Prolonged Prenatal Psychotropic Medication Exposure Alters Neonatal Acute Pain Response

Abstract

Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are frequently used to treat maternal depression during pregnancy, however the effect of increased serotonin (5HT) and ␥-amino-butyric acid (GABA) agonists in the fetal human brain remains unknown. 5HT and GABA are active during fetal neurologic growth and play early roles in pain modulation, therefore, if prolonged prenatal exposure alters neurodevelopment this may become evident in altered neonatal pain responses. To examine biologic and behavioral effects of prenatal exposure, neonatal responses to acute pain (phenylketonuria heel lance) in infants with prolonged prenatal exposure were examined. Facial action (Neonatal Facial Coding System) and cardiac autonomic reactivity derived from the relationship between respiratory activity and short term variations of heart rate (HRV) were compared between 22 infants with SSRI exposure (SE) [fluoxetine (n ϭ 7), paroxetine (n ϭ 11), sertraline (n ϭ 4)]; 16 infants exposed to SSRIs and clonazepam (SEϩ) [paroxetine (n ϭ 14), fluoxetine (n ϭ 2)]; and 23 nonexposed infants during baseline, lance, and recovery periods of a heel lance. Length of maternal SSRI use did not vary significantly between exposure groups-[mean (range)] SE:SEϩ 183 (31-281):141 (54 -282) d (p Ͼ 0.05). Infants exposed to SE and SEϩ displayed significantly less facial activity to heel lance than control infants. Mean HR increased with lance, but was significantly lower in SE infants during recovery. Using measures of HRV and the transfer relationship between heart rate and respiration, SSRI infants had a greater return of parasympathetic cardiac modulation in the recovery period, whereas a sustained sympathetic response continued in the control group. Prolonged prenatal SSRI exposure appears to be associated with reduced behavioral pain responses and increased parasympathetic cardiac modulation in recovery following an acute neonatal noxious event. Possible 5HT-mediated pain inhibition, pharmacologic factors and the developmental course remain to be studied. (Pediatr Res 51: 443-453, 2002) Abbreviations 5HT, 5 hydroxytryptamine (serotonin) BZ, benzodiazepine C, control (nonexposed) infants DA, dopamine GABA, ␥-amino-butyric acid HFP, high-frequency power HRV, heart rate variability LFP, low-frequency power NE, norepinephrine NFCS, Neonatal Facial Coding System NICU, neonatal intensive care unit PKU, phenylketonuria RP, respiratory power RSA, respiratory sinus arrhythmia SE, SSRI-exposed infants SE؉, SSRI-and BZ-exposed infants SSRI, selective serotonin reuptake inhibitors Maternal anxiety and depression are frequently treated during pregnancy with psychotropic medications such as SSRIs and BZs (1). Given that all psychotropic medications diffuse easily across the placenta, clinicians caring for women with psychiatric illness during their pregnancies are faced with the difficult task of making recommendations regarding psychotropic medication use with unknown effects on the growing fetus. To date, none of these medications have been appr...

Third Trimester Fetal Heart Rate and Doppler Middle Cerebral Artery Blood Flow Velocity Characteristics During Prenatal Selective Serotonin Reuptake Inhibitor Exposure

“…Widespread observations of neonatal neurobehavioral disturbances (4,5), altered infant stress regulation (6,7), and increased risk for neonatal persistent pulmonary hypertension (8) have been reported. Although persistent pulmonary hypertension in neonates has been supported by findings of increased pulmonary arterial wall thickness, associated with lower oxygen saturation and a higher mortality in fluoxetine-exposed (EXP) newborn rats (9), a subsequent human report did not replicate the earlier human reports (10).…”

Platelet Serotonin in Newborns and Infants: Ontogeny, Heritability, and Effect of In Utero Exposure to Selective Serotonin Reuptake Inhibitors

“…The impact of central serotonin 5-HT modulation by SSRI during critical periods of brain development is unknown. Although preclinical studies indicate that 5-HT plays important roles in neurogenesis and neural growth (14 -20), it is unclear how transporter inhibition affects early neurodevelopment in humans.Research on fetal and neonatal exposure to SSRI has been recently reviewed (10,11,21,22). Although substantial and physiologically meaningful infant SSRI exposure through breast-feeding by mothers receiving SSRI is probably infre- 0031-3998/04/5603-0418 PEDIATRIC RESEARCH Vol.…”

“…Research on fetal and neonatal exposure to SSRI has been recently reviewed (10,11,21,22). Although substantial and physiologically meaningful infant SSRI exposure through breast-feeding by mothers receiving SSRI is probably infre- 0031-3998/04/5603-0418 PEDIATRIC RESEARCH Vol.…”

“…Research on fetal and neonatal exposure to SSRI has been recently reviewed (10,11,21,22). Although substantial and physiologically meaningful infant SSRI exposure through breast-feeding by mothers receiving SSRI is probably infre-quent (9 -11, 23), gestational exposure has been reported to have marked biochemical effects and may have significant clinical effects (21,22).…”

Stereoselective Pharmacokinetics of Fluoxetine and Norfluoxetine Enantiomers in Pregnant Sheep

“…In contrast, third trimester exposure is associated with reduced birth weight and postnatal weight gain and an increased incidence of preterm delivery, admission to a special nursery, and poor neonatal adaptation (Chambers et al, 1996(Chambers et al, , 1999Cohen et al, 2000;Nordeng et al, 2001). Recently, we and our collaborators have reported altered facial and heart rate responses to painful medical procedures in infants exposed to FX and other SSRIs in utero (Oberlander et al, 2002). However, there are no reported effects of the drug on infant/child global IQ and language development (Nulman et al, 1997;Kulin et al, 1998).…”