The effect of sildenafil on amniotic fluid volume in cases of borderline oligohydramnios in uncomplicated pregnancies: a randomized clinical trial.

The effect of sildenafil on amniotic fluid volume in cases of borderline oligohydramnios in uncomplicated pregnancies: a randomized clinical trial. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The effect of sildenafil on amniotic fluid volume in cases of borderline oligohydramnios in uncomplicated pregnancies: a randomized clinical trial. Maryam Kashanian, Nooshin Eshraghi, Saeedeh Moslemi,, Narges Sheikhansari This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1480235/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Low amniotic fluid volume and oligohydramnios is important issue during pregnancy and is associated with an increase in fetal and neonatal mortality and morbidity. Finding a solution to it can improve fetal and neonatal outcomes. Objective: The purpose of the present study was to evaluate the effect of sildenafil on oligohydramnios in uncomplicated pregnancies. Methods : A placebo-controlled randomized clinical trial was performed on women with oligohydramnios and gestational age of 30 to 37 weeks and singleton pregnancy. The eligible women were randomly assigned into two groups. In the intervention group, 25 mg oral sildenafil was prescribed every 8 hours in conjunction with intravenous hydration therapy with 2 liters isotonic solution (normal saline) infused within 4 hours and in the control group, placebo and hydration therapy similar to the intervention group was prescribed. Amniotic fluid volume was re-evaluated 24 hours after treatment. If at least a 20% increase in amniotic fluid volume was detected by ultrasound, the woman was discharged; otherwise, the above regimen was repeated again for the next 24 hours. Discharged patients continued to take sildenafil or placebo at the same dose and consumption of 2 liters of oral fluids per day up to 37 weeks or delivery each happened earlier. Fetal monitoring was performed using non stress test (NST) twice a week, biophysical profile, and amniotic fluid volume measurement once a week. Amniotic fluid volume and pregnancy and neonatal outcomes were compared in the two groups. Results: One hundred ninety women finished the study. There was no statistically significant difference between the two groups in terms of maternal age, body mass index (BMI), parity, live birth rate, gestational age before the intervention, amniotic fluid index, and the type of pregnancy; spontaneous or using assisted reproductive technology (ART). In undelivered women, after the intervention, the amniotic fluid index was significantly higher in the case group than the control group. The number of women, whose pregnancies continued after the third week of intervention, were higher in the sildenafil group. At the end of the sixth week after intervention, 40 women (42.1%) in the case group continued their pregnancies versus 5 women (5.3%) in the control group (P = 0.001). Cesarean section rate, neonatal intensive care unit (NICU) admission, abnormal cardiotocography, umbilical cord pH less than 7.2, and Apgar score of less than 7 in 5 minutes, were less in the intervention group than the control group. While the mean gestational age at birth and birth weight was higher in the intervention group than the control group. There was no perinatal death in both groups. Abnormal cardiotocography (CTG) (AOR= 6.3, CI95% 2.4-15.1, P< 0.001), cesarean section rate (AOR= 4.2, CI95% 2.1-8.9, P< 0.001), birth weight of less than 2500 gram (AOR= 3.3, CI95% 1.6-6.9, P= 0.001), gestational age at birth of less than 37 weeks (AOR= 3.2, CI95% 1.5-6.9, P= 0.009 ), Apgar score of less than 7 in 5 minutes (AOR= 2.6, CI95% 1.1-6.4, P=0.037), umbilical cord pH of less than 7.2 (AOR= 2.5, CI95% 1.9-6.9, P=0.064), and NICU admission (AOR= 2.5, CI95% 1.1-5.9, P=0.032) were more in the control group. The most common maternal complication in patients was headache (15.8 vs. 7.4%) and headache (12.6 vs. 5.3%) which was more in the intervention group than the control group, but not statistically significant. Conclusion: In pregnant women with oligohydramnios, sildenafil may be associated with better pregnancy outcomes. Amniotic fluid volume sildenafil pregnancy outcomes oligohydramnios borderline amniotic fluid index umbilical cord pH cardiotocography (CTG) Figures Figure 1 Introduction: Oligohydramnios is an important issue during pregnancy and is associated with an increase in fetal and neonatal mortality and morbidity ( 1 ). Cord compression, NICU admission, cesarean delivery due to fetal distress, meconium aspiration syndrome, fetal growth restriction, preterm birth, and even fetal death have been reported in cases of oligohydramnios in different studies (1, 2, 3 ). AFI of 5 cm or less is defined as oligohydramnios ( 3 ) and borderline amniotic fluid index (AFI) or borderline ( marginal) oligohydramnios has been defined as 5.1 ≤ AFI ≤ 8.0 cm ( 4 , 5 ). Borderline oligohydramnios has been reported in some studies ( 3 , 6 , 7 , 8 ) as a risk factor for fetal wellbeing. However, the other studies did not propose such poor outcomes ( 4 , 5 , 9 , and 10 ). Correct and timely diagnosis of oligohydramnios and borderline oligohydramnios is associated with better outcomes in patients ( 4 , 5 ). Different methods have been proposed for treating oligohydramnios, among which non-invasive methods like hydration are more practical and more acceptable methods. Sildenafil citrate has been proposed as one of these medical treatments ( 11 , 12 , 13 ). Sildenafil inhibits phosphodiesterase type 5 (PDE5), which is an enzyme in the walls of blood vessels. PDE5 inhibitors (like sildenafil) block the PDE5 enzyme and this inhibition relaxes the blood vessels and increases blood flow as a result ( 13 ). Sildenafil is also currently used to treat pulmonary arterial hypertension ( 14 , 15 ). Using sildenafil leads to loosening the arterial wall, increasing uterine blood flow, and, uteroplacental perfusion as a consequence ( 11 , 12 ). However, there are not enough studies on the effect of sildenafil on oligohydramnios. The purpose of the present study was to evaluate the effect of sildenafil on the amount of amniotic fluid volume in cases of borderline oligohydramnios. Materials And Methods: This clinical trial was performed in Akbarabadi Training Hospital in Tehran, Iran on pregnant women with the diagnosis of borderline oligohydramnios. Inclusion criteria were singleton pregnancy, gestational age between 30 to 37 weeks, and diagnosis of borderline oligohydramnios (mean amniotic fluid index between 5–8 cm, measured by transabdominal ultrasound in the third trimester of pregnancy. Patients with fetal growth restriction, abnormal fetal Doppler, fetal anomaly, fetal distress, any systemic maternal disorders like chronic hypertension, pre-pregnancy diabetes; beginning of labor, rupture of the membranes, using prostaglandin synthetase inhibitors, any maternal cardiac, pulmonary, and kidney disorders, in which using bolus fluid is not safe, were excluded the study. Written informed consent was obtained from all participants before entering the study. Ethics Committee of Iran University of Medical Sciences confirmed conducting the study (IR.IUMS ID IR.IUMS.REC 1396.31246). The study was registered in the Iran Registry of Clinical Trials (IRCT) (IRCT ID IRCT20091023002624N21). Recruitment started in December 2017. 230 women were assessed for eligibility and 210 eligible women were assigned into the two groups (Fig. 1 ). One of the colleagues who was not aware of the study using block randomization performed randomization. Eligible women were randomly assigned into two groups (using sealed, sequentially distributed envelopes to which the letters A and B had been allocated: the letter A was assigned to the case group and the letter B was decided for the placebo group). The women and investigator were not aware of the study groups. In addition, a statistician who was not aware of the groups of the study performed statistical analysis. In the intervention group, 25 mg oral sildenafil was prescribed every 8 hours in conjunction with intravenous hydration therapy (2 liters isotonic solution (normal saline) infused within 4 hours) and in the control group, placebo and hydration therapy was prescribed similar to the intervention group. Betamethasone was administered for pregnancies with a gestational age of fewer than 34 weeks. The amniotic fluid index was re-evaluated 24 hours after the intervention. The women were discharged if at least a 20% increase in amniotic fluid was detected by ultrasound; otherwise, the above regimen was repeated again for the next 24 hours. Discharged women continued to take sildenafil or placebo with the same dosages and consumption of 2 liters of oral fluids per day up to 37 weeks or delivery, each happened earlier. Fetal wellbeing was monitored by using NST, twice a week, and performing biophysical profile and amniotic fluid volume measurement once a week. Amniotic fluid level and pregnancy and neonatal outcomes were compared in the two groups. The main outcome of the study was increasing in the amniotic fluid index (AFI). The other outcomes were pregnancy and neonatal outcomes including the interval between intervention to delivery, gestational age at birth, birth weight, umbilical artery pH, Apgar score, and neonatal intensive care unit admission. Data were statistically analyzed using STATA software version 14(Texas 77845 USA). The significance level was considered less and equal to 0.05. Quantitative data were displayed as mean and standard deviation and qualitative data were displayed as numbers and percentages. Quantitative variables between the two groups were statistically analyzed using t-test or Mann-Whitney test and qualitative data were analyzed using Chi-square or Fisher test. Logistic regression test and odds ratio with 95% confidence interval was used to evaluate the consequences. Results: One hundred ninety women finished the study. There was no statistically significant difference between the two groups in terms of maternal age, body mass index (BMI), parity, live birth rate, gestational age before the intervention, amniotic fluid index, and the type of pregnancy (spontaneous or using ART) (Table 1 ). In undelivered women, after the intervention, the amniotic fluid index was significantly higher in the case group than the control group (Table 2 ). The number of women, whose pregnancies continued after the third week of intervention, were higher in the sildenafil group (Table 3 ). Table 1 Comparison of baseline characteristics between the two groups. Characteristics Control group, n = 95 Intervention group, n = 95 P value Maternal age (year), mean ± SD 28.2 ± 7.4 (18–43) 26.7 ± 7.1(18–42) 0.179 BMI (kg/m 2 )؛ mean ± SD 25.1 ± 1.9 (22–30) 24.8 ± 1.7 (22–28) 0.368† Parity, mean ± SD 2.1 ± 1.5 (0–2) 2.0 ± 1.5 (0–2) 0.615† Gestational age (week) mean ± SD 32.9 ± 1.6 (30-35.5) 33.1 ± 1.7 (30-35.5) 0.401† AFI(cm) mean ± SD 5.4 ± 0.4 (5-6.5) 5.3 ±0.4 (5-6.9)0 0.422†† Spontaneous pregnancy, N (%) 83 (87.4) 80 (84.2) 0.533* Note: SD: standard deviation, AFI: amniotic fluid index, †: Mann-Whitney,*: chi 2 , ††: t-test Table 2 Amniotic fluid index in the two groups after treatment. Characteristics Control group, n = 95 Intervention group, n = 95 P value AFI Week 1 Mean ± SD 5.7 ± 0.9 6.2 ± 0.9 < 0.001 AFI Week 2 Mean ± SD 5.5 ± 1.1 7.0 ± 1.1 < 0.001 AFI Week 3 Mean ± SD 5.4 ± 1.1 7.4 ± 1.3 < 0.001 AFI Week 4 Mean ± SD 5.8 ± 1.1 9.4 ± 2.1 < 0.001 AFI Week 5 Mean ± SD 6.6 ± 1.9 10.1 ± 1.3 < 0.001 AFI Week 6 Mean ± SD 5.5 ± 0.4 10.9 ± 1.3 < 0001 Table 3 Number of undelivered women in the two groups. Undelivered, N (%) Control group, n = 95 Intervention group, n = 95 P value Week 1 92 (97.9) 95 (100.0) 0.497 Week2 92 (96.8) 95 (100.0) 0.264 Week3 76 (80.0) 95 (100.0) < 0.001 Week4 26 (27.4 ) 88 (92.6) < 0.001 Week5 8 (8.4) 72 (75.8) < 0.001 Week 6 5 (5.3) 40 (42.1) < 0001 At the end of the sixth week after intervention, 40 women (42.1%) in the case group continued their pregnancies versus 5 women (5.3%) in the control group (P = 0.001) (Table 3 ). Cesarean section rate, NICU admission, abnormal cardiotocography, umbilical cord pH less than 7.2, and Apgar score of less than 7 in 5 minutes, were less in the intervention group than the control group (Table 4 ). While the mean gestational age at birth and birth weight was higher in the intervention group than the control group. There was no perinatal death in both groups. Table 4 Comparison of maternal and neonatal outcomes in two groups. Outcome Control group, n = 95 Intervention group, n = 95 OR(95%CI) P Value Cesarean section, N (%) 58 (61.1) 27 (28.4) 3.9(2.15–7.2) < .001 Hemorrhage before delivery , N (%) 2 (2.1) 1 (1.1) 2.1(0.2–22.7) 1.00 Abnormal cardiotocography , N (%) 34 (35.8) 11 (11.6) 4.2(2.0-9.1) < 0.001 Apgar Score min 5 < 7, N (%) 30 (31.6) 13 (13.7) 2.9(1.4-6.0) 0.003 Abnormal Doppler, N (%) 5 (5.3) 0 - 0.06 PH < 7.2, N (%) 20 (21.0) 9 (9.5) 2.5 (1.1–5.9) 0.026 NICU admission, N (%) 31 (32.6) 15 (15.8) 2.6(1.3–5.2) 0.008 Birth Weight < 2500gr, N (%) 57 (60.0) 34 (35.8) 2.7(1.5–4.8) 0.001 Gestational age < 37 week, N (%) 61 (64.2) 34 (35.8) 3.2 (1.8–5.8) 0.001 Abnormal cardiotocography (CTG) (AOR = 6.3, CI95% 2.4–15.1, P < 0.001), cesarean section rate (AOR = 4.2, CI95% 2.1–8.9, P < 0.001), birth weight of less than 2500 gram (AOR = 3.3, CI95% 1.6–6.9, P = 0.001), gestational age at birth of less than 37 weeks (AOR = 3.2, CI95% 1.5–6.9, P = 0.009 ), Apgar score of less than 7 in 5 minute (AOR = 2.6, CI95% 1.1–6.4, P = 0.037), umbilical cord pH of less than 7.2 (AOR = 2.5, CI95% 1.9–6.9, P = 0.064), and NICU admission (AOR = 2.5, CI95% 1.1–5.9, P = 0.032) were more in the control group. The most common maternal complication in patients was headache (15.8 vs. 7.4%) and headache (12.6 vs. 5.3%) which in the intervention group was more than the control group, but not statistically significant. Discussion: The aim of the present study was to evaluate the effect of sildenafil on amniotic fluid volume in cases of borderline oligohydramnios and pregnancy outcome. The results of the study showed that sildenafil is associated with an increase in the amniotic fluid volume and better pregnancy outcomes. Amniotic fluid volume has an important role in the safety of the fetal environment ( 16 ) and its measurement is an important part of fetal and prenatal surveillance ( 17 ). Low volume of amniotic fluid including borderline oligohydramnios is an important issue during pregnancy and is associated with an increase in fetal and neonatal mortality and morbidity and poor pregnancy outcome ( 4 , 6 , 18 , and 19 ). Finding a way to increase the amount of amniotic fluid volume can improve pregnancy, fetal and neonatal outcomes ( 19 ). Amnioinfusion is an option for increasing amniotic fluid volume; however, it is an invasive procedure and has some probable risks. Using non-invasive methods (if effective) without hospitalization can be accompanied by fewer complications and more patient comfort and convenience. In some cases, the women need etiology-specific management of oligohydramnios like in cases of the ruptured membrane. However, there are some cases of the low volume of amniotic fluid where no specific cause is known. In these cases, increasing the amniotic fluid volume can improve the pregnancy outcome ( 1 , 19 , 20 ). Various modalities have been suggested for patients with oligohydramnios, including maternal hydration. Maternal hydration, particularly in cases of isolated oligohydramnios in the third trimester, can be effective in this way ( 1 , 19 , 20 , 21 , and 22 ). Hydration can increase the amniotic fluid volume both in women with oligohydramnios and normal amniotic fluid volume as well ( 22 ). It has been reported that a combination of intravenous hydration (for a duration of 1 day) and oral hydration (for a duration of at least 14 days) had better results ( 22 ). The effects of maternal hydration on amniotic fluid volume are temporary; therefore, oral hydration should continue until delivery ( 23 ). There is currently no known approved medication for increasing the amniotic fluid volume and treating oligohydramnios (including borderline oligohydramnios) ( 19 ). Prescription of L-arginine which is an amino acid and endogenous precursor of nitric oxide (NO) and other amino acids ( 24, 25, 26, 27), antioxidant supplements ( 28 ), and recently sildenafil ( 11 , 12 , 13 ), have been proposed in some studies for increasing the amniotic fluid volume and improving perinatal outcomes. Sildenafil increases the effects of nitric oxide (NO) which leads to arterial vasodilatation and therefore, can increase the uteroplacental perfusion as a consequence ( 11 , 12 ). This mechanism may increase the amniotic fluid volume and improve fetal growth and pregnancy outcome. The previous studies have used sildenafil in cases of intrauterine fetal growth restriction and reported successful outcomes ( 29 , 30 , and 31 ). In addition, a multicenter study ( 32 ) showed that sildenafil therapy could cause a significant improvement in perinatal outcome in women with oligohydramnios only, fetal growth restriction (FGR) only, and a combination of oligohydramnios and FGR. The results of these studies are in agreement with the present study and the other studies ( 6 , 11 , and 31 ). Vasodilation produced by sildenafil can improve blood supply to the placenta and uterine vasculature, which can lead to an increase in fetal renal blood flow, and consequently amniotic fluid ( 31 , 32 , and 33 ). In the present study, there were no significant side effects in women receiving sildenafil. Conducted studies have also shown that this treatment is safe ( 34 ). There are still many unanswered questions about the efficacy of sildenafil on oligohydramnios, and this study is a preliminary study on this subject. Further research is essential to build on the study’s results and future studies are required to reach robust conclusions on this matter. Declarations: Conflicts of interests: All authors declare no conflict of interest. Funding: This work has been supported by Iran University of Medical Sciences, Department of Research and Technology, Project No. 96-02-30-31246. Acknowledgments: The authors are grateful to the staff and residents of Akbarabadi Training Hospital for their sincere cooperation. Ethics approval: Institutional review board approval and institutional ethics committee approval was obtained. Ethics committee reference number: IR.IUMS.REC 1396.31246 Authors' Contribution: Maryam Kashanian : The conception and design of the study, data interpretation, writing of the paper. Nooshin Eshraghi: Data collection. Saeedeh Moslemi : Data analysis, Data collection Narges Sheikhansari: Data interpretation, writing, and revising. References: Rabie N, Magann E, Steelman S, Ounpraseuth S. Oligohydramnios in complicated and uncomplicated pregnancy: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2017; 49(4):442-9. Hughes DS, Magann EF. Antenatal fetal surveillance "Assessment of the AFV". Best Pract Res Clin Obstet Gynaecol. 2017 Jan; 38:12-23. Petrozella LN, Dashe JS, McIntire DD, Leveno KJ. 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A retrospective interventional study for evaluation of efficacy and safety of sildenafil citrate in improving intrauterine growth restriction and oligohydramnios using ultrasound Doppler velocimetry. International Journal of Basic & Clinical Pharmacology. 2019; 8:2736. Nath J, Chaube S, Rani N, Verma P. A Study on Sildenafil Citrate in the Treatment of IUGR & Oligohydramnios. IGRWH.000581. 4(2).2021. Dunn L, Greer R, Flenady V, Kumar S. Sildenafil in Pregnancy: A Systematic Review of Maternal Tolerance and Obstetric and Perinatal Outcomes. Fetal Diagn Ther 2017;41:81–88. Supplementary Files drmoslemi1.sav Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1480235","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":94409365,"identity":"751d44a6-e8d8-4c10-973a-7e0c9f9e032f","order_by":0,"name":"Maryam Kashanian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIiWNgGAWjYPCCBAYGCQglx8DAQ6IWYxK1AEFiAyEtuu1nn0n8zEmTl5/d/OzBg5o76RuOnz344AODnZxuA3YtZmfSzSR7t+UYbrhzzNwg4diz3A1n8pINZzAkG5sdwKHlQBqbBO+2CsYNEglmEglsh3M3HMgxk+ZhOJC4DZeW88/YJP9uq7CfPyP9m0TCv8PpBuffENByI41NmndbTmLDjRwzicS2wwkGNwjZcuMZs7XstrTkDTdyyiQS+w4bzrzxxthwhgEev5xPY7z5dluyLdBh2yR/fDssz3c+x/DBhwo7OVxagIBFAoWrAFZpgFM5CDB/QOHKN+BVPQpGwSgYBSMQAACsEGR1k2EDPQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-7181-0244","institution":"Iran University of Medical Sciences","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Maryam","middleName":"","lastName":"Kashanian","suffix":""},{"id":94409366,"identity":"f76ef56c-78ce-4332-a624-bf02dadcfd8f","order_by":1,"name":"Nooshin Eshraghi","email":"","orcid":"","institution":"Iran University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nooshin","middleName":"","lastName":"Eshraghi","suffix":""},{"id":94409367,"identity":"d4c9df07-69d8-47ce-b3b6-5b305d5bc267","order_by":2,"name":"Saeedeh Moslemi,","email":"","orcid":"","institution":"Iran University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"","middleName":"Saeedeh","lastName":"Moslemi","suffix":""},{"id":94409368,"identity":"83c760fc-f589-4a5b-a0b2-a32e2b9ace17","order_by":3,"name":"Narges Sheikhansari","email":"","orcid":"","institution":"University of Exeter Medical School","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Narges","middleName":"","lastName":"Sheikhansari","suffix":""}],"badges":[],"createdAt":"2022-03-23 06:23:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1480235/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1480235/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":19785876,"identity":"ac805571-8d18-444e-a9ab-b1debc994a16","added_by":"auto","created_at":"2022-03-30 17:52:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":156422,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe Consort Flowchart\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1480235/v1/65a46cc68b4067da47bf57c1.jpg"},{"id":19965267,"identity":"ca5d031f-6c07-473a-bd4b-30dc29156b01","added_by":"auto","created_at":"2022-04-05 09:19:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":530985,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1480235/v1/0262c758-9077-45aa-8b08-47a01d56bd79.pdf"},{"id":19785875,"identity":"bdf70309-c7eb-4768-a95a-845e28f194fb","added_by":"auto","created_at":"2022-03-30 17:52:37","extension":"sav","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":39913,"visible":true,"origin":"","legend":"","description":"","filename":"drmoslemi1.sav","url":"https://assets-eu.researchsquare.com/files/rs-1480235/v1/a99a30d6883cdd07a5841da6.sav"}],"financialInterests":"","formattedTitle":"The effect of sildenafil on amniotic fluid volume in cases of borderline oligohydramnios in uncomplicated pregnancies: a randomized clinical trial.","fulltext":[{"header":"Introduction:","content":"\u003cp\u003eOligohydramnios is an important issue during pregnancy and is associated with an increase in fetal and neonatal mortality and morbidity (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Cord compression, NICU admission, cesarean delivery due to fetal distress, meconium aspiration syndrome, fetal growth restriction, preterm birth, and even fetal death have been reported in cases of oligohydramnios in different studies (1, 2, 3 ). AFI of 5 cm or less is defined as oligohydramnios (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) and borderline amniotic fluid index (AFI) or borderline ( marginal) oligohydramnios has been defined as 5.1\u0026thinsp;\u0026le;\u0026thinsp;AFI\u0026thinsp;\u0026le;\u0026thinsp;8.0 cm (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Borderline oligohydramnios has been reported in some studies (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) as a risk factor for fetal wellbeing. However, the other studies did not propose such poor outcomes (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, and \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Correct and timely diagnosis of oligohydramnios and borderline oligohydramnios is associated with better outcomes in patients (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDifferent methods have been proposed for treating oligohydramnios, among which non-invasive methods like hydration are more practical and more acceptable methods. Sildenafil citrate has been proposed as one of these medical treatments (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Sildenafil inhibits phosphodiesterase type 5 (PDE5), which is an enzyme in the walls of blood vessels. PDE5 inhibitors (like sildenafil) block the PDE5 enzyme and this inhibition relaxes the blood vessels and increases blood flow as a result (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Sildenafil is also currently used to treat pulmonary arterial hypertension (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Using sildenafil leads to loosening the arterial wall, increasing uterine blood flow, and, uteroplacental perfusion as a consequence (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). However, there are not enough studies on the effect of sildenafil on oligohydramnios. The purpose of the present study was to evaluate the effect of sildenafil on the amount of amniotic fluid volume in cases of borderline oligohydramnios.\u003c/p\u003e"},{"header":"Materials And Methods:","content":"\u003cp\u003eThis clinical trial was performed in Akbarabadi Training Hospital in Tehran, Iran on pregnant women with the diagnosis of borderline oligohydramnios. Inclusion criteria were singleton pregnancy, gestational age between 30 to 37 weeks, and diagnosis of borderline oligohydramnios (mean amniotic fluid index between 5\u0026ndash;8 cm, measured by transabdominal ultrasound in the third trimester of pregnancy. Patients with fetal growth restriction, abnormal fetal Doppler, fetal anomaly, fetal distress, any systemic maternal disorders like chronic hypertension, pre-pregnancy diabetes; beginning of labor, rupture of the membranes, using prostaglandin synthetase inhibitors, any maternal cardiac, pulmonary, and kidney disorders, in which using bolus fluid is not safe, were excluded the study. Written informed consent was obtained from all participants before entering the study. Ethics Committee of Iran University of Medical Sciences confirmed conducting the study (IR.IUMS ID IR.IUMS.REC 1396.31246). The study was registered in the Iran Registry of Clinical Trials (IRCT) (IRCT ID IRCT20091023002624N21). Recruitment started in December 2017. 230 women were assessed for eligibility and 210 eligible women were assigned into the two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). One of the colleagues who was not aware of the study using block randomization performed randomization. Eligible women were randomly assigned into two groups (using sealed, sequentially distributed envelopes to which the letters A and B had been allocated: the letter A was assigned to the case group and the letter B was decided for the placebo group). The women and investigator were not aware of the study groups. In addition, a statistician who was not aware of the groups of the study performed statistical analysis. In the intervention group, 25 mg oral sildenafil was prescribed every 8 hours in conjunction with intravenous hydration therapy (2 liters isotonic solution (normal saline) infused within 4 hours) and in the control group, placebo and hydration therapy was prescribed similar to the intervention group. Betamethasone was administered for pregnancies with a gestational age of fewer than 34 weeks. The amniotic fluid index was re-evaluated 24 hours after the intervention. The women were discharged if at least a 20% increase in amniotic fluid was detected by ultrasound; otherwise, the above regimen was repeated again for the next 24 hours. Discharged women continued to take sildenafil or placebo with the same dosages and consumption of 2 liters of oral fluids per day up to 37 weeks or delivery, each happened earlier. Fetal wellbeing was monitored by using NST, twice a week, and performing biophysical profile and amniotic fluid volume measurement once a week. Amniotic fluid level and pregnancy and neonatal outcomes were compared in the two groups. The main outcome of the study was increasing in the amniotic fluid index (AFI). The other outcomes were pregnancy and neonatal outcomes including the interval between intervention to delivery, gestational age at birth, birth weight, umbilical artery pH, Apgar score, and neonatal intensive care unit admission. Data were statistically analyzed using STATA software version 14(Texas 77845 USA). The significance level was considered less and equal to 0.05. Quantitative data were displayed as mean and standard deviation and qualitative data were displayed as numbers and percentages. Quantitative variables between the two groups were statistically analyzed using t-test or Mann-Whitney test and qualitative data were analyzed using Chi-square or Fisher test. Logistic regression test and odds ratio with 95% confidence interval was used to evaluate the consequences.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Results:","content":"\u003cp\u003eOne hundred ninety women finished the study. There was no statistically significant difference between the two groups in terms of maternal age, body mass index (BMI), parity, live birth rate, gestational age before the intervention, amniotic fluid index, and the type of pregnancy (spontaneous or using ART) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e ). In undelivered women, after the intervention, the amniotic fluid index was significantly higher in the case group than the control group (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The number of women, whose pregnancies continued after the third week of intervention, were higher in the sildenafil group (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparison of baseline characteristics between the two groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl group,\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;95\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIntervention group,\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;95\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMaternal age (year), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4 (18\u0026ndash;43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1(18\u0026ndash;42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI (kg/m\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e)؛ mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9 (22\u0026ndash;30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 (22\u0026ndash;28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.368\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eParity, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 (0\u0026ndash;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 (0\u0026ndash;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.615\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGestational age (week) mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6 (30-35.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 (30-35.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.401\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAFI(cm) mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 (5-6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.3 \u0026plusmn;0.4 (5-6.9)0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.422\u0026dagger;\u0026dagger;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSpontaneous pregnancy, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e83 (87.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80 (84.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.533*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eNote: SD: standard deviation, AFI: amniotic fluid index, \u0026dagger;: Mann-Whitney,*: chi\u003csup\u003e2\u003c/sup\u003e, \u0026dagger;\u0026dagger;: t-test\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAmniotic fluid index in the two groups after treatment.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl group,\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;95\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIntervention group,\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;95\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAFI Week 1 Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAFI Week 2 Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAFI Week 3 Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAFI Week 4 Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAFI Week 5 Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAFI Week 6 Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eNumber of undelivered women in the two groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUndelivered,\u003c/p\u003e\n \u003cp\u003eN (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl group,\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;95\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIntervention group,\u003c/p\u003e\n \u003cp\u003en\u0026thinsp;=\u0026thinsp;95\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeek 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e92 (97.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e95 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.497\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeek2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e92 (96.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e95 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.264\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeek3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e76 (80.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e95 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeek4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26 (27.4 )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e88 (92.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeek5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (8.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72 (75.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeek 6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40 (42.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eAt the end of the sixth week after intervention, 40 women (42.1%) in the case group continued their pregnancies versus 5 women (5.3%) in the control group (P\u0026thinsp;=\u0026thinsp;0.001) (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Cesarean section rate, NICU admission, abnormal cardiotocography, umbilical cord pH less than 7.2, and Apgar score of less than 7 in 5 minutes, were less in the intervention group than the control group (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). While the mean gestational age at birth and birth weight was higher in the intervention group than the control group. There was no perinatal death in both groups.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab4\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparison of maternal and neonatal outcomes in two groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControl group, n\u0026thinsp;=\u0026thinsp;95\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIntervention group, n\u0026thinsp;=\u0026thinsp;95\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOR(95%CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP Value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCesarean section, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e58 (61.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (28.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.9(2.15\u0026ndash;7.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHemorrhage before delivery\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1(0.2\u0026ndash;22.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbnormal cardiotocography\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34 (35.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.2(2.0-9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eApgar Score min 5\u0026thinsp;\u0026lt;\u0026thinsp;7, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30 (31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.9(1.4-6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbnormal Doppler, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePH\u0026thinsp;\u0026lt;\u0026thinsp;7.2, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20 (21.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.5 (1.1\u0026ndash;5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNICU admission, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31 (32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.6(1.3\u0026ndash;5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBirth Weight\u0026thinsp;\u0026lt;\u0026thinsp;2500gr, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e57 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (35.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.7(1.5\u0026ndash;4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGestational age\u0026thinsp;\u0026lt;\u0026thinsp;37 week, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e61 (64.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34 (35.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.2 (1.8\u0026ndash;5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eAbnormal cardiotocography (CTG) (AOR\u0026thinsp;=\u0026thinsp;6.3, CI95% 2.4\u0026ndash;15.1, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), cesarean section rate (AOR\u0026thinsp;=\u0026thinsp;4.2, CI95% 2.1\u0026ndash;8.9, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), birth weight of less than 2500 gram (AOR\u0026thinsp;=\u0026thinsp;3.3, CI95% 1.6\u0026ndash;6.9, P\u0026thinsp;=\u0026thinsp;0.001), gestational age at birth of less than 37 weeks (AOR\u0026thinsp;=\u0026thinsp;3.2, CI95% 1.5\u0026ndash;6.9, P\u0026thinsp;=\u0026thinsp;0.009 ), Apgar score of less than 7 in 5 minute (AOR\u0026thinsp;=\u0026thinsp;2.6, CI95% 1.1\u0026ndash;6.4, P\u0026thinsp;=\u0026thinsp;0.037), umbilical cord pH of less than 7.2 (AOR\u0026thinsp;=\u0026thinsp;2.5, CI95% 1.9\u0026ndash;6.9, P\u0026thinsp;=\u0026thinsp;0.064), and NICU admission (AOR\u0026thinsp;=\u0026thinsp;2.5, CI95% 1.1\u0026ndash;5.9, P\u0026thinsp;=\u0026thinsp;0.032) were more in the control group. The most common maternal complication in patients was headache (15.8 vs. 7.4%) and headache (12.6 vs. 5.3%) which in the intervention group was more than the control group, but not statistically significant.\u003c/p\u003e"},{"header":"Discussion:","content":"\u003cp\u003eThe aim of the present study was to evaluate the effect of sildenafil on amniotic fluid volume in cases of borderline oligohydramnios and pregnancy outcome. The results of the study showed that sildenafil is associated with an increase in the amniotic fluid volume and better pregnancy outcomes.\u003c/p\u003e \u003cp\u003eAmniotic fluid volume has an important role in the safety of the fetal environment (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) and its measurement is an important part of fetal and prenatal surveillance (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Low volume of amniotic fluid including borderline oligohydramnios is an important issue during pregnancy and is associated with an increase in fetal and neonatal mortality and morbidity and poor pregnancy outcome (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, and \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Finding a way to increase the amount of amniotic fluid volume can improve pregnancy, fetal and neonatal outcomes (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Amnioinfusion is an option for increasing amniotic fluid volume; however, it is an invasive procedure and has some probable risks. Using non-invasive methods (if effective) without hospitalization can be accompanied by fewer complications and more patient comfort and convenience. In some cases, the women need etiology-specific management of oligohydramnios like in cases of the ruptured membrane. However, there are some cases of the low volume of amniotic fluid where no specific cause is known. In these cases, increasing the amniotic fluid volume can improve the pregnancy outcome (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Various modalities have been suggested for patients with oligohydramnios, including maternal hydration. Maternal hydration, particularly in cases of isolated oligohydramnios in the third trimester, can be effective in this way (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, and \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Hydration can increase the amniotic fluid volume both in women with oligohydramnios and normal amniotic fluid volume as well (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). It has been reported that a combination of intravenous hydration (for a duration of 1 day) and oral hydration (for a duration of at least 14 days) had better results (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The effects of maternal hydration on amniotic fluid volume are temporary; therefore, oral hydration should continue until delivery (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). There is currently no known approved medication for increasing the amniotic fluid volume and treating oligohydramnios (including borderline oligohydramnios) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrescription of L-arginine which is an amino acid and endogenous precursor of nitric oxide (NO) and other amino acids ( 24, 25, 26, 27), antioxidant supplements (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), and recently sildenafil (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), have been proposed in some studies for increasing the amniotic fluid volume and improving perinatal outcomes.\u003c/p\u003e \u003cp\u003eSildenafil increases the effects of nitric oxide (NO) which leads to arterial vasodilatation and therefore, can increase the uteroplacental perfusion as a consequence (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). This mechanism may increase the amniotic fluid volume and improve fetal growth and pregnancy outcome. The previous studies have used sildenafil in cases of intrauterine fetal growth restriction and reported successful outcomes (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, and \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). In addition, a multicenter study (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e) showed that sildenafil therapy could cause a significant improvement in perinatal outcome in women with oligohydramnios only, fetal growth restriction (FGR) only, and a combination of oligohydramnios and FGR. The results of these studies are in agreement with the present study and the other studies (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, and \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Vasodilation produced by sildenafil can improve blood supply to the placenta and uterine vasculature, which can lead to an increase in fetal renal blood flow, and consequently amniotic fluid (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, and \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the present study, there were no significant side effects in women receiving sildenafil. Conducted studies have also shown that this treatment is safe (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere are still many unanswered questions about the efficacy of sildenafil on oligohydramnios, and this study is a preliminary study on this subject. Further research is essential to build on the study\u0026rsquo;s results and future studies are required to reach robust conclusions on this matter.\u003c/p\u003e"},{"header":"Declarations:","content":"\u003cp\u003e\u003cstrong\u003eConflicts of interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work has been supported by Iran University of Medical Sciences, Department of Research and Technology, Project No. 96-02-30-31246.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to the staff and residents of Akbarabadi Training Hospital for their sincere cooperation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003c/strong\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInstitutional review board approval and institutional ethics committee approval was obtained.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics committee reference number:\u0026nbsp;\u003c/strong\u003eIR.IUMS.REC 1396.31246\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Contribution:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaryam Kashanian\u003c/strong\u003e: \u0026nbsp;The conception and design of the study, data interpretation, writing\u0026nbsp;of the paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNooshin Eshraghi:\u003c/strong\u003e Data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSaeedeh Moslemi\u003c/strong\u003e: Data analysis, Data collection\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNarges Sheikhansari:\u003c/strong\u003e Data interpretation, writing, and revising.\u003c/p\u003e"},{"header":"References:","content":"\u003col\u003e\n \u003cli\u003eRabie N, Magann E, Steelman S, Ounpraseuth S. Oligohydramnios in complicated and uncomplicated pregnancy: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2017; 49(4):442-9.\u003c/li\u003e\n \u003cli\u003eHughes DS, Magann EF. Antenatal fetal surveillance \u0026quot;Assessment of the AFV\u0026quot;. Best Pract Res Clin Obstet Gynaecol. 2017 Jan; 38:12-23.\u003c/li\u003e\n \u003cli\u003ePetrozella LN, Dashe JS, McIntire DD, Leveno KJ. Clinical significance of borderline amniotic fluid index and oligohydramnios in preterm pregnancy. Obstetrics \u0026amp; Gynecology, 2011. 117(2, Part 1): 338-342.\u003c/li\u003e\n \u003cli\u003eChoi SR. Borderline amniotic fluid index and perinatal outcomes in the uncomplicated term pregnancy. J Matern Fetal Neonatal Med . 2016;29(3):457-60.\u003c/li\u003e\n \u003cli\u003eSahin E, Madendag Y, Tayyar AT, Sahin ME, Madendag IC, Acmaz G. Perinatal outcomes in uncomplicated late preterm pregnancies with borderline oligohydramnios. J Matern Fetal Neonatal Med . 2018 Dec;31(23):3085-3088.\u003c/li\u003e\n \u003cli\u003eJamal A, Kazemi M, Marsoosi V, Eslamian L. Adverse perinatal outcomes in borderline amniotic fluid index. Int J Reprod Biomed. 2016 Nov; 14(11): 705\u0026ndash;708.\u003c/li\u003e\n \u003cli\u003eBanks EH, Miller DA. Perinatal risks associated with borderline amniotic fluid index. Am J Obstet Gynecol . 1999 Jun;180(6 Pt 1):1461-3.\u003c/li\u003e\n \u003cli\u003eAsgharnia M, Faraji R, Salamat F, Ashrafkhani B, Dalil Heirati SF, Naimian S. Perinatal outcomes of pregnancies with borderline versus normal amniotic fluid index. Iran J Reprod Med. 2013 Sep; 11(9): 705\u0026ndash;710.\u003c/li\u003e\n \u003cli\u003eWood SL, Newton JM, Wang L, Lesser K. Borderline amniotic fluid index and its relation to fetal intolerance of labor: a 2-center retrospective cohort study. J Ultrasound Med. 2014 Apr;33(4):705-11.\u003c/li\u003e\n \u003cli\u003eYin H , Zhao L , Lin Y , Wang Y , Hu Y , Sun G, et al. Perinatal outcomes following labor induction with dinoprostone in pregnancies with borderline amniotic fluid index at term: A clinical observation study. J Obstet Gynaecol Res. 2018 Aug; 44(8):1397-1403.\u003c/li\u003e\n \u003cli\u003eMaher MA, Sayyed TM, Elkhouly N. Sildenafil Citrate Therapy for Oligohydramnios: A Randomized Controlled Trial. Obstetrics \u0026amp; Gynecology. 2017;129(4):615-20.\u003c/li\u003e\n \u003cli\u003eMol BW , Walker SP. Sildenafil Citrate Therapy for Oligohydramnios: A Randomized Controlled Trial. Obstet Gynecol . 2017 Nov;130(5):1157.\u003c/li\u003e\n \u003cli\u003eJha N , Jha AK. Sildenafil Citrate Therapy for Oligohydramnios: A Randomized Controlled Trial. Obstet Gynecol. 2017 Jul; 130(1):219.\u003c/li\u003e\n \u003cli\u003eAla M, Mohammad Jafari R, Dehpour AR. Sildenafil beyond erectile dysfunction and pulmonary arterial hypertension: Thinking about new indications. Fundam Clin Pharmacol. 2021 Apr;35(2):235-259.\u003c/li\u003e\n \u003cli\u003eMohamed NA, Abou-Saleh H, Kameno Y, Marei I, de Nucci G, Ahmetaj-Shala B, et al. Studies on metal-organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension. Sci Rep. 2021 Feb 22;11(1):4336\u003c/li\u003e\n \u003cli\u003eWeiner E, Barrett J, Zaltz A, Ram M, Aviram A, Kibel M. et al. Amniotic fluid volume at presentation with early preterm prelabor rupture of membranes and association with severe neonatal respiratory morbidity. Ultrasound Obstet Gynecol. 2019 Dec; 54(6):767-773.\u003c/li\u003e\n \u003cli\u003eHughes DS, Magann EF. Antenatal fetal surveillance \u0026quot;Assessment of the AFV\u0026quot;. Best Pract Res Clin Obstet Gynaecol. 2017 Jan; 38:12-23.\u003c/li\u003e\n \u003cli\u003eAnsari S N, Baral J, Gurung G, Jha A. Comparison of Outcome of Borderline and Normal Amniotic Fluid Index in Term Pregnancy. Kathmandu Univ Med J (KUMJ). 2021 Jan.-Mar; 19(73):17-21.\u003c/li\u003e\n \u003cli\u003eKeilman C, Shanks AL. Oligohydramnios. StatPearls. Treasure Island (FL): StatPearls Publishing Copyright \u0026copy; 2021, StatPearls Publishing LLC. 2021.\u003c/li\u003e\n \u003cli\u003e\u0026Uuml;lker K. Maternal hydration therapy improves the quantity of amniotic fluid and the pregnancy outcome in third-trimester isolated oligohydramnios. J Ultrasound Med. 2014 May; 33(5):922.\u003c/li\u003e\n \u003cli\u003eJavadian.M. Effect of oral and intravenous maternal liquid treatment in Oligohydramnios. Journal of North Khorasan University of Medical Sciences 2011; 3(3):15-20.\u003c/li\u003e\n \u003cli\u003eGizzo S, Noventa M, Vitagliano A, Dall\u0026apos;Asta A, D\u0026apos;Antona D, Aldrich CJ. An Update on Maternal Hydration Strategies for Amniotic Fluid Improvement in Isolated Oligohydramnios and Normohydramnios: Evidence from a Systematic Review of Literature and Meta-Analysis. PLoS One. 2015 Dec 11; 10(12):e0144334. eCollection 2015.\u003c/li\u003e\n \u003cli\u003eNada Z. Oral and Intravenous Maternal Hydration in third trimester Idiopathic Oligohydramnios: Effects and Duration. IOSR; Journal of Nursing and Health Science (IOSR-JNHS). 2015; 4( 5) : 22-25\u003c/li\u003e\n \u003cli\u003eHebbar S, Rai L, Adiga P. Maternal hydration and L-arginine supplementation improves liquor volume in patients with decreased liquor and prolongs pregnancy. Med J DY Patil Univ. 2014;7(4):429-3.\u003c/li\u003e\n \u003cli\u003eIqbal S, Malik MA, Kaurani H, Chauhan D. Effect of oral L- arginine versus intravenous hydration on maternal and fetal outcome in idiopathic oligohydramnios. IJRCOG 2021; 10 ( 5).\u003c/li\u003e\n \u003cli\u003eHabib N, Syed S , Khurshid N ,Habib A. Efficacy of Intravenous Hydration Versus Amino Acid Infusion in Idiopathic Oligohydramnios. Ann Pak Inst Med Sci. 2021; 17 (1).\u003c/li\u003e\n \u003cli\u003eSharma A , Dashora S , Sharma R ,Chandra K , Gunawat MS. To Study The Effect of L-Arginine in Oligohydramnios To Improve Perinatal Outcome. IOSR Journal of Dental and Medical Sciences (IOSR-JDMS). 2017; 16(4): 16-19.\u003c/li\u003e\n \u003cli\u003eIsmail AM, Ramadan MF, Ali MK, Abbas AM, El Saman AM, Makarem MH. A randomized controlled study of the efficacy of 4 weeks of supplementation with \u0026omega;-3 polyunsaturated fatty acids in cases of unexplained oligohydramnios. Journal of Perinatology. 2016, 36: 944\u0026ndash;947.\u003c/li\u003e\n \u003cli\u003eVon Dadelszen P, Dwinnell S, Magee L, Carleton B, Gruslin A, Lee B, et al. Sildenafil citrate therapy for severe early‐onset intrauterine growth restriction. BJOG: An International Journal of Obstetrics \u0026amp; Gynaecology. 2011; 118(5):624-8.\u003c/li\u003e\n \u003cli\u003eWareing M, Myers JE, O\u0026rsquo;hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. The Journal of Clinical Endocrinology \u0026amp; Metabolism. 2005; 90(5):2550-5.\u003c/li\u003e\n \u003cli\u003eEl-Sayed MA, Abdel-Aty Saleh S, Maher MA, Khidre AM. Utero-placental perfusion Doppler indices in growth restricted fetuses: effect of sildenafil citrate. J Matern Fetal Neonatal Med. 2018 Apr; 31(8):1045-1050.\u003c/li\u003e\n \u003cli\u003eGanla KN, Choudhary RA, Desai KN, Kadam SB, Arunachalam K. A retrospective interventional study for evaluation of efficacy and safety of sildenafil citrate in improving intrauterine growth restriction and oligohydramnios using ultrasound Doppler velocimetry. International Journal of Basic \u0026amp; Clinical Pharmacology. 2019; 8:2736.\u003c/li\u003e\n \u003cli\u003eNath J, Chaube S, Rani N, Verma P. A Study on Sildenafil Citrate in the Treatment of IUGR \u0026amp; Oligohydramnios. IGRWH.000581. 4(2).2021.\u003c/li\u003e\n \u003cli\u003eDunn L, Greer R, Flenady V, Kumar S. Sildenafil in Pregnancy: A Systematic Review of Maternal Tolerance and Obstetric and Perinatal Outcomes. Fetal Diagn Ther 2017;41:81\u0026ndash;88.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Amniotic fluid volume, sildenafil, pregnancy outcomes, oligohydramnios, borderline amniotic fluid index, umbilical cord pH, cardiotocography (CTG)","lastPublishedDoi":"10.21203/rs.3.rs-1480235/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1480235/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eLow amniotic fluid volume and oligohydramnios is important issue during pregnancy and is associated with an increase in fetal and neonatal mortality and morbidity. Finding a solution to it can improve fetal and neonatal outcomes.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe purpose of the present study was to evaluate the effect of sildenafil on oligohydramnios in uncomplicated pregnancies.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e:\u003c/p\u003e\u003cp\u003eA placebo-controlled randomized clinical trial was performed on women with oligohydramnios and gestational age of 30 to 37 weeks and singleton pregnancy. The eligible women were randomly assigned into two groups. In the intervention group, 25 mg oral sildenafil was prescribed every 8 hours in conjunction with intravenous hydration therapy with 2 liters isotonic solution\u0026nbsp;(normal saline) infused within 4 hours and in the control group, placebo and hydration therapy similar to the intervention group was prescribed. Amniotic fluid volume was re-evaluated 24 hours after treatment. If at least a 20% increase in amniotic fluid volume was detected by ultrasound, the woman was discharged; otherwise, the above regimen was repeated again for the next 24 hours.\u003c/p\u003e\u003cp\u003eDischarged patients continued to take sildenafil or placebo at the same dose and consumption of 2 liters of oral fluids per day up to 37 weeks or delivery each happened earlier. Fetal monitoring was performed using non stress test (NST) twice a week, biophysical profile, and amniotic fluid volume measurement once a week. Amniotic fluid volume and pregnancy and neonatal outcomes were compared in the two groups.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eOne hundred ninety women finished the study. There was no statistically significant difference between the two groups in terms of maternal age, body mass index (BMI), parity, live birth rate, gestational age before the intervention, amniotic fluid index, and the type of pregnancy; spontaneous or using assisted reproductive technology (ART). In undelivered women, after the intervention, the amniotic fluid index was significantly higher in the case group than the control group. The number of women, whose pregnancies continued after the third week of intervention, were higher in the sildenafil group.\u003c/p\u003e\u003cp\u003eAt the end of the sixth week after intervention, 40 women (42.1%) in the case group continued their pregnancies versus 5 women (5.3%) in the control group (P = 0.001). Cesarean section rate, neonatal intensive care unit (NICU) admission, abnormal cardiotocography, umbilical cord pH less than 7.2, and Apgar score of less than 7 in 5 minutes, were less in the intervention group than the control group. While the mean gestational age at birth and birth weight was higher in the intervention group than the control group. There was no perinatal death in both groups.\u003c/p\u003e\u003cp\u003eAbnormal cardiotocography (CTG) (AOR= 6.3, CI95% 2.4-15.1, P\u0026lt; 0.001), cesarean section rate (AOR= 4.2, CI95% 2.1-8.9, P\u0026lt; 0.001), birth weight of less than 2500 gram (AOR= 3.3, CI95% 1.6-6.9, P= 0.001), gestational age at birth of less than 37 weeks (AOR= 3.2, CI95% 1.5-6.9, P= 0.009 ), Apgar score of less than 7 in 5 minutes (AOR= 2.6, CI95% 1.1-6.4, P=0.037), umbilical cord pH of less than 7.2 (AOR= 2.5, CI95% 1.9-6.9, P=0.064), and NICU admission (AOR= 2.5, CI95% 1.1-5.9, P=0.032) were more in the control group.\u003c/p\u003e\u003cp\u003eThe most common maternal complication in patients was headache (15.8 vs. 7.4%) and headache (12.6 vs. 5.3%) which was more in the intervention group than the control group, but not statistically significant.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eIn pregnant women with oligohydramnios, sildenafil may be associated with better pregnancy outcomes.\u003c/p\u003e","manuscriptTitle":"The effect of sildenafil on amniotic fluid volume in cases of borderline oligohydramnios in uncomplicated pregnancies: a randomized clinical trial.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-03-30 17:52:35","doi":"10.21203/rs.3.rs-1480235/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"92b47704-ddd4-459a-a414-e5696e670dfc","owner":[],"postedDate":"March 30th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-04-05T09:19:02+00:00","versionOfRecord":[],"versionCreatedAt":"2022-03-30 17:52:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1480235","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1480235","identity":"rs-1480235","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}