Multi-center, randomized non-inferiority trial of early treatment versus expectative management of patent ductus arteriosus in preterm infants.

Much controversy exists about the optimal management of a patent ductus
arteriosus (PDA) in preterm infants, especially in those born at a gestational
age < 28 weeks or with a birth weight <= 1000 grams. A common understanding is
that the actual approach with medical or surgical treatment of a PDA seems not
to reduce the risk of major neonatal morbidities. This might be related to the
fact that a substantial portion of preterm infants are probably treated
unnecessarily, because the PDA might have closed spontaneously without specific
interventions. This would imply over-treatment with an increase in iatrogenic
risk of adverse effects related to the used drugs and/or surgical ligation. An
expectative approach is gaining interest, although convincing evidence is still
lacking.

To investigate whether in preterm infants, born at a GA less than 28 completed
weeks, with a PDA (diameter >1.5 mm) an expectative management is not inferior
to early treatment with regard to the composite of mortality and/or NEC (Bell
stage * IIa) and/or BPD at a PMA of 36 weeks.

The design is a multicenter, randomized, non-inferiority study conducted in
neonatal intensive care units in the Netherlands and Belgium.

Patients randomized to the expectative management arm will not receive any COXi
and PDA management in this group can be characterized as *watchful waiting*.
This is not a unique approach, since a restrictive approach towards a PDA is
increasingly used in many centers worldwide without the observation of an
increased risk of neonatal mortality and morbidity, such as severe CLD, IVH,
NEC and ROP.
It is essential that neonatal management is similar in both study arms with the
exception of the prescription of COXi and echocardiography at the end of the
drug course in the medical treatment arm. It is of the upmost importance that
NO extra interventions are to be undertaken with the intention to
conservatively prevent or treat a (suspected) PDA in the expectative arm, such
as fluid restriction and diuretics for that reason. Moreover, it should be
noted that there is insufficient evidence that fluid restriction and/or
diuretics are of any benefit in patients with a (suspected) PDA.

When the patient is allocated to the medical treatment arm COX-inhibition is
prescribed and started as soon as possible, but no later than 3 hours after the
echocardiogram. We prefer to use Ibuprofen (IBU) for COX-inhibition in this
study. However, Indomethacin (INDO) can be prescribed for medical ductal
closure if this is preferred by a participating center. The medical treatment
is considered standard of care in many NICU*s worldwide.

All patients in this study are treated according current (inter)national
guidelines and local protocols regarding neonatal intensive care management.
The administration of ibuprofen or Indomethacin does not pose an extra burden
on the patient and is considered routine treatment in preterm infants with a
PDA in a majority of neonatal intensive care centers. No extra investigations
or interventions are needed in this study. Patients that aren*t treated with
COXi are refrained from potential side effects of this drug.
A restrictive approach towards a PDA is increasingly used in many centers
worldwide without an concomitant increase in mortality or morbidity related to
a PDA. No causal relationship has been proven between a (hemodynamically
significant) PDA and the risk of conditions related to pulmonary hyperperfusion
(f.e BPD and PH) and/or systemic hypoperfusion (f.e NEC, renal failure and
PVL). Many studies have provide us with conflicting data and treatment of a PDA
has not resulted in a decreased rate of these morbidities.
The study is group related because a patent ductus arteriosus is a condition
that specifically concerns newborn infants, especially preterms, without any
known variability related to sex or ethnicity.