S P E C I A L

C l i n i c a l

C a s e

F E A T U R E
S e m i n a r

Acute Diabetes Insipidus Mediated by Vasopressinase

After Placental Abruption
Amisha Wallia,* Aigerim Bizhanova,* Wenyu Huang, Susan L. Goldsmith,
Dana R. Gossett, and Peter Kopp
Division of Endocrinology, Metabolism, and Molecular Medicine (A.W., A.B., W.H., P.K.), and
Department of Obstetrics and Gynecology (S.L.G., D.R.G.), Feinberg School of Medicine, Northwestern
University, Chicago, Illinois 60611

Context: Postpartum, diabetes insipidus (DI) can be part of Sheehans syndrome or lymphocytic
hypophysitis in combination with anterior pituitary hormone deficiencies. In contrast, acute onset
of isolated DI in the postpartum period is unusual.
Case Presentation: This patient presented at 33 weeks gestation with placental abruption, prompting a cesarean delivery of twins. Immediately after delivery, she developed severe DI. The DI could
be controlled with the vasopressinase-resistant 1-deamino-8-D-arginine vasopressin (DDAVP), but
not with arginine vasopressin (AVP), and it resolved within a few weeks.
Objective: The aim of this study was to demonstrate that the postpartum DI in this patient was
caused by the release of placental vasopressinase into the maternal bloodstream.
Methods and Results: Cells were transiently transfected with the AVP receptor 2 (AVPR2) and
treated with either AVP or DDAVP in the presence of the patients serum collected postpartum or
10 weeks after delivery. The response to the different treatments was evaluated by measuring the
activity of a cAMP-responsive firefly luciferase reporter construct. The in vitro studies demonstrate
that the patients postpartum serum disrupts activation of the AVPR2 by AVP, but not by the
vasopressinase-resistant DDAVP.
Conclusions: Placental abruption can rarely be associated with acute postpartum DI caused by
release of placental vasopressinase into the bloodstream. This clinical entity must be considered in
patients with placental abruption and when evaluating patients presenting with DI after delivery.
(J Clin Endocrinol Metab 98: 881 886, 2013)

iabetes insipidus (DI) is an uncommon complication

of pregnancy and the postpartum period (1, 2). During pregnancy, arginine vasopressin (AVP) secretion and
thirst occur at a lower serum osmolality (35). In addition,
placental vasopressinase/oxytocinase, a leucine-aminopeptidase inactivating AVP, oxytocin, and other small
peptides, is produced by 7 weeks gestation by trophoblasts
and reaches maximal levels in the third trimester (6 10).
Consequently, clearance reaches a plateau at a 4-fold
higher rate by 2224 weeks and remains at this level until
delivery (9, 10), thereby prompting a compensatory rise in

AVP synthesis and secretion (6). Serum vasopressinase activity correlates with placental weight and is higher in multiple gestations (11).
Rarely, increased vasopressinase activity results in
transient gestational DI that remits after delivery (1, 12
15). This form of DI is associated with absent endogenous
AVP and is resistant to therapy with exogenous AVP but
responsive to 1-deamino-8-D-AVP (DDAVP) (10, 16, 17).
It is more commonly observed in women with multiple
gestations or impaired hepatic degradation of vasopressinase due to preeclampsia, eclampsia, HELLP syndrome

ISSN Print 0021-972X ISSN Online 1945-7197

Printed in U.S.A.
Copyright 2013 by The Endocrine Society
doi: 10.1210/jc.2012-3548 Received October 6, 2012. Accepted January 17, 2013.
First Published Online February 7, 2013

* A.W. and A.B. contributed equally to this study.

Abbreviations: AVP, arginine vasopressin; AVPR2, AVP receptor 2; DI, diabetes insipidus;
FL, firefly luciferase; MRI, magnetic resonance imaging; RL, renilla luciferase.

J Clin Endocrinol Metab, March 2013, 98(3):881 886

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Vasopressinase-Induced Acute Postpartum DI

J Clin Endocrinol Metab, March 2013, 98(3):881 886

(hemolysis, elevated liver enzymes, low platelet count), or

liver steatosis (1, 12, 13, 18). In addition, increased vasopressinase activity and/or diminished renal responsiveness
to AVP may occasionally unmask subclinical neurogenic
or nephrogenic DI in late gestation (19). The estimated
prevalence of vasopressinase-induced DI is thought to be
about 2 4 in 100 000 pregnancies (1, 13). After delivery,
vasopressinase activity declines and becomes undetectable
by 5 to 6 weeks postpartum (6).
In contrast to vasopressinase-induced transient DI during pregnancy, isolated DI with onset in the postpartum
period is unusual (1). Postpartum, DI can be part of Sheehans syndrome (pituitary necrosis with hypopituitarism)
or lymphocytic hypophysitis in combination with anterior
pituitary hormone deficiencies (20 22).

of placental abruption. She underwent an emergent cesarean section with delivery of viable twins; placental abruption was confirmed by gross inspection. She had an intraoperative blood loss of 2000 ml and received 1800 ml of
crystalloid/lactated ringer solution, 1000 ml of Hextend,
and 500 ml of 5% albumin solution (Figure 1). She did not
receive blood products. The placenta weighed 712 g and
was dichorionic and diamniotic. Her obstetric history was
notable for 2 prior miscarriages. She had had regular menstrual cycles and a normal hormonal evaluation before
pregnancy, but she required in vitro fertilization for secondary infertility of unknown etiology. During her pregnancy, the patient never developed apparent polyuria or
polydipsia.
Intraoperatively, she had a urine output of 300 ml (150
ml/h). During the first 6 hours postoperatively, she received 2000 ml of iv fluids, her urinary output increased to
5800 ml (967 ml/h), and she reported excessive thirst.
Intravenous fluids were discontinued, and the patient was
allowed to drink to satisfy thirst. During the next 7 hours,
her total fluid intake was 10.2 L (900 to 1500 ml/h), and

Clinical Presentation
This 31-year-old G3P0020 had an uncomplicated twin
pregnancy until she presented at 33 weeks gestation with
preterm labor. During her evaluation, she developed signs

Mean urinary output per hour

Urinary output (ml/hour)

1000

800

600

400

200

0
C-section Postoperative
2 hours
hour 1 to 6

Postoperative
hour 7 to 13

8 hour period
post 2 g of DDAVP s.c.

4 hour period
post 5 U AVP s.c.

Fluid intake and output

C-section
2 hours

Postoperative
hour 1 to 6

Postoperative
hour 7 to 13

8 hour period
post 2 g DDAVP s.c.

Intake

3,300 ml

2,000 ml

10,160 ml

680 ml

Intake/hour

1,650 ml

333 ml

1,451 ml
(900 to 1,500 ml)

85 ml

Output

Blood loss: 2,000 ml

Urine: 300 ml

5,800 ml

6,400 ml

530 ml

2,200 ml

Urine/hour

150 ml

967 ml

914 ml
(650 to 900 ml)

66 ml

275 ml

Balance

+1,000 ml

-3,800 ml

+3,700 ml

+150 ml

Oral intake

None

None

To thirst

To thirst

4 h period
post 5 U AVP s.c.

To thirst

Figure 1. Mean urinary output per hour (A) and fluid input and output (B) in the immediate postoperative period, under initial therapy with
DDAVP, and after the administration of AVP. C-section, cesarean section; DDAVP, desmopressin; *, incomplete documentation of oral intake.

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J Clin Endocrinol Metab, March 2013, 98(3):881 886

Table 1.

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883

Selected Biochemical Values

Day 1
2 h 30 min After
Cesarean
Section

Polyuria polydipsia thirst

Sodium (135145 meq/L)
Plasma osmolality
(275295 mOsm/kg)
Urine osmolarity
(50 1400 mOsm/L)
Urine specific gravity
(1.0051.035)
AVP (1.7 pg/mL)
Cortisol (525 g/dL)
ACTH (6 46 pg/mL)
TSH (0.4 4 mU/L)
T4 (6.112.2 g/dL)
FT4 (0.71.5 g/dL)
PRL (2.326.7 ng/mL)

139
288
(calculated)
147

12 h After
Cesarean
Section

Day 3
2 h 45 min
After 2 g
DDAVP sc

15 h After
2 g
DDAVP sc

1 h 30 min
After 5
U AVP

1 h 30 min
After 10 g
DDAVP i.n.

5 h 30 min
After 10 g
DDAVP i.n.

Month 5
Off DDAVP

Month 10
2nd
Pregnancy,
wk 5

Month 18
Post
Pregnancy

140
272

133
278

139
288

139

137

136

140
301

136
286

140
300

116

656

171

280

527

716

585

937

866

1.007

1.1a

1.4
11.2
27

8.1

0.93
7.9

2.7
7.8
9
0.93
1.14
6.7

133

18.4
0.48
0.96

Abbreviations: DDAVP, desmopressin; T4, total T4; FT4, free T4; PRL, prolactin; i.n., intranasal; , present; , absent.
a

About 9 h after administration of 12 mg of betamethasone.

her urinary output was 6.4 L (650 900 ml/h) (Figure 1).
Her systolic blood pressure ranged from 93 to 135 mm Hg.
Preoperatively, her white cell count was 14 500/l, her
hemoglobin was 14.8 g/dL, and her platelet count was
169 000/l. Immediately after the cesarean section, her sodium was 139 meq/L, urine osmolarity was 147 mOsm/L,
and a calculated serum osmolality was 288 mOsm/kg. Postoperatively, her hemoglobin dropped to 11.3 g/dL, and her
hematocrit was 32.6%. Her liver function tests were mildly
elevated (alanine transaminase, 110 U/L; aspartate
transaminase, 108 U/L; alkaline phosphatase, 112 U/L).
There was no proteinuria and no signs of disseminated
intravascular coagulopathy.
At the initial endocrine evaluation on postpartum day 1,
she reported excessive thirst but denied dizziness or lightheadedness. The patient was alert, had no neurological deficits, and had not begun to lactate. The laboratory findings
12 hours after surgery showed a serum sodium of 140 meq/L,
a serum osmolality of 272 mOsm/kg, a urine osmolarity of
116 mOsm/L, and a urine specific gravity of 1.007 (Table 1).
Her TSH was 0.93 mU/L (reference range, 0.4 4), total T4
was 7.9 g/dL (reference range, 6 12), and prolactin was
133 ng/ml. Her 8 AM cortisol was 1.1 g/dL (reference range,
525), but she had received 12 mg of betamethasone at 11 PM
the night before for fetal lung maturation. A repeat 8 AM
cortisol level was 8.1 g/dL on postpartum day 3.
Based on the abrupt onset of her extreme thirst, polydipsia, polyuria, and low urine osmolarity, a clinical diagnosis of
DI was made. The patient was given 2 g DDAVP sc, which
resulted in prompt resolution of her symptoms: her oral fluid
intake decreased to 85 ml/h, her urine output decreased to 66
ml/h, and her urine osmolarity increased to 656 mOsm/L
(Figure 1 and Table 1). The patient was then placed on 1 g
DDAVP iv twice daily.

A pituitary magnetic resonance imaging (MRI) showed

a slightly prominent pituitary gland consistent with normal findings in the postpartum period (Figure 2A). There
was no evidence of pituitary infarction or signs of lymphocytic infiltration. Precontrast T1-weighted sagittal images did not show a posterior pituitary bright spot.
In the absence of hypothalamic and pituitary lesions, and
the presence of normal anterior pituitary function, the etiology of the DI remained unclear. Suspecting that her DI could
have resulted from the release of vasopressinase into the
blood stream during the placental abruption, DDAVP was
held until she was again symptomatic because DDAVP, unlike AVP, is resistant to vasopressinase (6). After holding the
DDVAP, her urine osmolarity decreased to 171 mOsm/L,
and the patient became polyuric (Table 1). After the sc administration of 5 U of AVP, the equivalent of 1 g DDAVP
iv, she had persistent polyuria with a urine output of 275 ml/h
and a urine osmolarity of 280 mOsm/L (Figure 1). Four
hours later, the administration of 1 g DDAVP iv led to
prompt relief of her symptoms, and her urine osmolarity
increased to 716 mOsm/L.
Subsequently, her polyuria was well controlled on 10
g DDAVP intranasally 3 times daily and her sodium
ranged from 140 141 meq/L. While her milk production
was minimal during the first week after delivery, it increased and she fed both infants through breast milk alone
for nearly 6 months.
Six weeks postpartum, the DDAVP was gradually
weaned over a 4-week period. Off DDAVP, her oral intake
and urinary output remained normal. Five months postpartum, her sodium was 140 meq/L, her urine osmolarity
was 585 mOsm/L, and her AVP level was 1.4 pg/mL (Table 1). Ten months postpartum, her sodium was 136
meq/L, her urine osmolarity was 937 mOsm/L, and her

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Wallia et al

Vasopressinase-Induced Acute Postpartum DI

J Clin Endocrinol Metab, March 2013, 98(3):881 886

60

Luciferase Activity (Fold Activation)

50

40

30

20

10

0
-AVPR2

AVPR2
-AVP

AVPR2
-DDAVP

AVPR2
+AVP

FBS

AVPR2 AVPR2
+DDAVP +AVP

FBS

AVPR2
+DDAVP

Postnatal day 1

AVPR2
+AVP

AVPR2
+DDAVP

Postnatal week 10

Figure 2. A, Sagittal and coronal MRI views demonstrating a slightly prominent pituitary gland without signs of infarction or lymphocytic
infiltration. The precontrast T1-weighted sagittal images do not show a posterior pituitary bright spot. B, The ability of AVP and DDAVP to
stimulate AVPR2 activity and downstream cAMP production was determined in TSA cells transiently transfected with the AVPR2 and a cAMPresponsive luciferase reporter gene. Cells were treated with AVP or DDAVP in the presence of fetal bovine serum (FBS) or patient serum collected
on postpartum day 1 and 10 weeks after delivery. Treatment with AVP and DDAVP led to a significant increase in luciferase activity in the presence
of FBS. In the presence of patient serum collected at postpartum day 1, the stimulatory effect of AVP, but not DDAVP, was abrogated, suggesting
inactivation by vasopressinase. Coincubation with patient serum collected at 10 weeks postpartum did not reduce the ability of AVP to activate the
AVPR2. Values are shown as means SEM. Results were obtained in triplicate in more than 3 independent experiments, and firefly activity was
normalized for renilla activity.

AVP level was 2.7 pg/mL. Reevaluation of her anterior

pituitary function showed no abnormalities (Table 1).
Eight months after her cesarean delivery, the patient
conceived again without assistance. She did not develop
any signs or symptoms suggestive for DI during the subsequent pregnancy. At 28 weeks gestation, her sodium was
136 meq/L, her serum osmolality was 279 mOsm/kg, and
her urine osmolarity was 700 mOsm/L (Table 1). A 24hour urine collection at 30 weeks gestation was 2025 mL,

and her reported oral intake from the same period was
1800 mL.

Materials and Methods

The in vitro studies were approved by the Northwestern University Institutional Review Board, and the patient provided informed consent. Serum for in vitro studies was collected on day
1 and 10 weeks postpartum and stored at 20C.

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J Clin Endocrinol Metab, March 2013, 98(3):881 886

Cell culture and luciferase assay

TSA-201 human embryonic kidney 293 cells were seeded in
12-well tissue culture plates, grown to 80% confluency, and
transfected using the calcium phosphate method (23). Each well
was transfected with 500 ng of a pCDNA3.1 plasmid carrying
the arginine vasopressin receptor 2 (AVPR2) cDNA and 100 ng
of a cAMP-responsive firefly luciferase (FL) reporter construct
(23). To control for transfection efficiency, cells were cotransfected with 10 ng of a renilla luciferase (RL) reporter plasmid
(pRL-CMV). The empty pCDNA3.1 vector served as negative
control.
Twenty-four hours after transfection, cells were fed fresh medium and incubated in the absence or presence of 20 pg/mL AVP
or 25 pg/mL DDAVP alone or in combination with patient serum
collected on day 1 or week 10 postpartum (50 L/well) for 24
hours. Cells treated with AVP or DDAVP in combination with
the patients serum were incubated with medium lacking FBS.
After cell lysis, FL and RL activities were measured for 10
seconds, followed by a 2-second delay (Synergy 2 microplate
reader; Biotek Instruments, Winooski, Vermont). The FL activity was normalized to RL activity for each sample, and the values
are expressed as fold activation of FL activity over the empty
vector. All experiments were performed in triplicate.

Statistical analysis
Data are reported as means SEM. Statistical analysis was
performed by one-way ANOVA using Tukeys correction. Results were considered significant when P .05.

Results
Effect of AVP and DDAVP on AVPR2 activity in the
presence of patient serum
In cells expressing the AVPR2, a significant increase in
cAMP-responsive luciferase reporter activity was observed in response to stimulation with AVP (52-fold) or
DDAVP (53-fold) compared to untransfected cells (P
.001) (Figure 2B). In contrast, incubation with AVP and
the patients serum collected on postpartum day 1 did not
result in an increase in luciferase activity. Incubation with
DDAVP and the patients serum led to a 52-fold increase
in luciferase reporter activity, similar to the response obtained with AVP or DDAVP alone (P .001). Treatment
with AVP and the patients serum collected 10 weeks postpartum resulted in a 53-fold increase in luciferase reporter
activity (P .001 compared to control) similar to the
52-fold activation seen in cells treated with DDAVP (P
.001; Figure 2B).

Discussion
In a subset of women, increased degradation of AVP by
vasopressinase can result in transient gestational DI (1,
1215). This form of DI is more commonly observed in
women with multiple gestations, subclinical central DI, or

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885

impaired hepatic degradation of vasopressinase due to

preeclampsia, eclampsia, HELLP syndrome, or liver steatosis (1, 12, 13). After delivery, vasopressinase activity
declines and becomes undetectable by 5 to 6 weeks postpartum (6). In contrast to vasopressinase-induced transient DI during pregnancy, isolated DI with onset in the
postpartum period is unusual (1). It can rarely occur in
combination with anterior pituitary hormone deficiency
because of necrosis of the hypophysis (Sheehans syndrome) or lymphocytic hypophysitis (20 22).
In the patient reported here, DI developed acutely after
placental abruption. The biochemical findings and her pituitary MRI did not reveal findings supporting the presence of pituitary necrosis or infiltration, but demonstrated
an absent posterior pituitary bright spot (24). Based on
this unusual clinical presentation, we hypothesized that
sudden release of a large amount of vasopressinase secondary to placental abruption may have led to increased
degradation of AVP, which could not be compensated by
increased production and secretion of AVP. Consistent
with this hypothesis, the patient responded promptly to
DDAVP, but not to therapy with AVP (Figure 1 and Table
1). Compared to AVP, DDAVP has a modified amino terminus and is therefore resistant to degradation by vasopressinase (16). In agreement with the reported disappearance from the maternal circulation after delivery (6), the
patient was successfully weaned off DDAVP treatment 6
weeks postpartum, and on repeated testing there was no
evidence of subclinical neurogenic DI.
Formal proof that the maternal serum displays an AVPdegrading activity, presumably due to the release of placental vasopressinase during the abruption, is provided by
the in vitro assay (Figure 2B). In accordance with the clinical remission of the DI, patient serum collected at 10
weeks did not diminish the AVP-induced stimulation of
the AVPR2. Oxytocin degradation could not be formally
tested because of a lack of patient sera (25).
Placental abruptions are uncommon and vary greatly in
their severity and clinical significance. We speculate that a
large surface area may have been involved in this patient
and that the larger placental mass due to the twin gestation
may have been an additional contributing factor.
In conclusion, these findings demonstrate that placental abruption can rarely be associated with acute postpartum DI caused by release of vasopressinase into the bloodstream. This clinical entity must be considered in patients
with placental abruption and when evaluating patients
presenting with DI after delivery.

Acknowledgments
Address all correspondence and requests for reprints to: Peter
Kopp, MD, Division of Endocrinology, Metabolism and Mo-

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886

Wallia et al

Vasopressinase-Induced Acute Postpartum DI

lecular Medicine, Feinberg School of Medicine, Northwestern

University, Tarry 15, 303 East Chicago Avenue, Chicago, Illinois
60611. E-mail: p-kopp@northwestern.edu.
This work has been supported by a gift from Mr. David Wiener (to P.K.).
Disclosure Summary: The authors declare that there are no
competing financial interests.

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