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Article | Journal Club

Prenatal Effects of Selective Serotonin Reuptake Inhibitor Antidepressants, Serotonin Transporter Promoter Genotype (SLC6A4), and Maternal Mood on Child Behavior at 3 Years of Age FREE

Tim F. Oberlander, MD, FRCPC; Michael Papsdorf, PhD; Ursula M. Brain, BA; Shaila Misri, MD; Colin Ross, PhD; Ruth E. Grunau, PhD
[+] Author Affiliations

Author Affiliations: Early Human Experience Unit, Developmental Neurosciences and Child Health, and Department of Pediatrics (Drs Oberlander, Papsdorf, and Grunau and Ms Brain), and Centre for Molecular Medicine and Therapeutics (Dr Ross), Reproductive Mental Health, Department of Psychiatry, University of British Columbia, Vancouver (Dr Misri), British Columbia, Canada.


Arch Pediatr Adolesc Med. 2010;164(5):444-451. doi:10.1001/archpediatrics.2010.51.
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Objectives  To investigate whether prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure affects behavior in 3-year-olds of antenatally anxious or depressed mothers and whether risk was moderated by the serotonin transporter promoter (SLC6A4) genotype.

Design  Prospective longitudinal cohort design.

Setting  Vancouver.

Participants  Mothers and their 3-year-old children (n = 33 SSRI exposed and n = 42 nonexposed).

Main Exposures  Prenatal exposure to SSRI antidepressants and prenatal and postnatal maternal mood disturbances.

Main Outcome Measures  Parent report of child behavior (Child Behavior Checklist, ages 1.5-5 years) and the child SLC6A4 genotype. The covariates used were maternal mood during the third trimester, 3 months post partum, and at the 3-year follow-up study and the child's 5-minute Apgar score.

Results  Prenatal exposure to both maternal depressed mood and SSRI antidepressants were associated with increased internalizing behaviors during early childhood, whereas current maternal mood increased risk for externalizing behaviors. Increased child anxiety and depression symptoms were predicted by higher third-trimester maternal anxiety only in children with 2 short S alleles. In contrast, increased aggression and externalizing behaviors were predicted by third-trimester maternal anxiety only in children with 2 copies of the L allele.

Conclusions  Exposure to prenatal SSRIs and maternal mood had distinct effects on child behavior at 3 years of age, reflected in an increased level of internalizing behaviors. The impact of antenatal maternal anxiety on child mood was moderated by the child SLC6A4 genotype. Despite SSRI treatment for prenatal maternal mood disturbances, childhood behavior at 3 years of age remained at risk.

Figures in this Article

Exposure to maternal mood disturbances during pregnancy may be one of life's first adverse experiences that potentially sets a course of increased risk of childhood behavioral disturbances.14 In animal models, gestational stress is associated with behavioral disturbances and altered stress regulation in offspring.57 Similarly, in clinical studies,3,8 antenatal maternal mood disturbances set up developmental trajectories that affected cognitive, behavioral, and emotional outcomes throughout childhood, even when controlling for obstetric risk, psychosocial disadvantage, and postnatal maternal mood. Antenatal anxiety doubles the risk of hyperactivity and conduct and emotional problems during early childhood9 and school age.10 Together, such early adverse experience has a “fetal programming” effect on the developing brain.11 The magnitude of the effect is clinically significant, with approximately 15% of emotional behavioral problems in childhood attributable to antenatal anxiety.3

Antenatal mood disorders are increasingly being managed with selective serotonin reuptake inhibitor (SSRI) antidepressants, which are prescribed with an expectation that pharmacotherapy for maternal mood disturbances will “buffer” the developing child from the effects of maternal mental illness. Alternatively, because these medications alter central serotonergic (serotonin) tone during early brain growth, they may also contribute to developmental risk.12,13 Primarily, SSRIs act by blocking the serotonin transporter (5-HTT), consequently increasing extracellular serotonin levels.14 Because SSRIs readily cross the placenta and the blood-brain barrier,15 maternal SSRI treatment alters central serotonin signaling of the fetus.16 Undertreated antenatal maternal mood disturbances also alter neonatal serotonin levels,17 leaving critical questions unanswered about how the effects of prenatal SSRI exposure differ from the impact of the underlying maternal disorder.

Long before serotonin acts as a neurotransmitter, it has critical roles as a trophic factor directing neuronal growth.18 It is conceivable that altered serotonin levels during development affect subsequent serotonergic function and vulnerability to affective disorders.19 Genetically modified mice lacking the serotonin transporter (SERT), analogous to an SSRI-induced increase in intrasynaptic serotonin, are at increased risk for depressed and anxious behaviors in adulthood, suggesting links between early disrupted serotonin and subsequent behavioral disturbances.20 SERT, one of the key regulators of serotonin neurotransmission, is the membrane-bound 5-HTT protein that governs the reuptake of serotonin from the synaptic cleft, returning it to the presynaptic neuron. Altered 5-HTT and reduced serotonin levels have been associated with depression, and the function of this protein is closely tied to polymorphisms in the serotonin transporter gene (SLC6A4) promoter region (SLC6A4 OMIM21182138; 5-HTT).2225 Differences in transporter-dependent reuptake efficiency are related to 44–base pair (bp) insertion/deletion polymorphisms in a region of repetitive sequence in the proximal 5′ regulatory region in the promoter region of the SLC6A4 gene,19,25,26 leading to differential transporter gene expression and clinical differences in SSRI efficacy.22,27 The short (S) variant is associated with reduced transcription of SLC6A4 and approximately 50% reduction in serotonin reuptake compared with the long (L) variant.26,28 The ll genotype is associated with increased SSRI efficacy compared with the ss genotype,27,2931 although effects have been inconsistent.22,32 Individuals with 2 copies of the short allele of the serotonin transporter promoter, a condition associated with reduced SERT expression, have increased vulnerability to depression and other mood disorders after stressful events in early life.33 In SSRI-exposed neonates, risk of neonatal neurobehavioral disturbances may be moderated by reduced serotonin transporter (5HTT or SERT) expression (SLC6A4 genotype)34; however, this single polymorphism does not seem to account for all outcomes.

Beyond the newborn period, little is known about the impact of prenatal SSRI exposure on child development. For the most part, childhood behaviors seem to be best predicted by current levels of maternal mood and not by prenatal SSRI exposure; however, findings have been limited by the difficulty in accounting for prenatal and postnatal maternal mental health.13,3537 Increased externalizing symptoms were observed in SSRI-exposed 4-year-olds with increased cord SSRI drug levels and a history of neonatal withdrawal behaviors,13 suggesting possible sustained links between fetal SSRI exposure and childhood neurobehavior. Altered serotonin levels during early periods of brain development, possibly via prenatal SSRI exposure or genetic variations that modify serotonin transport, may change serotonin-related neurobehavioral development.

This study was undertaken to examine associations between prenatal SSRI exposure and behavioral outcomes in early childhood controlling for prenatal and postnatal maternal mood. A secondary objective sought to examine whether such risk was moderated by the child SLC6A4 genotype, reflecting genetic variations in the capacity to control the severity of serotonergic tone. We expected that prenatal SSRI exposure, especially combined with 2 copies of the short S allele (thereby reducing SLC6A4 transcription and transporter activity), would increase the risk of behavioral disturbances in early childhood.

PARTICIPANTS

With approval from the University of British Columbia Research Ethics Board and the Children's and Women's Health Centre of British Columbia Research Review Committee, and after receiving informed parent consent, we prospectively recruited a convenience sample of 98 mothers late in their second trimester (mean [SD], 24.2 [5.1] weeks) as part of a longitudinal study of the effects of antenatal SSRI exposure. Mothers were physician- and self-referred from the Reproductive Mental Health Clinic at British Columbia Women's Hospital & Health Centre, a tertiary care referral service, community midwife clinics, and family physician practices in the greater Vancouver metropolitan area. All SSRI-treated mothers started taking medication based on clinical need, had a diagnosis of a mood disorder, and were already taking antidepressant medications at the time of conception. The criterion for recruitment was the presence or absence of SSRI antidepressant treatment rather than a threshold for mood symptoms. Women in the non-SSRI group were recruited from family or midwifery practices and had a range of mood symptoms (mean [SD] Hamilton Rating Scale for Depression [HAMD] score, 5.6 [6.8]) at the time of recruitment. Cord and third-trimester maternal blood samples were obtained for DNA analysis. Of the original 98 pregnant mothers recruited, 4 withdrew before the baby was born, leaving 94 newborns in the longitudinal study. Four more children then withdrew from the study before the end of the first year of life, and an additional 15 children were unavailable for the 3-year study (11 families moved and could not be contacted, and 4 mothers refused consent to participate). At the 3-year follow-up visit, 75 children returned (33 children of depressed mothers treated with an SSRI during pregnancy and 42 children of non-SSRI–treated mothers). Mothers had been treated with 1 of 5 SSRIs, which included SSRIs and serotonin norepinephrine reuptake inhibitors. (For simplicity, the SSRI nomenclature is used). None of the mothers had taken other serotonergic medications or any other psychotropic or antidepressant medications during pregnancy.

SLC6A4 GENOTYPING

Genomic DNA was extracted from whole venous blood using the Flexigene DNA Blood Kit (Qiagen, Valencia, California). The L and S alleles of SLC6A4 were identified as previously described.24 Polymerase chain reaction was performed with oligonucleotide primers flanking the polymorphism (corresponding to nucleotide positions −1416 to −1397 [stpr5, 5′-GGCGTTGCCGCTCTGAATGC] and −910 to −888 [stpr3, 5′-GAGGGACTGAGCTGGACAACCAC]) of the 5′-flanking regulatory region of SLC6A4 to generate a 484-bp (S short allele) or a 528-bp (L long allele) polymerase chain reaction product. Polymerase chain reaction amplification was performed in a final volume of 30 μL with 50 ng of genomic DNA, 2.5mM deoxyribonucleotides (dGTP/7-deaza-2′-dGTP = l/l), 0.1 μg of sense and antisense primers, 10mM Tris hydrochloride (pH 8.3), 50mM potassium chloride, 1.5mM magnesium chloride, and 1 U of Taq DNA polymerase. As a quality control, 5% of the samples were randomly chosen and retested; their genotypes were consistent with previous results.

CHILD EMOTIONAL WELL-BEING AND BEHAVIOR

The Child Behavior Checklist (ages 1.5-5 years) (CBCL)38 was completed by the mother. This widely used and well-validated scale provides standardized ratings of behavior in children aged 1.5 to 5 years. The CBCL yields a total problem score, externalizing and internalizing scores, and subscale scores (emotionally reactive, depressed/anxious, withdrawn, somatic complaints, sleep problems, attention, and aggression). Scale scores were used in analyses. The CBCL also yields T scores, with the mean (SD) set at 50 (10). T scores were reported because of their widespread clinical application, and they were used only for descriptive purposes. Raw untransformed scores were used in the primary analyses.

MATERNAL MOOD

Maternal mood was assessed during the third trimester of pregnancy, a mean of 33.7 weeks' gestation, and again 3 months post partum using 4 instruments. During the pregnancy and 3 months post partum, the HAMD,39 a 21-item clinician-rated measure of depressive symptoms with a score ranging from 0 to 63, and the Hamilton Rating Scale for Anxiety (HAMA),40 a 14-item clinician-rated measure of anxiety with a score ranging from 0 to 56 (minimal to severe levels), were used. At the time of the 3-year follow-up study, maternal mood was assessed using the Beck Depression Inventory,41 a 21-question multiple-choice self-report inventory for measuring depression with scores ranging from 0 to 63, and the Beck Anxiety Inventory,42 a 21-question multiple-choice self-report inventory used for measuring severity of anxiety during the last week with scores also ranging from 0 to 63. Total scores were used in the analyses.

STATISTICAL ANALYSIS

Analyses were undertaken in 2 stages. In the first stage, analyses of covariance were used to examine group (SSRI-exposed vs nonexposed) differences in child behavior using measures of prenatal (third-trimester) and postnatal (3-month and 3-year) maternal mood and neonatal risk (5-minute Apgar score) as covariates. Measures of maternal anxious and depressed mood were used in separate models. Because maternal mood measures varied between groups and during the antenatal and postpartum periods, they were used as continuous covariate measures. In the second stage, similar analytical models (analyses of covariance) were used to examine interactions between exposure group and SLC6A4 genotype (ss, sl, and ll), testing the role of genotype as a possible moderator of the effects of prenatal exposure on behavior. In this stage, measures of prenatal (third-trimester) and postnatal (3-month and 3-year) maternal mood and neonatal risk (5-minute Apgar score) were used as covariates. We calculated effect sizes (η2) to examine the strength of these associations because the statistical significance of the findings would be affected by sample size and potentially by multiple comparisons.

MATERNAL AND CHILD CHARACTERISTICS

Except for mood symptoms, educational level, and antidepressant medication use, maternal characteristics did not vary significantly between groups (P > .05) (Table 1 and Table 2). The SSRI-treated mothers had approximately 2.5 fewer years of higher education (F = 9.1; P = .03, η2 = 0.09). Levels of maternal depression and anxiety symptoms during pregnancy and at 3 months post partum were 2 to 3 times higher in the SSRI-treated group than in the non-SSRI group (P < .001 for all), and they remained so 3 to 4 years post partum (P < .05 for all). All of the mothers took a prenatal vitamin containing the prenatal folic acid dose (0.8-1.0 mg). At the time of the 3-year study, most mothers in the prenatal SSRI-treated group were still taking medication, and 4 of the nonprenatally treated mothers had begun to take an SSRI (Table 2). Mothers in both groups were equally concerned about their child's development, and none of the children were taking psychotropic medications at the time of the study. No interactions between time and group for any measure were observed (P > .05 for all) (Table 3). At 3 years, 78% of SSRI-exposed and 79% of nonexposed children who had been studied as neonates returned for this follow-up study. Child characteristics did not differ significantly between those who were studied at 3 years and those who were not studied (P > .05) (Table 4).

Table Graphic Jump LocationTable 2. Maternal Mood From the Third Trimester to 3 Years Post Partum
Table Graphic Jump LocationTable 4. Characteristics of Children Studied vs Not Studied at 3 Years

SLC6A4 genotype ratios were distributed according to Hardy-Weinberg equilibrium for all 140 participants (68 children and 72 mothers: 7 child and 3 maternal samples were of poor quality and were not analyzed) together (allele frequency—children: L = 57.3% and S = 42.7%; maternal: L = 56.3% and S = 43.8%; and genotype frequency—child: ll = 32.4%, ls = 50.0%, and ss = 17.6%; maternal: ll = 33.3%, ls = 45.8%, and ss = 20.8%) and for mothers and infants separately (Tables 1 and 3). The allele frequency and genotype distribution was not different between SSRI-exposed and nonexposed mothers. Mean daily dose and length of prenatal SSRI exposure did not vary significantly between genotypes (P > .05).

MODEL 1: CHILD BEHAVIORAL OUTCOMES
Internalizing Behaviors

Higher internalizing scores were associated with prenatal SSRI exposure and increased levels of maternal anxiety at the time of the 3-year study (F = 3.978, P = .05, η2 = 0.06 and F = 4.517, P = .04, η2 = 0.07, respectively), controlling for third-trimester anxiety (HAMA) scores, 5-minute Apgar scores, and 3-month postpartum HAMA scores (Table 5). When controlling for prenatal and postnatal maternal depressed mood (HAMD) and 5-minute Apgar scores in a separate model, higher levels of internalizing symptoms were predicted by higher levels of maternal depression symptoms 3 years post partum (F = 5.816, P = .02, η2 = 0.08) but not by prenatal SSRI exposure (F = 3.396, P = .07, η2 = 0.05).

Externalizing Behaviors

Increased levels of externalizing behaviors were also associated with 3-year postpartum levels of maternal anxiety (Beck Anxiety Inventory) and depression symptoms (Beck Depression Inventory) using prenatal and postnatal HAMA and HAMD measures (in separate models) and 5-minute Apgar scores as covariates (F = 4.562, P = .04, η2 = 0.07 and F = 6.75, P = .01, η2 = 0.11 for Beck Anxiety Inventory/HAMA and Beck Depression Inventory/HAMD, respectively). Neither prenatal SSRI exposure nor maternal years of education contributed to externalizing symptoms in either model (P > .25) (Table 5).

CBCL Subscale Scores

Of the internalizing behavior subscales, prenatal SSRI exposure predicted increased levels of somatic complaints (F = 8.7, P < .01, η2 = 0.12) and sleep disturbances (F = 4.8, P = .03, η2 = 0.07). Increased maternal anxiety at the time of the 3-year study predicted child somatic (F = 7.918, P < .01, η2 = 0.11) and emotionally reactive (F = 5.8, P = .02, η2 = 0.08) symptoms. Similarly, in separate models, increased levels of maternal depressed mood at 3 years predicted increased emotionally reactive symptoms (F = 5.7, P = .02, η2 = 0.08), whereas withdrawal behaviors were not associated with prenatal SSRI exposure or maternal mood (P > .05). Externalizing subscale scores (aggression and attention) were not associated with prenatal SSRI exposure or measures of maternal mood (P > .05).

MODEL 2: EFFECT OF THE CHILD SLC6A4 GENOTYPE

When the child SLC6A4 genotype was added to the model, significant interactions with maternal third-trimester measures of mood emerged. Increased externalizing symptoms at 3 years were predicated by an interaction between third-trimester maternal anxiety and the child SLC6A4 genotype (F = 3.954, P = .03, η2 = 0.13). In particular, higher externalizing symptoms (F = 5.945, P = .03, η2 = 0.30) and increased aggressiveness (F = 4.97, P = .04, η2 = 0.26) were predicted by higher third-trimester maternal anxiety only in children with 2 long alleles (ll) (Figure 1).

Place holder to copy figure label and caption
Figure 1.

The child SLC6A4 genotype moderated the impact of third-trimester maternal anxiety on child anxiety behaviors at 3 years of age. HAMA indicates Hamilton Anxiety Scale.

Graphic Jump Location

Increased child anxiety and depression symptoms were predicted (in separate models) by the interaction between both third-trimester maternal anxiety and depression symptoms and the child SLC6A4 genotype (F = 6.055, P < .01, η2 = 0.19 and F = 6.328, P < .01, η2 = 0.20, respectively). Specifically, increased child anxiety and depression symptoms were predicted by higher third-trimester maternal anxiety and depression symptom scores only in children with 2 short alleles (ss) (F = 7.128, P = .04, η2 = 0.54) (Figure 2). No interactions were noted between child genotype and SSRI exposure in either model.

Place holder to copy figure label and caption
Figure 2.

The child SLC6A4 genotype moderated the impact of third-trimester maternal anxiety on child aggressive behaviors at 3 years of age. HAMA indicates Hamilton Anxiety Scale.

Graphic Jump Location

Child behavior and prenatal maternal anxiety were not associated in children with 1 long and 1 short allele (F = 0.048, P = .83, η2 = 0.002 for anxious/depressed behavior; F = 0.324, P = .57, η2 = 0.011 for aggressive behavior). Neither child sex nor maternal SLC6A4 genotype affected behavioral symptoms.

Prenatal SSRI exposure and higher current maternal anxiety contributed to increased internalizing behaviors in 3-year-old children. Increased levels of externalizing behaviors were also observed, but they were associated with current levels of 3-year postpartum maternal mood. Beyond the effects of prenatal exposure to SSRIs and maternal mood, the child SLC6A4 genotype moderated the impact of exposure to third-trimester maternal mood.

The SSRIs are often used to manage antenatal mood disturbances11 with the expectation that they optimize maternal mental health,10 thereby reducing child behavioral risk. However, child behavioral disturbances were still observed at 3 years even after prenatal and postpartum SSRI treatment, suggesting that such maternal antidepressant therapy did not buffer the children from the ongoing effects of maternal mood disturbances. Although maternal education differed between exposure groups, this did not contribute to child behavioral outcomes.

Children with poor or inefficient transcription of SLC6A4 (ss genotype), resulting in reduced levels of serotonin transporter protein and potentially reduced serotonin reuptake, coupled with third-trimester exposure to maternal anxiety, were seen as more anxious or depressed by their mothers, even controlling for prenatal SSRI exposure, perinatal risk, and postnatal (3-month) and 3-year postpartum maternal mood. This may reflect an effect related to increased intrasynaptic prenatal serotonin exposure and receptor sensitivity at critical periods of development, consistent with an extreme manipulation in central serotonin using a SLC6A4 knockout animal model.20 A child with 2 short alleles may have received a higher “effective” prenatal “serotonin dose” during fetal brain development, secondary to reduced serotonin transporter, thereby increasing risk of anxiety or depression symptoms during early childhood. In contrast, increased externalizing and aggressive behaviors were predicted by third-trimester maternal mood in children with 2 copies of the long allele, presumably reflecting the effect of relatively “increased” serotonin reuptake, leading to a “deficiency” in intrasynaptic serotonin, coupled with late gestational maternal anxious and depressed mood. This could be analogous to the low central serotonergic tone coupled with genetic and early rearing experiences (parental deprivation) that have been reported in nonhuman primates with impaired impulse control, aggression, and low social dominance.43 Similarly, early central serotonin alterations secondary to SSRI-related serotonin reuptake blockade could, via a variety of genetic and neurotransmitter-related mechanisms, lead to sustained developmental and behavioral consequences.20,44 Although the effects of prenatal SSRI exposure, which presumably also affected intrasynaptic serotonin levels in the developing brain, were not modified by SLC6A4 genotype, a direct prenatal effect of SSRIs on 5-HTT function as an influence on central serotonergic tone could not be ruled out, as has been reported in animal models.45,46

Beyond infancy, few studies report a main effect of SSRIs. Most such studies report that irrespective of prenatal exposure, maternal mood predicts childhood behavior. In SSRI-exposed infants aged 6 to 40 months,35 poorer psychomotor development (Psychomotor Developmental Index and Bayley Scales of Infant Development) was observed, although the contribution of postnatal maternal mood was unclear. Early gestational fluoxetine exposure did not affect IQ, language, or behavioral outcomes in preschool-aged children compared with children with other antidepressant (tricyclic antidepressant) exposure,47 although development was affected by longer or more frequent episodes of postnatal maternal depression.36 At age 4 years, internalizing and externalizing behaviors were predicted by current levels of maternal mood in prenatally exposed children13,37; however, externalizing behaviors and reduced task persistence and increased aggressiveness were associated with increased cord drug levels and a history of neonatal withdrawal symptoms, suggesting that early neurobehavioral and pharmacologic factors may predict subsequent behavioral vulnerability.13

Several limitations need mentioning. Measures of child behavior in this study were limited to maternal reports, which raises a key concern that child behavioral ratings may have been subject to reporter bias. Anxious and depressed mothers may have been more likely to either overreport or underreport behavioral disturbances. However, if such a bias existed, as has been previously observed,1 this would not explain the moderating effect of the SLC6A4 genotype. This study examined associations between antenatal exposure to SSRIs and maternal mood disturbances and, in this sense, was unable to address causality or direction of effect. The study cohort was a convenience sample, and several key unmeasured maternal characteristics may have affected child outcomes, such as social and family factors inherent to mental illness during and after pregnancy. Because the mothers in the SSRI-treated group were already symptomatic and taking SSRIs at the time of conception, there may have been factors that affected fetal development long before the mothers were recruited into this study or even before they conceived. Ideally, the use of a randomized controlled study design may be regarded as an appropriate study design; however, given the evanescent nature of perinatal maternal mood disorders, a randomized study examining the effects of prenatal antidepressant exposure was not considered appropriate for ethical, logistic, and medical reasons. Although differences between children lost to follow-up from the original cohort and those studied were nonsignificant, missing data may have introduced another limitation to the generalizability of these findings. Because we had no previous behavioral data, we did not impute the missing data.

In summary, prenatal exposure to both maternal mood and SSRI antidepressants were associated with increased internalizing behaviors during early childhood, whereas current maternal mood increased risk for externalizing behaviors. The impact of third trimester maternal anxiety on child mood was moderated by the child SLC6A4 genotype. In offspring with reduced 5-HTT expression (short alleles), antenatal maternal mood predicted increased vulnerability to anxiety at 3 years, whereas 2 long alleles predicted aggressive behaviors, suggesting fetal genotype-specific serotonergic programming. Even with prenatal maternal SSRI treatment, mothers continue to be symptomatic, and child behavior at 3 years of age continues to be at risk.

Correspondence: Tim F. Oberlander, MD, FRCPC, Early Human Experience Unit, Developmental Neurosciences and Child Health, Child and Family Research Institute, 4480 Oak St, Room L408, Vancouver, BC V6H 3V4, Canada.

Accepted for Publication: January 6, 2010.

Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Oberlander and Grunau. Acquisition of data: Oberlander, Brain, and Misri. Analysis and interpretation of data: Oberlander, Papsdorf, Ross, and Grunau. Drafting of the manuscript: Oberlander and Papsdorf. Critical revision of the manuscript for important intellectual content: Oberlander, Papsdorf, Brain, Misri, Ross, and Grunau. Statistical analysis: Oberlander and Papsdorf. Obtained funding: Oberlander. Administrative, technical, and material support: Oberlander, Brain, Misri, and Ross. Study supervision: Oberlander.

Financial Disclosure: None reported.

Funding/Support: This research was funded by grant 12-FY01-30 from the March of Dimes Foundation and by grants MOP 54490 and 57837 from the Canadian Institutes of Health Research. Dr Oberlander is supported by a Human Early Learning Partnership Senior Career Award and is the R. Howard Webster Professorship in Child Development (University of British Columbia, Faculty of Graduate Studies).

Role of the Sponsors: The study sponsors had no role in the study design; in the data collection, analysis, or interpretation; in the writing of the paper; or in the decision to submit the paper for publication.

Online-Only Material: This article is featured in the Archives Journal Club. Go here to download teaching PowerPoint slides.

Additional Contributions: Mary Beckingham, Ari Sanders, BSc, and Wendy Frasca, BA, contributed to the organizing and facilitating of this research program. We are grateful to the mothers and their infants who participated and contributed to this work.

O'Connor  TGHeron  JGlover  VAlspac Study Team, Antenatal anxiety predicts child behavioral/emotional problems independently of postnatal depression. J Am Acad Child Adolesc Psychiatry 2002;41 (12) 1470- 1477
PubMed Link to Article
O'Connor  TGBen Shlomo  YHeron  JGolding  JAdams  DGlover  V Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children. Biol Psychiatry 2005;58 (3) 211- 217
PubMed Link to Article
Talge  NMNeal  CGlover  VEarly Stress, Translational Research and Prevention Science Network: Fetal and Neonatal Experience on Child and Adolescent Mental Health, Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? J Child Psychol Psychiatry 2007;48 (3-4) 245- 261
PubMed Link to Article
Van den Bergh  BRMulder  EJMennes  MGlover  V Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms: a review. Neurosci Biobehav Rev 2005;29 (2) 237- 258
PubMed Link to Article
Maccari  SPiazza  PVKabbaj  MBarbazanges  ASimon  HLemoal  M Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress. J Neurosci 1995;15 (1, pt 1) 110- 116
PubMed
Schneider  MLMoore  CF Effect of prenatal stress on development: a nonhuman primate model. Nelson  CAEffects of Early Adversity on Neurobehavioral Development. Mahwah, NJ Lawrence Erlbaum Associates Inc2000;201- 244Minnesota Symposium on Child Psychologyvol 31
Weinstock  M Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog Neurobiol 2001;65 (5) 427- 451
PubMed Link to Article
Van den Bergh  BRMennes  MOosterlaan  J  et al.  High antenatal maternal anxiety is related to impulsivity during performance on cognitive tasks in 14- and 15-year-olds. Neurosci Biobehav Rev 2005;29 (2) 259- 269
PubMed Link to Article
O'Connor  TGHeron  JGolding  JGlover  VALSPAC Study Team, Maternal antenatal anxiety and behavioural/emotional problems in children: a test of a programming hypothesis. J Child Psychol Psychiatry 2003;44 (7) 1025- 1036
PubMed Link to Article
Van den Bergh  BRMarcoen  A High antenatal maternal anxiety is related to ADHD symptoms, externalizing problems, and anxiety in 8- and 9-year-olds. Child Dev 2004;75 (4) 1085- 1097
PubMed Link to Article
Ansorge  MSMorelli  EGingrich  JA Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice. J Neurosci 2008;28 (1) 199- 207
PubMed Link to Article
Oberlander  TFWarburton  WMisri  SAghajanian  JHertzman  C Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 2006;63 (8) 898- 906
PubMed Link to Article
Oberlander  TFReebye  PMisri  SPapsdorf  MKim  JGrunau  RE Externalizing and attentional behaviors in children of depressed mothers treated with a selective serotonin reuptake inhibitor antidepressant during pregnancy. Arch Pediatr Adolesc Med 2007;161 (1) 22- 29
PubMed Link to Article
Whitaker-Azmitia  PMDruse  MWalker  PLauder  JM Serotonin as a developmental signal. Behav Brain Res 1996;73 (1-2) 19- 29
PubMed Link to Article
Kim  JRiggs  KWMisri  S  et al.  Stereoselective disposition of fluoxetine and norfluoxetine during pregnancy and breast-feeding. Br J Clin Pharmacol 2006;61 (2) 155- 163
PubMed Link to Article
de Montigny  CChaput  YBlier  P Modification of serotonergic neuron properties by long-term treatment with serotonin reuptake blockers. J Clin Psychiatry 1990;51 ((suppl B)) 4- 8
PubMed
Field  TDiego  MDieter  J  et al.  Prenatal depression effects on the fetus and the newborn. Infant Behav Dev 2004;27 (2) 216- 229
Link to Article
Gaspar  PCases  OMaroteaux  L The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 2003;4 (12) 1002- 1012
PubMed Link to Article
Lesch  KPMossner  R Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders? Biol Psychiatry 1998;44 (3) 179- 192
PubMed Link to Article
Ansorge  MSZhou  MLira  AHen  RGingrich  JA Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 2004;306 (5697) 879- 881
PubMed Link to Article
 Online Mendelian Inheritance in Man (OMIM). Solute carrier family 6 (neurotransmitter transporter, serotonin), member 4; SLC6A4. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=182138.
Kim  DKLim  SWLee  S  et al.  Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 2000;11 (1) 215- 219
PubMed Link to Article
Ramamoorthy  SBauman  ALMoore  KR  et al.  Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A 1993;90 (6) 2542- 2546
PubMed Link to Article
Lesch  KPWolozin  BLEstler  HCMurphy  DLRiederer  P Isolation of a cDNA encoding the human brain serotonin transporter. J Neural Transm Gen Sect 1993;91 (1) 67- 72
PubMed Link to Article
Lesch  KPBengel  DHeils  A  et al.  Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996;274 (5292) 1527- 1531
PubMed Link to Article
Heils  ATeufel  APetri  S  et al.  Allelic variation of human serotonin transporter gene expression. J Neurochem 1996;66 (6) 2621- 2624
PubMed Link to Article
Pollock  BGFerrell  REMulsant  BH  et al.  Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000;23 (5) 587- 590
PubMed Link to Article
Collier  DAStober  GLi  T  et al.  A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1996;1 (6) 453- 460
PubMed
Yu  YWTsai  SJChen  TJLin  CHHong  CJ Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 2002;7 (10) 1115- 1119
PubMed Link to Article
Murphy  GM  JrHollander  SBRodrigues  HEKremer  CSchatzberg  AF Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry 2004;61 (11) 1163- 1169
PubMed Link to Article
Rausch  JLJohnson  MEFei  YJ  et al.  Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol Psychiatry 2002;51 (9) 723- 732
PubMed Link to Article
Smeraldi  EZanardi  RBenedetti  FDi Bella  DPerez  JCatalano  M Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 1998;3 (6) 508- 511
PubMed Link to Article
Caspi  ASugden  KMoffitt  TE  et al.  Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301 (5631) 386- 389
PubMed Link to Article
Oberlander  TFBonaguro  RJMisri  SPapsdorf  MRoss  CJSimpson  EM Infant serotonin transporter (SLC6A4) promoter genotype is associated with adverse neonatal outcomes after prenatal exposure to serotonin reuptake inhibitor medications. Mol Psychiatry 2008;13 (1) 65- 73
PubMed Link to Article
Casper  RCFleisher  BELee-Ancajas  JC  et al.  Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr 2003;142 (4) 402- 408
PubMed Link to Article
Nulman  IRovet  JStewart  DE  et al.  Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002;159 (11) 1889- 1895
PubMed Link to Article
Misri  SReebye  PKendrick  K  et al.  Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. Am J Psychiatry 2006;163 (6) 1026- 1032
PubMed Link to Article
Achenbach  TM Manual for the Child Behavior Checklist/2-3 and 1992 Profile.  Burlington Dept of Psychiatry, University of Vermont1992;
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol 1959;32 (1) 50- 55
PubMed Link to Article
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMed Link to Article
Beck  ATEpstein  NBrown  GSteer  RA An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988;56 (6) 893- 897
PubMed Link to Article
Higley  JDLinnoila  M Low central nervous system serotonergic activity is traitlike and correlates with impulsive behavior: a nonhuman primate model investigating genetic and environmental influences on neurotransmission. Ann N Y Acad Sci 1997;83639- 56
PubMed Link to Article
Borue  XChen  JCondron  BG Developmental effects of SSRIs: lessons learned from animal studies. Int J Dev Neurosci 2007;25 (6) 341- 347
PubMed Link to Article
Cabrera-Vera  TMBattaglia  G Prenatal exposure to fluoxetine (Prozac) produces site-specific and age-dependent alterations in brain serotonin transporters in rat progeny: evidence from autoradiographic studies. J Pharmacol Exp Ther 1998;286 (3) 1474- 1481
PubMed
Owens  MJKrulewicz  SSimon  JS  et al.  Estimates of serotonin and norepinephrine transporter inhibition in depressed patients treated with paroxetine or venlafaxine. Neuropsychopharmacology 2008;33 (13) 3201- 3212
PubMed Link to Article
Nulman  IRovet  JStewart  DE  et al.  Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997;336 (4) 258- 262
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

The child SLC6A4 genotype moderated the impact of third-trimester maternal anxiety on child anxiety behaviors at 3 years of age. HAMA indicates Hamilton Anxiety Scale.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

The child SLC6A4 genotype moderated the impact of third-trimester maternal anxiety on child aggressive behaviors at 3 years of age. HAMA indicates Hamilton Anxiety Scale.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 2. Maternal Mood From the Third Trimester to 3 Years Post Partum
Table Graphic Jump LocationTable 4. Characteristics of Children Studied vs Not Studied at 3 Years

References

O'Connor  TGHeron  JGlover  VAlspac Study Team, Antenatal anxiety predicts child behavioral/emotional problems independently of postnatal depression. J Am Acad Child Adolesc Psychiatry 2002;41 (12) 1470- 1477
PubMed Link to Article
O'Connor  TGBen Shlomo  YHeron  JGolding  JAdams  DGlover  V Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children. Biol Psychiatry 2005;58 (3) 211- 217
PubMed Link to Article
Talge  NMNeal  CGlover  VEarly Stress, Translational Research and Prevention Science Network: Fetal and Neonatal Experience on Child and Adolescent Mental Health, Antenatal maternal stress and long-term effects on child neurodevelopment: how and why? J Child Psychol Psychiatry 2007;48 (3-4) 245- 261
PubMed Link to Article
Van den Bergh  BRMulder  EJMennes  MGlover  V Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms: a review. Neurosci Biobehav Rev 2005;29 (2) 237- 258
PubMed Link to Article
Maccari  SPiazza  PVKabbaj  MBarbazanges  ASimon  HLemoal  M Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress. J Neurosci 1995;15 (1, pt 1) 110- 116
PubMed
Schneider  MLMoore  CF Effect of prenatal stress on development: a nonhuman primate model. Nelson  CAEffects of Early Adversity on Neurobehavioral Development. Mahwah, NJ Lawrence Erlbaum Associates Inc2000;201- 244Minnesota Symposium on Child Psychologyvol 31
Weinstock  M Alterations induced by gestational stress in brain morphology and behaviour of the offspring. Prog Neurobiol 2001;65 (5) 427- 451
PubMed Link to Article
Van den Bergh  BRMennes  MOosterlaan  J  et al.  High antenatal maternal anxiety is related to impulsivity during performance on cognitive tasks in 14- and 15-year-olds. Neurosci Biobehav Rev 2005;29 (2) 259- 269
PubMed Link to Article
O'Connor  TGHeron  JGolding  JGlover  VALSPAC Study Team, Maternal antenatal anxiety and behavioural/emotional problems in children: a test of a programming hypothesis. J Child Psychol Psychiatry 2003;44 (7) 1025- 1036
PubMed Link to Article
Van den Bergh  BRMarcoen  A High antenatal maternal anxiety is related to ADHD symptoms, externalizing problems, and anxiety in 8- and 9-year-olds. Child Dev 2004;75 (4) 1085- 1097
PubMed Link to Article
Ansorge  MSMorelli  EGingrich  JA Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice. J Neurosci 2008;28 (1) 199- 207
PubMed Link to Article
Oberlander  TFWarburton  WMisri  SAghajanian  JHertzman  C Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 2006;63 (8) 898- 906
PubMed Link to Article
Oberlander  TFReebye  PMisri  SPapsdorf  MKim  JGrunau  RE Externalizing and attentional behaviors in children of depressed mothers treated with a selective serotonin reuptake inhibitor antidepressant during pregnancy. Arch Pediatr Adolesc Med 2007;161 (1) 22- 29
PubMed Link to Article
Whitaker-Azmitia  PMDruse  MWalker  PLauder  JM Serotonin as a developmental signal. Behav Brain Res 1996;73 (1-2) 19- 29
PubMed Link to Article
Kim  JRiggs  KWMisri  S  et al.  Stereoselective disposition of fluoxetine and norfluoxetine during pregnancy and breast-feeding. Br J Clin Pharmacol 2006;61 (2) 155- 163
PubMed Link to Article
de Montigny  CChaput  YBlier  P Modification of serotonergic neuron properties by long-term treatment with serotonin reuptake blockers. J Clin Psychiatry 1990;51 ((suppl B)) 4- 8
PubMed
Field  TDiego  MDieter  J  et al.  Prenatal depression effects on the fetus and the newborn. Infant Behav Dev 2004;27 (2) 216- 229
Link to Article
Gaspar  PCases  OMaroteaux  L The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 2003;4 (12) 1002- 1012
PubMed Link to Article
Lesch  KPMossner  R Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders? Biol Psychiatry 1998;44 (3) 179- 192
PubMed Link to Article
Ansorge  MSZhou  MLira  AHen  RGingrich  JA Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 2004;306 (5697) 879- 881
PubMed Link to Article
 Online Mendelian Inheritance in Man (OMIM). Solute carrier family 6 (neurotransmitter transporter, serotonin), member 4; SLC6A4. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=182138.
Kim  DKLim  SWLee  S  et al.  Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 2000;11 (1) 215- 219
PubMed Link to Article
Ramamoorthy  SBauman  ALMoore  KR  et al.  Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A 1993;90 (6) 2542- 2546
PubMed Link to Article
Lesch  KPWolozin  BLEstler  HCMurphy  DLRiederer  P Isolation of a cDNA encoding the human brain serotonin transporter. J Neural Transm Gen Sect 1993;91 (1) 67- 72
PubMed Link to Article
Lesch  KPBengel  DHeils  A  et al.  Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996;274 (5292) 1527- 1531
PubMed Link to Article
Heils  ATeufel  APetri  S  et al.  Allelic variation of human serotonin transporter gene expression. J Neurochem 1996;66 (6) 2621- 2624
PubMed Link to Article
Pollock  BGFerrell  REMulsant  BH  et al.  Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000;23 (5) 587- 590
PubMed Link to Article
Collier  DAStober  GLi  T  et al.  A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1996;1 (6) 453- 460
PubMed
Yu  YWTsai  SJChen  TJLin  CHHong  CJ Association study of the serotonin transporter promoter polymorphism and symptomatology and antidepressant response in major depressive disorders. Mol Psychiatry 2002;7 (10) 1115- 1119
PubMed Link to Article
Murphy  GM  JrHollander  SBRodrigues  HEKremer  CSchatzberg  AF Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression. Arch Gen Psychiatry 2004;61 (11) 1163- 1169
PubMed Link to Article
Rausch  JLJohnson  MEFei  YJ  et al.  Initial conditions of serotonin transporter kinetics and genotype: influence on SSRI treatment trial outcome. Biol Psychiatry 2002;51 (9) 723- 732
PubMed Link to Article
Smeraldi  EZanardi  RBenedetti  FDi Bella  DPerez  JCatalano  M Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 1998;3 (6) 508- 511
PubMed Link to Article
Caspi  ASugden  KMoffitt  TE  et al.  Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301 (5631) 386- 389
PubMed Link to Article
Oberlander  TFBonaguro  RJMisri  SPapsdorf  MRoss  CJSimpson  EM Infant serotonin transporter (SLC6A4) promoter genotype is associated with adverse neonatal outcomes after prenatal exposure to serotonin reuptake inhibitor medications. Mol Psychiatry 2008;13 (1) 65- 73
PubMed Link to Article
Casper  RCFleisher  BELee-Ancajas  JC  et al.  Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr 2003;142 (4) 402- 408
PubMed Link to Article
Nulman  IRovet  JStewart  DE  et al.  Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002;159 (11) 1889- 1895
PubMed Link to Article
Misri  SReebye  PKendrick  K  et al.  Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications. Am J Psychiatry 2006;163 (6) 1026- 1032
PubMed Link to Article
Achenbach  TM Manual for the Child Behavior Checklist/2-3 and 1992 Profile.  Burlington Dept of Psychiatry, University of Vermont1992;
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol 1959;32 (1) 50- 55
PubMed Link to Article
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 571
PubMed Link to Article
Beck  ATEpstein  NBrown  GSteer  RA An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988;56 (6) 893- 897
PubMed Link to Article
Higley  JDLinnoila  M Low central nervous system serotonergic activity is traitlike and correlates with impulsive behavior: a nonhuman primate model investigating genetic and environmental influences on neurotransmission. Ann N Y Acad Sci 1997;83639- 56
PubMed Link to Article
Borue  XChen  JCondron  BG Developmental effects of SSRIs: lessons learned from animal studies. Int J Dev Neurosci 2007;25 (6) 341- 347
PubMed Link to Article
Cabrera-Vera  TMBattaglia  G Prenatal exposure to fluoxetine (Prozac) produces site-specific and age-dependent alterations in brain serotonin transporters in rat progeny: evidence from autoradiographic studies. J Pharmacol Exp Ther 1998;286 (3) 1474- 1481
PubMed
Owens  MJKrulewicz  SSimon  JS  et al.  Estimates of serotonin and norepinephrine transporter inhibition in depressed patients treated with paroxetine or venlafaxine. Neuropsychopharmacology 2008;33 (13) 3201- 3212
PubMed Link to Article
Nulman  IRovet  JStewart  DE  et al.  Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997;336 (4) 258- 262
PubMed Link to Article

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