Published online February 1, 2005
PEDIATRICS Vol. 115 No. 2 February 2005, pp. 411-425 (doi:10.1542/peds.2004-0420)
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Pain Reactivity in 2-Month-Old Infants After Prenatal and Postnatal Selective Serotonin Reuptake Inhibitor Medication Exposure

Tim F. Oberlander, MD*, Ruth Eckstein Grunau, PhD*, Colleen Fitzgerald, RN*, Michael Papsdorf, PhD{ddagger}, Dan Rurak, PhD§ and Wayne Riggs, PhD||

* Department of Pediatrics, Biobehavioral Research Unit, Centre for Community Child Health Research
§ Fetal Maternal Medicine, Research Institute for Children's and Women's Health, Vancouver, BC, Canada
{ddagger} Department of Psychology
|| Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada

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.

Key Words: infant pain • prenatal SSRI exposure • prenatal drug effects

Abbreviations: SSRI, selective serotonin reuptake inhibitor • 5HT, 5-hydroxytryptamine (serotonin) • CL, clonazepam • NFCS, Neonatal Facial Coding System • HR, heart rate • HRV, heart rate variability • TFA, transfer-function analysis • RP, respiratory power • HFP, high-frequency power • LFP, low-frequency power • pSE, prenatal selective serotonin reuptake inhibitor–exposed infants • ppSE, prenatal and postnatal selective serotonin reuptake inhibitor–exposed infants • HAMD, Hamilton Depression • bpm, beats per minute

Accepted Jul 9, 2004.




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