Abstract

Fetal growth restriction (FGR) is defined as the inability of a fetus to achieve its genetic growth potential and is associated with a significantly increased risk of morbidity and mortality. Clinically, FGR is diagnosed as a fetus falling below the 5th centile of customised growth charts. Sildenafil citrate (SC, Viagra™), a potent and selective phosphodiesterase-5 inhibitor, corrects ex vivo placental vascular dysfunction in FGR, demonstrating potential as a therapy for this condition. However, many FGR cases present without an abnormal vascular phenotype, as assessed by Doppler measures of uterine/umbilical artery blood flow velocity. Thus, we hypothesized that SC would not increase fetal growth in a mouse model of FGR, the placental-specific Igf2 knockout mouse, which has altered placental exchange capacity but normal placental blood flow. Fetal weights were increased (by 8%) in P0 mice following maternal SC treatment (0.4 mg/ml) via drinking water. There was also a trend towards increased placental weight in treated P0 mice (P = 0.056). Additionally, 75% of the P0 fetal weights were below the 5th centile, the criterion used to define human FGR, of the non-treated WT fetal weights; this was reduced to 51% when dams were treated with SC. Umbilical artery and vein blood flow velocity measures confirmed the lack of an abnormal vascular phenotype in the P0 mouse; and were unaffected by SC treatment. 14C-methylaminoisobutyric acid transfer (measured to assess effects on placental nutrient transporter activity) per g placenta was unaffected by SC, versus untreated, though total transfer was increased, commensurate with the trend towards larger placentas in this group. These data suggest that SC may improve fetal growth even in the absence of an abnormal placental blood flow, potentially affording use in multiple sub-populations of individuals presenting with FGR.

Highlights

  • Fetal growth restriction (FGR) is defined as a baby that fails to reach its genetic growth potential and affects approximately 5– 10% of pregnancies worldwide [1]

  • Fetal weight frequency distribution curves (Fig. 2B) demonstrated that 49% of P0 fetuses treated with sildenafil citrate (SC) were above the 5th centile of the untreated WT weights compared with 25% in the untreated P0 group

  • The fetal:placental (F:P) weight ratio was increased in P0 versus WT, independent of treatment (P,0.001) but was not altered following SC treatment in either WT (13.160.3 untreated versus 13.260.4 treated or P0 (14.460.4 treated versus 15.060.3 untreated) mice

Read more

Summary

Introduction

Fetal growth restriction (FGR) is defined as a baby that fails to reach its genetic growth potential and affects approximately 5– 10% of pregnancies worldwide [1]. Despite the significant risks associated with FGR-affected pregnancies, there remains no treatment. The only option currently available to clinicians is early delivery of the baby which is itself associated with increased morbidity and/or mortality [7,8]. There are still no drugs developed for obstetric conditions currently in clinical trials [9]. This has led to the assessment of drugs currently used in clinical practice for other diseases, to be assessed on a re-purpose basis as potential therapeutics in the treatment of FGR

Objectives
Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call