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Meta-Analysis
. 2023 Jul 10;7(7):CD014498.
doi: 10.1002/14651858.CD014498.

Interventions affecting the nitric oxide pathway versus placebo or no therapy for fetal growth restriction in pregnancy

Anouk Pels  1 , Wessel Ganzevoort  1 , Louise C Kenny  2 , Philip N Baker  3 , Peter von Dadelszen  4 , Christian Gluud  5 , Chirag T Kariya  6 , Aleid G Leemhuis  7 , Katie M Groom  8 , Andrew N Sharp  9 , Laura A Magee  4 , Janus C Jakobsen  10 , Ben Willem J Mol  11   12 , Aris T Papageorghiou  13
Affiliations
Meta-Analysis

Interventions affecting the nitric oxide pathway versus placebo or no therapy for fetal growth restriction in pregnancy

Anouk Pels et al. Cochrane Database Syst Rev. .

Abstract

Background: Fetal growth restriction (FGR) is a condition of poor growth of the fetus in utero. One of the causes of FGR is placental insufficiency. Severe early-onset FGR at < 32 weeks of gestation occurs in an estimated 0.4% of pregnancies. This extreme phenotype is associated with a high risk of fetal death, neonatal mortality, and neonatal morbidity. Currently, there is no causal treatment, and management is focused on indicated preterm birth to prevent fetal death. Interest has risen in interventions that aim to improve placental function by administration of pharmacological agents affecting the nitric oxide pathway causing vasodilatation.

Objectives: The objective of this systematic review and aggregate data meta-analysis is to assess the beneficial and harmful effects of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or different drugs affecting this pathway against each other, in pregnant women with severe early-onset FGR.

Search methods: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 July 2022), and reference lists of retrieved studies.

Selection criteria: We considered all randomised controlled comparisons of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or another drug affecting this pathway in pregnant women with severe early-onset FGR of placental origin, for inclusion in this review.

Data collection and analysis: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis.

Main results: We included a total of eight studies (679 women) in this review, all of which contributed to the data and analysis. The identified studies report on five different comparisons: sildenafil compared with placebo or no therapy, tadalafil compared with placebo or no therapy, L-arginine compared with placebo or no therapy, nitroglycerin compared with placebo or no therapy and sildenafil compared with nitroglycerin. The risk of bias of included studies was judged as low or unclear. In two studies the intervention was not blinded. The certainty of evidence for our primary outcomes was judged as moderate for the intervention sildenafil and low for tadalafil and nitroglycerine (due to low number of participants and low number of events). For the intervention L-arginine, our primary outcomes were not reported. Sildenafil citrate compared to placebo or no therapy (5 studies, 516 women) Five studies (Canada, Australia and New Zealand, the Netherlands, the UK and Brazil) involving 516 pregnant women with FGR were included. We assessed the certainty of the evidence as moderate. Compared with placebo or no therapy, sildenafil probably has little or no effect on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.80 to 1.27, 5 studies, 516 women); may reduce fetal mortality (RR 0.82, 95% CI 0.60 to 1.12, 5 studies, 516 women), and increase neonatal mortality (RR 1.45, 95% CI 0.90 to 2.33, 5 studies, 397 women), although the results are uncertain for fetal and neonatal mortality as 95% confidence intervals are wide crossing the line of no effect. Tadalafil compared with placebo or no therapy (1 study, 87 women) One study (Japan) involving 87 pregnant women with FGR was included. We assessed the certainty of the evidence as low. Compared with placebo or no therapy, tadalafil may have little or no effect on all-cause mortality (risk ratio 0.20, 95% CI 0.02 to 1.60, one study, 87 women); fetal mortality (RR 0.11, 95% CI 0.01 to 1.96, one study, 87 women); and neonatal mortality (RR 0.89, 95% CI 0.06 to 13.70, one study, 83 women). L-Arginine compared with placebo or no therapy (1 study, 43 women) One study (France) involving 43 pregnant women with FGR was included. This study did not assess our primary outcomes. Nitroglycerin compared to placebo or no therapy (1 studies, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. Sildenafil citrate compared to nitroglycerin (1 study, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups.

Authors' conclusions: Interventions affecting the nitric oxide pathway probably do not seem to influence all-cause (fetal and neonatal) mortality in pregnant women carrying a baby with FGR, although more evidence is needed. The certainty of this evidence is moderate for sildenafil and low for tadalafil and nitroglycerin. For sildenafil a fair amount of data are available from randomised clinical trials, but with low numbers of participants. Therefore, the certainty of evidence is moderate. For the other interventions investigated in this review there are insufficient data, meaning we do not know whether these interventions improve perinatal and maternal outcomes in pregnant women with FGR.

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Conflict of interest statement

Anouk Pels and Wessel Ganzevoort performed the assessment and data extraction of the studiesSharp 2018, Groom 2019 and von Dadelszen 2022. Aris Papageorghiou and Katie Groom performed the assessment and data extraction of Pels 2020.

Anouk Pels: was involved in the Dutch STRIDER trial, a randomised controlled trial investigating sildenafil versus placebo in severe, early‐onset fetal growth restriction. The Dutch STRIDER trial was eligible for inclusion in the systematic review. She was not involved in any decisions relating to the study (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the Dutch STRIDER trial.

Wessel Ganzevoort: has received government support for the conduct of investigator‐initiated clinical trials (Dutch STRIDER trial fund by ZonMW). He has also received free of charge supply of testing materials from Roche Diagnostics in clinical studies that focus on placental insufficiency. He reports not being involved in any decisions relating to the study (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the Dutch STRIDER trial.

Louise C Kenny is Executive Pro‐Vice Chancellor of the Faculty of Health and Life Sciences at the University of Liverpool and Professor of Maternal and Fetal Health and as such has numerous grant applications under review at any given time. Anouk Pels: has been paid by Alere to give invited symposia on a proprietary screening test for preeclampsia. She is the editor of Ten Teachers and has received royalties from the publishers. She is also a limited shareholder in Metabolomic Diagnostics, an SME who have licensed technology that she has developed pertaining to the screening of preeclampsia. She is a co‐investigator for the UK STRIDER trial, funded by the National Institute for Health Research and Medical Research Council. She reports not being involved in any decisions relating to the study (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the UK STRIDER trial.

Philip N Baker: received Health Research Council (NZ) funding to his previous institution (university of Auckland) for a randomised controlled trial of sildenafil therapy in severe, early onset intrauterine growth restriction. He is a minority shareholder in Metabolomic Diagnostics, which seeks to develop screening tests for major pregnancy complications, including fetal growth restriction. He also holds a patent (no monies received) for the diagnosis of pre‐eclampsia/fetal growth restriction (No. PCT/EP2010/070446). The patent application includes 14 metabolites as individual prognostic variables of pre‐eclampsia, and makes claims to combinations of key metabolites, which are likely to be employed in a prognostic product. He is a co‐investigator on the UK, NZ/Australia and Canadian STRIDER trials. He reports not being involved in any decisions relating to the study (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the UK and NZ/Australia STRIDER trials.

Peter von Dadelszen: is a co‐investigator on the UK and Canadian STRIDER trials. He reports not being involved in any decisions relating to the studies (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the UK and Canadian STRIDER trials.

Christian Gluud: is the Co‐ordinating Editor of the Cochrane Hepato‐Biliary Group and is a co‐investigator on the Dutch STRIDER trial. He reports not being involved in any decisions relating to the studies (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the Dutch STRIDER trial.

Chirag T Kariya: CTK is is a co‐investigator for the Canadian STRIDER trial, funded by Canadian Institute of Health Research (CIHR) grant to the University of British Columbia that included support to travel to meetings for the study, conducting study related activities and salary support. They report not being involved in any decisions relating to the study (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the Canadian STRIDER trial.

Aleid G Leemhuis: was involved in the Dutch STRIDER trial, a randomised controlled trial investigating sildenafil versus placebo in severe, early‐onset fetal growth restriction. The Dutch STRIDER trial was eligible for inclusion in the systematic review. She was not involved in any decisions relating to the study (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the Dutch STRIDER trial. Aleid is a Pediatrician and senior investigator in the Deparrment of Neonatology Amsterdam UMC.

Katie M Groom: I am an employee of the University of Auckland. I have received travel/accommodation/meeting expenses in my role as board member for the Australian Clinical Trials Alliance (2016‐2018). I am the lead author of the STRIDER New Zealand/Australia trial.I was not involved in any decisions relating to the study (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the New Zealand/Australia STRIDER trial.

Andrew N Sharp: Andrew Sharp is a co‐applicant on a NIHR EME funded randomised controlled trial of the effect of sildenafil on fetal growth in severe early‐onset IUGR (UK STRIDER). The results of this RCT are available for inclusion in this review. He reports not being involved in any decisions relating to the study (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the UK STRIDER trial.

Laura Magee: Consultancy: Legal work for the Canadian Medical Protective Associate in reviewing cases of colleagues. Management of hypertension is the area that I am most frequently asked to comment on. Employment: King’s College London. Obstetric physician and Professor of Women's Health Grants/grants pending: NIHR grant as CI. Other grants as co‐investigator (UKRI, Wellcome). WILL Trial PRECISE, PRECISE‐DYAD. Co‐investigator for Canadian STRIDER trial funded by Canadian Institute of Health Research (CIHR). She reports not being involved in any decisions relating to the study (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the Canadian STRIDER trial.

Janus C Jakobsen: is a contractor on the STRIDER consortium, but declares no other conflicts.

Ben Willem J Mol has received payment for consultancy from ObsEva Geneva (member of an advisory board since 2013), Guerbet (individual advice on Lipiodol), Merck (advisory activities) and IGenomix (member of advisory board since 2019). He has received payment for review preparation from the European Journal of Obstetrics and Gynaecology and has received travel/accommodation/meeting expenses for various non‐commercial scientific meetings (ASRM/ESHRE) as invited speaker. He has also received payment for expert testimony (Cicil cases in Australia). He is supported by a NHMRC Investigatorgrant (GNT1176437). He reports consultancy for ObsEva and Merck and travel support from Merck. He is an Editor for Cochrane Pregnancy and Childbirth, but was not involved in the editorial process for this review. He was involved in the organization of the STRIDER consortium, but was not involved as an author in the individual trials.

Aris T Papageorghiou: I am employed as a consultant in the NHS; and as an academic at the University. I also provide obstetric ultrasound in the private health sector. My research is mostly funded by public bodies, research councils, foundations and charities in the UK, Europe and USA (currently: HTA/NIHR; EPSRC/NIHR; RCUK/GCRF; NIHR/BRC; ERC; NIH; Bill & Melinda Gates Foundation). The NIHR funded the Maternal sildenafil for severe fetal growth restriction (STRIDER) trial, and this Cochrane review was conceived and planned during a STRIDER meeting, but not funded directly. I have previously participated in research where companies contributed to a grant (GE, Philips, Samsung, Premaitha Health). As an academic I often participate in research meetings at other hospitals or universities; these are unpaid but travel to attend meetings is usually provided. Some of these were sponsored by industry to the host institutions (Roche, Philips, Samsung, GE). I participate as a speaker in educational events that have, on occasion, received industrial sponsorship to cover travel, accomodation and honoraria. I receive royalties for medical text‐books I have published (Informa Healthcare, Oxford University Press). I am a co‐founder, shareholder, and senior scientific advisor for Intelligent Ultrasound, a company that aims to improve clinical ultrasound. For this I receive payments, managed through Oxford University Innovations, a subsidiary of the University of Oxford that manages technology transfer and academic consulting activities. Finally, I am a Editor‐in‐Chief for BJOG, for which I am paid a stipend; Visiting Professor at Beijing Capital University (not remunerated); a board member of the journal Ultrasound in Obstetrics and Gynecology (not remunerated); and Chair of the Expert Working Group, Obs & Gyn, Health & Social Care Information Centre (not remunerated). He reports not being involved in any decisions relating to the study (inclusion/exclusion, risk of bias, data extraction, GRADE) and these tasks were carried out by other members of the review team who were not directly involved in the UK STRIDER trial.

Figures

1
1
Applying the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool
2
2
Study flow diagram.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Sildenafil versus placebo or no therapy, Outcome 1: All‐cause mortality
1.2
1.2. Analysis
Comparison 1: Sildenafil versus placebo or no therapy, Outcome 2: Fetal mortality
1.3
1.3. Analysis
Comparison 1: Sildenafil versus placebo or no therapy, Outcome 3: Neonatal mortality
1.4
1.4. Analysis
Comparison 1: Sildenafil versus placebo or no therapy, Outcome 4: Proportion of women experiencing a maternal hypertensive disorder
1.5
1.5. Analysis
Comparison 1: Sildenafil versus placebo or no therapy, Outcome 5: Gestational age at delivery
1.6
1.6. Analysis
Comparison 1: Sildenafil versus placebo or no therapy, Outcome 6: Birthweight
1.7
1.7. Analysis
Comparison 1: Sildenafil versus placebo or no therapy, Outcome 7: Major neonatal morbidity
1.8
1.8. Analysis
Comparison 1: Sildenafil versus placebo or no therapy, Outcome 8: Maternal harmful effects or events
2.1
2.1. Analysis
Comparison 2: Tadalafil versus placebo or no therapy, Outcome 1: All‐cause mortality
2.2
2.2. Analysis
Comparison 2: Tadalafil versus placebo or no therapy, Outcome 2: Fetal mortality
2.3
2.3. Analysis
Comparison 2: Tadalafil versus placebo or no therapy, Outcome 3: Neonatal mortality
2.4
2.4. Analysis
Comparison 2: Tadalafil versus placebo or no therapy, Outcome 4: Proportion of women experiencing a maternal hypertensive disorder
2.5
2.5. Analysis
Comparison 2: Tadalafil versus placebo or no therapy, Outcome 5: Gestational age at delivery
2.6
2.6. Analysis
Comparison 2: Tadalafil versus placebo or no therapy, Outcome 6: Birthweight
2.7
2.7. Analysis
Comparison 2: Tadalafil versus placebo or no therapy, Outcome 7: Major neonatal morbidity
2.8
2.8. Analysis
Comparison 2: Tadalafil versus placebo or no therapy, Outcome 8: Maternal harmful effects or events
3.1
3.1. Analysis
Comparison 3: L‐Arginine versus placebo or no therapy, Outcome 1: Gestational age at delivery
3.2
3.2. Analysis
Comparison 3: L‐Arginine versus placebo or no therapy, Outcome 2: Birthweight
4.1
4.1. Analysis
Comparison 4: Nitroglycerin versus placebo or no therapy, Outcome 1: All‐cause mortality
4.2
4.2. Analysis
Comparison 4: Nitroglycerin versus placebo or no therapy, Outcome 2: Fetal mortality
4.3
4.3. Analysis
Comparison 4: Nitroglycerin versus placebo or no therapy, Outcome 3: Neonatal mortality
4.4
4.4. Analysis
Comparison 4: Nitroglycerin versus placebo or no therapy, Outcome 4: Gestational age at delivery
4.5
4.5. Analysis
Comparison 4: Nitroglycerin versus placebo or no therapy, Outcome 5: Birthweight
4.6
4.6. Analysis
Comparison 4: Nitroglycerin versus placebo or no therapy, Outcome 6: Major neonatal morbidity
4.7
4.7. Analysis
Comparison 4: Nitroglycerin versus placebo or no therapy, Outcome 7: Maternal harmful effects or events
5.1
5.1. Analysis
Comparison 5: Sildenafil versus nitroglycerin, Outcome 1: All‐cause mortality
5.2
5.2. Analysis
Comparison 5: Sildenafil versus nitroglycerin, Outcome 2: Fetal mortality
5.3
5.3. Analysis
Comparison 5: Sildenafil versus nitroglycerin, Outcome 3: Neonatal mortality
5.4
5.4. Analysis
Comparison 5: Sildenafil versus nitroglycerin, Outcome 4: Major neonatal morbidity
5.5
5.5. Analysis
Comparison 5: Sildenafil versus nitroglycerin, Outcome 5: Maternal harmful effects or events
6.1
6.1. Analysis
Comparison 6: Sensitivity analysis excluding studies without evidence of prospective trial registration: Sildenafil versus placebo or no therapy, Outcome 1: All‐cause mortality
6.2
6.2. Analysis
Comparison 6: Sensitivity analysis excluding studies without evidence of prospective trial registration: Sildenafil versus placebo or no therapy, Outcome 2: Fetal mortality
6.3
6.3. Analysis
Comparison 6: Sensitivity analysis excluding studies without evidence of prospective trial registration: Sildenafil versus placebo or no therapy, Outcome 3: Neonatal mortality
6.4
6.4. Analysis
Comparison 6: Sensitivity analysis excluding studies without evidence of prospective trial registration: Sildenafil versus placebo or no therapy, Outcome 4: Proportion of women experiencing a maternal hypertensive disorder
6.5
6.5. Analysis
Comparison 6: Sensitivity analysis excluding studies without evidence of prospective trial registration: Sildenafil versus placebo or no therapy, Outcome 5: Gestational age at delivery
6.6
6.6. Analysis
Comparison 6: Sensitivity analysis excluding studies without evidence of prospective trial registration: Sildenafil versus placebo or no therapy, Outcome 6: Birthweight
6.7
6.7. Analysis
Comparison 6: Sensitivity analysis excluding studies without evidence of prospective trial registration: Sildenafil versus placebo or no therapy, Outcome 7: Major neonatal morbidity
6.8
6.8. Analysis
Comparison 6: Sensitivity analysis excluding studies without evidence of prospective trial registration: Sildenafil versus placebo or no therapy, Outcome 8: Maternal harmful effects or events
7.1
7.1. Analysis
Comparison 7: Sensitivity analysis major neonatal morbidity: Sildenafil versus placebo or no therapy, Outcome 1: IVH grade 3 or more
7.2
7.2. Analysis
Comparison 7: Sensitivity analysis major neonatal morbidity: Sildenafil versus placebo or no therapy, Outcome 2: PVL grade 2 or more
7.3
7.3. Analysis
Comparison 7: Sensitivity analysis major neonatal morbidity: Sildenafil versus placebo or no therapy, Outcome 3: Moderate or severe BPD
7.4
7.4. Analysis
Comparison 7: Sensitivity analysis major neonatal morbidity: Sildenafil versus placebo or no therapy, Outcome 4: NEC grade 2 or more
7.5
7.5. Analysis
Comparison 7: Sensitivity analysis major neonatal morbidity: Sildenafil versus placebo or no therapy, Outcome 5: Persistent pulmonary hypertension of the neonate
7.6
7.6. Analysis
Comparison 7: Sensitivity analysis major neonatal morbidity: Sildenafil versus placebo or no therapy, Outcome 6: ROP treated by surgery or laser therapy
8.1
8.1. Analysis
Comparison 8: Sensitivity analysis major neonatal morbidity: tadalafil versus placebo or no therapy, Outcome 1: IVH grade 3 or more
8.2
8.2. Analysis
Comparison 8: Sensitivity analysis major neonatal morbidity: tadalafil versus placebo or no therapy, Outcome 2: PVL grade 2 or more
8.3
8.3. Analysis
Comparison 8: Sensitivity analysis major neonatal morbidity: tadalafil versus placebo or no therapy, Outcome 3: Persistent pulmonary hypertension of the neonate
8.4
8.4. Analysis
Comparison 8: Sensitivity analysis major neonatal morbidity: tadalafil versus placebo or no therapy, Outcome 4: ROP treated by surgery or laser therapy
8.5
8.5. Analysis
Comparison 8: Sensitivity analysis major neonatal morbidity: tadalafil versus placebo or no therapy, Outcome 5: NEC grade 2 or more
9.1
9.1. Analysis
Comparison 9: Sensitivity analysis major neonatal morbidity: Nitroglycerin versus placebo or no therapy, Outcome 1: IVH grade 3 or more
9.2
9.2. Analysis
Comparison 9: Sensitivity analysis major neonatal morbidity: Nitroglycerin versus placebo or no therapy, Outcome 2: PVL grade 2 or more
9.3
9.3. Analysis
Comparison 9: Sensitivity analysis major neonatal morbidity: Nitroglycerin versus placebo or no therapy, Outcome 3: Moderate or severe BPD
9.4
9.4. Analysis
Comparison 9: Sensitivity analysis major neonatal morbidity: Nitroglycerin versus placebo or no therapy, Outcome 4: NEC grade 2 or more
9.5
9.5. Analysis
Comparison 9: Sensitivity analysis major neonatal morbidity: Nitroglycerin versus placebo or no therapy, Outcome 5: Persistent pulmonary hypertension of the neonate
9.6
9.6. Analysis
Comparison 9: Sensitivity analysis major neonatal morbidity: Nitroglycerin versus placebo or no therapy, Outcome 6: ROP treated by surgery or laser therapy
10.1
10.1. Analysis
Comparison 10: Sensitivity analysis major neonatal morbidity: Sildenafil versus Nitroglycerin, Outcome 1: IVH grade 3
10.2
10.2. Analysis
Comparison 10: Sensitivity analysis major neonatal morbidity: Sildenafil versus Nitroglycerin, Outcome 2: PVL grade 2 or more
10.3
10.3. Analysis
Comparison 10: Sensitivity analysis major neonatal morbidity: Sildenafil versus Nitroglycerin, Outcome 3: Moderate or severe BPD
10.4
10.4. Analysis
Comparison 10: Sensitivity analysis major neonatal morbidity: Sildenafil versus Nitroglycerin, Outcome 4: NEC grade 2 or more
10.5
10.5. Analysis
Comparison 10: Sensitivity analysis major neonatal morbidity: Sildenafil versus Nitroglycerin, Outcome 5: Persistent pulmonary hypertension of the neonate
10.6
10.6. Analysis
Comparison 10: Sensitivity analysis major neonatal morbidity: Sildenafil versus Nitroglycerin, Outcome 6: ROP treated by surgery or laser therapy
11.1
11.1. Analysis
Comparison 11: Sensitivity analysis studies with low risk of bias only: Sildenafil versus placebo or no therapy, Outcome 1: All‐cause mortality
11.2
11.2. Analysis
Comparison 11: Sensitivity analysis studies with low risk of bias only: Sildenafil versus placebo or no therapy, Outcome 2: Fetal mortality
11.3
11.3. Analysis
Comparison 11: Sensitivity analysis studies with low risk of bias only: Sildenafil versus placebo or no therapy, Outcome 3: Neonatal mortality
11.4
11.4. Analysis
Comparison 11: Sensitivity analysis studies with low risk of bias only: Sildenafil versus placebo or no therapy, Outcome 4: Proportion of women experiencing a maternal hypertensive disorder
11.5
11.5. Analysis
Comparison 11: Sensitivity analysis studies with low risk of bias only: Sildenafil versus placebo or no therapy, Outcome 5: Gestational age at delivery
11.6
11.6. Analysis
Comparison 11: Sensitivity analysis studies with low risk of bias only: Sildenafil versus placebo or no therapy, Outcome 6: Birthweight
11.7
11.7. Analysis
Comparison 11: Sensitivity analysis studies with low risk of bias only: Sildenafil versus placebo or no therapy, Outcome 7: Major neonatal morbidity
11.8
11.8. Analysis
Comparison 11: Sensitivity analysis studies with low risk of bias only: Sildenafil versus placebo or no therapy, Outcome 8: Maternal harmful effects or events
12.1
12.1. Analysis
Comparison 12: Sensitivity analysis major neonatal morbidity, excluding studies with a slightly different definition: Sildenafil versus placebo or no therapy, Outcome 1: Major neonatal morbidity
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References

References to studies included in this review

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    1. EUCTR2012-004112-63-NL. Sildenafil for early severe fetal growth restriction [The Dutch STRIDER (Sildenafil TheRapy In Dismal prognosis Early-onset intrauterine growth Restriction) Trial - Dutch STRIDER]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2012-004112-63-NL (first received 2014). [CENTRAL: CN-01842313]
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    1. NTR4751. Does Sildenafil improve the neonatal prognosis in severe early onset growth restriction? [The Dutch STRIDER (Sildenafil TheRapy In Dismal prognosis Early-onset fetal growth Restriction) - The Dutch STRIDER]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=NTR4751 (first received 2014). [CENTRAL: CN-01874095]
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    1. Pels A, Derks J, Elvan-Taspinar A, Drongelen J, Boer M, Duvekot H, et al. Maternal sildenafil vs placebo in pregnant women with severe early-onset fetal growth restriction: a randomized clinical trial. JAMA Network Open 2020;3(6):e205323. [CENTRAL: CN-02129709] [PMID: ] - PMC - PubMed
Sharp 2018 {published data only}
    1. EUCTR2013-005398-32-GB. STRIDER - Sildenafil therapy for treatment of intrauterine growth restriction [A randomised controlled trial of sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction - STRIDER version 2.0]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2013-005398-32-GB (first received 2015). [CENTRAL: CN-01910167]
    1. ISRCTN39133303. Sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction [A randomised controlled trial of sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=ISRCTN39133303 (first received 2014). [CENTRAL: CN-01861980]
    1. Khalil A, Sharp A, Cornforth C, Jackson R, Mousa H, Stock S, et al. Effect of sildenafil on maternal hemodynamics in pregnancies complicated by severe early-onset fetal growth restriction: planned subgroup analysis from a multicenter randomized placebo-controlled double-blind trial. Ultrasound in Obstetrics & Gynecology 2019;55(2):198-209. [CENTRAL: CN-01987894] [EMBASE: 629130284] [PMID: ] - PubMed
    1. Khalil A, Sharp A, Cornforth C, Jackson R, Mousa H, Stock S, et al. Maternal cardiovascular changes secondary to sildenafil intake in pregnancies complicated by severe fetal growth restriction: STRIDER trial. BJOG: an international journal of obstetrics and gynaecology 2018;125(Suppl 2):25. [CENTRAL: CN-01607684] [EMBASE: 622019719]
    1. Sharp A, Cornforth C, Jackson R, Harrold J, Turner MA, Kenny LC, et al. Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial. Lancet Child and Adolescent Health 2018;2(2):93-102. [CENTRAL: CN-01982155] [EMBASE: 620544342] [PMID: ] - PubMed
Trapani 2016a {published data only}
    1. Trapani A Jr, Goncalves LF, Trapani TF, Franco MJ, Galluzzo RN, Pires MM. Comparison between transdermal nitroglycerin and sildenafil citrate in intrauterine growth restriction: effects on uterine, umbilical and fetal middle cerebral artery pulsatility indices. Ultrasound in Obstetrics & Gynecology 2016;48(1):61-5. - PubMed
von Dadelszen 2022 {published data only}
    1. NCT02442492. Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction (STRIDERCan). https://clinicaltrials.gov/ct2/show/ (first received 2015 May 5).
    1. Dadelszen P, Audibert F, Bujold E, Bone JN, Sandhu A, Li J, et al. Halting the Canadian STRIDER randomised controlled trial of sildenafil for severe, early-onset fetal growth restriction: ethical, methodological, and pragmatic considerations. BMC Research Notes 2022;15(1):244. [CENTRAL: CN-02420483] [PMID: ] - PMC - PubMed
Winer 2009 {published data only}
    1. NCT00549575. L-arginine treatment for severe vascular fetal intrauterine growth restriction: a randomized double bind controlled trial (L arginine in IUGR) [L-Arginine Treatment for Severe Vascular Fetal Intrauterine Growth Restriction: a Randomized Double Bind Controlled Trial]. Https://clinicaltrials.gov/show/NCT00549575 (first received 2007 Oct 24). [CENTRAL: CN-02013934]
    1. Winer N, Branger B, Azria E, Roze JC, Descamps P, Philippe HJ, et al. Treatment of severe vascular fetal intrauterine growth restriction with L-arginine: a multicenter prospective double-blind randomized placebo-controlled study. Ultrasound in Obstetrics & Gynecology 2007;30:381. [CENTRAL: CN-00615736]
    1. Winer N, Branger B, Azria E, Tsatsaris V, Philippe HJ, Roze JC, et al. L-Arginine treatment for severe vascular fetal intrauterine growth restriction: a randomized double-blind controlled trial. Clinical Nutrition (Edinburgh, Scotland) 2009 Jun;28(3):243-8. [CENTRAL: CN-00706952] [EMBASE: 50473765] [PMID: ] - PubMed

References to studies excluded from this review

Babar 2018 {published data only}
    1. Babar A, Bujold E, Leblanc V, Lavoie-Lebel E, Paquette J, Bazinet L, et al. Changes in endothelial function, arterial stiffness and blood pressure in pregnant women after consumption of high-flavanol and high-theobromine chocolate: a double blind randomized clinical trial. Hypertension in Pregnancy 2018;37(2):68-80. [CENTRAL: CN-01642877] [EMBASE: 621712092] [PMID: ] - PubMed
Bowkalow 2018 {published data only}
    1. Bowkalow S, Schleussner E, Kahler C, Schneider U, Lehmann T, Groten T. Pentaerythrityltetranitrate (PETN) improves utero- and feto-placental Doppler parameters in pregnancies with impaired utero-placental perfusion in mid-gestation - a secondary analysis of the PETN-pilot trial. Journal of Perinatal Medicine 2018;46(9):1004-9. [CENTRAL: CN-01708467] [PMID: ] - PubMed
Bujold 2016 {published data only}
    1. Bujold E, Babar A, Lavoie E, Girard M, Leblanc V, Lemieux S, et al. High-flavanol chocolate to improve placental function and to decrease the risk of preeclampsia: a double blind randomized clinical trial. American Journal of Obstetrics and Gynecology 2016;214(1 Suppl):S23-24, Abstract no: 32.
Camarena‐Pulido 2016 {published data only}
    1. Pulido EE, Benavides LG, Baron JG, Gonzalez SP, Saray AJ, Padilla FE, et al. Efficacy of l-arginine for preventing preeclampsia in high-risk pregnancies: a double-blind, randomized, clinical trial. Hypertension in Pregnancy 2016;35(2):217-25. [CENTRAL: CN-01166503] [EMBASE: 20160242492] [PMID: ] - PubMed
Decano 2000 {published data only}
    1. Decano MB, Cabrera LT. The effects of transdermal nitroglycerin (nitrol patch) on the uterine and umbilical artery blood flow in preeclampsia: a randomized double blind placebo controlled study [abstract]. In: XVI FIGO World Congress of Obstetrics & Gynecology; 2000 Sept 3-8; Washington DC, USA (Book 1). 2000:26. [CENTRAL: CN-00355035]
DRKS00011374 {published data only}
    1. DRKS00011374. Pentaeritrithyl tetranitrate (PETN) for secondary prevention of intrauterine growth restriction [Pentaeritrithyl tetranitrate (PETN) for secondary prevention of intrauterine growth restriction - PETN Trial]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00011374 (first received 2017). [CENTRAL: CN-01888570]
El‐Hamedi 2001 {published data only}
    1. El-Hamedi A, Shillito TJA, Simpson NAB, Walker JJ. A prospective randomised controlled trial of nitric oxide donors in at risk pregnancy [abstract]. Journal of Obstetrics and Gynaecology 2001;21 Suppl 1:S22. [CENTRAL: CN-00363807]
El‐Sayed 2018a {published data only}
    1. El-Sayed MA, Saleh SA, Maher MA, Khidre AM. Effect of sildenafil citrate on uteroplacental perfusion Doppler indices in growth-restricted fetuses. Menoufia Medical Journal 2018;31(1):31-7. - PubMed
EUCTR2014‐003138‐18‐IE {published data only}
    1. EUCTR2014-003138-18-IE. STRIDER Ireland [STRIDER Ireland: A randomised controlled trial of sildenafil therapy In dismal prognosis early-0nset intrauterine growth restriction]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-003138-18-IE (first received 2015). [CENTRAL: CN-01904581]
Furuhashi 2021 {published data only}
    1. Furuhashi F, Tanaka H, Maki S, Tsuji M, Magawa S, Kaneda MK, et al. Tadalafil treatment for preeclampsia (medication in preeclampsia; MIE): a multicenter phase II clinical trial. Journal of Maternal-fetal & Neonatal Medicine 2021;34(22):3709-15. [CENTRAL: CN-02006473] [EMBASE: 2003630970] [PMID: ] - PubMed
Groten 2012 {published data only}
    1. Groten T, Fitzgerald J, Lehmann T, Schneider U, Kahler C, Schleussner E. Reduction of preeclampsia related complications with with the NO-donor penterythriltetranitrat (petn) in risk pregnancies - A prospective randomized double-blind placebo pilot study. Pregnancy Hypertension 2012;2(3):181. [CENTRAL: CN-02093669] - PubMed
Groten 2019 {published data only}
    1. Groten T, Lehmann T, Schleussner E, Pecks U, Von Kaisenberg C, Condic M, et al. Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial. BMC Pregnancy and Childbirth 2019;19(1):336. [CENTRAL: CN-01987100] [EMBASE: 629299641] [PMID: ] - PMC - PubMed
    1. Groten T, Schleussner E. Pentaerithrityl tetranitrate (PETN) for secondary prevention of intrauterine growth restriction (PETN-Trial). Placenta 2019;83:e80. [CENTRAL: CN-01996848] [EMBASE: 2002510233]
Hladunewich 2006 {published data only}
    1. Hladunewich MA, Derby GC, Lafayette RA, Blouch KL, Druzin ML, Myers BD. Effect of L-arginine therapy on the glomerular injury of preeclampsia: a randomized controlled trial. Obstetrics and Gynecology 2006;107(4):886-95. [CENTRAL: CN-00556006] [EMBASE: 2006242132] [PMID: ] - PubMed
IRCT20120215009014N419 {published data only}
    1. IRCT20120215009014N419. Effect of L-arginine versus placebo on intrauterine growth of the fetus in primigravid women. https://trialsearch.who.int/Trial2.aspx?TrialID=IRCT20120215009014N419 (first received 2022). [CENTRAL: CN-02410603]
IRCT20140317017034N9 {published data only}
    1. IRCT20140317017034N9. Effect of pentoxifiyllin on fetal growth restriction [The effect of Pentoxifiylline administration on placenta circulation and pregnancy out come in Fetal Growth Restriction]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=IRCT20140317017034N9 (first received 2019). [CENTRAL: CN-02069014]
jRCTs041180121 {published data only}
    1. jRCTs041180121. Prevention for Recurrence Of The preEClampsia with TAdalafil [A study on Prevention of Hypertensive Disorders of Pregnancy who have a history of severe hypertensive disorders of pregnancy -Pre-test for multicenter trial- - PROTECTA]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-jRCTs041180121 (first received 2019). [CENTRAL: CN-01972419]
Khachaturyan 2011 {published data only}
    1. Khachaturyan L, Groten T, Kahler C, Bulagay-Morschel M, Schneider U, Schleussner E. Reduction of intrauterine growth retardation (IUGR) in a high-risk group with the NO-donor penterythriltetranitrat (PETN) - A prospective randomized double-blind placebo trial. Geburtshilfe und Frauenheilkunde 2011;71(10):895. [CENTRAL: CN-01034461] [EMBASE: 70703843]
Lees 1998 {published data only}
    1. Lees C, Valensise H, Black R, Harrington K, Byiers S, Romanini C, et al. The efficacy and fetal-maternal cardiovascular effects of transdermal glyceryl trinitrate in the prophylaxis of pre-eclampsia and its complications: a randomized double-blind placebo-controlled trial. Ultrasound in Obstetrics & Gynecology 1998;12(5):334-8. [CENTRAL: CN-00157005] [PMID: ] - PubMed
Lopez‐Molina 2008 {published data only}
    1. Lopez-Molina K, Gonzalez-Altamirano JC, Valdivia-Silva JE. Early L-arginine therapy improves notably the fetal growth in preeclamptic women. A randomized controlled trial. In: 55th Annual Meeting of the Society of Gynecologic Investigation; 2008 March 26-29; San Diego, USA. 2008:Abstract no: 801. [CENTRAL: CN-00653551]
Madhubala 2006 {published data only}
    1. Madhubala M. Use of L. Arginine in oligohydramnios [abstract]. In: 49th All India Congress of Obstetrics and Gynaecology; 2006 January 6-9; Cochin, Kerala State, India. 2006:42. [CENTRAL: CN-00582409]
Monari 2021 {published data only}
    1. Monari F, Menichini D, Pignatti L, Basile L, Facchinetti F, Neri I. Effect of L-Arginine supplementation in pregnant women with chronic hypertension and previous placenta vascular disorders receiving aspirin prophylaxis: a randomized control trial. Minerva Obstetrics and Gynecology 2021;73:782-9. [CENTRAL: CN-02279076] [PMID: ] - PubMed
NCT01355822 {published data only}
    1. NCT01355822. Impact of the NO-donor Pentaerythrithyltetrantrate on perinatal outcome in high-risk pregnancies [Impact of the NO-donor Pentaerythrithyltetrantrate on Perinatal Outcome in High-risk Pregnancies: a Prospective Randomized Pilot Study]. Https://clinicaltrials.gov/show/NCT01355822 (first received 2011 May 16). [CENTRAL: CN-01486553]
NCT02782559 {published data only}
    1. NCT02782559. Efficacy of sildenafil in preterm preeclampsia. Https://clinicaltrials.gov/show/NCT02782559 (first received 11 February 2016). [CENTRAL: CN-01558533]
NCT02801695 {published data only}
    1. NCT02801695. Evaluation of the efficacy of citrulline supplementation on the delay of delivery for women hospitalized for pre-eclampsia (CITRUPE). Https://clinicaltrials.gov/show/nct02801695 (first received 2016 Jun 3). [CENTRAL: CN-01578215]
NCT03262961 {published data only}
    1. NCT03262961. Use of sildenafil citrate in management of mild pre-eclampsia [Use of Sildenafil Citrate in Management of Mild Pre-eclampsia: A Randomized Controlled Trial]. Https://clinicaltrials.gov/show/nct03262961 (first received 19 August 2017). [CENTRAL: CN-01586413]
NCT03669185 {published data only}
    1. NCT03669185. Pentaerithrityl Tetranitrate (PETN) for secondary prevention of intrauterine growth restriction [Pentaerithrityltetranitrat (PETN) Zur Sekundarprophylaxe Der Intrauterinen Wachstumsretardierung]. Https://clinicaltrials.gov/show/nct03669185 (first received 2018 Sep 13). [CENTRAL: CN-01663222]
Neri 2010 {published data only}
    1. Neri I, Monari F, Sgarbi L, Berardi A, Masellis G, Facchinetti F. L-arginine supplementation in women with chronic hypertension: impact on blood pressure and maternal and neonatal complications. Journal of Maternal-fetal & Neonatal Medicine 2010;23(12):1456-60. [CENTRAL: CN-00772723] [PMID: ] - PubMed
Picciolo 2000 {published data only}
    1. Picciolo C, Roncaglia N, Neri I, Pasta F, Arreghini A, Facchinetti F. Nitric oxide in the prevention of pre-eclampsia. Prenatal and Neonatal Medicine 2000;5(4):212-5. [CENTRAL: CN-00399568] [EMBASE: 30809202]
Razik 2016 {published data only}
    1. Razik MA, El-Berry S, Abosereah M, Edris Y, Sharafeldeen A. Prophylactic treatment for preeclampsia in high-risk teenage primigravidae with nitric oxide donors: a pilot study. Journal of Maternal-fetal & Neonatal Medicine 2016;29(16):2617-20. [CENTRAL: CN-01264685] [PMID: ] - PubMed
Reyna‐Villasmil 2001 {published data only}
    1. Reyna-Villasmil E, Prieto-Franchi M, Guerra-Velazquez M, Torres-Montilla M. Effect of transdermal nitroglycerin on umbilical artery blood flow in preeclampsia [abstract]. Journal of Perinatal Medicine 2001;29 Suppl 1(Pt 2):486. [CENTRAL: CN-00363873]
Rytewski 2005 {published data only}
    1. Rytlewski K, Olszanecki R, Korbut R, Zdebski Z. Effects of prolonged oral supplementation with L-arginine on blood pressure and nitric oxide synthesis in preeclampsia. European Journal of Clinical Investigation 2005;35(1):32-7. [CENTRAL: CN-00575546] [EMBASE: 40187952] [PMID: ] - PubMed
Samangaya 2009a {published data only}
    1. Samangaya RA, Wareing M, Skillern L, Baker PN. Phosphodiesterase inhibitor effect on small artery function in preeclampsia. Hypertension in Pregnancy 2011;30(2):144-52. [CENTRAL: CN-00783854] - PubMed
Samangaya 2009b {published data only}
    1. Samangaya RA, Mires G, Shennan A, Skillern L, Howe D, McLeod A, et al. A randomised, double-blinded, placebo-controlled trial of the phosphodiesterase type 5 inhibitor sildenafil in the treatment of preeclampsia. Hypertension in Pregnancy 2009;28:369-82. [CENTRAL: CN-00740358] - PubMed
Schlembach 2013 {published data only}
    1. Schlembach D, Groten T, Lehmann T, Schneider U, Schleussner E. Impact of the NO-donor pentaerythrithyltetranitrate on perinatal outcome in high-risk pregnancies: a prospective randomized double blinded pilot study. Pregnancy Hypertension 2013;3(2):62. [CENTRAL: CN-02093670] - PubMed
Schleussner 2014 {published data only}
    1. Schleussner E, Kaehler C, Bulgay-Moerschel M, Schneider U, Hoyer H, Groten T. Reduction of intrauterine growth retardation (IUGR) in a high-risk group with the no-donor penterythriltetranitrat (PETN) - a prospective randomized double-blind placebo trial. Placenta 2010;31(9):A.82. [CENTRAL: CN-00795536]
    1. Schleussner E, Lehmann T, Kahler C, Schneider U, Schlembach D, Groten T. Erratum: Impact of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk pregnancies: A prospective, randomized, double-blinded trial (Journal of Perinatal Medicine 42:4 (507-514) DOI: 10.1515/jpm-2013-0212). Journal of Perinatal Medicine 2015;43(5):641. [CENTRAL: CN-01129520] [EMBASE: 605946537] [PMID: ] - PubMed
    1. Schleussner E, Lehmann T, Kahler C, Schneider U, Schlembach D, Groten T. Impact of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk pregnancies: a prospective, randomized, double-blinded trial. Journal of Perinatal Medicine 2014;42(4):507-14. [CENTRAL: CN-00999631] [EMBASE: 2014468781] [PMID: ] - PubMed
Staff 2004 {published data only}
    1. Staff AC, Berge L, Haugen G, Lorentzen B, Mikkelsen B, Henriksen T. Dietary supplementation with L-arginine or placebo in women with pre-eclampsia. Acta Obstetricia et Gynecologica Scandinavica 2004;83(83):103-7. [CENTRAL: CN-00459625] [PMID: ] - PubMed
Tan 2000 {published data only}
    1. Tan Y, Zhang W, Lu B. Treatment of intrauterine growth retardation with magnesium sulfate. Zhonghua Fu Chan Ke za Zhi 2000 Nov;35(11):664-6. [CENTRAL: CN-00408397] [PMID: ] - PubMed
Teichert 2019 {published data only}
    1. Teichert V, Gutierrez-Samudio R, Pastuschek J, Markert U, Groten T. PETN induced HO-1 expression in endothelial cells as a target for secondary prevention of endothelial dysfunction. Placenta 2019;83:e80. [CENTRAL: CN-01999164] [EMBASE: 2002510299]
Trapani 2016b {published data only}
    1. RBR-8qj4p5. Evaluation of blood pressure, blood flow fetal and neonatal outcome with the use of a phosphodiesterase type 5 inhibitor in the treatment of women with preeclampsia [Hemodynamics and perinatal assessment of phosphodiesterase type 5 inhibitors in pregnant women with preeclampsia]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=RBR-8qj4p5 (first received 2016). [CENTRAL: CN-01841864]
    1. Trapani A, Goncalves LF, Trapani TF, Vieira S, Pires M, Pires MM. Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment: a randomized controlled trial. Obstetrics and Gynecology 2016;128(2):253-9. [CENTRAL: CN-01379691] [PMID: ] - PubMed
    1. Vigil-De Gracia P, Ludmir J. Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment: a randomized controlled trial. Obstetrics and Gynecology 2016;128(5):1181-2. [PMID: ] - PubMed
Valdivia‐Silva 2009 {published data only}
    1. Valdivia-Silva JE, Lopez-Molina K, Macedo R. Effect of early L-arginine therapy on intrauterine growth restriction in preeclampsia. A randomized controlled trial in Latin-American women. [Spanish] [Efecto de la terapia temprana con L-arginina en el crecimiento intrauterino restringido en la preclampsia. Estudio aleatorizado en mujeres latinoamericanas]. Progresos en Obstetricia y Ginecologia 2009;52(2):89-98. [CENTRAL: CN-00754747] [EMBASE: 354306780]
Valensise 2005 {published data only}
    1. Valensise H, Vasapollo B, Novelli GP, Altomare F, Arduini D. Nitric oxide donors and fluid therapy increase fetal growth in gestational hypertension [abstract]. Ultrasound in Obstetrics & Gynecology 2005;26(4):440. [CENTRAL: CN-00550253]
Xiao 2005 {published data only}
    1. Xiao XM, Li LP. L-arginine treatment for asymmetric fetal growth restriction. International Journal of Gynaecology and Obstetrics 2005;88(1):15-8. [CENTRAL: CN-00550215] - PubMed

References to studies awaiting assessment

CTRI/2019/09/021382 {published data only}
    1. CTRI/2019/09/021382. Treatment of intra uterine growth retardation using vidaryadi ghrita and L-Arginne. https://trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2019/09/021382 (first received 2019). [CENTRAL: CN-02349424]
CTRI/2022/03/041053 {published data only}
    1. CTRI/2022/03/041053. Evaluate the effect of Madhumalinivasanta rasa along with Yastimadhuadi siddha ghrita matra basti in Upavistaka(intra-uterine growth restriction) compaire with L-arginine sachet. https://trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2022/03/041053 (first received 2022). [CENTRAL: CN-02409098]
Dastjerdi 2012a {published data only}
    1. Dastjerdi MV, Hosseini S, Bayani L. Sildenafil citrate and uteroplacental perfusion in fetal growth restriction. Journal of Research in Medical Sciences 2012;17(7):632-6. [CENTRAL: CN-00902193] [EMBASE: 365723451] - PMC - PubMed
El‐Sayed 2018b {published data only}
    1. El-Sayed MA, Saleh SA, Maher MA, Khidre AM. Utero-placental perfusion Doppler indices in growth restricted fetuses: effect of sildenafil citrate. Journal of Maternal-fetal & Neonatal Medicine 2018;31(8):1045-50. [CENTRAL: CN-01628070] [PMID: ] - PubMed
    1. NCT02362399. Effect of Sildenafil citrate on uteri- placental perfusion, Doppler indices in growth restricted fetuses [Effect of Sildenafil Citrate on Uteri- Placental perfusion, Doppler indices in growth restricted fetuses]. Https://clinicaltrials.gov/show/NCT02362399 (first received 2015 Feb 5). [CENTRAL: CN-01552114]
El‐Shalakany 2018 {published data only}
    1. El-Shalakany A, Abd El Aleem MM, Zaifer M, Bawady A. Sildenafil citrate and uteroplacental perfusion in fetal growth restriction. Egyptian Journal of Hospital Medicine 2018;71(4):2989-95.
Eshraghi 2021 {published data only}
    1. Eshraghi N, Mohamadianamiri M, Ebrahimi M, Karimi F. The effect of sildenafil on intrauterine growth restriction (IUGR) of fetus with gestational age above 28 weeks and neonatal outcomes. International Journal of Pediatrics 2021;9(6):13643-51.
    1. TCTR20200526006. The effect of sildenafil on intrauterine growth restriction (IUGR) of fetus with gestational age above 28 weeks and neonatal outcomes [Effect of Sildenafil on Intrauterine Growth Restriction (IUGR) of Fetus]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=TCTR20200526006 (first received 2020). [CENTRAL: CN-02189826]
Gupta 2017 {published data only}
    1. Gupta S, Chauhan M, Sen J, Nanda S. Effect of transdermal nitroglycerine on doppler velocity waveforms of the uterine, umbilical and fetal middle cerebral arteries in patients with chronic placental insufficiency: a prospective RCT. Journal of Clinical and Diagnostic Research : JCDR 2017;11(7):QC13-7. [CENTRAL: CN-01403941] [EMBASE: 617499160] - PMC - PubMed
Huras 2014 {published data only}
    1. Huras H, Kalinka J, Radon-Pokracka M, Kusmierska-Urban K, Kufelnicka-Babout M, Nowak M, et al. Effects of pentoxifylline and docosahexaenoic acid supplemental treatment in intrauterine growth restriction. Journal of Maternal-fetal & Neonatal Medicine 2014;27(Suppl 1):131. [CENTRAL: CN-01064457] [EMBASE: 71504804]
Naseef 2022 {published data only}
    1. Naseef P, El Fatah IA, Tharwat A, El Sayed M. Difference between oral isosorbide mononitrate & sildenafil citrate therapy in reducing umbilical artery doppler indices in pregnancies with fetal growth restriction; a prospective randomized control trial. Egyptian Journal of Hospital Medicine 2022;88(1):2958-63.
NCT01107782 {published data only}
    1. NCT01107782. Sildenafil and uteroplacental perfusion [Phase 2 Study of Fetal Growth Retardation Treatment by Sildenafil]. Https://clinicaltrials.gov/show/NCT01107782 (first received 2010 Jan 13). [CENTRAL: CN-01529139]
NCT02590536 {published data only}
    1. NCT02590536. A trial evaluating the role of sildenafil in the treatment of fetal growth restriction [A randomized controlled trial evaluating the role of sildenafil in the treatment of fetal growth restriction]. Https://clinicaltrials.gov/show/NCT02590536 (first received 2015 Oct 21). [CENTRAL: CN-01493354]
PACTR201705002278236 {published data only}
    1. PACTR201705002278236. Sildenafil citrate for the treatment of asymmetrical intrauterine growth restriction: a randomized controlled trial. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=PACTR201705002278236 (first received 2017). [CENTRAL: CN-01895111]
Rasheedy 2019 {published data only}
    1. NCT03230162. Sildenafil versus low molecular weight heparin in fetal growth restriction treatment. https://clinicaltrials.gov/show/NCT03230162 (first received 2017 July 26). [CENTRAL: CN-02420461]
    1. Rasheedy R, El Bishry G, Tarek R. Maternal low molecular weight heparin versus sildenafil citrate for fetal growth restriction: a randomized, parallel groups, open-label clinical trial. Journal of Perinatology 2019;40(5):715-23. [CENTRAL: CN-02008477] [EMBASE: 2003558866] [PMID: ] - PubMed
Serey 1980 {published data only}
    1. Serey C, Saling E. Human placental lactogen (HPL) levels in the maternal serum following long-term intake of xantinol nicotinate (Complamin Retard) [Hpl-verhalten im mutterlichen serum nach langzeitiger gabe von xantinol-nicotinat (complamin retard)]. Zeitschrift fur Geburtshilfe und Perinatologie 1980;184:283-9. [CENTRAL: CN-00465639] - PubMed
Shehata 2018 {published data only}
    1. NCT03153215. Sildenafil in severe intrauterine growth retardation [Evaluation of addition of Sildenafil Citrate for treatment of severe intrauterine growth restriction]. Https://clinicaltrials.gov/show/nct03153215 (first received 2017 May 5). [CENTRAL: CN-01575093]
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References to ongoing studies

IRCT20160524028038N6 {published data only}
    1. IRCT20160524028038N6. Sildenafil citrate with melatonin and intrauterine growth restriction [Evaluation of the effect of Sildenafil Citrate with melatonin on intrauterine growth restriction]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=IRCT20160524028038N6 (first received 2020). [CENTRAL: CN-02170379]
IRCT20210730052014N1 {published data only}
    1. IRCT20210730052014N1. Comparison of the effect of pomegranate juice with sildenafil in the treatment of intrauterine growth restriction. https://trialsearch.who.int/Trial2.aspx?TrialID=IRCT20210730052014N1 (first received 2021). [CENTRAL: CN-02351408]
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    1. jRCTs041190065. Tadalafil for fetus with early-onset growth restriction (TADAFER IIb) [The clinical trial of tadalafil treatment for fetus with early-onset growth restriction placebo-controlled ramdomized multicenter phase II trial- - TADAFER IIb]. Http://www.who.int/trialsearch/Trial2.aspx?TrialID=JPRN-jRCTs041190065 (first received 2019). [CENTRAL: CN-01970876]
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NCT02678221   {published data only}
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NCT03177824 {published data only}
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NCT03321292 {published data only}
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NCT05029778 {published data only}
    1. NCT05029778. Arginine + citrulline as a supplement for weight gain in fetus with a decrease in their growth curve [Efficacy L-arginine + L-citrulline as a Dietary Supplement vs Placebo for Weight Gain in Fetus With a Decrease in Their Growth Curve in the Third Trimester of Pregnancy]. Https://clinicaltrials.gov/show/NCT05029778 (first received 2021 September 01). [CENTRAL: CN-02307577]
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UMIN000023778 {published data only}
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References to other published versions of this review

Pels 2020
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