Intrauterine growth restriction (IUGR) complicates up to 10% of pregnancies, accounting for over one-quarter of all stillbirths.1,2 With no effective treatment available, up to 70% of pregnant women with IUGR diagnosed in the early third trimester require delivery before 32 weeks’ gestation.3 It is well documented that these infants have substantially increased risks of neonatal death, major morbidity and prolonged neonatal admission compared with preterm infants of appropriate birthweight.4
Early-onset IUGR most commonly occurs when the placental transfer of nutrients and oxygen is impaired due to inadequate placental implantation. The resulting fetal malnutrition and hypoxia are considered untreatable in utero. The only current option is an elective preterm delivery in order to rescue the baby from an adverse intrauterine environment. IUGR and the associated indicated preterm birth expose the fetus and neonate to significant mortality and morbidity. This diagnosis causes an important management dilemma: early delivery causes extreme prematurity with all its sequelae while delivering the baby too late risks intrauterine death or morbidity secondary to critical fetal hypoxia.
Being born too small and too early can pose significant health risks throughout the child’s life. In particular, IUGR has adverse effects on brain structure and function, which are independent of gestational age at birth5 and often compounded by poor postnatal growth, ultimately leading to an increased risk of neurological impairment, cognitive impairment, inattention and specific difficulties with executive functions and impulsivity.6
Between 25% and 40% of surviving growth-restricted very preterm infants have developmental delay,7,8 in particular in the areas of fine and gross motor difficulties, attentional difficulties5 and language delay9 with a mean difference in intelligence quotient (IQ) of almost one standard deviation (SD) by the time they reach school age compared with preterm and term appropriate for gestational age (AGA) controls.10,11
Intrauterine growth restriction is a key risk factor for adult diseases such as hypertension, diabetes and ischaemic heart disease due to its ability to permanently alter organ capacity and neuroendocrine regulation leading to an adverse cardiometabolic phenotype that predisposes to adult disease12 and alters reproductive health with evidence of impaired fetal growth in future generations.13 There is strong evidence that the adverse consequences of placental insufficiency, leading to fetal growth restriction, extends beyond infancy to childhood and even adulthood. This adverse effect is above and beyond the effect of prematurity.14 Only children who were growth restricted during their fetal life, among those born preterm, have increased arterial stiffness and evidence of metabolic dysfunction.14 They also demonstrate greater aortic wall thickening progression, suggestive of preclinical atherosclerosis which leads to a higher risk of developing hypertension later in life.15 To date, there has been limited progress in developing interventions to reverse the lifelong effects of IUGR.
Intrauterine growth restriction is most commonly caused by abnormal placental development and invasion of the maternal blood vessels. This process leads to placental dysfunction and poor fetal nutrition. Preclinical work16–18 and pilot studies19–21 have shown that sildenafil, a phosphodiesterase inhibitor and vasodilator, may improve uteroplacental circulation and increase fetal growth.
Sildenafil potentiates the effect of nitrous oxide (NO) and thus may cause vasodilatation of vessels responsive to NO. The incomplete remodelling of maternal spiral arteries in IUGR results in vessels with intact or partially intact muscular layers, which remain responsive to regional vascular control. Sildenafil has the potential to increase uteroplacental circulation and perfusion resulting in improved gaseous and nutrient exchange and improved fetal growth and well-being.
Use of sildenafil in an obstetric population has been limited, but several case reports and small studies now exist. Sildenafil has been used in selected cases for the treatment of maternal pulmonary arterial hypertension where there are growing data on both its safety and efficacy to improve both maternal and fetal outcomes. There are also limited data suggesting that sildenafil has the potential to increase fetal weight.
The identification of an effective therapy (such as sildenafil) could improve both the short- and long-term health outcomes for these children in addition to significantly reducing the emotional and financial burden for such individuals, their families, and the wider community.
STRIDER UK assessed the effect of sildenafil in severe early-onset fetal growth restriction where the only available treatment is early delivery. It is well documented that IUGR is often accompanied by complications such as fetal hypoxia, acidosis and inflammation, all of which are thought to have a detrimental effect on brain growth and development. Consequently, there may be a complex trade-off between the effects of longer gestational length and ongoing exposure to a suboptimal fetal environment that should be considered.22,23 It is therefore important to evaluate long-term outcomes, regardless of short-term results, to ensure the overall balance of benefits and risks associated with sildenafil treatment are examined.
The international STRIDER collaboration included studies in the UK, Australia/New Zealand, the Netherlands and Canada with each country funding their own trial but all following a similar protocol.24 Data from all trials will be published independently and then included in a high-quality pre-planned individual participant data (IPD) meta-analysis.25 All trials were funded by their government funding bodies. Recruitment took place in five countries (UK, Australia, New Zealand, the Netherlands and Canada) with STRIDER UK completing recruitment first.
