Background & Aims

Prematurity concerns 15 million infants per year, which is defined as birth before 37 completed weeks of gestation (1). Neurological maturation mostly takes place during the third trimester of pregnancy and may be affected by preterm infant birth (2). Preterm infants live many painful experiences during their hospitalization in the neonatal intensive care unit (3). To manage their pain, pharmacological and non-pharmacological interventions are used in the neonatal unit (4). However, pharmacological interventions could induce adverse effects, such as an impact on the neurodevelopment (5). To our knowledge, no systematic review has been conducted on this subject. This systematic review aimed to evaluate the impact of pharmacological interventions for pain management on neurodevelopmental outcomes.

Methods

This systematic review was conducted in accordance with the Joanna Briggs Institute methodology for systematic reviews of etiology and risk (6). We followed the recommendation of the PRISMA (7, 8). This systematic review focused on preterm infants (<37 weeks of gestation). Prospective and retrospective observational studies were considered in this systematic review. The primary outcome is neurodevelopment, which can be measured at three time points: 1) Short-term (before term equivalent age), 2) Mid-term (term equivalent age up to three years), 3) Long-term (after three years). Various indicators of neurodevelopment are considered: brain structure, brain electrical activity, neurological examinations, and developmental examinations. An electronic search was conducted from inception to August 2023 in CINAHL, PubMed, MEDLINE, Embase and Cochrane Central Register of controlled trials. Study selection, data extraction and critical appraisal was conducted by two independent reviewers.

Results

A total of 42 448 records were identified, and 34 707 records remained after removing duplicates. We excluded 34 406 studies during the first selection (title and abstract), 9 reports were not retrieved, and 285 studies were assessed for eligibility in a final selection (full-texts). Among these studies, a total of 22 studies met the inclusion criteria and were included. Studies were published between 2004 and 2022. Morphine was the drug the most frequently reported, followed by fentanyl and midazolam. A negative impact of theses drugs was found on neurodevelopmental outcomes, namely on brain structure (IRM results) and developmental examinations (e.g. language, internalizing behaviours, socioemotional indicators). No result was found on brain electronical activity.

Conclusions

Managing pain in the neonatal intensive care unit is a current challenge. A lot of improvements have been made on managing acute pain with non-pharmacological interventions, with a very low odd of adverse events. Prolonged pain such as mechanical ventilation, necrotising enterocolitis, surgical operations, require pharmacological interventions. This systematic review highlight that these drugs have a negative impact on neurodevelopment. More rigorous studies with a focus on the different conditions of prolonged pain and a statistical control of non-pharmacological interventions are required for a better understanding of the neurological impact of pharmacological interventions.

References

1.Chawanpaiboon S, Vogel JP, Moller A-B, Lumbiganon P, Petzold M, Hogan D, et al. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. The Lancet Global Health. 2019;7(1):e37-e46.
2.Kenner C, McGrath JM. Developmental Care of Newborns & Infants: a guide for health professionals. 2 ed. National Association of Neonatal N, editor: St. Louis, MO : Mosby; 2011.
3.Cruz MD, Fernandes A, Oliveira CJEJoP. Epidemiology of painful procedures performed in neonates: a systematic review of observational studies. 2016;20(4):489-98.
4.Ojha S, Abramson J, Dorling JJBPO. Sedation and analgesia from prolonged pain and stress during mechanical ventilation in preterm infants: is dexmedetomidine an alternative to current practice? 2022;6(1).
5.Duerden EG, Guo T, Dodbiba L, Chakravarty MM, Chau V, Poskitt KJ, et al. Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants. 2016;79(4):548-59.
6.Moola S, Munn Z, Tufanaru C, Aromataris E, Sears K, Sfetcu R, et al. Chapter 7: Systematic reviews of etiology and risk. In: Aromataris E, Munn Z, editors. Joanna Briggs Institute Reviewer’s Manual The Joanna Briggs Institute,; 2017.
7.Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Journal of clinical epidemiology. 2009;62(10):1006-12.
8.Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS medicine. 2009;6(7):e1000100.

Presenting Author

Gwenaelle De Clifford-Faugere

Poster Authors

Gwenaelle DE CLIFFORD-FAUGERE, RN, PhD

Ph.D.

Faculty of Nursing, Université du Québec en Abitibi-Témiscamingue (UQAT)

Lead Author

Alexandra Breton-Piette

UdeM

Lead Author

Geneviève Laporte

UdeM

Lead Author

Émile Rioux

UdeM

Lead Author

Andréane Lavallée

Lead Author

Marilyn Aita

Lead Author

Topics

  • Treatment/Management: Pharmacology: Opioid