An international consensus is lacking about what constitutes pulmonary hypertension (PH) in newborns, according to a review study, which recommends the use of standardized criteria to define the disease in these patients.
The systematic review, “Variation in the definition of pulmonary hypertension and clinical indications for the use of nitric oxide in neonatal clinical trials,” was published in the journal Acta Paediatrica.
Statistics indicate that respiratory failure associated with PH may affect up to seven newborns per 1,000 live births. However, unlike older patients with the disease, there is no clear criteria for PH in newborns.
“The terms ‘pulmonary hypertension’ and ‘persistent pulmonary hypertension of the newborn‘ (PPHN) are often used interchangeably, and this probably reflects the absence of clear case definitions,” the researchers wrote.
“The lack of a standardized definition precludes meaningful interpretation of clinical trials in this field, because it is difficult to compare trials with different entry criteria, perform subgroup analyses stratified by disease severity, and adjust for confounding variables,” they added.
In the review, investigators from the Liverpool Women’s Hospital, in the U.K., described how PH was defined in newborns included in different clinical trials testing inhaled nitric oxide (iNO), a licenced gas treatment for infants born at 34 weeks or more of gestation who experienced hypoxic respiratory failure associated with PH.
The researchers also assessed and compared the eligibility criteria used in the different trials to select participants.
A systematic search in three large online databases (Pubmed, Cochrane Library, and clinicaltrials.gov) yielded 1,021 hits, and 32 studies (26 placebo-controlled trials and six comparative studies) were selected for the review.
Nearly all of the studies (30 of 32) included gestational age in their inclusion criteria, and 22 enrolled newborns who were born at more than 34 weeks of gestation.
“Various criteria were used in defining PH and/or hypoxaemic respiratory failure in these trials including measures of arterial oxygenation, ventilator support, radiographic findings and echocardiographic parameters,” the investigators wrote.
Although the majority of these trials (21 out of 32) used echocardiographic parameters to define and diagnose PH, there was a high degree of variability in the type of parameters chosen, as well as in the threshold values that had been selected for some of them.
Of note, echocardiography is a test that uses sound waves to produce a moving image of the heart. This allows physicians to measure the pressure in the pulmonary arteries — the arteries that connect the heart to the lungs — and check how well the heart is pumping blood. It is one of the standard tests used to diagnose PH.
According to the researchers, this high degree of criteria variability in clinical trials may be problematic, and could be part of the reason why iNO has failed to show efficacy in some patient groups, especially among preterm babies born before 34 weeks’ gestation.
“This study demonstrates the wide variation in clinical thresholds and echocardiographic criteria used to select neonates for inclusion in randomized clinical trials involving iNO,” the researchers wrote.
“Given the number and variety of echocardiographic parameters used to define neonatal PH identified in this study, we recommend an international consensus be reached on which parameters should be used and the thresholds defining severity of disease,” they added.