Вы находитесь на странице: 1из 6

Original Research

Sildenafil Citrate Therapy


for Oligohydramnios
A Randomized Controlled Trial
Mohammad Ahmed Maher, MD, Tarek Mohammad Sayyed, MD, and Nabih Elkhouly, MD

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,

VOL. 129, NO. 4, APRIL 2017 OBSTETRICS & GYNECOLOGY 615

Copyright ª by The American College of Obstetricians


and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
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 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

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

Copyright ª by The American College of Obstetricians


and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
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 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

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

VOL. 129, NO. 4, APRIL 2017 Maher et al Effect of Sildenafil Citrate on Oligohydramnios 617

Copyright ª by The American College of Obstetricians


and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
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 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

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

Copyright ª by The American College of Obstetricians


and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
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– Fig. 3. Kaplan–Meier estimate for the proportion of deliv-
eries at different gestational ages among the study partic-
hydration group (Fig. 3; P for log rank test,.001; ipants. Comparison of the two survival curves was done
Table 2). Maternal and neonatal outcomes were gen- using a log-rank test (P5.001).
erally better in the sildenafil–hydration group Maher. Effect of Sildenafil Citrate on Oligohydramnios. Obstet
(Table 3). Gynecol 2017.
The adverse effects reported in sildenafil–
hydration group were similar to that reported in the
hydration-only group and included headaches and 25 pregnant women at 3, 24, and 48 hours after hydra-
flushing. These were self-limited and did not require tion and stated that although hydration increased AFI,
treatment. this effect lasted less than 24 hours. Again, Wolman
et al8 demonstrated that although fasting reduced the
DISCUSSION AFI, this effect lasted for only 1 week. However, oral
The results of the current study have shown an hydration therapy by Ghafarnejad et al9 maintained
improvement in AFI after intravenous hydration, the significantly increased AFI after 48 hours and 1
which was not maintained unless sildenafil citrate week after therapy.
was added. However, our study did not address the Considering the enigma of idiopathic oligohy-
exact mechanism by which sildenafil can maintain dramnios, although our results showed improved out-
such increment, which is not fully understood. We comes in women treated with hydration plus sildenafil,
suggest that maternal hydration and sildenafil vasodi- other authors did not confirm such results. Kreiser
latation may result in improved uteroplacental perfu- et al10 compared the outcomes of 57 pregnancies with
sion, causing increased fetal renal blood flow and fetal AFI 5 cm or less with 93 pregnancies with AFI greater
urine production that maintained the increased AFI. than 5 cm but less than the 2.5th centile (borderline
These improvements in AFI were associated with AFI) and they concluded that with close antepartum
better obstetric and neonatal outcomes. monitoring (one to three times weekly), the perinatal
Maintaining such an increase in AFI is the main outcome in low-risk pregnancies with isolated oligohy-
problem facing treating physicians because the coun- dramnios appears to be good with the only abnormal-
terregulatory mechanisms in the form of increased ity being more common antepartum variable
intramembranous absorption and fetal swallowing decelerations with AFI 5 cm or less (63.1% compared
will start to work shortly after the increase of AFI with 45.1%; P5.007). Also, Conway et al11 found iso-
has been issued.6 Malhotra and Deka7 assessed AFI of lated oligohydramnios in normal term pregnancy not

VOL. 129, NO. 4, APRIL 2017 Maher et al Effect of Sildenafil Citrate on Oligohydramnios 619

Copyright ª by The American College of Obstetricians


and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
to be a marker for fetal compromise and only cesarean standardized during hospital therapy, so contribution
delivery rates were significantly higher with otherwise of this factor to increased AFI was not certain; 4)
comparable neonatal outcomes, but they reported that compliance with treatment was not assessed; 5) the
the increased need for operative delivery was not characteristics of amniotic fluid, such as solute con-
attributable to an increase in fetal distress in the oligo- tents after treatment, were not studied; 6) only AFI
hydramnios group. The difference between our find- indices and not the actual amniotic fluid volume were
ings and what was reported by these authors may be used to reflect improvement after therapy; and 7) no
because our patients could represent a group of late placebo was given to the hydration-only group.
placental insufficiency in which fetuses do not neces- In conclusion, our findings suggested that sildenafil
sarily become growth-restricted under the definition of may offer a new opportunity to improve pregnancy
less than the 10th centile. Neonatal outcomes, there- outcomes for women with oligohydramnios.
fore, improved markedly when sildenafil was added,
hence the importance of the study in showing sildenafil REFERENCES
effect in late fetal growth restriction. 1. McCurdy CM Jr, Seeds JW. Oligohydramnios: problems and
Regarding the effective dose and administration treatment. Semin Perinatol 1993;17:183–96.
regimen of sildenafil, data in pregnancy are limited; 2. Underwood MA, Gilbert WM, Sherman MP. Amniotic fluid:
the circulating plasma volume is increased in preg- not just fetal urine any more. J Perinatol 2005;25:341–8.
nancy, which may alter the drug pharmacokinetics. 3. Wareing M, Myers JE, O’Hara M, Baker PN. Sildenafil citrate
The data suggested that 100 mg sildenafil produces (Viagra) enhances vasodilatation in fetal growth restriction.
J Clin Endocrinol Metab 2005;90:2550–5.
a plasma concentration in excess of 100 nmol/L for 4–
4. Ülker K, Özdemir IA._ The relation of intrapartum amniotic
5 hours after oral dosage,12 a concentration that is fluid index to perinatal outcomes. Kafkas J Med Sci 2011;1:
100-fold less than that required for nonspecific inhibi- 1–7.
tion of other phosphodiesterase isoforms.13 5. Kilpatrick SJ, Safford KL, Pomeroy T, Hoedt L, Scheerer L,
Common adverse reactions associated with silde- Laros RK. Maternal hydration increases amniotic fluid index.
nafil administration are headache, flushing, dyspepsia, Obstet Gynecol 1991;78:1098–102.
nasal congestion, urinary tract infection, and diarrhea, 6. Doi S, Osada H, Seki K, Sekiya S. Effect of maternal hydration
on oligohydramnios: a comparison of three volume expansion
which have been reported by clinical trials.12 Regard- methods. Obstet Gynecol 1998;92:525–9.
ing its risks, a systematic review14 found no terato- 7. Malhotra B, Deka D. Duration of the increase in amniotic fluid
genic or fetotoxic effects in experimental animal index (AFI) after acute maternal hydration. Arch Gynecol
models at dose levels much higher than those used Obstet 2004;269:173–5.
in humans, and case reports in pregnant women did 8. Wolman I, Groutz A, Gull I, Gordon D, Geva E, Lessing JB,
not show any deleterious effects on the mother or et al. Is amniotic fluid influenced by a 24-hour fast? J Reprod
Med 2000;45:685–7.
offspring exposed late in utero when administered in
9. Ghafarnejad M, Tehrani MB, Anaraki FB, Mood NI, Nasehi L.
the third trimester with the risk for gross malforma- Oral hydration therapy in oligohydramnios. Obstet Gynaecol
tions almost over. Res 2009;35:895–900.
The strengths of our study include the following: 10. Kreiser D, el-Sayed Y, Sorem KA, Chitkara U, Holbrook RH
1) it was randomized with adequate randomization Jr, Druzin ML. Decreased amniotic fluid index in low-risk preg-
method (computer-based), 2) a power calculation was nancy. J Reprod Med 2001;46:743–6.
performed, 3) determination of either persistently or 11. Conway DL, Adkins WB, Schroeder B, Langer O. Isolated
oligohydramnios in the term pregnancy: is it a clinical entity?
just temporarily increased AFI by continually follow- J Matern Fetal Med 1998;7:197–200.
ing patients until delivery, 4) a wide range of 12. Boyce EG, Umland EM. Sildenafil citrate: a therapeutic update.
gestational ages were included (30 weeks or more), Clin Ther 2001;23:2–23.
and 5) the clinical importance of improving AFI was 13. Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution
assessed. However, there are still negative aspects: 1) of phosphodiesterase families and the effects of sildenafil on
AFI measurement is subjective and difficult as a result tissue cyclic nucleotides, platelet function, and the contractile
responses of trabeculae carneae and aortic rings in vitro. Am J
of fetal movement, with poor correlation between Cardiol 1999;83:3C–12C.
ultrasonography and actual amniotic fluid volume,15 14. Villanueva-García D, Mota-Rojas D, Hernández-González R,
which makes these findings less than reliable; how- Sánchez-Aparicio P, Alonso-Spilsbury M, Trujillo-Ortega ME,
ever, we tried to overcome such difficulties by select- et al. A systematic review of experimental and clinical studies of
sildenafil citrate for intrauterine growth restriction and pre-term
ing an ultrasonographer blinded to the treatment labour. J Obstet Gynaecol 2007;27:255–9.
arms; 2) normal pregnancies before 30 weeks of ges-
15. Horsager R, Nathan L, Leveno KJ. Correlation of measured
tation and pregnancies with maternal or fetal compli- amniotic fluid volume and sonographic predictions of oligohy-
cations were excluded; 3) maternal position was not dramnios. Obstet Gynecol 1994;83:955–8.

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

Copyright ª by The American College of Obstetricians


and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.