The effect of antenatal acetaminophen administration on breathing effort of premature infants at birth: a pilot study

Premature infants (<37 weeks' gestation) struggle to establish independent gas
exchange with spontaneous breathing at birth, because of their immature
respiratory systems, what puts them at risk for hypoxia. One of the major
reasons for prematurity is chorioamnionitis, inflammation of the fetal
membranes and amniotic fluid, which produces prostaglandins (inflammatory
mediators) that inhibit respiratory drive. As prostaglandins are also produced
during hypoxia and labour, premature infants are often exposed to prostaglandin
concentrations that could suppress breathing.

A possible way to stimulate breathing at birth is paracetamol. Paracetamol is
an acetanilide derivate with antipyretic and analgesic properties, because it
lowers central prostaglandin concentrations (in the brain). Therefore,
paracetamol may reduced the inflammatory-mediated respiratory depression and
act as a respiratory stimulator. Previous studies reported that paracetamol
could lower incidence of apnoea in infants and that premature infants
antenatally exposed to paracetamol had improved respiratory function at birth
and during intensive care admission. Additionally, paracetamol improved fetal
breathing in animal studies.

Paracetamol is safe during pregnancy and has studies with paracetamol
administration during labour only reported positive results, i.e. less pain
during labour and faster delivery after paracetamol administration (plausibly
due to lower pain). Paracetamol likely acts optimally as a respiratory
stimulator at birth if administered 0.5-2 hours prior to birth. Therefore, in
this study, we will evaluate the feasibility and effect of antenatal
paracetamol administration.

The primary objective of this study is to evaluate the feasibility of antenatal
paracetamol/placebo administration to pregnant women 0.5-2 hours prior to birth.
The secondary objective of this study is to compare the effect of antenatal
acetaminophen administration to placebo on breathing effort, expressed as
minute volume of spontaneous breathing, in the first 1-5 minutes during
stabilisation of premature infants at birth.

We will perform a single centre, triple-blind randomised and placebo controlled
pilot study, without placebo and partial blinding.

The intervention comprises administration of 1000 mg paracetamol 0.5-2 hours
prior to expected birth.
The control group receives placebo with 0.9% NaCl concentrate (physiological
saline).

Risk: The burden and risks are expected to be equal between the groups based on
previous studies and the recommendations of the EMA and FDA. Paracetamol use is
allowed during pregnancy by the EMA and FDA in the lowest effective possible
dose, shortest possible time and the lowest possible frequency, to which this
study adheres by administering a maximum of 3 dosages of 1000 mg acetaminophen
intravenously. Paracetamol administration during labour (in the same dosage as
our study) has not been associated with adverse outcomes, but only with
positive effects consisting of less pain during labour and a faster labour
duration. Moreover, in a study with 604 pregnant women using paracetamol in the
3rd trimester, none of the pregnancies had any adverse fetal effects.
Furthermore, paracetamol administration already occurs in 20% of all deliveries
<31 week*s gestation in the LUMC. As other aspects of care for pregnant women
and neonates are according to standard care and follow local and international
guidelines, we expect no additional risk of the intervention to standard care.

Burden: We expect the burden of participants to be experienced as light,
because the only burden they receive involves: i) reading the participant
information form; ii) answering a short questionnaire with 3 questions; iii)
and no intake of paracetamol without a doctor's consent just before expected
birth.

Benefit and group relatedness: The study population was selected in infants <31
weeks* gestation, because they are often born due to preterm labour and are at
risk for both hypoxia and inflammation, which all increase the exposure of the
infant to prostaglandins. Paracetamol can improve breathing in premature
infants, which decreases the risk of hypoxia and related complications (e.g.
potentially injurious and invasive ventilation).