Pharmacovigilance has benefits beyond the direct improvements in the safety of medicines for neonates and recognition of adverse drug reactions has been a key driver of legislation that now protects the entire population.
The World Health Organization defines adverse drug reactions (ADRs) as ‘a response to a drug which is noxious, and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function’.1
Recognition of ADRs in neonates and young children has been a key driver of legislation that now protects the entire population, and ‘Elixir’ of sulphanilamide and thalidomide are important examples of this.2,3 Thus pharmacovigilance in neonates has benefits beyond the direct improvements in the safety of medicines in neonates. However, there remain many unanswered questions about the safety of medicines given to neonates.
The term ‘neonates’ can refer to several different populations of young babies. The standard epidemiological definition of a neonate is a baby within 28 days of birth. However, this definition ignores prematurity (defined as birth before 37 completed weeks of gestation). For this article, we will therefore be using the more clinically relevant definition of ‘a baby within 28 days of expected date of delivery’, as this captures those babies born prematurely.
Neonates may be exposed to medications from a variety of sources, which are broadly categorised as:
- Direct administration: Suspected medication given to the neonate with therapeutic intent
- Vaccination: Where a vaccine is administered to a neonate to prevent illness
- Maternal: The suspected medication was taken by the mother at any time from conception to delivery (this is most often transplacental exposure)
- Transmammary: Where the suspected medication was taken by a breastfeeding mother after delivery
- Paternal: Where the suspected medication was taken at the time of conception by the father
- Medication error: Wrong patient administration.
ADRs are known to be responsible for approximately 2% of paediatric hospital admissions (compared with 4–7% of adult admissions),4–6 but there is considerable variation depending on the paediatric specialty involved. It is very unusual for a neonate to be admitted for a suspected ADR, it represents only 0.2% of all neonatal admissions.6 The focus with neonates is likely to be on inpatient stays that are complicated by an ADR. For paediatrics overall, 15–18% of inpatient episodes are associated with an ADR,7,8 but there is no prospective work assessing the frequency of ADRs on neonatal units specifically, and there is a desire to improve reporting of suspected ADRs in this population.9
We are aware that the current frequency of reporting of suspected ADRs in neonates is low. The average number of reports for neonates (any route of exposure) in the UK over a ten-year period (2001–10) was less than one per day nationally, while a recent French study (direct administration only) showed approximately one report every five days nationally (1986–2012).10,11
For children of any age, 28% of reported inpatient ADRs have been reviewed and classified as severe;12 however, within the neonatal population, the French study suggested that nearly 60% of the reports received were severe. This large proportion of severe ADRs may be caused by several factors: physiological differences in neonates predisposing to severe ADRs for a particular drug; differences in the medicines used in neonates; under-reporting; difficulty in identifying ADRs in neonates; or a combination of these factors. We will consider each of these in turn and the contribution pharmacists can make to improve reporting.
Physiological differences in neonates
Profound and rapid physiological changes occur in the neonatal period. These include changes in renal function, altered expression of cytochrome P450 enzymes in the liver, increase in skin thickness and hydration, and changes in body composition (neonates have more fluid than older children and adults).
Prescribing in this group therefore poses different risks compared with older children and adults with respect to drug pharmacokinetics (absorption, distribution, metabolism, excretion), pharmacodynamics, and toxicity.13 The developmental changes, and pharmacological implications associated with them are complex, and there are several detailed reviews in this area.14,15
Pharmacists can improve safety in this regard by ensuring the use of established formularies, and through the development and implementation of guidelines relevant to neonates.
Differences in the medicines used in neonates
Neonates have a very high rate of use of unlicensed and off label medications,16 and there is some evidence that use of these medications may increase the risk of an ADR.17 Unlike many adult patients, children receive routine vaccination, with a schedule of administration commencing shortly after birth. For premature babies, these vaccinations are given according to chronological age (not corrected for prematurity), so the recipients would be considered as neonates in our definition. For well neonates receiving a vaccination, any symptom(s) experienced is an ADR (as there is no disease to treat), and hence the pattern of ADRs will be different. In addition, there has been recent focus on the excipients in medicines received by neonates, and the potential harm they may cause.18,19
Pharmacists possess specialist knowledge related to formulation, and few clinicians would be aware of whether the medication used is a licensed medication or an unlicensed ‘special’, and the relative risks associated. There is now evidence that in neonates, alteration of formulation can reduce exposure to potentially harmful excipients.20
For all suspected ADRs, there is a well-recognised under-reporting, with estimates of 95% of all suspected ADRs not reported. However, there appears to be a particular problem in neonates, with some examples of much larger under-reporting rates.
For example, approximately 7% of neonates receive antibiotics to treat suspected infection. However, on average, only one report of a suspected ADR to antibiotics per year was generated in the UK, when approximately 40,000 babies per year receive antibiotics.10 There were also no UK reports of a suspected ADR relating to surfactant over ten years (2001–10), despite at least 93,000 neonates being likely to have received it.10,21
Hospital pharmacists have been able to report ADRs on yellow cards since 1997, contributing directly to the identification and reporting of suspected ADRs in neonates. While it is not possible to draw any definitive conclusions about whether the frequency of reports from pharmacists is equivalent in neonates to other children, they appear broadly similar. Within the UK, for all children and young people, pharmacists consistently report 5–8% of all the suspected ADRs,22 but within this population over 50% of the ADRs are noted to be secondary to vaccination, and therefore likely undertaken in primary care or community where pharmacist overview is minimal.
In the French neonatal study that considered only medications directly administered to neonates, pharmacists reported 8% of the total number of reports, and in the UK study, if only reports for directly administered medicines are considered, pharmacists reported 15% of the total.10,11
However, the differences in the clinical roles of pharmacists compared with doctors and nurses mean that they are less likely to witness an ADR in a hospitalised neonate first hand. By contrast, a pharmacist’s understanding of the medicines prescribed, and overview of current prescriptions (including changes such as withdrawal or substitution of a medicine), might highlight ADRs not reported by the medical or nursing teams. Hence optimal reporting will only be achieved with close collaborative working between medical, nursing and pharmacy teams.
Difficulty in identifying ADRs in neonates
Neonates present unique difficulties in the identification of ADRs. In the neonatal period, the patient cannot communicate, and there is little evidence to guide clinicians on likely ADRs from early phase clinical studies. In addition, the drug exposure may be limited to the neonatal period, and it is possible that there are ADRs that only produce effects that are notable later in life (for example, behavioural difficulties, infertility, or intellectual impairment), and separating these from the effects of prematurity or other clinical events that have occurred in the child’s life is very difficult.
However, this does not mean that it is pointless to consider ADRs, as the current reporting data suggests that there are a disproportionate number of potentially related deaths. For directly administered medicines, there was a fatal outcome recorded in 3–5% of all reports, a much higher proportion than at any other point in childhood.10,11 It is even higher if transplacental medication exposure is included, where 11% of all the reports from the UK cohorts had a fatal outcome recorded (and will include many congenital anomalies).10
Pharmacists highlighting that an ADR may be a possible explanation of symptoms, thereby increasing awareness in other healthcare professionals, can help in this regard.
Despite these difficulties, spontaneous reporting of suspected ADRs in neonates has identified numerous harmful effects of medications. These include ceftriaxone and calcium co-administration (associated with neonatal deaths23), chloral hydrate (associated with encephalopathy24), chloramphenicol (Grey-baby syndrome25,26), EMLA (methaemoglobinaemia27), as well as others.9 In the UK, the Medicines and Healthcare Regulatory Agency (MHRA) is the national regulatory that runs the spontaneous reporting scheme.
Currently, the MHRA advice for the reporting of suspected ADRs is as follows:
- All suspected ADRs that are serious or result in harm. Serious reactions are those that are fatal, life-threatening, disabling or incapacitating, those that cause a congenital abnormality or result in hospitalisation, and those that are considered medically significant for any other reason.
- All suspected ADRs associated with new drugs and vaccines identified by the black triangle symbol (). Black triangle drugs are either new to the market, or the UK/European regulators have requested additional post-marketing surveillance.
- The MHRA also advises reporters that if there is any doubt as to whether a suspected ADR was serious or harmful, it should be reported on a Yellow Card anyway.
This includes suspected adverse drug reactions associated with misuse, overdose, medication errors or from use of unlicensed and off label medicines.28
How can this be improved?
Although under-reporting in spontaneous reporting schemes is prevalent for all populations, the data suggest that neonates have even lower rates than most. Therefore, an increase in the number of reports is important. Within the current systems, this will require additional attention to be paid to the possibility of ADRs in this vulnerable population.
Additional systems that would complement spontaneous reports have been suggested, but there are none currently set up in Europe or the US.10 Canada does have an additional system, but this is focused on pharmacogenomics rather than neonates specifically.29 Additional research will be required to try to identify barriers to reporting, and to consider other routes of reporting that are not currently used, such as parental reporting.
In terms of the quality of information, gestational age has been identified as being particularly poorly recorded, completed on only 0.8% of reports.10 Attention to details such as these that are specific to neonates, as well as consideration of the full spectrum of possible exposures once an ADR is suspected, will lead to greater quality of reports, and in conjunction with schemes to increase the quantity, hopefully drive forward improvements in drug safety for neonates in Europe and around the world.
- Pharmacists are uniquely placed to contribute to the identification of adverse drug reactions (ADRs) in hospitalised neonates, but reports are low.
- Understanding of the formulation and substitution to avoid exposure to harmful excipients is required.
- Pharmacists can improve awareness among clinicians of the possibility of an ADR and push towards formulary-based prescribing.
- Pharmacists’ knowledge of the licensed status of a medicine and the increased potential risks associated with unlicensed/off label medicines is important.
- Direct reporting by pharmacists and close working with medical and nursing teams to increase the identification and reporting of ADRs are both important.
Dan Hawcutt BSc (Hons) MB ChB MD MRCPCH
Department of Women’s and Children’s Health, University of Liverpool; NIHR Alder Hey Clinical Research Facility, Alder Hey Children’s Hospital, UK
Judith Martin MPharm
Medication Safety Pharmacist, Alder Hey Children’s Hospital, UK
Catrin Barker MSc PGDip Clin Pharm
Chief Pharmacist, Department of Pharmacy, Alder Hey Children’s Hospital, UK
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- Geiling E, Cannon PR. Pathologic effects of elixir of sulfanilamide (diethylene glycol) poisoning: a clinical and experimental correlation: final report. JAMA 1938;111(10):919–26.
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- Pirmohamed M et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18,820 patients. BMJ 2004;329(7456):15–19.
- Mitchell AA et al. Adverse drug-reactions in children leading to hospital admission. Pediatrics 1988;82(1):24–9.
- Gonzalez-Martin G, Caroca CM, Paris E. Adverse drug reactions (ADRs) in hospitalized pediatric patients. A prospective study. Int J Clin Pharmacol Ther 1998;36(10):530–3.
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- Hawcutt DB et al. Spontaneous adverse drug reaction reports for neonates and infants in the UK 2001–2010: content and utility analysis. Br J Clin Pharmacol 2016;82(6):1601–12.
- Kaguelidou F et al. Neonatal adverse drug reactions: an analysis of reports to the French pharmacovigilance database. Br J Clin Pharmacol 2016;82(4):1058–68.
- Martinez-Mir I et al. A prospective study of adverse drug reactions in hospitalized children. Br J Clin Pharmacol 1999;47(6):681–8.
- Ward RM et al. Criteria supporting the study of drugs in the newborn. Clin Ther 2006;28(9):1385–98.
- Wood AJ et al. Developmental pharmacology – drug disposition, action, and therapy in infants and children. N Engl J Med 2003;349(12):1157–67.
- Allegaert K et al. Developmental pharmacology and therapeutics in neonatal medicine. In Buonocore G, Bracci R, Weindling M (eds) Neonatology: A Practical Approach to Neonatal Diseases. Springer International Publishing 2016:1–15.
- Choonara I, Conroy S. Unlicensed and off-label drug use in children – Implications for safety. Drug Saf 2002;25(1):1–5.
- Horen B. Montastruc JL, Lapeyre-Mestre M. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol 2002;54(6):665–70.
- Turner M et al. European study of neonatal exposure to excipients: an update. Int J Pharmaceutics 2013;457(1):357.
- Turner MA, Storme T. European study for neonatal excipient exposure (ESNEE). EJHP 2012;19(2):67-67.
- Nellis G et al. Product substitution as a way forward in avoiding potentially harmful excipients in neonates. Pediatric Drugs 2016;18(3):221–30.
- Sweet D et al. European consensus guidelines on the management of neonatal respiratory distress syndrome. J Perinatal Med 2007;35(3):175–86.
- Hawcutt DB et al. Reported paediatric adverse drug reactions in the UK 2000–2009. Br J Clin Pharmacol 2012;73(3):437–46.
- Bradley JS et al. Intravenous ceftriaxone and calcium in the neonate: assessing the risk for cardiopulmonary adverse events. Pediatrics 2009;123(4):e609–e613.
- Laptook A, Rosenfeld C. Chloral hydrate toxicity in a preterm infant. Pediatric Pharmacol 1983;4(3):161–5.
- Sutherland JM et al. Toxicity of chloramphenicol for the newborn infant. Amer J Dis Child 1959;98:64.
- Burns LE, Hodgman JE, Cass AB. Fatal circulatory collapse in premature infants receiving chloramphenicol. N Engl J Med 1959;261(26):1318–21.
- Taddio A et al. A systematic review of lidocaine-prilocaine cream (EMLA) in the treatment of acute pain in neonates. Pediatrics 1998;101(2):e1-e1.
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