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Sildenafil citrate therapy in absent end diastolic flow in umbilical artery in an early onset fetal growth restriction (FGR) fetus

The incidence of intrauterine fetal growth restriction (IUGR/ FGR) is quite high in Indian population. A definitive consensus on this clinical condition has yet not been established inspite of the currently available management options. Some pregnancies with fetal growth restriction (FGR) have elevated peripheral maternal vascular resistance in uterine arteries and hence poor perinatal outcome. Placental insufficiency might result in further deterioration of fetal growth and lowbirth weight during gestation. Abnormal umbilical artery flow with absent or reversed end-diastolic velocity (AREDV) on Doppler USG during pregnancy is an indication of placental insufficiency. When AREDV occurs, a close follow-up or expeditious delivery should be contemplated. These premature neonates are at an increased risk for intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, respiratory distress syndrome or long-term neuro development impairment. Hence pregnancy prolongation is of significant value in such cases. Also according to classical definition of IUGR, increase in fetal birth weight is associated with improved pregnancy outcomes. Sildenafil was initially studied for use in hypertension (high blood pressure) and angina pectoris (a symptom of ischaemic heart disease). Studies have shown that Sildenafil citrate increases uterine blood flow and potentiates estrogen-induced vasodilatation. Authors present a case of early onset fetal growth ABSTRACT


INTRODUCTION
The incidence of intrauterine fetal growth restriction (IUGR/ FGR) is quite high in Indian population. 1 A definitive consensus on this clinical condition has yet not been established inspite of the currently available management options. Some pregnancies with fetal growth restriction (FGR) have elevated peripheral maternal vascular resistance in uterine arteries and hence poor perinatal outcome. Placental insufficiency might result in further deterioration of fetal growth and lowbirth weight during gestation. Abnormal umbilical artery flow with absent or reversed end-diastolic velocity (AREDV) on Doppler USG during pregnancy is an indication of placental insufficiency. When AREDV occurs, a close follow-up or expeditious delivery should be contemplated. These premature neonates are at an increased risk for intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, respiratory distress syndrome or long-term neuro development impairment. Hence pregnancy prolongation is of significant value in such cases. 2 Also according to classical definition of IUGR, increase in fetal birth weight is associated with improved pregnancy outcomes. 3 Sildenafil was initially studied for use in hypertension (high blood pressure) and angina pectoris (a symptom of ischaemic heart disease). 4 Studies have shown that Sildenafil citrate increases uterine blood flow and potentiates estrogen-induced vasodilatation. 5 Authors present a case of early onset fetal growth restriction (FGR) where administration of vaginal Sildenafil citrate could normalize the uteroplacental insufficiency with a favorable fetal outcome.

CASE REPORT
A 33 years old lady had conceived with in vitro fertilization in view of poor ovarian reserve. Her antenatal course was uneventful, but her 22 weeks scan (foetal 2D echo) showed increased resistance in left uterine artery. She was started on vasodilators like nitric oxide donor (L-arginine) 3 g daily. Four weeks later, there was clinical suspicion of intrauterine FGR and oligohydramnios, hence an early Doppler ultrasonography was done (Figure 1 and 2).   To reduce risk of foetal mortality and morbidity, the patient was kept on aspirin 75mg once daily along with other supportive measures like bed rest, increased protein diet, alamine infusion (once a week), hydration (minimum intake of 3-4 litres of fluid daily), and Larginine was continued. Her Doppler ultrasonography was repeated after 2 weeks (28 weeks of gestation). Sonography revealed further worsening of the Doppler parameters with mild oligohydramnios (AFI-7). There was asymmetric IUGR with expected foetal weight (EFW) of 745±116 g and lag of 2 weeks. The S/D ratio was further increased in the umbilical arteries suggestive of deteriorating perfusion to the fetus. This sonography showed S/D ratio of 4.2 (PI 1.3, RI 0.7) in left umbilical artery and 4.6 (PI 1.4, RI 0.7) in the right umbilical artery. The left uterine artery S/D ratio was 3.5 (PI -1.3, RI-0.7) while it was 2.1 in the right uterine artery (PI-1.0, RI-0.5). However, the middle cerebral artery (MCA) circulation was still preserved.
In view of FGR and prematurity, injection betamethasone 12 mg two doses was given 24 hours apart. The supportive measures were continued along with strict monitoring of foetal movements by daily foetal kick count (DFKC) for 2 weeks when a USG Doppler was repeated. This Doppler ultrasonography (30 weeks of gestation), showed absent diastolic flow in the umbilical arteries ( Figure 3) with brain sparing effect ( Figure 4). Foetal MCA systolic velocity 23cm/s and diastolic velocity 9.7cm/s with S/D ratio of 2.59 (PI-0.99, RI0.61). The AFI was 6 and EFW 986±120 g.    Thus, Sildenafil citrate can be agent behind the slight improvement in Doppler parameters and flow pattern. It was probably acting at these vessels at the placenta myometrial junction and hence there was prevention of further deterioration along with some improvement in the Doppler parameters and foetal growth. The Doppler ultrasound was repeated weekly as tabulated (Table 1).
Sildenafil citrate was stopped at 37 weeks and patient delivered by cesarean section at 37 weeks. A male baby of 2 kgs with APGAR 8/10 at birth was born. Baby was admitted in NICU for observation and had an uneventful course. He was discharged on day 5. In this patient, authors managed to prolong pregnancy for almost 51 days, improve Doppler indices slightly even after absent end diastolic flow (AEDF) in both umbilical arteries along with brain sparing effect in the fetus. Neither the patient, nor the fetus showed any side effects to vaginal Sildenafil citrate. The baby was followed up for over 14 months and has normal milestones.

DISCUSSION
Adequate blood flow in uteroplacental vascular function is essential to achieve optimal fetal growth. Abnormal vasculature adaptation during embryogenesis and placentation, resulting in aberrant blood flow, has been implicated as a possible cause of fetal growth restriction (FGR). 6 Absent end diastolic flow (AEDF) or Reversed end diastolic flow (REDF) result when either fetoplacental arteriolar pressure is equal to (AEDF) or exceeds (REDF) umbilical artery diastolic pressure. This increase in resistance to umbilical artery blood flow is determined by the existing degree of hypoxemic fetoplacental vasoconstriction (HFPV). Unresolving HFPV can cause umbilical arterial hypertension and right heart failure in the fetus or corplacental. 7,8 A study by Wareing M et al reported that in pregnancies with fetal growth restriction and without preeclampsia, there was a reversible increased myometrial arterial tone by phosphodiesterase inhibition in vitro. 9 Sildenafil citrate is a phosphodiesterase (PDE5) inhibitor. 9 PDE5 is responsible for the degradation of cGMP to guanosine monophosphate. 10,11 Therefore, inhibiting PDE5 delays the breakdown of cGMP and hence increases vasodilation. 10,11 A recent report suggested that Sildenafil citrate stimulates vasodilation in myometrial biopsies collected from IUGR pregnancies at the time of Cesarean section. 9 Further animal studies have shown that PDE5 inhibition by sildenafil has shown to counter fetoplacental vasoconstriction induced by both 5-hydroxytryptamine and hypoxic conditions. 7 Therefore, the alteration of fetal blood distribution by PDE5 inhibition would enhance fetal oxygenation and modulation of HFPV, while simultaneously improving fetal nutrition and hence improve FGR.
In present case, Sildenafil citrate was used in fetal growth restriction in an attempt to induce vasodilatation and improve uteroplacental perfusion resulting in improved Doppler indices. Sildenafil citrate vasodilates the vessels at the myometrio-placental junction in women with IUGR-complicated pregnancies. 12 Thus it showed improvement in amniotic fluid, as was also seen in a study by von Dadelszen P et al. 7,13 Hence, authors were able to prolong pregnancy by 51 days even after the Doppler indices showed absent end diastolic flow in both umbilical arteries and prevent prematurity, with the use of vaginal Sildenafil citrate without any side effects to the mother as well as the fetus.

CONCLUSION
Long term fetal complications are associated with severe IUGR/ FGR and prematurity. Authors were able to prevent these complications by prolonging pregnancy and thereby increasing EFW in the patient by using Sildenafil citrate 25 mg thrice daily vaginally. Sildenafil citrate, as a vasodilator has emerged as a potential management option in the treatment of IUGR/ FGR.