Post partum haemorrhage (PPH) prevention: oxytocin pharmacokinetics and maternal body mass index (BMI).

It has been reported that both the occurrence of primary postpartum haemorrhage (PPH) (birth to 24 hours postpartum) and rates of maternal overweight and obesity are increasing. For the ‘routine’ management of the third stage of labour and primary post partum haemorrhage prophylaxis, mothers are usually given the same dose of oxytocin without consideration of their weight or body mass index (BMI), which many other pharmaceutical products require. We propose that for those whose body mass index (BMI) would classify them as being either overweight/pre-obese (BMI 25.00-29.99 Kg/m2) or obese (BMI equal to, or more than, 30Kg/m2), that this ‘standard dose’ for all maybe insufficient to attain the therapeutic levels of oxytocin necessary to invoke uterine contractility, thereby predisposing this cohort of mothers to atonic PPH. The research study is an investigator initiated, single centre (Monash Health), phase 4, open label, prospective, randomized controlled trial, to evaluate the relationship between participant (maternal) BMI and the pharmacokinetics (PK) of a single dose of oxytocin administered either as: a 'slow' bolus (1-2 minutes) intravenous (IV) injection or an intramuscular (IM) injection, given for primary postpartum haemorrhage prophylaxis following birth. The trial seeks to collect blood samples from n=120 participants: Those who are having an elective (no labour) caesarean section (n=100) under regional anaesthesia, and are representative of BMIs: normal range, (BMI 18.5-24.99 Kg/m2), overweight/pre-obese (BMI 25.00-29.99 Kg/m2), obese class I (BMI 30- 34.99 Kg/m2) obese class II (BMI 35-39 Kg/m2) or obese class III (equal to, or more than, 40.00 Kg/m2). Those who are having a vaginal birth (n=20) and composed of only of those who have a BMI that is within the normal range (18.5-24.9 Kg/m2). Ultimately, there will be n=20 participants in each of the six study groups. Of these, following randomisation, each study group, will be composed of n=10 participants who have received 5 IU of oxytocin via a ‘slow bolus’ (1-2 minutes) intravenous (IV) injection, and n=10 who have been given 10 IU oxytocin through an intramuscular (IM) injection. Blood samples will be collected from participants for pharmacokinetic (PK) analysis: before birth (1 hour, or less) and then following birth, and timed from the commencement of oxytocin administration, at a 'desired' nine further targeted time points of: 3 (+/-0) minutes, 5 (+/-1) minutes, 10 (+/-2) minutes, 15 (+/-2) minutes, 20 (+/-2) minutes, 30 (+/-3) minutes, 60 (+/-5) minutes, 120 (+/-5) minutes and 180 (+/-5) minutes. Pharmacokinetic parameters include: Absolute bioavailability (F), absorption rate constant, (Ka), clearance (Cl) and volume of distribution (Vd). Bioanalysis and modelling will be used to determine maximum plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration-time curve (AUC) and terminal phase half-life (t1/2).