Acta Pædiatrica ISSN 0803-5253

REGULAR ARTICLE

The effects of olfactory stimulation and gender differences on pain responses in full-term infants Olga Romantsik ([email protected])1, Richard H. Porter2,*, Heili Varendi1 1.Department of Pediatrics, University of Tartu, Tartu, Estonia 2.Centre National de la Recherche Scientifique, Nuozilly, France

Keywords Gender differences, Newborns, Olfaction, Pain

ABSTRACT Aim: Studies have reported conflicting findings on whether different smells can reduce

Correspondence Olga Romantsik, Department of Pediatrics, University of Tartu, Lunini 6, 51014 Tartu, Estonia. Tel: +372 7 319610 | Fax: +372 7 319608 | Email: [email protected]

distress when infants undergo painful procedures. Our study assessed the impact of vanilla on infants’ responses to a painful toe lance, including possible gender differences. Methods: We measured the pain responses of 69 full-term infants – 34 girls and 35 boys – during toe lance, using two multidimensional scales – the Neonatal Facial Coding System and Behavioural Indicators of Infant Pain – together with crying duration and hand movements. Three sets of data were collected during baseline, toe lance and recovery, while the babies were exposed to the odour of vanilla (n = 39) or odourless water (n = 30). Results: Pain responses increased significantly during toe lance, then declined during recovery. Crying duration correlated significantly with finger splaying/fisting and both pain scale scores, with boys displaying higher pain scores than girls. Vanilla had no impact on pain levels. Conclusion: Crying and finger splaying/fisting were observable responses that may be useful for screening pain or distress in healthy neonates. Increased pain reactions by boys may reflect higher irritability. Exposure to an unfamiliar odour did not have a calming effect on full-term neonates.

Received 15 April 2013; revised 16 June 2014; accepted 21 July 2014. DOI:10.1111/apa.12759 *Retired.

INTRODUCTION Overt responses to olfactory cues have been documented in full-term newborns, as well as preterm infants whose gestational age was >28–29 weeks (1,2). Goubet et al. (3) observed that familiar vanilla odour reduced crying by premature infants during venipuncture. When subjected to a more painful heelstick, preterm neonates displayed heightened indices of distress that were not affected by odour exposure. In subsequent experiments, the familiar odour of mother’s milk or vanilla had a calming effect on full-term infants undergoing a heelstick procedure (4) and the odour of the infant’s mother’s milk was more effective than the scent of milk from another lactating woman (5). In a further study, the behavioural responses of full-term infants to heelsticks were not significantly affected by the unfamiliar odour of lavender, but cortisol levels were lower in the group exposed to the odour (6). Various authors have noted differences in the behaviour of boys and girls during the early postpartum period. Girls scored higher than boys on several items of the Brazelton

Abbreviations BIIP, Behavioural Indicators of Infant Pain; NFCS, Neonatal Facial Coding System.

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Neonatal Behavioral Assessment Scale, including Alertness, Auditory Orientation and State Regulation, and boys had higher Irritability scores (7). Further published accounts of newborn infants’ reactions to painful stimulation have provided no consistent pattern of gender effects. Guinsburg et al. (8) reported that newborn girls displayed greater facial indices of pain than boys, but another study showed that boys showed facial reactions more quickly than girls following capillary puncture (9). However, gender differences in the pain responses of preterm neonates are usually not observed (10,11). Relevant data are limited on the impact of odour, but suggest that newborn boys and girls

Key notes 





Studies have reported conflicting findings on whether odours can reduce infants’ distress during painful procedures, and this study assessed the effect of olfactory stimulation on newborns undergoing a toe lance. We found that an unfamiliar vanilla odour did not alleviate pain responses in neonates and that boys exhibited greater expressions of pain than girls. Crying and finger splaying were observable responses to pain and are useful for screening neonatal distress.

©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1130–1135

Romantsik et al.

may not respond to olfactory cues in an identical manner (12,13). However, in the above-cited investigations of the effects of olfactory stimulation on pain responses, only Kawakami et al. (6) assessed possible gender effects. These authors found no significant differences between infant boys and girls. A simple, cost-effective olfactory intervention to alleviate the pain reactions of neonates would, potentially, be of considerable clinical importance. The literature reviewed above tentatively suggests that the effectiveness of particular odour treatments might differ for boys and girls. This study had two inter-related goals. The first was to assess the influence of exposure to a novel odour on full-term neonates’ overt behavioural responses to a painful clinical procedure. A novel artificial scent was selected as the olfactory stimulus, rather than a natural maternal odour, as it would be equally unfamiliar and readily available for both breastfed and bottlefed neonates. The second was to provide additional insights into the question of possible gender differences in neonates’ responses to a painful event.

MATERIALS AND METHODS Participants The study took place on the maternity ward of Tartu University Woman’s hospital in spring 2006. We originally considered a potential subject population of 86 newborn infants, but 17 were excluded, because of technical/procedural problems (n = 15) or parental refusal (n = 2). Finally, 69 healthy full-term newborn infants – 34 girls and 35 boys – were recruited. To achieve a clinically significant change in pain scores between the groups of 20% with 80% power and a p value of 0.05, we estimated that it would be necessary to have a sample size of 35 babies per group. The inclusion criteria were gestational age ≥ 37 weeks, birth weight appropriate for gestational age, an Apgar score of >7 at 5 min, no need of resuscitation or intensive care, no major congenital malformations, absence of familial disturbance of the olfactory system and a non-smoking mother. The clinical data of the studied newborns are presented in Table 1. All infants underwent toe lance to obtain capillary blood as part of routine screening for phenylketonuria and hypothyreosis. At this time, no routine measures for analgesia were used in the unit. In accordance with ethical standards, parents were informed and gave written consent for their infant to participate in the study. The study was approved by the local research ethics committee. Procedure The newborn infants of each gender were randomly assigned to the odour exposure (n = 39) and water control groups (n = 30). Commercially produced vanilla aroma oil (GIES Kerzen GmbH D-21509, Germany) was used as the odour stimulus. Vanilla odour was chosen because it appears to be hedonically pleasant for full-term and preterm infants (14,15,16) and evokes reliable facial reactions (17,18,19).

Olfactory stimulation and pain

Table 1 Clinical characteristics of the study groups given either as mean  SD or as actual number Control group (N = 30) Maternal age (years) Gestational age (days) Girls/boys Birth weight (g) Apgar score at 1 min Apgar score at 5 min Number of infants born by caesarean section (boys/girls) Age at testing, h

26.1 280 15/15 3722 8.3 8.8 4 58  7

(6.9) (7.5) (530) (0.9) (0.4) (1/3)

Vanilla exposure group (N = 39) 26.7 281 19/20 3659 8.2 8.7 10

(5.4) (8.1) (466) (0.9) (0.6) (8/2)

55  7

Prior to the study, 10 staff members rated the odour of one drop of vanilla at various time intervals. Equal intensity ratings were given at the moment when the stimulus pad was treated and 5 min later. The assisting nurse perceived the odour during the blood sampling procedure at a distance of around 50 cm from the odourised pad. The toe lance was performed in a quiet room when the babies’ postnatal age was 56  7 h (mean  SD). They were breastfed 30–40 min before the observation, and none had received analgesic or sedative drugs. For testing, babies were placed in a supine position, free to move. The neonates rested for 5 min before the experimental treatment began. At that time, all of the infants in the two groups were in states one to five, as described by the Als manual (18). One minute before the toe lance, a gauze pad (7.5 9 7.5 cm) treated with either one drop of vanilla oil or one drop of sterile water was placed 7 cm from the infant’s nose. In this manner, the newborns were continuously exposed to the odour stimulus, or water control, during the 3-min study session, which consisted of a 60-sec baseline period, a 60-sec interval immediately following the initiation of the toe lance and a final 60-sec recovery period, after a plaster was fixed to the wound. These periods were consistent with studies that used a similar design (19,20). Although human neonates display decreased responses to an odour that is repeatedly presented at short intervals, which is habituation (21), enduring responses following a longer period of odour exposure have also been reported. In the above-cited study by Kawakami et al. (6), saliva samples collected from neonates 15 min after heelstick contained reduced cortisol levels when the painful procedure had been paired with an odour stimulus. Moreover, infants who were exposed to an odour for 30 min within the first hour after birth subsequently responded preferentially to that same scent in tests conducted 2–3 days later (22). A paper by Sobel et al. (23) discusses the separable neurophysiological processes implicated in short-term habituation and sustained responsiveness to odour stimuli. The toe lance was performed by an experienced nurse, on the top of the left big toe as the preferred method for capillary blood sampling on the Guthrie card. Only one

©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1130–1135

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attempt at capillary puncture was performed in all patients, and the toe was squeezed throughout the 60-sec recording period. After the plaster was applied, the infants were followed for 3 min and then given to their mothers. Only six babies cried more than 60 sec. This was routine practice in our unit at the time of the study and has been discontinued. The infants’ responses throughout the procedure were videotaped using a portable video camera with a built-in chronometer placed at the foot of the cot. The camera position was tested before each test trial to ensure a good image of facial expressions. For pain assessment, facial expressions, hand movements and duration of crying were measured as described below.  Total crying durations were recorded for each 60-sec interval.  The Neonatal Facial Coding System (9) that was used to record facial expressions includes ten movements: brow bulge, eye squeeze, nasolabial furrow, open lips, vertical mouth stretch, horizontal mouth stretch, lip purse, taut tongue, chin quiver and tongue protrusion. Each facial action was coded as 1 (occurred) or 0 (did not occur) during each of the three 60-sec periods (baseline, lance, recovery).  Hand movements were coded according to the procedures previously described by Warnock (24) and Als (18). Finger splay was defined as hyperextension of the fingers/widening of spaces between finger(s). Fisting referred to tight closing and flexing of the fingers to form a fist. Hand–mouth movement was, as defined by the Newborn Individualized Developmental Care and Assessment Program, an active movement of either hand to the mouth. The hand had to touch the mouth and was not coded if it was already on the mouth or if it only touched the face. Each action was coded as 1 or 0 during each period.  We also used the multidimensional Behavioral Indicators of Infant Pain (BIIP) scale that has been validated for preterm infants (11,19). There were no prior data regarding the BIIP in term infants so, therefore, this was a first attempt to assess the appropriateness of this scale for term neonates. This composite scale, which has a maximum score of nine, combines measures of sleep/ wake state (including crying), five facial actions included in the Neonatal Facial Coding System (NFCS) (brow

bulge, eye squeeze, naso-labial furrow, horizontal mouth stretch, taut tongue) and two hand movements (finger splay, fisting). Crying duration, infant’s state, facial expressions and hand movements were analysed from coded tapes offline, using a video cassette recorder in frame-by-frame mode, as well as in real time, by two independent observers who were blind to the exposure conditions and child gender. For all measures, interobserver (21 parallel measurements, a random sample of 10% of the data) and intra-observer (20 repeated measurements) reliability was >95%. Cohen’s kappa coefficient (j value range = 0.91–0.97) for categorical measures (NFCS and hand movements) and Pearson correlation coefficient (r = 0.96) for crying duration were used to calculate these reliability indices. Statistical analysis As the data were not normally distributed, the nonparametric Mann–Whitney U-test was used to compare crying duration, NFCS, BIIP and hand movement scores. Spearman correlation coefficients were calculated between crying duration 9 BIIP, NFCS and hand movements. The level of significance for all analyses was p < 0.05 (Table 2). RESULTS Effects of odour exposure Vanilla exposure had no significant effect on any of the behavioural measures. During each of the three periods, no reliable differences were found between the vanilla and water conditions. Scores for infants in the vanilla and water groups were therefore combined for comparisons across the three study periods and the analysis of gender differences. Behavioural responses to toe lance Infants showed high levels of distress during the first minute of blood collection after toe lance. An analysis of the total sample indicated that infants cried more during toe-lance blood collection (median = 53 sec) than during baseline (median = 0 sec; p < 0.0001) and post-collection recovery (median = 24; p < 0.0001). In a similar manner, NFCS scores were significantly higher during lance (median = 10 points) than during baseline (0 points; p < 0.001) and recovery (median = 6 points, p < 0.001).

Table 2 The effect of odour exposure on crying duration, Neonatal Facial Coding System (NFCS), Behavioral Indicators of Infant Pain (BIIP) and hand movements in three study periods, data given as median (range) or % of occurrence Baseline

Crying duration NFCS BIIP Hand–mouth occurred Finger splaying occurred

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Lance

Recovery

Control (n = 30)

Vanilla (n = 39)

Control (n = 30)

Vanilla (n = 39)

Control (n = 30)

Vanilla (n = 39)

0 (0–15.4) – 0 (0–4) 47% –

0 (0–0) – 0 (0–3) 62% –

52.9 (5.7–60.0) 10 (6–10) 9 (6–9) 60% 70%

53.4 (0–60) 10 (1–10) 9 (1–9) 74% 56%

24.7 (0–60) 6 (0–10) 5 (0–9) 73% 17%

23.3 (0–60) 6 (0–10) 6 (0–9) 77% 33%

©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1130–1135

Romantsik et al.

Olfactory stimulation and pain

the boys were also significantly greater than those for the girls during the lance period (p < 0.02). No gender differences were observed during baseline or recovery.

Figure 1 Occurrence (% of newborns) of hand–mouth movement and finger splaying during the three study periods. *Finger splaying in the toe lance vs recovery periods: p < 0.0001 [v2 = 18.5; odds ratio (OR) 4.7]. **Finger splaying vs hand–mouth movement in the baseline and recovery period: p < .0001 [OR 8.5 (95% CI 3.8–20.1)]. Occurrence of finger splaying during baseline – 0.

BIIP scores (maximum = 9) increased significantly from the median level of zero at baseline to nine following the lance (p < 0.0001), then decreased to six (p < 0.001) during the recovery period. Crying duration correlated significantly with NFCS and BIIP scores during both the lance (r = 0.63 and 0.44, respectively; p < 0.0001) and recovery periods (r = 0.67 and 0.76, respectively; p < 0.0001). Hand–mouth movements were registered in 55% of the infants at baseline and remained frequent throughout lance (68%) and recovery (75%) (Fig. 1). Finger splay and fisting were observed more often during lance than during baseline (p < 0.0001) and recovery (p < 0.01). No occurrences of finger splay/fisting were recorded during baseline, whereas 62% of the infants displayed this behaviour after lance and the rate decreased to 26% during the recovery period. Crying duration correlated significantly with rates of finger splay/fisting during both the lance (r = 0.30; p < 0.01) and recovery periods (r = 0.45; p < 0.0001) (Table 2). Maternal age, delivery mode or analgesia during delivery did not significantly influence the results. Gender differences Boys reacted after lance with a significantly higher NFCS compared with girls (p < 0.02; Table 3). The BIIP scores of

DISCUSSION Most of the behavioural response measures were heightened immediately following the painful toe-lance procedure. When compared to the baseline period, crying duration, finger splaying/fisting, NFCS and BIIP scores were significantly greater during the lance. Although they all declined significantly during the recovery period, they still remained elevated relative to baseline values. Thus, the maximum responses occurred during the blood collection interval, when perceived pain was presumably most intense, then diminished rapidly as the pain lessened. The only behavioural category that remained constant during the three periods was hand-to-mouth movement. Overall, these results support previous studies that assessed similar overt responses to painful stimuli by preterm and full-term neonates (9,19). The significant correlations between crying duration multiplied by the NFCS, BIIP and finger-splaying/fisting scores in both the lance and recovery periods further indicate that the typical behavioural profile associated with pain includes a combination of facial expressions, hand movements and vocal activity. Nevertheless, the crying and finger-splay/fisting data presented above, also reported in a related study (24), are of particular interest as these clear behavioural responses are readily observable and thus may be useful for cursory screening of pain/distress in full-term newborns. Finger splaying also appears to be a reliable indicant of pain in preterm infants (18); however, crying may have less clinical significance in this population. Our BIIP data for full-term infants also differ from results reported for preterm newborns (11), who experienced a less intensive response to pain (BIIP 5.1) than in the healthy term infants in our study (BIIP 8.6), shortly after lance and during recovery (BIIP 1.6 versus 5.4, respectively). This may be because our healthy full-term infants continued to show agitation and high hand–mouth movements because the pain did not entirely disappear shortly after squeezing was finished, while preterm infants

Table 3 The effect of gender on crying duration, Neonatal Facial Coding System (NFCS), Behavioral Indicators of Infant Pain (BIIP) and hand movements in three study periods, data given as median (range) or % of occurrence Baseline

Crying duration NFCS BIIP Hand–mouth occurred Finger splaying occurred

Lance

Recovery

Boys (n = 35)

Girls (n = 34)

Boys (n = 35)

Girls (n = 34)

Boys (n = 35)

Girls (n = 34)

0 (0–15.4) – 0 (0–4) 57% –

0 (0–5.7) – 0 (0–3) 53% –

54.0 (21.3–60.0) 10 (6–10)* 9 (7–9)* 63% 69%

52.3 (0–59.7) 10 (1–10)* 8 (1–9)* 74% 56%

24.4 (0–60) 6 (0–10) 6 (0–9) 71% 29%

23.9 (0–60) 6 (0–10) 6 (0–9) 79% 24%

*p < .05, difference between boys and girls, Mann–Whitney U-test.

©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1130–1135

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Acta Pædiatrica ISSN 0803-5253

REGULAR ARTICLE

The effects of olfactory stimulation and gender differences on pain responses in full-term infants Olga Romantsik ([email protected])1, Richard H. Porter2,*, Heili Varendi1 1.Department of Pediatrics, University of Tartu, Tartu, Estonia 2.Centre National de la Recherche Scientifique, Nuozilly, France

Keywords Gender differences, Newborns, Olfaction, Pain

ABSTRACT Aim: Studies have reported conflicting findings on whether different smells can reduce

Correspondence Olga Romantsik, Department of Pediatrics, University of Tartu, Lunini 6, 51014 Tartu, Estonia. Tel: +372 7 319610 | Fax: +372 7 319608 | Email: [email protected]

distress when infants undergo painful procedures. Our study assessed the impact of vanilla on infants’ responses to a painful toe lance, including possible gender differences. Methods: We measured the pain responses of 69 full-term infants – 34 girls and 35 boys – during toe lance, using two multidimensional scales – the Neonatal Facial Coding System and Behavioural Indicators of Infant Pain – together with crying duration and hand movements. Three sets of data were collected during baseline, toe lance and recovery, while the babies were exposed to the odour of vanilla (n = 39) or odourless water (n = 30). Results: Pain responses increased significantly during toe lance, then declined during recovery. Crying duration correlated significantly with finger splaying/fisting and both pain scale scores, with boys displaying higher pain scores than girls. Vanilla had no impact on pain levels. Conclusion: Crying and finger splaying/fisting were observable responses that may be useful for screening pain or distress in healthy neonates. Increased pain reactions by boys may reflect higher irritability. Exposure to an unfamiliar odour did not have a calming effect on full-term neonates.

Received 15 April 2013; revised 16 June 2014; accepted 21 July 2014. DOI:10.1111/apa.12759 *Retired.

INTRODUCTION Overt responses to olfactory cues have been documented in full-term newborns, as well as preterm infants whose gestational age was >28–29 weeks (1,2). Goubet et al. (3) observed that familiar vanilla odour reduced crying by premature infants during venipuncture. When subjected to a more painful heelstick, preterm neonates displayed heightened indices of distress that were not affected by odour exposure. In subsequent experiments, the familiar odour of mother’s milk or vanilla had a calming effect on full-term infants undergoing a heelstick procedure (4) and the odour of the infant’s mother’s milk was more effective than the scent of milk from another lactating woman (5). In a further study, the behavioural responses of full-term infants to heelsticks were not significantly affected by the unfamiliar odour of lavender, but cortisol levels were lower in the group exposed to the odour (6). Various authors have noted differences in the behaviour of boys and girls during the early postpartum period. Girls scored higher than boys on several items of the Brazelton

Abbreviations BIIP, Behavioural Indicators of Infant Pain; NFCS, Neonatal Facial Coding System.

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Neonatal Behavioral Assessment Scale, including Alertness, Auditory Orientation and State Regulation, and boys had higher Irritability scores (7). Further published accounts of newborn infants’ reactions to painful stimulation have provided no consistent pattern of gender effects. Guinsburg et al. (8) reported that newborn girls displayed greater facial indices of pain than boys, but another study showed that boys showed facial reactions more quickly than girls following capillary puncture (9). However, gender differences in the pain responses of preterm neonates are usually not observed (10,11). Relevant data are limited on the impact of odour, but suggest that newborn boys and girls

Key notes 





Studies have reported conflicting findings on whether odours can reduce infants’ distress during painful procedures, and this study assessed the effect of olfactory stimulation on newborns undergoing a toe lance. We found that an unfamiliar vanilla odour did not alleviate pain responses in neonates and that boys exhibited greater expressions of pain than girls. Crying and finger splaying were observable responses to pain and are useful for screening neonatal distress.

©2014 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2014 103, pp. 1130–1135

Romantsik et al.

12. Varendi H, Porter RH, Winberg J. Natural odor preferences of newborn infants change over time. Acta Paediatr 1997; 86: 985–90. 13. Balogh RD, Porter RH. Olfactory preferences resulting from mere exposure in human neonates. Infant Behav Dev 1986; 9: 395–401. 14. Bartocci M, Winberg J, Ruggiero C, Bergqvist LL, Serra G, Lagercrantz H. Activation of olfactory cortex in newborn infants after odor stimulation: a functional near-infrared spectroscopy study. Pediatr Res 2000; 48: 18–23. 15. Marlier L, Gaugler C, Messer J. Olfactory stimulation prevents apnea in premature newborns. Pediatrics 2005; 115: 83–8. 16. Goubet N, Strasbaugh K, Chesney J. Familiarity breeds content? Soothing effect of a familiar odor on full-term newborns. J Dev Behav Pediatr 2007; 28: 189–94. 17. Soussignan R, Schaal B, Marlier L, Jiang T. Facial and autonomic responses to biological and artificial olfactory stimuli in human neonates: re-examining early hedonic discrimination of odors. Physiol Behav 1997; 62: 745–58. 18. Als H. Manual for the naturalistic observation of newborn behavior (preterm and full term infants). Boston: The Children’s Hospital, 1984. 19. Holsti L, Grunau RE. Initial validation of the Behavioural Indicators of Infant Pain (BIIP). Pain 2007; 132: 264–72. 20. Bucher HU, Baumgartner R, Bucher N, Seiler M, Fauchere JC. Artificial sweetener reduces nociceptive reaction in term newborn infants. Early Hum Dev 2000; 59: 51–60.

Olfactory stimulation and pain

21. Engen T, Lipsitt LP. Decrement and recovery of responses to olfactory stimuli in the human neonates. J Comp Physiol Psychol 1965; 59: 312–6. 22. Romantsik O, Porter R, Tillmann V, Varendi H. Preliminary evidence of a sensitive period for olfactory learning by human newborns. Acta Paediatr 2007; 96: 372–6. 23. Sobel N, Prabhakaran V, Zhao Z, Desmond JE, Glover GH, Sullivan EV, et al. Time course of odorant-induced activation in the human primary olfactory cortex. J Neurophysiol 2000; 83: 537–51. 24. Warnock F, Sandrin D. Comprehensive description of newborn distress behavior in response to acute pain (newborn male circumcision). Pain 2004; 107: 242–55. 25. Butterworth G, Hopkins B. Hand-mouth coordination in the new-born baby. Br J Dev Psychol 1988; 6: 303–14. 26. Bellieni CV, Tei M, Coccina F, Buonocore G. Sensorial saturation for infants’ pain. J Matern Fetal Neonatal Med 2012; 25(Suppl 1): 79–81. 27. Kudielka BM, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol 2005; 69: 113–32. 28. Bartocci M, Bergqvist LL, Lagercrantz H, Anand KJS. Pain activates cortical areas in the preterm newborn brain. Pain 2006; 122: 109–17. 29. Bellieni CV, Aloisi AM, Ceccarelli D, Valenti M, Arrighi D, Muraca MC, et al. Intramuscular injections in newborns: analgesic treatment and sex-linked response. J Matern Fetal Neonatal Med 2013; 26: 419–22.

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The effects of olfactory stimulation and gender differences on pain responses in full-term infants.

Studies have reported conflicting findings on whether different smells can reduce distress when infants undergo painful procedures. Our study assessed...
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