This study presents a comprehensive evaluation of drug use in neonatal units in England and Wales. We found a high burden of medication exposure, especially for those born preterm. Extremely preterm infants receive, on average, 17 different drugs and spend 94% of their time on medications despite the exclusion of routine prescriptions such as multivitamins. A study from Germany reported 11 drugs per infant in two cohorts (2004 and 2014) [9]. Other studies have also reported a high burden of drug use in preterm infants. Daniell and Darlow [10] reported 14.5 drugs per infant in New Zealand while Warrier et al. reported 9.9 drugs per infant in the extremely preterm group in the USA [11] and Puia-Dumitrescu found that infants born at 22–24 weeks were exposed to 13 distinct medications [12]. Although it is difficult to compare these figures because of the wide heterogeneity of the included populations and drugs, many show an inverse relationship between GA and the number of drugs per infant [13]. Exposure to such a high number of drugs, often simultaneously and for prolonged periods, increases the risks of drug interactions and adverse reactions.
Polypharmacy and failure to adhere to evidence-based practice and clinical guidelines in starting and stopping medicines are indicators of irrational practices and it is common to administer medicines outside their authorisation [14]. Generation of high-quality evidence of drug efficacy and safety need to be combined with rational prescribing tools [15] and continuous monitoring of drug use with data that explore implementation of recommended practices [16].
No included medications were recorded for 31% of infants admitted to the neonatal units. These infants were more mature, larger and stayed in the neonatal unit for shorter periods of time compared to those who received at least one included drug. These infants are likely to be the term and near-term infants who are admitted to the neonatal unit for brief periods of observations where their clinical condition improves and therefore medications are not required.
Not surprisingly, antibiotics emerged as the most frequently used drugs and several appeared in the top ten for all GA groups. Extremely preterm infants receive, on average, 5 different antibiotics and spend nearly 30% of their care on antibiotics. Use of second- and third-line antibiotics such as cefotaxime and vancomycin has also increased. Our analyses show large increases in use of benzylpenicillin and gentamicin. A proportion of this increase is due to the larger numbers of term infants in the later years of the study who often receive antibiotics due to risk factors for early onset sepsis. The UK National Institute of Health and Care Excellence (NICE) issued guidelines for management of infants at risk of early onset sepsis in 2012 [17] which aimed to quickly treat suspected early onset sepsis and, inadvertently, led to 9% more lumbar punctures and longer durations of antibiotic treatment and hospital stay [18]. The revised NICE 2021 guidance [19] and the popular implementation of the Kaiser-Permanente sepsis risk calculator [20] have reduced antibiotic use in term and near-term infants at risk of early onset sepsis but further efforts are needed to ensure that those at risk are adequately protected while unnecessary antibiotic use is simultaneously minimised.
However, even after excluding the more mature infants, we found that the use of antibiotics has increased among those born <32 weeks’ GA. Due to their high susceptibility to infections, antibiotics are often prescribed empirically to preterm infants. Rigorous antibiotic stewardship programs tailored to the preterm population with emphasis on both reducing antibiotic initiation and shortening the duration of treatment can be effective in reducing the burden of unnecessary antibiotics in this population [21] While the benefits of antibiotic therapy, when needed, are clearly enormous, widespread use raises concerns of emergence of resistant strains, and risks of developmental and immune dysregulation with changes in gut microbiota which may have long term implications [22].
Caffeine is the preferred drug for apnoea of prematurity and was prescribed at almost the same or greater frequency as antibiotics among extremely and very preterm infants. In these groups, it was also one of the drugs given for the longest duration and its use increased during the study period. This widespread, prolonged and increase in use is likely to be the influence of evidence that demonstrated safety, efficacy and some long-term benefits [23]. However, controversies about optimal timing, dosage and duration of use remain [24] with the need for further research into optimising caffeine use.
We found that diuretics, including spironolactone and chlorthiazide, are given to most preterm infants and often for prolonged periods. Slaughter et al. reported that among <29 week infants with bronchopulmonary dysplasia in 35 USA hospitals, 86% had received diuretic therapy and although furosemide was given to most infants, chlorthiazide was given for longer duration [25]. Diuretics that act on distal tubules such as spironolactone and thiazides are less potent than loop diuretics e.g., furosemide but cause less electrolyte imbalance and hence are preferred for prolonged treatment. A few weeks’ treatment with thiazides and spironolactone can improve pulmonary mechanics; however, there is very little evidence of any sustained benefit while they can cause significant electrolyte imbalances and other adverse effects [26]. Nevertheless, our findings and other studies [25] show that diuretics remain in popular use.
Similarly, widespread use of anti-reflux medications is supported by little evidence of benefit and observational studies have shown potential for harm [27]. Santos et al. pooled results from 10 studies and found that use of H2RAs was associated with an increased odds of NEC (odds ratio (OR) 2.81, 95% confidence interval (CI) 1.19 to 6.64) and infection (OR 2.09, 95% CI 1.35 to 3.24) [28]. Gastro-oesophageal reflux disease (GORD) remains an area fraught with diagnostic and management conundrums and this high use of anti-reflux medications despite the lack of evidence for benefit and associations with harm reflects these uncertainties [29].
We found that some drugs such as domperidone decreased in use, perhaps following the evidence of lack of efficacy and associate risks of cardiac arrythmias [30]. The rapid decline is use was probably driven by alerts and the UK Medicines and Healthcare products Regulatory Agency stipulation that domperidone was no longer licensed for use in children younger than 12 years or those weighing less than 35 kg [31]. This was supported by guidance from leading national organisations such as the UK National Paediatric Pharmacists Group and the Royal College of Paediatrics and Child Health. Such whole system approaches that bring together a range of stakeholders and develop a shared understanding of the problem can bring about sustainable change in practice with direct benefit to patients. However, tacking one drug by itself is not sufficient, as in the case of anti-reflux medications, lack of continued monitoring of drug use for GORD shift in practice to avoid domperidone has led to another irrational practice to creep in i.e., the increasing use of antacids such as proton-pump inhibitors [14, 29].
Patterns of use of agents used for closure of PDA have also changed with decreased use of indomethacin and increased use of ibuprofen. Among infants born <32 weeks’ GA, we found a large increase in use of surfactant recorded in the database. While this may be due to an actual increase in use, it is possible that it represents a shift from using surfactant at delivery, which would not be recorded in this dataset, to giving surfactant after admission to the neonatal unit which would be recorded in the list of daily drugs. This change is in keeping with the increasing trend of use of non-invasive ventilation to initiate respiratory support in preterm infants [32].
There are other limitations of this study due to the manner in which data are entered into the NNRD. The database records information from all infants admitted to the unit and does not cover drugs given to infants on the postnatal wards. The drugs given each day are entered without any information on doses, regimens or method of administration. All these data would be required to assess if drug use describe here was or was not ‘rational’. The indications of use are also not defined and cannot be directly linked to diagnoses entered. Another limitation is that we excluded data on vitamin supplementation and vaccinations, both of which are vital drug groups that are frequently prescribed. We opted to exclude these drugs from the analysis because the entry of these drugs in to the NNRD is known to be inconsistent and the information available in the database was very likely to be incomplete. Despite these limitations, with the available data, this study describes the largest study of drug use in neonatal units and highlights areas from improving practice and research to optimise rational drug use.