Sildenafil: how to make a bad situation worse

During pregnancy, fetal growth and development are reliant on in utero oxygen and nutrient supply. When this substrate supply is impaired, it is most commonly a consequence of placental insufficiency where there is a failure of the fetus to reach its genetic growth potential resulting in fetal growth restriction (FGR). Notably, FGR is characterised by chronic hypoxaemia, which induces what has classically been termed the fetal 'brain-sparing' response. Here, blood flow is either differentially distributed through peripheral vasoconstriction or preferentially streamed from the ductus venosus toward the most vital organs including the brain (Giussani, 2016). This response is thought of as a survival mechanism to ensure that the growth and development of these organs is spared albeit at the expense of the liver and periphery. Given that FGR is a significant risk factor for both poor short- and long-term outcomes such as still birth and later life chronic disease, there is much interest surrounding interventions aiming to improve fetal substrate supply in pregnancies complicated by placental insufficiency. One way of doing this may be to increase uterine artery blood flow, which has been shown to increase fetal growth (Darby et al. 2019), or directly improve placental perfusion. Of the potential interventions against placental insufficiency-induced FGR, sildenafil citrate (SC) has recently gained widespread media attention due to the poor prognosis at interim analysis in the Dutch arm of the Sildenafil TheRapy in Dismal prognosis Early-onset fetal growth Restriction (STRIDER) consortium of clinical trials. Whilst the UK and Australia/New Zealand consortium arms showed no observable positive or negative impacts of antenatal SC supplementation in severe FGR pregnancies, the Dutch STRIDER trial was halted due to increased rates of persistent pulmonary hypertension in newborns and elevated albeit not significant rates of neonatal death. The mechanism behind these poor outcomes has not yet been fully elucidated. However, the capacity of SC to cross the placenta into the fetal circulation (Inocencio et al. 2019) and the persistent vascular alterations in SC-treated neonates has raised concerns that SC may have unintended detrimental consequences on the fetal vasculature instead of an isolated action on the uterine/placental circulation itself. In this issue of Journal of Physiology, Inocencio et al (2020) performed an elegant study utilising a well-characterised sheep model of FGR (single umbilical artery ligation, SUAL) in combination with chronic fetal instrumentation and a sheep equivalent SC STRIDER trial dosing regimen to determine how clinically relevant SC exposure impacted on both maternal and fetal haemodynamics in pregnancies complicated by FGR (Inocencio et al. 2020). In this model of FGR, SUAL fetuses are chronically hypoxaemic and smaller than their appropriately grown counterparts. Concerningly, intervention with SC further exacerbated the SUAL-induced drop in both fetal oxygenation and weight; this outcome may have been predicted given previous work by this research group investigating the impact of acute SC exposure on uterine artery blood flow (Miller et al. 2009). Here they found that SC exposure decreased uterine artery blood flow irrespective of fetal growth status, a mechanism that may underlie the exacerbation of FGR and may also suggest that this potential adversity is not limited to the FGR fetus. Importantly, given the hypoxaemic insult of the SUAL procedure, SUAL fetuses exhibited the well-characterised fetal brain-sparing response through peripheral vasoconstriction in an attempt to redistribute more blood flow and thus substrate supply toward the brain. In those pregnancies exposed to STRIDER-equivalent SC doses, fetuses were unable to mount this protective brain-sparing response at the level of the periphery. This confirms the ability for SC to have a direct effect on the fetal vasculature, in this case causing global vasodilatation and impairing the in utero survival mechanism that is brain-sparing physiology (Giussani, 2016). Apart from the cerebral circulation, which is likely to be already maximally dilated in response to fetal hypoxaemia, the SC-induced vasodilatation is likely to be global and incorporate the pulmonary vasculature. Pulmonary haemodynamics were not assessed in this well thought-out study. However, one could speculate that the induction of in utero pulmonary vasodilatation may create a new normal for regulation of pulmonary vascular tone and thus predispose to the persistent pulmonary hypertension that the Dutch arm of the STRIDER consortium reported. Nevertheless, this study and others performed by the same research group (Miller et al. 2009; Inocencio et al. 2019; Inocencio et al. 2020) have provided strong evidence for the necessity of not only utilising a large animal model of human pregnancy complications in perinatal research but also in having these preclinical studies inform the choice to commence clinical trials. None. Sole author. None.