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Annales d’Endocrinologie 77 (2016) 135–138

Klotz Communications: Pituitary and Pregnancy

Diabetes insipidus and pregnancy

Diabète insipide et grossesse
Philippe Chanson a,b,∗ , Sylvie Salenave a
a Service d’endocrinologie et des maladies de la reproduction, centre de référence des maladies endocriniennes rares de la croissance, hôpital de Bicêtre, hôpitaux
universitaires Paris-Sud, Assistance publique–Hôpitaux de Paris (PC), 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France
b Inserm 1185, faculté de médecine Paris-Sud, université Paris-Saclay, 94276 Le Kremlin-Bicêtre, France

Abstract
Diabetes insipidus (DI) is a rare complication of pregnancy. It is usually transient, being due to increased placental production of vasopressinase
that inactivates circulating vasopressin. Gestational, transient DI occurs late in pregnancy and disappears few days after delivery. Acquired central
DI can also occur during pregnancy, for example in a patient with hypophysitis or neuroinfundibulitis during late pregnancy or postpartum.
Finally, pre-existing central or nephrogenic DI may occasionally be unmasked by pregnancy. Treatment with dDAVP (desmopressin, Minirin® )
is very effective on transient DI of pregnancy and also on pre-existing or acquired central DI. Contrary to vasopressin, dDAVP is not degraded
by vasopressinase. Nephrogenic DI is insensitive to dDAVP and is therefore more difficult to treat during pregnancy if fluid intake needs to be
restricted.
© 2016 Elsevier Masson SAS. All rights reserved.

Keywords: Diabetes insipidus; Pregnancy; Arginine vasopressine; Vasopressinase; Placenta; Hypophysitis

Résumé
Le diabète insipide (DI) est une complication rare de la grossesse. Le plus souvent il s’agit d’un DI transitoire de la grossesse, en rapport avec
une augmentation de la production, par le placenta, de vasopressinases qui inactivent la vasopressine circulante. Le DI gestationnel survient en fin
de grossesse et disparaît en quelques jours après l’accouchement. Il peut s’agir également de DI centraux acquis pendant la grossesse, par exemple
dans le cadre d’hypophysites ou de neuro-infundibulites de fin de grossesse ou au moment du postpartum. Plus rarement il s’agit de DI centraux
ou néphrogéniques préexistant à la grossesse qui se démasquent pendant la grossesse. Le traitement par dDAVP (desmopressine, Minirin® ) est très
efficace en cas de DI transitoire de la grossesse ou de DI central acquis ou préexistant car les vasopressinases ne détruisent pas la dDAVP comme
elles le font de la vasopressine. Les DI néphrogéniques, insensibles à la dDAVP, sont plus difficiles à traiter pendant la grossesse si l’accès à l’eau
doit être limité.
© 2016 Elsevier Masson SAS. Tous droits réservés.

Mots clés : Diabète insipide ; Grossesse ; Arginine vasopressine ; Vasopressinase ; Placenta ; Hypophysite

1. Introduction unnoticed, either because of the subclinical nature of DI, or

Onset of diabetes insipidus (DI) during pregnancy is a very
rare occurrence. The few available data suggest a prevalence
of about 4 cases per 100,000 pregnancies [1]. The real figure
is probably higher, however, as many cases are likely to go
∗ Corresponding author.
E-mail address: philippe.chanson@bct.aphp.fr (P. Chanson).
http://dx.doi.org/10.1016/j.ando.2016.04.005
0003-4266/© 2016 Elsevier Masson SAS. All rights reserved.
because some obstetricians may overlook this diagnosis.
By definition, patients with DI eliminate large quantities
(> 2–2.5 L per 24 hours, or 30 to 40 mL/kg of body weight)
of hypotonic, hypo-osmolar urine (< 250–300 mOsm/kg H2 O)
[2–6]. This is a non-osmotic polyuria, contrary to osmotic
polyuria (solute excretion >60 mmol/h) where urine contains
large amounts of osmotic substances, which may be either
endogenous (urea, glucose. . .) or exogenous (glycerol, manni-
tol, radiological contrast media).
136 P. Chanson, S. Salenave / Annales d’Endocrinologie 77 (2016) 135–138
2. Water homeostasis during pregnancy [7,8]
Water intake is regulated by thirst, which is controlled by
specific hypothalamic centers sensitive to osmolality [9]. Water
excretion by the kidneys is regulated by the antidiuretic hor-
mone, arginine vasopressin (AVP). AVP is synthesized in the
neurons located in the supraoptic and paraventricular hypothal-
amic nuclei, and migrates along axons, through the pituitary
stalk, to the posterior pituitary, where it is stored [3]. During
its transport along axons, AVP is also matured. AVP is released
by exocytosis in response to increased plasma osmolality. It is
then transported by the circulation to the kidney, at the level of
collecting duct where it activates AVP receptors (V2 receptors).
These seven-transmembrane-domains receptors are coupled to
adenylate cyclase and to cAMP production, and allow water
reabsorption by mobilizing aquaporin 2 [3,10].
During normal pregnancy, human chorionic gonadotropin
(hCG) lowers the plasma osmolality threshold at which AVP
release and thirst are triggered [11–13]. This contributes to
reductions in natremia (by about 5 mmol/L) and plasma osmo-
lality (by about 10 mOsmol/kg) [13,14].
The placenta plays another important role in water homeo-
stasis during pregnancy by producing vasopressinase (a
trophoblast-derived aminopeptidase), which inactivates endoge-
nous vasopressin [15]. Vasopressinase is produced as early as
the seventh week of gestation, reaching its maximum concen-
tration during the third trimester [15–18]. At 22–24 weeks of
pregnancy, vasopressin degradation reaches a plateau that per-
sists until delivery, resulting in a compensatory increase in AVP
synthesis and secretion [17,19].
Serum vasopressinase activity correlates with placental
weight and is higher during multiple pregnancies [20].
Placenta-derived vasopressinase concentrations collapse
after delivery.
3. Diagnosis of DI in a pregnant woman with hypotonic
polyuria
Investigation of a polyurodipsic state during pregnancy must
first establish that it is secondary to hypotonic polyuria and not to
osmotic polyuria (by checking glycosuria, for example). Indeed,
urine osmolarity is low in this setting (< 300 mOsm/L), con-
trasting with high plasma osmolality (> 280 mOsm/L) and with
rather high serum sodium levels (often > 140 mmol/L), which,
in the context of pregnancy, is unusual (natremia is usually in
the lower range of normal during pregnancy).
If hypotonic polyuria is confirmed, then primary polydipsia,
which is often accompanied by potomania, can be rapidly ruled
out in the absence of psychiatric disorders, and a diagnosis of
authentic DI can be made. AVP assay is not contributory, and
copeptin assay has not been reported in this context of central
DI [6,21]. A water deprivation test is contraindicated during
pregnancy because of the risk of hypernatremia, neurological
disorders, and fetal harm.
Transient DI of pregnancy is confirmed by the therapeu-
tic efficacy of dDAVP, which increases urine osmolarity and
reduces diuresis (vasopressinase does not inactivate dDAVP)
and by the fact that dDAVP can safely be withdrawn in the post-
partum, which is not the case in patients with pre-existing central
DI.
Nephrogenic DI is accompanied by high AVP or copeptin
concentrations.
The possibility of DI (whatever its etiology) should also be
raised in case of unexplained polyhydramnios [22,23].
4. Etiologic diagnosis of DI during pregnancy
4.1. Transient DI of pregnancy
Transient DI of pregnancy, or gestational DI, usually occurs
during the third trimester. It is the most common form of DI
during pregnancy [7,24] and is therefore the first diagnosis to be
considered.
Transient diabetes insipidus of pregnancy is associated with
an increased vasopressinase concentration [25,26], secondary
to an increase in placental production, in case of multiple
pregnancies for example, or impaired hepatic vasopressinase
degradation due to pre-eclampsia, eclampsia or the HELLP syn-
drome [24,27–32].
Vasopressinase activity usually declines after delivery and
becomes undetectable within 5–6 weeks postpartum [33].
Cases of isolated DI occurring not at the end of pregnancy
but in the immediate postpartum have also been described, again
related to an increase in vasopressinase activity [33]. This situ-
ation must be distinguished from DI associated with Sheehan’s
syndrome or with lymphocytic hypophysitis, which is also more
frequent in the postpartum; these forms are often associated with
other pituitary disorders and persist for after delivery. In a recent
study of HEK293 cells transfected with the AVP V2 receptor
coupled to luciferase, the serum of a patient with transient DI was
unable to activate luciferase, contrary to normal serum or stimu-
lation with AVP or dDAVP, which produce a ∼ 50-fold increase
[33]. A few days after delivery, once the polyurodipsic syn-
drome had disappeared, the patient’s serum recovered its ability
to stimulate luciferase activity, confirming the disappearance of
vasopressinase [32].
Symptoms resolve spontaneously and the response to fluid
restriction normalizes in the weeks following delivery, further
confirming the diagnosis of transient DI of pregnancy [30]. Tran-
sient DI does not usually recur during subsequent pregnancies.
4.2. Central DI during pregnancy
During normal pregnancy, AVP release increases to maintain
water reabsorption and thus to prevent polyuria. However, when
AVP secretion is impaired, either because of DI onset (due to
neuroinfundibulitis of pregnancy for example) or because of pre-
existing subclinical DI (central or nephrogenic), the pregnancy
can unmask polyuria and polydipsia [34].
Common causes of central DI include tumors, pituitary infil-
trations, sequelae of infundibulitis, and genetic abnormalities
[6].
 P. Chanson, S. Salenave / Annales d’Endocrinologie 77 (2016) 135–138
4.3. Nephrogenic diabetes insipidus and pregnancy
Nephrogenic diabetes insipidus, due to antidiuretic hormone
resistance, may be familial (associated with mutations of the
vasopressin or aquaporin genes) or acquired (secondary to
chronic renal disorders, such as polycystic kidney disease), or
be an adverse effect of lithium therapy [4,10]. Polyuria is com-
pensated by equivalent polydipsia and cannot be treated with
dDAVP because, by definition, the kidneys are insensitive to
vasopressin.
Like central DI, pre-existing nephrogenic diabetes insipidus
can worsen during pregnancy before improving after delivery.
4.4. Treatment of DI during pregnancy
dDAVP (desmopressin, Minirin® ) is the mainstay of treat-
ment for DI during pregnancy, whether transient or pre-existing,
and whether unmasked or exacerbated by the pregnancy. Unlike
vasopressin itself, this AVP analog is resistant to vasopressinase
[15,17,33,35].
When pre-existing central DI is controlled by dDAVP before
conception, treatment can be continued during pregnancy,
although it is sometimes necessary to increase the dose.
Treatment with dDAVP during pregnancy is introduced in
the same way as outside of pregnancy [36]. dDAVP is nor-
mally administered intranasally or sublingually, but sometimes
has to be injected [37–44]. For nasal administration, the patient
may use either a graduated tube (allowing a variable amount of
product to be administered) or a nasal spray, each puff deliver-
ing about 10 ␮g of drug. The sublingual route uses lyophilized
Minirinmelt® , which dissolves under the tongue and is avail-
able at doses of 60, 120 and 240 ␮g. The sublingual route has
the advantage of simpler and more discreet administration.
The standard doses are between 1 and 2 ␮g once or twice a
day by injection; 5 to 20 ␮g twice or three times a day by the
nasal route; and 60 to 120 ␮g two or three times a day by the
sublingual route. Higher doses may sometimes be needed: the
effective dosage depends on the severity of DI (partial or total
AVP deficit) and on individual parameters, such as absorption,
which affect the pharmacokinetics and pharmacodynamics of
the drug. Efficacy is maintained in the long term [41].
The dose is tailored to symptoms, with the aim of eliminating
the polyurodipsic syndrome without risking overdose. It is usu-
ally the patient herself who finds the optimal dose; she should
be advised first to increase the evening dose gradually until she
no longer has to get up at night to drink and urinate, and then to
use the same procedure during daytime.
The main adverse effect of dDAVP is water intoxication
due to overdose, leading to a mismatch between water elimi-
nation (limited by desmopressin, which blocks water diuresis)
and a larger volume of water intake, resulting in hemodilution.
This can cause headache and nausea, and hyponatremia [45].
If left untreated, confusion or seizures due to cerebral edema
may occur. Patients should thus be advised to suspend treatment
if they experience nausea or headache. Treatment interruption
leads to the reappearance of polyuria, which eliminates the fluid
overload and quickly corrects symptoms, allowing treatment to
137
be resumed. It may be advisable to monitor the serum sodium
level because of the risk of water intoxication and hemodilu-
tion in case of uncompensated adrenocorticotropic deficiency.
To avoid the risk of water intoxication, the patient should be
advised to drink only when thirsty. It is also recommended to
reduce the dose of one intake or to “miss” an intake regularly,
once a week for example. By provoking transient polyuria, this
helps to eliminate any fluid overload that has gradually accumu-
lated, thereby correcting the fluid balance. The patient can then
resume the usual dose of desmopressin.
The few available data on the safety of dDAVP for the mother
and unborn child are reassuring [35,46].
Hydrochlorothiazide therapy can be continued in case of
nephrogenic DI, which can create difficult problems during labor
and delivery if it becomes impossible to balance the abundant
polyuria by equivalent fluid intake [47].
5. Conclusion
Diabetes insipidus occurring during pregnancy can be due
to aggravation or unmasking of pre-existing central DI, nephro-
genic DI, or, most often, to placental vasopressinase release,
responsible for transient DI of pregnancy.
Timely diagnosis is important, as treatment with dDAVP is
extremely simple and provides symptom relief.
Disclosure of interest
The authors declare that they have no competing interest.
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