Pain Reactivity in 2-Month-Old Infants After Prenatal and Postnatal Selective Serotonin Reuptake Inhibitor Medication Exposure
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《小儿科》
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
Department of Psychology Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
ABSTRACT
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
Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat antenatal and postpartum depression. Given the importance of treating depression and promoting breastfeeding in this setting, transplacental1 and breast milk2 transfer of these medications have raised concerns about the effects of such exposure on the developing brain during and after pregnancy. To date these medications have been considered safe and long-term adverse neurobehavioral effects have not been widely documented.3 Previously, we reported altered behavioral and physiologic responses to a routine painful event in newborns after prenatal exposure to SSRI medications.4 These findings raised questions about whether these outcomes were a transient pharmacologic effect reflecting transplacental exposure or extended long-term alterations in brain function. To broaden these findings, we studied pain reactivity in the same cohort at 2 months of age during a heel-lance.
To date, little is known about the long-term neurobehavioral outcomes after in utero exposure to SSRIs,5–7 or the effects of continued postnatal exposure via breast milk.8,9 Transplacental and breast milk transfer of SSRIs have been widely reported1,10; however, infant serum SSRI drug levels at birth and during the first year of life are low or below levels of quantitation.1,2,11 Prenatal SSRI exposure has been associated with congenital malformations12,13 in some reports, and others report little or no increased risk.12–15 Neonatal transient irritability, increased motor activity, disrupted sleep regulation,16 and elevated drug levels in prenatally exposed newborns17–20 have been reported. Late-gestation exposure to fluoxetine and paroxetine20–24 has been associated with poor neonatal adaptation, lower birth weights, and higher rates of preterm birth and admission to special-care nurseries.20 In a recent study of biobehavioral outcomes, Zeskind and Stephens25 reported an increase in tremulousness and altered behavioral state organization in newborns with SSRI exposure.25 Although these might be transient pharmacologic mediated outcomes, they may also reflect altered state and autonomic regulatory capacities associated with prenatal exposure.
Beyond the newborn period little is known about the long-term neurobehavioral outcomes after in utero SSRI exposure.5–7 Links between prenatal SSRI exposure and cognitive and language development have not been shown.26,27 A single study has shown subtle decreases in fine motor development after third-trimester SSRI exposure, whereas other investigations have not linked prenatal exposure with cognitive and neurobehavioral outcomes27 during childhood. SSRI levels in breast milk are typically low,2,11,28 and with the exception of case reports,18,29–31 altered neurobehavioral sequelae, or the neurobehavioral effects of continued postnatal exposure via breast milk,8,9,32 have not been reported.
SSRI medications act by inhibiting the reuptake of serotonin (5-hydroxytrypamine [5HT]) at the presynaptic junction, which leads to increased concentrations of this neurotransmitter in the synaptic cleft.33 5HT plays diverse roles in the developing and mature organism. It regulates cardiovascular function and acts as a key inhibitory neurochemical, regulating pain signals in the fetal and infant brain.34–36 5HT modulates nociception extending from cutaneous surfaces through the dorsal horn of the spinal cord to the thalamus and higher limbic cortical structures responsible for conscious appreciation of pain.37 Before assuming its role as a neurotransmitter, 5HT appears early in embryogenesis as a developmental signal involved in regulating the morphogenesis of monoamine (ie, 5HT, norepinephrine, and dopamine) systems.38–44 Given that SSRIs readily cross the placenta, it is conceivable that prenatal exposure alters central 5HT levels and influences development in monoaminergic-rich regions of the brain at crucial periods of neural ontogeny, which in turn leads to sustained changes that manifest themselves as altered 5HT-mediated behaviors (ie, pain reactivity) beyond the newborn period. We hypothesized that prenatal exposure to SSRIs at developmentally sensitive periods would be associated with a blunted infant pain response beyond the newborn period. To examine this question we compared biobehavioral pain responses at 2 months of age after a heel-lance blood collection in infants with prenatal SSRI exposure alone, responses from infants with continued exposure via breast milk, and responses of nonexposed control infants from our original cohort. To assist in determining the role of concurrent drug exposure, maternal, infant, and breast milk medication levels were also measured.
METHODS
Subjects
With approval from the University of British Columbia Research Ethics Board, the Children's and Women's Health Centre of British Columbia Research Review Committee, and informed parental consent, a consecutive cohort of mothers and their infants were recruited during pregnancy as a part of a prospective longitudinal study of prenatal psychotropic medication use. Mothers and their infants in the control group were eligible if no psychotropic or antidepressant medication use occurred during the pregnancy, the pregnancy was term in length (37–42 weeks), and there was no history of maternal mental illness. The original criteria for inclusion in the newborn pain study was a birth weight 2500 g and/or 37 weeks' gestational age at birth, absence of other prenatal psychotropic drug exposure (opioids, antipsychotic medications, cocaine, etc), congenital heart defects, and/or central nervous system lesions. Based on earlier outcomes at birth and again here at 2 months of age, no significant differences in behavior between those with and without clonazepam (CL) exposure were found; therefore, CL exposure was included in the analysis as a covariate.
Infants were studied while undergoing blood collection by heel-lance for a concurrent study of immune function at 2 months of age. Each infant was seated on his or her mother's lap during the procedure in an awake, alert, noncry state.45 Three groups of infants were studied (Table 1): (1) infants with prenatal SSRI exposure alone (n = 11; paroxetine [n = 9]; fluoxetine [n = 2]); (2) infants with postnatal exposure via breastfeeding (n = 30; paroxetine [n = 20]; fluoxetine [n = 6]; and sertraline [n = 4]); and (3) healthy controls (n = 22). At the 2-month study, maternal mood was assessed by using the Hamilton Rating Scale for Depression46 by a psychiatrist from the Reproductive Mental Health Clinic at the Children's and Women's Health Centre of British Columbia.
Of the original 72 infant-mother pairs studied on day 2 of life, 64 were eligible for inclusion at 2 months of age. An additional 8 infants were included at 2 months who had not been available for study at birth (early discharge, maternal refusal: 7 infants in the medication-exposed group and 1 in the control group). However, by 2 months of age, 4 had dropped out of the study (2 medication-exposed and 2 control infants), leaving 68 available for study at 2 months of age.
Behavioral Data Acquisition
The infant's face was video recorded during baseline, lance, and recovery periods of the blood collection, and detailed facial activity was assessed by using the Neonatal Facial Coding System (NFCS).47,48 NFCS-trained coders, masked to the subject group and all information about the infants, coded the presence or absence of a discrete set of precisely defined facial actions (brow bulge, eye squeeze, nasolabial furrow, open mouth, vertical mouth stretch, horizontal mouth stretch, taut tongue). These 7 facial actions were coded because they have been associated with reactivity to nociceptive procedures in infants up to 18 months of age.49–52
Facial action during the last 20 seconds of baseline, the first 20 seconds from the lance, and the first 20 seconds of the recovery were coded in random order. Coders conducted video coding of the NFCS after reaching interrater reliability during training of >0.85, using the conservative reliability formula following Grunau and Craig.47
Physiologic Signal Acquisition
Analyses of short-term variations in heart rate (HR) were used to examine the cardiac autonomic responses to the acute noxious event as previously described.53 In this study, variations in HR that occur with respiration (ie, 0.15–1.0 Hz, respiratory sinus arrhythmia) were used to quantify measures of parasympathetic cardiac modulation.54–56 Previously, mean HR and heart rate variability (HRV) that occurs with respiration have been used to study development and behavior of healthy and "at-risk" infants57,58 and pain reactivity in infants.59 Lower vagal tone in neonates at birth is associated with greater central nervous system dysfunction, emotional reactivity,60–62 and poorer developmental outcomes54,63 and may be an indicator of overall health status.64 To account for the empirical limitations of spectral analysis of HRV, additional measures of cardiac autonomic reactivity were derived from the relationship between short-term changes in HR and respiratory activity using transfer-function analysis (TFA).65–67 This technique has been used to examine sympathetic modulation of HR during quiet sleep in healthy preterm infants67 and the autonomic effects of noxious events and anesthesia in term and former preterm infants.65,66,68 The HR and respiratory signals were collected, sampled, and normalized as described previously.65,66,69
Epochs of HR and respiratory activity were selected from the resting baseline period within 5 minutes before the lance, a lance period starting within 20 seconds after the lance, and a recovery period within 30 seconds after the end of handling by the blood-collection technician.65,66 Epoch selection criteria were based on quantitative assessment of signal stability and the absence of gross movement artifact as previously described.53 Similar measures of respiratory activity were tabulated from the respiratory power (RP) spectrum to yield total RP. TFA of the effects of respiratory activity on HR was used to assess the sympathetic and parasympathetic components of HR modulation.70
TFA of the effects of respiratory activity on HR was used to assess sympathetic and parasympathetic components to HR modulation. Autospectra of the HR and respiratory signals and the cross spectrum between them were estimated for each 128-second (512 points) segment as previously described.70 Quantitative measures of parasympathetic and sympathetic cardiac control were derived from the average coherence weighted transfer gains of the 2.2-minute segments of data.66,71 Previous work with this technique during pharmacologic treatment of adults, with atropine while upright or propranolol while supine, demonstrated transfer gain and phase plots characteristic of pure parasympathetic and pure sympathetic modulation of HR,53 respectively. A pure sympathetic HR response (during standing with atropine) was characterized by a reduced gain at frequencies >0.01 Hz and a phase delay. In contrast, under pure vagal conditions (supine plus propranolol), the HR response was characterized by higher gain at all frequencies and no phase delay. This technique has been used previously to study pain reactivity and responses to anesthetics in infants.65,66,71
Pharmocologic Data
During the pregnancy, maternal levels were typically drawn before their morning dose, thereby representing a trough level. During the remainder of the study, maternal (5 mL) and infant (1 mL) blood and breast milk (10 mL) samples were collected during the study sessions for infant assessments and were not referenced to the time of maternal drug dosing. All blood samples were collected in Vacutainer tubes without additives and allowed to clot for 30 minutes. The serum was then separated after centrifugation at 3000g for 10 minutes and transferred into a glass tube. Milk samples were collected (foremilk) by manual expression or breast pump at the same time as blood sampling and transferred to glass tubes. All serum and milk samples were stored at –20°C until analysis. Fluoxetine and norfluoxetine isomer concentrations were measured using stereoselective gas chromatography-mass spectrometry electron-impact ionization.72 A similar gas chromatography-mass spectrometry assay using either electron-impact or negative-ion chemical ionization with selective ion monitoring was used for paroxetine.73 Sertraline and its metabolite desmethylsertraline (norsertraline) were measured by using liquid chromatography-mass spectrometry.
Statistical Analysis
A group (SSRI versus control) by phase (baseline, lance, recovery) repeated-measure analysis of variance was used to compare outcome measures across study periods. Post hoc comparisons were conducted where appropriate, and a difference was considered statistically significant for P < .05. To examine differencesbetween the groups across phases of blood collection, factorial analyses of variance were conducted; analyses of covariance were used when it was deemed important to control for the influence of maternal mood and concurrent CL use.
Behavioral Data
To examine the pattern of facial response across phase, occurrence of each of the 7 NFCS facial actions were summed within each of 10 segments of 2-second duration to yield 10 facial scores, each with a possible range of 0 to 7, for each event. When the infant's face was out of view, missing data for that event were replaced with the mean value of their respective exposure group.
Physiologic Reactivity and Recovery Regulation
The mean and SEM of the HR, respiratory activity, and power spectra for each data segment were calculated. For the purposes of display, group average transfer function estimates of both gain and phase from each experimental epoch were computed as previously described.53 Simple change scores were used to study whether cardiovascular response from the lance to recovery was associated with pharmacologic or behavioral variables. Simple change scores for each of HR, high-frequency power (HFP), and low-frequency power (LFP), respectively (ie, HRlance–recovery), were derived from the difference between cardiac autonomic measures obtained at the lance period and the recovery period and used in regression analyses.
Pharmacologic Data
Mean plasma drug levels were tabulated from maternal and infant levels at the time of the 2-month study. Expressed breast milk levels were used to tabulate infant drug dose (Cmilk x Vmilk) where Cmilk is the milk concentration of medication (ng/mL) and Vmilk is the volume of milk (mL) ingested per day based on 150 mL/kg per day. Drug ratios were also tabulated to compare infant drug exposure to milk and maternal levels.
RESULTS
Characteristics of infants and their mothers did not differ significantly between groups (Table 1). At the time of the study, all infants were in good health and in all groups mean maternal mood was rated as nonclinically depressed (ie, symptoms reported <16), although mean Hamilton Depression (HAMD) scores were significantly lower in control subjects than in the 2 exposure groups (P < .05). Prenatal SSRI medication exposure occurred in the last 2 trimesters, and the length of maternal SSRI use or medication dose did not vary significantly between the 2 exposure groups (P > .05). Similarly, length of SSRI use did not vary between exposure groups (P > .05). All mothers reported taking their prescribed medication in the 3 days before the study, and thus maternal medication levels, and presumably breast milk levels, were considered to be at a steady state at the time of the study. Given the extra blood collection needed for drug levels, the heel-lance blood collection took longer among the infants with postnatal drug exposure (means: 104.3 ± 18 vs 109.7 ± 25 vs 146 ± 48 seconds for control, prenatal selective serotonin reuptake inhibitor–exposed infants [pSE], and prenatal and postnatal selective serotonin reuptake inhibitor–exposed infants [ppSE] groups, respectively).
Behavioral Pain Response
The overall pattern of infant facial-activity responses showed a significant increase from baseline to lance and a decrease from lance to recovery in all groups (F = 170.5; df [2,112]; P < .01). Group differences in facial action emerged when 10 segments of 2-second duration for each study epoch were examined (Fig 1). During baseline, facial action remained low in all groups and no group differences were present (F = 1.5; df [9,513]; P > .05), but increased significantly from baseline to lance in all groups (F = 2.7; df [9,531]; P < .05). During the lance phase, facial action was significantly lower among the pSE group, compared with controls and infants with ppSE infants (P < .05). In recovery, facial action was lower among pSE infants, but differences among exposure groups were not significant (F = 1.6; df [2,58]); P > .20).
Physiologic Data
Mean HR
Mean HR increased significantly with lance and fell in recovery in all groups (F = 6.27; df [4,120]; P < .01). In the recovery period, mean HR was significantly lower among both exposure groups (F = 7.1; df [2,60]; P < .05); differences between exposure groups were not significant (P > .05; Fig 2).
Power Spectral Estimates
In all groups, LFP decreased significantly from baseline to lance and increased again in the recovery period (F = 5.8; df [2,120]; P < .01), but there were no significant differences between groups (P > .15; Fig 3). Mean HFP remained stable (F = 2.2; df [2,120]; P > .10) in response to the lance among the control and the pSE groups. In contrast, among the ppSE group, HFP decreased significantly from the baseline to the lance and increased during the recovery (F = 147; df [2,29]; P > .10). In all groups mean LFP/HFP ratios decreased with the lance (F = 3.9; df [2,120]; P < .05; Fig 3). Post hoc tests showed a significantly lower mean ratio among the ppSE group compared with controls (P < .05). Total RP increased significantly from the baseline to the lance and decreased in the recovery period in all groups (F = 8.2; df [2,120]; P < .01). Post hoc tests showed lower mean RP among both exposed groups of infants compared with controls in recovery (P < .05; Fig 4).
Transfer-Function Estimates of Respiratory Sinus Arrhythmia
Transfer gain and phase graphs are presented in Fig 5. Qualitatively, during baseline, transfer gain was high at all frequencies in exposed and control groups. Phase began at 0° at 0 Hz and decreased slightly with increasing frequencies, illustrating a predominance of vagal cardiac modulation in the baseline condition in all infants.
In response to the lance, transfer gain decreased across all frequencies and became very low in the HF range, suggesting increased sympathetic modulation in all groups. Transfer phase remained stable, suggesting that increased sympathetic cardiac modulation was accompanied by a minimal withdrawal of parasympathetic activity. No group differences were apparent.
In the recovery period, group differences emerged. Among both groups of exposed infants, mean transfer gain increased from the lance period across all frequencies, whereas phase remained at 0°, consistent with a return to baseline levels of parasympathetic and relative stability of sympathetic cardiac modulation. Transfer gain increased significantly (P < .05; Table 2) compared with controls, reflecting a return to greater levels of parasympathetic modulation. In contrast, among control infants, transfer gain did not increase substantially, and phase remained <0° with a negative slope across increasing frequencies. These data suggest sustained or increased sympathetic cardiac modulation associated with a minimal return of parasympathetic activity, particularly evident in the ppSE group.
In summary, based on the transfer-function results, both exposed and nonexposed infants responded to the heel-lance with increased sympathetic and reduced cardiac parasympathetic modulation. However, exposed infants showed a recovery pattern characterized by an early return to baseline levels of parasympathetic modulation when compared with control infants for whom substantial sympathetic modulation continued. These results are consistent with the lower mean HR and facial action observed during recovery, particularly in the ppSE group.
Pharmacologic Variables and Pain Reactivity
Medication levels in infant serum and maternal breast milk in the ppSE group were substantially lower than maternal serum levels. Mean maternal and infant medication doses and levels for infants with postnatal exposure are shown in Table 3. Among breastfeeding infants, only 30% had detectable drug levels, and when these levels were present, infant medication levels were substantially lower than milk and maternal levels (Table 4).
To explore whether biobehavioral pain response was related to pharmacologic variables, measures of cardiac autonomic change from lance to recovery were tabulated to yield simple () change scores for HR, LFP, and HFP, respectively. Simple change scores were used because there were no significant group differences in these measures during the lance period.74 Greater change in mean HRlance–recovery (r = 0.322; P < .05) was associated with increased days of prenatal SSRI exposure. Maternal drug levels during the third trimester, maternal dose, and infant dose at 2 months were not associated with measures of cardiac reactivity or facial recovery (P > .10). When infant drug levels were detectable (ie, levels >0.01 ng/dL), mean HRlance–recovery and HFP HRlance–recovery were significantly greater among exposed infants compared with infants for whom the levels were below limits of quantitation (F = 5.4; df [2,47]; P < .01; and F = 4.62; df [2,47]; P < .05, HR and HFP, respectively) (Fig 6). Measures of facial reactivity did not differ between infants with or without detectable drug levels. When maternal symptoms of depression (HAMD) at 2 months or during pregnancy were added as covariates, group differences in HRlance–recovery scores remained significant (P < .05).
Previously, we observed that 15 infants (1 control, 6 prenatal only, 8 ppSE) in our original cohort had symptoms of poor neonatal adaptation.19 To examine whether such symptoms were related to pain reactivity we compared facial action and changes in cardiac autonomic reactivity scores at 2 months between infants with and without symptoms in the newborn period. Differences in pain reactivity between these groups were not significant (P > .05).
DISCUSSION
At 2 months of age, infants with prenatal and continued postnatal SSRI exposure exhibited attenuated biobehavioral pain responses after an acute noxious event. Reduced immediate facial-action response to the lance was observed among infants with prenatal exposure alone. Blunted cardiac autonomic responses were observed in the recovery period in infants with both prenatal and postnatal drug exposure. Compared with controls, cardiac autonomic responses in the recovery period were shorter and less intense, as reflected by a lower mean HR, a greater reduction in HR from lance to recovery, and increased parasympathetic cardiac modulation among exposed infants. The shorter cardiac autonomic response among exposed infants may reflect a possible increased capacity to modulate responses to a noxious event. It is important to note that differences in cardiac autonomic responses between infants with prenatal exposure alone and prenatal and postnatal exposure were nonsignificant. When postnatal exposure continued, infant drug levels were substantially lower than milk or maternal levels or even nondetectable. However, when drug levels could be detected, greater HR and HRV reactivity between lance and recovery periods were observed. In addition, increased HRV responses from lance to recovery were associated with increased length of prenatal SSRI exposure. These differences remained significant after controlling for prenatal and postnatal CL exposure or maternal symptoms of depression.
The mechanisms underlying group differences in facial responses between exposure groups remain a matter of speculation. Although reduced facial reactivity was only observed during the immediate lance period among the pSE group, this finding was not entirely unexpected given that the time course for a facial action is substantially briefer (ie, more proximal to the noxious event) than for cardiac autonomic responses.51 Differences in postlance handling time were observed between groups. However, among infants with longer handling time (ie, postnatal drug exposure required us to obtain drug levels), biobehavioral pain outcomes reflected greater parasympathetic modulation and lower HR during recovery (ie, increased modulation of response) rather than an increased or continued arousal that one would have expected with longer handling times. Moreover, our findings were observed in infants who were typically developing infants at 2 and 8 months as assessed by the Bayley Scales of Infant Development-II.
Previously, for the same cohort, we reported an attenuated biobehavioral pain reactivity in newborns with prenatal SSRI exposure, which was reflected by blunted facial-action responses and less parasympathetic withdrawal during the lance period and increased parasympathetic modulation during the recovery period.4 No differences in outcome were seen between the different SSRIs alone or when exposure included the benzodiazepine CL. Given the findings in this report, prenatal and combined postnatal SSRI medication exposure seems to alter biobehavioral infant pain responses at 2 months of age. To date, no previous work has assessed biobehavioral pain reactivity after prenatal and postnatal SSRI exposure; therefore, mechanisms that could account for our findings remain a matter of discussion.
Our findings raise the possibility that the blunted facial and cardiac autonomic reactivity to a noxious event may reflect alterations to pain-response systems after fetal and/or continued postnatal SSRI exposure at 2 months of age. In this sense, these findings may reflect an increased capacity to modulate responses to a painful event, consistent with changes to autonomic regulation recently reported by Zeskind.25 In the current study infant pain reactivity was used as probe of biobehavioral reactivity to a stressful event rather than nociception per se. Infant pain reactivity can be regarded as a final common pathway that reflects a variety of emerging neurologic capacities. There is considerable evidence that descending 5HT modulates central nociception,75 and antinociceptive effects have been demonstrated by 5HT antagonists such as SSRIs in preclinical models76 and humans.77 Therefore, our findings might reflect that even very minimal exposure to a 5HT agonist might have an acute antinociceptive effect.
Direct Pharmacologic Effects
The relationships between maternal and infant drug levels raise the possibility that our findings reflect a direct pharmacologically mediated antinociceptive phenomenon related to ongoing SSRI exposure via breast milk. Potential effects may be linked to the SSRI-related inhibition of 5HT reuptake by presynaptic neurons and desensitization of presynaptic 5HT1a receptors that inhibit cell firing78 demonstrated in animal models. Although SSRIs differ in their potency and inhibition of 5HT reuptake,79,80 all SSRIs are thought to increase synaptic 5HT concentrations in the brain.80
SSRIs readily enter breast milk,1 and it is conceivable that prenatal exposure influences development and function of monoaminergic-rich regions of the brain. SSRIs used in this study are lipid soluble and readily excreted in breast milk11,30,81; therefore, infant exposure via this route at the time of 2-month testing was minimal, and thus such exposure would not be considered a substantial source of postnatal exposure.31 Mean maternal levels were well within the usual adult therapeutic range for paroxetine (20–200 ng/mL82) or fluoxetine (37–301 ng/mL83). Therapeutic range for all SSRIs for infants have not been established.84,85 Levels of SSRIs varied, presumably reflecting differences in metabolism; in vitro potency for 5HT reuptake differs between medications,79 raising the possibility that even at concentrations below the limit of quantitation of the current assay methods these medications could elicit effects.1
Postnatal effects via breast milk have been reported; however, with the exception of isolated cases,18 detailed descriptions of the neurobehavioral and developmental effects of postnatal SSRI exposure have not yet been found.9 Given that the effects of postnatal exposure on platelet 5HT transport blockade were limited,86 effects of postnatal exposure via breast milk seem to be minimal and as such are unlikely to explain altered pain responses in infants who continued to breastfeed. Pharmacologic variables could continue to have some influence, although it remains uncertain to what extent these current findings reflect an ongoing acute pharmacologic phenomenon or sustained alterations in monoaminergic function.
Long-Term Effects of Prenatal Exposure
Length of prenatal SSRI exposure in our study was related to cardiac autonomic reactivity measures, possibly reflecting sustained alterations to monoaminergic ontogeny in the developing infant brain. Animal and human studies have demonstrated that exposure to substances that increase the presence, enhance, or block the action of neurochemicals during crucial periods of fetal brain growth may alter brain structure and function, and subsequent behavior.39,87 Examining the influence of prenatal medication exposure in human infants offers opportunities to investigate how levels of neurochemicals (ie, central 5HT), altered by the pharmacologic action of specific medications, influence the neural ontogeny and subsequent development of particular behaviors (eg, regulation of pain response) mediated by those neurotransmitters. Because of the dual roles of 5HT as a pain inhibitory neurotransmitter and as a trophic developmental signal, prenatal increased levels may lead to altered receptor numbers and/or function or postreceptor mechanisms, thereby altering postnatal function.
Although SSRIs differ in their potency and inhibition of 5HT reuptake, all SSRIs are thought to increase synaptic 5HT concentrations in the brain.80 With increased levels of 5HT after SSRI exposure, cortical morphology in monoaminergic-rich regions of the brain may be effected. This, in turn, may lead to altered general monoaminergic ontogeny and function. Given the inhibitory role 5HT plays at multiple levels of the neuraxis in the pain system, the observed blunted pain reactivity may reflect an increased or altered capacity to modulate pain signals. Prenatal fluoxetine exposure in animal models results in neuroanatomic alterations to key somatosensory structures,88 monoamine receptors,89–91 5HT content, and receptor binding92 and of 5HT transporters,93 as well as altered behaviors.94 It is interesting to note that both understimulation of 5HT receptors (due to 5HT depletion) and overstimulation (by 5HT agonists) during prenatal development has a lasting postnatal impact on 5HT-receptor function.95 A study of the cardiovascular and behavioral effects of an intravenous infusion of fluoxetine in pregnant sheep showed decreased fetal low-voltage electrocortical activity and rapid eye movements and increased quiet sleep,96 similar to reports in adult humans.97 Increased responsiveness to anxiety testing and aggressive behavior98 have also been reported, whereas others have not found cognitive changes in other animal models.89,99 In an analogous setting, Butkevich et al100 studied the effects of prenatal exposure to the 5HT synthesis inhibitor, paracholophenylanline, in rats and noted that changes in 5HT levels were associated with a significant decrease in the intensity and duration of response to formalin-induced pain.101 These effects are thought to reflect changes in the hypothalamic-pituitary-adrenal axis, serotonergic pathways in the brain and spinal cord that lead to impaired function in the descending serotonergic system.
Evidence of long-term neurobehavioral effects after prenatal exposure in humans is limited. To date, no studies have reported effects on developmental delay in the first 2 years of life102 or cognitive or language development after prenatal SSRI exposure up to 71 months of age.27 In a single study, subtle decreases in fine motor development and control in children between 6 and 40 months of age were noted, whereas mental development was unaffected after the third trimester of SSRI exposure.103
Infant pain reactivity was used in this study as a biobehavioral probe to study the infant nervous system and should be regarded as the final common behavioral expression of multiple emerging neurobehavioral processes. The capacity to regulate responses to external stimuli is a key developmental task of infancy, and infant pain behavior may be directly and interactively (indirectly) affected by an emerging capacity to regulate levels of arousal (behavioral states) and emotion during infancy.104,105 Monoaminergic-rich regions of the brain (ie, striatum, locus coeruleus, and posterior parietal cortex) regulate attention, and exposure to SSRIs may only indirectly influence nociception via altered regulations of arousal. Moreover, independent of prenatal exposure to psychotropic medications, in utero exposure to maternal stress106 may alter neuroregulatory mechanisms that interfere with arousal, which subsequently manifest as altered pain reactivity. Pain and stress responses are interactively related to the development of systems governing the regulation of attention, emotion,107 and distress in infancy.108 Studies of early arousal regulation in preterm infants suggest that abnormal patterns of brain organization109 and behavioral state are closely related to pain reactivity. Infants in quiet sleep are less reactive to a noxious event than are infants in active sleep/alert states.47 Our findings also may reflect an altered hypothalamic-pituitary-adrenal axis stress response110,111 observed in animal models after postnatal SSRI exposure or an extension of the altered neurobehavioral indices of autonomic and arousal regulation recently observed by Zeskind et al25 in newborns with prenatal SSRI exposure. In this sense, changes in pain reactivity may reflect altered arousal regulation; however, additional studies of infant arousal regulation after prenatal SSRI exposure are required to better understand these relationships.
Limitations
The human models needed to understand the neurobehavioral effects of prenatal SSRI exposure are complex, and models that account for multiple neurologic, developmental, maternal genetic, and prenatal and postnatal environmental factors are far beyond the scope of a single study. In this study we were not able to distinguish the effects of SSRIs from complex and concurrent family mental health influences, and we only measured postnatal depression. Because we did not study a depressed but nonpharmacologically treated group of mothers, we were not able to assess the effects of prenatal maternal stress alone, which may have also affected fetal development. Substantial evidence links infant exposure to maternal depression and adverse behavioral and psychological developmental outcomes.
Our understanding of prenatal SSRI exposure cannot be easily separated from the concurrent influences of maternal mood during and after pregnancy. The impact of parental depression on child development has received considerable attention.112–114 Convergent evidence from animal and human studies suggest that chronic unpredictable physiologic stress during pregnancy may have long-lasting effects on biogenic amine neurotransmitter system function and behavior in offspring.115–117 Newborns of depressed mothers have increased difficulties with self-regulation,115,116 irritable neonatal behavior,117 and reduced alertness,118–120 which suggests links between prenatal maternal mood and altered autonomic regulation in offspring that continue during the first year.121–123 It is important that even in the presence of prenatal fluoxetine exposure it has been found that the duration of the maternal depression and number of depressive episodes lead to altered child developmental outcomes and not the exposure itself.124 Although mean levels of depressive symptoms in our study were not associated with pain reactivity, we were not able to examine whether altered infant pain behavior was independently influenced by sustained exposure to depressed maternal mood either before or after birth. Additional study of maternal mood, mother-infant interaction, and infant pain behaviors is required to assess this as a possible mechanism underlying our findings. In this current study pain responses did not vary when the presence of benzodiazepine was included as a covariate; however, because we did not have a benzodiazepine-alone exposure group, it is not possible on the basis of this study to determine the specific effects -amino-butyric acid agonists have on the developing pain system. Differences in caregiving related to breastfeeding or maternal response to their infant's distress at the time of the blood collection could have been another covariate. The long-term developmental significance of a reduced or blunted pain response or its relationship to other key aspects of arousal and emotional regulation also remain unclear. Pain reactivity is a function of multiple domains of behavior and development. It is interesting that at 2 months of age a biological-behavioral discordance seems to have emerged. In contrast to the outcomes at birth, facial-reactivity patterns appeared only slightly lower in the recovery period, suggesting that behavioral responses may have "normalized" with time. The discordance between behavioral and biological responses among infants with prenatal and continued postnatal exposure requires additional study. It is possible that altered pain reactivity in this setting is a reflection of altered arousal regulation, a 5HT-mediated process that alters facial expression in ways that might be different from cardiac autonomic responses. To address these questions, complex models that study interactions between multiple maternal, pharmacologic, environmental, and biological variables are required.
CONCLUSIONS
Infants with prenatal and postnatal SSRI exposure had diminished facial and cardiac autonomic responses to the pain of a heel-lance at 2 months of age. These findings are consistent with the blunted pain reactivity observed in the same cohort of infants studied in the newborn period. At this time it remains unclear whether these outcomes resulted from altered brain development due to prolonged in utero SSRI exposure or continued postnatal medication exposure or are indirectly related to changes in arousal-state regulation. The effects of exposure to depressed maternal mood cannot be excluded as a contributing factor. Regardless of the mechanisms that may underlie these findings or the long-term consequences, our findings should not prejudice the clinical urgency of treating maternal depression during and after pregnancy with or without medication. The known risks of untreated or undertreated maternal depression both to the mother and her offspring currently outweigh any known adverse effects of the SSRIs. Additionally, it should be emphasized that these findings should not reduce the importance of promoting breastfeeding even in the presence of SSRI use. Breastfeeding is universally regarded as optimal nutrition for infant growth and development and is considered safe during SSRI use.125 At this time, it remains important to recognize that we do not have a clear understanding of the mechanisms that explain our findings or their long-term implications for infant development. Larger cohorts of exposed infants are required to replicate these findings and to understand the effects of prenatal psychotropic medication exposure on infant development.
ACKNOWLEDGMENTS
We thank Victoria Nethercot, MSc, Ursula Brain, Mary Beckingham, and Phil Saul, MD, for editorial assistance and Sandy Pitfield, MSc, MD, for assistance in editing and analysis of the physiologic signals.
This work was funded by the British Columbia Medical Services Foundation.
FOOTNOTES
Accepted Jul 9, 2004.
No conflict of interest declared.
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Fetal Maternal Medicine, Research Institute for Children's and Women's Health, Vancouver, BC, Canada
Department of Psychology Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
ABSTRACT
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
Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat antenatal and postpartum depression. Given the importance of treating depression and promoting breastfeeding in this setting, transplacental1 and breast milk2 transfer of these medications have raised concerns about the effects of such exposure on the developing brain during and after pregnancy. To date these medications have been considered safe and long-term adverse neurobehavioral effects have not been widely documented.3 Previously, we reported altered behavioral and physiologic responses to a routine painful event in newborns after prenatal exposure to SSRI medications.4 These findings raised questions about whether these outcomes were a transient pharmacologic effect reflecting transplacental exposure or extended long-term alterations in brain function. To broaden these findings, we studied pain reactivity in the same cohort at 2 months of age during a heel-lance.
To date, little is known about the long-term neurobehavioral outcomes after in utero exposure to SSRIs,5–7 or the effects of continued postnatal exposure via breast milk.8,9 Transplacental and breast milk transfer of SSRIs have been widely reported1,10; however, infant serum SSRI drug levels at birth and during the first year of life are low or below levels of quantitation.1,2,11 Prenatal SSRI exposure has been associated with congenital malformations12,13 in some reports, and others report little or no increased risk.12–15 Neonatal transient irritability, increased motor activity, disrupted sleep regulation,16 and elevated drug levels in prenatally exposed newborns17–20 have been reported. Late-gestation exposure to fluoxetine and paroxetine20–24 has been associated with poor neonatal adaptation, lower birth weights, and higher rates of preterm birth and admission to special-care nurseries.20 In a recent study of biobehavioral outcomes, Zeskind and Stephens25 reported an increase in tremulousness and altered behavioral state organization in newborns with SSRI exposure.25 Although these might be transient pharmacologic mediated outcomes, they may also reflect altered state and autonomic regulatory capacities associated with prenatal exposure.
Beyond the newborn period little is known about the long-term neurobehavioral outcomes after in utero SSRI exposure.5–7 Links between prenatal SSRI exposure and cognitive and language development have not been shown.26,27 A single study has shown subtle decreases in fine motor development after third-trimester SSRI exposure, whereas other investigations have not linked prenatal exposure with cognitive and neurobehavioral outcomes27 during childhood. SSRI levels in breast milk are typically low,2,11,28 and with the exception of case reports,18,29–31 altered neurobehavioral sequelae, or the neurobehavioral effects of continued postnatal exposure via breast milk,8,9,32 have not been reported.
SSRI medications act by inhibiting the reuptake of serotonin (5-hydroxytrypamine [5HT]) at the presynaptic junction, which leads to increased concentrations of this neurotransmitter in the synaptic cleft.33 5HT plays diverse roles in the developing and mature organism. It regulates cardiovascular function and acts as a key inhibitory neurochemical, regulating pain signals in the fetal and infant brain.34–36 5HT modulates nociception extending from cutaneous surfaces through the dorsal horn of the spinal cord to the thalamus and higher limbic cortical structures responsible for conscious appreciation of pain.37 Before assuming its role as a neurotransmitter, 5HT appears early in embryogenesis as a developmental signal involved in regulating the morphogenesis of monoamine (ie, 5HT, norepinephrine, and dopamine) systems.38–44 Given that SSRIs readily cross the placenta, it is conceivable that prenatal exposure alters central 5HT levels and influences development in monoaminergic-rich regions of the brain at crucial periods of neural ontogeny, which in turn leads to sustained changes that manifest themselves as altered 5HT-mediated behaviors (ie, pain reactivity) beyond the newborn period. We hypothesized that prenatal exposure to SSRIs at developmentally sensitive periods would be associated with a blunted infant pain response beyond the newborn period. To examine this question we compared biobehavioral pain responses at 2 months of age after a heel-lance blood collection in infants with prenatal SSRI exposure alone, responses from infants with continued exposure via breast milk, and responses of nonexposed control infants from our original cohort. To assist in determining the role of concurrent drug exposure, maternal, infant, and breast milk medication levels were also measured.
METHODS
Subjects
With approval from the University of British Columbia Research Ethics Board, the Children's and Women's Health Centre of British Columbia Research Review Committee, and informed parental consent, a consecutive cohort of mothers and their infants were recruited during pregnancy as a part of a prospective longitudinal study of prenatal psychotropic medication use. Mothers and their infants in the control group were eligible if no psychotropic or antidepressant medication use occurred during the pregnancy, the pregnancy was term in length (37–42 weeks), and there was no history of maternal mental illness. The original criteria for inclusion in the newborn pain study was a birth weight 2500 g and/or 37 weeks' gestational age at birth, absence of other prenatal psychotropic drug exposure (opioids, antipsychotic medications, cocaine, etc), congenital heart defects, and/or central nervous system lesions. Based on earlier outcomes at birth and again here at 2 months of age, no significant differences in behavior between those with and without clonazepam (CL) exposure were found; therefore, CL exposure was included in the analysis as a covariate.
Infants were studied while undergoing blood collection by heel-lance for a concurrent study of immune function at 2 months of age. Each infant was seated on his or her mother's lap during the procedure in an awake, alert, noncry state.45 Three groups of infants were studied (Table 1): (1) infants with prenatal SSRI exposure alone (n = 11; paroxetine [n = 9]; fluoxetine [n = 2]); (2) infants with postnatal exposure via breastfeeding (n = 30; paroxetine [n = 20]; fluoxetine [n = 6]; and sertraline [n = 4]); and (3) healthy controls (n = 22). At the 2-month study, maternal mood was assessed by using the Hamilton Rating Scale for Depression46 by a psychiatrist from the Reproductive Mental Health Clinic at the Children's and Women's Health Centre of British Columbia.
Of the original 72 infant-mother pairs studied on day 2 of life, 64 were eligible for inclusion at 2 months of age. An additional 8 infants were included at 2 months who had not been available for study at birth (early discharge, maternal refusal: 7 infants in the medication-exposed group and 1 in the control group). However, by 2 months of age, 4 had dropped out of the study (2 medication-exposed and 2 control infants), leaving 68 available for study at 2 months of age.
Behavioral Data Acquisition
The infant's face was video recorded during baseline, lance, and recovery periods of the blood collection, and detailed facial activity was assessed by using the Neonatal Facial Coding System (NFCS).47,48 NFCS-trained coders, masked to the subject group and all information about the infants, coded the presence or absence of a discrete set of precisely defined facial actions (brow bulge, eye squeeze, nasolabial furrow, open mouth, vertical mouth stretch, horizontal mouth stretch, taut tongue). These 7 facial actions were coded because they have been associated with reactivity to nociceptive procedures in infants up to 18 months of age.49–52
Facial action during the last 20 seconds of baseline, the first 20 seconds from the lance, and the first 20 seconds of the recovery were coded in random order. Coders conducted video coding of the NFCS after reaching interrater reliability during training of >0.85, using the conservative reliability formula following Grunau and Craig.47
Physiologic Signal Acquisition
Analyses of short-term variations in heart rate (HR) were used to examine the cardiac autonomic responses to the acute noxious event as previously described.53 In this study, variations in HR that occur with respiration (ie, 0.15–1.0 Hz, respiratory sinus arrhythmia) were used to quantify measures of parasympathetic cardiac modulation.54–56 Previously, mean HR and heart rate variability (HRV) that occurs with respiration have been used to study development and behavior of healthy and "at-risk" infants57,58 and pain reactivity in infants.59 Lower vagal tone in neonates at birth is associated with greater central nervous system dysfunction, emotional reactivity,60–62 and poorer developmental outcomes54,63 and may be an indicator of overall health status.64 To account for the empirical limitations of spectral analysis of HRV, additional measures of cardiac autonomic reactivity were derived from the relationship between short-term changes in HR and respiratory activity using transfer-function analysis (TFA).65–67 This technique has been used to examine sympathetic modulation of HR during quiet sleep in healthy preterm infants67 and the autonomic effects of noxious events and anesthesia in term and former preterm infants.65,66,68 The HR and respiratory signals were collected, sampled, and normalized as described previously.65,66,69
Epochs of HR and respiratory activity were selected from the resting baseline period within 5 minutes before the lance, a lance period starting within 20 seconds after the lance, and a recovery period within 30 seconds after the end of handling by the blood-collection technician.65,66 Epoch selection criteria were based on quantitative assessment of signal stability and the absence of gross movement artifact as previously described.53 Similar measures of respiratory activity were tabulated from the respiratory power (RP) spectrum to yield total RP. TFA of the effects of respiratory activity on HR was used to assess the sympathetic and parasympathetic components of HR modulation.70
TFA of the effects of respiratory activity on HR was used to assess sympathetic and parasympathetic components to HR modulation. Autospectra of the HR and respiratory signals and the cross spectrum between them were estimated for each 128-second (512 points) segment as previously described.70 Quantitative measures of parasympathetic and sympathetic cardiac control were derived from the average coherence weighted transfer gains of the 2.2-minute segments of data.66,71 Previous work with this technique during pharmacologic treatment of adults, with atropine while upright or propranolol while supine, demonstrated transfer gain and phase plots characteristic of pure parasympathetic and pure sympathetic modulation of HR,53 respectively. A pure sympathetic HR response (during standing with atropine) was characterized by a reduced gain at frequencies >0.01 Hz and a phase delay. In contrast, under pure vagal conditions (supine plus propranolol), the HR response was characterized by higher gain at all frequencies and no phase delay. This technique has been used previously to study pain reactivity and responses to anesthetics in infants.65,66,71
Pharmocologic Data
During the pregnancy, maternal levels were typically drawn before their morning dose, thereby representing a trough level. During the remainder of the study, maternal (5 mL) and infant (1 mL) blood and breast milk (10 mL) samples were collected during the study sessions for infant assessments and were not referenced to the time of maternal drug dosing. All blood samples were collected in Vacutainer tubes without additives and allowed to clot for 30 minutes. The serum was then separated after centrifugation at 3000g for 10 minutes and transferred into a glass tube. Milk samples were collected (foremilk) by manual expression or breast pump at the same time as blood sampling and transferred to glass tubes. All serum and milk samples were stored at –20°C until analysis. Fluoxetine and norfluoxetine isomer concentrations were measured using stereoselective gas chromatography-mass spectrometry electron-impact ionization.72 A similar gas chromatography-mass spectrometry assay using either electron-impact or negative-ion chemical ionization with selective ion monitoring was used for paroxetine.73 Sertraline and its metabolite desmethylsertraline (norsertraline) were measured by using liquid chromatography-mass spectrometry.
Statistical Analysis
A group (SSRI versus control) by phase (baseline, lance, recovery) repeated-measure analysis of variance was used to compare outcome measures across study periods. Post hoc comparisons were conducted where appropriate, and a difference was considered statistically significant for P < .05. To examine differencesbetween the groups across phases of blood collection, factorial analyses of variance were conducted; analyses of covariance were used when it was deemed important to control for the influence of maternal mood and concurrent CL use.
Behavioral Data
To examine the pattern of facial response across phase, occurrence of each of the 7 NFCS facial actions were summed within each of 10 segments of 2-second duration to yield 10 facial scores, each with a possible range of 0 to 7, for each event. When the infant's face was out of view, missing data for that event were replaced with the mean value of their respective exposure group.
Physiologic Reactivity and Recovery Regulation
The mean and SEM of the HR, respiratory activity, and power spectra for each data segment were calculated. For the purposes of display, group average transfer function estimates of both gain and phase from each experimental epoch were computed as previously described.53 Simple change scores were used to study whether cardiovascular response from the lance to recovery was associated with pharmacologic or behavioral variables. Simple change scores for each of HR, high-frequency power (HFP), and low-frequency power (LFP), respectively (ie, HRlance–recovery), were derived from the difference between cardiac autonomic measures obtained at the lance period and the recovery period and used in regression analyses.
Pharmacologic Data
Mean plasma drug levels were tabulated from maternal and infant levels at the time of the 2-month study. Expressed breast milk levels were used to tabulate infant drug dose (Cmilk x Vmilk) where Cmilk is the milk concentration of medication (ng/mL) and Vmilk is the volume of milk (mL) ingested per day based on 150 mL/kg per day. Drug ratios were also tabulated to compare infant drug exposure to milk and maternal levels.
RESULTS
Characteristics of infants and their mothers did not differ significantly between groups (Table 1). At the time of the study, all infants were in good health and in all groups mean maternal mood was rated as nonclinically depressed (ie, symptoms reported <16), although mean Hamilton Depression (HAMD) scores were significantly lower in control subjects than in the 2 exposure groups (P < .05). Prenatal SSRI medication exposure occurred in the last 2 trimesters, and the length of maternal SSRI use or medication dose did not vary significantly between the 2 exposure groups (P > .05). Similarly, length of SSRI use did not vary between exposure groups (P > .05). All mothers reported taking their prescribed medication in the 3 days before the study, and thus maternal medication levels, and presumably breast milk levels, were considered to be at a steady state at the time of the study. Given the extra blood collection needed for drug levels, the heel-lance blood collection took longer among the infants with postnatal drug exposure (means: 104.3 ± 18 vs 109.7 ± 25 vs 146 ± 48 seconds for control, prenatal selective serotonin reuptake inhibitor–exposed infants [pSE], and prenatal and postnatal selective serotonin reuptake inhibitor–exposed infants [ppSE] groups, respectively).
Behavioral Pain Response
The overall pattern of infant facial-activity responses showed a significant increase from baseline to lance and a decrease from lance to recovery in all groups (F = 170.5; df [2,112]; P < .01). Group differences in facial action emerged when 10 segments of 2-second duration for each study epoch were examined (Fig 1). During baseline, facial action remained low in all groups and no group differences were present (F = 1.5; df [9,513]; P > .05), but increased significantly from baseline to lance in all groups (F = 2.7; df [9,531]; P < .05). During the lance phase, facial action was significantly lower among the pSE group, compared with controls and infants with ppSE infants (P < .05). In recovery, facial action was lower among pSE infants, but differences among exposure groups were not significant (F = 1.6; df [2,58]); P > .20).
Physiologic Data
Mean HR
Mean HR increased significantly with lance and fell in recovery in all groups (F = 6.27; df [4,120]; P < .01). In the recovery period, mean HR was significantly lower among both exposure groups (F = 7.1; df [2,60]; P < .05); differences between exposure groups were not significant (P > .05; Fig 2).
Power Spectral Estimates
In all groups, LFP decreased significantly from baseline to lance and increased again in the recovery period (F = 5.8; df [2,120]; P < .01), but there were no significant differences between groups (P > .15; Fig 3). Mean HFP remained stable (F = 2.2; df [2,120]; P > .10) in response to the lance among the control and the pSE groups. In contrast, among the ppSE group, HFP decreased significantly from the baseline to the lance and increased during the recovery (F = 147; df [2,29]; P > .10). In all groups mean LFP/HFP ratios decreased with the lance (F = 3.9; df [2,120]; P < .05; Fig 3). Post hoc tests showed a significantly lower mean ratio among the ppSE group compared with controls (P < .05). Total RP increased significantly from the baseline to the lance and decreased in the recovery period in all groups (F = 8.2; df [2,120]; P < .01). Post hoc tests showed lower mean RP among both exposed groups of infants compared with controls in recovery (P < .05; Fig 4).
Transfer-Function Estimates of Respiratory Sinus Arrhythmia
Transfer gain and phase graphs are presented in Fig 5. Qualitatively, during baseline, transfer gain was high at all frequencies in exposed and control groups. Phase began at 0° at 0 Hz and decreased slightly with increasing frequencies, illustrating a predominance of vagal cardiac modulation in the baseline condition in all infants.
In response to the lance, transfer gain decreased across all frequencies and became very low in the HF range, suggesting increased sympathetic modulation in all groups. Transfer phase remained stable, suggesting that increased sympathetic cardiac modulation was accompanied by a minimal withdrawal of parasympathetic activity. No group differences were apparent.
In the recovery period, group differences emerged. Among both groups of exposed infants, mean transfer gain increased from the lance period across all frequencies, whereas phase remained at 0°, consistent with a return to baseline levels of parasympathetic and relative stability of sympathetic cardiac modulation. Transfer gain increased significantly (P < .05; Table 2) compared with controls, reflecting a return to greater levels of parasympathetic modulation. In contrast, among control infants, transfer gain did not increase substantially, and phase remained <0° with a negative slope across increasing frequencies. These data suggest sustained or increased sympathetic cardiac modulation associated with a minimal return of parasympathetic activity, particularly evident in the ppSE group.
In summary, based on the transfer-function results, both exposed and nonexposed infants responded to the heel-lance with increased sympathetic and reduced cardiac parasympathetic modulation. However, exposed infants showed a recovery pattern characterized by an early return to baseline levels of parasympathetic modulation when compared with control infants for whom substantial sympathetic modulation continued. These results are consistent with the lower mean HR and facial action observed during recovery, particularly in the ppSE group.
Pharmacologic Variables and Pain Reactivity
Medication levels in infant serum and maternal breast milk in the ppSE group were substantially lower than maternal serum levels. Mean maternal and infant medication doses and levels for infants with postnatal exposure are shown in Table 3. Among breastfeeding infants, only 30% had detectable drug levels, and when these levels were present, infant medication levels were substantially lower than milk and maternal levels (Table 4).
To explore whether biobehavioral pain response was related to pharmacologic variables, measures of cardiac autonomic change from lance to recovery were tabulated to yield simple () change scores for HR, LFP, and HFP, respectively. Simple change scores were used because there were no significant group differences in these measures during the lance period.74 Greater change in mean HRlance–recovery (r = 0.322; P < .05) was associated with increased days of prenatal SSRI exposure. Maternal drug levels during the third trimester, maternal dose, and infant dose at 2 months were not associated with measures of cardiac reactivity or facial recovery (P > .10). When infant drug levels were detectable (ie, levels >0.01 ng/dL), mean HRlance–recovery and HFP HRlance–recovery were significantly greater among exposed infants compared with infants for whom the levels were below limits of quantitation (F = 5.4; df [2,47]; P < .01; and F = 4.62; df [2,47]; P < .05, HR and HFP, respectively) (Fig 6). Measures of facial reactivity did not differ between infants with or without detectable drug levels. When maternal symptoms of depression (HAMD) at 2 months or during pregnancy were added as covariates, group differences in HRlance–recovery scores remained significant (P < .05).
Previously, we observed that 15 infants (1 control, 6 prenatal only, 8 ppSE) in our original cohort had symptoms of poor neonatal adaptation.19 To examine whether such symptoms were related to pain reactivity we compared facial action and changes in cardiac autonomic reactivity scores at 2 months between infants with and without symptoms in the newborn period. Differences in pain reactivity between these groups were not significant (P > .05).
DISCUSSION
At 2 months of age, infants with prenatal and continued postnatal SSRI exposure exhibited attenuated biobehavioral pain responses after an acute noxious event. Reduced immediate facial-action response to the lance was observed among infants with prenatal exposure alone. Blunted cardiac autonomic responses were observed in the recovery period in infants with both prenatal and postnatal drug exposure. Compared with controls, cardiac autonomic responses in the recovery period were shorter and less intense, as reflected by a lower mean HR, a greater reduction in HR from lance to recovery, and increased parasympathetic cardiac modulation among exposed infants. The shorter cardiac autonomic response among exposed infants may reflect a possible increased capacity to modulate responses to a noxious event. It is important to note that differences in cardiac autonomic responses between infants with prenatal exposure alone and prenatal and postnatal exposure were nonsignificant. When postnatal exposure continued, infant drug levels were substantially lower than milk or maternal levels or even nondetectable. However, when drug levels could be detected, greater HR and HRV reactivity between lance and recovery periods were observed. In addition, increased HRV responses from lance to recovery were associated with increased length of prenatal SSRI exposure. These differences remained significant after controlling for prenatal and postnatal CL exposure or maternal symptoms of depression.
The mechanisms underlying group differences in facial responses between exposure groups remain a matter of speculation. Although reduced facial reactivity was only observed during the immediate lance period among the pSE group, this finding was not entirely unexpected given that the time course for a facial action is substantially briefer (ie, more proximal to the noxious event) than for cardiac autonomic responses.51 Differences in postlance handling time were observed between groups. However, among infants with longer handling time (ie, postnatal drug exposure required us to obtain drug levels), biobehavioral pain outcomes reflected greater parasympathetic modulation and lower HR during recovery (ie, increased modulation of response) rather than an increased or continued arousal that one would have expected with longer handling times. Moreover, our findings were observed in infants who were typically developing infants at 2 and 8 months as assessed by the Bayley Scales of Infant Development-II.
Previously, for the same cohort, we reported an attenuated biobehavioral pain reactivity in newborns with prenatal SSRI exposure, which was reflected by blunted facial-action responses and less parasympathetic withdrawal during the lance period and increased parasympathetic modulation during the recovery period.4 No differences in outcome were seen between the different SSRIs alone or when exposure included the benzodiazepine CL. Given the findings in this report, prenatal and combined postnatal SSRI medication exposure seems to alter biobehavioral infant pain responses at 2 months of age. To date, no previous work has assessed biobehavioral pain reactivity after prenatal and postnatal SSRI exposure; therefore, mechanisms that could account for our findings remain a matter of discussion.
Our findings raise the possibility that the blunted facial and cardiac autonomic reactivity to a noxious event may reflect alterations to pain-response systems after fetal and/or continued postnatal SSRI exposure at 2 months of age. In this sense, these findings may reflect an increased capacity to modulate responses to a painful event, consistent with changes to autonomic regulation recently reported by Zeskind.25 In the current study infant pain reactivity was used as probe of biobehavioral reactivity to a stressful event rather than nociception per se. Infant pain reactivity can be regarded as a final common pathway that reflects a variety of emerging neurologic capacities. There is considerable evidence that descending 5HT modulates central nociception,75 and antinociceptive effects have been demonstrated by 5HT antagonists such as SSRIs in preclinical models76 and humans.77 Therefore, our findings might reflect that even very minimal exposure to a 5HT agonist might have an acute antinociceptive effect.
Direct Pharmacologic Effects
The relationships between maternal and infant drug levels raise the possibility that our findings reflect a direct pharmacologically mediated antinociceptive phenomenon related to ongoing SSRI exposure via breast milk. Potential effects may be linked to the SSRI-related inhibition of 5HT reuptake by presynaptic neurons and desensitization of presynaptic 5HT1a receptors that inhibit cell firing78 demonstrated in animal models. Although SSRIs differ in their potency and inhibition of 5HT reuptake,79,80 all SSRIs are thought to increase synaptic 5HT concentrations in the brain.80
SSRIs readily enter breast milk,1 and it is conceivable that prenatal exposure influences development and function of monoaminergic-rich regions of the brain. SSRIs used in this study are lipid soluble and readily excreted in breast milk11,30,81; therefore, infant exposure via this route at the time of 2-month testing was minimal, and thus such exposure would not be considered a substantial source of postnatal exposure.31 Mean maternal levels were well within the usual adult therapeutic range for paroxetine (20–200 ng/mL82) or fluoxetine (37–301 ng/mL83). Therapeutic range for all SSRIs for infants have not been established.84,85 Levels of SSRIs varied, presumably reflecting differences in metabolism; in vitro potency for 5HT reuptake differs between medications,79 raising the possibility that even at concentrations below the limit of quantitation of the current assay methods these medications could elicit effects.1
Postnatal effects via breast milk have been reported; however, with the exception of isolated cases,18 detailed descriptions of the neurobehavioral and developmental effects of postnatal SSRI exposure have not yet been found.9 Given that the effects of postnatal exposure on platelet 5HT transport blockade were limited,86 effects of postnatal exposure via breast milk seem to be minimal and as such are unlikely to explain altered pain responses in infants who continued to breastfeed. Pharmacologic variables could continue to have some influence, although it remains uncertain to what extent these current findings reflect an ongoing acute pharmacologic phenomenon or sustained alterations in monoaminergic function.
Long-Term Effects of Prenatal Exposure
Length of prenatal SSRI exposure in our study was related to cardiac autonomic reactivity measures, possibly reflecting sustained alterations to monoaminergic ontogeny in the developing infant brain. Animal and human studies have demonstrated that exposure to substances that increase the presence, enhance, or block the action of neurochemicals during crucial periods of fetal brain growth may alter brain structure and function, and subsequent behavior.39,87 Examining the influence of prenatal medication exposure in human infants offers opportunities to investigate how levels of neurochemicals (ie, central 5HT), altered by the pharmacologic action of specific medications, influence the neural ontogeny and subsequent development of particular behaviors (eg, regulation of pain response) mediated by those neurotransmitters. Because of the dual roles of 5HT as a pain inhibitory neurotransmitter and as a trophic developmental signal, prenatal increased levels may lead to altered receptor numbers and/or function or postreceptor mechanisms, thereby altering postnatal function.
Although SSRIs differ in their potency and inhibition of 5HT reuptake, all SSRIs are thought to increase synaptic 5HT concentrations in the brain.80 With increased levels of 5HT after SSRI exposure, cortical morphology in monoaminergic-rich regions of the brain may be effected. This, in turn, may lead to altered general monoaminergic ontogeny and function. Given the inhibitory role 5HT plays at multiple levels of the neuraxis in the pain system, the observed blunted pain reactivity may reflect an increased or altered capacity to modulate pain signals. Prenatal fluoxetine exposure in animal models results in neuroanatomic alterations to key somatosensory structures,88 monoamine receptors,89–91 5HT content, and receptor binding92 and of 5HT transporters,93 as well as altered behaviors.94 It is interesting to note that both understimulation of 5HT receptors (due to 5HT depletion) and overstimulation (by 5HT agonists) during prenatal development has a lasting postnatal impact on 5HT-receptor function.95 A study of the cardiovascular and behavioral effects of an intravenous infusion of fluoxetine in pregnant sheep showed decreased fetal low-voltage electrocortical activity and rapid eye movements and increased quiet sleep,96 similar to reports in adult humans.97 Increased responsiveness to anxiety testing and aggressive behavior98 have also been reported, whereas others have not found cognitive changes in other animal models.89,99 In an analogous setting, Butkevich et al100 studied the effects of prenatal exposure to the 5HT synthesis inhibitor, paracholophenylanline, in rats and noted that changes in 5HT levels were associated with a significant decrease in the intensity and duration of response to formalin-induced pain.101 These effects are thought to reflect changes in the hypothalamic-pituitary-adrenal axis, serotonergic pathways in the brain and spinal cord that lead to impaired function in the descending serotonergic system.
Evidence of long-term neurobehavioral effects after prenatal exposure in humans is limited. To date, no studies have reported effects on developmental delay in the first 2 years of life102 or cognitive or language development after prenatal SSRI exposure up to 71 months of age.27 In a single study, subtle decreases in fine motor development and control in children between 6 and 40 months of age were noted, whereas mental development was unaffected after the third trimester of SSRI exposure.103
Infant pain reactivity was used in this study as a biobehavioral probe to study the infant nervous system and should be regarded as the final common behavioral expression of multiple emerging neurobehavioral processes. The capacity to regulate responses to external stimuli is a key developmental task of infancy, and infant pain behavior may be directly and interactively (indirectly) affected by an emerging capacity to regulate levels of arousal (behavioral states) and emotion during infancy.104,105 Monoaminergic-rich regions of the brain (ie, striatum, locus coeruleus, and posterior parietal cortex) regulate attention, and exposure to SSRIs may only indirectly influence nociception via altered regulations of arousal. Moreover, independent of prenatal exposure to psychotropic medications, in utero exposure to maternal stress106 may alter neuroregulatory mechanisms that interfere with arousal, which subsequently manifest as altered pain reactivity. Pain and stress responses are interactively related to the development of systems governing the regulation of attention, emotion,107 and distress in infancy.108 Studies of early arousal regulation in preterm infants suggest that abnormal patterns of brain organization109 and behavioral state are closely related to pain reactivity. Infants in quiet sleep are less reactive to a noxious event than are infants in active sleep/alert states.47 Our findings also may reflect an altered hypothalamic-pituitary-adrenal axis stress response110,111 observed in animal models after postnatal SSRI exposure or an extension of the altered neurobehavioral indices of autonomic and arousal regulation recently observed by Zeskind et al25 in newborns with prenatal SSRI exposure. In this sense, changes in pain reactivity may reflect altered arousal regulation; however, additional studies of infant arousal regulation after prenatal SSRI exposure are required to better understand these relationships.
Limitations
The human models needed to understand the neurobehavioral effects of prenatal SSRI exposure are complex, and models that account for multiple neurologic, developmental, maternal genetic, and prenatal and postnatal environmental factors are far beyond the scope of a single study. In this study we were not able to distinguish the effects of SSRIs from complex and concurrent family mental health influences, and we only measured postnatal depression. Because we did not study a depressed but nonpharmacologically treated group of mothers, we were not able to assess the effects of prenatal maternal stress alone, which may have also affected fetal development. Substantial evidence links infant exposure to maternal depression and adverse behavioral and psychological developmental outcomes.
Our understanding of prenatal SSRI exposure cannot be easily separated from the concurrent influences of maternal mood during and after pregnancy. The impact of parental depression on child development has received considerable attention.112–114 Convergent evidence from animal and human studies suggest that chronic unpredictable physiologic stress during pregnancy may have long-lasting effects on biogenic amine neurotransmitter system function and behavior in offspring.115–117 Newborns of depressed mothers have increased difficulties with self-regulation,115,116 irritable neonatal behavior,117 and reduced alertness,118–120 which suggests links between prenatal maternal mood and altered autonomic regulation in offspring that continue during the first year.121–123 It is important that even in the presence of prenatal fluoxetine exposure it has been found that the duration of the maternal depression and number of depressive episodes lead to altered child developmental outcomes and not the exposure itself.124 Although mean levels of depressive symptoms in our study were not associated with pain reactivity, we were not able to examine whether altered infant pain behavior was independently influenced by sustained exposure to depressed maternal mood either before or after birth. Additional study of maternal mood, mother-infant interaction, and infant pain behaviors is required to assess this as a possible mechanism underlying our findings. In this current study pain responses did not vary when the presence of benzodiazepine was included as a covariate; however, because we did not have a benzodiazepine-alone exposure group, it is not possible on the basis of this study to determine the specific effects -amino-butyric acid agonists have on the developing pain system. Differences in caregiving related to breastfeeding or maternal response to their infant's distress at the time of the blood collection could have been another covariate. The long-term developmental significance of a reduced or blunted pain response or its relationship to other key aspects of arousal and emotional regulation also remain unclear. Pain reactivity is a function of multiple domains of behavior and development. It is interesting that at 2 months of age a biological-behavioral discordance seems to have emerged. In contrast to the outcomes at birth, facial-reactivity patterns appeared only slightly lower in the recovery period, suggesting that behavioral responses may have "normalized" with time. The discordance between behavioral and biological responses among infants with prenatal and continued postnatal exposure requires additional study. It is possible that altered pain reactivity in this setting is a reflection of altered arousal regulation, a 5HT-mediated process that alters facial expression in ways that might be different from cardiac autonomic responses. To address these questions, complex models that study interactions between multiple maternal, pharmacologic, environmental, and biological variables are required.
CONCLUSIONS
Infants with prenatal and postnatal SSRI exposure had diminished facial and cardiac autonomic responses to the pain of a heel-lance at 2 months of age. These findings are consistent with the blunted pain reactivity observed in the same cohort of infants studied in the newborn period. At this time it remains unclear whether these outcomes resulted from altered brain development due to prolonged in utero SSRI exposure or continued postnatal medication exposure or are indirectly related to changes in arousal-state regulation. The effects of exposure to depressed maternal mood cannot be excluded as a contributing factor. Regardless of the mechanisms that may underlie these findings or the long-term consequences, our findings should not prejudice the clinical urgency of treating maternal depression during and after pregnancy with or without medication. The known risks of untreated or undertreated maternal depression both to the mother and her offspring currently outweigh any known adverse effects of the SSRIs. Additionally, it should be emphasized that these findings should not reduce the importance of promoting breastfeeding even in the presence of SSRI use. Breastfeeding is universally regarded as optimal nutrition for infant growth and development and is considered safe during SSRI use.125 At this time, it remains important to recognize that we do not have a clear understanding of the mechanisms that explain our findings or their long-term implications for infant development. Larger cohorts of exposed infants are required to replicate these findings and to understand the effects of prenatal psychotropic medication exposure on infant development.
ACKNOWLEDGMENTS
We thank Victoria Nethercot, MSc, Ursula Brain, Mary Beckingham, and Phil Saul, MD, for editorial assistance and Sandy Pitfield, MSc, MD, for assistance in editing and analysis of the physiologic signals.
This work was funded by the British Columbia Medical Services Foundation.
FOOTNOTES
Accepted Jul 9, 2004.
No conflict of interest declared.
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