Neonatal pulmonary hypertension after severe early-onset fetal growth restriction: post hoc reflections on the Dutch STRIDER study

Abstract

The aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02).Conclusion: Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a “rebound” vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action. What is Known:• In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo. What is New:• The current analysis focuses on the distinction between PPHN and pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia and on timing of diagnosis and aims to identify the infants at risk for developing pulmonary hypertension.• The diagnosis pulmonary hypertension is complex, especially in infants born after severe early-onset fetal growth restriction. The research field could benefit from an unambiguous consensus definition and standardized screening in infants at risk is proposed.

LncRNA H19 improves angiogenesis in mouse pulmonary artery endothelial cells by regulating the HIF-1α/VEGF signaling pathway

“…Impaired relaxation of the pulmonary vasculature in the early postnatal period leads to pulmonary circulatory resistance exceeding body circulatory resistance, resulting in severe hypoxemia and respiratory distress, and ultimately PPHN (3). Currently, the clinical treatment strategy for PPHN is focused on mechanical ventilation to maintain systemic circulatory pressure and reduce pulmonary hypertension (41). Neonatal care, including the use of inhaled NO and other vasodilators, improves the prognosis of infants with PPHN (42).…”

Intravenous sildenafil for treatment of early pulmonary hypertension in preterm infants

“…PH was defined as evidence of echocardiographic signs of PH and classified as early PH when appearance was in the first 28 DOL. These definition were adopted from the definition of PH in preterm infants described elsewhere 10 , 11 , 22 . Echocardiographic PH assessment is described below in detail.…”

Intravenous sildenafil for treatment of early and late pulmonary hypertension in preterm infants

“…PH was de ned as evidence of echocardiographic signs of PH and classi ed as early PH (appearance <28 DOL) and late-onset PH (appearance ≥28 DOL). These de nition were adopted from the de nition of PH in preterm infants described elsewhere [10,11,22]. Echocardiographic PH assessment is described below in detail.…”