Prenatal Selective Serotonin Reuptake Inhibitors Exposure Research Articles

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

Prenatal selective serotonin reuptake inhibitor (SSRI) exposure increases the risk for adverse neonatal behavioral outcomes; although it is unknown whether altered brain function is present before birth. We investigated fetal vascular and heart rate changes at 36-wk gestation in SSRI-treated women with mood disorders (n = 29) [exposed (EXP)] and controls (n = 45) [non-EXP (NEXP)]. Fetal middle cerebral artery (MCA) flow parameters and heart rate characteristics were obtained during pre-SSRI dose morning and postdose afternoon sessions. Maternal mood and cord Hb and hematocrit were measured. Basal fetal heart rate (fHR) did not differ between groups or across the day. The fHR short- and long-term variations, accelerations, and duration of high variability episodes remained lower and did not change across the day in EXP, whereas all increased significantly in NEXP. In both groups, MCA flow velocity and volume flow increased significantly across the day. EXP MCA pulsatility index was significantly lower, as was MCA cross-sectional area. EXP cord Hb and hematocrit were significantly increased. Prenatal SSRI exposure reduced fetal MCA flow resistance and fHR variability, before and after an SSRI dose, controlling for maternal mood. These changes and the SSRI-related increased red cell indices suggest possible fetal hypoxia.

Sustained Neurobehavioral Effects of Exposure to SSRI Antidepressants During Development: Molecular to Clinical Evidence

Selective serotonin reuptake inhibitor (SSRI) antidepressants are frequently used in the management of antenatal maternal mood disturbances. SSRIs readily cross the placenta and increase central serotonergic tone in the fetus. Given serotonin's key neurodevelopmental role, such prenatal exposure raises concerns about its impact on child development. Preclinical studies report enduring molecular, physiological, and behavioral consequences of developmental SSRI exposure. In humans, sustained developmental outcomes remain largely unstudied, and distinguishing between the effects of prenatal SSRI exposure and the impact of maternal mental illness remains a key challenge.

Neonatal S100B Protein Levels After Prenatal Exposure to Selective Serotonin Reuptake Inhibitors

This study investigated neonatal S100B levels as a biomarker of prenatal selective serotonin reuptake inhibitor (SSRI) exposure. Maternal (delivery; N = 53) and neonatal (cord; N = 52) serum S100B levels were compared between prenatally SSRI-exposed (maternal, N = 36; neonatal, N = 37; duration: 230 +/- 71 days) and nonexposed (maternal, N = 17; neonatal, N = 15) groups. Measures of maternal depression and anxiety symptoms were assessed during the third trimester (33-36 weeks), and neonatal outcomes, including Apgar scores, birth weight, gestational age at birth, and symptoms of poor neonatal adaptation, were recorded. S100B levels were significantly lower in prenatally SSRI-exposed neonates than in nonexposed neonates, controlling for gestational age and third-trimester maternal mood (P = .036). In contrast, SSRI-exposed mothers had significantly higher maternal serum S100B levels, compared with nonexposed mothers (P = .014), even controlling for maternal mood in the third trimester. S100B levels were not associated with maternal or neonatal drug levels, duration of prenatal exposure, demographic variables, or risk for poor neonatal adaptation. Prenatal SSRI exposure was associated with decreased neonatal serum S100B levels, controlling for prenatal maternal mood. Neonatal S100B levels did not reflect neonatal behavioral outcomes and were not related to pharmacologic indices. These findings are consistent with prenatal alcohol and cocaine exposures, which also alter central serotonin levels.

Hypothalamic–pituitary–adrenal (HPA) axis function in 3-month old infants with prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure

Background Prenatal exposure to stress and selective serotonin reuptake inhibitors (SSRIs) alter hypothalamic–pituitary–adrenal (HPA) stress reactivity in offspring, however, the effects of combined exposure to HPA activity in human infants is unknown. Objective To examine HPA basal levels and stress responsiveness in 3-month olds with prenatal exposure to SSRIs. Methods Salivary cortisol levels in infants of SSRI treated mothers ( n = 31, mean exposure 230.2 ± 72.2 days) were compared with non-SSRI exposed ( n = 45) infants in response to a challenge (infant-controlled habituation task) and under basal conditions in the late afternoon/early evening. Mode of feeding, to account for possible postnatal drug exposure via breast milk, as well as measures of pre and postnatal maternal mood, were included as covariates. Results Lower post-stress cortisol levels were observed in non-SSRI exposed/non-breastfed infants compared with non-SSRI exposed infants who were breastfed at 3 months of age. Stress reactivity patterns among SSRI exposed infants did not differ with mode of feeding. The cortisol reactivity slope (CRS) was significantly lower among non-SSRI exposed non-breastfed infants compared with non-SSRI exposed breastfed infants. Early evening basal cortisol levels were lower in SSRI exposed infants than in non-SSRI exposed infants, controlling for maternal mood and mode of feeding. Postnatal SSRI exposure (infant SSRI drug levels) via breast milk was not associated with stress or basal cortisol levels. Total cortisol, reflected by the AUC measure, did not differ significantly between exposure groups. Conclusions Prenatal SSRI exposure altered HPA stress response patterns and reduced early evening basal cortisol levels. Stress challenge HPA response differences only became apparent when the moderating effect of method of feeding was accounted for. These findings suggest an early “programming” effect of antenatal maternal mood, prenatal SSRI exposure and postnatal maternal care giving on the HPA system.

Externalizing and Attentional Behaviors in Children of Depressed Mothers Treated With a Selective Serotonin Reuptake Inhibitor Antidepressant During Pregnancy

To evaluate attentional and activity behaviors in 4-year-olds following prenatal selective serotonin reuptake inhibitor (SSRI) exposure. Prospective cohort design. Tertiary care center. Twenty-two 4-year-olds with prolonged prenatal SSRI medication exposure and 14 children without prenatal exposure. Prenatal SSRI exposure. Group differences in externalizing behaviors (according to the Child Behavior Checklist) and direct observations of child attention, activity, and impulsiveness in a laboratory setting using the procedure by Crowell and colleagues were compared, including measures of the duration of prenatal SSRI exposure, umbilical cord drug levels, a history of poor neonatal adaptation, and maternal mood. Externalizing behaviors did not differ between groups. Maternal depression and anxiety at the 4-year follow-up were associated with increased reports of externalizing behaviors. Increased externalizing behaviors were associated with increased umbilical cord drug levels (F(1,34) = 6.3; P = .02), but when controlling for maternal depressed mood at the 4-year follow-up, such levels only accounted for 11.2% of the behavioral outcomes (P>.05). On direct observation, the persistence score for child behavior was significantly lower in the exposed group. Increased aggressiveness scores were associated with a history of poor neonatal adaptation, even when parental report of stress was added to the model (F(1,34) = 4.0; P = .03); however, neither parental report of stress nor poor neonatal adaptation were significant (both P = .09), suggesting that both are important, if not unique, predictors of child behavior. These findings suggest that the best predictors of externalizing behaviors at age 4 years are current maternal mood and parental stress, regardless of prenatal depressed mood and SSRI treatment during pregnancy. It remains uncertain whether poor neonatal adaptation can be excluded as a possible predictor of externalizing behaviors.

Neonatal Outcomes After Prenatal Exposure to Selective Serotonin Reuptake Inhibitor Antidepressants and Maternal Depression Using Population-Based Linked Health Data

Prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants and maternal depression both alter neonatal health, and distinguishing the effects of each influence remains challenging. To determine whether exposure to SSRIs and depression differs from exposure to maternal depression alone. Using population health data, records of neonatal birth outcomes were linked to records of maternal health and prenatal maternal prescriptions for SSRIs. Population of British Columbia, Canada. Mothers and their infants, representing all live births during a 39-month period (N = 119,547) (1998-2001). Outcomes from infants of depressed mothers treated with SSRIs (SE-D) were compared with outcomes from infants of depressed mothers not treated with medication (DE) and nonexposed controls. To control for maternal mental illness severity, propensity score matching was used to identify a comparison group of DE mothers who were similar to the SE-D mothers in characteristics in the year preceding and during pregnancy. Fourteen percent of mothers were diagnosed as having depression during their pregnancy, and the incidence of prenatal SSRI exposure increased from 2.3% to 5.0% during a 39-month period. Birth weight and gestational age for SE-D infants were significantly less than for DE infants, as was the proportion of infants born at less than 37 weeks (95% confidence interval [CI], -1 to -64, -0.25 to -0.45, and -0.009 to -0.04, respectively), although differences in the incidence of birth weight less than the 10th percentile for gestational age were not significant. An increased proportion of SE-D infants had neonatal respiratory distress (13.9% vs 7.8%), jaundice (9.4% vs 7.5%), and feeding problems (3.9% vs 2.4%) compared with DE infants (95% CI of difference, 0.042-0.079, 0.003-0.334, and 0.005-0.025, respectively). When outcomes were compared between SE-D and propensity score-matched DE neonates, SE-D was associated with increased incidence of birth weight below the 10th percentile and rates of respiratory distress. With linked population health data and propensity score matching, prenatal SE-D exposure was associated with an increased risk of low birth weight and respiratory distress, even when maternal illness severity was accounted for.

Internalizing Behaviors in 4-Year-Old Children Exposed in Utero to Psychotropic Medications

Internalizing behaviors in children between 4 and 5 years of age who had been prenatally exposed to psychotropic medications were investigated. The authors had previously reported the effects of prenatal medication exposure in this same cohort when they were newborns and infants at 3 and 8 months of age. Parental/teacher reports and a clinical measure of mother and child interactions were used to assess levels of internalizing behaviors (e.g., depression, anxiety, withdrawal). Outcomes were compared between children with prenatal selective serotonin reuptake inhibitor (SSRI) exposure (N=22) and nonexposed children of healthy, nondepressed, nonmedicated mothers (N=14). Measures of maternal mood were obtained. Ordered logistic regressions, independent-sample t tests, and univariate ANOVAs were used to compare outcomes between groups. Pearson correlations were used to determine associations between maternal mood and child behaviors. Levels of internalizing behaviors did not differ significantly between children with prenatal psychotropic medication exposure and those not exposed. However, as symptoms of maternal anxiety and depression increased, so did reported internalizing behaviors in their children. Prenatal exposure to psychotropic medications was not associated with increased reports of internalizing behaviors at 4 years of age, whereas impaired maternal mood did have an identified impact on child behavior. Further study of complex associations between maternal psychiatric disorders, prenatal SSRI exposure, and childhood internalizing behaviors is required to understand if the child outcome is affected by the illness, medications, or a combination of both.

Internalizing Behaviors in 4-Year-Old Children Exposed in Utero to Psychotropic Medications

Internalizing behaviors in children between 4 and 5 years of age who had been prenatally exposed to psychotropic medications were investigated. The authors had previously reported the effects of prenatal medication exposure in this same cohort when they were newborns and infants at 3 and 8 months of age.Parental/teacher reports and a clinical measure of mother and child interactions were used to assess levels of internalizing behaviors (e.g., depression, anxiety, withdrawal). Outcomes were compared between children with prenatal selective serotonin reuptake inhibitor (SSRI) exposure (N=22) and nonexposed children of healthy, nondepressed, nonmedicated mothers (N=14). Measures of maternal mood were obtained. Ordered logistic regressions, independent-sample t tests, and univariate ANOVAs were used to compare outcomes between groups. Pearson correlations were used to determine associations between maternal mood and child behaviors.Levels of internalizing behaviors did not differ significantly between children with prenatal psychotropic medication exposure and those not exposed. However, as symptoms of maternal anxiety and depression increased, so did reported internalizing behaviors in their children.Prenatal exposure to psychotropic medications was not associated with increased reports of internalizing behaviors at 4 years of age, whereas impaired maternal mood did have an identified impact on child behavior. Further study of complex associations between maternal psychiatric disorders, prenatal SSRI exposure, and childhood internalizing behaviors is required to understand if the child outcome is affected by the illness, medications, or a combination of both.

Antidepressant Treatment During Pregnancy: Between Scylla and Charybdis

Antidepressant Treatment During Pregnancy: Between Scylla and Charybdis

Is Prenatal SSRI Exposure Harmful to Newborns

When taken by pregnant women, selective serotonin reuptake inhibitors (SSRIs) cross the placenta and have the potential to affect newborns. Although

Pain Reactivity in 2-Month-Old Infants After Prenatal and Postnatal Selective Serotonin Reuptake Inhibitor Medication Exposure

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. 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. 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. 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.

Findings From Selective Serotonin Reuptake Inhibitor–Exposed Neonates Should Be Interpreted With Caution

In Reply .— I am pleased that the letter by Norton et al gives us the opportunity to clarify the significance and limitations of the findings of our study on the association between maternal use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and neonatal neurobehavior. As we described in our article, maternal depression during pregnancy is an important public health concern, with implications not only for the health of the mother but also for the health and development of the infant. Treatment of this condition has focused on mothers using SSRIs, with the assumption that these medications are safe for the developing fetus. Our concern is that this assumption is based on research that indicates that prenatal SSRI exposure has little or no impact on development, because exposed infants are born mostly of full birth weight, at full term, and show few physical anomalies. However, over the past 30 years, significant research literature has demonstrated that, in addition to these measures, neurobehavioral assessments provide a measure of …

Prolonged prenatal psychotropic medication exposure alters neonatal acute pain response.

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