Documente Academic
Documente Profesional
Documente Cultură
OBJECTIVE: To compare sildenafil plus hydration with RESULTS: From February 24, 2015, through April 2016,
hydration alone in improving the amniotic fluid index 196 women were screened and 184 were randomized.
and neonatal outcomes in pregnancies complicated by Follow-up was completed in 166 (90%): 82 in the
idiopathic oligohydramnios ( amniotic fluid index less sildenafil group and 84 in the hydration group. Baseline
than 5 cm without underlying maternal or fetal causes characteristics were similar between groups. The amni-
and with normal fetal growth). otic fluid volume was higher in the sildenafil group at the
METHODS: This was an open-label randomized trial for final assessment (11.5 compared with 5.4 cm, P5.02). The
women carrying singleton pregnancies at 30 weeks of sildenafil group delivered later (38.3 compared with 36.0
gestation or more with idiopathic oligohydramnios de- weeks of gestation, P5.001), had a lower rate of cesarean
tected during routine ultrasonogram. Women received delivery (28% compared with 73%), and their neonates
either oral sildenafil citrate (25 mg every 8 hours) plus were less likely to be admitted to the neonatal intensive
intravenous infusion of 2 L isotonic solution or fluids care unit (11% compared with 41%, P5.001).
only until delivery. The primary study outcome was the CONCLUSION: Sildenafil citrate increases amniotic fluid
amniotic fluid volume at 6 weeks of follow-up or the final volume in pregnancies complicated by oligohydramnios.
volume before delivery, whichever occurred first. Second-
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,
ary outcomes were duration of pregnancy prolongation,
www.clinicaltrials.gov, NCT02372487.
mode of delivery, and select neonatal outcomes. The
(Obstet Gynecol 2017;129:615–20)
study was powered to detect a 45% difference between
DOI: 10.1097/AOG.0000000000001928
groups, so, at an a level of 0.05 and 80% power, a sample
O
size of 167 women was required.
ligohydramnios without membranes rupture is
defined as amniotic fluid index (AFI) of less than
5 cm or AFI below the 5th percentile for gestational
From the Obstetrics and Gynecology Department, Faculty of Medicine, Menoufia age. It complicates 3–5% of all pregnancies and may be
University, Shebin-Elkom, Egypt. secondary to ruptured membranes, placental insuffi-
The authors thank all nurses, doctors, study coordinators, and hospital staff at the ciency, congenital anomalies such as bilateral renal
Obstetrics and Gynecology Department and Radiology Department, Faculty of agenesis, postterm, drugs as prostaglandin synthase
Medicine, Menoufia University, Shebin-Elkom, Egypt, who helped in diagnosing,
admitting, and monitoring patients during the hospital treatment until their inhibitors, twin-to-twin transfusion, fetal demise, or
discharge as well as during data collection, and Dr. Sally Waheed El-khadry, idiopathic.1
assistant lecturer of epidemiology and biostatistics at National Liver Institute, The pathophysiology of oligohydramnios is not
Menoufia University, Shebin-Elkom, Egypt, who performed the statistical part of
the manuscript. well understood, but when detected in the absence of
Each author has indicated that he or she has met the journal’s requirements for rupture of membranes has been considered to be
authorship. a sign of chronic suboptimal placental function.2
Corresponding author: Mohammad Ahmed Maher, MD, Obstetrics and Sildenafil citrate (Viagra) is a selective inhibitor of
Gynaecology, Faculty of Medicine, Menoufia University, Gamal Abdel Nasser the type V cyclic guanosine monophosphate-specific
Street, Shebin Elkom, Egypt; email: mohamaher2010@yahoo.com.
phosphodiesterase. Sildenafil enhances the effect of
Financial Disclosure
The authors did not report any potential conflicts of interest.
nitric oxide by inhibiting phosphodiesterase type 5,
which is responsible for degradation of cyclic guano-
© 2017 by The American College of Obstetricians and Gynecologists. Published
by Wolters Kluwer Health, Inc. All rights reserved. sine monophosphate. With the use of sildenafil, cyclic
ISSN: 0029-7844/17 guanosine monophosphate levels remain elevated,
which leads to vascular relaxation and increased using GE Voluson 730 with an abdominal convex
uterine blood flow.3 probe of 3.5 MHz. This ultrasonographer was
The aim of our study was to compare sildenafil blinded to the treatment groups and performed
hydration therapy with hydration alone in improving AFI measurements in a standardized fashion.4 Mea-
the AFI in pregnancies complicated by idiopathic surement of AFI was performed twice on each occa-
oligohydramnios and to assess pregnancy outcomes of sion, and mean AFI was obtained by averaging the
both groups. two measurements.
All participants were admitted for at least 24
MATERIALS AND METHODS hours for intravenous hydration therapy. Patients in
This was an open-label randomized trial approved by the sildenafil–hydration group received sildenafil cit-
the institutional review board at Menoufia University rate as 25 mg every 8 hours orally plus an intravenous
Hospitals and registered at Clinical Trials.gov: infusion of 2 L isotonic solution over a period of 4
NCT02372487. All participants provided written hours (250 mL/h), whereas patients in the hydration-
informed consent. Eligible women had a singleton only group received the intravenous infusion alone.
pregnancy, at a gestational age of 30 weeks or more, During hospitalization, maternal monitoring was done
with an AFI less than 5 cm, which was discovered for early detection of any manifestations of fluid over-
during routine third-trimester ultrasonography. load, whereas fetal monitoring was done using non-
Oligohydramnios associated with fetal growth stress tests. Any patient less than 34 completed weeks
restriction or anomalies, or with abnormal fetal of gestation received dexamethasone in a total dose of
Doppler or a nonreactive nonstress test, treatment 24 mg to enhance fetal lung maturity in case expe-
with prostaglandin synthase inhibitors, rupture of dited delivery was needed.
membranes, active labor, chronic hypertension, pre- Patients in both groups had ultrasonography 24
gestational diabetes, or maternal diseases contraindi- hours after receiving the hospital treatment to reassess
cating bolus fluid therapy (kidney, lung, or heart AFI and those who showed improvement of at least
disease) were all exclusion criteria. 20% were discharged home; for those who showed no
Enrolled women were randomly allocated to one improvement, the same regimen to which they were
of two treatment groups (sildenafil hydration or assigned was repeated.
hydration alone) according to a trial sequence deter- Discharged patients in the sildenafil–hydration
mined through a computer-generated random num- group were asked to continue sildenafil as 25 mg
ber table. Group allocation occurred through the use three times daily plus a daily oral fluid intake of 2 L,
of opaque sequenced envelopes; each envelope con- whereas those in the hydration-only group were in-
tained an assignment for a single patient. structed to drink 2 L of fluids daily. Outpatient mon-
One ultrasonographer was assigned to evaluate all itoring in both groups consisted of twice weekly
participants (to eliminate the interobserver variation) nonstress tests and once weekly AFI and biophysical
profiles. Readmission was advised for persistent delivery interval, mode of delivery, gestational age at
decreased fetal movement or an abnormal nonstress birth, and neonatal outcomes (neonatal weight, Apgar
test. Increased bed rest and daily fetal kicks were rec- scores, umbilical artery pH, and admission to the
ommended for all patients. neonatal intensive care unit).
The primary study outcome was the amniotic In a randomized trial, maternal hydration therapy
fluid volume at 6 weeks of follow-up or the final increased the mean AFI by 30%.5 We assumed that
volume before delivery, whichever occurred first. sildenafil when combined with hydration would
Secondary outcome measures were randomization to increase the AFI by 45%. At a two-sided a level of
VOL. 129, NO. 4, APRIL 2017 Maher et al Effect of Sildenafil Citrate on Oligohydramnios 617
0.05 with study power of 80%, a sample size of 167 Kaplan–Meier estimate was used to detect the pro-
women was required, but this sample size was portion of deliveries at different gestational ages
increased to 184 women after considering a possible among the studied participants; comparison of the two
dropout rate of 10%. survival curves was done using a log-rank test.
Results were collected, tabulated, and statistically
analyzed using SPSS 20. Qualitative data were ex- RESULTS
pressed as percentages and x2 test or Fisher exact test From February 24, 2015, through April 2016, 196
was used to test for differences as appropriate. Quan- women were screened and 184 were randomized.
titative data were examined using the Kolmogorov- Follow-up was completed in 166 (90%): 82 in the
Smirnov test to detect whether the data were normally sildenafil group and 84 in the hydration group (Fig. 1).
distributed; parametric data were expressed as the The groups had similar baseline characteristics
mean6standard deviation and Student t test was used (Table 1).
for comparison; nonparametric data were expressed The amniotic fluid volume was higher in the
as median (range) and Mann-Whitney test was used sildenafil group at the final assessment (11.5 com-
for their comparison. P values ,.05 were considered pared with 5.4 cm, P5.02). A significant difference in
significant. Odds ratio and 95% confidence interval the rate of remaining undelivered was detected from 3
were calculated for qualitative data (if possible). A weeks onward for those allocated to sildenafil
VOL. 129, NO. 4, APRIL 2017 Maher et al Effect of Sildenafil Citrate on Oligohydramnios 619