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7/26/2018

Sildenafil Versus Low Molecular Weight Heparin in Fetal Growth Restriction Treatment - Tabular View - ClinicalTrials.gov

Trial record 1 of 3 for:    sildenafil, pregnant
Previous Study | Return to List | Next Study
Sildenafil Versus Low Molecular Weight Heparin in Fetal Growth Restriction
Treatment

The safety and scientific validity of this
study is the responsibility of the study
sponsor and investigators. Listing a
study does not mean it has been
evaluated by the U.S. Federal
Government. Know the risks and
potential benefits of clinical studies
and talk to your health care provider
before participating. Read our
disclaimer for details.

ClinicalTrials.gov Identifier:
NCT03230162
Recruitment Status : Recruiting
First Posted : July 26, 2017
Last Update Posted : July 26,
2017
See Contacts and Locations

Sponsor:

Ain Shams University

Information provided by (Responsible Party):
Radwa Rasheedy Ali, Ain Shams University

Study Details

Tabular View

No Results Posted

Disclaimer
How to Read a Study Record

Tracking Information
First Submitted Date

May 28, 2017

ICMJE
ICMJE

July 26, 2017

Last Update Posted Date

July 26, 2017

Actual Study Start Date

June 1, 2017

First Posted Date

ICMJE

https://www.clinicaltrials.gov/ct2/show/record/NCT03230162?term=sildenafil%2C+pregnant&rank=1&view=record

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Sildenafil Versus Low Molecular Weight Heparin in Fetal Growth Restriction Treatment - Tabular View - ClinicalTrials.gov

Estimated Primary

May 1, 2018 (Final data collection date for primary outcome measure)

Completion Date
Current Primary Outcome
Measures

Neonatal birth weight in grams [ Time Frame: At time of Delivery ]

ICMJE

(submitted: July 23, 2017)
Original Primary Outcome
Measures

Change History
Current Secondary
Outcome Measures

Same as current

ICMJE

ICMJE

(submitted: July 23, 2017)

No Changes Posted

The change in Doppler velocity indices, [ Time Frame: 24 week till 35 weeks ]
Fetal growth velocity [ Time Frame: weekly till time of delivery ]
Gestational age at delivery, [ Time Frame: at time of delivery ]
APGAR score [ Time Frame: at 1 and 5 min of life ]
Neonatal complication rates [ Time Frame: The first 28 day of delivery ]
respiratory distress syndrome, intraventricular hemorrhage (IVH),
neonatal necrotizing enterocolitis (NEC), neonatal anemia, and neonatal
blood transfusion
Neonatal ICU admission rate [ Time Frame: The first 28 day of delivery ]
the interval between the diagnosis and delivery [ Time Frame: at time of
delivery ]

Original Secondary
Outcome Measures

Current Other Outcome
Measures

ICMJE

Original Other Outcome
Measures

Same as current

ICMJE

ICMJE

Not Provided
Not Provided

 
Descriptive Information
Brief Title

ICMJE

Sildenafil Versus Low Molecular Weight Heparin in Fetal Growth Restriction
Treatment

Official Title

ICMJE

Sildenafil Versus Low Molecular Weight Heparin in Fetal Growth Restriction
Treatment

Brief Summary

comparing the effect of using sildenafil citrate and LMWH in treatment of cases of
IUGR due to placental insufficiency

Detailed Description

One hundred pregnant women with documented intrauterine growth restriction
due to placental insufficiency at 28-35 weeks of gestation will be distributed into
two groups:

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Group S: 50 women will receive Sildenafil citrate 25 mg tab 3 times daily.
Group H: 50 women will receive single dose of LMWH subcutaneous daily.
Both groups will undergo strict fetal surveillance in the form of:
Umbilical artery Doppler (UAD) is the primary surveillance tool in the FGR fetus:
middle cerebral artery (MCA) Doppler, ultrasound for (AC, EFW, and deepest
vertical pocket (DVP) for amniotic fluid) and non stress test and Biophysical
profile (BPP)
Study Type

ICMJE

Study Phase
Study Design

ICMJE

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment

Condition

ICMJE

Fetal Growth Abnormality
Fetal Growth Restriction

Intervention

ICMJE

Drug: Sildenafil
sildenafil citrate 25 mg every 8 hours (Silden EIPICO co.) orally, starting at
the diagnosis of FGR till delivery
Other Name: Silden EIPICO co.
Drug: low molecular weight heparin
a single daily dose of LMWH (tinzaparin) (Innohep LEO pharmaceutical
products.) subcutaneously starting at diagnosis of FGR till delivery
Other Names:
tinzaparin
Innohep LEO pharmaceutical products

Study Arms

Experimental: sildenafil citrate
50 pregnant female will be treated with sildenafil citrate 25 mg every 8
hours (Silden EIPICO co.) orally, starting at the diagnosis of FGR till
delivery.
Intervention: Drug: Sildenafil
Experimental: low molecular weight heparin
50 pregnant female will be treated with a single daily dose of LMWH
(tinzaparin) (Innohep LEO pharmaceutical products.) subcutaneously
starting at diagnosis of FGR till delivery according to body weight as

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follow < 50 kg 3500 units daily 50-90 kg 4500 units daily 91-130 kg 7000
units daily 131-170 kg 9000 units daily > 170 kg 75 u/kg/day
Intervention: Drug: low molecular weight heparin
Publications *

Not Provided

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov
Identifier (NCT Number) in Medline.

 
Recruitment Information
Recruitment Status

ICMJE

Estimated Enrollment

Recruiting
100

ICMJE

(submitted: July 23, 2017)
Original Estimated
Enrollment

Same as current

ICMJE

Estimated Study

May 1, 2018

Completion Date
Estimated Primary

May 1, 2018 (Final data collection date for primary outcome measure)

Completion Date
Eligibility Criteria

ICMJE

Inclusion Criteria:
Maternal age between 20-35 years.
Being at a gestational age 28-35wks.
Singleton pregnancy.
Fetal growth restriction diagnosed by ultrasound with estimated fetal weight
below the 10th percentile, and/or fetal abdominal circumference at or below
the tenth percentile.
Exclusion Criteria:
Maternal age less than 20 years or more than 35 years.
Undetermined gestational age.
Multiple gestation.
Chronic diseases with pregnancy e.g. Chronic hypertension, diabetes type 1 or
2.
Etiologies of FGR other than placental insufficiency as fetal malformations,
aneuploidy or infections.
Suspected fetal compromise requiring emergency delivery.

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Any contraindication to the use of sildenafil e.g. known significant maternal
cardiac disease, le ventricular outflow tract obstruction, concomitant
treatment with nitrates or previous allergy to sildenafil.
Any contraindication to the use of LMWH e.g. known bleeding disorder, active
antenatal bleeding or at increased risk of major hemorrhage (e.g. placenta
praevia), thrombocytopenia, severe renal or hepatic disease.
Drug or alcohol abuse.
Patient refusing to participate in the study or unable to consent.
Sex/Gender

Ages
Accepts Healthy

Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
20 Years to 35 Years (Adult)
No

Volunteers
Contacts

ICMJE

Listed Location
Countries

Contact: Radwa R Ali, MD 01283492979 ext +202 radwaebed@yahoo.com
Egypt

ICMJE

Removed Location
Countries

 
Administrative Information
NCT Number

ICMJE

Other Study ID Numbers

NCT03230162
Ain shams university maternity

ICMJE

Has Data Monitoring
Committee
U.S. FDA-regulated
Product
IPD Sharing Statement
Responsible Party

Not Provided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: Undecided
Radwa Rasheedy Ali, Ain Shams University

Study Sponsor

ICMJE

Ain Shams University

Collaborators

ICMJE

Not Provided

Investigators

ICMJE

Not Provided

PRS Account
Verification Date

Ain Shams University
July 2017

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ICMJE

Sildenafil Versus Low Molecular Weight Heparin in Fetal Growth Restriction Treatment - Tabular View - ClinicalTrials.gov

Data element required by the International Committee of Medical Journal Editors and the World

Health Organization ICTRP

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Use of Sildenafil Citrate in Management of Mild Pre-eclampsia - Tabular View - ClinicalTrials.gov

Trial record 1 of 1 for:    Use of Sildenafil Citrate in management of mild pre-eclampsia | Egypt
Previous Study | Return to List | Next Study
Use of Sildenafil Citrate in Management of Mild Pre-eclampsia

The safety and scientific validity of this
study is the responsibility of the study
sponsor and investigators. Listing a study
does not mean it has been evaluated by
the U.S. Federal Government. Know the
risks and potential benefits of clinical
studies and talk to your health care
provider before participating. Read our
disclaimer for details.

ClinicalTrials.gov Identifier:
NCT03262961
Recruitment Status : Recruiting
First Posted : August 28, 2017
Last Update Posted : August 28,
2017
See Contacts and Locations

Sponsor:

Assiut University

Information provided by (Responsible Party):
Fady Nasef Tous Abdallah, Assiut University

Study Details

Tabular View

No Results Posted

Disclaimer

How to Read a Study Record

Tracking Information
First Submitted Date

ICMJE

August 19, 2017

First Posted Date

ICMJE

August 28, 2017

Last Update Posted Date

August 28, 2017

Actual Study Start Date

ICMJE

Estimated Primary

September 15, 2016
December 15, 2017 (Final data collection date for primary outcome measure)

Completion Date
Current Primary Outcome
Measures

ICMJE

(submitted: August 24, 2017)

Gestational age at time of termination and maternal outcome. [ Time Frame: up to 37
weeks of gestation ]

Gestational age at time of termination and maternal outcome in terms of whether
the disease would progress to severe pre-eclampsia or not.

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Use of Sildenafil Citrate in Management of Mild Pre-eclampsia - Tabular View - ClinicalTrials.gov

Original Primary Outcome
Measures

Change History
Current Secondary Outcome
Measures

Same as current

ICMJE

ICMJE

(submitted: August 24, 2017)

No Changes Posted

Neonatal outcome. [ Time Frame: up to 37 weeks of gestation ]
Neonatal outcome in terms of survival and neonatal well-being ( by
obtaining the birth weight and the apgar score at 1 and 5 minutes and direct
postnatal need to NICU).
Control of maternal blood pressure. [ Time Frame: up to 37 weeks of gestation ]
Control of maternal blood pressure.
Method of termination of pregnancy. [ Time Frame: up to 37 weeks of
gestation ]
Method of termination of pregnancy.
Identification of the side effects from the use of sildenafil citrate.
[ Time Frame: up to 37 weeks of gestation ]
Identification of possible maternal side effects from the use of sildenafil
citrate i.e.; headache, flushing and dyspepsia.
Evaluation of the effect of sildenafil citrate on the feto-maternal circulation
through the Doppler ultrasound. [ Time Frame: up to 37 weeks of gestation ]
Evaluation of the effect of sildenafil citrate on the feto-maternal circulation
through the Doppler ultrasound.

Original Secondary Outcome
Measures

Current Other Outcome
Measures

ICMJE

Original Other Outcome
Measures

Same as current

ICMJE

ICMJE

Not Provided
Not Provided

 
Descriptive Information
Brief Title

ICMJE

Use of Sildenafil Citrate in Management of Mild Pre-eclampsia

Official Title

ICMJE

Use of Sildenafil Citrate in Management of Mild Pre-eclampsia: A Randomized
Controlled Trial

Brief Summary

Mild pre-eclampsia represents 75% of cases with pre-eclampsia, possible
progression to severe pre-eclampsia makes mild pre-eclampsia a serious

problem that requires attention.
Previous studies have shown that expectant and conservative management of
pre-eclampsia in the context of extreme prematurity may improve perinatal
outcomes. Indeed, it has been estimated that for each additional day of
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pregnancy prolongation between 24 and 32 weeks of gestation, there is a
nonlinear corresponding gain of 1% in fetal survival.
Sildenafil citrate has been used for increasing utero-placental perfusion in cases
with intrauterine growth restriction, which makes it a promising drug in
management of mild pre-eclampsia.
Detailed Description

- Pre-eclampsia affects approximately 2-8% of all pregnancies worldwide. In Egypt,
the prevalence of pre-eclampsia is 10.7% in a community based study. While, in
hospital based studies it ranged from 9.1% to 12.5% of all deliveries. The incidence of
pre-eclampsia has risen in the developing countries and even in the developed
countries as the USA since the 1990s. Among the hypertensive disorders that
complicate pregnancy, pre-eclampsia and eclampsia stand as major causes of
maternal and perinatal morbidity and mortality worldwide. Nearly one tenth of all
maternal deaths in Africa and Asia and one quarter in Latin America are associated
with hypertensive diseases in pregnancy, a category that includes pre-eclampsia and
the complications that are related to it.
However, the pathogenesis of pre-eclampsia is only partially understood and it is
related to disturbances in placentation at the beginning of pregnancy, followed by
generalized inflammation and progressive endothelial damage. There are other
uncertainties too: the diagnosis, screening and management of pre-eclampsia
remain controversial, as does the classification and the degree of its severity.
However, it is generally accepted as published in the different journals and in the
WHO recommendations that the onset of a new episode of hypertension during
pregnancy (with persistent systolic blood pressure 140 mm Hg and diastolic blood
pressure 90 mm Hg or more) with the occurrence of substantial proteinuria (>0.3
g/24 h or confirmation of proteinuria by semiquantitative urine dipstick analysis
with a result of at least 1+) can be used as criteria for identifying pre-eclampsia.
Although pathophysiological changes (e.g. inadequate placentation) exist from very
early stages of the pregnancy, hypertension and proteinuria usually become
apparent in the second half of pregnancy.
Complications of pre-eclampsia can affect both the mother and the fetus. Acutely,
pre-eclampsia can be complicated by eclampsia , the development of HELLP
Syndrome , hemorrhagic or ischemic stroke, liver damage and dysfunction, acute
kidney injury and Acute Respiratory Distress Syndrome (ARDS).
So early detection of pre-eclampsia and prevention of the occurrence of any of its
complications would save the lives of many women and prevent the possible
devastating maternal and neonatal outcome of pre-eclampsia, That's why we are
concerned in our study with pre-eclampsia, covering the gestational age from 28 - 36
weeks.
Mild pre-eclampsia represents 75% of cases with pre-eclampsia, possible
progression to severe pre-eclampsia makes mild pre-eclampsia a serious problem
that requires attention.

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Previous studies have shown that expectant and conservative management of preeclampsia in the context of extreme prematurity may improve perinatal outcomes.
Indeed, it has been estimated that for each additional day of pregnancy
prolongation between 24 and 32 weeks of gestation, there is a nonlinear
corresponding gain of 1% in fetal survival.
Sildenafil citrate has been used for increasing utero-placental perfusion in cases with
intrauterine growth restriction, which makes it a promising drug in management of
mild pre-eclampsia.
Its action is similar to the action of nitric oxide, which is a potent vasodilator,
especially for the venules, besides being an inhibitor of platelet aggregation. During
pregnancy, nitric oxide is synthesized in in utero-placental tissues and endothelial
cells, helping to maintain low vascular resistance in the utero- and fetoplacental
circulations. Phosphodiesterase metabolizes cyclic guanosine monophosphate;
therefore, phosphodiesterase type 5 inhibition leads to cyclic guanosine
monophosphate increase with associated vasodilation, independently of nitric
oxide. Therefore, phosphodiesterase type 5 inhibitors have the potential to achieve
similar therapeutic goals when compared with nitric oxide.
A potential advantage of phosphodiesterase type 5 inhibitors is that they may
overcome the main limitation to nitric oxide use in pregnancy, which is tolerance and
headaches. The most studied phosphodiesterase type 5 inhibitor is sildenafil citrate,
which has previously shown promising outcomes both in vitro and in animal studies.
That is why we decided to study the role of Sildenafil Citrate in expectant and
conservative management of mild pre-eclampsia, as it has shown its ability to be
beneficial to both the mother and the fetus through increasing the maternofetal
circulation perfusion and achieving a maternal hemodynamic stability and compare
it to the current NICE (National Institute for Health and Care Excellence) guidelines
that are currently used, that recommends conservative management of mild preeclampsia through control of maternal blood pressure and frequent screening of
maternal laboratory investigations' abnormalities to detect possible progression to
severe pre-eclamptic toxemia.
Study Type

ICMJE

Study Phase

Interventional
Phase 2
Phase 3

Study Design

ICMJE

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

- Double blinded, randomized, placebo-controlled trial.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

- It's a double blinded, randomized, placebo-controlled trial.
Primary Purpose: Treatment
Condition

ICMJE

Pre-Eclampsia; Mild

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Intervention

ICMJE

Drug: Sildenafil 20 MG
Other Name: Sildenafil Citrate 20 mg ( Respatio® 20 mg)
Drug: Placebo Oral Tablet
Other Name: Placebo drug

Study Arms

Active Comparator: Intervention Group
• The intervention group will be supplied with Sildenafil Citrate (Respatio®
20mg tablets manufactured by Pharma Right Group , Egypt) according to the
patient's weight by the rate of (1.5 mg/kg/day) divided into three doses per
day ( every 8 hours) till termination of pregnancy.
Intervention: Drug: Sildenafil 20 MG
Placebo Comparator: Control Group
- The control group will be supplied with a placebo drug that has the same
shape, size and color but without the active ingredient and it would also be
taken in a similar way. The placebo tablet will be manufactured at the faculty
of pharmacy, Assiut University.
Intervention: Drug: Placebo Oral Tablet

Publications *

Eiland E, Nzerue C, Faulkner M. Preeclampsia 2012. J Pregnancy.
2012;2012:586578. doi: 10.1155/2012/586578. Epub 2012 Jul 11. Review.
El-Moselhy, E; Khalifa, H; Amer, S (2011). "Risk Factors and Impacts of PreEclampsia: An Epidemiological Study among Pregnant Mothers in Cairo, Egypt"
J Am Sci 7(5): 311-323.
Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet.
2010 Aug 21;376(9741):631-44. doi: 10.1016/S0140-6736(10)60279-6. Epub 2010
Jul 2. Review.
Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of
causes of maternal death: a systematic review. Lancet. 2006 Apr
1;367(9516):1066-74. Review.
Campbell OM, Graham WJ; Lancet Maternal Survival Series steering group.
Strategies for reducing maternal mortality: getting on with what works. Lancet.
2006 Oct 7;368(9543):1284-99. Review.
Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia. Lancet.
2001 Jan 6;357(9249):53-6. Review.
Arulkumaran N, Lightstone L. Severe pre-eclampsia and hypertensive crises.
Best Pract Res Clin Obstet Gynaecol. 2013 Dec;27(6):877-84. doi:
10.1016/j.bpobgyn.2013.07.003. Epub 2013 Aug 17. Review.
Mustafa R, Ahmed S, Gupta A, Venuto RC. A comprehensive review of
hypertension in pregnancy. J Pregnancy. 2012;2012:105918. doi:
10.1155/2012/105918. Epub 2012 May 23. Review.

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Report of the National High Blood Pressure Education Program Working Group
on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000 Jul;183(1):S1S22.
Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: Lessons learned
from recent trials. Am J Obstet Gynecol. 2004 Jun;190(6):1520-6. Review.
American College of Obstetricians and Gynecologists; Task Force on
Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American
College of Obstetricians and Gynecologists’ Task Force on Hypertension in
Pregnancy. Obstet Gynecol. 2013 Nov;122(5):1122-31. doi:
10.1097/01.AOG.0000437382.03963.88.
Sibai BM, Mercer BM, Schiff E, Friedman SA. Aggressive versus expectant
management of severe preeclampsia at 28 to 32 weeks' gestation: a
randomized controlled trial. Am J Obstet Gynecol. 1994 Sep;171(3):818-22.
Haddad B, Deis S, Goffinet F, Paniel BJ, Cabrol D, Siba BM. Maternal and
perinatal outcomes during expectant management of 239 severe preeclamptic
women between 24 and 33 weeks' gestation. Am J Obstet Gynecol. 2004
Jun;190(6):1590-5; discussion 1595-7.
Manktelow BN, Seaton SE, Field DJ, Draper ES. Population-based estimates of
in-unit survival for very preterm infants. Pediatrics. 2013 Feb;131(2):e425-32.
doi: 10.1542/peds.2012-2189. Epub 2013 Jan 14.
Cauli O, Herraiz S, Pellicer B, Pellicer A, Felipo V. Treatment with sildenafil
prevents impairment of learning in rats born to pre-eclamptic mothers.
Neuroscience. 2010 Dec 1;171(2):506-12. doi:
10.1016/j.neuroscience.2010.08.065. Epub 2010 Sep 9.
Coppage KH, Sun X, Baker RS, Clark KE. Expression of phosphodiesterase 5 in
maternal and fetal sheep. Am J Obstet Gynecol. 2005 Sep;193(3 Pt 2):1005-10.
Samangaya RA, Mires G, Shennan A, Skillern L, Howe D, McLeod A, Baker PN. A
randomised, double-blinded, placebo-controlled study of the
phosphodiesterase type 5 inhibitor sildenafil for the treatment of
preeclampsia. Hypertens Pregnancy. 2009 Aug;28(4):369-82. doi:
10.3109/10641950802601278.
Trapani A Jr, Gonçalves 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 Obstet Gynecol. 2016
Jul;48(1):61-5. doi: 10.1002/uog.15673.
Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T,
Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G; Sildenafil
Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate
therapy for pulmonary arterial hypertension. N Engl J Med. 2005 Nov
17;353(20):2148-57. Erratum in: N Engl J Med. 2006 Jun 1;354(22):2400-1.
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American College of Obstetricians and Gynecologists. ACOG Practice bulletin
no. 134: fetal growth restriction. Obstet Gynecol. 2013 May;121(5):1122-33. doi:
10.1097/01.AOG.0000429658.85846.f9.
Matt H, Nigel J. (2016) "Renal disease in pregnancy" ;Obstet Gynaecol Reprod
Med; 26:46-52
Dastjerdi MV, Hosseini S, Bayani L. Sildenafil citrate and uteroplacental
perfusion in fetal growth restriction. J Res Med Sci. 2012 Jul;17(7):632-6.
McKeeman GC, Ardill JE, Caldwell CM, Hunter AJ, McClure N. Soluble vascular
endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation
in patients who have preeclampsia develop. Am J Obstet Gynecol. 2004
Oct;191(4):1240-6.
Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993
Dec 30;329(27):2002-12. Review.
Learmont JG, Poston L. Nitric oxide is involved in flow-induced dilation of
isolated human small fetoplacental arteries. Am J Obstet Gynecol. 1996
Feb;174(2):583-8.
Lees C, Valensise H, Black R, Harrington K, Byiers S, Romanini C, Campbell S.
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 Obstet Gynecol.
1998 Nov;12(5):334-8.
Trapani A Jr, Gonçalves LF, Pires MM. Transdermal nitroglycerin in patients with
severe pre-eclampsia with placental insufficiency: effect on uterine, umbilical
and fetal middle cerebral artery resistance indices. Ultrasound Obstet Gynecol.
2011 Oct;38(4):389-94. doi: 10.1002/uog.8983.
Wareing M, Myers JE, O'Hara M, Baker PN. Sildenafil citrate (Viagra) enhances
vasodilatation in fetal growth restriction. J Clin Endocrinol Metab. 2005
May;90(5):2550-5. Epub 2005 Feb 15.
Trapani A Jr, Gonçalves LF, Trapani TF, Vieira S, Pires M, Pires MM. Perinatal and
Hemodynamic Evaluation of Sildenafil Citrate for Preeclampsia Treatment: A
Randomized Controlled Trial. Obstet Gynecol. 2016 Aug;128(2):253-9. doi:
10.1097/AOG.0000000000001518.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier
(NCT Number) in Medline.

 
Recruitment Information
Recruitment Status

ICMJE

Recruiting

Estimated Enrollment

ICMJE

80

(submitted: August 24, 2017)
https://www.clinicaltrials.gov/ct2/show/record/NCT03262961?term=Use+of+Sildenafil+Citrate+in+management+of+mild+pre-eclampsia&cntry=EG…

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7/26/2018

Use of Sildenafil Citrate in Management of Mild Pre-eclampsia - Tabular View - ClinicalTrials.gov

Original Estimated
Enrollment

Same as current

ICMJE

Estimated Study Completion

January 15, 2018

Date
Estimated Primary

December 15, 2017 (Final data collection date for primary outcome measure)

Completion Date
Eligibility Criteria

ICMJE

Inclusion Criteria:
1. Uncomplicated mild pre-eclampsia; No clinical or investigatory findings
suggestive severe pre-eclamptic toxemia.
2. Gestational age of 28 - 36 weeks by good dates according to ACOG's committee on obstetric practice - Method for Estimating Due Date (2014) who
will receive the study's drug for at least one week before termination.
3. Singleton viable pregnancy.
4. Age: 18-35 years.
Exclusion Criteria:
1. Severe pre-eclamptic toxemia (according to the NICE guidelines (2010):
Hypertension in pregnancy: diagnosis and management)
2. Intrauterine growth retardation.
3. Use of medication that could interact with sildenafil citrate such as nitrates
erythromycin, ketoconazole, itraconazole, antiretroviral agents and others.
4. Presence of maternal co-morbidity disease as: DM, chronic hypertension,
congestive heart failure, chronic kidney disease and SLE.
5. Placenta previa.
6. The patient is using aspirin.
7. The presence of a contraindication to the use of sildenafil citrate:
Hypersensitivity to sildenafil citrate or any of the tablet ingredients.
Patients with severe cardiovascular disease such as established cardiac
failure and unstable angina pectoris.
Previous episode of non-arteritic anterior ischaemic optic neuropathy.
Severe hepatic impairment.
Hypotension (blood pressure <90/50 mmHg).
Hypertension (blood pressure >170/110 mmHg).
Recent history of stroke or myocardial infarction.
Known hereditary degenerative retinal disorders such as retinitis
pigmentosa.

Sex/Gender

Sexes Eligible for Study:
Female
Gender Based Eligibility:
Yes
Gender Eligibility Description: Pregnant females

Ages
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18 Years to 35 Years (Adult)
Accepts Healthy Volunteers
Contacts

ICMJE

Listed Location Countries

No

Contact: Fady Abdallah
00201002837042 fady.nasif@yahoo.com
Contact: Hisham Abou-Taleb 00201003332139 hishamaboutaleb1@yahoo.com
Egypt

ICMJE

Removed Location Countries

 
Administrative Information
NCT Number

ICMJE

Other Study ID Numbers

NCT03262961
assiutu252

ICMJE

Has Data Monitoring

Yes

Committee
U.S. FDA-regulated Product

IPD Sharing Statement
Responsible Party

Plan to Share IPD: No
Fady Nasef Tous Abdallah, Assiut University

Study Sponsor

ICMJE

Assiut University

Collaborators

ICMJE

Not Provided

Investigators

ICMJE

Principal Investigator: Fady Abdallah
Assiut University
Study Director:
Hasan Kamel
Assiut University
Study Director:
Hisham Abou-Taleb Assiut University

PRS Account
Verification Date

ICMJE

Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.: No

Assiut University
August 2017

Data element required by the International Committee of Medical Journal Editors and the World Health

Organization ICTRP

https://www.clinicaltrials.gov/ct2/show/record/NCT03262961?term=Use+of+Sildenafil+Citrate+in+management+of+mild+pre-eclampsia&cntry=EG…

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Use of Sildenafil Citrate in management of mild
pre-eclampsia: A randomized controlled trial

Submitted By

Fady Nasef Tous Abdallah
M.B.B.CH, Resident of Obstetrics and Gynecology
Faculty of Medicine, Assiut University

Under Supervision of

Prof.Dr. Hasan Salah Kamel Abdel-Nasser
Professor of Obstetrics and Gynecology
Faculty of Medicine, Assiut University

Dr. Hisham Ahmed El-Sayed Abou-Taleb
Lecturer of Obstetrics and Gynecology
Faculty of Medicine, Assiut University

2016

Introduction
Pre-eclampsia affects approximately 2–8% of all pregnancies worldwide (1). In
Egypt, the prevalence of pre-eclampsia is 10.7% in a community based study (Gadalla
et al., 1986). While, in hospital based studies it ranged from 9.1% (Mahaba et al.,
2001) to 12.5% (El-Houseinie et al., 1994) of all deliveries (2). The incidence of preeclampsia has risen in the developing countries and even in the developed countries
as the USA since the 1990s (3). Among the hypertensive disorders that complicate
pregnancy, pre-eclampsia and eclampsia stand as major causes of maternal and
perinatal morbidity and mortality worldwide (1). Nearly one tenth of all maternal
deaths in Africa and Asia and one quarter in Latin America are associated with
hypertensive diseases in pregnancy, a category that includes pre-eclampsia and the
complications that are related to it (4)(5).
However, the pathogenesis of pre-eclampsia is only partially understood and it is
related to disturbances in placentation at the beginning of pregnancy, followed by
generalized inflammation and progressive endothelial damage. There are other
uncertainties too: the diagnosis, screening and management of pre-eclampsia
remain controversial, as does the classification and the degree of its severity (5).
However, it is generally accepted as published in the different journals and in the
WHO recommendations that the onset of a new episode of hypertension during
pregnancy (with persistent systolic blood pressure 140 mm Hg and diastolic blood
pressure 90 mm Hg or more) with the occurrence of substantial proteinuria (>0.3
g/24 h or confirmation of proteinuria by semiquantitative urine dipstick analysis with
a result of at least 1+) can be used as criteria for identifying pre-eclampsia (6).
Although pathophysiological changes (e.g. inadequate placentation) exist from very
early stages of the pregnancy, hypertension and proteinuria usually become
apparent in the second half of pregnancy (3).
Complications of pre-eclampsia can affect both the mother and the fetus. Acutely,
pre-eclampsia can be complicated by eclampsia , the development of HELLP

Syndrome , hemorrhagic or ischemic stroke, liver damage and dysfunction, acute
kidney injury and Acute Respiratory Distress Syndrome (ARDS) (7)(8).
So early detection of pre-eclampsia and prevention of the occurrence of any of its
complications would save the lives of many women and prevent the possible
devastating maternal and neonatal outcome of pre-eclampsia, That's why we are
concerned in our study with pre-eclampsia, covering the gestational age from 28 –
36 weeks (6) (9).
Mild pre-eclampsia represents 75% of cases with pre-eclampsia, possible
progression to severe pre-eclampsia makes mild pre-eclampsia a serious problem
that requires attention (10).
Previous studies have shown that expectant and conservative management of
pre-eclampsia in the context of extreme prematurity may improve perinatal
outcomes (11–13). Indeed, it has been estimated that for each additional day of
pregnancy prolongation between 24 and 32 weeks of gestation, there is a nonlinear
corresponding gain of 1% in fetal survival (14).
Sildenafil citrate has been used for increasing utero-placental perfusion in cases
with intrauterine growth restriction, which makes it a promising drug in
management of mild pre-eclampsia (15).
Its action is similar to the action of nitric oxide, which is a potent vasodilator,
especially for the venules, besides being an inhibitor of platelet aggregation (16).
During pregnancy, nitric oxide is synthesized in in utero-placental tissues and
endothelial cells, helping to maintain low vascular resistance in the utero- and
fetoplacental circulations (17-19). Phosphodiesterase metabolizes cyclic guanosine
monophosphate; therefore, phosphodiesterase type 5 inhibition leads to cyclic
guanosine monophosphate increase with associated vasodilation, independently of
nitric oxide. Therefore, phosphodiesterase type 5 inhibitors have the potential to
achieve similar therapeutic goals when compared with nitric oxide.
A potential advantage of phosphodiesterase type 5 inhibitors is that they may
overcome the main limitation to nitric oxide use in pregnancy, which is tolerance and
headaches. The most studied phosphodiesterase type 5 inhibitor is sildenafil citrate,

which has previously shown promising outcomes both in vitro (20) and in animal
studies (21) (22).
That is why we decided to study the role of Sildenafil Citrate in expectant and
conservative management of mild pre-eclampsia, as it has shown its ability to be
beneficial to both the mother and the fetus through increasing the maternofetal
circulation perfusion and achieving a maternal hemodynamic stability (23) and
compare it to the current NICE (National Institute for Health and Care Excellence)
guidelines that are currently used, that recommends conservative management of
mild pre-eclampsia through control of maternal blood pressure and frequent
screening of maternal laboratory investigations' abnormalities to detect possible
progression to severe pre-eclamptic toxemia (NICE guidelines 2010 [CG107]).

Aim of the work
- Aim of our study is to investigate if the use of sildenafil citrate in cases with mild
pre-eclampsia is useful in pregnancy prolongation through prevention of its
progression to severe pre-eclampsia and improved maternal and perinatal outcomes
or not.

Subjects and methods
Study design
- Double blinded, randomized, placebo-controlled trial.

Settings and locations
- Obstetrics and Gynecology Department, Woman Health Hospital, Assiut University,
Egypt.

Eligible Participants:
Inclusion criteria
1- Uncomplicated mild pre-eclampsia; No clinical or investigatory findings
suggestive severe pre-eclamptic toxemia.
2- Gestational age of 28 – 36 weeks by good dates according to ACOG's –
committee on obstetric practice – Method for Estimating Due Date (2014) who will
receive the study’s drug for at least one week before termination. (23)
3- Singleton viable pregnancy.
4- Age: 18-35 years.

Exclusion criteria
1- Severe pre-eclamptic toxemia (according to the NICE guidelines (2010):
Hypertension in pregnancy: diagnosis and management)
2- Intrauterine growth retardation (23) (24).
3- Use of medication that could interact with sildenafil citrate such as nitrates
erythromycin, ketoconazole, itraconazole, antiretroviral agents and others.
4- Presence of maternal co-morbidity disease as: DM, chronic hypertension,
congestive heart failure, chronic kidney disease and SLE.
5- Placenta previa.
6- The patient is using aspirin.
7- The presence of a contraindication to the use of sildenafil citrate:
- Hypersensitivity to sildenafil citrate or any of the tablet ingredients.
- Patients with severe cardiovascular disease such as established cardiac failure and
unstable angina pectoris.
- Previous episode of non-arteritic anterior ischaemic optic neuropathy.
- Severe hepatic impairment.
- Hypotension (blood pressure <90/50 mmHg).
- Hypertension (blood pressure >170/110 mmHg).
- Recent history of stroke or myocardial infarction.

- Known hereditary degenerative retinal disorders such as retinitis pigmentosa.

Sample size
- Alpha error of 5%
- Power of study 95%
- Sample size: 80 patients who meet the criteria of the study would be randomized
into the two groups (intervention and control group) with 40 patients in each group,
in the Obstetrics and Gynecology Department, Woman Health Hospital, Assiut
University, Egypt.

Interventions
Preliminary assessment of patient
 The patient will be admitted to the department of obstetrics and gynecology in
Assiut University and will undergo the following:
- Evaluation of vital signs of patient:
- Pulse: Regular and the rate is between 60-100 beat/minute by palpating the radial
artery.
- Blood pressure: Maternal blood pressure would be measured as recommended by
the NICE in the ‘’Antenatal care’’ (2008):
Blood pressure should be measured as outlined below:
• The patient would sit with her left arm stretched.
• Remove tight clothing, ensure arm is relaxed and supported at heart level.
• Use cuff of appropriate size.
• Inflate cuff to 20–30 mmHg above palpated systolic blood pressure.
• Lower column slowly, by 2 mmHg per second or per beat.
• Read blood pressure to the nearest 2 mmHg
• Measure diastolic blood pressure as disappearance of sounds (phase V).

- Temperature: axillary temperature measurement using medical thermometer with
range from 36° to 37°.
- Weight & height: to calculate the patient's BMI by dividing the patient's weight in
kg by square her height in meters (kg/m²).
 Ultrasound assessment: (Using the Medison SonoAce R5® ultrasound system)
- Fetal viability.
- Placental site.
- Fetal biometry: Biparietal diameter, Femur length, Abdominal circumference
(using Hadlock formulas).
- Amniotic fluid index measured by the 4 quadrant view: more than or equal to 5
cm (ACOG guidelines on antepartum fetal surveillance (2014)).
 Doppler ultrasound assessment of the uterine, umbilical, aortic and middle
cerebral arteries (Using the Medison SonoAce X8® ultrasound system): pulsatility
(PI) and resistance (RI) indices and systolic/diastolic velocity (S/D) ratio, whatever
suitable in each case condition by a well-qualified sonographer according to the
standards of the ISUOG (2013).
 Investigations:
- Complete blood count: Hemoglobin level, white blood cells' count, platelets'
count and blood film.
- Coagulation profile: Prothrombin time and concentration and INR.
- Screening for gestational DM.
- Kidney function tests: Blood urea and serum Creatinine.
- Serum uric acid.
- Liver function tests: AST, ALT, serum bilirubin (total, direct and indirect), serum
total protein and albumin.
- Urine analysis and 24- hour's urine collection for: 24-hours protein collection in
urine, urine output in 24-hours and creatinine clearance.

Randomization
- The patients will randomly allocated to either the control group or intervention
group using computer generated random number tables and opaque sealed
envelopes containing the patients’ group allocation. The envelopes will be prepared
and sent to an assigned nurse, who opens each envelope when a patient – who
meets the criteria of the study- comes. All patients will be blinded to the allocation
to avoid bias.
 The patients will be divided into a red group and a blue group where the
intervention group would not be known by the clinician. (double-blinded)
 The intervention group will be supplied with Sildenafil Citrate (Respatio® 20mg
tablets manufactured by Pharma Right Group , Egypt) according to the patient's
weight by the rate of (1.5 mg/kg/day) divided into three doses per day ( every 8
hours) (25-28). While the control group will be supplied with a placebo drug that
has the same shape, size and color but without the active ingredient and it would
also be taken in a similar way. The placebo tablet will be manufactured at the
faculty of pharmacy, Assiut University.
 The patients of each group would stay in the hospital for 48 hours after the
beginning of the medication for blood pressure monitoring (4 times per day) and to
record any side effects detected from the medication taken.

Follow up visits:
1) The patients would be followed up at the obstetric outpatient clinic every 2
weeks till delivery. (According to the NICE guidelines “Hypertension in pregnancy”
(2010) and the NICE guidelines “Antenatal care” (2008))

2) The follow up visits will include:
 Blood pressure measurement and review the patient's blood pressure
measurements in the past 2 weeks (the blood pressure would be measured 3 times
a week in any easily accessible facility to the patient).


Urine dipstick analysis.



Complete blood count.



Serum creatinine & blood urea.



AST & ALT.



Serum uric acid.



Obstetric ultrasound and doppler ultrasound.

- Compliance to treatment will be ensured by checking the remainder of the
medication strip.

Termination of pregnancy:
 If the patient developed any sign or investigatory/laboratory finding that
represent severe pre-eclamptic toxemia:
1) Persistent elevated blood pressure more than 160/110 mmHg.
2) HELLP syndrome.
3) Eclampsia.
4) Intrauterine fetal death.
5) Abrupt body swelling.
6) Sever headache, epigastric pain and/or right hypochondrial tenderness.
7) Elevated liver enzymes: ALT or AST rising to above 70 iu/litre.
8) Platelet count falling to below 100 x10⁹ per litre.

9) Serum creatinine >125 mmol/litre (29).
- If no complications occurred and the maternal blood pressure is controlled on the
medication , termination would be after completion of 36 weeks and 6 days as
recommended by the NICE guidelines (2010) : “Hypertension in pregnancy :
Diagnosis and management”

Primary outcome
Gestational age at time of termination and maternal outcome in terms of whether
the disease would progress to severe pre-eclampsia or not.

Secondary outcomes
1- Neonatal outcome in terms of survival and neonatal well-being ( by obtaining the
birth weight and the apgar score at 1 and 5 minutes and direct postnatal need to
NICU).
2- Control of maternal blood pressure.
3- Method of termination of pregnancy.
4- Identification of possible maternal side effects from the use of sildenafil citrate
i.e.; headache, flushing and dyspepsia.
5- Evaluation of the effect of sildenafil citrate on the feto-maternal circulation
through the Doppler ultrasound.

Final status:
- We will specify the number of patients who were candidates for the study ,the
number of patients who were excluded for not meeting the criteria ,the number of
patients who were included the study, the number of patients who were excluded
for lack compliance to treatment or dropped follow-up visits and the number of
patients who successfully completed the study till delivery.

THE TRIAL FLOW CHART

Enrollment

Assessed for eligibility (n= )

Excluded (n= )
 Not meeting inclusion criteria
(n= )
 Declined to participate (n= )
 Other reasons (n= )
Randomized (n= )

Allocated to intervention (n= )
 Received allocated intervention (n= )
 Did not receive allocated intervention
(give reasons) (n= )

Allocation

Allocated to intervention (n= )
 Received allocated intervention
(n= )
 Did not receive allocated intervention
(give reasons) (n= )

Follow-Up
Lost to follow-up (give reasons) (n= )
Discontinued intervention (give reasons)
(n= )

Analysed (n= )
 Excluded from analysis (give reasons)
(n= )

Lost to follow-up (give reasons) (n= )
Discontinued intervention (give
reasons) (n= )

Analysis

Analysed (n= )
 Excluded from analysis (give
reasons) (n= )

Approval of Ethical Considerations
The pregnant women who enter the study will be given verbal and written information
about the study and written informed consent of enrollment in the study will be
obtained. The patient will be handled an explanation of the study. All the patients'
personal data will be confidential and wouldn't be exposed to the public. The patients
will have their freedom to withdraw from the trial at any time.

Statistical Analysis
Data entry and analysis will be carried out using SPSS version 20. Quantitative
variables will be presented in terms of, mean± standard and qualitative variables will
be expressed as frequency and percentage. Tests of significance (T-test and chisquare) will be calculated. Significance level will be set at 0.05.

References
1. Eiland, E; Nzerue, C; Faulkner, M (2012). "Preeclampsia 2012". J Pregnancy: 1–7.
2. El-Moselhy, E; Khalifa, H; Amer, S (2011). “Risk Factors and Impacts of Pre-Eclampsia: An
Epidemiological Study among Pregnant Mothers in Cairo, Egypt” J Am Sci 7(5): 311-323.
3. Steegers, E; von Dadelszen, P; Duvekot, J et al (2010). "Pre-eclampsia". Lancet 376 (9741): 631–644.
4. Khan K, Wojdyla D, Say L, et al (2006) . “WHO analysis of causes of maternal death: a systematic
review.” Lancet, Apr 1; 367(9516):1066–1074.
5. Campbell O & Graham W (2006) ;“Strategies for reducing maternal mortality: getting on with what
works.” Lancet, 368 (9543):1284–1299.
6. Roberts J, Cooper D. (2001) “Pathogenesis and genetics of pre-eclampsia.” Lancet;357(9249):53–6.

7. Arulkumaran, N.& Lightstone, L. (2013). "Severe pre-eclampsia and hypertensive crises". Best Practice
& Research Clinical Obstetrics & Gynaecology 27 (6): 877–884.
8. Mustafa, R; Ahmed, S; Gupta, A , et al (2012). "A Comprehensive Review of Hypertension in
Pregnancy". J Pregnancy: 1–19.
9.”Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure
in Pregnancy.” Am J Obstet Gynecol (2000); 183(1):S1–S22.
10. Sibai B (2004). “Magnesium sulfate prophylaxis in preeclampsia: lessons learned from recent trials”.
Am J Obstet Gynecol; 190:1520.
11.”Executive summary: hypertension in pregnancy.” ACOG. Obstet Gynecol 2013; 122:1122–31.
12. Sibai B, Mercer B, Schiff E,et al (1994). “Aggressive versus expectant management of severe
preeclampsia at 28 to 32 weeks’ gestation: a randomized controlled trial.” Am J Obstet Gynecol;
171:818–22.
13. Haddad B, Deis S, Goffinet F, et al (2004). “Maternal and perinatal outcomes during expectant
management of 239 severe preeclamptic women between 24 and 33 weeks’ gestation.” Am J Obstet
Gynecol; 190:1590–5.
14. Manktelow B, Seaton S, Field D,et al (2013). “Population based estimates of in-unit survival for very
preterm infants.” Pediatrics; 131:e425–32.
15. Dastjerdi M, Hosseini S,and Bayani L (2012); “Sildenafil citrate and uteroplacental perfusion in fetal
growth restriction” J Res Med Sci.; 17(7): 632–636.
16. McKeeman G, Ardill J, Caldwell C, et al (2004). “Soluble vascular endothelial growth factor receptor-1
(sFlt-1) is increased throughout gestation in patients who have preeclampsia develop.” Am J Obstet
Gynecol; 191:1240–6.
17. Moncada S, Higgs A. (1993) “The L-arginine-nitric oxide pathway.” N Engl J Med; 329:2002–12.
18. Learmont J, Poston L.(1996) “Nitric oxide is involved in flowinduced dilation of isolated human small
fetoplacental arteries.” Am J Obstet Gynecol; 174:583–8.
19. Lees C, Valensise H, Black R, et al. (1998) “The efficacy and fetal–maternal cardiovascular effects of
transdermal glyceryl trinitrate in the prophylaxis of preeclampsia and its complications: a randomized

doubleblind placebo-controlled trial.” Ultrasound Obstet Gynecol; 12:334–8.
20. Trapani A, Gonçalves L, Pires M. (2011) “Transdermal nitroglycerin in patients with severe preeclampsia with placental insufficiency: effect on uterine, umbilical and fetal middle cerebral artery
resistance indices.” Ultrasound Obstet Gynecol; 38:389–94.
21. Wareing M, Myers J, O’Hara M, et al. (2005) “Sildenafil citrate (Viagra) enhances vasodilatation in
fetal growth restriction.” J Clin Endocrinol Metab; 90:2550–5.
22. Cauli O, Herraiz S, Pellicer B,et al. (2010) “Treatment with sildenafil prevents impairment of learning
in rats born to pre-eclamptic mothers.” Neuroscience; 171:506–12.
23. Trapani A, Gonçalves L, Trapani T, et al (2016). “Perinatal and Hemodynamic Evaluation of Sildenafil
Citrate for Preeclampsia Treatment: A Randomized Controlled Trial.” Am J Obstet Gynecol; 128:253-9
24. Coppage K, Sun X, Baker R, et al. (2005) “Expression of phosphodiesterase 5 in maternal and fetal
sheep.” Am J Obstet Gynecol; 193:1005–10.
25. Samangaya R, Mires G, Shennan A, et al. (2009) “A randomised, double-blinded, placebo-controlled
study of the phosphodiesterase type 5 inhibitor sildenafil for the treatment of preeclampsia”. Hypertens
Pregnancy; 28:369–82.
26. Trapani A, Gonçalves L, Trapani T, et al. (2016) “Comparison between transdermal nitroglycerin and
sildenafil citrate in intrauterine growth restriction: effect on uterine, umbilical and fetal middle cerebral
artery pulsatility index.” Ultrasound Obstet Gynecol; 48:61-65.
27. Galiè N, Ghofrani H, Torbicki A, et al. (2005) “Sildenafil citrate therapy for pulmonary arterial
hypertension.” N Engl J Med; 353:2148–57.
28. “Fetal growth restriction”. Practice Bulletin No. 134. ACOG. Obstet Gynecol; 121:1122–33.
29. Matt H, Nigel J. (2016) “Renal disease in pregnancy” ;Obstet Gynaecol Reprod Med; 26:46-52.

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Appendix
-Safety of Sildenafil Citrate in pregnancy:
1) FDA:
“Pregnancy Category B. VIAGRA® (sildenafil citrate) is not indicated for use in
women. There are no adequate and well-controlled studies of sildenafil in pregnant
women. Risk Summary: Based on animal data, VIAGRA® is not predicted to increase
the risk of adverse developmental outcomes in humans. Animal Data: No evidence
of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits
which received up to 200 mg/kg/day during organogenesis. These doses represent,
respectively, about 20 and 40 times the Maximum Recommended Human Dose
(MRHD) on a mg/m2 basis in a 50 kg subject. In the rat pre-and postnatal
development study, the no observed adverse effect dose was 30 mg/kg/day given
for 36 days. In the nonpregnant rat the AUC at this dose was about 20 times human
AUC.”
2) Australian drug authority (TGA):
“Use in Pregnancy: Pregnancy Category B1. VIAGRA® is not indicated for use by
women. No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed
in rats and rabbits which received up to 200 mg/kg/day during organogenesis. The
dose results in total systemic drug exposure (AUC) for unbound sildenafil and its
major metabolite of greater than 60 times the exposure observed in human males
given the maximum recommended human dose (MRHD) of 100 mg. In the rat preand post natal development study, the no observed adverse effect dose was 30
mg/kg/day given for 36 days. In non-pregnant rat the AUC at this dose was about
20 times human AUC. There are no adequate and well controlled studies of
sildenafil in pregnant women. “

3) United Kingdom:
“VIAGRA® is not indicated for use by women. There are no adequate and wellcontrolled studies in pregnant or breast-feeding women. No relevant adverse
effects were found in reproduction studies in rats and rabbits following oral
administration of sildenafil.”

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Med. J. Cairo Univ., Vol. 85, No. 7, December: 2461-2467, 2017
www.medicaljournalofcairouniversity.net

Sildenafil Citrate versus Aspirin/Heparin Combination for Fetal
Growth Restriction: A Randomized Clinical Trial
HEND A. SHALABY, M.D.
The Department of Obstetrics and Gynaecology, Faculty of Medicine, Mansoura University, Egypt

Abstract

Introduction

Objective: To investigate the effectiveness of Sildenafil
vs Heparin/Aspirin combination in pregnancies complicated
by IUGR.

FETAL Growth Restriction (FGR) is a problem
where the fetus fails to attain its normal growth
potential and this affects nearly about 8% of all
pregnancies [1-3] . The growth restricted fetuses are
almost suffering a poor pregnancy outcome being
at increased risk of perinatal complications mainly,
fetal distress, asphyxia, neonatal hypoglycemia as
well as poor feeding [3] . Second; they are more
prone to long-term neurological and developmental
disorders, increased incidence of hypertension,
diabetes mellitus and coronary heart disease in
adulthood [3,4] .

Subjects and Mothods: The study was conducted at Mansoura University Hospitals, Mansoura, Egypt December 2015
to November 2016. One hundred patients (50 in each arm of
the study), who had proven intrauterine growth restriction,
were selected and enrolled into a randomized clinical trial.
Patients were allocated into two groups using computergenerated tables; Group A n=40: Received Sildenafil citrate
orally 20mg every 8 hours from inclusion till delivery and
the dose was adjusted according to maternal perception of
side effects. Group B n=43: Received prophylactic dose of
low molecular weight Heparin 40mg/day (Clexane 40mg) as
subcutaneous injection once daily plus low dose Aspirin 75mg
orally once daily also from the time of inclusion till delivery.
Cases were subjected to fetal and maternal surveillance and
the frequency was depending on the result of preliminary
assessment.
Results: Patients' age, parity, BMI, gestational age and
other demographic data were similar in both groups, p>0.05.
Sildenafil treatment group show significant increase in AC
and EFW (188.7mm vs 206.8mm and 926gm vs 1105gm
respectively p=0.001). Also there was significant increase in
AFI and umbilical artery Doppler parameters. Group 2
(heparin/aspirin) also show significant improvement in fetal
biometry and Doppler parameters but when comparing the
differences between the two groups, none of these changes
were statistically significant. The time between enrolment in
the study and delivery was significantly longer in heparin
group (25.4 days vs 21.7 days p=0.04) and the sildenafil group
experienced significant side effects (13 cases vs none).
Conclusion: From the results of our study we concluded
that sildenafil alone or heparin and aspirin combination has
beneficial effects in the treatment strategy of growth restricted
fetuses with improvement of fetal growth parameters and
reduction of NICU admissions, none of the treatment options
is found superior to the other.

Abnormal formation and function of the placenta with subsequent placental insufficiency is
considered as the main pathogenic mechanism
involved in FGR. These pregnancies are commonly
associated with elevated peripheral vascular resistance in the maternal arterial system as seen in
pregnancies complicated with preeclampsia [5] .
The trophoblastic production of nitric oxide in
normal pregnancy plays an important role in vasodilatation at the feto-placental circulation, thus
improving fetal oxygen and nutritional supply [6] .
This effect, in fact, is attributed to its potent relaxing
effect on arterial and venous smooth muscle and
perhaps inhibiting platelets aggregation and adhesiveness [7] . To date no available therapy addressed
with demonstrable effectiveness that makes monitoring and timely delivered growth restricted fetus
to be an easy and optimistic clinical entity [8] .
However evidences from in vitro and in vivo
studies suggested sildenafil citrate as one of the
potent therapeutic strategies to improve uteroplacental blood flow, fetal growth with meaningful
pregnancy outcomes [8] . This is because sildenafil
citrate, a selective inhibitor of cyclic Guanosine
Mono Phosphate (cGMP)-specific phosphodieste-

Key Words: Fetal growth restriction – Prophylactic heparin
aspirin – Outcome.

Correspondence to: Dr. Hend A. Shalaby,
E-Mail: henshalaby@yahoo.com

2461

2462

Sildenafil Citrate versus Aspirin/Heparin Combination for Fetal Growth Restriction

rase (PDE)-5 is found to enhance the relaxation
and accumulation of neural-released nitric oxide
and consequently increases uterine blood flow and
also potentiates estrogen-induced vasodilation [9] .
Also; intra-vaginal administration of sildenafil in
some cases is proved to increase the success of in
vitro fertilization with no deleterious effects on
the mother or the fetus [10] .
On the basis of these preliminary researches,
some centers are now adopting the treatment with
sildenafil in cases of FGR; however, there is significant uncertainty as regard the true health benefits. Moreover, the potential harm is not yet excluded [11] . Some other studies found improved
pregnancy outcome with FGR with or without
preeclampsia when low molecular weight heparin
and low dose aspirin were used in comparison with
the control groups [12,13] .
To the best of our knowledge no study compared
the effect of sildenafil citrate and heparin/aspirin
combination in the management of fetal growth
restriction, hence the aim to conduct our study.
Material and Methods
This prospective randomized cohort clinical
trial was conducted at the Department of Obstetrics
and Gynecology, Mansoura University Hospitals,
Mansoura, Egypt from December 2015 to November 2016. The study was approved by the Ethics
Committee of the Department and by Institutional
Research Board (certificate number: R/16.09.27).
Patients were first verbally advocated and consented
about the study and then agreed participants were
given a written consent before to be included.
Moreover; everyone had the right to be withdrawn
from the study at any time according her own will.
A total sample size of 90 patients (45 per group)
was calculated by using a formula for the difference
in the mean of the proposed variables that would
provide 80% power to detect a 5% difference at
a=0.05 and which assumed that 10% of women
would not respond [14] . By this; we selected 100
pregnant patients having IUGR fetuses with estimated fetal weight or abdominal circumference
below 10 th centile for gestational age. They were
allocated and divided randomly via computergenerated random numeric tables prepared by a
statistician with concealment of method option by
the use of sealed opaque envelopes that were given
to a third party (nurse) who assigned patients into
2 equal study arms.Group A n=40: (Sildenafil
group): Each case received Sildenafil citrate orally
20mg every 8 hours (Respatio tablet, pharma Egypt
group) started and continued till delivery and the

dose adjusted according to maternal perception of
side effects. Group B n=43: (Heparin/Aspirin
group) where each case received prophylactic low
molecular weight heparin 40mg/day (Clexane
40mg, Sanofi eventis company) as subcutaneous
injection once daily plus low dose Aspirin 75mg
(Aspocid 75mg tablet, CID pharmaceutical) orally
once daily from the time of inclusion till delivery.
After recruitment; cases were subjected to fetal
and maternal surveillance and the frequency was
depending on the result of preliminary assessment.
Patients excluded from our study were those
who had multiple pregnancies, any previous medication supposed to improve utero-placental blood
flow, suspected chromosomal or fetal congenital
anomalies documented by level II ultrasound examination and those who had maternal or fetal
emergencies necessitating delivery at time of recruitment in the study.
Fetal surveillance on follow-up was depending
on weekly fetal biometry via measuring Abdominal
Circumference (AC), Bi-Parietal Diameter (BPD),
Femur Length (FL), Estimated Fetal Weight (EFW),
amniotic fluid index. Umbilical artery, middle
cerebral artery and ductus venosus Doppler indices
were estimated at inclusion and then repeated twice
weekly or more frequently if abnormal indices
were encountered. Maternal surveillance was obtained by measuring blood pressure, urine test for
proteinuria by dipsticks. Appearance of drug side
effects; flushing, light headache and orifices bleeding, were indications for immediate stoppage.
Antenatal corticosteroid for lung maturation was
administered routinely in patients who were after
24 weeks gestation to enhance lung maturity and
in cases where sudden preterm labor would be
decided. Data were collected for comparison between 2 groups and we used the data at inclusion
in the study and the follow-up after 2 weeks of
treatment cases who necessitate delivery before
completing two weeks of treatment were excluded
from the study. Primary outcome measures included
increase in AC and EFW after 2 weeks of therapy,
number of surviving neonates in each group and
duration of stay in NICU.
Statistical analysis:
Data were collected, tabulated and statistically
analyzed by IBM computer using the Statistical
Package for the Social Sciences (SPSS Version
17). Chi-square test was used to compare the association between categorical variables in both groups
and Fisher exact test was used where necessary.
Student t-test was used to compare means of quan-

2463

Hend A. Shalaby

titative variables in parametric data. Pre and post
treatment AC and EFW were calculated using
paired t-test. p-value <0.05 was set significant.
Results
The study included 100 cases with fetal intrauterine growth restriction 50 cases in the sildenafil
treatment group and 50 cases in the heparin/low
dose aspirin group. They met the inclusion criteria
and received the planned treatment protocol. Seventeen cases delivered before completed two weeks
of treatment and follow-up, so excluded from
statistical analysis of data (10 cases in the sildenafil
group and 7 cases in the heparin group). The two
groups were comparable regarding maternal age,
parity, presence of medical disease namely diabetes,
systemic lupus erythematosus and preeclampsia
(p-value >0.05), (Table 1).
Table (2) shows the difference in fetal biometry
by ultrasound and changes in Doppler indices in
Sildenafil group before and after treatment (Group
A). There is significant increase in AC and EFW
(188.7mm vs 206.8mm and 926gm vs 1105gm
respectively p=0.001). Umbilical artery Doppler
indices are improved and this appeared statistically
significant despite worsening in 11 cases (22%)
that developed absent/reversed end diastolic flow
and 5 cases that had absent ductus venosus a wave.
The changes in MCA Doppler indices were not
significant (p>0.05). Amniotic fluid index significantly increased after treatment with sildenafil
(4.3cm vs 5.7cm p=0.001).
Group B (Heparin/Aspirin) shows a significant
increase in fetal growth parameters after treatment
as AC and EFW were 201 vs 218 (p=0.03) and
996gm vs 1187 (p=0.001) respectively. Significant
changes in umbilical artery S/D ratio PI but not
RI as shown in (Table 3). Significant change in
MCA PI was observed and 8 cases had absent/
reversed EDF and 4 cases had worsening ductus
venosus Doppler indices. Also there was improvement in AFI (p=0.001). There was no statistically
significant difference between the two groups
before starting treatment regarding fetal biometry
(BPD, FL, AC and EFW) by ultrasound. Also
Doppler indices were comparable; none of the two
groups shows AREDF in umbilical artery or absent
a wave in ductus venosus. Only AFI was significantly lower in the heparin treated group (p=0.04)
(Table 4).
Table (5) compares the changes in the study
variables after treatment between the two groups
where there is no statistically significant difference

except for the femur length measurement. The time
between enrolment in the study and delivery was
significantly longer in heparin group (25.4 days
vs 21.7 days p=0.04) and the sildenafil group
experienced significant side effects (13 cases vs
none). There were no differences in NICU admission, survivals, early neonatal death or still birth
between the two groups (Table 6).
Table (1): Patients' characteristics of both studied groups.
Heparin+
aspirin
group
(no=43)

pvalue

Maternal age (years ± SD) 27.7±5.2
Gravidity (median & range) 4 (1-6)
Parity (median & range)
1 (0-3)

28.6±4.1
3 (1-8)
2 (0-5)

0.35
0.8
0.06

Medical disease:
No disease
With disease

22 (55%)
18 (45%)

28 (65.1%) 0.8
15 (34.9%) 0.8

Medication

18 (45%)

15 (34.9%) 0.9

Gestational age
(days since LMP &
in weeks)

212.1 ± 19.1 218± 15.4
(30.3±2.7) (31.1 ±2.1)

GA Biometry
(BPD, FL, AC)

180.2±23.2 186.4±21.8 0.2
(25.7±3.2) (26.6±3.1)

Sildenafil
group
(no=40)

Variable

Abbreviations:
LMP : Last Menstrual Period.
GA : Gestational Age.
BPD : Bi-Parietal Diameter.

0.12

FL : Femur Length.
AC: Abdominal Circumference.

Table (2): Study variables in Sildenafil group before and after
treatment.
Variable

Before
treatment

2w after
treatment

pvalue

Fetal biometry:
BPD/mm
FL/mm
AC/mm
EFW/gm

64.1 ±6.2
44.6±7.2
188.7±40.5
926.8±453.2

69.5± 8.4
49.4±7.6
206.8±32.4
1105.3 ±429.3

0.001
0.001
0.002
0.001

UA Doppler:
S/D
PI
RI
AREDF

4.3 (2.2-5.7)
1.6±0.6
0.8±0. 1
0

3.2 (2.1-4.2)
1.4±0.5
0.7±0.1
11 (27.5%)

0.001
0.001
0.003
0.001

MCA Doppler:
PI
RI

1.5±0.2
0.76±0.3

1.3 ±0.3
0.81 ±0.2

0.06
0.055

DV/absent a wave
AFI cm

0
4.3 ± 1.1

5 (12.5%)
5.7 ± 1.2

0.055
0.001

Abbreviations:
BDP : Bi-Parietal Diameter.
FL : Femur Length.
AC : Abdominal Circumference.
EFW : Estimated Fetal Weight.
UA : Umbilical Artery.
S/D : Systolic Diastolic Ratio.

PI: Pulsatility Index.
RI: Resistance Index.
AREDF: Absent Reversed End
Diastolic Flow.
MCA: Middle Cerebral Artery.
DV : Ductus Venosus.
AFI : Amniotic Fluid Index.

2464

Sildenafil Citrate versus Aspirin/Heparin Combination for Fetal Growth Restriction

Table (3): Study variables in heparin, aspirin group before
and after treatment.
Variable
Fetal biometry:
BPD mm
FL mm
AC mm
EFW gm
UA Doppler:
S/D
PI
RI
AREDF

Before
treatment

2w after
treatment

pvalue

Variable

66.7±8.2
48.4±9.2
201.3 ± 43.1
996.1 ± 394

70.5±8.1
51.9± 10.3
218.4±49.8
1187.07±389.8

0.001
0.001
0.03
0.001

3.9 (2.5-5.7)
1.5±0.65
0.7±0.14
0

3.4 (2.5-5.3)
1.3 ±0.56
0.7±0.13
8 (18.6 %)

0.001
0.001
0.025
0.002

MCA Doppler:
PI
RI

1.3±0.3
0.7±0.12

1.2±0. 35
0.72±0.2

0.02
0.068

DV/absent a wave
AFI

0
3.8± 1.9

4 (9.3%)
5.6±0.69

0.053
0.001

Abbreviations:
BDP : Bi-Parietal Diameter.
FL : Femur Length.
AC : Abdominal Circumference.
EFW : Estimated Fetal Weight.
UA : Umbilical Artery.
S/D : Systolic Diastolic Ratio.

PI: Pulsatility Index.
RI: Resistance Index.
AREDF: Absent Reversed End
Diastolic Flow.
MCA: Middle Cerebral Artery.
DV : Ductus Venosus.
AFI : Amniotic Fluid Index.

Table (4): Comparison of study variables between the two
groups before treatment.
Variable

Table (5): Comparison of study variables between the two
groups after treatment.

Sildenafil
group

Heparin aspirin
group

pvalue

Sildenafil
group

Heparin aspirin
group

pvalue

Fetal biometry:
BPD/mm
FL/mm
AC/mm
EFW/gm

69.5± 8.4
49.4±7.6
206.8±32.4
1105.3 ±429.3

70.5±8.1
51.9± 10.3
218.4±49.8
1187.07±3 89.8

0.09
0.04
0.06
0.3

UA Doppler:
S/D
PI
RI
AREDF

3.2 (2.1-4.2)
1.4±0.5
0.7±0.1
11 (27.5%)

3.4 (2.5-5.3)
1.3±0.56
0.7±0.13
8 (18.6%)

0.5
0.8
0.6
0.3

MCA Doppler:
PI
RI

1.3 ±0. 3
0.81 ±0.2

1.2±0.35
0.72±0.2

0.06
0.19

DV/absent a wave
AFI

5 (12.5%)
5.7± 1.2

4 (9.3%)
5.6±0.69

0.6
0.4

Abbreviations:
BDP : Bi-Parietal Diameter.
FL : Femur Length.
AC : Abdominal Circumference.
EFW : Estimated Fetal Weight.
UA : Umbilical Artery.
S/D : Systolic Diastolic Ratio.

PI: Pulsatility Index.
RI: Resistance Index.
AREDF: Absent Reversed End
Diastolic Flow.
MCA: Middle Cerebral Artery.
DV : Ductus Venosus.
AFI : Amniotic Fluid index.

Table (6): Comparison of the outcome of the two groups.
Variable

Sildenafil
group (40)

Heparin
aspirin
group (43)

Time to delivery (days)
NICU admission (days)
Survivals (alive)
END
ND
SB
Side effects

21.7±3.1
7 (0-24)
19 (47.5%)
5 (12.5%)
4 (10%)
12 (30%)
13 (32.5%)

25.4±2.8
9 (0-20)
26 (60.5%)
9 (20.9%)
3 (7%)
5 (11.6%)
0

pvalue
0.04
0.8
0.2
0.21
0.2

Fetal biometry:
BPD/mm
FL/mm
AC/mm
EFW'/gm

64.1 ±6.2
44.6±7.2
188.7±40.5
926.8±453.2

66.7±8.2
48.4±9.2
201.3 ±43.1
996.1 ±394

UA Doppler:
S/D
PI
RI
AREDF

0.15
0.08
0.2
0.45
0.1

4.3 (2.2-5.7)
1.6±0.6
0.8±0. 1
0

3.9 (2.5-5.7)
1.5±0.65
0.7±0.14
0

0.86
0.76
0.44

MCA Doppler:
PI
RI

1.5±0.2
0.6±0.3

1.3 ±0.3
0.7±0.12

0.08
0.04

DV/absent a wave
AFI

0
4.3 ± 1.1

0
3.8± 1.9

Intrauterine growth restriction is the second
common cause of perinatal morbidity following
prematurity [15] . Currently, no specific evidence
based therapies are available for severe IUGR and
the interventions widely used are not based on
evidence from randomized controlled trials [16] .

PI: Pulsatility Index.
RI: Resistance Index.
AREDF: Absent Reversed End
Diastolic Flow.
MCA: Middle Cerebral Artery.
DV : Ductus Venosus.
AFI : Amniotic Fluid Index.

Our study was conducted to compare two therapies with different mechanisms directed to increase
utero-placental perfusion and thereafter improving
perinatal outcome in growth restricted fetuses,
Sildnafil citrate (a vasodilator drug) and the heparin/
aspirin combination (antithrombotic drugs). The

Abbreviations:
BDP : Bi-Parietal Diameter.
FL : Femur Length.
AC : Abdominal Circumference.
EFW : Estimated Fetal Weight.
UA : Umbilical Artery.
S/D : Systolic Diastolic Ratio.

0.03*

Abbreviations:
NICU : Neonatal Intensive Care Unit.
END : Early Neonatal Death.
SB
: Stillbirth.

Discussion

2465

Hend A. Shalaby

maternal characteristic of the studied groups were
not significantly different. Despite Dadelsezen et
al., in 2011 [16] studied earlier gestational age
(22 ± 4 weeks) complicated by IUGR and evaluated
the effect of sildenafil on severe early onset IUGR
but our patients in both groups were at more than
30 weeks (30.3 ±2.7 in Group A vs 31.1 ±2.1 in
Group B). This may be explained by the fact that
we selected elder gestational age due to poor neonatal outcome in our locality with a similar earlier
gestational age.
Our results also proved a significant increase
in fetal growth measurements and estimated fetal
weight after sildenafil citrate treatment ( p=0.002,
0.001 respectively) and this comes in accordance
with that conducted by Dadelsezen 2011 [16] who
documented an improving effect of sildenafil on
fetal growth measurements mainly AC & EFW
versus no treatment. Another an important finding
in our results was the effect of Sildenafil citrate
on placental perfusion evaluated by changes in
umbilical artery Doppler and middle cerebral artery
Doppler where significant changes in Doppler
indices occurred after treatment as shown. Table
(2). This latter finding comes in accordance with
a study investigated also the effect of Sildenafil
citrate on utero-placental perfusion in cases of
FGR pregnancies [17,18] . Contrary to this a recent
meta-analysis conducted to evaluate the use of
sildenafil in IUGR, though they found improvement
in fetal growth and Doppler velocimetries, but the
authors concluded a limited information on the
efficacy of sildenafil citrate for treating IUGR [19] .
The use of low molecular weight heparin with
or without small dose aspirin to improve maternal
and perinatal outcomes in cases at risk for placental
insufficiency has been extensively studied in the
past years on the assumption that heparin prevent
placental infarctions with subsequent increased
placental perfusion [20,21] . In the current study, the
second group that received heparin aspirin combination showed a significant increase in fetal AC,
EFW as well as acceptable changes in Doppler
indices (p-values <0.05). On the other hand, some
other studies found no beneficial effect from the
addition of heparin to the standard obstetric care
in the view of increasing fetal weight or placental
perfusion [22,23] . This is not coping with the result
of the current study.
To the best of our knowledge there is no study
comparing the effects of the use of the previous
medications in IUGR at least in our locality. Although our results show a significant improvement
in fetal growth parameters and Doppler indices in

each group separately but these changes are not
significantly different when comparing the two
groups together, Tables (4,5). In addition, the
duration of admission to NICU and neonatal survival were not significantly different between both
groups. Heparin/Aspirin treatment group shows
prolongation of pregnancy than the sildenafil treated
group also with significant side effects observed
in the Sildenafil treated group, (Table 6). These
side effects of Sildenafil were also observed in
many other studies but did not require discontinuation of the treatment [18,24] .
Despite our results seem promising and convenient, but there are some limitations and drawbacks of this study. These mainly include relatively
low number included, being 50 cases only in each
group, and also being a single center rather than
multicenter study that will be more informative
when gathering data and comparing all results.
From the results of our study we concluded
that sildenafil alone or heparin and aspirin combination has beneficial effects in the treatment strategy of growth restricted fetuses with improvement
of fetal growth parameters and reduction of NICU
admissions, none of the treatment options is found
superior to the other, however sildenafil carries
more side effects despite tolerated.
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V, BENACHI A., BRETELLE F., GRIS J.C. and BASTUJI-GARIN S.: Enoxaparin and Aspirin Compared With
Aspirin Alone to Prevent Placenta-Mediated Pregnancy
Complications: A Randomized Controlled Trial. Ob. Stet.
Gynecol. Nov., 128 (5): 1053-63, 2016.
24- BOYCE E.G. and UMLAND E.M.: Sildenafil citrate: A
therapeutic update. Clin. Ther., 23: 2-23, 2001.

Hend A. Shalaby

2467

The Egyptian Journal of Hospital Medicine (April 2018) Vol. 71 (4), Page 2989-2995

Sildenafil Citrate and Uteroplacental Perfusion in Fetal Growth Restriction
Amr Hasan El-Shalakany, Mohamed Mahmoud Abd El Aleem,
Mohamed Zaifer Ali Bawady
Obstetrics and Gynecology Department, Faculty of Medicine, Ain Shams University
*Corresponding author: Mohamed Zaifer Ali Bawady. Email: bawady2010@yahoo.com. Mobile: 01272794654

ABSTRACT
Background: Severe early-onset fetal growth restriction can lead to a range of adverse outcomes including
fetal or neonatal death, neurodisability, and lifelong risks to the health of the affected child. Sildenafil, a
phosphodiesterase type 5 inhibitor, potentiates the actions of nitric oxide, which leads to vasodilatation of the
uterine vessels and might improve fetal growth in utero.
Objective: To evaluate effectiveness and safety of Sildenafil citrate for treatment of intrauterine growth
restriction (IUGR). Design: A prospective randomized control study.
Setting: At Ain shams University hospital and Kafr Aldwwar main Hospital in El-Beheria governorate.
Subjects: Eighty pregnant women with gestational age between 24 and 34 weeks having singleton pregnancy
and suffering from IUGR attending an antenatal clinic.
Methods: Eighty pregnant women with FGR and abnormal umbilical artery Doppler between 24and34 weeks
were randomly allocated to sildenafil (n= 40) 25mg tid or placebo (n=40) with a plenty of fluids until delivery.
Main outcome measure: Length of pregnancy, neonatal weight and ICU admission.
Results: Sildenafil treatment was associated with a significant increase in length of pregnancy (P> 0.05) and a
significant increase in estimated fetal weight by ultrasound (P<0.05), and was associated with a significant
decrease in neonatal ICU admission (P=0.218) and neonatal mortality (P=0.290).
Conclusion: Sildenafil citrate can improve utero-placental perfusion and length of pregnancy in pregnancies
complicated by IUGR. It appears to have a significantly positive effect on fetal weight. Sildenafil treatment
may offer a new opportunity to improve perinatal outcomes, for pregnancies complicated by IUGR. However
these observations require further studies on wide scale.
Keywords: Sildenafil Citrate, Uteroplacental Perfusion, Fetal Growth Restriction.
INTRODUCTION
Intrauterine growth restriction (IUGR) is a fetal
weight that is below the10th percentile for
gestational age as determined by ultrasound. This
can also be called small for gestational age (SGA)
or fetal growth Restriction (FGR)[1] , while
Samangaya et al. [2] defined FGR as one or more of
the following: fetal abdominal circumference <5th
percentile. Amniotic fluid index < 5th percentile or
Doppler umbilical artery pulsatility index > 95th
percentile for gestational age. It affects up to 7-8%
of all pregnancies [3, 4]. Fetal growth restriction
(FGR) complicates 7-15% of pregnant women and
in its early and severs form the risk of perinatal
morbidity and mortality is increased [5].
Causes of FGR are classified to fetal factor as:
chromosomal abnormalities, multiple pregnancies,
fetal structural anomalies and fetal infections.
Maternal factors as: hypertension anemia, diabetes
mellitus, chronic lung diseases and heart. Placental
factor as: Chorioangioma, infarction, circumvallate
placenta, confined placental mosaicism, obliterative
vasculopathy of placental bed [6].
Umbilical artery Doppler has been the mainstay for
diagnosing placental insufficiency for 2 decades.
Consequently, fetuses with normal UA Doppler,
normally defined as small for gestational age (SGA),
have long been considered to be constitutionally

small fetuses with a good prognosis [7] Therefore, all
Doppler indices of the umbilical artery can be used to
distinguish between the high-risk small fetus that is
truly growth-restricted and the lower-risk small fetus
[8]
.
Several new vasodilator drugs have recently been
suggested to augment blood flow to tissues, one of
these drugs is sildenafil citrate (Viagra) [9].
Sildenafil citrate is a selective inhibitor of cyclic
guanosine monophosphate (cGMP) formation
through inhibition of type 5phosphodiesterase
(PDE5) [9]. It increases uterine blood flow and
potentiates estrogen-induced vasodilatation [10].
Several studies postulated that Sildenafil citrate may
offer a potential therapeutic strategy to improve
utero placental blood flow in FGR pregnancies [11. 12
&13]
.
AIM OF THE WORK
The aim of this study is to asses the efficacy of
sildenafil citrate therapy in prolonging pregnancy in
women with fetal growth restriction.
Research hypothesis
Sildenafil citrate may prolong pregnancy in women
with fetal growth restriction and abnormal umbilical
artery Doppler.

2989
Received:20 / 3 /2018
Accepted:30 /3 /2018

DOI: 10.12816/0046152

Sildenafil Citrate…
Research Question
Does sildenafil citrate prolong pregnancy in women
with fetal growth restriction and abnormal umbilical
artery Doppler?
PATIENTS AND METHODS
Research Design
A prospective randomized clinical trial. The
study was approved by the Ethics Board of Ain
Shams University.
Research setting
The study was conducted at the Department of
Obstetrics and Gynecology in Ain shams University
Hospital and Kafr Aldwwar General Hospital in
Elbeheira Governorate. And recruitment of cases
started in September 2016 and ended in December
2017.
Population of the study
All pregnant women who attended outpatient
clinic, presented in the emergency room, or those
referred to the hospital from other place. Pregnant
female diagnosed as SGA during u/s examination
and Underwent umbilical artery Doppler
velocimetry. Patient with decreased umbilical flow
were submitted to:
1) Detailed complete history taking
2) Clinical Examination:
a.
General examination
b. Abdominal
examination (Symphysis-fundal height)
3) Investigation
a.
Ultrasound assessment to evaluate gestational
age (GA), abdominal circumference (AC), fetal
weight, amniotic fluid index (AFI).
b.
Basal complete blood picture, blood serum
creatinine, uric acid, aspartate transaminase,
bilirubin, albumin, urine analysis and random blood
sugar.
4) Fetal Doppler indices measurement.
For Umbilical vessels the following indices were
measured:

The Systolic/Diastolic (S/D) ratio.

Resistance index (RI).

Pulsatility index (PI).
All three indices are highly correlated. PI shows a
linear correlation with vascular resistance as
opposed to both S/D ratio and RI, which show a
parabolic relationship with increasing vascular
resistance. Abnormal umbilical artery Doppler
indices were defined as S/D ratio greater than 2 and
RI greater than 0.7, so all these pregnancies were
the candidates of our study [14].
After evaluation the patient fulfilling the following
CCC was included in the research.
Inclusion criteria:
SGA fetus diagnosed by:

Confirmed GA (1st day LMP- U/S).
2990


AC below 10th percentile.
Reduced umbilical artery Doppler blood flow
velocimetry.
Regular menstrual pattern before pregnancy.
Gestational age (GA) between 24-36 weeks.
Singleton pregnancy.
Ability to attend follow up as planned.
Exclusion criteria
Normal or Reversed umbilical artery Doppler
blood flow velocimetry.
Uncertain gestational age.
Maternal cardiovascular morbidity.
Known or suspected fetal anomalies.
Where urgent delivery is indicated.
Usage of any vasodilator medication.
Smoking.
Drug or alcohol abusers.
Obstetrical
complications
(intrauterine
infection, bleeding, premature rupture of
membranes).
Follow up of the patient was difficult.
Patients fulfilled the inclusion and exclusion criteria
were offered to share in the study after full
explanation regarding study design and possibly
expected benefits and risks, those who agreed
should signed a special consent form.
Eighty pregnant women, suffering from intrauterine
growth restriction (IUGR) with gestational age
between 24-34 weeks as determined by the 1st day
of last menstrual period and confirmed by
ultrasound before the 20th week of gestation signed
the consent.
Allocation and Concealment:
Eighty sequential numbered opaque sealed
envelopes were numbered serially and in each
envelope the corresponding letter which donates the
allocated group was put according to randomization
table then all envelopes were closed and put in one
box. When the first patient arrived, the first
envelope was opened and the patient was allocated
to the letter inside.
Randomization:
Was done using computer generated randomization
sheet using MepCalc software version 12.5.
Intervention:
Participants were randomized into one of the
following drug regime:
Group (A): "sildenafil citrate group" included 40
patients that received a 25 mg tablet of sildenafil
citrate orally. Umbilical artery Doppler velocimetry
measured before and after 2 hours of sildenafil
ingestion. If no significant side effects were
recorded, the protocol was repeated 48 hours after
the 1st tablet ingestion. In cases of positive and
encouraging results and if no serious side effects are

Amr El-Shalakany et al.
detected, we used 25 mg sildenafil three times daily
until delivery [15]. Each patient was instructed for
bed rest and nutritional supplementation including
excessive oral fluid intake around the time of each
tablet ingestion with the aim of increase of amniotic
fluid index [16]. Pregnancy was allowed to continue
until fetal maturity as long as fetal growth continues
and fetal evaluation remains normal.
Group (B): "placebo group": This group consisted
of 40 women who received oral dose of placebo.
Blinding:
Both sildenafil and placebo tablets having an
identical appearance. Both the care giver and the
patient didn’t know the nature of medication
(Double blind study).
Follow up:
All patients were followed up by
1)
Ultrasonic fetal growth assessment: Growth
of bi-parietal diameter (BPD), head circumference
(HC), AC, femur length (FL), HC/AC ratio, FL/AC
ratio and EFW. If AC increases by at least 1cm / 2
weeks the growth is satisfactory. If it is less than
1cm/ 2 weeks or growth is arrested termination of
pregnancy is recommended irrespective of the
results of antenatal testing for fetal surveillance [17].
2)
Umbilical
Doppler
velocimetry
(for
surveillance of fetal hypoxemia/ acidaemia):
When umbilical artery end diastolic flow
indices are normal it is reasonable to repeat
surveillance every 14 days.
When umbilical artery end diastolic flow
indices are decreased and delivery is not indicated
repeat surveillance twice weekly.

When umbilical artery end diastolic flow
indices are absent or reversed urgent delivery to be
done [18].
3)
Fetal lung maturity score as described by [19].
All patient were followed tell the end of the
pregnancy and after delivery neonatal weight &
neonatal care were evaluated.
Outcome Measures
Primary outcome measure:
1Length of pregnancy.
Secondary outcome measures:
1Neonatal birth weight.
2Neonatal ICU admission.
Statistical analysis
Data were collected, revised, coded and entered to
the Statistical Package for Social Science (IBM
SPSS) version 23. The quantitative data were
presented as mean, standard deviations and ranges
when their distribution found parametric while
qualitative data were presented as number and
percentages.
The comparison between two independent groups
with qualitative data was done by using Chi-square
test and/or Fisher exact test only when the expected
count in any cell found less than 5.
The comparison between two independent groups
with quantitative data and parametric distribution
was done by using Independent t-test.
The confidence interval was set to 95% and the
margin of error accepted was set to 5%. So, the pvalue was considered significant as the following: P
> 0.05: Non-significant. P < 0.05: Significant. P <
0.01:
Highly
significant.

RESULTS
Table (1): Comparison between the two studied groups regarding base line gestational age and estimated fetal
weight estimated by u/s on admission.
Sildenafil Group
Placebo Group
Test of
P“n=37”
“n=36”
significance
value
Gestational age on admission
Range
25-34
26-33
t=0.328
0.744
Mean ±S.D.
32.00±4.1
31.72±3.11
Estimated fetal weight on
admission
T=1.333
0.187
Range
900-1250
950-1200
Mean ±S.D.
1060.0±122.6
1100.0±133.6
Table (2): Comparison between the two studied groups regarding the gestational age at delivery.
Gestational age at delivery
Sildenafil Group
Placebo Group
(weeks)
“n=37”
“n=36”
Range
36-40
34-39
Mean ±S.D.
38.2±1.36
37.4±1.42
T
2.459
P
0.016*

2991

Sildenafil Citrate…
Table (3): Comparison between the two studied groups regarding the Birth weight (gm)
Sildenafil Group
Placebo Group
Birth weight (gm)
“n=37”
“n=36”
Range
1100-2850
1030-2680
Mean ±S.D.
2070.5±450.3
1842.2±352.0
T
2.409
P
0.019*
Table (4): Comparison between the two studied groups regarding the newborn ICU admission and mortality
Sildenafil Group
Placebo Group
“n=37”
“n=36”
X2
P-value
No.
%
No
%
Newborn ICU admission
2
5.4%
5
13.9%
1.515
0.218
Mortality
1
2.7%
3
8.3%
1.117
0.290
Table (5): Comparison between sildenafil group regarding the maternal complaints before and after treatment
Before treatment
After treatment
pX2
value
No.
%
No
%
Headache
14
37.8%
29
78.4%
12.491
<0.001
Epigastric discomfort
16
43.2%
16
43.2%
0.000
1.000
Vomiting
2
5.4%
5
13.5%
1.42
0.233
Visual disturbance
2
5.4%
8
21.6%
4.163
0.041
Diarrhea
3
8.1%
5
13.5%
0.561
0.453
Irregular uterine Contractions
9
24.3%
6
16.2%
0.753
0.386
Painful uterine Contractions
3
8.1%
1
2.7%
1.057
0.303
Increase or change in vaginal
13
35.1%
7
18.9%
2.467
0.116
discharge
Decreased fetal movements
4
10.8%
2
5.4%
0.725
0.394
In our study there was significant increase in
length of pregnancy in sildenafil group compared
to placebo group. The mean gestational age in
sildenafil group were 38.2±1.36 weeks and in
placebo group were 37.4±1.42 weeks (p =0.016),
and neonatal birth weight was significantly
increased in sildenafil group than placebo group.
Mean birth weight in sildenafil group was
2070.5±450.3, while in placebo group was
1842.2±352.0 (p<0.05).
In addition there is significant decrease in
neonatal ICU admission and mortality in
sildenafil group than placebo group, in sildenafil
group 2 cases admitted to ICU compared with 5
cases in placebo group (p=0.218), and only one
IUFD in sildenafil group compared with three
IUFDs in placebo (p=0.290).
Regarding maternal safety, sildenafil was
well tolerated and no women withdraw from the
study due to side effects.
Headache was the commonest side effect
(78.4%) followed by visual disturbance and
gastrointestinal tract symptoms.
2992

DISCUSSION
To achieve optimal fetal growth, adequate
blood flow in uteroplacental vascular function is
essential. Abnormal vasculature adaptation,
resulting in aberrant blood flow, has been
implicated as a possible cause of fetal growth
restriction (FGR). Sildenafil, as a vasodilator,
should be an alternative in the treatment of IntraUterine-Growth-Retardation
(IUGR)
and
preeclampsia by later normalization in velocimetric
profile.
As a therapeutic agent in FGR gestations by
promoting myometrial small artery vasodilatation,
reducing in maternity peripheral resistance and
increasing flow within the uteroplacental bed, can
improve uteroplacental perfusion. PDE-5 inhibitors
can reduce vasoconstriction and improve relaxation
of FGR myometrial small arteries [2].
Parallel to our study case report study of
pregnant female with IUGR and oligohydramnios
received sildenafil citrate 25 mg vaginally twice a
day started on 27 weeks gestation showed a
consistent increase in fetal weight and AFI with
sildenafil citrate without any adverse fetal outcome.

Amr El-Shalakany et al.
An elective cesarean section was done at 37th week
for breech presentation, and a healthy female child
of 2.3 kg was delivered. Baby cried immediately
after birth, and Apgar score was 7/10 and 9/10 at 1
and 5 minutes, respectively. It increases the window
of fetal maturity and hence reduces neonatal
morbidity and mortality due to prematurity [20].
El-Sayed et al. [21] in a randomized controlled
trial of 54 patients at 24 weeks or more complicated
by FGR and abnormal Doppler indices were
randomly allocated 1:1 into an intervention arm
(receive sildenafil citrate, 50 mg) or a control arm
(receive placebo). there was a significant pregnancy
prolongation in sildenafil group, increased GA at
delivery, mean GA at delivery for sildenafil and
placebo was 32 + 2 and 30 + 5 weeks, respectively
(with standard deviation of 12 days, p=0. 004),
improved neonatal weight (p=. 0001), and found
less admission to neonatal intensive care unit (7%
and 30% of the cases required NICU admission, p<
0.03), not only the majority of these babies were
preterm, but they were also FGR.
In sildenafil group mothers reported mild
adverse reactions in the form of headache (3
patients), flushing (1patient), flushing with diarrhea
(1 patient), while placebo group reported nausea (3
patients), all were self-limited with no needed
treatment.
Trapani et al. [22] in a randomized control study
of 100 cases with preeclampsia. found that sildenafil
citrate given to women with preeclampsia with a
severe feature at an oral dose of 50 mg every 8
hours allows the prolongation of pregnancy by an
average of 4 days (14.4 days compared with 10.4
days, P=.008). We speculate that this prolongation
may be the result of better control of blood pressure,
improvement of maternal and fetal blood flow, or a
combination of both. The medication was well
tolerated. There was no difference in the incidence
of adverse events between the groups. Only three
patients suspended the medication as a result of
possible side effects (severe headache): one in the
study group and two in the control group.
In another Study of 100 pregnant women with
severe early and late onset fetal growth restriction
and oligohydramnios. Intervention included
administration of Sildenafil citrate 25mg three times
daily until delivery, found that sildenafil prolong the
length of pregnancy. GA at delivery since LMP 30
to 36 weeks. Sildenafil treatment improved perinatal
outcome by improving fetal growth velocity as
assessed by serial AC measurements by ultrasound.
There was improvement in AFI and fetal Doppler
parameters (p<0.05). Sildenafil therapy reduced
NICU admissions and mortality (98 live birth all
2993

discharged to home versus only 2 still birth) and 3
years follow up shows no effect on the overall
development of the babies. Maternal side effect is
almost negligible. Those who complained of head
ache and palpitation the dose of Sildenafil was
reduced from three times a day to two times a day.
Therefore Sildenafil represent a novel intervention
for the pregnancies with IUGR [23].
In another case control study of 27 pregnant
females with FGR., Sildenafil citrate (25 mg three
times daily until delivery) was given to 10 women
another 17 women received placebo treatment.
Sildenafil treatment was associated with increased
post-eligibility fetal AC growth velocity [9/10
(treated) versus 7/17 (naive). odds ratio, 12.9 (95%
CI, 1.3, 126)]. We also examined post-eligibility
fetal growth velocity using individual pregnancies
as their own controls com-pared with pre-eligibility
growth velocity. Sildenafil therapy was associated
with a significant increase in fetal growth velocity,
expressed as equivalent daily AC growth [preeligibility median, 0.59 (interquartile range, 0.37,
0.79)., post-eligibility median, 0.94 (0.78, 1.39).,
Wilcoxon P = 0.0039., n = 9), but remaining
Sildenafil-naive was not [pre-eligibility median,
0.71 (0.48, 0.85)., post-eligibility median, 0.58
(0.38, 0.77)., Wilcoxon P = 0.2513., n = 17]. Both
survival to, and intact survival at, hospital discharge
tended to be more frequent in the fetuses/neonates
exposed to Sildenafil in utero, there were no adverse
maternal side-effects of medication reported in the
treated group [24].
Panda et al. [11] a case control study of
pregnant female with FGR, sildenafil citrate 50 mg
tid was used. Doppler showed improved
uteroplacental blood flow with estimated fetal
weight of around 800 gm and hence pregnancy
could be continued to another 3 weeks. A live male
baby of 800 gr was delivered and shifted to
Neonatal Intensive Care Unit (NICU) for further
management. After 80 days of NICU care, the baby
was finally discharged healthy with a weight of 2.3
kg. After 1 month of discharge, mother and infant
came for follow up and both were doing perfectly
well. Also, the infant was checked by pediatrician
and was found healthy.
In contrary to our study Andrew et al. [25] a
multicenter,
randomized,
placebo-controlled,
double-blind trial done between Nov 21, 2014, and
July 6, 2016, recruited 135 women and randomly
assigned 70 women to sildenafil and 65 women to
placebo. Found no difference in the median
randomisation to delivery interval between women
assigned to sildenafil (17 days [IQR 7–24]) and
women assigned to placebo (18 days [8–28].,

Sildenafil Citrate…
p=0·23). Live births (relative risk [RR] 1·06, 95%
CI 0·84 to 1·33., p=0·62), fetal deaths (0·89, 0·54 to
1·45., p=0·64), neonatal deaths (1·33, 0·54 to 3·28.,
p=0·53), and birth weight (–14 g,–100 to 126.,
p=0·81) did not differ between groups. No
differences were found for any other secondary
outcomes. Eight serious adverse events were
reported during the course of the study (six in the
placebo group and two in the sildenafil group).
Interpretation., Sildenafil did not prolong pregnancy
or improve pregnancy outcomes in severe earlyonset fetal growth restriction and therefore it should
not be prescribed for this indication outside of
research studies with explicit participants’ consent.
In this study fetal growth restriction defined as a
combination of estimated fetal weight or abdominal
circumference below tenth percentile and absent or
reversed end-diastolic blood flow in the umbilical
artery on Doppler velocimetry which is exclusion
criteria in our study
These findings were not consistent with Miller
et al. [26] who found in an experimental animal study
that Sildenafil reduced uterine blood flow and this
was associated with significant deterioration in fetal
wellbeing. They explained their findings by the
action of Sildenafil on maternal systemic
circulation, altering it and resulting in blood flow
“steal” from the uteroplacental circulation to the
systemic vascular circulation that has lowered its
resistance
due
to
widespread
systemic
vasodilatation. They also provided an alternative
explanation for the decrease in UBF which is the
extensive cellular and tissue distribution of the
PDE-5 enzyme throughout the body and therefore
lack of relative specificity within the uteroplacental
circulation. These findings of Miller et al. [26] in the
animal study couldn’t be confirmed in human.
Samangaya et al. [2] concluded that oral
sildenafil in an escalating dose regime of 20–80 mg
tid daily does not prolong pregnancy in women with
preterm preeclampsia. The medication was well
tolerated, and no women withdrew from the trial
due to side effects. Up-titration to a maximal dose
of 80mg tid was tolerated well by all women except
one in the sildenafil group, who was down-titrated
due to heartburn. Maternal adverse events occurred
with a similar frequency in each group. Treatment
had no effect on the condition of the babies at birth
using Apgar scores at 1 and 5 minutes, and cord
artery and vein pH samples. Most babies had at least
one adverse event, with a similar incidence within
each group. There was one neonatal death in the
sildenafil group (extreme prematurity), and two in
the placebo group (respiratory distress syndrome
and a liver capsule tear). Although the sample size
2994

was small, the study was adequately powered to
detect a difference of at least 5 days between treated
and control groups in the time from randomization
to delivery.
There are several explanations why this
escalating regime of sildenafil did not affect
outcome in women with preterm preeclampsia.
Firstly, women may have been too far along the
pathophysiological process, such that improving
uteroplacental blood flow had no effect on release
of circulating factors or on established endothelial
dysfunction. Second the dosing regimen may not
have achieved efficacious drug concentrations
rapidly enough to slow progression, also within the
study group there was a wide range of gestational
ages, severity of preeclampsia and presence of fetal
growth restriction. This reflects the heterogeneity of
preeclampsia but may also have reduced the
potential to demonstrate any effect of sildenafil [2].
Thus, from the obtained results, it is evident
that sildenafil citrate treatment may offer a new
opportunity to improve perinatal out comes for
women whose pregnancies are complicated by
IUGR.
CONCLUSION
To achieve optimal fetal growth, adequate blood
flow in utero- placental vascular function is
essential. Many authors have implicated abnormal
vasculature adaptation, resulting in aberrant blood
flow, as a possible cause of fetal growth restriction
(FGR). Sildenafil citrate, as a vasodilator has also
emerged as a potential management option in the
treatment of FGR by normalization of fetal Doppler
velocimetric profile.
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