Oligohydramnios 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 insufficiency, 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 guanosine monophosphate. With the use of sildenafil, cyclic guanosine monophosphate levels remain elevated, 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, pregestational diabetes, or maternal diseases contraindicating 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 determined through a computer-generated random number table. Group allocation occurred through the use of opaque sequenced envelopes; each envelope contained 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 Measurement of AFI was performed twice on each occasion, 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 citrate 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 overload, whereas fetal monitoring was done using nonstress 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 expedited 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 instructed to drink 2 L of fluids daily. Outpatient monitoring in both groups consisted of twice weekly nonstress tests and once weekly AFI and biophysical profiles. Readmission was advised for persistent decreased fetal movement or an abnormal nonstress test. Increased bed rest and daily fetal kicks were recommended 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 α level of 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 expressed as percentages and χ2 test or Fisher exact test was used to test for differences as appropriate. Quantitative data were examined using the Kolmogorov-Smirnov test to detect whether the data were normally distributed; parametric data were expressed as the mean±standard 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 proportion of deliveries at different gestational ages among the studied participants; comparison of the two survival curves was done using a log-rank test.
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 compared with 5.4 cm, P=.02). A significant difference in the rate of remaining undelivered was detected from 3 weeks onward for those allocated to sildenafil (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 generally 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.
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 vasodilatation may result in improved uteroplacental perfusion, 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 counterregulatory 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 25 pregnant women at 3, 24, and 48 hours after hydration 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 oligohydramnios, although our results showed improved outcomes 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 oligohydramnios appears to be good with the only abnormality being more common antepartum variable decelerations with AFI 5 cm or less (63.1% compared with 45.1%; P=.007). Also, Conway et al11 found isolated oligohydramnios in normal term pregnancy not 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 oligohydramnios group. The difference between our findings 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 necessarily become growth-restricted under the definition of less than the 10th centile. Neonatal outcomes, therefore, 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 pregnancy, 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 inhibition of other phosphodiesterase isoforms.13
Common adverse reactions associated with sildenafil administration are headache, flushing, dyspepsia, nasal congestion, urinary tract infection, and diarrhea, which have been reported by clinical trials.12 Regarding its risks, a systematic review14 found no teratogenic 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 malformations 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 following 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; however, we tried to overcome such difficulties by selecting an ultrasonographer blinded to the treatment arms; 2) normal pregnancies before 30 weeks of gestation and pregnancies with maternal or fetal complications were excluded; 3) maternal position was not 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 contents 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.
1. McCurdy CM Jr, Seeds JW. Oligohydramnios: problems and treatment. Semin Perinatol 1993;17:183–96.
2. Underwood MA, Gilbert WM, Sherman MP. Amniotic fluid: not just fetal urine any more. J Perinatol 2005;25:341–8.
3. Wareing M, Myers JE, O'Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab 2005;90:2550–5.
4. Ülker K, Özdemir İA. The relation of intrapartum amniotic fluid index to perinatal outcomes. Kafkas J Med Sci 2011;1:1–7.
5. Kilpatrick SJ, Safford KL, Pomeroy T, Hoedt L, Scheerer L, Laros RK. Maternal hydration increases amniotic fluid index. Obstet Gynecol 1991;78:1098–102.
6. Doi S, Osada H, Seki K, Sekiya S. Effect of maternal hydration on oligohydramnios: a comparison of three volume expansion methods. Obstet Gynecol 1998;92:525–9.
7. Malhotra B, Deka D. Duration of the increase in amniotic fluid index (AFI) after acute maternal hydration. Arch Gynecol Obstet 2004;269:173–5.
8. Wolman I, Groutz A, Gull I, Gordon D, Geva E, Lessing JB, et al. Is amniotic fluid influenced by a 24-hour fast? J Reprod Med 2000;45:685–7.
9. Ghafarnejad M, Tehrani MB, Anaraki FB, Mood NI, Nasehi L. Oral hydration therapy in oligohydramnios. Obstet Gynaecol Res 2009;35:895–900.
10. Kreiser D, el-Sayed Y, Sorem KA, Chitkara U, Holbrook RH Jr, Druzin ML. Decreased amniotic fluid index in low-risk pregnancy. J Reprod Med 2001;46:743–6.
11. Conway DL, Adkins WB, Schroeder B, Langer O. Isolated oligohydramnios in the term pregnancy: is it a clinical entity? J Matern Fetal Med 1998;7:197–200.
12. Boyce EG, Umland EM. Sildenafil citrate: a therapeutic update. Clin Ther 2001;23:2–23.
13. Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 1999;83:3C–12C.
14. Villanueva-García D, Mota-Rojas D, Hernández-González R, Sánchez-Aparicio P, Alonso-Spilsbury M, Trujillo-Ortega ME, et al. A systematic review of experimental and clinical studies of sildenafil citrate for intrauterine growth restriction and pre-term labour. J Obstet Gynaecol 2007;27:255–9.
© 2017 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
15. Horsager R, Nathan L, Leveno KJ. Correlation of measured amniotic fluid volume and sonographic predictions of oligohydramnios. Obstet Gynecol 1994;83:955–8.