-D of pregnancy will improve with desmopressin treatment. Improvement in polyuria with desmopressin could also indicate preexisting AVP-D or preexisting partial AVP-R. Conversely, a complete lack of response to desmopressin indicates the presence of preexisting complete AVP-R. (See 'Management' below.)

Patients with polyuria and a normal serum sodium might have primary polydipsia instead of an AVP disorder (see 'Differential diagnosis' below). In such patients, administration of desmopressin in the setting of continued polydipsia can produce acute hyponatremia, which may lead to cerebral edema. Thus, a trial of empiric desmopressin should be initiated in the hospital with close monitoring of water intake and serum sodium.

Copeptin, a stable protein cosecreted with AVP, is a biomarker that can distinguish AVP-D from AVP-R in patients with polyuria/polydipsia. There are no data on use of this assay in pregnant patients for the evaluation of polyuria, although it has been studied as a predictor of preeclampsia [4,18]. Theoretically, copeptin levels would be expected to be elevated in transient AVP-D of pregnancy, as they are in AVP-R, because AVP production by the pituitary is intact (and likely enhanced). However, diagnostic cutoffs have not been established in pregnancy. Additionally, the stimulated copeptin assay requires administration of either hypertonic saline or arginine, both of which are typically avoided in pregnancy given the lack of diagnostic cutoffs values in pregnancy. Thus, diagnostic evaluation with the stimulated copeptin assay, as with the traditional water restriction test, is best deferred to the postpartum period if polyuria does not resolve.

Patients with hypernatremia — While most patients have a normal serum sodium, hypernatremia can develop if access to water is restricted (eg, in patients undergoing cesarean birth) or if the patient is unable to drink (eg, hyperemesis). (See 'Clinical presentation' above.)

In patients with hypernatremia, urine osmolality is also measured. If the urine osmolality is >600 mOsmol/kg, then the patient has a solute diuresis rather than an AVP disorder. (See "Etiology and evaluation of hypernatremia in adults", section on 'Osmotic diuresis'.)

If the urine osmolality is <600 mOsmol/kg, then the patient has a water diuresis, and response to desmopressin (10 mcg intranasally or 4 mcg subcutaneously or intravenously) may be assessed. (See "Evaluation of patients with polyuria", section on 'Patients with hypernatremia'.)

DIFFERENTIAL DIAGNOSIS — 

When evaluating pregnant patients for a possible arginine vasopressin (AVP) disorder, the clinician should consider and exclude the following:

●Primary polydipsia – Primary polydipsia, or psychogenic polydipsia, is a disorder of increased water intake, leading to increased urine output. In patients with primary polydipsia, reducing water intake results in a rapid improvement in polyuria and an increase in urine osmolality. Primary polydipsia does not cause hypernatremia and can be distinguished from AVP disorders in nonpregnant patients using the water restriction test. In pregnancy, primary polydipsia does not require diagnostic or therapeutic intervention unless hyponatremia occurs. (See 'Subsequent evaluation in patients with a water diuresis' above and "Causes of hypotonic hyponatremia in adults", section on 'Primary polydipsia due to psychosis'.)

●Urinary frequency without polyuria – Urinary frequency is almost universal in pregnancy but does not usually reflect a pathologic increase in urine volume. Urinary frequency is distinguished from true polyuria by urine output <3 L/day in a 24-hour urine collection.

●Hypernatremia due to inadequate water intake – Hypernatremia (without polyuria) can develop in individuals with inadequate free water intake, particularly if excess gastrointestinal water loss is also present, such as in a patient with hyperemesis gravidarum. This is easily distinguished from an AVP disorder by the presence of an appropriately concentrated urine (ie, urine osmolality >600 mOsm/kg). In these cases, polyuria is absent and patients are often oliguric. Loop diuretics decrease urinary concentrating ability and must be held for this to be reliable. (See "Etiology and evaluation of hypernatremia in adults", section on 'Gastrointestinal losses'.)

MANAGEMENT — 

Management includes treatment of hypernatremia (if present) followed by treatment of the underlying cause.

●Hypernatremia – Hypernatremia in pregnancy, regardless of etiology, should be corrected by replacing free water. This may be done either orally or intravenously with hypotonic intravenous fluids (eg, 5% dextrose in water). Acute hypernatremia can be corrected rapidly. By contrast, chronic hypernatremia should be corrected slowly to reduce the risk of cerebral edema, a complication that has been reported primarily in infants. (See "Treatment of hypernatremia in adults", section on 'Choosing a rate of correction'.)

In addition to correcting the free water deficit, ongoing free water losses from urine output and insensible losses should be replaced. An indwelling bladder catheter may be needed for accurate measurement of urine output if the patient is unable to cooperate with urine output measurement. (See "Treatment of hypernatremia in adults", section on 'Approach to therapy'.)

●Transient AVP-D of pregnancy – Polyuria due to transient AVP-D of pregnancy can be effectively treated with desmopressin (DDAVP), a vasopressin analog, which is resistant to degradation by vasopressinase [6,8,19].

For patients with intact thirst and access to water, a reasonable starting dose of desmopressin is 5 mcg intranasally or 0.05 mg orally, either at bedtime or twice daily. The dose should be titrated to achieve relief of polyuria and a serum sodium of 133 to 140 mEq/L, targeting the mild physiologic hyponatremia of pregnancy [4,14]. Doses equal to or slightly higher than those used to treat AVP-D in nonpregnant patients are typically required [4]. The dose and dosing interval are adjusted to allow mild polyuria between doses and thus avoid severe hyponatremia.

No adverse maternal or fetal effects from desmopressin use during pregnancy have been reported, although trial data are lacking [20]. Although desmopressin has a structure similar to oxytocin, use of intranasal desmopressin has not been associated with induction of labor [4]. (See "Arginine vasopressin deficiency (central diabetes insipidus): Treatment", section on 'Desmopressin'.)

●AVP-R – Management of polyuria in pregnant patients with AVP-R in pregnancy can be difficult. Treatment strategies in nonpregnant patients include thiazide diuretics and nonsteroidal anti-inflammatory agents, but these agents are generally avoided in pregnancy (see "Arginine vasopressin resistance (nephrogenic diabetes insipidus): Treatment"). Similarly, a low-protein, low-sodium diet may decrease polyuria; nutritional needs in pregnancy are discussed separately. (See "Nutrition in pregnancy: Dietary requirements and supplements".)

Patients should be encouraged to drink to thirst, with continuous access to water, to avoid hypernatremia. If access to water is impaired, then hypotonic intravenous fluid should be given to match urine output to avoid hypernatremia, with close monitoring of the serum sodium.

COMPLICATIONS

●Hypernatremia – Hypernatremia can occur if water intake is restricted, as it often is in the peripartum period [14,16,21]. Neurologic consequences of hypernatremia, as well as management of hypernatremia, are discussed separately. (See "Manifestations of hyponatremia and hypernatremia in adults", section on 'Hypernatremia' and 'Management' above and "Treatment of hypernatremia in adults", section on 'Choosing a rate of correction'.)

●Obstetric complications – While the overall risk of obstetric complications is similar for patients with and without these disorders, limited data suggest an association between transient AVP-D of pregnancy and preeclampsia [4,17,22,23]. Oligohydramnios has also been reported [21,24]. (See "Preeclampsia: Clinical features and diagnosis" and "Preeclampsia: Antepartum management and timing of delivery" and "Oligohydramnios: Etiology, diagnosis, and management in singleton gestations".)

PROGNOSIS — 

Transient AVP-D in pregnancy typically resolves postpartum. There are no prospective studies regarding the likelihood of recurrence in subsequent pregnancies, although there are case reports describing recurrence [25-27]. Patients with preexisting AVP-D or AVP-R exacerbated by pregnancy are likely to have recurrent polyuria with future pregnancies, though data are also limited to case reports.

SUMMARY AND RECOMMENDATIONS

●Definition – Urinary frequency in pregnancy is common and caused by hormonal and anatomic changes to the urinary tract. Urinary frequency that is accompanied by polyuria (urine output that exceeds 3 L per 24 hours) can be due to primary polydipsia or to a pathologic process caused by deficiency of the antidiuretic hormone vasopressin (AVP-D), resistance of the kidneys to the hormone (AVP-R), or increased metabolic clearance of AVP (transient AVP-D of pregnancy) (table 1). (See 'Introduction' above and 'Definition' above.)

●Clinical presentation – The typical presenting features of AVP disorders are polydipsia and polyuria. Patients generally report thirst and increased urinary output that are far greater than those normally seen in pregnancy. Some patients may present with hypernatremia if access to water is restricted. (See 'Clinical presentation' above.)

●Diagnostic evaluation – Evaluation for an AVP-D or AVP-R disorder should be considered in any patient reporting excessive thirst or excessive urine output.

•Confirm polyuria – Evaluation begins with a 24-hour urine collection to measure urine volume. As polyuria is defined as urine output >3 liters per 24 hours, if urine output is <3 liters per 24 hours the patient can be reassured their symptoms reflect normal pregnancy physiology. If polyuria is present, measurement of plasma glucose and sodium concentrations is also performed. (See 'Confirmation of polyuria' above.)

•Patients with normal serum sodium – For patients with normal serum sodium, the next step is to confirm a water diuresis. This is described in the algorithm (algorithm 1). (See 'Confirm the presence of a water diuresis' above.)

-For patients with intact thirst and unrestricted access to water, subsequent evaluation can usually be safely deferred until postpartum, if polyuria does not resolve. (See 'Subsequent evaluation in patients with a water diuresis' above.)

-For patients without intact thirst or for whom access to water is restricted, subsequent evaluation is often with an empiric trial of vasopressin. Empiric vasopressin should be administered in a hospital setting where fluid intake and serum sodium can be closely monitored, to avoid the development of severe hyponatremia. (See 'Subsequent evaluation in patients with a water diuresis' above.)

•Patients with hypernatremia – For patients with hypernatremia, measure urine osmolality. Response to desmopressin (10 mcg intranasally or 4 mcg subcutaneously or intravenously) may be assessed in those with a water diuresis (urine osmolality <600 mOsm/kg). (See 'Patients with hypernatremia' above.)

●Differential diagnosis – When evaluating pregnant patients for a possible AVP disorder, the clinician should consider and exclude the following: primary polydipsia, urinary frequency (without polyuria), and hypernatremia due to inadequate water intake. (See 'Differential diagnosis' above.)

●Management – Management includes treatment of hypernatremia, if present, with free water (either oral or intravenous), followed by treatment of the underlying cause. This is presented in the table (table 1) and discussed in detail separately. (See 'Management' above and "Treatment of hypernatremia in adults".)

●Complications – Hypernatremia, which can occur if water intake is restricted, can result in serious neurologic consequences in the mother. While the overall risk of obstetric complications is similar for patients with and without an AVP disorder in pregnancy, limited data suggest an association between transient AVP-D of pregnancy and preeclampsia or oligohydramnios. (See 'Complications' above.)

●Prognosis – Transient AVP-D of pregnancy resolves postpartum. The risk of recurrence in future pregnancies has not been established. (See 'Prognosis' above.)