European Journal of Obstetrics & Gynecology

and Reproductive Biology 52 (1993) 175-180

Efficacy and safety of indomethacin therapy for polyhydramnios

F. Carmona* a, S. Martinez-Romin”, C. Morterab, B. Puertoa, V. Cararach”,

X. Iglesias”
“Department of Obstetrics and Gynecology, bDepartment of Pediatrics. Hospital Clinic i Provincial, Faculty of
Medicine - University of Barcelona, C/ Villarroel 170. Barcelona 08036, Spain

(Accepted 24 September 1993)

Abstract

The maternal and perinatal outcome of seven gravidas receiving 2.2-2.5 mg/kg per day of indomethacin for polyhy-
dramnios are reported. Such therapy was started between 26 and 33 weeks of gestational age (mean, 30.4 weeks) and
lasted for 20.1 days (range, 2-37 days). Median of amniotic fluid index ranged from 47 at the start of therapy (range,
32-53) to 15 (range, 2-50) when indomethacin was ended. Interval between the end of the therapy and the delivery
ranged from 0 to 45 days (mean, 15 days). On average, pregnancies were prolonged by 5.1 weeks (range, 2-8 weeks).
The newborn weight was 2678 g on average (range, 620-3700 g). Oligohydramnios was seen in two instances; one
patient developed constriction of the fetal ductus arteriosus, which returned to normality after indomethacin supres-
sion; one newborn in which other casuses of neonatal bleeding could be excluded, developed a diseminated intravascu-
lar coagulation and died 15 h after birth. Finally, one mother presented an acute renal failure immediately after
indomethacin administration; this patient completely recovered after indomethacin withdrawal. Thus, the benefit of
pregnancy prolongation should be balanced against the increased risks for the newborn, mainly fetal ductus arteriosus
constriction and possible bleeding disorders. A causal relationship of indomethacin administration to the latter com-
plication warrants further investigation.

Key words: Indomethacin therapy; Polyhydramnios

1. Introduction ties. Aditionally, premature uterine contractions

may lead to premature rupture of membranes and
Polyhydramnios is defined as amniotic fluid premature birth. Furthermore, sudden decompres-
(AF) in excess of 1.5-2 1 and is associated with in- sion of the uterus can cause abruptio placentae.
creased perinatal morbidity and mortality [l]. This Classical management of patients with polyhy-
excess of fluid is associated with maternal discom- dramnios is based on repeated amniocentesis. Un-
fort resulting from the pressure of the AF on the fortunately, re-accumulation of fluid can occur
diaphragm, which may lead to respiratory difficul- within 48 h, requiring multiple punctures and in-
creasing the risk of the infection and premature
* Corresponding author. rupture of membranes [ 11. Recently, some authors

0028-2243/93/$06.00 Elsevier Scientific Publishers Ireland Ltd.

SSDI 0028-2243(93)0 170 I-T
176 F. Carmona et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 52 (1993)
have proposed the use of indomethacin as an alter-
native to serial amniocentesis in the treatment of
polyhydramnios [2,3]. In this way, AF volume can
be reduced in 95% of cases and pregnancy can be
prolonged by 12-101 days [4].
However, potentially dangerous maternal and
fetal side-effects have been related with the use of
indomethacin during pregnancy [5-81. In this
paper we describe our experience with in-
domethacin therapy for polyhydramnios, focusing
attention on maternal/neonatal effects of this drug.
This report suggests that indomethacin may be as-
sociated with significant maternal and fetal side-
effects, and the benefits are weighed against the
risks.
2. Patients and methods
Candidates for indomethacin therapy were re-
quired to have symptomatic polyhydramnios con-
firmed by ultrasonography. Polyhydramnios was
defined in our study as an AF index (AFI) of 24
cm or more, according the criteria of Carlson et al.
[9]. All patients underwent level III ultra-
sonographic examination to rule out fetal anomal-
ies. Cytogenetic studies of the fetuses by amnio-
centesis was used to exclude chromosomic
alterations. All patients were evaluated for other
causes of polyhydramnios, as maternal diabetes,
Rh isoimmnunization, STORCH infections or pla-
cental abnormalities.
Indomethacin was administered orally at a dose
of 2.2-2.5 mg/kg/day. If oligohydramnios, fetal
ductus constriction, fetal distress or serious mater-
nal side-effects were noted during treatment, either
the dose of indomethacin was decreased or the
therapy was discontinued. Patients were admitted
to the hospital for bed rest and close surveillance
of both mother and fetus. Mothers were evaluated
daily for clinical symptoms, fundal height and
weight. Red and white cell and platelet count,
creatinine and electrolytes were estimated at ad-
mission and twice weekly. Thereafter, AFI was
also measured twice a week. Fetuses were
monitored by daily fetal movement count and car-
diotocography. Doppler blood flow waveforms
were obtained twice a week. Fetal growth was
assessed weekly.
175-180
Fetal ductus arteriosus was monitored by
echocardiography. Fetal echocardiograms were
performed using two-dimensional, directed, con-
tinuous wave and pulsed Doppler. Ductal con-
striction was defined as the presence of fetal ductal
systolic velocity over 1.4 m/s in conjunction with a
dyastolic velocity of >0.35 m/s. Tricuspid
regurgitation was diagnosed when a holosystolic
regurgitant wave was detected within the right
cavities. Fetal echocardiography was performed
before the initiation of indomethacin therapy, and
then weekly provided that the fectal ductus
arteriosus remained patent. After birth, infants
were observed for any evidence of persistent fetal
circulation. This included clinical assesment, chest
X-ray examination and blood gas determination.
Renal function and coagulation parameters were
also determined.
3. Results
During the period from January 1991 to
December 1992 seven patients were considered
eligibles for treatment with indomethacin. Table 1
shows the main characteristics of these patients
and the evolution of AFI. Polyhydramnios was
diagnosed between 26 and 33 weeks of gestation in
all seven patients. The longest duration of therapy
was 37 days and the shortest was 2 days. The mean
time of prolongation of pregnancy was 5.1 weeks.
Pregnancy was electively terminated before term
(37 or more weeks) in three patients (in Cases 6
and 7 because of difficult metabolic control and in
Case 4 because of fetal distress). Thus, pregnancy
reached term in four cases.
Reduction of AF volume was seen in all patients
but Case 4 (the patient with the shortest duration
of indomethacin administration). Median of AFI
ranged from 47 at the start of therapy to 15 when
indomethacin was ended.
Table 2 shows pregnancy outcome and maternal
and newborn complications. In all cases fetal
echocardiography performed prior to the treat-
ment showed ductal patency; however, in Case 5
constriction of fetal ductus arteriosus associated
with tricuspid regurgitation was noted 8 days after
the start of indomethacin. Both ductal constriction
and tricuspid regurgitation resolved spontaneous-
F. Carmona et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 52 (1993) 175-180 177

Table I
Main characteristics of our patients

Patient Etiology Gestational age (weeks) Duration Interval AFI

of end
Start End Delivery treatment therapy- Start End
(days) delivery
(days)

I Chorioangioma 31 36 31 36 9 53 5
2 Idiopathic 33 36 37 22 10 31 4
3 Diabetes 33 35 37 IO 16 53 2
4 Twin-twin transfusion 26 26 28 2 II 50 50
5 Idiopathic 32 33 40 IO 45 47 24
6 Diabetes 27 33 35 37 16 32 IS
7 Diabetes 31 35 35 24 0 38 19

AFI, Amniotic fluid index.

ly after cessation of therapy. Oligohydramnios In Patient 7 indomethacin was continued until

(AFI <5) was present in two cases (2 and 3). In
both cases termination of treatment resulted in re-
accumulation of fluid. In Case 4 (a multiple preg-
nancy complicated with a twin-twin transfusion
syndrome) both fetuses suffered serious hyaline
membrane disease, requiring ventilatory support,
and intraventricular hemorrhage. One of them
recovered completely and is currently well 10
months after delivery, but the smaller one died at
26 days of life.
delivery at 35th gestational week when an elective
cesarean section was performed because of dif-
ficult maternal metabolic management. The neo-
nate weighed 1850 g and his Apgar’s scores were
normal. However, soon after birth, petechiae and
subcutaneous bruising appeared spontaneously;
the baby bled easily from puncture sites and hypo-
tension and signs of intra-abdominal bleeding
developed 10 h after birth. Premortem and
postmortem blood cultures were negative. Clotting

Table 2
Pregnancy outcome and maternal and newborn complications

Patient Olygo- Fetal ductus End of preg- Newborn Newborn complications Mother complications
hydramnios constriction nancy (indication) weight (g)

I No No s 2530 None Pyrosis

2 Yes No s 2520 None Pyrosis
3 Yes No s 3460 None None
4 No No M (Fetal distress) 1090 Hyaline membrane disease Functional renal failure
Intraventricular haemorrhage
620 Hyaline membrane disease
Intraventricular haemorrhage
Neonatal death at 26 days
5 No Yes* s 3700 None None
6 No No M (Diabetes) 2980 None None
7 No No M (Diabetes) 1850 Bleeding disorder None
Neonatal death at 15 h

S, spontaneous; M, medical.
*Resolved spontaneously before delivery after indomethacin withdrawal.
178 F. Carmona et al. /Eur.
studies showed disseminated intravascular coagu-
lation and, despite intensive treatment, the baby
died 15 h after delivery. Autopsy showed no sign
of sepsis. Fetal cardiac function at birth and clini-
cal evaluation revealed signs of premature closure
of the ductus arteriosus in no cases. Urinary pro-
duction was also normal. Follow-up examinations
of surviving infants at 3 and 6 months were within
normal limits.
Patients 1 and 2 presented mild pyrosis but ter-
mination of therapy was not necessary. Two days
after indomethacin was started, Patient 4
developed olyguria (diuresis less than 20 ml/h) and
her plasmatic creatinine rose to 300.56 pmol/l. So-
dium excretion disminished to 2.7 mmol/day and
urine/plasma osmolality was 2.1. At admission, the
glomerular filtration rate, as estimated by serum
levels of creatinine and blood urea nitrogen, and
plasma electrolytes were normal. Thus, a diagnosis
of acute prerenal failure, probably associated with
indomethacin treatment, was established and the
drug was discontinued after the patient has receiv-
ed a total dose of 300 mg. Intravenous furosemide
was given to promote diuresis. Renal function
recovered steadily after indomethacin withdrawal.
4. Discussion
Indomethacin was successful in decreasing the
AF volume in six of the seven patients included in
this series. Our results are in agreement with those
previously reported in the literature showing that
indomethacin is useful in the treatment of
idiopathic polyhydramnios or hydramnios related
to maternal diabetes, fetal nephrogenic diabetes
insipidus, fetal gastrointestinal obstruction distal
to the stomach or other causes [2,3,10-131. How-
ever, a limited response was observed when poly-
hydramnios was related to conditions in which
poor fetal swallowing is believed to be the cause of
the excessive amount of AF [lo]. Similarly, in the
report by Kirshon et al. [I I], as in this series, in-
domethacin was not effective in the treatment of
the severe twin-twin transfusion syndrome.
By reducing the volume of AF, indomethacin
can also prevent the perinatal morbidity and mor-
tality associated with preterm labor. In an recent
literature review, Rodriguez [4] found that preg-
nancies complicated with polyhydramnios and
J. Obstet. Gynecol. Reprod. Biol. 52 (1993) 17S-180
treated with indomethacin were prolonged 9.9
weeks on average. In our series, pregnancies were
prolonged 5 weeks, allowing prevention of neona-
tal mortality secondary to preterm delivery in most
cases.
The precise mechanism for the indomethacin
effect is unclear, but, because AF volume is largely
dependent on fetal urine production, it is probably
mediated by reducing fetal urine output, as shown
by Kirshon et al. [14], who performed ultrasonic
measurements of fetal urine output during mater-
nal indomethacin therapy. However, studies in pa-
tients with idiopathic hydramnios do not show
elevated fetal urine production [IS]; thus, other
mechanisms may be related. Mamopoulos et al. (31
proposed two other possible mechanisms for the
therapeutic effect of indomethacin on polyhy-
dramnios: (i) the enhanced effect of indomethacin
on fetal breathing movements, resulting in an
increase in the AF reabsorption by the lungs, or
(ii) action on the fetal membranes, which are
known to contain large amounts of pro-
staglandins.
Oligohydramnios associated with nonsteroidal
anti-inflammatory drug treatment has previously
been reported in animal and human studies
[16-201. This complication was present in two
cases in our series. Oligohydramnios was reversi-
ble with cessation of the drug. Lange et al. [I31 and
Kirshon et al. [ 1I] noted the development of oligo-
hydramnios in one of six cases and in one of eight
cases, respectively. Mamopoulos et al. [3] describ-
ed the development of oligohydramnios in five of
their patients. Although in all these cases reduc-
tion in AF was not detrimental to the fetus, oligo-
hydramnios may place the fetus in jeopardy for the
development of pulmonary hypoplasia and umbili-
cal cord compromise and it has been proposed the
medication be discontinued if severe oligohydram-
nios developed.
One important role of prostaglandins during
fetal life is to maintain the patency of the ductus
arteriosus [21]. Indomethacin, therefore, has the
potential to cause ductal constriction. Constric-
tion of the ductus arteriosus using pulsed Doppler
ultrasound has been shown during indomethacin
therapy in patients with preterm delivery [22] and
in patients with polyhydramnios [23]. In all cases,
constriction resolved within 24 h of stopping in-
F. Carmona et al. /Eur. J. Obsiet. Gynecol. Reprod.
domethacin. In our series, one fetus developed
ductus constriction and tricuspid regurgitation. As
in the above mentioned cases, this alteration
resolved spontaneuosly after indomethacin
withdrawal. Recent data suggest that fetal ductus
constriction mediated by indomethacin is related
to gestational age, and it has been calculated that
the risk of ductal constriction is 5% between 26
and 27 weeks gestation but increases to nearly 50%
by 32 weeks [lo]. Thus, it has been sugested that
fetal echocardiograms should be done in the first
24 h after the initiation of indomethacin and then
weekly.
In this series one preterm infant developed a
bleeding disorder immediately after birth. Clotting
studies showed disseminated intravascular coagu-
lation. The baby died 15 h after delivery. This con-
dition can be related to neither diabetic pregnancy
or neonatal complications associated with bleed-
ing such as neonatal sepsis. Although some reports
suggested that neonatal bleeding disorders may be
causally related to indomethacin [ 18,241, the ma-
jority of clinical reports in the literature have fail-
ed to identify bleeding diathesis as a complication
in neonates after treatment with non-steroidal
antiinflammatory drugs. Even more, recent data
suggest that indomethacin may actually reduce the
incidence of intraventricular hemorrhage in high-
risk neonates [25]. Although in our case platelet-
aggregation was not assessed and a causal rela-
tionship can not be established, indomethacin was
administered very close to the time of delivery,
making it possible that the bleeding disorder
observed was the result of prenatal exposure to
indomethacin.
Prostaglandins are ubiquitous in the body.
Their biological activity is exerted primarily at the
site of synthesis, since they have a short half-life in
the circulation. The kidney is extremely active in
the synthesis of prostaglandins. These compounds
participate in several processes in renal physi-
ology, including autoregulation of renal blood
flow and glomerular filtration. In high-renin state,
the renal vasconstrictive influence of the renin-
angiotensin system is mitigated by its simultaneous
stimulation of vasodilatory renal prostaglandins.
Renal blood flow and glomerular filtration rate
are thus maintained. When the protective
modulating intrarenal action of prostaglandins is
Biol. 52 (1993) 175-180 179
supressed by drugs which inhibit cyclooxygenase,
impairment of renal haemodynamics may result
WI.
Although an increase in the synthesis of renal
vasodilatory prostaglandins seems to be a plausi-
ble cause of the increase in glomerular filtration
rate and renal blood flow during pregnancy (a
well-known high-renin state), various authors
(27,281 were unable to reduce the rise in
glomerular filtration rate or renal blood flow in
animals by administering inhibitors of psostaglan-
dins synthesis. However, Moise [lo] has reported
a woman who developed renal failure after in-
domethacin administration for tocolysis, and the
results of Sorensen et al. [29] indicate that treat-
ment with indomethacin increases maternal
peripheral vascular resistance, a finding consistent
with the theory that agents such as prostacyclin
exert a tonic vasodilatory effect that could be
blocked by indomethacin. In our Case 4, urinary
indices (diuresis, creatinine, blood urea nitrogen)
and urinary and plasmatic sodium were normal at
admission. In addition, the fluid intake of this
patient was normal and all parameters returned to
normality after indomethacin withdrawal. Thus,
the appearance of prerenal oliguria in our patient
on the second day of indomethacin administration
was probably caused by acute blockade of pro-
stagladin synthesis by indomethacin.
In summary, our report clearly shows that there
are definite risks for both mother and fetus when
indomethacin is used to treat polyhydramnios.
Thus, the drug should be used cautiously in cases
of polhydramnios. Its effect on the ductus
arteriosus must be monitored. AFI should be
estimated frequently in order to avoid oligohy-
dramnios. The use of indomethacin immediately
before delivery seems to increase the risks to the
newborn; thus, postponement of delivery for at
least one week at the end of treatment could pre-
vent the neonatal complications associated with
prenatal exposure to indomethacin.
5. References
Cardwell MS. Polyhydramnios: a review. Obstet Gynecol
1
Surv 1987; 42: 612-7.
2 Cabrol D, Landesman R, Muller J, Uzan M. Sureau C.
Saxena BB. Treatment of polyhydramnios with pro-
I80 F. Carmona et al. /Eur.
staglandin synthetase inhibitor (indomethacin). Am J
Obstet Gynecol 1987; 157: 422-6.
3 Mamopoulos M, Assimakopoulos E, Reece A, Andreou
A, Zheng XZ, Mantalenakis S. Maternal indomethacin
therapy in the treatment of polyhydramnios. Am J Obstet
Gynecol 1990; 162: 1225-9.
4 Rodriguez MH. Polyhydramnios: does reducing the
amniotic fluid volume decrease the incidence of prematu-
rity?. Clin Perinatol 1992; 19: 359-66.
5 Nordstrom L, Weestgren M. Indomethacin treatment for
polyhydramnios. Effective but potentially dangerous?.
Acta Obstet Gynecol Stand 1992; 71: 239-41.
6 Restaino I, Kaplan BS, Kaplan P, Rosehberg HK,
Witzleben C, Ronerts N. Renal dysgenesis in a
monozygotic twin. Association with in utero exposure to
indomethacin. Am J Med Genet 1991; 39: 252-7.
7 Smith LG Jr, Kirshon B, Cotton DB. Indomethacin treat-
ment for polyhydramnios and subsequent infantile
nephrogenic diabetes insipidus. Am J Obstet Gynecol
1990; 98-9.
8 Carlan SJ, Stromquist C, Angel JL, Harris M, O’Brien
WF. Cocaine and indomethacin: fetal anuria, neonatal
edema, and gastrointestinal bleeding. Obstet Gynecol
1991; 78: 501-3.
9 Carlson DE, Platt LD, Medearis AL, Horenstein J. Quan-
tifiable polyhydramnios: diagnosis and management.
Obstet Gynecol 1990; 75: 989-93.
IO Moise KJ Jr. lndomethacin therapy in the treatment of
symptomatic polyhydramnios. Clin Obstet Gynecol 1991;
34: 310-8.
11 Kirshon B, Mari G, Moise KJ Jr. Indomethacin therapy
in the treatment of symptomatic polyhydramnios. Obstet
Gynecol 1990; 75: 202-5.
12 Kirshon B, Cotton DB. Polyhydramnios associated with
a ring chromosome managed with indomethacin. Am J
Obstet Gynecol 1988; 158: 1063-4.
I3 Lange IR, Harman CR, Ash KM, Manning FA, Men-
ticoglou S. Twin with hydramnios: treating premature
labor at source. Am J Obstet Gynecol 1989; 160: 552-7.
14 Kirshon B, Moise KJ Jr, Wasserstrum M, Ou CN, Hutha
JC. Influence of short-term indomethacin therapy on fetal
urine output. Obstet Gynecol 1988; 72: 51-3.
I5 Kirshon B. Fetal urine output in hydramnios. Obstet
Gynecol 1989; 73: 240-2.
16 Hickok DE, Hollenbach KA, Reilley SF, Nyberg DA.
The association between decreased amniotic fluid volume
and treatment with nonsteroidal anti-inflammatory agents
for preterm labor. Am J Obstet Gynecol 1989; 160:
1525-3 I.
J. Obstet. Gynecol. Reprod. Biol. 52 (1993) I75- I80
I7 Novy MJ. Effects of indomethacin on labor, fetal ox-
ygenation, and fetal development in rhesus monkeys. Adv
Prostaglandin Thromboxane Leukotriene Res 1978; 4:
285-300.
I8 Vanhaesebrouck P, Thiery M, Leroy JG et al. Oligohy-
dramnios, renal insufficiency, and ileal perforation in
preterm infants after intrauterine exposure to in-
domethacin. J Pediatr 1988; 113: 738-43.
I9 Goldenberg RL, Davis RO, Baker RL. Indomethacin in-
duced oligohydramnios. Am J Obstet Gynecol 1989; 160:
1196-7.
20 Istkowits J, Abramovici H, Brandes JM. Oligohydram-
nios, meconium and perinatal death concurrent with in-
domethacin treatment in human pregnancy. J Reprod
Med 1980; 24: 137-40.
21 Sideris EB, Yokochi K, Van Helder T, Coceani F, Olley
PH. Effects of indomethacin and prostaglandin El, I, and
Dz on the fetal circulation. Adv Prostaglandin Throm-
boxane Leukotriene Res 1983; 12: 477-81.
22 Moise KJ Jr, Hutha JC, Sharif DS et al. Indomethacin in
the treatment of premature labor. Effects on fetal ductus
arteriosus. N Engl J Med 1988; 319: 327-31.
23 Kirshon B, Mari G, Moise KJ Jr, Wasserstrum N. Effect
of indomethacin on the fetal ductus arteriosus during
treatment of symptomatic polyhydramnios. J Reprod
Med 1990; 35: 529-32.
24 Friedman Z, Whitman V, Maisels MJ, Beman W Jr,
Marks KH, Vesell ES. Indomethacin disposition and
indomethacin-induced platelet dysfunction in premature
infants. J Clin Pharmacol 1978; 18: 272-9.
25 Hanningan WC, Kennedy G, Roemish F, Anderson D,
Cusack T, Powers W. Administration of indomethacin for
the prevention of periventricular hemorrhage in high-risk
neonates. J Pediatr 1988; 112: 941-7.
26 Clive DM, Staff JS. Renal syndromes associated with
nosteroidal antiinflammatory drugs. N Engl J Med 1984;
310: 564-72.
27 Venuto RC, Donker AJ. Prostaglandin E2, plasma renin
activity, and renal function throughout rabbit pregnancy.
J Lab Clin Med 1982; 99: 239-46.
28 Conrad KP, Colpoys MC. Evidence against the hypothe-
sis that prostaglandins are the vasodepressor agents of
pregnancy: serial studies in chronically instrumented, con-
scious rats. J Clin Invest 1986; 77: 236-45.
29 Sorensen TK, Easterling TR, Carlson KL, Brateng DA,
Benedetti TJ. The maternal hemodynamic effect of in-
domethacin in normal pregnancy. Obstet Gynecol 1992;
79: 661-3.