Colleen Fitzgerald

Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU

Data from animal models indicate that neonatal stress or pain can permanently alter subsequent behavioral and/or physiological reactivity to stressors. However, cumulative effects of pain related to acute procedures in the neonatal intensive care unit (NICU) on later stress and/or pain reactivity has received limited attention. The objective of this study is to examine relationships between prior neonatal pain exposure (number of skin breaking procedures), and subsequent stress and pain reactivity in preterm infants in the NICU. Eighty‐seven preterm infants were studied at 32 (±1 weeks) postconceptional age (PCA). Infants who received analgesia or sedation in the 72 h prior to each study, or any postnatal dexamethasone, were excluded. Outcomes were infant responses to two different stressors studied on separate days in a repeated measures randomized crossover design: (1) plasma cortisol to stress of a fixed series of nursing procedures; (2) behavioral (Neonatal Facial Coding System; NFCS) and cardiac reactivity to pain of blood collection. Among infants born ≤28 weeks gestational age (GA), but not 29–32 weeks GA, higher cumulative neonatal procedural pain exposure was related to lower cortisol response to stress and to lower facial (but not autonomic) reactivity to pain, at 32 weeks PCA, independent of early illness severity and morphine exposure since birth. Repeated neonatal procedural pain exposure among neurodevelopmentally immature preterm infants was associated with down‐regulation of the hypothalamic–pituitary–adrenal axis, which was not counteracted with morphine. Differential effects of early pain on development of behavioral, physiologic and hormonal systems warrant further investigation.

Pain reactivity in 2-month-old infants after prenatal and postnatal serotonin reuptake inhibitor medication exposure.

Objective. In this prospective study, we examined biobehavioral responses to acute procedural pain at 2 months of age in infants with prenatal and postnatal selective serotonin reuptake inhibitor (SSRI) medication exposure. Based on previous findings showing reduced pain responses in newborns after prenatal exposure, we hypothesized that altered pain reactivity would also be found at 2 months of age. Methods. Facial action (Neonatal Facial Coding System) and cardiac autonomic reactivity derived from the respiratory activity and heart rate variability (HRV) responses to a painful event (heel-lance) were compared between 3 groups of infants: (1) infants with prenatal SSRI exposure alone (n = 11; fluoxetine, n = 2; paroxetine, n = 9); (2) infants with prenatal and postnatal SSRI (via breast milk) exposure (total n = 30; fluoxetine, n = 6; paroxetine, n = 20; sertraline, n = 4); and (3) control infants (n = 22; nonexposed) during baseline, lance, and recovery periods. Measures of maternal mood and drug levels were also obtained, and Bayley Scales of Infant Development-II were administered at ages 2 and 8 months. Results. Facial action increased in all groups immediately after the lance but was significantly lower in the pSE group during the lance period. HR among infants in the pSE and ppSE groups was significantly lower during recovery. Using measures of HRV and the transfer relationship between heart rate and respiration, exposed infants had a greater return of parasympathetic cardiac modulation in the recovery period, whereas a sustained sympathetic response continued in control infants. Although postnatal exposure via breast milk was extremely low when infant drug levels could be detected in ppSE infants, changes in HR and HRV from lance to recovery were greater compared among infants with levels too low to be quantified. Neither maternal mood nor the presence of clonazepam influenced pain responses. Conclusions. Blunted facial-action responses were observed among infants with prenatal SSRI exposure alone, whereas both prenatal and postnatal exposure was associated with reduced parasympathetic withdrawal and increased parasympathetic cardiac modulation during recovery after an acute noxious event. These findings are consistent with patterns of pain reactivity observed in the newborn period in the same cohort. Given that postnatal exposure via breast milk was extremely low and altered biobehavioral pain reactivity was not associated with levels of maternal reports of depression, these data suggest possible sustained neurobehavioral outcomes beyond the newborn period. This is the first study of pain reactivity in infants with prenatal and postnatal SSRI exposure, and our findings were limited by the lack of a depressed nonmedicated control group, small sample size, and understanding of infant behaviors associated with pain reactivity that could have also have been influenced by prenatal SSRI exposure. The developmental and clinical implications of our findings remain unclear, and the mechanisms that may have altered 5-hydroxytryptamine-mediated pain modulation in infants after SSRI exposure remain to be studied. Treating maternal depression with antidepressants during and after pregnancy and promoting breastfeeding in this setting should remain a key goal for all clinicians. Additional study is needed to understand the long-term effects of prenatal and early postnatal SSRI exposure.

Prolonged prenatal psychotropic medication exposure alters neonatal acute pain response

Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are frequently used to treat maternal depression during pregnancy, however the effect of increased serotonin (5HT) and γ-amino-butyric acid (GABA) agonists in the fetal human brain remains unknown. 5HT and GABA are active during fetal neurologic growth and play early roles in pain modulation, therefore, if prolonged prenatal exposure alters neurodevelopment this may become evident in altered neonatal pain responses. To examine biologic and behavioral effects of prenatal exposure, neonatal responses to acute pain (phenylketonuria heel lance) in infants with prolonged prenatal exposure were examined. Facial action (Neonatal Facial Coding System) and cardiac autonomic reactivity derived from the relationship between respiratory activity and short term variations of heart rate (HRV) were compared between 22 infants with SSRI exposure (SE) [fluoxetine (n = 7), paroxetine (n = 11), sertraline (n = 4)]; 16 infants exposed to SSRIs and clonazepam (SE+) [paroxetine (n = 14), fluoxetine (n = 2)]; and 23 nonexposed infants during baseline, lance, and recovery periods of a heel lance. Length of maternal SSRI use did not vary significantly between exposure groups—[mean (range)] SE:SE+ 183 (31–281):141 (54–282) d (p > 0.05). Infants exposed to SE and SE+ displayed significantly less facial activity to heel lance than control infants. Mean HR increased with lance, but was significantly lower in SE infants during recovery. Using measures of HRV and the transfer relationship between heart rate and respiration, SSRI infants had a greater return of parasympathetic cardiac modulation in the recovery period, whereas a sustained sympathetic response continued in the control group. Prolonged prenatal SSRI exposure appears to be associated with reduced behavioral pain responses and increased parasympathetic cardiac modulation in recovery following an acute neonatal noxious event. Possible 5HT-mediated pain inhibition, pharmacologic factors and the developmental course remain to be studied.

Pain reactivity in former extremely low birth weight infants at corrected age 8 months compared with term born controls

Abstract The aim was to examine whether early and prolonged exposure to pain in preterm infants has long lasting biobehavioral consequences at 8 months corrected age. Facial and cardiac autonomic responses to blood collection in former extremely low birth weight (ELBW; ≤800g) infants were compared with term born infants. Overall, the pattern of behavioral and cardiac responses to the lance were similar between the groups, however the ELBW infants displayed significantly higher basal heart rate, qualitative differences in heart rate variability during finger lance and recovery, and faster behavioral and physiological recovery. Furthermore, among the ELBW infants, higher number of previous invasive procedures experienced since birth was associated with dampened facial and heart rate reactions to finger lance. Higher resting heart rate among the ELBW infants suggests a possible “resetting” of autonomic regulation.