Accepted Manuscript

Diabetes Insipidus During Pregnancy

Sonia Ananthakrishnan, MD, Assistant Professor of Medicine

PII: S1521-690X(16)00010-5
DOI: 10.1016/j.beem.2016.02.005
Reference: YBEEM 1079

To appear in: Best Practice & Research Clinical Endocrinology & Metabolism

Please cite this article as: Ananthakrishnan S, Diabetes Insipidus During Pregnancy, Best Practice &
Research Clinical Endocrinology & Metabolism (2016), doi: 10.1016/j.beem.2016.02.005.

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 ACCEPTED MANUSCRIPT

Diabetes Insipidus During Pregnancy

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Author:

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Sonia Ananthakrishnan, MD

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Corresponding Author:

Sonia Ananthakrishnan, MD
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Assistant Professor of Medicine

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Section of Endocrinology, Diabetes and Nutrition

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Boston University School of Medicine/Boston Medical Center

88 East Newton Street

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H-3600

Boston MA, 02118

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Tel: 617-414-3790
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Fax 617-638-7221

Soniaa@bu.edu

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Abstract:

Diabetes insipidus (DI) in pregnancy is a heterogeneous syndrome, most classically

presenting with polyuria and polydipsia that can complicate approximately 1 in 30,000

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pregnancies. The presentation can involve exacerbation of central or nephrogenic DI

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during pregnancy, which may have been either overt or subclinical prior to pregnancy.

Women without preexisting DI can also be affected by the actions of placental

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vasopressinase which increases in activity between the 4th and 38th weeks of gestation,

leading to accelerated metabolism of AVP and causing a transient form of DI of

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pregnancy. This type of DI may be associated with certain complications during
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pregnancy and delivery, such as preeclampsia. Management of DI of pregnancy depends

on the pathophysiology of the disease; forms of DI that lack AVP can be treated with
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desmopressin (DDAVP), while forms of DI that involve resistance to AVP require

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evaluation of the underlying causes.

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Key words:
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Diabetes insipidus, Pregnancy, Vasopressin (AVP), Polyuria, Polydipsia, Pituitary,

Desmopressin

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Introduction:

Diabetes insipidus is part of a spectrum of disorders that presents with polyuria and

polydipsia and is related to insufficient secretion of or impaired renal response to

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vasopressin (AVP, anti-diuretic hormone/ADH). This condition can also present during

pregnancy, due to normal human gestation causing a variety of effects on the maternal

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hypothalamic-pituitary axis and the metabolism of AVP. Diabetes insipidus was first

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reported in pregnancy in 1942, and has subsequently been shown to complicate at least 4

out of 100,000 cases of pregnancy. 1,2 Because of changes to maternal volume status and

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hemodynamics, as well as osmotic homeostasis, it is important for health care providers
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to quickly identify, evaluate and manage DI during pregnancy. This review focuses on a

brief overview of vasopressin physiology and its relevance to pregnancy followed by a

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review of the clinical presentation of DI during pregnancy, including the

pathophysiology, epidemiology and management of the several of subtypes of DI in

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pregnancy.
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Vasopressin (AVP) Physiology

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Vasopressin (AVP, i.e., anti-diuretic hormone/ADH), is synthesized in a circadian

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manner in the neurosecretory magno-cellular neurons of the lateral and superior regions

of the paraventricular nuclei and the supraoptic nuclei of the hypothalamus.3 As the

synthesized prohormone is transported down the neurohypophyseal axons in

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neurosecretory vesicles, it is cleaved to produce AVP on its way to storage in the

posterior pituitary.4 This entire process takes 1-2 hours from synthesis to storage.5

Nearby but distinct nuclei within these regions of the hypothalamus produce oxytocin,

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the other hormone secreted by the posterior pituitary. Oxytocin regulates smooth muscle

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contractions during gestation, leading to both uterine contractions as well as milk-let-

down post partum.6 Following synthesis of AVP and oxytocin in the cell bodies of the

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hypothalamus, the hormone-containing secretory granules migrate from the

hypothalamus down the supraopticohypophyseal tract into the posterior pituitary, where

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these hormones are stored prior to release into the systemic circulation.
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AVP release from the posterior pituitary via exocytosis is stimulated by increased plasma
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osmolality (based on signaling from osmoreceptors of the anterior pituitary), decreased

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circulating volume, nausea, vomiting, stress, hypoxia and exercise.7 Its release is
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inhibited by reduced plasma osmolality, increased plasma volume and substances such as

alcohol and opiates.8 Plasma osmolality is tightly regulated and there is a threshold
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plasma osmolality level above which AVP is released in proportion to increases in

plasma osmolality. A change as small as a 1% increase in osmolality above 280

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mOsm/kg will cause the osmoreceptors to signal AVP release.9 Thirst is stimulated at an
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equivalent or slightly higher plasma osmolality.

AVP is released from the posterior pituitary, and its effects are mediated via 4 different

G-protein coupled receptors. The V1a receptor’s most well-defined roles include

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activating vasoconstriction, gluconeogenesis, platelet aggregation, hypothermia and

appetite.5,4 The V1b receptor primarily potentiates the action of corticotrophin releasing

hormone, releasing ACTH from the anterior pituitary.10 The majority of AVP’s osmotic

regulatory effects occur via activation of the V2 receptors located primarily in the distal

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convoluted tubules, the collecting ducts of the kidney and the vascular endothelium. This

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receptor signals the insertion of previously formed aquaporin-2 channels into the apical

membrane of renal tubular cells to stimulate water absorption, thus maintaining plasma

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volume and urine osmolality.11.

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With relevance to pregnancy, AVP also has affinity to the oxytocin receptor at a similar
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affinity compared to oxytocin though the converse does not prove true, with oxytocin

having a 30-fold lower affinity to the V1a receptor compared with AVP itself.12 AVP,
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with a half-life of 10-35 minutes, is eventually metabolized by endogenous

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vasopressinases in the kidneys and liver.13

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Pregnancy Related Changes in Osmotic Homeostasis

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Major changes occur in the pituitary gland during pregnancy, altering the anatomy and
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physiology of the gland. The posterior pituitary specifically is affected by the resetting,
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namely reduction, of the set point of the osmoregulatory system during pregnancy.14, 15

As a result, AVP is released at a lower concentration.

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Maternal physiology is altered as well, with shifts in maternal blood volume in addition

to osmoregulation. A further contributing factor is the thirst mechanism, which changes

during pregnancy resulting in a reduced threshold for thirst, with more thirst at a lower

serum osmolality and serum sodium compared to the non-pregnant state. These effects

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may be mediated by an effect of human chorionic gonadotropin (HCG). 16,17,18 Maternal

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urine output may be increased due to an increased glomerular filtration rate and increased

renal prostaglandin E2 during pregnancy. Clinically, this results in increased polydipsia

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and polyuria, with increased water retention, a decreased plasma sodium concentration

(approximately 4-5 mEq/L), and decreased plasma osmolality (approximately 10

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mOsm/kg) observed in normal pregnant women by the 2nd to 4th week of gestation.19,20
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The appearance of placental vasopressinase, also called placental cystine aminopeptidase
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or oxytocinase, also significantly changes maternal osmoregulation in pregnancy. This

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unique enzyme increases the metabolic clearance of endogenous AVP.21 Placental

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vasopressinase is an aminopeptidase produced by placental tissue (trophoblasts). As

trophoblastic mass in pregnancy increases approximately 1000-fold between the 6th and
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24th week of gestation, there is a rapid rise in plasma vasopressinase activity during this

time.22 Placental vasopressinase is detectable by week 10 of pregnancy, and increases

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by 300-fold by the late second or early third trimester.23 Given that the production of this
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enzyme is proportional to the amount of placental mass, multi-fetus pregnancies with

greater placental masses are associated with higher levels of placental vasopressinase.24

This enzyme inactivates AVP, oxytocin, and some other small peptides, although its

actual physiological importance remains unclear. Although placental vasopressinase can

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degrade oxytocin, women with elevated levels have not been noted to have a decreased

rate of spontaneous labor. Following delivery, a decrease of 25% per day of placental

vasopressinase is observed.25

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Despite the numerous physiologic changes that occur in pregnancy (increased volume,

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increased glomerular filtration rate, increased placental vasopressinase metabolizing

AVP), most women are able to maintain a steady urine and serum concentration during

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the course of pregnancy. Increased AVP production and release from the hypothalamus

and pituitary, a four-fold rise during pregnancy, likely accounts for this equilibrium.

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While most women are able to keep up with the increased demand for AVP in order to
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maintain sufficient water reabsorption, some women with impaired AVP reserve will

experience new worsening in polyuria and polydipsia during pregnancy, which suggests
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the unmasking of either overt or subclinical pre-existing central DI.26 More rarely, a
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similar exacerbation can be seen during pregnancy due to decreased or partial renal
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responsiveness to AVP because of preexisting subclinical or overt nephrogenic DI. 27,28

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As described above, placental vasopressinase levels increase during pregnancy, and the

net result is an increased rate of AVP degradation, which is about 4-fold higher by the 2nd
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trimester. Despite the increased central production of AVP, in some pregnancies AVP
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levels may be undetectable. 29 Infusion clearance studies have been performed on female

subjects in the third trimester and peri-partum periods, when placental vasopressinase

levels peak, and subsequently repeated at weeks 6 and 12 post partum (when placental

vasopressinase disappeared). Results demonstrate that treatment with 1-deamino 8-D

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arginine vasopressin (DDAVP or desmopressin) is able to preserve urine osmolality at

higher concentrations, compared with lower urine osmolalities seen in subjects who

received an infusion of exogenous AVP. This suggests that placental vasopressinase

increases the clearance and shortens the half-life of both endogenous and exogenous AVP

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during pregnancy, while DDAVP is resistant to this degradation.23,30

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Pathophysiology of Diabetes Insipidus in Pregnancy: 3 Subtypes (Table 1)

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The syndrome of DI is characterized by polyuria and polydipsia, and is associated with a

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loss of the concentrating ability of the kidneys and aquaresis. AVP levels in pregnancy
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can be affected by a variety of causes, namely decreased levels of AVP, either from

reduced release due to central DI or increased AVP destruction with transient DI of

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pregnancy. AVP resistance can result from nephrogenic DI. In all causes, the result is a
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reduced permeability of the renal collecting ducts and a decrease in the rate of water
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resorption. Dilute urine flow may increase, and urine osmolality can decrease to less than

100 mOsm/kg, with a specific gravity of <1.010. 31

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Central DI in Pregnancy
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Central or neurogenic DI is more common in the non-pregnant patient when compared to

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nephrogenic DI. Central DI with deficient synthesis or release of AVP may be the result

of trauma (surgical or head trauma), infarction, inflammation, mass effect on the

hypothalamus and/or pituitary, or mutations in the AVP gene.32 Depending on its cause,

central DI may not affect fertility, and it is well-describe that patients with pre-existing

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central DI can have successful pregnancies with spontaneous deliveries.1,2 The diagnosis

of central DI may be known prior to pregnancy, but in rare cases, pregnancy can unmask

subclinical central DI as the advent of placental vasopressinase further decreases the

already low AVP levels as the gestation progresses.33 An insufficient reserve of AVP

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associated with central DI should be suspected when signs and symptoms of DI appear

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early during pregnancy, prior to placental vasopressinase achieving the typical high levels

seen in the third trimester. Patients with overt or subclinical central DI who have

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previously been maintained on small replacement doses of exogenous vasopressin or

DDAVP may have increased requirements of this medication during pregnancy.

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Nephrogenic DI in Pregnancy
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Nephrogenic DI manifests with AVP levels appropriate to the osmolality, but with a lack
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of renal response to circulating AVP. Drug effects (most commonly lithium, also
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demeclocycline), chronic hypokalemia, chronic hypercalcemia, chronic medullary renal

diseases (e.g. polycystic kidney disease) and hereditary gene mutations have all been
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associated with nephrogenic DI.32 Chronic lithium therapy, even at therapeutic levels is

the most common cause of nephrogenic DI, due to decreased renal aquaporin-2
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expression, and has a female predominance.34 The most frequent congenital cause is an
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inherited X-linked recessive mutation of the renal AVPR 2 gene encoding the V2 receptor

(Chapter 8) that can lead to a wide spectrum of renal AVP resistance and concentrating

difficulties.35,36

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This form of DI typically has a milder presentation than central DI with levels of polyuria

less than 3-4 L/day.32 Patients may have no overt symptoms as they are well

compensated by chronic water drinking, until pregnancy and its associated physiologic

changes exacerbate the clinical course.37 The renal resistance to AVP cannot be treated

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with DDAVP therapy, and instead other drugs such as thiazide diuretics as well as

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amiloride may alleviate symptoms while the underlying etiology of nephrogenic DI is

identified and managed (see below in Treatment). Improvement of symptoms to pre-

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pregnancy levels typically occurs post partum.

Transient DI of Pregnancy
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Transient DI of pregnancy, or gestational DI, is the most common form of DI in

pregnancy. 38 It may have first been identified 200 years ago, but its first description in
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the literature dates back to 1942.33,1 It typically presents at the end of the second or
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during the third trimester of pregnancy and may extend into the early postpartum period.
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As the pregnancy progresses, vasopressinase levels can rise up to 300 times the levels

seen in normal pregnancy, causing an 80-85% decrease in circulating AVP.39 This type
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of DI may be more common in multi-fetal gestations, as vasopressinase activity has been

noted to be significantly higher, related to increased placental mass seen in women

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carrying multiple fetuses.24 Physiologic gestational hypertrophy and hyperplasia of the

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anterior pituitary with compression of the posterior lobe and increased concentrations of

corticosteroids and progesterone during pregnancy antagonizing AVP are other purported

contributors to this form of DI.33

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This subtype of DI classically presents in patients with no known DI history prior to

pregnancy and with intense polydipsia and polyuria near the end of their gestation.

Transient DI of pregnancy may have an increased association with preeclampsia (see

below). Symptoms will typically resolve within days to a few weeks after delivery.39

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Finally, transient DI of pregnancy has been reported in successive pregnancies, and one

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case report described a more severe presentation when symptoms appeared in a

subsequent pregnancy.40

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Complications Related to Diabetes Insipidus during Pregnancy

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DI during pregnancy due to any of the above mentioned subtypes has not been associated

with an overall increase in maternal and fetal related complications when compared to the
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general population in pregnancy.

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However, there may be an association, albeit with limited supporting data, between pre-

eclampsia and transient DI of pregnancy.41, 42 Related to this, transient DI of pregnancy

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has also been associated with eclampsia, acute fatty liver in pregnancy and the “HELLP”

syndrome, comprised of hemolysis, elevated liver enzymes and low platelets.43,44 The
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liver dysfunction seen in these conditions may lead to decreased hepatic degradation of
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placental vasopressinase, leading to the worsening gestational polyuria and polydipsia in

DI.45,46

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Severe oligohydramnios in combination with maternal hypernatremia with serum sodium

levels as high as 153 mEq/L has been associated with transient diabetes insipidus in the

third trimester, and this promptly resolved with the initiation of therapy for the DI. These

cases went on to successful deliveries of healthy infants.47,48 There is one report of a

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stillbirth associated with DI during pregnancy. 49

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While transient DI of pregnancy is mostly seen prior to delivery, there are rare case

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reports describing symptoms of DI developing acutely after delivery, typically in the

setting of Sheehan syndrome.50 Pathologically, posterior pituitary necrosis is commonly

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seen with Sheehan syndrome, and while many of these patients may have reduced urine
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osmolalities, clinical presentation with DI is only rarely reported in about 5% of

cases.51,52,53 In these cases, postpartum hemorrhage leading to Sheehan syndrome and

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necrosis of the pituitary with resultant loss of AVP production and/or storage is typically
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described.50 Administration of steroids to treat glucocorticoid deficiency may transiently

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worsen the DI symptoms and increase the DDAVP requirements due to negative

feedback inhibiting corticotropin-releasing hormone and AVP synthesis in the

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hypothalamus. Acute onset of postpartum DI has also been described in a patient with

twin gestations who experienced placental abruption.44 It was suspected that the DI
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resulted from sudden release of excess placental vasopressinase from the larger placental
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mass (due to twin gestation) into the systemic circulation during the abruption, acutely

overwhelming the available supply of endogenous AVP. This patient was successfully

treated with a temporary course of DDAVP.

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Assessment and Management of DI in Pregnancy

Diagnostic Evaluation: Differential Diagnosis

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In developing the differential diagnosis in a pregnant patient presenting with hypotonic

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polyuria and polydipsia, a detailed history should be obtained from the patient to evaluate

causes associated with each of the three subtypes of DI as well as primary polydipsia.

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Primary polydipsia differs from other causes of DI in that there is no pathologic

deficiency of AVP secretion or activity, but rather excessive fluid intake over an

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extended time period, which can rarely occur de novo in pregnancy.32 Primary polydipsia
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patients may have a defective thirst mechanism with an unknown motive for polydipsia,

that may be associated with psychiatric disorders such as previously diagnosed

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schizophrenia, CNS trauma, or eating disorders.54,55 In addition, the primary polydipsia

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may be iatrogenic, with dry mouth symptoms as a side effect of medication leading to the
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increased fluid intake.32

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Diagnostic Evaluation: Testing

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There is no single gold standard test to confirm the diagnosis of DI, in either a pregnant
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or non-pregnant patient.32 Assessment in a pregnant patient who has suspected

inappropriate water diuresis should begin with confirmation of stable hemodynamics

followed by investigation of serum electrolytes, serum osmolality and urine osmolality as

well as urine analysis including specific gravity. Measurement of a 24 hour urine for

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volume will confirm polyuria if the urine output exceeds 2.5 L/day. “Normal” values of

lab testing in pregnant patients should be interpreted appropriately, given the typical

resetting of the osmostat seen during gestation. Thus, an increased serum sodium > 140

mEq/L, increased serum osmolality >280 mOsm/kg, and a reduced urine osmolality less

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than serum osmolality or <300 mOsm/kg can raise suspicion for DI during pregnancy.19

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Measurement of plasma AVP levels to help identifying the subtype of DI in pregnancy is

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controversial, as there are many concerns about reliability of the laboratory assays to

determine AVP concentrations. Serum AVP measurements may be low in central DI and

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transient DI during pregnancy due to deficiency and/or degradation by placental
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vasopressinase, but may be appropriate relative to the serum osmolality in nephrogenic

DI in pregnancy. However, because AVP is unstable and rapidly cleared even at low
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temperatures, sandwich immunoassay and other radioimmunoassay protocols are

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complex and prone to discrepant results, especially when compared to urine

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concentration levels.56,32 The clinical utility of plasma AVP measurement is questionable

during pregnancy because placental vasopressinase may make the concentration of AVP
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undetectable, or falsely elevated if inactive fragments are measured. The assay for

copeptin, a glycopeptide comprising the C-terminal part of the AVP prohormone, may be
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a useful surrogate of AVP concentration, but its utility in pregnancy is still unknown.57
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Water restriction testing, while important in confirming the diagnosis of DI in a non-

pregnant patient with polyuria and polydipsia, should be used more judiciously during

pregnancy due to the risks of overnight water restriction causing dehydration,

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hypernatremia and associated complications, primarily neurologic, in both mother and

fetus.40,46 DI will be confirmed in a water restriction test if the urine osmolality does not

increase to >500 mOsm/L, despite an elevated serum osmolality (>295 mOsm/kg). To

further characterize the subtype of DI in pregnancy, DDAVP can be used diagnostically

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to identify central DI and transient DI of pregnancy. In these cases, urine osmolality will

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increase with DDAVP administration given its intact endogenous sensitivity to AVP and

resistance of DDAVP to degradation by placental vasopressinase.

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In addition to serum and urine osmotic measurements, a complete blood count, liver

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enzymes, uric acid and urine analysis for protein level are recommended in addition to
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monitoring of maternal and fetal vital signs, to assess for complications associated with

DI during pregnancy, such as pre-eclampsia (see Complications).

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Imaging with MRI of the brain is typically not necessary in the evaluation of DI during
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pregnancy unless trauma, hemorrhage or mass (due to adenoma, neoplasm or infiltrative

process) are suspected as etiologies. The pituitary gland volume should be appropriately
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increased based on gestational period in comparison with a non-gravid healthy adult.

Absent posterior pituitary bright spot, suggesting absence or deficiency of neuro-

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secretory granules of AVP, would be expected in cases of central DI during pregnancy.

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(see Figure 1)

Treatment

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Initial therapy for diabetes insipidus dating back to the 18th century was aggressive

hydration and increased fluid intake. In the early 1900s, posterior pituitary extract was

used to treat DI and this was considered one of the first successful therapies directed at a

hormone deficiency condition.4 However, because this bovine or porcine extract

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contained oxytocin in addition to vasopressin, use of this extract sometimes carried the

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potential risk of unexpected complications in pregnancy. More recently, exogenous

forms of vasopressin such as synthetic pitressin, 8-lysine vasopressin or the formerly

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used pitressin tannate oil have been shown to be susceptible to rapid catabolism by

placental vasopressinase, similar to endogenous AVP.29,58 Thus, patients who have been

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treated prior to pregnancy with these agents typically will not achieve control of their
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disease with these drugs as they progress through pregnancy, due to rising levels of

placental vasopressinase during gestation.59

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The preferred medical treatment for patients with either transient DI or central DI in
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pregnancy is DDAVP, the selective V2 receptor activator. This is a vasopressin analog

with a modified N-terminus and an alteration to arginine at the 8 position, leading to

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resistance against metabolism by placental vasopressinase.60 DDAVP can be

administered intranasally, subcutaneously, intravenously or orally, with a starting dose of

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10 mcg intranasally at bedtime to prevent nocturia. The preferred form of delivery is the
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intranasal delivery system, though case studies have reported experiences with both

intravenous and oral forms of dDAVP in pregnancy.40 Subsequent morning doses can be

added based on response, as typical action time is 8-24 hours.61 Doses are typically

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slightly greater that what might be required in the non-pregnant patient due to the

presence of placental vasopressinase metabolizing any endogenous AVP.

There is no antidote to reverse the effects of DDAVP administration other than fluid

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restriction; thus patients need to monitored closely for hyponatremia, oliguria, edema,

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headache, lethargy, nausea and vomiting.62 Overdosing DDAVP can rarely lead to

seizures and coma as a result of severe hyponatremia. Close monitoring of urine output,

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fluid restriction as well as serum sodium and osmolality and urine osmolality

measurements can minimize the risk for osmotic complications related to the use of

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DDAVP in pregnant women with DI.40 In the case of transient DI of pregnancy, DDAVP
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can typically be stopped within days to weeks of delivery, after placental vasopressinase

levels disappear.58, 44 DDAVP can be administered to lactating mothers without

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significant risk to the fetus, as very little appears in breast milk. 63

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DDAVP is currently categorized as pregnancy class B, and there continues to be a lack of

controlled studies to provide data on its safety for mother and fetus. This medication is a
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more selective activator of the non-pressor V2 receptor, thus avoiding stimulation of

blood pressure or uterine contractions in comparison to exogenous forms of AVP. The

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largest single assessment of DDAVP safety comes from a review that assessed 20 articles
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which included data on 49 live births with DDAVP use for DI during pregnancy. 64 82%

of the women used DDAVP from the first trimester onwards, and the approximate daily

dose of DDAVP during gestation was 29 mcg intranasally to achieve control of

symptoms. Preeclampsia was noted in 3 mothers, and though available data on the

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included pregnant women was limited, this rate is not significantly different from the

expected rate in the general population of 5-8%.65 No serious maternal hypertension was

reported, highlighting DDAVP’s non-vasopressor effects.

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Stimulation of uterine contractility has been a concern with use of DDAVP in late

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pregnancy due to its oxytocin-like structure. DDAVP has been reported to be 75 times

less oxytocic than oxytocin, and any oxytocic effect has been reported more prominently

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with intravenous rather than intranasal DDAVP.59 There have been no reports of

induction of labor due to the potential oxytocin-like effects of DDAVP.

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Nephrogenic DI is unsuccessfully treated with DDAVP, thus correcting underlying

causes, for example correcting calcium or potassium abnormalities, is an important first

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step. Hydrochlorothiazide is commonly used in non-pregnant patients with nephrogenic

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DI, but in pregnancy, while it is considered class B, it is used judiciously to avoid

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hypovolemia and hyponatremia in mother and fetus. It may be useful late in gestation for

resistant DI prior to delivery.66, 67

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Summary
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Diabetes insipidus can rarely affect pregnancy, causing loss of a large volume of dilute

urine. There are a variety of etiologies of DI during pregnancy and exacerbation of mild

underlying forms of DI that predate the pregnancy can be manifested due to the

physiologic changes with water balance that occur in pregnancy. There may be a

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decreased central secretory reserve (central DI) or impaired renal responsiveness

(nephrogenic DI) to AVP, a hormone that is critical for water balance. Additionally, AVP

may be degraded more rapidly during pregnancy due to placental vasopressinase levels

rising throughout pregnancy. Providers, including those in primary care, endocrinology

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and obstetrics, need to promptly evaluate intractable polyuria and polydipsia in the

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pregnant patient in order to identify this condition. There is no gold standard test

available to identify DI in pregnancy, but a detailed history and physical exam along with

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serum and urine osmolality testing are useful diagnostic tools. Currently, the available

literature supports the use of DDAVP during pregnancy. Close follow-up in a multi-

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disciplinary approach can help to efficiently establish the diagnosis and limit the
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morbidity by instituting the appropriate therapy.
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Practice Points

Rapid assessment of polyuria and polydipsia and identification of DI subtype

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during pregnancy can prevent significant osmotic dysregulation in the

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pregnant patient.

Placental vasopressinase, which increases during pregnancy, plays a major

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role in causing or exacerbating many forms of overt or subclinical DI.

Transient DI during pregnancy occurs more commonly in multi-fetal

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pregnancies, where a larger placental mass produces higher levels of placental
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vasopressinase.

Serum sodium, serum osmolality and urine osmolality are three appropriate
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initial tests to assist in identifying a patient with DI during pregnancy. The

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diagnosis is suspected when inappropriately dilute urine is seen in a pregnant

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patient with concentrated serum.

Additional testing to confirm the diagnosis and identify the subtype of DI

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during pregnancy includes the careful use of water restriction testing and

measurement of urine osmolality after DDAVP administration. Plasma AVP

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measurements are not always reliable.

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Based on current available data, DDAVP is the therapy of choice in treating

DI during pregnancy.

Research Agenda

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The physiologic role of placental vasopressinase is unknown, and its effects

on both AVP and oxytocin are not completely charaterized.

DI in pregnancy is relatively rare, but its associations with more common

complications of pregnancy (pre-eclampsia, HELLP syndrome) needs to be

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further elucidated.

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Further advances in plasma AVP measurement and copeptin measurement can

assist in correctly classifying the subtype of gestational DI in order to more

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effectively guide therapy.

Additional controlled studies are needed to understand the safety of DDAVP

in pregnancy and lactation.

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More targeted and safe therapies in the treatment of nephrogenic DI in

pregnancy are needed.

M
D

Conflict of interest statement:

TE

No conflicts of interest
C EP
AC

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Table 1:

DI in Pregnancy: A Comparison of Central Diabetes Insipidus, Nephrogenic

Diabetes Insipidus and Transient Diabetes Insipidus of Pregnancy

PT
Central DI Nephrogenic DI Transient DI of

RI
(CDI) in Pregnancy (NDI) in Pregnancy

Pregnancy

SC
Associations Surgical trauma, head trauma, AVPR2 and May be associated

pituitary adenoma, Aquaporin- 2 gene with preeclampsia

autoimmune or other
U mutations, lithium and/or liver
AN
infiltration, idiopathic, AVP toxicity, medullary abnormalities.
M

gene mutation, Wolfram cystic kidney Can result in post

syndrome, anorexia nervosa, disease, polycystic partum DI due to

D

toxin (alcohol, snake venom) kidney, placental abruption

TE

hypokalemia, resulting in release of

hypercalcemia, vasopressinase
EP

sickle cell disease

or trait
C

Vasopressin Sensitive: Decreased Resistant: Renal Sensitive: Increased

AC

Sensitivity: secretory reserve of AVP resistance to AVP placental

Pathophysiology from pituitary; AVP levels vasopressinase

may be further decreased by mediated clearance of

clearance by placental AVP

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vasopressinase

Timing of May present in any trimester, May present in any Typically presents in

PT
Presentation May be recurrent trimester, May be the 3rd trimester,

RI
recurrent though symptoms may

be as early as 4th week

SC
of gestation.

Rarely occurs post

U partum (placental
AN
abruption)
M

Diagnosis: Urine osmolality normalized No change to urine Urine osmolality

Response to osmolality normalized

D

DDAVP
TE

Administration

Diagnosis: Low to absent Normal to high Low to absent

EP

Plasma AVP

level
C

Management Responds to DDAVP, may May be resistant to Responds to DDAVP,

AC

respond to AVP (although the both AVP and resistant to AVP

latter can be destroyed by DDAVP; consider

placental vasopressinase hydrochlorothiazide

during pregnancy) or amiloride

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Figure 1: Figure 1 shows the high-resolution T1-weighted sagittal pituitary MRI of a 32-

year old female at 14-weeks gestation whose pre-existing central diabetes insipidus

complicated her pregnancy. No pituitary lesions are seen, but the posterior pituitary

bright spot, representing the accumulation of neuro-secretory granules of AVP, is not

PT
seen. Although absence of the bright spot does not necessarily imply impaired activity of

RI
AVP, it has been associated with DI in many cases. She was treated successfully with

DDAVP.

U SC
AN
M
D
TE
C EP
AC

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