British Journal of Clinical Pharmacology
Br J Clin Pharmacol (2016) 82 1058–1068
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DRUG SAFETY Neonatal adverse drug reactions: an analysis of reports to the French pharmacovigilance database Correspondence Dr Florentia Kaguelidou, Department of Pediatric Pharmacology and Pharmacogenetics, Clinical Investigations Center, CIC Inserm 1426, Hôpital Robert Debré 48 boulevard Sérurier 75019, Paris France. Tel.: +33 1 4003 4142; Fax: +33 1 4003 2424; E-mail: fl[email protected] Received 28 September 2015; Revised 23 May 2016; Accepted 6 June 2016
Florentia Kaguelidou1,2,3, Frédérique Beau-Salinas4, Annie Pierre Jonville-Bera4 and Evelyne Jacqz-Aigrain1,2,3 1
EA 08, University of Paris Diderot, Sorbonne Paris Cité, F-75010, Paris, 2Inserm, CIC 1426, F-75019, Paris, 3Department of Pediatric Pharmacology and Pharmacogenetics, AP-HP, Hôpital Robert Debré, F-75019, Paris, and 4CHRU of Tours, Department of Clinical Pharmacology, Regional Centre of
Pharmacovigilance, F-37 044, Tours, France
Keywords adverse drug reactions, neonates, pharmacovigilance, spontaneous reporting
AIM Term and preterm neonates are at high risk for serious adverse drug reactions (ADRs).
METHODS A descriptive study of reports registered in the French pharmacovigilance database from 1986 to 2012 were obtained. All reports concerning neonates (≤1 month of life) with direct drug exposure were retrieved. Characteristics of the reports, including reported ADR(s), drug(s) and the causality assessment using the French causality assessment method, were described.
RESULTS A total of 1688 reports were analyzed and more than half of them were classified as serious (n = 995). Median age at ADR occurrence was 9 days. Overall, 3127 ADRs were described in these reports in relation to 2238 suspect/interacting drugs. The most commonly reported system organ classes (SOCs) were injury, poisoning and procedural complications (16%), general disorders and administration site conditions (12.5%) and blood and lymphatic system disorders (12%). In the majority of ADRs reported (73%), infants fully recovered and less than 4% of neonates deceased as a consequence of the reported ADR. One out of five ADRs was associated with drug administration errors. Therapeutic classes commonly incriminated were anti-infectives, nervous system and alimentary tract drugs. Substances most frequently related to serious ADRs were zidovudine, ibuprofen and nevirapine. Among the 10 most frequently encountered drug ADR pairs, two substances were mainly implicated, zidovudine in haematological adverse reactions and phytomenadione in maladministrations.
CONCLUSIONS Anti-infective drugs, mainly antiretroviral therapy, account for the majority of ADRs reported in neonates. The specific issue of drug maladministration and medication errors remains to be addressed in neonates.
DOI:10.1111/bcp.13034
© 2016 The British Pharmacological Society
Neonatal pharmacovigilance reporting
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Previous pharmacovigilance studies reported that in children approximately one ADR notification out of four concerns infants under the age of 1 year. • No study has focused on describing ADRs following direct drug exposure in neonates more in-depth.
WHAT THIS STUDY ADDS • The majority of neonatal ADR reports were classified as serious and 3.7% of neonates deceased as a consequence of an ADR. • Anti-infective medicines, mainly antiretroviral therapy, account for the large majority of reported ADRs and ADR fatalities. • Vitamins such as phytomenadione also account for a large number of ADR reports mainly associated witho drug administration errors without clinical consequences.
Introduction There are many reasons why neonates may face a higher risk for adverse drug reactions (ADRs) than other age groups. Their organ immaturity and the rapid developmental changes that occur after birth may impact on both drug pharmacokinetics and pharmacodynamics [1]. Sick neonates often require treatment with a substantial number of drugs because of the complexity and seriousness of their conditions and most prescribed drugs have never been specifically evaluated in this neonatal population. Indeed, the percentage of patients receiving at least one unlicensed or ‘off-label’ drug ranges from 80% to 100% in neonatology units [2–4]. Spontaneous reporting systems are an important source of information on drug safety and detection of safety signals. This is essential for products that have not undergone a marketing authorization process, the most commonly encountered situation in paediatric practice. Previous pharmacovigilance (PV) studies reported that in children approximately one ADR notification out of four concerns infants under the age of 1 year [5–7] but few studies specifically described reports in neonates [8–10]. In these studies assessing ADRs after in utero and direct exposure, congenital disorders and reactions related to pregnancy were predominant. Currently, no study has focused on describing ADRs following direct drug exposure in neonates more in-depth. Consequently, the objective of this study was to describe the nature of all ADRs and drug/ADR pairs reported in neonates following direct drug exposure and included in the French pharmacovigilance database.
Methods The French pharmacovigilance database This is a descriptive study of reports registered in the French pharmacovigilance database (FPVDB). This national database was set up in 1985–1986 to allow online input of spontaneous ADR reports from a network of 31 regional PV centres. Reporting of serious and/or unexpected ADRs has been compulsory for physicians, dentists and midwifes since 1984 and for pharmacists since 1995. Also, nurses (since 1995) and patients, families and associations (since 2011) can contribute on a voluntary basis. PV reports include ADRs following drug
use in usual conditions but also medication errors and overdoses. Spontaneous ADR reports are sent to the regional PV centres mainly by means of a standardized form. Each report is validated and a drug causality assessment is performed by qualified personnel before anonymous storage in the national database.
Database search For the present study, reports contained in the FPVDB were extracted from January 1 1986 to November 30 2012. To focus on the neonatal population, the database was searched for all notifications with a reported age at the occurrence of the ADR of equal to or less than 30 days, 1 month or 4 weeks. To avoid neonatal ADRs secondary to maternal drug intake, reports classified as related to ‘pregnancy’ or ‘breastfeeding’ were discarded.
Data collection Data were recorded in four relational tables: ‘report’, ‘drugs’, ‘ADRs’ and ‘medical history’ tables. Thus, a single report can be linked to one or more drugs, ADRs and previous medical history. The ‘report’ table contains information about 1) the notification: date of initial reporting, date of last follow-up, regional PV centre of registration, type of the reporter, type of the reporter’s practice, global seriousness of the ADR report and criteria for seriousness [11] and type of the ADR and 2) the patient: date of birth, reported age at ADR occurrence, gender, date and cause of death when applicable. Patient information was completed by data from the ‘medical history’ table. For each reported drug, information from the ‘drugs’ table was retrieved: active substance, brand name, dates of beginning of treatment and drug withdrawal, drug indication, frequency and route of administration, role of the drug (suspect, concomitant, interacting) and causality assessment according to the French causality assessment method [12]. This is an algorithmic method that combines semiological and chronological criteria to give an ‘intrinsic score’ (0: excluded, 1: doubtful, 2: possible, 3: probable, 4: certain) and then adds bibliographic data from standardized sources to give an ‘extrinsic score’ (0: never described before, 1: not described, 2: not well known, 3: well known). The ‘ADRs’ table includes information on each reported ADR: date of Br J Clin Pharmacol (2016) 82 1058–1068
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occurrence, date of resolution if applicable, type of the ADR and outcome of the patient. All medical history, causes of death, drug indications and type of ADRs are coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 15.1 (http:// www.meddra.org/). This dictionary is built as a five-level scale comprising 26 system organ classes (SOC) divided into high level group terms (HLGT), high level terms (HLT), preferred terms (PT) and finally lowest level terms (LLT). The term often used to describe an ADR in spontaneous reporting systems is the PT because it corresponds to a single medical concept. Anatomical therapeutic chemical (ATC) codes for drugs were computed as the FPVDB does not include this information. Recoding to the ATC coding system was possible for 97.6%, not applicable for 0.5% and not possible for 2.1% of reported drugs. Throughout the paper, the word ‘drug’ will denote the ATC substance level or else as mentioned. Medical history of neonates was classified based on PTs to three major groups: prematurity, infectious disease and genetic and/or congenital abnormality. We excluded from analysis 26 reports (1.5%) where time between occurrence of the reported ADR and date of reporting to the FPVDB had a negative value or a value of more than 10 years. Time between the beginning of drug administration and occurrence of the reported ADR was assessed only for 767 drugs as from the remaining information on dates was missing.
Data analysis A primary descriptive analysis was performed on the entire dataset between 1986 and 2012. However, during the calendar year 2001, an over-reporting of ADRs in neonates was observed mainly due to the retrospective reporting of ADRs in relation to antiretroviral therapy. Therefore, a secondary descriptive analysis was performed excluding ADRs reports from that specific year. Results of the primary and secondary analysis were compared. Descriptive data include absolute numbers (percentages) for categorical variables and medians [1st quartile (Q1)3rd
quartile (Q3)] for continuous variables or else as mentioned. To apprehend the impact of impaired medical condition on adverse drug outcomes, differences in mortality between neonates with and those without medical history were tested using the chi-square test. For the description of drug-ADR pairs, we only retained suspect and interacting drugs. Analysis was performed with SAS version 9.2 software (SAS Inc, Cary, North Carolina, USA.).
Results Characteristics of ADR reports From 1986 to 2012, a total of 2019 notifications were retrieved from the FPVDB. After discarding cases of maternal exposure to drugs during pregnancy and duplicate reports, notifications for 1688 neonates were analyzed. More than half of these reports (995, 59%) were rated as serious. Trends over time in the number and characteristics of notified ADRs are reported in Figure 1 and Table 1, respectively. Taking into account the number of neonates in France (http://www.insee.fr), 778.468 and 792.996 in 1986 and 2011 respectively, the notification rate increased from 0.03 to 0.17 per 1000 neonates. Median age at occurrence of ADR was 9 days and a slight predominance of male neonates was noted (male : female ratio: 1.3). A medical history was specified for 240 (14%) neonates. Among those, 111 presented a preterm birth (46%), 26 an infection (11%) and 50 a genetic and/or congenital abnormality (21%). The median number of reports per regional PV centre was 36 (20.5–48.5). However, two centres accounted for 37% of all reports (320 and 297, respectively) assessed over the study period, whereas the total number of reports for the remaining centres ranged between 5 and 102. Overall, 88 neonates deceased at a median age of 14 days [7–27] of life, after median of 1 day (0–9 days) from first reported ADR occurrence and with a predominance of male neonates (ratio 1.5). Approximately 72% (n = 63) of these deaths
Figure 1 Trends over time in the number of ADR reports in neonates. number of reports with non-serious ADRs, number of reports with serious ADRs 1060
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Table 1
Type of ADRs reported
Characteristics of reports of adverse drug reactions (ADRs) in neonates
Characteristics of reports (n = 1688)
347
20.4
10
0.6
A total of 3127 ADRs were reported (median of one ADR per report [1–3)]) which corresponded to 479 distinct PT codes. Median time between date of reporting and date of occurrence of the ADR was 21 days (6–103). The most commonly reported system organ class was injury, poisoning and procedural complications (n = 492, 16%), followed by general disorders and administration site conditions (n = 391, 12.5%), blood and lymphatic system disorders (n = 373, 12%), gastrointestinal disorders (n = 255, 8.2%), investigations (n = 251, 8%) and nervous system disorders (n = 245, 8%). The other system organ classes were involved less commonly (100%
Table 5 The three most frequently reported drugs per type of ADRs according to MedDRA system organ class (SOCs) (suspect and interacting drugs only)
SOCs
Total n
Drug
n
Drug
n
Drug
n
Blood and lymphatic system disorders
587
Zidovudine
239
Nevirapine
62
Lamivudine
48
Injury, poisoning and procedural complications
527
Phytomenadione
173
Chlorhexidine
31
Zidovudine
22
General disorders and administration site conditions
478
Phytomenadione
50
Chlorhexidine
24
Solutions for parenteral nutrition
17
Investigations
346
Zidovudine
107
Stavudine
24
Nevirapine
24
Nervous system disorders
326
Zidovudine
19
Midazolam
15
Ergocalciferol
11
Gastrointestinal disorders
321
Ibuprofen
55
Zidovudine
54
Ergocalciferol
20
Cardiac disorders
279
Diphemanil methylsulfate
17
Caffeine
17
Combinations of vitamins
15
Respiratory, thoracic and mediastinal disorders
268
Ergocalciferol
22
Carbocisteine
13
Combinations of vitamins
11
Metabolism and nutrition disorders
224
Zidovudine
33
Stavudine
16
Nevirapine
16
Skin and subcutaneous tissue disorders
190
Chlorhexidine
9
Amoxicillin
9
Cefotaxime
9
Renal and urinary disorders
136
Ibuprofen
24
Amikacin
9
Fentanyl
9
Vascular disorders
96
Midazolam
6
Doxapram
6
Labetalol
5
Musculoskeletal and connective tissue disorders
72
Sufentanil
5
Potassium clorazepate
5
Diazepam
3
Eye disorder
56
Oxytetracycline
Chlorhexidine
5
Hepatobiliary disorders
54
Methylthioninium chloride
Infections and infestations
52
BCG vaccine
Psychiatric disorders
51
Caffeine
12
Zidovudine
4
Ceftriaxone
3
Paracetamol
3
i.v. solution additives
6
Amino acids IV solutions
3
Zidovudine
4
Phytomenadione
3
16 5
Remaining SOCs account for less than 50/4106 drug-ADR pairs
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administration, which may be related to incomplete reporting but also errors during data capture and transfer. Yet, compared with previous paediatric PV studies [5], rates of missing data were very low in the FPVDB, only 2.1% for drugs and 0.01% for ADRs. Notwithstanding these limitations, spontaneous reporting databases are currently the most valuable source of drug safety information in neonates [30, 36, 37]. Development of a paediatric PV expertise and interactions with specialised pharmacologists in PV centres should be further encouraged in order to address the need to increase physicians’ and nurses’ awareness and to train them to diagnose and report better ADRs in neonates. To enhance further collection of informative reporting, another proposition would be the elaboration of a specific neonatal PV report comprising fields of information which are currently absent in the generic PV form but are essential to the drug–event causality assessment with respect to neonatal specificities. In conclusion, this is a unique overview of neonatal ADRs after direct drug exposure. Reporting of ADRs in neonates is increasing. The majority of reports are classified as serious and a subsequent proportion is associated with drug administration errors. Anti-infective medicines, mainly antiretroviral therapy, account for the majority of reported ADRs and ADR fatalities. Although based on national data, our results inform clinicians and stakeholders about the safety of drug use in neonates and the challenges of neonatal pharmacovigilance.
Competing Interests All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf and declare
no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work. The French Medicines Agency (ANSM) provided the data and approved the conduct of the study but was not involved in data analysis and elaboration of this publication. The sole responsibility for the content of this publication lies with the authors. This analysis of the French pharmacovigilance database was made possible thanks to the work of the 31 regional pharmacovigilance centres and the French Medicines Agency (ANSM). The authors acknowledge the support and assistance of Professor Elisabeth Autret-Leca, Department of Clinical Pharmacology Regional Centre of Pharmacovigilance of Tours and Mrs Geneviève Brizion, Centre de Documentation MédicoPharmaceutique, AGEPS.
Funding No sources of funding were used to assist in the preparation of this study and the drafting of the article.
Contributors FK designed the study, conducted data analysis and interpretation of results. FB-S, APJ-B and EJ-A contributed to data analysis and interpretation. The manuscript was initially drafted by FK and was critically reviewed and subsequently approved by each co-author in its final form.
Appendix Most frequently reported drugs and MedDRA high-level terms (HLT) pairs (suspect and interacting drugs only) after exclusion of calendar year 2001
Adverse drug reaction
Drug
ATC
Number of reports
% of the reports (n = 1688)*
Medication errors NEC
Phytomenadione
B02BA01
84
5.0
Maladministration
Phytomenadione
B02BA01
71
4.2
Anaemias NEC
Zidovudine
J05AF01
60
3.6
Adverse effect absent
Phytomenadione
B02BA01
39
2.3
Neutropenias
Zidovudine
J05AF01
31
1.8
Renal failure and impairment
Ibuprofen
C01EB16
24
1.4
Intestinal ulcers and perforation NEC
Ibuprofen
C01EB16
20
1.2
Maladministration
Chlorhexidine
D08AC02
17
1.0
Infections NEC
BCG vaccine
L03AX03
16
0.9
Colitis (excluding infective)
Zidovudine
J05AF01
15
0.9
*Because individual reports may contain more than one active substance – HLT pair, the sum of all percents would be >100% NEC not elsewhere classified.
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DRUG SAFETY Neonatal adverse drug reactions: an analysis of reports to the French pharmacovigilance database Correspondence Dr Florentia Kaguelidou, Department of Pediatric Pharmacology and Pharmacogenetics, Clinical Investigations Center, CIC Inserm 1426, Hôpital Robert Debré 48 boulevard Sérurier 75019, Paris France. Tel.: +33 1 4003 4142; Fax: +33 1 4003 2424; E-mail: fl[email protected] Received 28 September 2015; Revised 23 May 2016; Accepted 6 June 2016
Florentia Kaguelidou1,2,3, Frédérique Beau-Salinas4, Annie Pierre Jonville-Bera4 and Evelyne Jacqz-Aigrain1,2,3 1
EA 08, University of Paris Diderot, Sorbonne Paris Cité, F-75010, Paris, 2Inserm, CIC 1426, F-75019, Paris, 3Department of Pediatric Pharmacology and Pharmacogenetics, AP-HP, Hôpital Robert Debré, F-75019, Paris, and 4CHRU of Tours, Department of Clinical Pharmacology, Regional Centre of
Pharmacovigilance, F-37 044, Tours, France
Keywords adverse drug reactions, neonates, pharmacovigilance, spontaneous reporting
AIM Term and preterm neonates are at high risk for serious adverse drug reactions (ADRs).
METHODS A descriptive study of reports registered in the French pharmacovigilance database from 1986 to 2012 were obtained. All reports concerning neonates (≤1 month of life) with direct drug exposure were retrieved. Characteristics of the reports, including reported ADR(s), drug(s) and the causality assessment using the French causality assessment method, were described.
RESULTS A total of 1688 reports were analyzed and more than half of them were classified as serious (n = 995). Median age at ADR occurrence was 9 days. Overall, 3127 ADRs were described in these reports in relation to 2238 suspect/interacting drugs. The most commonly reported system organ classes (SOCs) were injury, poisoning and procedural complications (16%), general disorders and administration site conditions (12.5%) and blood and lymphatic system disorders (12%). In the majority of ADRs reported (73%), infants fully recovered and less than 4% of neonates deceased as a consequence of the reported ADR. One out of five ADRs was associated with drug administration errors. Therapeutic classes commonly incriminated were anti-infectives, nervous system and alimentary tract drugs. Substances most frequently related to serious ADRs were zidovudine, ibuprofen and nevirapine. Among the 10 most frequently encountered drug ADR pairs, two substances were mainly implicated, zidovudine in haematological adverse reactions and phytomenadione in maladministrations.
CONCLUSIONS Anti-infective drugs, mainly antiretroviral therapy, account for the majority of ADRs reported in neonates. The specific issue of drug maladministration and medication errors remains to be addressed in neonates.
DOI:10.1111/bcp.13034
© 2016 The British Pharmacological Society
Neonatal pharmacovigilance reporting
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Previous pharmacovigilance studies reported that in children approximately one ADR notification out of four concerns infants under the age of 1 year. • No study has focused on describing ADRs following direct drug exposure in neonates more in-depth.
WHAT THIS STUDY ADDS • The majority of neonatal ADR reports were classified as serious and 3.7% of neonates deceased as a consequence of an ADR. • Anti-infective medicines, mainly antiretroviral therapy, account for the large majority of reported ADRs and ADR fatalities. • Vitamins such as phytomenadione also account for a large number of ADR reports mainly associated witho drug administration errors without clinical consequences.
Introduction There are many reasons why neonates may face a higher risk for adverse drug reactions (ADRs) than other age groups. Their organ immaturity and the rapid developmental changes that occur after birth may impact on both drug pharmacokinetics and pharmacodynamics [1]. Sick neonates often require treatment with a substantial number of drugs because of the complexity and seriousness of their conditions and most prescribed drugs have never been specifically evaluated in this neonatal population. Indeed, the percentage of patients receiving at least one unlicensed or ‘off-label’ drug ranges from 80% to 100% in neonatology units [2–4]. Spontaneous reporting systems are an important source of information on drug safety and detection of safety signals. This is essential for products that have not undergone a marketing authorization process, the most commonly encountered situation in paediatric practice. Previous pharmacovigilance (PV) studies reported that in children approximately one ADR notification out of four concerns infants under the age of 1 year [5–7] but few studies specifically described reports in neonates [8–10]. In these studies assessing ADRs after in utero and direct exposure, congenital disorders and reactions related to pregnancy were predominant. Currently, no study has focused on describing ADRs following direct drug exposure in neonates more in-depth. Consequently, the objective of this study was to describe the nature of all ADRs and drug/ADR pairs reported in neonates following direct drug exposure and included in the French pharmacovigilance database.
Methods The French pharmacovigilance database This is a descriptive study of reports registered in the French pharmacovigilance database (FPVDB). This national database was set up in 1985–1986 to allow online input of spontaneous ADR reports from a network of 31 regional PV centres. Reporting of serious and/or unexpected ADRs has been compulsory for physicians, dentists and midwifes since 1984 and for pharmacists since 1995. Also, nurses (since 1995) and patients, families and associations (since 2011) can contribute on a voluntary basis. PV reports include ADRs following drug
use in usual conditions but also medication errors and overdoses. Spontaneous ADR reports are sent to the regional PV centres mainly by means of a standardized form. Each report is validated and a drug causality assessment is performed by qualified personnel before anonymous storage in the national database.
Database search For the present study, reports contained in the FPVDB were extracted from January 1 1986 to November 30 2012. To focus on the neonatal population, the database was searched for all notifications with a reported age at the occurrence of the ADR of equal to or less than 30 days, 1 month or 4 weeks. To avoid neonatal ADRs secondary to maternal drug intake, reports classified as related to ‘pregnancy’ or ‘breastfeeding’ were discarded.
Data collection Data were recorded in four relational tables: ‘report’, ‘drugs’, ‘ADRs’ and ‘medical history’ tables. Thus, a single report can be linked to one or more drugs, ADRs and previous medical history. The ‘report’ table contains information about 1) the notification: date of initial reporting, date of last follow-up, regional PV centre of registration, type of the reporter, type of the reporter’s practice, global seriousness of the ADR report and criteria for seriousness [11] and type of the ADR and 2) the patient: date of birth, reported age at ADR occurrence, gender, date and cause of death when applicable. Patient information was completed by data from the ‘medical history’ table. For each reported drug, information from the ‘drugs’ table was retrieved: active substance, brand name, dates of beginning of treatment and drug withdrawal, drug indication, frequency and route of administration, role of the drug (suspect, concomitant, interacting) and causality assessment according to the French causality assessment method [12]. This is an algorithmic method that combines semiological and chronological criteria to give an ‘intrinsic score’ (0: excluded, 1: doubtful, 2: possible, 3: probable, 4: certain) and then adds bibliographic data from standardized sources to give an ‘extrinsic score’ (0: never described before, 1: not described, 2: not well known, 3: well known). The ‘ADRs’ table includes information on each reported ADR: date of Br J Clin Pharmacol (2016) 82 1058–1068
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occurrence, date of resolution if applicable, type of the ADR and outcome of the patient. All medical history, causes of death, drug indications and type of ADRs are coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 15.1 (http:// www.meddra.org/). This dictionary is built as a five-level scale comprising 26 system organ classes (SOC) divided into high level group terms (HLGT), high level terms (HLT), preferred terms (PT) and finally lowest level terms (LLT). The term often used to describe an ADR in spontaneous reporting systems is the PT because it corresponds to a single medical concept. Anatomical therapeutic chemical (ATC) codes for drugs were computed as the FPVDB does not include this information. Recoding to the ATC coding system was possible for 97.6%, not applicable for 0.5% and not possible for 2.1% of reported drugs. Throughout the paper, the word ‘drug’ will denote the ATC substance level or else as mentioned. Medical history of neonates was classified based on PTs to three major groups: prematurity, infectious disease and genetic and/or congenital abnormality. We excluded from analysis 26 reports (1.5%) where time between occurrence of the reported ADR and date of reporting to the FPVDB had a negative value or a value of more than 10 years. Time between the beginning of drug administration and occurrence of the reported ADR was assessed only for 767 drugs as from the remaining information on dates was missing.
Data analysis A primary descriptive analysis was performed on the entire dataset between 1986 and 2012. However, during the calendar year 2001, an over-reporting of ADRs in neonates was observed mainly due to the retrospective reporting of ADRs in relation to antiretroviral therapy. Therefore, a secondary descriptive analysis was performed excluding ADRs reports from that specific year. Results of the primary and secondary analysis were compared. Descriptive data include absolute numbers (percentages) for categorical variables and medians [1st quartile (Q1)3rd
quartile (Q3)] for continuous variables or else as mentioned. To apprehend the impact of impaired medical condition on adverse drug outcomes, differences in mortality between neonates with and those without medical history were tested using the chi-square test. For the description of drug-ADR pairs, we only retained suspect and interacting drugs. Analysis was performed with SAS version 9.2 software (SAS Inc, Cary, North Carolina, USA.).
Results Characteristics of ADR reports From 1986 to 2012, a total of 2019 notifications were retrieved from the FPVDB. After discarding cases of maternal exposure to drugs during pregnancy and duplicate reports, notifications for 1688 neonates were analyzed. More than half of these reports (995, 59%) were rated as serious. Trends over time in the number and characteristics of notified ADRs are reported in Figure 1 and Table 1, respectively. Taking into account the number of neonates in France (http://www.insee.fr), 778.468 and 792.996 in 1986 and 2011 respectively, the notification rate increased from 0.03 to 0.17 per 1000 neonates. Median age at occurrence of ADR was 9 days and a slight predominance of male neonates was noted (male : female ratio: 1.3). A medical history was specified for 240 (14%) neonates. Among those, 111 presented a preterm birth (46%), 26 an infection (11%) and 50 a genetic and/or congenital abnormality (21%). The median number of reports per regional PV centre was 36 (20.5–48.5). However, two centres accounted for 37% of all reports (320 and 297, respectively) assessed over the study period, whereas the total number of reports for the remaining centres ranged between 5 and 102. Overall, 88 neonates deceased at a median age of 14 days [7–27] of life, after median of 1 day (0–9 days) from first reported ADR occurrence and with a predominance of male neonates (ratio 1.5). Approximately 72% (n = 63) of these deaths
Figure 1 Trends over time in the number of ADR reports in neonates. number of reports with non-serious ADRs, number of reports with serious ADRs 1060
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Table 1
Type of ADRs reported
Characteristics of reports of adverse drug reactions (ADRs) in neonates
Characteristics of reports (n = 1688)
347
20.4
10
0.6
A total of 3127 ADRs were reported (median of one ADR per report [1–3)]) which corresponded to 479 distinct PT codes. Median time between date of reporting and date of occurrence of the ADR was 21 days (6–103). The most commonly reported system organ class was injury, poisoning and procedural complications (n = 492, 16%), followed by general disorders and administration site conditions (n = 391, 12.5%), blood and lymphatic system disorders (n = 373, 12%), gastrointestinal disorders (n = 255, 8.2%), investigations (n = 251, 8%) and nervous system disorders (n = 245, 8%). The other system organ classes were involved less commonly (100%
Table 5 The three most frequently reported drugs per type of ADRs according to MedDRA system organ class (SOCs) (suspect and interacting drugs only)
SOCs
Total n
Drug
n
Drug
n
Drug
n
Blood and lymphatic system disorders
587
Zidovudine
239
Nevirapine
62
Lamivudine
48
Injury, poisoning and procedural complications
527
Phytomenadione
173
Chlorhexidine
31
Zidovudine
22
General disorders and administration site conditions
478
Phytomenadione
50
Chlorhexidine
24
Solutions for parenteral nutrition
17
Investigations
346
Zidovudine
107
Stavudine
24
Nevirapine
24
Nervous system disorders
326
Zidovudine
19
Midazolam
15
Ergocalciferol
11
Gastrointestinal disorders
321
Ibuprofen
55
Zidovudine
54
Ergocalciferol
20
Cardiac disorders
279
Diphemanil methylsulfate
17
Caffeine
17
Combinations of vitamins
15
Respiratory, thoracic and mediastinal disorders
268
Ergocalciferol
22
Carbocisteine
13
Combinations of vitamins
11
Metabolism and nutrition disorders
224
Zidovudine
33
Stavudine
16
Nevirapine
16
Skin and subcutaneous tissue disorders
190
Chlorhexidine
9
Amoxicillin
9
Cefotaxime
9
Renal and urinary disorders
136
Ibuprofen
24
Amikacin
9
Fentanyl
9
Vascular disorders
96
Midazolam
6
Doxapram
6
Labetalol
5
Musculoskeletal and connective tissue disorders
72
Sufentanil
5
Potassium clorazepate
5
Diazepam
3
Eye disorder
56
Oxytetracycline
Chlorhexidine
5
Hepatobiliary disorders
54
Methylthioninium chloride
Infections and infestations
52
BCG vaccine
Psychiatric disorders
51
Caffeine
12
Zidovudine
4
Ceftriaxone
3
Paracetamol
3
i.v. solution additives
6
Amino acids IV solutions
3
Zidovudine
4
Phytomenadione
3
16 5
Remaining SOCs account for less than 50/4106 drug-ADR pairs
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administration, which may be related to incomplete reporting but also errors during data capture and transfer. Yet, compared with previous paediatric PV studies [5], rates of missing data were very low in the FPVDB, only 2.1% for drugs and 0.01% for ADRs. Notwithstanding these limitations, spontaneous reporting databases are currently the most valuable source of drug safety information in neonates [30, 36, 37]. Development of a paediatric PV expertise and interactions with specialised pharmacologists in PV centres should be further encouraged in order to address the need to increase physicians’ and nurses’ awareness and to train them to diagnose and report better ADRs in neonates. To enhance further collection of informative reporting, another proposition would be the elaboration of a specific neonatal PV report comprising fields of information which are currently absent in the generic PV form but are essential to the drug–event causality assessment with respect to neonatal specificities. In conclusion, this is a unique overview of neonatal ADRs after direct drug exposure. Reporting of ADRs in neonates is increasing. The majority of reports are classified as serious and a subsequent proportion is associated with drug administration errors. Anti-infective medicines, mainly antiretroviral therapy, account for the majority of reported ADRs and ADR fatalities. Although based on national data, our results inform clinicians and stakeholders about the safety of drug use in neonates and the challenges of neonatal pharmacovigilance.
Competing Interests All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf and declare
no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work. The French Medicines Agency (ANSM) provided the data and approved the conduct of the study but was not involved in data analysis and elaboration of this publication. The sole responsibility for the content of this publication lies with the authors. This analysis of the French pharmacovigilance database was made possible thanks to the work of the 31 regional pharmacovigilance centres and the French Medicines Agency (ANSM). The authors acknowledge the support and assistance of Professor Elisabeth Autret-Leca, Department of Clinical Pharmacology Regional Centre of Pharmacovigilance of Tours and Mrs Geneviève Brizion, Centre de Documentation MédicoPharmaceutique, AGEPS.
Funding No sources of funding were used to assist in the preparation of this study and the drafting of the article.
Contributors FK designed the study, conducted data analysis and interpretation of results. FB-S, APJ-B and EJ-A contributed to data analysis and interpretation. The manuscript was initially drafted by FK and was critically reviewed and subsequently approved by each co-author in its final form.
Appendix Most frequently reported drugs and MedDRA high-level terms (HLT) pairs (suspect and interacting drugs only) after exclusion of calendar year 2001
Adverse drug reaction
Drug
ATC
Number of reports
% of the reports (n = 1688)*
Medication errors NEC
Phytomenadione
B02BA01
84
5.0
Maladministration
Phytomenadione
B02BA01
71
4.2
Anaemias NEC
Zidovudine
J05AF01
60
3.6
Adverse effect absent
Phytomenadione
B02BA01
39
2.3
Neutropenias
Zidovudine
J05AF01
31
1.8
Renal failure and impairment
Ibuprofen
C01EB16
24
1.4
Intestinal ulcers and perforation NEC
Ibuprofen
C01EB16
20
1.2
Maladministration
Chlorhexidine
D08AC02
17
1.0
Infections NEC
BCG vaccine
L03AX03
16
0.9
Colitis (excluding infective)
Zidovudine
J05AF01
15
0.9
*Because individual reports may contain more than one active substance – HLT pair, the sum of all percents would be >100% NEC not elsewhere classified.
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