|Year : 2019 | Volume
| Issue : 4 | Page : 1343-1349
Effect of transdermal nitroglycerin compared with sildenafil citrate on Doppler indices in intrauterine growth restriction
Zakaria F Sanad1, Hamed E El-lakwa1, Hesham S E Mahmoud1, Ahmed Z Nofal1, Mustafa Abd El-Hakeem Muhammad2
1 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Obstetrics and Gynecology, Ghamra Military Hospital, Cairo, Egypt
|Date of Submission||16-Jul-2018|
|Date of Decision||08-Aug-2018|
|Date of Acceptance||13-Aug-2018|
|Date of Web Publication||31-Dec-2019|
Mustafa Abd El-Hakeem Muhammad
Department of Obstetrics and Gynecology, Ghamra Military Hospital, Cairo 32511
Source of Support: None, Conflict of Interest: None
This study aimed to compare the effect of sildenafil citrate on pulsatility index of uterine, umbilical and middle cerebral arteries to that of nitroglycerine in cases of intrauterine growth restriction (IUGR).
IUGR is one of the most common and serious complications of pregnancy. Sildenafil citrate and nitroglycerine are emerging as potential candidates for the treatment of IUGR through improving uteroplacental blood flow.
Participants and methods
Ninety singleton pregnancies, with IUGR and abnormal uterine and umbilical arteries Doppler, were included in the study and randomized into three groups to receive either oral sildenafil citrate (50 mg), a transdermal nitroglycerine patch (10 mg), or placebo. Maternal mean arterial blood pressure and the pulsatility index (PI) of uterine (Ut.A), umbilical (UA) and fetal middle cerebral (MCA) arteries were measured before and two hours after application of drugs.
A significant reduction of Ut.A-PI occurred after application of both sildenafil citrate (16.7%, P = 0.001) and nitroglycerine (18.7%, P = 0.001). UA-PI also showed a significant decrease with both sildenafil citrate (17.8%, P = 0.001) and nitroglycerine (17.03%, P = 0.001), with no significant difference between the two drugs. No changes were observed in Doppler velocimetry in the placebo group, and no significant change in MCA-PI was observed in any group. Maternal arterial blood pressure decreased significantly with administration of both sildenafil citrate and nitroglycerine.
Sildenafil citrate has an effect similar to nitroglycerine in improving Doppler indices and blood flow of uterine and umbilical arteries in growth-restricted fetuses.
Keywords: doppler ultrasonography, fetal growth restriction, nitroglycerine, phosphodiesterase inhibitors, sildenafil citrate
|How to cite this article:|
Sanad ZF, El-lakwa HE, Mahmoud HS, Nofal AZ, Muhammad MA. Effect of transdermal nitroglycerin compared with sildenafil citrate on Doppler indices in intrauterine growth restriction. Menoufia Med J 2019;32:1343-9
|How to cite this URL:|
Sanad ZF, El-lakwa HE, Mahmoud HS, Nofal AZ, Muhammad MA. Effect of transdermal nitroglycerin compared with sildenafil citrate on Doppler indices in intrauterine growth restriction. Menoufia Med J [serial online] 2019 [cited 2020 Feb 16];32:1343-9. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1343/274238
| Introduction|| |
Intrauterine growth restriction (IUGR) occurs when fetal optimal growth potential is not achieved. It is one of the most common and serious complications of pregnancy .
The most common etiology for IUGR is placental insufficiency, which is frequently associated with impaired placental blood flow .
Growth-restricted fetuses with severely impaired umbilical artery (UA) blood flow are at high risk of adverse outcomes such as intrauterine fetal demise and neonatal death, as well as increased neonatal morbidity, including hyperbilirubinemia, hypoglycemia, hypothermia, necrotizing enterocolitis, intraventricular hemorrhage, sepsis, seizures and respiratory distress syndrome .
Epidemiological studies have shown that growth-restricted fetuses are at risk of cognitive delay in childhood as well as adulthood diseases (e.g. obesity, type 2 diabetes mellitus, coronary artery disease and stroke) .
In normal pregnancy, the trophoblast produces nitric oxide (NO), which is a potent venous and arterial vasodilator that also inhibits platelet aggregation .
In pregnancies complicated by pre-eclampsia or IUGR, inflammation leads to endothelial dysfunction and placental hypoxia, which are associated with decreased release of NO and increased activity of phosphodiesterase type 5 (PDE-5) .
NO donors, which are known PDE-5 inhibitors, have the potential for prevention as well as treatment of IUGR. Nitroglycerin (GTN) produces NO through a biotransformation pathway; hence, it has the same potential . One of nitroglycerine's limitations is the development of tolerance, which can be reduced by intermittent administration. In addition, headache is a frequent side-effect that limits the use of nitroglycerin during pregnancy .
PDE-5 is an enzyme that metabolizes cyclic GMP. Inhibition of PDE-5 results in an increase in cGMP and consequent vasodilatation. The most-studied PDE-5 inhibitor is sildenafil citrate, which has shown promising outcomes, in both in vitro and animal studies . Therefore, sildenafil has the potential to reach similar therapeutic goals in cases of IUGR, if compared with nitroglycerine, but, potentially, without its limitations (i.e. tolerance and headaches).
We aimed in this study to compare the effects of sildenafil citrate and transdermal GTN pregnancies complicated with IUGR, associated with placental insufficiency. We compared maternal blood pressure and uterine, umbilical and fetal middle cerebral arteries' Doppler indices before and after the administration of sildenafil citrate, transdermal GTN or placebo in a randomized manner.
| Participants and Methods|| |
This prospective randomized placebo-controlled trial was conducted at the department of Obstetrics and Gynecology at Ghamra Military Hospital, which is a tertiary hospital in Cairo, Egypt. The study was approved by the Research Ethics Committee of Faculty of Medicine, Menoufia University, Egypt. Patients who attended the outpatient clinic, and fulfilled the inclusion criteria, were offered to participate in the study after full explanation with regard to the study design and possibly expected benefits, and those who agreed signed a special consent form. Recruitment of cases started in May 2017 and ended in March 2018.
Ninety singleton pregnancies (gestational age ≥24 weeks) with IUGR and abnormal uterine and umbilical arteries' Doppler waveforms were included in the study. IUGR was defined as estimated fetal weight less than 10th percentile by ultrasound . Uterine artery (Ut.A) and Umbilical artery (UA) Doppler was considered abnormal if pulsatility index (PI) was greater than 95th percentile ,. Pregnancies complicated with: multifetal pregnancies, fetal infection, congenital fetal anomalies, maternal medical diseases that contraindicate the use of sildenafil citrate or nitroglycerine, reversed flow of umbilical artery Doppler, and those receiving drugs that interacted with nitroglycerine or sildenafil citrate were excluded from the study.
Gestational age was calculated from the date of the last menstrual period and was confirmed by ultrasound examination performed in the first half of the pregnancy. BMI as maternal weight divided by maternal height squared (kg/m 2).
Study participants were randomized into one of three treatment regimen groups (a) sildenafil group to receive a single oral dose of 50 mg sildenafil citrate (Silden 50 mg; EPICO, 10th of Ramadan City, Egypt), (b) nitroglycerine group to receive a single dose of transdermal nitroglycerine patch 10 mg (Nitroderm tts 10 mg; Novartis Pharma, Cairo, Egypt) applied to abdominal skin, or (c) placebo group to receive a single dose of oral placebo. The placebo tablets contained starch and were manufactured to the international standards, packaged, and blinded in such a manner that both sildenafil and placebo tablets had an identical appearance. Sildenafil citrate and Nitroglycerine doses were selected on the basis of the safety profile and favorable results from previous studies ,,. The sildenafil and placebo groups were double blinded. Patients were assigned to each treatment group on the basis of blocked randomization using sealed opaque envelopes.
The patients were followed-up over a 2 h period; they were observed for occurrence of any side effects; we compared maternal arterial blood pressure and the pulsatility index (PI) of Ut.A, UA and fetal MCA, before and 2 h after application of oral sildenafil citrate 50 mg, a transdermal nitroglycerine patch 10 mg applied to the skin of the abdomen, or placebo.
The same sonographer was assigned to evaluate all women included in the study using a GE Voluson 730 pro ultrasound scanner and a 3.5 MHz abdominal convex transducer (General Electric Medical Systems, Chicago, Illinois, United States). For obtaining uterine artery Doppler, the probe was placed longitudinally in the lower lateral quadrant of the abdomen, angled medially. Color flow mapping was used to identify the uterine artery at the point of crossing the external iliac artery. The sample volume was placed 1 cm downstream from this crossover point.
For obtaining umbilical artery Doppler, measurements were made in a free cord loop during fetal quiescence. Five to six uniform waveforms were obtained greater than or equal to 3 times in succession, and measurements were performed. The waveform envelope that had the highest measured peak systolic velocity was considered for analysis, assuming that the highest measured velocity represents the lowest angle of insonation.
For obtaining fetal middle cerebral artery Doppler, an axial section of the brain, including the thalami and the sphenoid bone wings, was obtained and magnified. Color flow mapping was used to identify the circle of Willis and the proximal MCA. The pulsed-wave Doppler gate was then placed at the proximal third of the MCA, close to its origin in the internal carotid artery.
Estimated fetal weight (EFW) was calculated using the modified Hadlock formula, which requires measurement of the head, abdomen, and femur ,.
Maternal blood pressure was measured using auscultatory method with a sphygmomanometer and a stethoscope (mercury column, always on the left arm, with the patient sitting and supported, legs not crossed). First Korotkoff sound was used to determine systolic blood pressure, fifth Korotkoff sound was used to determine diastolic blood pressure and mean arterial blood pressure (MAP) [diastolic pressure +1/3 (systolic pressure − diastolic pressure)] was used for comparisons between groups.
The primary outcome of the study was to evaluate the effects of sildenafil citrate and transdermal nitroglycerin (GTN) on Doppler velocity waveforms of the uterine (Ut.A), umbilical (UA) and fetal middle cerebral (MCA) arteries in pregnancies complicated with IUGR. The secondary outcome was comparing the effect of the two drugs on maternal blood pressure.
MedCalc version 220.127.116.11 program (MedCalc Software, Acacialaan 22 8400 Ostend, Belgium) was used for calculations of sample size based on 95% confidence interval and power of the study 80% with α error 5%. Sample size was 86 cases which was enough to detect a variation in mean Ut.A-PI of 00.20 (20%). Assuming a drop-out ratio of 5%, the sample size was estimated to be 90 cases (30 cases in each group).
Statistical analysis of results was performed by the statistical package for social sciences, version 20.0 (SPSS Inc., Chicago, Illinois, USA). Quantitative data were expressed as mean ± SD. Qualitative data were expressed as frequency and percentage. Analysis of variance test was used when comparing between more than two means. Paired sample t-test of significance was used when comparing between related samples. χ2-Test of significance was used in order to compare proportions between two qualitative parameters.
| Results|| |
Ninety singleton pregnancies met the inclusion criteria and were divided into three groups receiving sildenafil citrate, transdermal nitroglycerine, or placebo [Table 1]. Headache was the most prominent side-effect in our study: 13 (43.3%) cases in the nitroglycerine group and only five (16.6%) in the sildenafil group (χ2 test, P = 0.024). Two (6.7%) patients in the nitroglycerine group and three (10%) in the sildenafil group had significant facial flushing (χ2 test, P = 0. 0.23) [Table 2]. Ut.A PI decreased significantly after application of both sildenafil citrate (16.7%, P = 0.001) and nitroglycerine (18.7%, P = 0.001). UA PI also showed a significant reduction with both sildenafil citrate (17.8%, P = 0.001) and nitroglycerine (17.03%, P = 0.001), with no significant difference between the two drugs [Table 3]. No changes in Doppler velocimetry were observed in the placebo group, and no significant change in MCA-PI was observed in any group [Table 3]. Maternal arterial blood pressure decreased with administration of both sildenafil citrate (from 89.05 ± 7.99 to 82.78 ± 7.14, P = 0.001) and nitroglycerine (from 90.52 ± 6.95 to 83.18 ± 6.52, P = 0.001) [Table 4]. Baseline maternal heart rate was 82 ± 6 beats per minute and did not change significantly at any point in the study. No fetal tachycardia or bradycardia occurred during the study.
|Table 1: Baseline characteristics and demographic data of 90 singleton growth-restricted pregnancies included in the study|
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|Table 2: Mean arterial pressure before and two hours after administration of sildenafil citrate, transdermal nitroglycerine, or placebo|
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|Table 3: Maternal side effects following administration of sildenafil citrate (50 mg), transdermal nitroglycerine (10 mg), or placebo|
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|Table 4: Pulsatility indices of uterine, umbilical, and fetal middle cerebral arteries before and two hours after administration of sildenafil citrate (50 mg), transdermal nitroglycerine (10 mg), or placebo|
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| Discussion|| |
A drug that could improve the hemodynamics of fetomaternal circulation in cases of IUGR has the potential benefit for at least palliation, if not also treatment, of such a harmful condition. We aimed in our study to evaluate and compare the effect of oral sildenafil and transdermal nitroglycerine as potential treatment options in cases of IUGR.
The drop in maternal blood pressure following sildenafil or nitroglycerine administration was of concern to us, because if not met by a concomitant increase in utero placental blood flow, it could aggravate the condition. The expected decrease in both Ut.A PI and UA PI after application of sildenafil may be attributed to its vasodilator effect, which has been shown previously in nonpregnant female individuals by Hale et al. , and on small myometrial arteries from pregnant women with IUGR in a study by Waering et al. .
The positive effect of sildenafil on fetal growth was reported in some animal studies by Sánchez-Aparicio et al. . It was also reported in a previous case–control study by Von Dadelszen et al. , in which the use of sildenafil citrate (25 mg, three times daily until delivery) in pregnancies complicated by severe IUGR, was associated with a significant increase in abdominal circumference compared with that of the control group (odds ratio: 12.9; 95% CI: 1.3–126). However, hemodynamic changes to the uteroplacental, fetoplacental or fetal cerebral circulation were not evaluated in this study.
A decrease in Ut.A-PI and UA-PI with the use of sildenafil has been shown previously in an in-vivo animal study by Stanley et al. , as well as some case reports by Panda et al. , and Lin et al. .
Going with our results, Dastjerdi et al. , El-Sayed et al. , and Premalatha et al.  showed that a significant decrease in the uterine and umbilical arteries pulsatility indices ingrowth restricted pregnancies treated with sildenafil citrate.
Sildenafil, as a vasodilator has also arisen as a possible treatment choice in the management of fetal growth restriction and pre-eclampsia by later normalization in velocimetric profile; this was shown in studies by Gillis et al.  and Trapani et al. . In contrast, Samangaya et al.  concluded that the use of sildenafil in women with established pre-eclampsia is not recommended, as 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; however, the drug showed some effect on fetal growth.
Mahmoud et al.  also reported a significant decrease in both Ut.A and UA PI with sildenafil treatment in 50 women with high risk for development of IUGR and 50 others with already diagnosed IUGR (EFW ≤10th percentile). They also observed a significant reduction in maternal blood pressure with sildenafil use. There was enhancement of restricted growth, as well as prevention of IUGR development in high-risk pregnancies, supporting not only the use of sildenafil citrate for treatment of IUGR, but also its use for IUGR prevention in high-risk pregnancies.
A decrease in utero placental vascular resistance has also been demonstrated with the use of intravenous, sublingual and transdermal nitroglycerine, in previous studies, with a smaller sample size and more heterogeneous enrollment criteria, as in the study by Johal et al. .
Grunewald et al.  have also shown a significant improvement in umbilical artery blood flow with the use of nitroglycerine in women with severe pre-eclampsia. They demonstrated that the decrease in the PI of the umbilical artery was more pronounced in patients who already had abnormal Doppler waveforms before the initiation of therapy, as was the case in our study. They hypothesized that women with endothelial dysfunction may need a smaller endothelial concentration of nitric oxide for the same response as healthy women.
Furthermore, the effect of transdermal nitroglycerine was studied on pregnancies with severe pre-eclampsia and documented abnormal uterine and umbilical arteries' Doppler waveforms. Trapani et al. , Gupta et al. , and Cacciatore et al.  observed a significant reduction in the PI of the uterine arteries. No significant change in the PI of the middle cerebral artery was observed. All of these are similar results to the present study.
In pregnancies not complicated with pre-eclampsia, Kähler et al.  demonstrated that transdermal nitroglycerine did not affect umbilical artery RI, but only affected mean Ut.A RI and nonplacental side Ut.A RI, both of which decreased significantly. The difference in their results from ours may be due to use of RI to evaluate arteries while we used PI, also may be due to the less powerful study design and the smaller sample size they had (a prospective observational study including only twenty-five pregnant women at risk for preterm delivery).
Lees et al.  also studied the effect of transdermal nitroglycerine (5 mg) in 40 healthy normotensive women at high risk of pre-eclampsia at 24–26 weeks of gestation. They reported no significant change in Ut.A, UA or MCA Doppler, and no significant change in maternal blood pressure. The patients were selected on the basis of abnormal Doppler studies, which they defined as women with waveforms revealing the presence of bilateral notches, and the mean uterine artery resistance index (RI) was two standard deviations above the population mean. They did not refer to the normal reference range that they adapted, whether for uterine or umbilical arteries. Moreover, women whose pregnancies were complicated with IUGR or who even had a history of a previous growth-restricted baby were excluded from the study.
Previous studies by Cacciatore et al. , Lees et al. , Luzi et al. , and Trapani et al. , showed that the PI of the middle cerebral artery remained unaltered following nitroglycerine administration, indicating that the fetal cerebral arterial vascular tonus is not dependent on external nitric oxide supply. The similar results from our study give further support to this observation.
Harman et al.  found that when fetal hypoxemia occurs, there is a decrease in cerebral vascular resistance as a defense mechanism. As nitroglycerine improves uterine and umbilical blood flow, a decrease in the compensatory central vasodilatation could be expected. We speculate that the improvement in uterine and umbilical blood flow was not sufficient to reverse the brain-sparing effect during the study period.
With regard to side effects, headache was the most prominent side-effect in our study: thirteen (43.3%) cases in the nitroglycerine group and only five (16.6%) in the sildenafil group (χ2 test, P = 0.024). Two (6.7%) patients in the nitroglycerine group and three (10%) in the sildenafil group had significant facial flushing (χ2 test, P = 0.0.23). This high prevalence of headaches in women using nitroglycerine, which is the main limiting factor for its clinical application in the context of placental vasculopathy, has also been reported in previous studies by Samangaya et al. , Mahmoud et al. , Johal et al. , Grunewald et al. , and Gupta et al. . It was, however, reassuring that use of both drugs caused no severe hypotension or tachycardia in any patient. Headaches were tolerated and well controlled using common analgesics and disappeared or decreased with adaptation to the medication.
To our knowledge, only one study, before ours, compared the effects of sildenafil citrate and nitroglycerine on pregnant women, and their results were similar to ours. Trapani et al.  compared maternal arterial blood pressure as well as Z-scores for the PI of the Ut.A, UA, and MCA in 35 singleton pregnancies complicated with IUGR and abnormal Ut.A and/or UA Doppler waveforms before and after application of either a transdermal nitroglycerin patch (average dose 0.4 mg/h), oral sildenafil citrate (50 mg), or placebo. They found a significant decrease in Ut.A-PI after application of transdermal nitroglycerine (21.0%, P < 0.001) and sildenafil citrate (20.4%, P < 0.001). A significant reduction in UA-PI was also observed for both transdermal nitroglycerine (19.1%, P < 0.001) and sildenafil citrate (18.2%, P < 0.001). There was no difference in Ut.A-PI and UA-PI when the sildenafil and nitroglycerine groups were compared. No changes in Doppler velocimetry were observed in the placebo group, and no significant change in MCA-PI was observed in any group. They also found that maternal arterial blood pressure decreased significantly with administration of both sildenafil citrate and nitroglycerine in pre-eclamptic patients. Headache was the most common side-effect: five (45.5%) cases in the nitroglycerine group, two (16.7%) in the sildenafil group and one (8.3%) in the placebo group (Fisher's exact test, P = 0.21).
The significant reduction in MAP observed in patients with hypertension and IUGR, without compromising Ut.A blood flow, suggests that either sildenafil or nitroglycerine may be useful as an antihypertensive drug in the context of placental vascular insufficiency.
It was important to show that sildenafil has a hemodynamic action that is similar to that of nitroglycerine because it has a better therapeutic profile. Double-blind randomized studies with early initiation of medication and evaluation of neonatal outcomes are needed to confirm the therapeutic potential of sildenafil in IUGR.
| Conclusion|| |
The use of oral sildenafil citrate and transdermal nitroglycerine improved Doppler and hence blood flow of uterine and umbilical arteries in growth-restricted fetuses, with no effect on middle cerebral artery circulation and its Doppler indices, confirming that sildenafil citrate and nitroglycerine have the same potential as treatment options in cases of IUGR associated with abnormal Doppler.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]