Morphine Exposure and Flash Visual Evoked Potentials in Preterm Infants

doi:10.21203/rs.3.rs-1656604/v1

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Morphine Exposure and Flash Visual Evoked Potentials in Preterm Infants

https://doi.org/10.21203/rs.3.rs-1656604/v1

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Background: Morphine is one of the most common analgesic drug, used to minimizing pain and stress in the hospitalized infants, however, concerns on its role on brain development have been expressed. Aim of the present study was to evaluate the effect of morphine exposure during NICU stay on flash visual evoked potentials (VEP) at term equivalent age (TEA), and on visual outcomes at 9 months corrected age (CA) in preterm infants.

Methods: Infants with a gestational age (GA) at birth <30 weeks were prospectively enrolled. Latencies of N1, N2, P2 were measured, as P2 amplitude. N3 was categorized present/absent. Morphine cumulative dose (mg/kg) was calculated as average daily dose adjusted for patient’s weight during the NICU stay. Multivariate regression analyses were performed to assess the association between morphine exposure and VEP components, and visual outcomes.

Results: Sixty infants were enrolled. Thirteen infants received morphine (22.8.%). N1, P2 and N2 latency had a positive association with morphine, even after correcting for GA, postmenstrual age at VEP registration, days of ventilation (DOV), retinopathy of prematurity and painful procedures (R=0.42, R=0.47, R=0.43 respectively, and p=0.048, p=0.001, p=0.006 respectively). Presence of N3 component was associated with higher number of DOV (R=0.38, p=0.004). No association was found between morphine and P2 amplitude, and with ophthalmic evaluation.

Conclusion: Higher morphine dose predicted longer N1, N2 and P2 latency at TEA. However morphine was not correlated with altered ophthalmic evaluation at 9 months.

Visual evoked potentials

morphine

preterm infants

Recent advances in perinatal and neonatal care have improved the survival of preterm infants, however children born preterm are still at risk for neurodevelopmental disabilities, including motor, cognitive, and visual deficits [1,2]. Preterm infants are exposed to hospitalization for several weeks in the neonatal intensive care unit (NICU) during a period of rapid brain growth and development, and they routinely undergo invasive and painful procedures to treat critical illnesses. Extensive data have demonstrated the adverse effect of pain and stress on short- and long-term outcome, thus the control of pain has become strongly recommended in the NICU [3–6]. Morphine is one of the most common and well-studied opioid analgesic drugs, however concerns about its role in brain development have been widely expressed [7,8].

Visual evoked potentials (VEP) are an accurate and non-invasive method to evaluate the maturity and integrity of the visual pathway [9]. VEPs are electrophysiological responses elicited by visual stimuli extrapolated from electroencephalographic activity recorded from the scalp overlying the occipital cortex [10]. The appearance of a VEP after a flash or pattern reversal stimulus indicates that visual information has efficaciously reached and activated the cortex. In pediatric population, the use of flash VEP for clinical and research purposes is often preferred for practical reasons: responses are quick, less influenced by fixation, and less dependent on alertness state [10–12]. Therefore, this neurophysiological technique has been widely applied in preterm and term infants and several studies have demonstrated its usefulness for early identification of newborns at high risk of neurodevelopmental impairment [13–16]. Indeed, infants who suffered severe brain injury exhibit immature or abnormal or poor flash VEP waveforms [14,17–21]. Flash VEP can be recorded in infants as preterm as 24 weeks of gestation and related waveforms change with the progression of maturation of the visual pathways [22]. The first wave that can be registered is a single monophasic negative peak with a latency of approximately 300 msec (N3) at about 24 weeks of gestation. N3 peak gradually reduces and disappears at term. After 27 weeks, a large positive biphasic waveform at the latency of 400 msec (P3) appears and remains stable until term [22]. From 30 to 35 weeks of gestation a positive wave is observed whose latency shows progressive shortening, reaching the latency of 200 msec (P2) near the term [22]. Wave P2 is present in all healthy infants born from 37 weeks of gestational age (GA) onwards, whose latency shows a low variability making it a reliable biomarker of impaired neonatal brain maturation [12].

The effect of morphine exposure on flash VEP in preterm infants has never been studied and, therefore, it cannot be excluded that VEP abnormalities may be due to its effect in treated patients. Thus, the aim of this study was to evaluate the effect of cumulative dose of morphine during the NICU stay on VEP waves and morphology at term equivalent age (TEA), and on visual outcomes at 9 months corrected age (CA).

Study population

We prospectively studied infants with GA <30 weeks who were born between September 2018 and May 2021 and admitted to the third level NICU of Careggi University Hospital of Florence. Written parental informed consent and permission from the local ethics committee medical were obtained for this study.

Exclusion criteria were the presence of major congenital malformations or syndromes, transfer to other hospitals, or death before 36 weeks of postmenstrual age (PMA). Infants with severe brain injury, defined as the occurrence of intraventricular hemorrhage (IVH) >3 grade [23] and cystic periventricular leukomalacia (PVL) [24] were also excluded, since previous works reported immature or abnormal flash VEP waveforms in the these patients [14,17,18].

Medical and nursing chart review was carried out and for each infant the following perinatal data were obtained: GA, birth weight, gender, type of delivery, need and duration of mechanical ventilation, postnatal steroids, occurrence of bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), sepsis, necrotizing enterocolitis (NEC), and grade of IVH. BPD was defined as oxygen requirement at 36 weeks PMA [25]. PDA was diagnosed by echocardiography and considered clinically significant when it required medical or surgical treatment. NEC was defined as Bell’s stage 2 or higher [26]. Sepsis was diagnosed when patients developed clinical signs and symptoms associated with a positive blood and/or cerebrospinal fluid culture. IVH was graded following the classification of Papile et al. [23]. Birth weight and head circumference z-scores were computed according to the INES charts [27]. PVL was diagnosed according to De Vries et al. [24]. Retinopathy of prematurity (ROP) was graded according to the International Classification of ROP [28].

Ophthalmology follow-up was performed by a pediatric ophthalmologist at 9 months of CA. Assessment of anterior segment, fundus oculi, ocular motility, and refraction were performed. Ophthalmic evaluation was categorized as normal or abnormal.

Pain evaluation and management

The exposure to painful procedures was evaluated during the whole hospitalization period by recording the number of the following invasive procedures: heel pricks, peripheral or central venous catheter insertion, endotracheal intubation, intra-muscular injection, chest tube insertion and urinary catheter insertion, lumbar puncture, and eye examination.

In our NICU, pain and stress were managed following the guidelines of the Italian Society of Neonatology [29]. Neonatal Pain Agitation and Sedation Scale (N-PASS) was applied for acute pain evaluation [30]. Opioids, such as fentanyl and morphine, were used in mechanically ventilated infants, according to pain scores and clinical indications. Fentanyl was administrated as first choice, as bolus (0.5-3 mcg/kg/dose) and/or continuous infusion (0.5–5 mg/kg/h). In case of prolonged ventilator dependence and to avoid fentanyl tolerance or tachyphylaxis, morphine was introduced and administered intravenously starting with a loading dose (0.05-0.1 mg/kg/dose) followed by a continuous infusion (0.01-0.05 mg/kg/h). The cumulative dose of morphine (intravenous dose plus converted oral dose) was calculated as the average daily dose adjusted for patient’s weight during the NICU stay.

Visual evoked potentials recordings

VEP recordings were performed at TEA using Nemus-EB Neuro polygraph and GalNT / EP EXAM software. All infants were clinically stable, and none received drugs influencing brain activity, such as morphine, benzodiazepines, and barbiturates during the exam. VEPs were performed during active sleep state, while the newborns were lying in their cot in a supine position in a dark room

Electrode landmarks were identified at the level of the occipital scape according to the International System 10-20 [31,32]. Disposable surface electrodes in O1-O2-Oz were placed with reference Fz and impedances <10 kΩ; the Flash-Lamp stimulator (stimulus surface 12x4 cm) was positioned at 30 cm from the neonate's eyes and flashes of light at low frequency of 1 Hz were sent to obtain a transient response. The recording parameters were analysis time 1 s, band pass filter 1-200 Hz, sensitivity 50 µV. To avoid habituation related to high stimulation rate and high number of stimuli, and to ensure reproducibility of the traces, the average consisted of two series of 30 responses.

The flash VEP waveforms obtained in our population consisted of four separate phases, a first negative deflection named N1, followed by a prominent positive wave called P2, a later negative deflection named N2, and a further negative deflection named N3. Latencies of N1, N2, P2 were measured, as P2 amplitude. N3 wave was categorized as present or absent. Each flash VEP was also categorized by waveform morphology. Descriptive categories were: regular, immature, atypical, not detectable [12,33].

Statistical analysis

The infants’ clinical characteristics were described as mean and standard deviation, median and interquartile range (IQR) or rate and percentage. Infant data were first grouped according to whether they had received morphine or not. The t test and chi square test were used to compare continuous normally distributed data and categorical data, respectively. Then, univariate regression analyses were performed to assess the association between cumulative morphine dose (as independent variables), VEP components and ophthalmic evaluation (as dependent variables). For each, N1 latency, N2 latency, P2 latency and amplitude, N3 wave (present/absent), and VEP morphology at TEA were studied. Finally, multivariate regression analyses were performed and GA, days of ventilation (DOV), PMA at VEP registration, painful procedures, and ROP (any grade) were entered into the model as independent variables. Results are presented as coefficients of independent variables with 95% confidence intervals (CI). Condition indexes and the variance inflation factor of the regression model were computed to detect multi-collinearity. Condition Index <30 and variance inflation factor <5 values indicated that regression models did not have significant multicollinearity. Data analysis was performed using IBM SPSS Statistics version 20.

In total, 60 infants were eligible for the study, all with good quality VEP. Thirteen infants received morphine (22.8%) at a mean dose of 26.7 ± 27.0 mg/kg (range 0.1–83.2) for a mean of 40±24 days (range 1–90) during their NICU stay. Neonates who were exposed to morphine had lower GA, were more frequently born by spontaneous delivery, had lower weight and head circumference at birth and at VEP registration, were ventilated for a longer period, had higher incidence of PDA, IVH, BPD, ROP, underwent more frequent painful procedures, and had a longer stay in the NICU compared to their pair who were not exposed (Table 1).

Table 1

Clinical characteristics of studied infants. Mean ± SD, median and (IQR), or rate and (%).
	No Morphine (N 47, 78.3%)	Morphine (N 13, 22.8%)	p value
Gestational age (wks)	27.6 ± 1.3	25.8 ± 2.2	0.011
Male	25 (53)	9 (69)	0.290
Birth weight (gr)	955 ± 227	763 ± 246	0.023
Birth weight, Z score	0.07 ± 0.90	0.18 ± 0.80	0.073
Head circumference at birth (cm)	25 ± 2	23 ± 2	0.006
Head circumference, z score at birth	-0.21 ± 1.2	-0.35 ± 0.81	0.757
Caesarean section	35 (74)	6 (46)	0.033
Apgar score at 5 min	8 (8–8)	6.5 (7–8)	0.462
Mechanical ventilation	18 (38)	13 (100)	< 0.001
Mechanical ventilation (d)	1 (0–3)	28 (15–46)	< 0.001
NICU stay (d)	85 ± 25	121 ± 29	< 0.001
PMA at VEP registration (wks)	39.3	39.9	0.067
Weight at VEP registration (g)	2231 ± 361	2140 ± 392	0.494
Weight z-score at VEP registration	-2.20 ± 1.23	-3.15 ± 1.18	0.037
Head circumference at VEP registration (cm)	31.8 ± 1.5	30.8 ± 1.6	0.082
Head circumference z-score at VEP registration	-1.6 ± 1.4	-3.4 ± 1.7	0.002
PDA requiring treatment	24 (51)	11 (85)	0.023
NEC	1 (2)	1 (8)	0.163
BPD	15 (32)	9 (69)	0.013
Sepsis	22 (47)	8 (61)	0.320
IVH grade I grade II	2 (4) 0 (0)	2 (15) 1 (8)	0.015
ROP grade 1 grade 2 grade 3	0 (0) 1 (2) 0 (0)	0 (0) 5 (38) 0 (0)	< 0.001
Postnatal steroids	8 (17)	11 (85)	< 0.001
N° painful procedures	88 ± 39	209 ± 83	0.001
PMA, post menstrual age; VEP, visual evoked potentials; PDA, patent ductus arteriosus; NEC, necrotizing enterocolitis; BPD, bronchopulmonary dysplasia; IVH: intraventricular hemorrhage; ROP: retinopathy of prematurity.

No significant differences were observed in N1, N2 latency, N3 component (presence/absence), P2 latency, and amplitude and VEP morphology between infants who received morphine and infants who did not (Table 2). N3 component was recorded overall in ten infants (16%).

Table 2

Flash VEP characteristics of morphine-untreated and treated infants. Mean ± SD or rate and (%).
	No morphine (n = 47)	Morphine (n = 13)	P
N1 latency (msec)	169 ± 22	185 ± 29	0.136
P2 latency (msec)	208 ± 21	216 ± 44	0.462
N2 latency (msec)	255 ± 36	268 ± 62	0.438
N3 component presence /absence	6/41 (13/87)	4/9 (31/69)	0.220
Morphology regular immature atypical undetectable	40 (85) 3 (6) 4 (9) 0 (0)	11 (85) 2 (15) 0 (0) 0 (0)	0.729
P2 amplitude (msec)	7.1 ± 6.1	7.1 ± 3.4	0.982

Univariate analyses showed that N1 (R = 0.36, P = 0.006), P2 (R = 0.43, P = 0.001), and N2 (R = 0.38, P = 0.005) latency had a positive association with cumulative morphine, and these correlations remained significant after adjusting for GA, PMA, DOV, ROP and painful procedures (R = 0.42, p = 0.048; R = 0.47, P = 0.001; R = 0.43, P = 0.006) (Table 3).

Table 3

Univariate and multivariate linear regression analyses between morphine cumulative dose and flash VEP.
Univariate regression
	N1 Latency			P2 Latency			N2 Latency			N3 Latency			Morphology			P2 amplitude
	R = 0.36			R = 0.43			R = 0.38			R = 0			R = 0			R = 0
	B	95% CI	p	B	95% CI	p	B	95%CI	p	B	95%CI	p	B	95%CI	p	B	95%CI	p
Morphine cumulative dose (mg/kg)	0.72	0.21–1.2	0.006	0.88	0.38–1.38	0.001	1.24	0.40–2.09	0.005	0.01	−0.07–0.08	0.941	−0.004	−0.02 − 0.01	0.575	−0.03	−0.16 − 0.11	0.647
Multivariate regression
	N1 Latency			P2 Latency			N2 Latency			N3 Latency			Morphology			P2 amplitude
	R = 0.42			R = 0.47			R = 0.43			R = 0.38			R = 0.32			R = 0.18
	B	95% CI	p	B	95% CI	p	B	95%CI	p	B	95%CI	p	B	95%CI	p	B	95%CI	p
Morphine cumulative dose (mg/kg)	0.55	0.01−1.10	0.048	0.87	−6.02−9.72	0.001	1.23	−4.06−21.35	0.006	0.017	0.002–0.031	0.070	−0.02	−0.46 − 0.002	0.067	−0.11	−0.39 − 0.17	0.436
GA	−3.58	−7.71 − 0.54	0.087	0.45	−5.44−6.34	0.878	2.71	−7.40-12.8	0.592	0.08	−0.08–0.10	0.873	−0.07	−0.22 − 0.08	0.356	−0.08	−1.66–1.50	0.917
PMA	−2.66	−10.94–5.61	0.520	−4.83	−12.2–2.58	0.196	−8.94	−21.6–3.77	0.164	−0.05	−0.12 − 0.11	0.936	−0.02	−0.22 − 0.16	0.777	0.88	−1.11–2.87	0.378
DOV	0.12	−1.53–1.77	0.883	0.48	−1.13–2.11	0.548	0.90	−1.88–3.68	0.516	0.02	−0.002–0.049	0.004	0.02	0.05–0.32	0.068	0.18	−0.25–0.61	0.406
ROP	15.7	−17.9–49.5	0.351	−4.26	−37.2–28.7	0.797	0.84	−54.5–56.2	0.976	0.32	−0.17–0.83	0.197	−0.25	−1.12–0.61	0.554	0.09	−8.78–8.98	0.983
Painful procedures	−0.03	−0.23 − 0.16	0.726	0.04	−0.19–0.19	0.966	0.00	−0.32–0.32	0.999	0.00	−0.003–0.003	0.978	−0.002	−0.007 − 0.004	0.541	−0.02	−0.07 − 0.03	0.398
GA, gestational age; PMA, post menstrual age; DOV, days of ventilation; ROP, retinopathy of prematurity

N3 component was not associated with cumulative morphine dose, but after adjustment its presence was predicted by longer duration of mechanical ventilation (R = 0.38, p = 0.004). No association was found between cumulative morphine and P2 amplitude or VEP morphology.

Fifty infants (83%) had ophthalmology follow-up at 9 months of CA, and among them 10 (20%) were exposed to morphine. No difference was observed on visual outcomes between infants who received morphine and infants who did not (P = 0.573). Six patients (10%) developed ROP (one in morphine-untreated infants and five in morphine-treated infants), but a complete regression of ROP occurred in all infants. In the exposed group, one infant developed hyperopic astigmatism, while alternating esotropia occurred in one infant in the not exposed group. None of the infants developed nystagmus. Cumulative morphine dose was not associated with abnormal ophthalmic evaluation at 9 months of CA (R = 0.05, p = 0.696), also after adjustment for clinical risk factors (R = 0.24, p = 0.205) (Table 4).

Table 4

Univariate and multivariate linear regression analyses evaluating possible correlation between morphine cumulative dose and ophthalmic evaluation at 9 months of corrected age.
Univariate regression
	Ophthalmic evaluation
	R = 0.05
	B	95% CI	P
Morphine cumulative dose (mg/kg)	−0.001	−004-.003	0.696
Multivariate regression
	Ophthalmic evaluation
	R = 0.24
	B	95% CI	P
Morphine cumulative dose (mg/kg)	−0.004	−0.010 − 0.002	0.205
Gestational age	0.002	−0.043–0.047	0.931
Days of mechanical ventilation	0.008	−0.003–0.19	0.134
ROP	−0.113	−0.344 − 0.199	0.334
Number of painful procedures	0.000	−0.231–0.818	0.134
ROP, retinopathy of prematurity.

The primary aim of our study was to investigate the impact of morphine exposure during NICU stay on flash VEP in preterm infants and we demonstrated that a higher cumulative morphine dose predicted longer N1, N2, and P2 latency at TEA. These correlations were found to be independent from clinical risk factors since they persisted after adjusting for variables reflecting neonatal morbidities.

Studies in animal models demonstrated the susceptibility of the visual pathways to morphine exposure. Opiate receptors have been found in the visual systems of rats, cats, and macaques suggesting that the visual pathways are subjected to opiate modulation [34–36]. Chronic morphine exposure caused the degradation of the receptive field of lateral geniculate nucleus cells [37] and a decrease in total dendritic length and spine density in the visual cortex [38]. Furthermore, prenatal exposure to morphine has been shown to reduce the total length of the basal dendrites of the layer II/III in the lateral secondary visual area in young rats [39].

Studies in humans have demonstrated that children with prenatal history of opioid exposure present a higher risk of visual impairment, including reduced visual acuity, strabismus, and nystagmus [40–42]. The neural substrate for the development of visual defects is still not well-defined [35]. A recent functional MRI study found smaller network volumes particularly in the primary visual network in infants prenatally exposed to opioids compared to their unexposed pairs [43]. Furthermore, a long term follow-up research revealed that children randomized to early morphine infusion exhibited lower scores at the visual analysis subtest of IQ at 5 years of age, compared to unexposed infants [44], although this result was not confirmed at 8–9 years of age [45].

Abnormal visual electrophysiology was a frequent finding in infants prenatally exposed to opioids [42,46,47]. Previous research from McGlone et al. found that VEPs of infants prenatally exposed to methadone were more likely to have immature waveform and to be smaller in overall amplitude at birth in comparison to unexposed infants [33]. However, most of the drug-exposed infants had additionally received other illicit drugs and alcohol in utero.

Opioid receptors are expressed in the human brain at cortex level, lateral geniculate nucleus, and midbrain [48]. The opioid system is crucial for neuronal maturation and modulates GABAergic synaptic transmission. Excitatory and inhibitory GABA synaptic transmission is fundamental for the development and maintenance of visual cortical function [49,50]. In addition, there is increasing evidence of the crucial role of the endogenous opioid system on myelination. Neural stem cells and oligodendroglial lineage cells express opioid receptors and their modulation in culture has been shown to have mitogenic and differentiating properties [51–54]. These findings suggest that any interference with the endogenous opioid system by drug abuse or treatments might influence brain myelination.

Parameters such as VEP latencies and amplitudes of the response components have been correlated to white matter maturation and synaptic transmission [55–57]. Specifically, prolonged latencies have been associated with poorer myelination and reduced amplitudes with axonal loss, respectively [58]. Thus, the increased latency might reflect a delayed myelination of the primary visual pathways in morphine exposed infants [59–61].

We did not find differences in latency, amplitude and morphology between exposed- and unexposed-morphine infants. This result might be due to the small number (thirteen infants) of morphine-exposed infants and the great variability of morphine dose received in our population (mean dose of 26.7 mg/kg, range 0.1–83.2).

Overall, N3 component was recorded in 10 newborns (16%) and its presence was associated with prolonged mechanical ventilation. N3 component is a primitive wave that can be evoked as early as 24 weeks GA [22,62,63]. This wave is preceded or replaced in the healthy term newborn by the positive wave P2 as result of the neuronal maturation of the neonatal visual cortex.[64] Thus, its persistence indicates a delay maturation of visual pathways. Gambi et al. studied a group of preterm and term infants with respiratory distress syndrome (RDS) and found that flash VEP in infants with more severe RDS lost their maturational characteristics, which were then gradually reacquired with clinical improvement [65]. Moreover, this result was confirmed by Hrbek et al. who reported a decrease of amplitude and an increase of latency of VEP during hypoxia in preterm infants with RDS [66].

The secondary aim of our study was to assess the effect of cumulative morphine dose on clinical visual outcomes at 9 months CA. The ophthalmology examination did not differ between morphine- exposed and unexposed infants. Moreover, we failed to demonstrate an effect of morphine on visual outcomes. Conversely, Mc Glone et al. showed that VEP alterations remained at six months of CA together with clinical visual defects such as strabismus, reduced visual acuity, and nystagmus, indicating a teratogenic effect of prenatal drug exposure on the developing visual system [47]. The possible explanation for these conflicting results might be the higher number of patients enrolled in their study (81 patients) compared to our population; the different studied opioid, since methadone might have a more detrimental effect than morphine on developing visual function; the exposure to opioids (and possibly other substances) throughout the pregnancy, while in our study morphine was given only after birth and for a limited time (mean 40±24 days).

Limitations of this study include the small sample size, which might have limited the possibility of detecting a significant role of other comorbidities and variables. Moreover, we did not repeat VEP test at 9 months CA to evaluate whether the observed electrophysiological abnormalities were transient. On the other hand, the lack of longer ophthalmology follow-up data did not allow assessment of the possible correlation between electrophysiological abnormalities and the risk of developing visual abnormalities.

In conclusion, a higher cumulative morphine dose predicted longer VEP latency at TEA in preterm infants. These findings suggest that infants exposed to morphine may undergo a delay in visual pathways maturation. Cumulative morphine dose was not associated with abnormal ophthalmic evaluation at 9 months of CA. Our study supports the need for further studies investigating the possible long-term effects of morphine on the visual system in this vulnerable population.

NICU: neonatal intensive care unit; VEP: visual evoked potential; TEA: term equivalent age; GA: gestational age; PMA: postmenstrual age; CA: corrected age; DOV: days of ventilation; IVH: intraventricular haemorrhage; PVL: cystic periventricular leukomalacia; BPD: bronchopulmonary dysplasia; PDA: patent ductus arteriosus; NEC: necrotizing enterocolitis.

Ethical approval

The local Ethical Committee of Meyer Children Hospital approved this study. Written informed consent was obtained from the parents of the enrolled infants. The study was carried out in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Consent for publication

Not applicable

Data availability

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding source

The study was not specifically funded.

Financial Disclosure Statement

Authors declare that they do not have any financial relationships that could be broadly relevant to this work.

Conflict of interest

The authors declare no conflict of interest in relation to the manuscript.

Author Contributions

Conceptualization, C.Cov., S.L., G.B. and C.D.; methodology C.Cov., L.S., G.B. and C.D.; data curation, C.Cov., S.G., M.B., C.Cos., S.C., S.M. and S.F.; writing—original draft preparation, C.Cov., S.L., G.B. and C.D.; All authors read and approved the final manuscript.

Acknowledgements

None

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Morphine Exposure and Flash Visual Evoked Potentials in Preterm Infants

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Abstract

Introduction

Methods

Study population

Pain evaluation and management

Visual evoked potentials recordings

Statistical analysis

Results

Discussions

Conclusions

Abbreviations

Declarations

References

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