Original Research
Sildenafil Citrate Therapy
for Oligohydramnios
A Randomized Controlled Trial
Mohammad Ahmed Maher, MD, Tarek Mohammad Sayyed,
OBJECTIVE: To compare sildenafil plus hydration with
hydration alone in improving the amniotic fluid index
and neonatal outcomes in pregnancies complicated by
idiopathic oligohydramnios ( amniotic fluid index less
than 5 cm without underlying maternal or fetal causes
and with normal fetal growth).
METHODS: This was an open-label randomized trial for
women carrying singleton pregnancies at 30 weeks of
gestation or more with idiopathic oligohydramnios de-
tected during routine ultrasonogram. Women received
either oral sildenafil citrate (25 mg every 8 hours) plus
intravenous infusion of 2 L isotonic solution or fluids
only until delivery. The primary study outcome was the
amniotic fluid volume at 6 weeks of follow-up or the final
volume before delivery, whichever occurred first. Second-
ary outcomes were duration of pregnancy prolongation,
mode of delivery, and select neonatal outcomes. The
study was powered to detect a 45% difference between
groups, so, at an a level of 0.05 and 80% power, a sample
size of 167 women was required.
From the Obstetrics and Gynecology Department, Faculty of Medicine, Menoufia
University, Shebin-Elkom, Egypt.
The authors thank all nurses, doctors, study coordinators, and hospital staff at the
Obstetrics and Gynecology Department and Radiology Department, Faculty of
Medicine, Menoufia University, Shebin-Elkom, Egypt, who helped in diagnosing,
admitting, and monitoring patients during the hospital treatment until their
discharge as well as during data collection, and Dr. Sally Waheed El-khadry,
assistant lecturer of epidemiology and biostatistics at National Liver Institute,
Menoufia University, Shebin-Elkom, Egypt, who performed the statistical part of
the manuscript.
Each author has indicated that he or she has met the journal’s requirements for
authorship.
Corresponding author: Mohammad Ahmed Maher, MD, Obstetrics and
Gynaecology, Faculty of Medicine, Menoufia University, Gamal Abdel Nasser
Street, Shebin Elkom, Egypt; email: mohamaher2010@yahoo.com.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2017 by The American College of Obstetricians and Gynecologists. Published
by Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0029-7844/17
VOL. 129, NO. 4, APRIL 2017
Copyright ª by The American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
MD, and Nabih Elkhouly, MD
RESULTS: From February 24, 2015, through April 2016,
196 women were screened and 184 were randomized.
Follow-up was completed in 166 (90%): 82 in the
sildenafil group and 84 in the hydration group. Baseline
characteristics were similar between groups. The amni-
otic fluid volume was higher in the sildenafil group at the
final assessment (11.5 compared with 5.4 cm, P5.02). The
sildenafil group delivered later (38.3 compared with 36.0
weeks of gestation, P5.001), had a lower rate of cesarean
delivery (28% compared with 73%), and their neonates
were less likely to be admitted to the neonatal intensive
care unit (11% compared with 41%, P5.001).
CONCLUSION: Sildenafil citrate increases amniotic fluid
volume in pregnancies complicated by oligohydramnios.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,
www.clinicaltrials.gov, NCT02372487.
(Obstet Gynecol 2017;129:615–20)
DOI: 10.1097/AOG.0000000000001928
O
ligohydramnios without membranes rupture is
defined as amniotic fluid index (AFI) of less than
5 cm or AFI below the 5th percentile for gestational
age. It complicates 3–5% of all pregnancies and may be
secondary to ruptured membranes, placental insuffi-
ciency, congenital anomalies such as bilateral renal
agenesis, postterm, drugs as prostaglandin synthase
inhibitors, twin-to-twin transfusion, fetal demise, or
idiopathic.1
The pathophysiology of oligohydramnios is not
well understood, but when detected in the absence of
rupture of membranes has been considered to be
a sign of chronic suboptimal placental function.2
Sildenafil citrate (Viagra) is a selective inhibitor of
the type V cyclic guanosine monophosphate-specific
phosphodiesterase. Sildenafil enhances the effect of
nitric oxide by inhibiting phosphodiesterase type 5,
which is responsible for degradation of cyclic guano-
sine monophosphate. With the use of sildenafil, cyclic
guanosine monophosphate levels remain elevated,
OBSTETRICS & GYNECOLOGY 615
Fig. 1. The randomization process, treatment, and follow-up of the study participants.
Maher. Effect of Sildenafil Citrate on Oligohydramnios. Obstet Gynecol 2017.

which leads to vascular relaxation and increased
uterine blood flow.3
The aim of our study was to compare sildenafil
hydration therapy with hydration alone in improving
the AFI in pregnancies complicated by idiopathic
oligohydramnios and to assess pregnancy outcomes of
both groups.
MATERIALS AND METHODS
This was an open-label randomized trial approved by
the institutional review board at Menoufia University
Hospitals and registered at Clinical Trials.gov:
NCT02372487. All participants provided written
informed consent. Eligible women had a singleton
pregnancy, at a gestational age of 30 weeks or more,
with an AFI less than 5 cm, which was discovered
during routine third-trimester ultrasonography.
Oligohydramnios associated with fetal growth
restriction or anomalies, or with abnormal fetal
Doppler or a nonreactive nonstress test, treatment
with prostaglandin synthase inhibitors, rupture of
membranes, active labor, chronic hypertension, pre-
gestational diabetes, or maternal diseases contraindi-
cating bolus fluid therapy (kidney, lung, or heart
disease) were all exclusion criteria.
Enrolled women were randomly allocated to one
of two treatment groups (sildenafil hydration or
hydration alone) according to a trial sequence deter-
mined through a computer-generated random num-
ber table. Group allocation occurred through the use
of opaque sequenced envelopes; each envelope con-
tained an assignment for a single patient.
One ultrasonographer was assigned to evaluate all
participants (to eliminate the interobserver variation)
using GE Voluson 730 with an abdominal convex
probe of 3.5 MHz. This ultrasonographer was
blinded to the treatment groups and performed
AFI measurements in a standardized fashion.4 Mea-
surement of AFI was performed twice on each occa-
sion, and mean AFI was obtained by averaging the
two measurements.
All participants were admitted for at least 24
hours for intravenous hydration therapy. Patients in
the sildenafil–hydration group received sildenafil cit-
rate as 25 mg every 8 hours orally plus an intravenous
infusion of 2 L isotonic solution over a period of 4
hours (250 mL/h), whereas patients in the hydration-
only group received the intravenous infusion alone.
During hospitalization, maternal monitoring was done
for early detection of any manifestations of fluid over-
load, whereas fetal monitoring was done using non-
stress tests. Any patient less than 34 completed weeks
of gestation received dexamethasone in a total dose of
24 mg to enhance fetal lung maturity in case expe-
dited delivery was needed.
Patients in both groups had ultrasonography 24
hours after receiving the hospital treatment to reassess
AFI and those who showed improvement of at least
20% were discharged home; for those who showed no
improvement, the same regimen to which they were
assigned was repeated.
Discharged patients in the sildenafil–hydration
group were asked to continue sildenafil as 25 mg
three times daily plus a daily oral fluid intake of 2 L,
whereas those in the hydration-only group were in-
structed to drink 2 L of fluids daily. Outpatient mon-
itoring in both groups consisted of twice weekly
nonstress tests and once weekly AFI and biophysical

616 Maher et al Effect of Sildenafil Citrate on Oligohydramnios OBSTETRICS & GYNECOLOGY

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Table 1. Baseline Characteristics of the Study Participants

Characteristic Sildenafil–Hydration Group (n582) Hydration-Only Group (n584)

Maternal age (y) 29 (20–46) 31 (20–43)

Parity 2 (0–7) 2 (0–6)
BMI (kg/m2) 24.962.3 24.962.1
Mode of conception
Spontaneous 79 (96.3) 77 (91.7)
ART 3 (3.7) 7 (8.3)
Gestational age at randomization (wk) 32.4 (30.1–35.3) 32.4 (30.4–35.9)
AFI at randomization (cm) 3.660.7 3.460.7
BMI, body mass index; ART, assisted reproductive technology; AFI, amniotic fluid index.
Data are median (range), mean6standard deviation, or n (%).

profiles. Readmission was advised for persistent
decreased fetal movement or an abnormal nonstress
test. Increased bed rest and daily fetal kicks were rec-
ommended for all patients.
The primary study outcome was the amniotic
fluid volume at 6 weeks of follow-up or the final
volume before delivery, whichever occurred first.
Secondary outcome measures were randomization to
delivery interval, mode of delivery, gestational age at
birth, and neonatal outcomes (neonatal weight, Apgar
scores, umbilical artery pH, and admission to the
neonatal intensive care unit).
In a randomized trial, maternal hydration therapy
increased the mean AFI by 30%.5 We assumed that
sildenafil when combined with hydration would
increase the AFI by 45%. At a two-sided a level of

Table 2. Results After Therapy

Result Sildenafil–Hydration Group (n582) Hydration-Only Group (n584) P

Duration of admission (d) 1 (1–2) 1 (1–3) .84*

No. of readmissions
0 74 (90.2) 41 (48.8) .001†
1 8 (9.8) 30 (35.7)
2 0 13 (15.5)
Complications during therapy 0 0 —
AFI after 1st treatment (cm) 6.6 (5.5–7.6) 6.5 (5–7) .07*
Difference in AFI (cm) 2.8 (1.3–4.7) 2.9 (1.1–4.4) .725*
After 1 wk
No. remaining 82 (100) 84 (100) —
AFI (cm) 8.260.7 6.360.6 .001‡
After 2 wk
No. remaining 82 (100) 83 (98.9) .322†
AFI (cm) 9 (6–12) 5.4 (3–7) .001*
After 3 wk
No. remaining 82 (100) 67 (79.8) .001§
AFI (cm) 9.85 (4–13) 5.25 (2–7) .001*
After 4 wk
No. remaining 76 (92.7) 28 (33.3) .001§
AFI (cm) 10.8 (5–15) 5.25 (2–7) .001*
After 5 wk
No. remaining 65 (79.3) 6 (7.1) .001§
AFI (cm) 11.5 (5–15) 4.45 (3–6) .001*
After 6 wk
No. remaining 33 (40.2) 2 (2.4) .001§
AFI (cm) 11.5 (8–15) 5.35 (5–6) .02*
AFI, amniotic fluid index.
Data are median (range), mean6standard deviation, or n (%).
* Mann-Whitney test.
†
Fisher exact test.
‡
Student t test.
x test.
§ 2

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Table 3. Maternal and Fetal Outcomes According to Treatment Assignment

Sildenafil–Hydration Group Hydration-Only Group

Outcome (n582) (n584) P OR (95% CI)

Gestational age at delivery (wk) 38.29 (36.6–40.1) 35.95 (33.4–38.9) .001*

Pregnancy prolongation (d) 40 (22–63) 22 (10–42) .001*
Meconium staining 11 (13.4) 47 (56.0) .001†
Type of delivery
Spontaneous 71 (86.6) 36 (42.9)
Indicated 11 (13.4) 48 (57.1)
Abnormal CTG 3 (3.7) 40 (47.6) .001†
Abnormal Doppler 0 4 (4.8)
Antepartum hemorrhage 1 (1.2) 0
ROM 5 (6.1) 4 (4.8)
PIH 2 (2.4) 0
Mode of delivery
Spontaneous vaginal 55 (67.1) 22 (26.2)
Instrumental 4 (4.9) 1 (1.2) .001‡
Cesarean 23 (28.0) 61 (72.6)
Causes of cesarean delivery
Repeat 16 (69.7) 13 (21.2)
Failure to progress 3 (13.0) 4 (6.6)
Abnormal CTG 3 (13.0) 40 (65.6) .001‡
Abnormal Doppler 0 4 (6.6)
Preterm breech 1 (4.3) 0
5-min Apgar score less than 7 8 (9.8) 26 (31.0) .001† 0.2 (0.1–0.6)
Umbilical artery pH less than 7.2 6 (7.3) 17 (20.2) .016† 0.3 (0.1–0.8)
Neonatal weight (g) 2,742.76252.4 2,335.76317.0 .001§
Admission to NICU 9 (11.0) 34 (40.5) .001† 0.2 (0.1–0.4)
Length of NICU stay (d) 0.461.2 2.062.7 .001*
0 (0–6) 0 (0–10)
Neonatal mortality 0 0
Potential side effects 0 0
OR, odds ratio; CI, confidence interval; CTG, cardiotocography; ROM, rupture of membranes; PIH, pregnancy-induced hypertension;
NICU, neonatal intensive care unit.
Data expressed as mean6standard deviation, median (range), or n (%).
* Mann-Whitney test.
† 2
x test.
‡
Fisher exact test.
§
Student t test.

0.05 with study power of 80%, a sample size of 167
women was required, but this sample size was
increased to 184 women after considering a possible
dropout rate of 10%.
Results were collected, tabulated, and statistically
analyzed using SPSS 20. Qualitative data were ex-
pressed as percentages and x2 test or Fisher exact test
was used to test for differences as appropriate. Quan-
titative data were examined using the Kolmogorov-
Smirnov test to detect whether the data were normally
distributed; parametric data were expressed as the
mean6standard deviation and Student t test was used
for comparison; nonparametric data were expressed
as median (range) and Mann-Whitney test was used
for their comparison. P values ,.05 were considered
significant. Odds ratio and 95% confidence interval
were calculated for qualitative data (if possible). A
Kaplan–Meier estimate was used to detect the pro-
portion of deliveries at different gestational ages
among the studied participants; comparison of the two
survival curves was done using a log-rank test.
RESULTS
From February 24, 2015, through April 2016, 196
women were screened and 184 were randomized.
Follow-up was completed in 166 (90%): 82 in the
sildenafil group and 84 in the hydration group (Fig. 1).
The groups had similar baseline characteristics
(Table 1).
The amniotic fluid volume was higher in the
sildenafil group at the final assessment (11.5 com-
pared with 5.4 cm, P5.02). A significant difference in
the rate of remaining undelivered was detected from 3
weeks onward for those allocated to sildenafil

618 Maher et al Effect of Sildenafil Citrate on Oligohydramnios OBSTETRICS & GYNECOLOGY

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Fig. 2. Median amniotic fluid index values at randomiza-
tion and during follow-up for 6 weeks. Numbers at the
points denote number remaining at each week for both
groups.
Maher. Effect of Sildenafil Citrate on Oligohydramnios. Obstet
Gynecol 2017.
(P,.001; Fig. 2). Thus, women in the hydration-only
group delivered earlier than those in the sildenafil–
hydration group (Fig. 3; P for log rank test,.001;
Table 2). Maternal and neonatal outcomes were gen-
erally better in the sildenafil–hydration group
(Table 3).
The adverse effects reported in sildenafil–
hydration group were similar to that reported in the
hydration-only group and included headaches and
flushing. These were self-limited and did not require
treatment.
DISCUSSION
The results of the current study have shown an
improvement in AFI after intravenous hydration,
which was not maintained unless sildenafil citrate
was added. However, our study did not address the
exact mechanism by which sildenafil can maintain
such increment, which is not fully understood. We
suggest that maternal hydration and sildenafil vasodi-
latation may result in improved uteroplacental perfu-
sion, causing increased fetal renal blood flow and fetal
urine production that maintained the increased AFI.
These improvements in AFI were associated with
better obstetric and neonatal outcomes.
Maintaining such an increase in AFI is the main
problem facing treating physicians because the coun-
terregulatory mechanisms in the form of increased
intramembranous absorption and fetal swallowing
will start to work shortly after the increase of AFI
has been issued.6 Malhotra and Deka7 assessed AFI of
VOL. 129, NO. 4, APRIL 2017
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Fig. 3. Kaplan–Meier estimate for the proportion of deliv-
eries at different gestational ages among the study partic-
ipants. Comparison of the two survival curves was done
using a log-rank test (P5.001).
Maher. Effect of Sildenafil Citrate on Oligohydramnios. Obstet
Gynecol 2017.
25 pregnant women at 3, 24, and 48 hours after hydra-
tion and stated that although hydration increased AFI,
this effect lasted less than 24 hours. Again, Wolman
et al8 demonstrated that although fasting reduced the
AFI, this effect lasted for only 1 week. However, oral
hydration therapy by Ghafarnejad et al9 maintained
the significantly increased AFI after 48 hours and 1
week after therapy.
Considering the enigma of idiopathic oligohy-
dramnios, although our results showed improved out-
comes in women treated with hydration plus sildenafil,
other authors did not confirm such results. Kreiser
et al10 compared the outcomes of 57 pregnancies with
AFI 5 cm or less with 93 pregnancies with AFI greater
than 5 cm but less than the 2.5th centile (borderline
AFI) and they concluded that with close antepartum
monitoring (one to three times weekly), the perinatal
outcome in low-risk pregnancies with isolated oligohy-
dramnios appears to be good with the only abnormal-
ity being more common antepartum variable
decelerations with AFI 5 cm or less (63.1% compared
with 45.1%; P5.007). Also, Conway et al11 found iso-
lated oligohydramnios in normal term pregnancy not
Maher et al Effect of Sildenafil Citrate on Oligohydramnios 619
to be a marker for fetal compromise and only cesarean
delivery rates were significantly higher with otherwise
comparable neonatal outcomes, but they reported that
the increased need for operative delivery was not
attributable to an increase in fetal distress in the oligo-
hydramnios group. The difference between our find-
ings and what was reported by these authors may be
because our patients could represent a group of late
placental insufficiency in which fetuses do not neces-
sarily become growth-restricted under the definition of
less than the 10th centile. Neonatal outcomes, there-
fore, improved markedly when sildenafil was added,
hence the importance of the study in showing sildenafil
effect in late fetal growth restriction.
Regarding the effective dose and administration
regimen of sildenafil, data in pregnancy are limited;
the circulating plasma volume is increased in preg-
nancy, which may alter the drug pharmacokinetics.
The data suggested that 100 mg sildenafil produces
a plasma concentration in excess of 100 nmol/L for 4–
5 hours after oral dosage,12 a concentration that is
100-fold less than that required for nonspecific inhibi-
tion of other phosphodiesterase isoforms.13
Common adverse reactions associated with silde-
nafil administration are headache, flushing, dyspepsia,
nasal congestion, urinary tract infection, and diarrhea,
which have been reported by clinical trials.12 Regard-
ing its risks, a systematic review14 found no terato-
genic or fetotoxic effects in experimental animal
models at dose levels much higher than those used
in humans, and case reports in pregnant women did
not show any deleterious effects on the mother or
offspring exposed late in utero when administered in
the third trimester with the risk for gross malforma-
tions almost over.
The strengths of our study include the following:
1) it was randomized with adequate randomization
method (computer-based), 2) a power calculation was
performed, 3) determination of either persistently or
just temporarily increased AFI by continually follow-
ing patients until delivery, 4) a wide range of
gestational ages were included (30 weeks or more),
and 5) the clinical importance of improving AFI was
assessed. However, there are still negative aspects: 1)
AFI measurement is subjective and difficult as a result
of fetal movement, with poor correlation between
ultrasonography and actual amniotic fluid volume,15
which makes these findings less than reliable; how-
ever, we tried to overcome such difficulties by select-
ing an ultrasonographer blinded to the treatment
arms; 2) normal pregnancies before 30 weeks of ges-
tation and pregnancies with maternal or fetal compli-
cations were excluded; 3) maternal position was not
620 Maher et al Effect of Sildenafil Citrate on Oligohydramnios
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standardized during hospital therapy, so contribution
of this factor to increased AFI was not certain; 4)
compliance with treatment was not assessed; 5) the
characteristics of amniotic fluid, such as solute con-
tents after treatment, were not studied; 6) only AFI
indices and not the actual amniotic fluid volume were
used to reflect improvement after therapy; and 7) no
placebo was given to the hydration-only group.
In conclusion, our findings suggested that sildenafil
may offer a new opportunity to improve pregnancy
outcomes for women with oligohydramnios.
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