ORIGINAL ARTICLE | https://doi.org/10.5005/jp-journals-10006-1976 |
Role of Sildenafil Citrate Therapy in Early-onset Fetal Growth Restriction
1Department of Obstetrics and Gynecology, Ganesh Shankar Vidyarthi Memorial Medical College, Kanpur, Uttar Pradesh, India
2Department of Pediatrics, Ganesh Shankar Vidyarthi Memorial Medical College, Kanpur, Uttar Pradesh, India
3Depart of Obstetrics and Gynecology, Tata Main Hospital, Jamshedpur, Jharkhand, India
Corresponding Author: Rashmi Yadav, Department of Obstetrics and Gynecology, Ganesh Shankar Vidyarthi Memorial Medical College, Kanpur, Uttar Pradesh, India, Phone: +91 7393056066, e-mail: dryadavrashmi@gmail.com
How to cite this article: Yadav R, Yadav A, Kumari A. Role of Sildenafil Citrate Therapy in Early-onset Fetal Growth Restriction. J South Asian Feder Obst Gynae 2021;13(6):392–395.
Source of support: Dr Sangeeta Singhal, Ex Head of the Department, Obstetrics and Gynaecology, Tata Main Hospital, Jamshedpur, Jharkhand, for his heartfelt support extended to us for conducting this study.
Conflict of interest: None
ABSTRACT
Objective: Fetal growth restriction (FGR) refers to a condition in which a fetus is unable to achieve its genetically determined potential size. The common consequences of FGR are neonatal mortality and neurological and neurodevelopmental delays. In this study, we investigated the use of sildenafil citrate therapy in the management of early-onset FGR.
Methods: In this prospective randomized controlled study, women aged 20–35 years with singleton pregnancy with 22–32 weeks gestation age, who were having abdominal circumference (AC) less than the 10th percentile, effective fetal weight (EFW) less than the 10th percentile, or amniotic fluid index (AFI) less than or equal to 7 cm were enrolled in the study after obtaining written informed consent. These patients were randomized according to a computer-generated random numbers table and were divided into two groups, namely, group A and group B. Group A women were treated with sildenafil citrate 25 mg per oral three times daily until delivery. Group B women were not treated with sildenafil.
Results: On follow-up, the abdominal circumference growth was significantly higher in group A (p = 0.0001) than in group B. Enrollment to delivery duration was average 64.85 ± 13.86 days in group A and 55.35 ± 16.18 days in group B, which is statistically significant (p = 0.0001). Mean birth weight of babies was 2040.92 ± 478.73 g in group A and 1665.60 ± 464.74 g in group (p = 0.007).
Conclusion: Sildenafil therapy 25 mg twice a day from the diagnosis of FGR to delivery was beneficial to pregnant women in terms of increase in fetal AC, fetal weight, and pregnancy duration.
Clinical significance: Sildenafil therapy 25 mg twice a day from the diagnosis of FGR to delivery was beneficial to pregnant women with FGR in terms of increase in fetal AC, fetal weight, AFI, and pregnancy duration (gain in intrauterine life).
Keywords: Amniotic fluid index (AFI), Effective fetal weight (EFW), Fetal growth restriction (FGR), Sildenafil citrate
INTRODUCTION
Fetal growth restriction is a pathological condition in which a fetus has not achieved its genetic growth potential regardless of fetal size.1 FGR generally refers to a fetus that has failed to reach its biological growth potential because of placental dysfunction.2 There is no clinical test to reliably predict the onset of FGR, or even to reliably detect it, when present in late gestation. FGR has considerable overlap with short for gestational age (SGA) but is more difficult to define in practice as not all FGR infants have a birth weight less than the 10th centile.3–5 The common consequences of FGR are neonatal mortality and poor neurological and cardiovascular outcomes. Infants born SGA have higher rates of neurodevelopmental delay, poor school performance, childhood and adult obesity, and metabolic disease.6–8 The incidence of FGR is between 3 and 9% of pregnancies in high-resource settings, but in low-resource settings the rates are as high as 30% of pregnancies.9
Early FGR by definition is diagnosed at or below 32 weeks and differs from late-onset FGR also in terms of its clinical manifestations, association with hypertension, patterns of deterioration, and severity of placental dysfunction.
Ultrasound Doppler analysis in FGR pregnancies suggests placental hypoperfusion. Currently there are no specific evidence-based therapies for placental insufficiency and early-onset severe FGR. Nonspecific interventions include primarily lifestyle modifications, such as reducing or stopping work, plenty of fluid intake, stopping aerobic exercise, rest at home, and hospital admission for rest and surveillance. Some evidence suggests sildenafil citrate as a therapeutic strategy to improve uteroplacental blood flow, fetal growth, and meaningful outcomes in FGR pregnancies. There is no evidence that sildenafil in second trimester has significant fetotoxicity.
In this study, we examined the use of sildenafil citrate therapy in the management of early-onset FGR and compared the outcomes of sildenafil-treated pregnancies that remain sildenafil naive.
MATERIALS AND METHODS
This prospective randomized controlled study was conducted in the Department of Obstetrics and Gynecology, Tata Main Hospital, which is a 940-bedded hospital in Jamshedpur, Jharkhand, India.
The inclusion criteria were as follows:
Women aged 20–35 years with singleton pregnancy of 22–32 weeks gestation age having any of the following USG findings:
Effective fetal weight below the 10th percentile for gestational age
Abdominal circumference less than the 10th percentile
AFI ≤7 cm
The exclusion criteria included the following:
Women with fetal or chromosomal abnormalities
Any cardiovascular morbidity
Users of any vasodilator agents
Women with diastolic blood pressure more than 110 mm Hg
Women with body mass index (BMI) greater than 34
Women with any chronic illness
Women with twin pregnancy
Women with leaking per vaginum
Women who are not willing to give consent for participation in the study
Methodology
During antenatal check-up, for the women who were having symphysio-fundal height less than the GA (2 weeks lag) confirmation of the GA was made with last menstrual period (LMP) and first (or early second) trimester ultrasound. Ultrasound was done to asses AC, EFW, and AFI and to rule out any gross congenital anomaly (in the patients who were not having anomaly scan prior). Women with AC <10th percentile, EFW <10th percentile, or AFI ≤7 cm were enrolled in the study after obtaining written informed consent. The participants were randomized according to a computer-generated random numbers table and were divided into two groups, group A and group B. Group A women were treated with sildenafil citrate 25 mg per oral three times daily until delivery. Group B women were not treated with sildenafil.
Other than sildenafil therapy, management was similar between the two groups, including increased fluid intake and adequate rest in left lateral position. Women in the sildenafil group were asked to take 25 mg sildenafil tablet three times a day after meals and were asked to monitor fetal movement or any side effects such as flushing, light headedness, dyspepsia, and visual disturbance. In those who complained of headache and palpitation, the dose of sildenafil was reduced from three times a day to two times a day for 1 week and then resumed to the previous dose.
Maternal Monitoring
Blood pressure measurement, proteinuria (dipstick and random protein), complete blood count, serum creatinine, serum uric acid, bilirubin, aspartate transaminase, alanine transaminase, albumin, globulin, albumin/globulin (A/G) ratio were done and repeated according to the severity or damage to the organs.
Ultrasound Monitoring
USG monitoring every 14 days for outpatients and at weekly for inpatients to asses fetal growth by an increase in the AC, EFW, and AFI to compare fetal growth in both groups was done. AC, EFW, and AFI were compared in both groups at 2 weeks interval, and AC growth velocity was estimated in both groups by formulas. Injection betamethasone was given to all patients who delivered before 34 weeks or who were planned for elective lower segment Cesarean section at any gestational age.
Outcome
The primary outcome of this study was observed as an increase in AC, AC growth velocity, fetal weight gain, AFI, and gestational age at delivery in both groups.
Statistical Analysis
The results are presented in frequencies, percentages, and mean ± SD. The Chi-squared test was used to compare categorical variables between the groups. The unpaired t test was used to compare continuous variables between the groups. p value less than 0.05 was considered significant. All the analysis was carried out on SPSS 16.0 version (IBM Corporation, Chicago, IL, USA).
Ethical Approval
Approval was obtained from the ethics board committee of the Tata Main Hospital, Jamshedpur, before data extraction was performed.
RESULTS
The study was conducted on a total of 130 pregnant women (65 in group A and 65 in group B). In our study, the mean age of pregnant women at enrollment in group A was 26.06 ± 3.10 years and in group B it was 25.80 ± 3.46 years. Both groups were comparable as there was no significant (p >0.05) difference in age at enrollment. In this study, more than half of the pregnant women were nullipara. In group A, 66.2% and in group B 58.5% women were primipara There was no significant (p >0.05) difference in parity between the groups showing comparability of the groups in terms of parity. In our study, the mean GA at enrollment in group A was 26.48 ± 1.72 weeks and in group B it was 26.80 ± 2.09 weeks. There was no significant (p >0.05) difference in GA enrollment between the groups as shown in Table 1.
| Group A | Group B | p value | |
|---|---|---|---|
| Age in years at enrollment (Mean ± SD) | 26.06 ± 3.10 | 25.80 ± 3.46 | 0.65 |
| Gestation age in weeks at enrollment (Mean ± SD) | 26.48 ± 1.72 | 26.80 ± 2.09 | 0.34 |
| Gestation age in weeks at delivery (Mean ± SD) | 35.74 ± 1.91 | 34.75 ± 1.97 | 0.004 |
In this study, AC at enrollment was 193.43 ± 23.37 cm in group A and 191.57 ± 29.05 cm in group B (p = 0.68). On follow-up, the AC growth was significantly higher in group A (p = 0.0001) than in group B. These results are shown in Table 2. AFI was assessed in all the patients (by USG) at enrollment, and the average AFI was 7.83 ± 2.47 cm in group A and 8.75 ± 2.47 cm in group B. On an average, it was a little higher in group B (p = 0.06) and was not significant, so both the groups were comparable at the time of enrollment. At 32 weeks (p = 0.01), 34 weeks (p = 0.01), and 36 weeks (p = 0.01), the difference was statistically significant (Table 3).
| Time periods | Group A | Group B | p value |
|---|---|---|---|
| At enrollment | 193.43 ± 23.37 | 191.57 ± 29.05 | 0.68 |
| At 26 weeks | 188.21 ± 3.01 | 187.25 ± 5.75 | 0.59 |
| At 28 weeks | 213.47 ± 11.59 | 207.02 ± 17.85 | 0.03 |
| At 30 weeks | 237.48 ± 10.24 | 226.38 ± 20.45 | 0.0001 |
| At 32 weeks | 263.40 ± 40.60 | 243.61 ± 20.14 | 0.001 |
| At 34 weeks | 279.58 ± 15.52 | 263.96 ± 22.48 | 0.0001 |
| At 36 weeks | 302.95 ± 15.28 | 282.88 ± 25.72 | 0.0001 |
| At 38 weeks | 324.85 ± 30.65 | 263.40 ± 37.32 | 0.002 |
| At delivery | 294.43 ± 31.04 | 267.40 ± 27.22 | 0.0001 |
| Time periods | Group A | Group B | p value |
|---|---|---|---|
| At enrollment | 9.26 ± 2.48 | 9.03 ± 2.19 | 0.58 |
| At 26 weeks | 7.12 ± 1.13 | 7.34 ± 1.07 | 0.61 |
| At 28 weeks | 8.85 ± 2.49 | 8.41 ± 1.93 | 0.33 |
| At 30 weeks | 8.21 ± 2.08 | 7.94 ± 1.85 | 0.44 |
| At 32 weeks | 7.81 ± 1.92 | 7.34 ± 1.49 | 0.13 |
| At 34 weeks | 7.16 ± 1.82 | 6.53 ± 1.35 | 0.04 |
| At 36 weeks | 6.83 ± 1.78 | 6.09 ± 1.38 | 0.08 |
| At 38 weeks | 6.03 ± 1.99 | 5.82 ± 1.07 | 0.82 |
| At delivery | 6.36 ± 1.63 | 6.05 ± 1.26 | 0.23 |
In our study, the GA at delivery was 35.74 ± 1.91 weeks in group A and 34.75 ± 1.97 weeks in group B. The GA was significantly higher (p = 0.004) in group A (sildenafil group). Enrollment to delivery duration, that is gain in intrauterine life, was on average 64.85 ± 13.86 days in group A and 55.35 ± 16.18 days in group B, which was statistically significant (p = 0.0001). According to results, sildenafil citrate is effective in the prolongation of pregnancy. At delivery, mean birth weights in babies were 2040.92 ± 478.73 g in group A and 1665.60 ± 464.74 g in group B, implying that the association was statistically significant (p = 0.007) as shown in Table 4.
| Group A | Group B | p value | |
|---|---|---|---|
| Enrollment to delivery interval (days) | 64.85 ± 13.86 | 55.35 ± 16.18 | 0.0001 |
| GA in weeks at delivery | 35.74 ± 1.91 | 34.75 ± 1.97 | 0.004 |
| Birth weight in g | 2040.92 ± 478.73 | 1665.60 ± 464.74 | 0.007 |
In this study, headache was the most common side effect experienced by group A women (15.4%), flushing in 6.2%, and dyspepsia in 3.1% whereas 75.4% of women had no side effects. There were no side effects in patients of group B. The association of pregnancy-induced hypertension (PIH) was the same in both groups and was 61.5%. Therefore, sildenafil might not have any effect in the development of PIH.
DISCUSSION
In this study, at enrollment the mean GA in group A and group B was 26.48 ± 1.72 weeks and 26.80 ± 2.09 weeks, respectively. There was no significant (p >0.05) difference in GA enrollment between the groups showing comparability of the groups in terms of GA at enrollment.
At enrollment, the mean fetal AC was 193.43 ± 23.37 cm in group A and 191.57 ± 29.05 cm in group B; thus, there was no significant (p = 0.68) difference between the groups. AC growth, that is, increment in AC from enrollment to delivery (mean) was 102.31 ± 28.08 mm in group A and 78.20 ± 26.57 mm in group B (p = 0.0001), that is, statistically significant. AC growth velocity, which was calculated by AC growth/delivery to enrollment interval was 1.55 ± 0.25 cm/day in group A and 1.41 ± 0.31 cm/day in group B, which was statistically significant (p = 0.004). In a study by von Dadelszen et al.,10 increased AC growth velocity post eligibility on sildenafil was 90% in the sildenafil group and 41% in the sildenafil-naïve group, that is, a significant increase in AC compared with that of the control group (odds ratio: 12.9 [95% CI]). Michiko Kubo et al.11 in their study have shown that fetal growth velocity from enrollment to birth was significantly higher in the sildenafil group than in the conventional management group. These studies favor the results of our study. Mohammed et al.12 obtained the increase in AC (mean ± SD) as 0.75 ± 0.10 mm in the sildenafil group and 0.71 ± 0.16 mm in the control group. They found no significant difference in both the groups.
At enrollment, the AFI was 7.83 ± 2.47cm and 8.75 ± 2.21cm in groups A and B, respectively. This difference was nonsignificant (p = 0.06). An association between pathological fetal growth restriction and oligohydramnios has long been recognized. In a study by Premalatha et al.,13 AFI was increased in 20% cases in the sildenafil group, and there was no control arm in this study. Chaudhary et al.14 in their case study have also noted a consistent increase in AFI with sildenafil citrate. In Maher et al.’s15 study, the amniotic fluid volume was higher in the sildenafil group at the final assessment (11.5 compared with 5.4 cm, p = 0.02). These results are similar to our study. In Mohammed et al.’s12 study, pretreatment AFI and post-treatment AFI did not show statistically significant difference.
At enrollment, the fetal weight was 690.57 ± 145.79 g and 721.95 ± 204.98 g, respectively, in groups A and B; they were comparable as the difference was nonsignificant (p = 0.31). Weight growth velocity was calculated by weight growth/enrollment to delivery interval, which was 19.90 ± 5.63 g/day in group A and 16.76 ± 6.53 g/day in group B (p = 0.004), which was statistically significant. The results were similar to the studies conducted by Ferreira et al.16 and Mohammed et al.12
In our study, from enrollment to delivery, the mean GA increased from 26.48 ± 1.72 weeks to 35.74 ± 1.91 weeks in group A whereas in group B the GA increased from 26.80 ± 2.09 weeks to 34.75 ± 1.97 weeks. The mean GA at delivery was 35.74 ± 1.91 weeks in group A and 34.75 ± 1.97 weeks in group B. The GA at delivery was significantly higher (p = 0.004) in group A (sildenafil group). In agreement with our study, in Maher et al.’s15 study, too, the sildenafil group delivered later (38.3 weeks compared with 36.0 weeks of gestation, p = 0.001). In the study by von Dadelszen et al.,10 GA at delivery since LMP was (25 weeks + 6 days) in the sildenafil-naïve group and (27 weeks + 1 day) in the sildenafil group, which was very early. In this study, enrollment to delivery duration, that is, gain in intrauterine life was on average 64.85 ± 13.86 days in group A and 55.35 ± 16.18 days in group B, which was statistically significant (p = 0.0001). According to our results, sildenafil citrate is effective in the prolongation of pregnancy.
Birth weight was between 2000 and 2500 g in 44.6% in group A and in 23.1% in group B, and the association was statistically significant (p = 0.007) as the mean birth weight in the sildenafil group was 2040.92 ± 478.75 g and 1665.60 ± 464.74 g in the without-sildenafil group. In the sildenafil group, 75.4% women did not have any significant side effect. Headache was the most common complaint (15.4%), which was mild and tolerable. Flushing and dyspepsia were reported in 6.2% and 3.1%, respectively, in group A.
CONCLUSION
The overall outcome of the study was evaluated in terms of increase in fetal weight, fetal AC, AFI, total duration of pregnancy, and birth weight. Most of the results were in accordance with major studies that have proved that sildenafil therapy was useful in FGR pregnancies and improvement in fetal outcomes. However, a few results which differed from published studies could be due to the inclusion of early FGR (before 32 weeks of gestation) and rural background. Sildenafil did not have any significant side effect in pregnant women. Hence, sildenafil therapy 25 mg twice a day from the diagnosis of FGR to delivery was beneficial to pregnant women with FGR treated (group A) as compared to the group not treated in the form of increase in fetal AC, fetal weight, AFI, and pregnancy duration (gain in intrauterine life).
The main limitations of our study were smaller sample size, so results cannot be generalized and adverse drug reaction could not be studied as it requires a longer follow-up. We therefore recommend more studies with larger sample sizes and in rural setting to confirm the results of our study.
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