Sarah M Hutchison
email: shutchison@bcchr.ca

Louise C Mâsse
email: lmasse@bcchr.ubc.ca

Jodi L Pawluski
email: j.pawluski@gmail.com

Tim F Oberlander
email: toberlander@bcchr.ca

Perinatal Selective Serotonin Reuptake Inhibitor (SSRI) and Other Antidepressant Exposure Effects on Anxiety and Depressive Behaviors in Offspring: A Review of Findings in Humans and Rodent Models

Perinatal selective serotonin reuptake inhibitor (SSRI) and other antidepressant exposure effects on anxiety and depressive behaviors in offspring: A review of findings in humans and rodent models

Introduction

Up to 20% of pregnant mothers experience depressed mood [START_REF] Pawluski | The neurobiology of postpartum anxiety and depression[END_REF] and are commonly treated with selective serotonin reuptake inhibitor antidepressant medications (SSRIs) (i.e. fluoxetine, paroxetine, sertraline, citalopram) [START_REF] Charlton | Selective serotonin reuptake inhibitor prescribing before, during and after pregnancy: A population-based study in six European regions[END_REF]Oberlander, Warburton, Misri, Aghajanian, & Hertzman, 2006) . SSRI use by pregnant women ranges between 5 and 13% in Australia and the USA, and between 2 and 7% in Canada and Western European countries [START_REF] Charlton | Selective serotonin reuptake inhibitor prescribing before, during and after pregnancy: A population-based study in six European regions[END_REF]Cooper et al., 2007;Hayes et al., 2012;Lupattelli et al., 2014;[START_REF] Misri | Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications[END_REF]Zoega et al., 2015). These medications readily cross the placenta and have been reported in breast milk (Kim et al., 2006a;b;[START_REF] Rampono | Placental transfer of SSRI and SNRI antidepressants and effects on the neonate[END_REF]. SSRIs inhibit the reuptake of serotonin (5-HT), via 5-HT transporter blockade at presynaptic neurons, thereby increasing synaptic 5-HT concentrations (Whitaker- [START_REF] Whitaker-Azmitia | Serotonin as a developmental signal[END_REF]. 5-HT is a key neurotransmitter [START_REF] Hellendall | Prenatal expression of 5-HT1C and 5-HT2 receptors in the rat central nervous system[END_REF] widely distributed throughout key brain regions that influence cognition, attention, stress, and emotion regulation (Lesch, 2007;[START_REF] Lucki | The spectrum of behaviors influenced by serotonin[END_REF].

Serotonergic neurons appear as early as 5 weeks gestation (Lira et al., 2003) and setting appropriate 5-HT levels during early brain growth is central to the regulation of social/emotional and cognitive development (i.e. amygdala, prefrontal cortex) [START_REF] Mart N-Ruiz | Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism[END_REF][START_REF] Miller | Development of specificity and stereoselectivity of rat brain dopamine receptors[END_REF]. 5-HT is implicated in the pathophysiology of numerous psychiatric and developmental disorders [START_REF] Azmitia | Serotonin neurons, neuroplasticity, and homeostasis of neural tissue[END_REF][START_REF] Curtius | Serotonin and dopamine synthesis in phenylketonuria[END_REF][START_REF] Nielsen | Biochemical and clinical effects of tyrosine and tryptophan in the Rett syndrome[END_REF] and is a target of numerous pharmacological therapies. Long before 5-HT becomes a neurotransmitter in the mature brain, it plays a role as a neurodevelopmental signal and regulates cell growth [START_REF] Pino | Roles for serotonin in neurodevelopment: more than just neural transmission[END_REF][START_REF] Huether | Administration of tryptophan-enriched diets to pregnant rats retards the development of the serotonergic system in their offspring[END_REF][START_REF] Whitaker-Azmitia | Serotonin as a developmental signal[END_REF]. In the fetal brain, 5-HT and its receptors are over-expressed and widespread in regions where they are absent in adults [START_REF] Miller | Development of specificity and stereoselectivity of rat brain dopamine receptors[END_REF][START_REF] Seeman | Human brain dopamine receptors in children and aging adults[END_REF] pointing to a time-dependent specificity to 5-HT expression during development. Thus, early alterations of 5-HT, either via environmental or genetic manipulations, can change neural development [START_REF] Oberlander | Sustained neurobehavioral effects of exposure to SSRI antidepressants during development: molecular to clinical evidence[END_REF]. Manipulating prenatal1 5-HT levels in animal models using genetic variations, 5-HT agonists, or SSRI exposure, alters brain morphology and may constrain 5-HT maturation in ways that result in increased risk of anxietyand depressive-like behaviors (Homberg, Schubert, & Gaspar, 2010).

In humans, there have been reports that prenatal SSRI exposure is associated with increased internalizing and anxiety behaviors during early childhood [START_REF] Brandlistuen | Behavioural effects of fetal antidepressant exposure in a Norwegian cohort of discordant siblings[END_REF][START_REF] Hanley | Prenatal exposure to serotonin reuptake inhibitor antidepressants and childhood behavior[END_REF][START_REF] Hermansen | Behavior and inhibitory control in children with prenatal exposure to antidepressants and medically untreated depression[END_REF] and higher rates of depression diagnoses [START_REF] Malm | Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: a national register-based study[END_REF], but this is not always the case [START_REF] Grzeskowiak | Prenatal antidepressant exposure and child behavioural outcomes at 7 years of age: A study within the Danish National Birth Cohort[END_REF][START_REF] Lupattelli | Effect of time-dependent selective serotonin reuptake inhibitor antidepressants during pregnancy on behavioral, emotional, and social development in preschool-aged children[END_REF][START_REF] Misri | Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications[END_REF][START_REF] Nulman | Neurodevelopment of children following prenatal exposure to venlafaxine, selective serotonin reuptake inhibitors, or untreated maternal depression[END_REF][START_REF] Glover | Prenatal stress and its effects on the fetus and the child: possible underlying biological mechanisms[END_REF]Pedersen et al., 2013). In rodent models there are also reports that pre-and post-natal2 SSRI exposure impacts affective behaviors in offspring, but these effects vary based on methodological factors (Gemmel et al., 2017;[START_REF] Popa | Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: Evidence from sleep, stress, and behavior[END_REF]Rayen et al., 2013;Boulle et al., 2016). In addition, while there is a possible direct impact of perinatal (i.e. pre-and post-natal) exposure to SSRIs on affective behaviors, anxiety, and depressive behaviors, these behaviors can also be influenced by indirect mechanisms that include maternal depressive symptoms, maternal stress, maternal-offspring interactions, and gene x environment variations.

For example, maternal stress influences the developing serotonergic system (St-Pierre, Laurent, [START_REF] St-Pierre | Effects of prenatal maternal stress on serotonin and fetal development[END_REF] and there is a large literature on maternal stress effects on offspring outcomes [START_REF] Glover | Prenatal stress and its effects on the fetus and the child: possible underlying biological mechanisms[END_REF][START_REF] Maccari | Prenatal stress and long-term consequences: Implications of glucocorticoid hormones[END_REF][START_REF] Weinstock | The potential influence of maternal stress hormones on development and mental health of the offspring[END_REF].

Recent reviews have reported the effects of perinatal SSRI exposure on offspring social behaviors, neurodevelopmental disorders, anxious behavior, and cognition [START_REF] Gemmel | Perinatal selective serotonin reuptake inhibitor medication (SSRI) effects on social behaviors, neurodevelopment and the epigenome[END_REF][START_REF] Grieb | The effects of perinatal SSRI exposure on anxious behavior and neurobiology in rodent and human offspring[END_REF][START_REF] Millard | The effects of maternal antidepressant use on offspring behaviour and brain development: Implications for risk of neurodevelopmental disorders[END_REF][START_REF] Ramsteijn | Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: a systematic review and meta-analyses of animal studies[END_REF]. This review focuses on the effects of perinatal SSRI exposure on both anxiety and depression in offspring as there is considerable overlap between these two affective behaviors, possibly reflecting a common stressrelated origin [START_REF] Smoller | The genetics of stress-related disorders: PTSD, depression, and anxiety disorders[END_REF]. We also review the effects of other common antidepressant treatments for perinatal depression and/or anxiety on offspring behavioral outcomes in rodents as this has not been done before. We will focus on associations between perinatal SSRI exposure and offspring affective behaviors that include anxiety, depression, and maternal/offspring interactions using evidence from human and rodent studies (see Fig. 1). 3 We will also review the limited literature investigating the effects of perinatal exposure to other antidepressant medications on offspring affective outcomes.

When reviewing findings from studies in humans and rodent models we will consider: 1) how to distinguish effects of maternal mood symptoms from perinatal SSRI (and other antidepressant medications) effects on offspring outcomes, 2) how rodent development during the postnatal period may be similar to brain development during the third trimester in humans, and 3) how models of maternal stress in rodents may compare with the human experience of depression.

In humans, separating the impact of perinatal maternal affective disturbances and/ or mood symptoms from the impact of antidepressant medication exposure raises critical methodological challenges [START_REF] Grzeskowiak | Long term impact of prenatal exposure to SSRIs on growth and body weight in childhood: Evidence from animal and human studies[END_REF] as randomizing prenatal SSRI exposures is not feasible and ethical. Animal models provide a valuable resource in this regard as one can control for SSRI exposures and maternal stress factors. In addition, it is important to consider environmental factors and offspring characteristics (age and sex/gender) when investigating the risks and benefits of SSRI medication use to treat maternal mood disorders. Thus, understanding of the longitudinal developmental impact of perinatal SSRI exposure in the context of a variety of factors will allow us to illustrate why some children may be vulnerable to prenatal SSRI exposure effects while others remain resilient or even show a developmental benefit.

Perinatal SSRIs, Anxiety, and Depressive Behavior in Children

There is a growing body of clinical research investigating how perinatal SSRI exposure affects childhood anxiety and depression risk (see Table 1). Recent findings have shown that prenatal SSRI exposure was linked with higher levels of internalizing (anxious and depressive) behavior in young children [START_REF] Hermansen | Behavior and inhibitory control in children with prenatal exposure to antidepressants and medically untreated depression[END_REF], increased risk of psychiatric disorders (e.g., mood; behavioural and emotional) in children up to 16 years of age [START_REF] Liu | Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study[END_REF], and higher rates of depression diagnoses, but not anxiety diagnoses, in children and youth up to 14 years of age [START_REF] Malm | Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: a national register-based study[END_REF]. It is important to note that these three studies were limited as they did not account for the impact of maternal mood, namely confounding by indication: whereby, women with higher levels of depression symptoms are more likely to be treated with SSRIs and it could be that the higher levels of depression symptoms, rather than the medication itself that could be contributing to group differences.

As randomizing parental exposures is not possible for ethical and logistical reasons, stringent analytic approaches have been used to address potential differences that exist between depressed mothers treated and not treated with an antidepressant during pregnancy. These approaches include high-dimensional propensity scores [START_REF] Schneeweiss | High-dimensional propensity score adjustment in studies of treatment effects using health care claims data[END_REF], discordant sibling matches (an extension of matched case-control design, see [START_REF] Sujan | Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring[END_REF] or comparison groups of mothers with a psychiatric history and discontinued SSRIs before pregnancy [START_REF] Malm | Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: a national register-based study[END_REF][START_REF] Malm | Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: a national register-based study[END_REF]. Interestingly, even while these approaches attenuated some of the associations between SSRI exposure and child behavior [START_REF] Brown | Association between serotonergic antidepressant use during pregnancy and autism spectrum disorder in children[END_REF][START_REF] Malm | Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: a national register-based study[END_REF][START_REF] Sujan | Associations of maternal antidepressant use during the first trimester of pregnancy with preterm birth, small for gestational age, autism spectrum disorder, and attention-deficit/hyperactivity disorder in offspring[END_REF], confounding continued to contribute to developmental outcomes, suggesting that even with such optimal methodological approaches, unaccounted maternal and environmental factors continue to play a role and illustrate the limits to how successfully residual confounding can be eliminated.

Clinical studies have generally reported that maternal depression symptoms and not SSRI exposure are related to childhood anxiety and depression outcomes. Cross-sectional and population-based studies showed that maternal depressive symptoms, and not prenatal SSRI exposure, were related to higher levels of internalizing behavior [START_REF] Grzeskowiak | Prenatal antidepressant exposure and child behavioural outcomes at 7 years of age: A study within the Danish National Birth Cohort[END_REF][START_REF] Misri | Internalizing behaviors in 4-year-old children exposed in utero to psychotropic medications[END_REF][START_REF] Nulman | Neurodevelopment of children following prenatal exposure to venlafaxine, selective serotonin reuptake inhibitors, or untreated maternal depression[END_REF][START_REF] Glover | Prenatal stress and its effects on the fetus and the child: possible underlying biological mechanisms[END_REF] or higher levels of conduct and prosocial problems in children (Pedersen et al., 2013). In a similar vein, another population-base study found that maternal depressive symptoms, not SSRI exposure, were associated with more maternal reported affective problems during early childhood (age 1.5-6 years), and these results were also observed using paternal reported affective problems [START_REF] El Marroun | Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children[END_REF]. Other smaller clinical studies have shown that in a longitudinal cohort, prenatal SSRI exposure was associated with increased anxiety behaviors at three years, but did not persist to 6 years [START_REF] Hanley | Prenatal exposure to serotonin reuptake inhibitor antidepressants and childhood behavior[END_REF][START_REF] Oberlander | Prenatal effects of selective serotonin reuptake inhibitor antidepressants, serotonin transporter promoter genotype (SLC6A4), and maternal mood on child behavior at 3 years of age[END_REF]. In the same cohort, higher levels of depressive symptoms at 3 years were also reported [START_REF] Hanley | Prenatal exposure to serotonin reuptake inhibitor antidepressants and childhood behavior[END_REF]. Another study found increased risk of prenatal SSRIs exposure affecting childhood anxiety (at 5 years) has been suggested to be due to SSRI exposure during late pregnancy (28 weeks or more), and not at other time points in the pregnancy [START_REF] Lupattelli | Effect of time-dependent selective serotonin reuptake inhibitor antidepressants during pregnancy on behavioral, emotional, and social development in preschool-aged children[END_REF]. Besides population-based and cohort based clinical studies, one study compared children exposed prenatally to SSRIs with those siblings not exposed to SSRIs and reported that prenatal antidepressant exposure was associated with increased anxiety behaviors in three year olds compared to non-exposed siblings [START_REF] Brandlistuen | Behavioural effects of fetal antidepressant exposure in a Norwegian cohort of discordant siblings[END_REF], regardless of maternal mood symptoms.

In summary, the majority of studies in humans suggest that prenatal SSRI exposure does not increase risk for internalizing and anxious behaviors in young children when maternal mood is taken into account. However, as risk for internalizing or anxious behavior may emerge later in life. Thus, additional research involving adolescents with prenatal SSRI exposure is urgently needed. It should also be noted that only one population based study investigated depressive symptoms in children after prenatal SSRI exposure. They found that prenatal SSRI exposure was related to increased rate of diagnosed depression in children less than 14 years of age [START_REF] Malm | Gestational exposure to selective serotonin reuptake inhibitors and offspring psychiatric disorders: a national register-based study[END_REF]. Taken together, the majority of research on how prenatal SSRI exposure affects childhood affective behaviors has examined internalizing and anxious behaviors and further research on prenatal SSRI exposure effects on depressive behavior in children is urgently needed. Given the impact that maternal mood symptoms can have on both the mother and child, it is also clear that effectively treating maternal mental illness should be a priority.

Perinatal SSRIs, Anxiety, and Depressive Behavior Research in Rodent Offspring

Rodent models investigating perinatal SSRI exposure have examined the impact on internalizing-like behaviors in offspring (i.e., anxiety, anhedonia) using a variety of SSRIs including: fluoxetine, fluvoxamine, citalopram, paroxetine, zimelidine, escitalopram, Lu10-134-C, reboxetine, and sertraline (see Table 2). Other studies have examined the impact of other antidepressant medications that also alter 5-HT signaling (though not exclusively) . These include: clomipramine, desipramine, clorgyline, imipramine, bupropion, and buspirone (Table 3). For simplicity, we will categorize the rodent lifespan with pre-weaning at postnatal day (P) P0-P21, juvenile at P21-P50, and adult at P50 and beyond [START_REF] Sengupta | The laboratory rat: relating its age with human's[END_REF]. It is generally agreed that P0 to P14 is similar to human fetal brain development during the third trimester [START_REF] Romijn | At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby?[END_REF]. In the sections below, we will first briefly describe the typical tasks used to measure anxiety and depression in rodent models (3.1), then compare possible patterns of results between: pre-versus post-natal SSRI exposure (3.2), male versus female offspring (3.3), studies that include models of maternal stress (3.4), studies that use non-SSRI medications (3.5), and then conclude with a summary of findings (3.6).

Measures of Anxiety and Depressive Behavior

There are six tasks typically used to measure anxiety-like behavior in rodents: Elevated Plus Maze (EPM), Elevated Zero Maze (EZM), Open Field Test (OFT), Novelty-Suppressed Feeding (NSF), Light-dark Choice test, and Marble Burying. In brief, EPM, EZM, and OFT assess rodents' conflict between withdrawal and approach tendencies in novel, potentially threatening environments [START_REF] Rodgers | Anxiety, defence and the elevated plus-maze[END_REF]. Rodents that are more anxious spend less time exploring potentially threatening parts of the test apparatus (e.g., open arms of the EPM or EZM, central regions of the OFT,) and spend more time in safer areas (e.g., enclosed arms of the EPM or EZM, corners of the OFT). 4 The NSF (also known as the novelty-induced hypophagia test) is a task with a 12-24 hour food-deprived rodent who is placed in a novel environment with food to measure how long the rodent takes to obtain the food (Lee, & Lee, 2012). Rodents that are more anxious take more time to start feeding. In the light-dark choice test, rodents are placed in a box divided equally into bright and dark compartments for five minutes [START_REF] Holmes | Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background[END_REF]. Rodents that are more anxious spend less time in the light compartment. The marble burying task places rodents in a standard rat cage filled with clean bedding and 18 marbles [START_REF] Borsini | Do animal models of anxiety predict anxiolytic-like effects of antidepressants?[END_REF]Njung'e and Handley, 1991). After 20 minutes, the number of marbles that are at least two-thirds buried is recorded. Rodents that are more anxious will bury more marbles as this task tests defensive anxiety and repetitive behavior.5 There are two other tasks: Fear to Novel Tone task (Khatri et al., 2014;[START_REF] Rodriguez-Porcel | Neonatal exposure of rats to antidepressants affects behavioral reactions to novelty and social interactions in a manner analogous to autistic spectrum disorders[END_REF][START_REF] Simpson | Perinatal antidepressant exposure alters cortical network function in rodents[END_REF] and the Defensive Withdrawal Test [START_REF] Capello | Serotonin transporter occupancy in rats exposed to serotonin reuptake inhibitors in utero or via breast milk[END_REF], which will not be included in this review, as they are not standard measures of anxiety.

In general, three tasks are frequently used to indicate depressive-or despair-like behavior in rodents. These are the forced swim test (FST), tail suspension test (TST), and the sucrose preference test (SPT). The FST [START_REF] Porsolt | Depression: a new animal model sensitive to antidepressant treatments[END_REF] requires rodents to swim in an inescapable cylinder of water. After a period of vigorous activity (e.g., climbing, swimming), the rodent eventually becomes immobile (e.g., moving just enough to keep its head above water).

The amount of time spent immobile in the FST is interpreted as a rodent's level of despair or helplessness, whereby the rodent 'gives up' struggling to escape. The TST requires mice to be suspended by the tail with adhesive tape to a hook connected to a strain gauge that computes the total duration of immobility during a brief period of time [START_REF] El Yacoubi | Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression[END_REF][START_REF] Alexandre | Early life blockade of 5-hydroxytryptamine 1A receptors normalizes sleep and depression-like behavior in adult knock-out mice lacking the serotonin transporter[END_REF]. As the loss of pleasure (anhedonia) is a core feature of depression, this can be measured in rodent models by using the SPT [START_REF] Kalueff | Are serotonin transporter knockout mice 'depressed'?: Hypoactivity but no anhedonia[END_REF]. To do this, rodents are given a choice between water or sucrose solution (typically 1% or 2% in water) and the preference for sucrose over water is calculated as the volume of sucrose solution consumed relative to the total volume of liquid consumed. Reduced sucrose consumption is thought to indicate more anhedonia and increased depressive-like behavior. There is an urgent need for more tests of depressive-like behaviors in rodent models such as working memory and motivation that would provide greater insight into depressive phenotypes, particularly when looking at research on prenatal SSRI exposure on development.

Anxiety and depressive-like behaviors after Pre-and/or Post-natal SSRI exposure

There is a growing body of research in rodent models examining perinatal SSRI effects on anxiety-like behavior and results are mixed (see Table 2). We have organized this information based on the time point of behavioral testing (pre-weaning, juvenile, or adult) as it is possible that the impact of SSRI exposure may emerge at different time points depending on various factors (e.g., timing of SSRI exposure, SSRI dose etc). It should be noted that the majority of this early research did not consider maternal stress or 'mood' as a factor on offspring outcomes and thus SSRIs were given to healthy rodents. Although interesting, translation of these findings to the clinic should be done with caution.

There have been two studies conducted during the pre-weaning period. One study found that lower doses of prenatal fluoxetine exposure increased anxiety-like behavior in mice offspring [START_REF] Noorlander | Modulation of serotonin transporter function during fetal development causes dilated heart cardiomyopathy and lifelong behavioral abnormalities[END_REF]. However, another study failed to find significant differences in offspring anxiety behaviors [START_REF] Bairy | Developmental and behavioral consequences of prenatal fluoxetine[END_REF].

There have been many studies conducted with rodents during the juvenile period.

Prenatal and/or postnatal SSRI exposure has been associated with increased anxiety during adolescence [START_REF] Bairy | Developmental and behavioral consequences of prenatal fluoxetine[END_REF][START_REF] Butkevich | Effect of fluoxetine in prenatal period on nociceptive system reactivity and psychoemotional behavior in young female rats[END_REF]Francis-Oliveira et al., 2013;[START_REF] Millard | Perinatal exposure to fluoxetine increases anxiety-and depressive-like behaviours and alters glutamatergic markers in the prefrontal cortex and hippocampus of male adolescent rats: A comparison between Sprague-Dawley rats and the Wistar-Kyoto rat model of depression[END_REF]Lee et al., 2009;2012). Conversely, other studies have failed to find significant differences between groups (prenatal and/or postnatal SSRI exposure) in adolescent offspring [START_REF] Avitsur | Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance[END_REF][START_REF] Coleman | Behavioral changes in developing mice after prenatal exposure to paroxetine (Paxil)[END_REF][START_REF] Ehrlich | Prenatal stress, regardless of concurrent escitalopram treatment, alters behavior and amygdala gene expression of adolescent female rats[END_REF][START_REF] Forcelli | Teratogenic effects of maternal antidepressant exposure on neural substrates of drug-seeking behavior in offspring[END_REF]Lisboa et al., 2007;Mikhailenko & Butkevich, 2019;[START_REF] Toffoli | Maternal exposure to fluoxetine during gestation and lactation affects the DNA methylation programming of rat's offspring: modulation by folic acid supplementation[END_REF]Lee et al., 2012;[START_REF] Popa | Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: Evidence from sleep, stress, and behavior[END_REF][START_REF] Rayen | Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence[END_REF].

There has also been substantial research on perinatal SSRI exposure effects in adult offspring using rodent models. Many studies that examined prenatal and/or postnatal SSRI exposure reported increased anxiety in adult offspring [START_REF] Bairy | Developmental and behavioral consequences of prenatal fluoxetine[END_REF][START_REF] Cagiano | Neurofunctional effects in rats prenatally exposed to fluoxetine[END_REF][START_REF] Noorlander | Modulation of serotonin transporter function during fetal development causes dilated heart cardiomyopathy and lifelong behavioral abnormalities[END_REF]Olivier et al., 2011b;[START_REF] Smit-Rigter | Prenatal fluoxetine exposure induces life-long serotonin 5-HT3 receptordependent cortical abnormalities and anxiety-like behaviour[END_REF][START_REF] Sprowles | Perinatal exposure to the selective serotonin reuptake inhibitor citalopram alters spatial learning and memory, anxiety, depression, and startle in Sprague-Dawley rats[END_REF][START_REF] Gentile | Untreated depression during pregnancy: Short-and long-term effects in offspring. A systematic review[END_REF]. (Ko et al., 2014;[START_REF] Soga | Early-life citalopraminduced impairments in sexual behavior and the role of androgen receptor[END_REF][START_REF] Gobinath | Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis[END_REF][START_REF] Sarkar | Postnatal fluoxetine-evoked anxiety is prevented by concomitant 5-HT2A/C receptor blockade and mimicked by postnatal 5-HT2A/C receptor stimulation[END_REF][START_REF] Karpova | Long-lasting behavioural and molecular alterations induced by early postnatal fluoxetine exposure are restored by chronic fluoxetine treatment in adult mice[END_REF][START_REF] Rebello | Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function[END_REF][START_REF] Rebello | Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function[END_REF]Boulle et al., 2016a). Conversely, others have reported that perinatal SSRI exposure decreased anxiety during adulthood (Kiryanova et al., 2014;[START_REF] Smoller | The genetics of stress-related disorders: PTSD, depression, and anxiety disorders[END_REF][START_REF] Mcallister | Behavioural outcomes of perinatal maternal fluoxetine treatment[END_REF]. Still yet other studies report no effect of pre-or post-natal SSRI exposure on anxiety-like behaviors in adult offspring [START_REF] Ansorge | Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice[END_REF][START_REF] Avitsur | Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance[END_REF]Boulle et al., 2016b;Bourke et al., 2013b;[START_REF] Coleman | Behavioral changes in developing mice after prenatal exposure to paroxetine (Paxil)[END_REF][START_REF] Ehrlich | Prenatal stress, regardless of concurrent escitalopram treatment, alters behavior and amygdala gene expression of adolescent female rats[END_REF]Francis-Oliveira et al., 2013;[START_REF] Glover | Early-life exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats[END_REF][START_REF] Hansen | Neonatal administration of the selective serotonin reuptake inhibitor Lu 10-134-C increases forced swimming-induced immobility in adult rats: a putative animal model of depression?[END_REF][START_REF] Harris | Dose-dependent effects of neonatal SSRI exposure on adult behavior in the rat[END_REF]Kiryanova et al., 2014;[START_REF] Smoller | The genetics of stress-related disorders: PTSD, depression, and anxiety disorders[END_REF]Ko et al., 2014;Lisboa et al., 2007;[START_REF] Meyer | Perinatal SSRI exposure permanently alters cerebral serotonin receptor mRNA in mice but does not impact adult behaviors[END_REF]Olivier et al., 2011b;[START_REF] Salari | Fluoxetine normalizes the effects of prenatal maternal stress on depression-and anxiety-like behaviors in mouse dams and male offspring[END_REF][START_REF] Sprowles | Perinatal exposure to the selective serotonin reuptake inhibitor citalopram alters spatial learning and memory, anxiety, depression, and startle in Sprague-Dawley rats[END_REF][START_REF] Gentile | Untreated depression during pregnancy: Short-and long-term effects in offspring. A systematic review[END_REF]Zohar et al., 2016). Thus, there are a number of studies with varied outcomes related to whether or not perinatal SSRI exposure affects anxiety-like behaviors in offspring, as measured in these rodent models.

Despite the lack of research in humans on perinatal SSRI effects on the development of depression, there is a rather large body of research investigating how early life exposure to SSRI medications may impact depressive-like behaviors in rodent models with a focus on juvenile and adult offspring (Table 2). One study conducted with rodents during the juvenile period have reported associations between prenatal SSRIs and increased depressive-like behavior [START_REF] Millard | Perinatal exposure to fluoxetine increases anxiety-and depressive-like behaviours and alters glutamatergic markers in the prefrontal cortex and hippocampus of male adolescent rats: A comparison between Sprague-Dawley rats and the Wistar-Kyoto rat model of depression[END_REF]. Conversely, other studies have reported that prenatal SSRI exposure decreased depressive-like behavior during adolescence (Butkevich & Mikhailenko, 2019;Mikhailenko & Butkevich, 2019), while other studies have failed to find significant effects of perinatal SSRIs on depressive-like behaviors in adolescent offspring [START_REF] Avitsur | Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance[END_REF][START_REF] Butkevich | Effect of fluoxetine in prenatal period on nociceptive system reactivity and psychoemotional behavior in young female rats[END_REF]Francis-Oliveira et al., 2013;Lisboa et al., 2007, males only). For postnatal SSRI exposure, one study failed to find significant effects of SSRIs exposure [START_REF] Rayen | Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence[END_REF].

In terms of perinatal SSRI effects on depressive-like behavior in adult offspring, some studies have shown associations between prenatal SSRIs and higher levels of depressive-like behavior [START_REF] Bhagya | The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits, biochemical changes, and hippocampal synaptic plasticity in an animal model of depression[END_REF][START_REF] Glover | Early-life exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats[END_REF]Lisboa et al., 2007;[START_REF] Sprowles | Perinatal exposure to the selective serotonin reuptake inhibitor citalopram alters spatial learning and memory, anxiety, depression, and startle in Sprague-Dawley rats[END_REF]Zohar et al., 2016). Yet, other studies have reported that prenatal SSRI exposure decreased depressive-like behavior during adulthood [START_REF] Avitsur | Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance[END_REF][START_REF] Mcallister | Behavioural outcomes of perinatal maternal fluoxetine treatment[END_REF]. Finally, other studies have failed to find significant effects of perinatal SSRIs on depressive-like behaviors in adult offspring [START_REF] Coleman | Behavioral changes in developing mice after prenatal exposure to paroxetine (Paxil)[END_REF]Francis-Oliveira et al., 2013;Olivier et al., 2011b;[START_REF] Salari | Fluoxetine normalizes the effects of prenatal maternal stress on depression-and anxiety-like behaviors in mouse dams and male offspring[END_REF][START_REF] Sprowles | Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open-field activity in Sprague-Dawley rats[END_REF].

Regarding postnatal SSRI exposure in rodent models, the results are more consistent with postnatal SSRI exposure being associated with increased immobility in adult rat offspring [START_REF] Bhagya | The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits, biochemical changes, and hippocampal synaptic plasticity in an animal model of depression[END_REF][START_REF] Glover | Early-life exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats[END_REF]HIlakivi et al., 1987;Ko et al., 2014;[START_REF] Rebello | Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function[END_REF][START_REF] Sarkar | Postnatal fluoxetine-evoked anxiety is prevented by concomitant 5-HT2A/C receptor blockade and mimicked by postnatal 5-HT2A/C receptor stimulation[END_REF]Boulle et al 2016, Females). Conversely, two studies have reported that postnatal SSRI exposure decreased depressive-like behavior in adult offspring [START_REF] Karpova | Long-lasting behavioural and molecular alterations induced by early postnatal fluoxetine exposure are restored by chronic fluoxetine treatment in adult mice[END_REF][START_REF] Mendes-Da-Silva | Neonatal treatment with fluoxetine reduces depressive behavior induced by forced swim in adult rats[END_REF], while another study failed to find significant differences between groups during adulthood (Boulle et al., 2016a). In sum, it is evident the perinatal exposure to SSRIs does not consistently alter anxiety or depressive-like behaviors in offspring.

These inconsistencies may be due to a number of methodological factors and further research is needed to fully determine the impact of perinatal SSRIs and maternal mood symptoms on offspring outcomes.

Sex Differences

There are marked sex differences in affective disorders such as anxiety and depression and thus it is always important to consider sex as a biological variable. Although a majority of studies in rodent models have been carried out in male offspring, five perinatal SSRI studies have revealed sex differences in adult offspring (Boulle et al.,2016a,b;[START_REF] Gobinath | Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis[END_REF][START_REF] Rayen | Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence[END_REF][START_REF] Sprowles | Perinatal exposure to the selective serotonin reuptake inhibitor citalopram alters spatial learning and memory, anxiety, depression, and startle in Sprague-Dawley rats[END_REF]. Sprowles and colleagues (2016) found that female (not male) rats with prenatal SSRI exposure had increased anxiety-like behavior in the OFT compared to controls; however, both sexes were more anxious on the marble burying task and no differences were found on the EPM compared to controls. This study illustrates how results can vary within one study depending on sex and types of tasks used to measure anxiety. Another study with rats reported that only males (not females) with postnatal SSRI exposure were more anxious during the EPM (less time in open arms) than controls, yet, both sexes were more anxious on the NSF task (increased latency to feed) compared to controls [START_REF] Gobinath | Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis[END_REF]. Boulle et al (2016a, b) also performed similar studies in male and female offspring and showed that exposure to fluoxetine after birth via administration to the rat dam resulted in increased anxiety-like behavior in adult male, but not female, offspring. Taken together, these sex differences in the long-term effects of perinatal exposure to SSRIs indicate the importance of future researchers to include sex specific analyses.

Although limited, perinatal SSRIs have been reported to have sexually differentiated effects on depressive-like behavior in rodent offspring. As mentioned previously, Lisboa et al.

(2007) found that prenatal fluoxetine was associated with increased depressive-like behavior in adolescent female, not male, mice. Boulle et al (2016a,b) also showed that early postnatal SSRIs, regardless of maternal stress, increased depressive-like behavior in adult female, but not male, rat offspring. Postnatal SSRI exposure via lactation, as performed in Boulle et al (2016a,b), had no effect on depressive-like behavior in adolescent male or female rat offspring [START_REF] Rayen | Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence[END_REF] suggesting a possible post-pubertal effect of SSRIs on depression. Future research considering sex of the offspring is vital to determine how early life exposures alter developmental trajectories.

Models of Maternal Stress

Maternal mood is an important factor to consider when looking at perinatal SSRI effects on development. In rodent models, maternal stress has been used to model aspects of maternal depression and maternal stress itself can also affect anxiety and depressive outcomes in offspring. When taking maternal gestational stress exposure into account, recent studies have found that perinatal SSRI exposure protected against the effects of maternal stress by reducing anxiety-like behaviors induced by maternal stress (Boulle et al., 2016a;Butkevich & Mikhailenko, 2019;Kiryanova et al., 2016;Mikhailenko & Butkevich, 2019;[START_REF] Rayen | Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence[END_REF][START_REF] Salari | Fluoxetine normalizes the effects of prenatal maternal stress on depression-and anxiety-like behaviors in mouse dams and male offspring[END_REF]Zohar et al., 2016), while others found that perinatal SSRIs did not protect against the effects of prenatal stress on anxiety outcomes in offspring [START_REF] Avitsur | Prenatal SSRI alters the hormonal and behavioral responses to stress in female mice: Possible role for glucocorticoid resistance[END_REF]Boulle et al., 2016b;Bourke et al., 2013b;[START_REF] Ehrlich | Prenatal stress, regardless of concurrent escitalopram treatment, alters behavior and amygdala gene expression of adolescent female rats[END_REF]Zohar et al., 2016). One study has reported that prenatal SSRI exposure exacerbated the effects of exposure to maternal depression in a rodent model of endogenous high levels of depression [START_REF] Millard | Perinatal exposure to fluoxetine increases anxiety-and depressive-like behaviours and alters glutamatergic markers in the prefrontal cortex and hippocampus of male adolescent rats: A comparison between Sprague-Dawley rats and the Wistar-Kyoto rat model of depression[END_REF]. The differences in results from these studies may be due to sex of the offspring tested, stress paradigm used, SSRI dose, offspring age and testing paradigms.

Interestingly, the effects of perinatal SSRIs on offspring anxiety and depressive-like behaviors are not always in the same direction. For example, Zohar and colleagues (2016) found that prenatal SSRI exposure protected against prenatal stress effects on anxiety (EPM), but not on depressive-like behavior; whereas, Boulle et al. (2016b) showed that regardless of maternal stress exposure adult female offspring exposed via lactation to SSRIs did not differ in levels of anxiety-like behaviors but did show increases in immobility. Taken together, the majority of this limited number of studies suggest that prenatal SSRI exposure may buffer against the negative impact of maternal stress during pregnancy on rodent offspring anxious behavior, but sexspecific effects are evident.

Perinatal exposure to other antidepressant medications

When looking at the effects of other pharmacotherapies to treat perinatal anxiety and depression symptoms and their effects on anxious behavior in rodent offspring (Table 3), mixed results are also evident. One study reported that only male rats with prenatal venlafaxine exposure (7.5mg/kg) were less anxious during the Light Dark task (more time in light) compared to controls, while female rats with prenatal venlafaxine exposure at a higher dosage (37.5mg/kg) were less anxious on this same task compared to controls [START_REF] Bogi | Perinatal exposure to venlafaxine leads to lower anxiety and depression-like behavior in the adult rat offspring[END_REF]. This study illustrates how results can vary within one study by both sex and dosage of medication exposure.

However, other studies with buspirone or buspirone combined with fluoxetine administered perinatally reported no significant differences in anxiety in juvenile offspring (Mikhailenko & Butkevich, 2019;[START_REF] Sprowles | Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open-field activity in Sprague-Dawley rats[END_REF]. Postnatal clorgyline, an anti-anxiety or antidepressant medication, administration after birth resulted in increased anxiety in adult offspring [START_REF] Rebello | Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function[END_REF]. As there only a few studies examining the relation between other anti-depressant or antianxiety medications (administered pre-or post-natal) more research is needed before stronger conclusion can be drawn.

In terms of perinatal antidepressant medication effects on offspring depressive-like behavior (Table 3), some researchers have reported that perinatal exposure to non-SSRIs reduced depressive-like behaviors in juvenile offspring (Mikhailenko & Butevich, 2019;Butkevich & Mikhailenko, 2019) while others failed to find significant effects of perinatal antidepressant medication exposure on depressive-like behavior [START_REF] Sprowles | Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open-field activity in Sprague-Dawley rats[END_REF]. Other researchers have reported the perinatal non-SSRI exposure increased depressive-like behaviors in adult offspring [START_REF] Bhagya | The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits, biochemical changes, and hippocampal synaptic plasticity in an animal model of depression[END_REF]Hilakivi et al., 1987b;Limón-Morales et al., 2014;[START_REF] Vázquez-Palacios | Antidepressant effects of nicotine and fluoxetine in an animal model of depression induced by neonatal treatment with clomipramine[END_REF][START_REF] Velazquez-Moctezuma | Neonatal treatment with clomipramine increased immobility in the forced swim test: an attribute of animal models of depression[END_REF]Yang et al., 2008). Conversely, adult female rat offspring with prenatal venlafaxine (37.5mg/kg) exposure were less depressed (reduced immobility) than male offspring [START_REF] Bogi | Perinatal exposure to venlafaxine leads to lower anxiety and depression-like behavior in the adult rat offspring[END_REF]. Interestingly, Bhagya and colleagues (2015) found that prenatal exposure to clomipramine was associated with increased depressive-like behaviors, which was reversed in offspring with a combination of clomipramine and reboxetine treatment during adulthood, suggesting that reboxetine may be beneficial to treat those with prenatal exposure to antidepressants, but this needs to be supported with additional research before firmer conclusions can be drawn. To date, no studies with non-SSRIs have examined possible sex differences or included models of maternal stress in relation to depressive-like behavioral outcomes in offspring. These factors need to be addressed by future research.

Summary of Findings

Rodent studies suggest that perinatal SSRIs, and other types of antidepressant medications to treat maternal stress-related disorders, are not consistently associated with changes in offspring anxiety as the majority of tasks administered report null results (n = 75, 56%, see Figure 2). These conclusions are consistent with a recent meta-analyses that found no significant differences between animals with and without perinatal SSRI exposure in relation to anxiety behaviors (p = .06; [START_REF] Ramsteijn | Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: a systematic review and meta-analyses of animal studies[END_REF]. However, our conclusion diverges from [START_REF] Grieb | The effects of perinatal SSRI exposure on anxious behavior and neurobiology in rodent and human offspring[END_REF] who suggest that perinatal SSRI treatment modifies anxiety behaviors as our count of null results (n = 75) exceed the count of tasks demonstrating increased and decreased anxiety behaviors (total n = 45, 14, respectively). One possibility to explain this discrepancy is that we chose to count all tasks within a study indicating outcomes in anxiety behaviors, while [START_REF] Grieb | The effects of perinatal SSRI exposure on anxious behavior and neurobiology in rodent and human offspring[END_REF] provided only a summary outcome of each study when two or more tasks were in the same direction. Their type of global summary underestimates the total number of anxiety behavior outcomes. Our review also includes more recent studies (e.g., [START_REF] Millard | Perinatal exposure to fluoxetine increases anxiety-and depressive-like behaviours and alters glutamatergic markers in the prefrontal cortex and hippocampus of male adolescent rats: A comparison between Sprague-Dawley rats and the Wistar-Kyoto rat model of depression[END_REF], which would not have been available to [START_REF] Grieb | The effects of perinatal SSRI exposure on anxious behavior and neurobiology in rodent and human offspring[END_REF].

In terms of depressive-like behavior, the majority of rodent studies suggest that perinatal SSRIs, and other antidepressant medications to treat maternal mental illnesses, may increase depressive-like behavior in offspring (n = 30, 47%, see Figure 2). As this is the first review of these outcomes in animal models, no cross-review comparisons can be made. While there are more instances of increased depressive-like behavior associated with perinatal SSRI and non-SSRI exposure, there are also a substantial number of null results (n = 16; 25%). It is also possible that the number of null results may be underestimated as it is typically more challenging to publish non-significant findings. A similar number of studies reported that perinatal SSRIs, and other antidepressant medications to treat maternal mental illnesses, may decrease depressivelike behavior in offspring (n = 18; 28%). Discrepancies between study results may be due to a number of factors but clearly more research is needed that considers maternal mood/stress, medication type and dose, timing of exposure and sex of the offspring before stronger conclusions about perinatal SSRI exposure effects on anxiety and depressive-like behavior in offspring can be made.

Perinatal SSRIs, Maternal Depressive Symptoms, and Mother-Child Interactions

Mother-child interactions, as well as father-child interactions, are important as they contribute to the security of children's attachment (e.g., [START_REF] Bowlby | Attachment and loss[END_REF] and insecure attachment has been linked with higher rates of specific anxiety symptoms in children, including: separation anxiety [START_REF] Moss | Attachment and behavior problems in middle childhood as reported by adults and child informants[END_REF], school phobia (Bar-Heim, Dan, Eshel, & Sagi-Schwartzl, 2007), and social anxiety (Bar-Heim et al., 2007;[START_REF] Bohlin | Attachment and social functioning: A longitudinal study from infancy to middle childhood[END_REF]Brumariu & Kerns, 2008). As 5-HT modulates maternal mood and several socially motivated behaviors, it is not surprising that it plays a role in the transition to motherhood and the regulation of mother-child interactions thereafter [START_REF] Pawluski | Serotonin and motherhood: From molecules to mood[END_REF]. In addition, mothers with anxiety, depression, and stress frequently demonstrate changes in their offspring caregiving behaviors [START_REF] Pawluski | The neurobiology of postpartum anxiety and depression[END_REF][START_REF] Hillerer | From stress to postpartum mood and anxiety disorders: how chronic peripartum stress can impair maternal adaptations[END_REF][START_REF] Talge | Early Stress, Translational Research and Prevention Science Network: Fetal and Neonatal Experience on Child and Adolescent Mental Health[END_REF]. Specifically, anxious and depressed mothers often respond more negatively, and less sensitively, to their infants compared to non-depressed mothers [START_REF] Field | Psychologically depressed parents[END_REF][START_REF] Field | Behavior-state matching and synchrony in mother-infant interactions of nondepressed versus depressed dyads[END_REF][START_REF] Fleming | Postpartum adjustment in first time mothers: relations between mood, maternal attitudes and mother-infant interactions[END_REF]. In terms of interactions, depressed mother-infant dyads often have reduced mutual attention, vocal and visual communications, touching, and smiling when compared to healthy controls [START_REF] Field | Psychologically depressed parents[END_REF][START_REF] Field | Behavior-state matching and synchrony in mother-infant interactions of nondepressed versus depressed dyads[END_REF].

While clinical studies are scarce, it has been reported that during free-play and feeding, mothers treated with SSRIs do not differ in negative or positive interaction compared to mothers not treated with SSRIs, yet, mothers treated with SSRIs and Rivotal (a benzodiazepine derivative) show more inconsistent negative and positive messages towards their infants [START_REF] Reebye | Affect expression in prenatally psychotropic exposed and non exposed mother-infant dyads[END_REF]. Another study which controlled for maternal depressive symptoms found that SSRI treated mothers interrupted their infants more than control dyads [START_REF] Weikum | The impact of prenatal serotonin reuptake inhibitor (SRI) antidepressant exposure and maternal mood on mother-infant interactions at 3 months of age[END_REF]. Further, maternal depression was related to poorer infant readiness to play in both control and SSRI treated dyads [START_REF] Weikum | The impact of prenatal serotonin reuptake inhibitor (SRI) antidepressant exposure and maternal mood on mother-infant interactions at 3 months of age[END_REF], suggesting a complex relationship between SSRIs, maternal mood, and mother-child interactions.

There is growing evidence that gestational stress is associated with postpartum depression-like behavior and altered maternal interactions in rodent models. For example, daily restraint stress during pregnancy affects nursing, nest building, and other aspects of caring for offspring [START_REF] Belnoue | Plasticity in the olfactory bulb of the maternal mouse is prevented by gestational stress[END_REF][START_REF] Champagne | Stress during gestation alters postpartum maternal care and the development of the offspring in a rodent model[END_REF][START_REF] Hillerer | From stress to postpartum mood and anxiety disorders: how chronic peripartum stress can impair maternal adaptations[END_REF][START_REF] Smith | Gestational stress induces post-partum depression-like behaviour and alters maternal care in rats[END_REF]. These maternal care-giving behaviors can have long-term effects on offspring neurobehavioral development including disorganized attachment patterns [START_REF] Meaney | Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations[END_REF][START_REF] O'donnell | The maternal adversity, vulnerability and neurodevelopment project: theory and methodology[END_REF][START_REF] Rifkin-Graboi | Maternal sensitivity, infant limbic structure volume and functional connectivity: a preliminary study[END_REF][START_REF] Wazana | The interplay of birth weight, dopamine receptor D4 gene (DRD4), and early maternal care in the prediction of disorganized attachment at 36 months of age[END_REF]. SSRI treatment to rodent dams during pregnancy has also been associated with increased nesting, licking and touching offspring (high doses only) and maternal aggression [START_REF] Johns | The effects of dopaminergic/serotonergic reuptake inhibition on maternal behavior, maternal aggression, and oxytocin in the rat[END_REF]. Others have reported that gestational SSRI treatment to dams reduces time nursing (Kott et al., 2018). When SSRIs are administered during the postpartum, increased active nursing behaviors (i.e. arched-back nursing) and decreased passive nursing behavior have been reported (Pawluski et al., 2012b;Workman et al., 2016). Interestingly, one study in adult female offspring exposed to SSRIs prenatally, found delayed maternal behavior particularly in pup retrieval in the early postpartum period [START_REF] Svirsky | Prenatal exposure to selective serotonin reuptake inhibitors (SSRI) increases aggression and modulates maternal behavior in offspring mice[END_REF]). This suggests a potential long-term effect of SSRIs on maternal behavior across generations.

Although sparse, there is evidence from rodent research that SSRIs combined with maternal stress can affect maternal offspring-directed caregiving behaviors (for review see Pawluski et al 2019) but much more research is needed in this area. Regardless, differences in maternal care-giving behaviors in rodent models during the first week of life may mediate and moderate the effects of perinatal exposures on developmental outcomes.

Perinatal SSRIs, Maternal Depressive Symptoms, and Gene/ Environment Variation

While alterations in 5-HT signaling associated with developmental exposure to SSRIs may shape vulnerability for anxiety and depressive disturbances in childhood or across the life span, such exposures alone do not explain why some children are at risk and others remain resilient. Thus, incorporating information about interactions between genetic variations and the perinatal environment may offer a window into explaining heterogeneity in developmental outcomes [START_REF] Boyce | Biological sensitivity to context: I. An evolutionarydevelopmental theory of the origins and functions of stress reactivity[END_REF][START_REF] Moffitt | Strategy for investigating interactions between measured genes and measured environments[END_REF]. Allelic variations influence susceptibility to environmental context (i.e. Gene Environment (G x E) interactions) [START_REF] Belsky | Beyond diathesis stress: differential susceptibility to environmental influences[END_REF][START_REF] Caspi | Gene-environment interactions in psychiatry: joining forces with neuroscience[END_REF][START_REF] Moffitt | Strategy for investigating interactions between measured genes and measured environments[END_REF] and allelic variations in SLC6A4 (serotonin transporter gene) in particular have been widely studied as a key moderator of early life environmental influences. [START_REF] Caspi | Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene[END_REF] reported that childhood maltreatment predicts adult depression among individuals with at least one copy of the short allele. Building on this seminal paper, the short allele has been widely studied as a crucial moderator of mental illness risk in adulthood [START_REF] Karg | The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation[END_REF][START_REF] Kendler | Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice[END_REF][START_REF] Kendler | Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice[END_REF]Lesch, 2011;[START_REF] Schinka | A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety[END_REF]. However, not all outcomes associated with having the short allele are negative [START_REF] Risch | Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: A meta-analysis[END_REF] and not all studies have replicated these relationships [START_REF] Willis-Owen | The serotonin transporter length polymorphism, neuroticism, and depression: A comprehensive assessment of association[END_REF], raising questions about the role of other factors that may underlie G x E interactions [START_REF] Duncan | Paying attention to all results, positive and negative[END_REF], such as maternal mood disturbances and/ or perinatal SSRI exposure.

In line with this, higher levels of prenatal maternal anxiety predicted higher levels of negative emotionality in 6 month old infants with two short alleles than those with long alleles [START_REF] Pluess | Serotonin transporter polymorphism moderates effects of prenatal maternal anxiety on infant negative emotionality[END_REF]. However, when there was low maternal stress, genotype failed to have an impact, suggesting that infant genotype only mattered in the context of prenatal maternal mood.

Similarly, [START_REF] Weikum | The impact of prenatal serotonin reuptake inhibitor (SRI) antidepressant exposure and maternal mood on mother-infant interactions at 3 months of age[END_REF] showed that 6 years olds with the short allele of SLC6A4 (reflecting reduced levels of 5-HT reuptake) showed resilience to increased maternal depressive symptoms in mothers, as they did not exhibit compromised executive function. In contrast, children with two long alleles (reflecting greater availability of serotonin transporter) who were exposed to mothers with fewer depressive symptoms had higher scores on executive function tasks, while exposure to greater depressive symptoms correlated with the lowest executive function scores, suggesting higher sensitivity of the L allele to maternal depressive symptoms.

Beyond genetic factors, everyday context also matters. For example, a recent study examined associations between day-to-day home environment and child self-regulation skills in 6 year olds [START_REF] Dhaliwal | Household chaos, maternal depression and prenatal ssri exposure interact to affect executive function of 6 year old children[END_REF]Dhaliwal et al., in press). Interestingly, children of mothers with higher prenatal depressive symptoms (regardless of SSRI treatment) were less susceptible to the everyday chaos at home (e.g., household noise, disorganization, etc). In contrast, children of mothers with lower levels of prenatal mood symptoms were much more susceptible to the household environment and in this setting this effect was moderated by prenatal exposure to SSRIs. This suggests that prenatal SSRI exposure with lower depressive symptoms serves as a risk factor for greater sensitivity to house chaotic environment, while prenatal maternal mood regardless to SSRI exposure may "buffer" the child's outcomes from the current house environment. Taken together, both variation in genetics and environment (maternal depressive symptoms and/ or SSRI exposure) can influence children's outcomes and this needs to be the focus of future research in order to determine risk and reliance.

Limitations and Strengths

Our aim was to provide a review of human and animal literature that reports effects of perinatal SSRIs on anxiety and depression in offspring. In doing so we chose the most significant measures of anxiety and depression in animal models and summarized these in Tables 2 and3.

Other reviews on this topic have used only one behavioral test per study (e.g., [START_REF] Ramsteijn | Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: a systematic review and meta-analyses of animal studies[END_REF] only use data from the first time a behavioral test was administered, unless there was a learning component, to provide a "snap shot" of each study) or the overall results of a study [START_REF] Grieb | The effects of perinatal SSRI exposure on anxious behavior and neurobiology in rodent and human offspring[END_REF]; whereas, we chose to treat each assessment within a study as a separate task as it occurred at a different developmental time point. For example, [START_REF] Bairy | Developmental and behavioral consequences of prenatal fluoxetine[END_REF] measured anxiety during pre-weaning (P18) using one task and the juvenile stage (P30) using two tasks. Thus, we counted all three tasks as only counting the first assessment point would underestimate our knowledge of anxiety behaviors in rodents throughout their lifespan. We also chose to focus on summarizing the research results and we chose not to weigh results according to sample size as this was beyond the scope of the review; however, future researchers should consider this option.

It remains difficult to generalize rodent literature to wide variations of symptoms and environmental factors inherent to human clinical setting. We acknowledge that while preclinical research is incredibly valuable for further investigation in the clinic, these are models that provide insight into the human condition but may be fraught with limitations due to testing paradigms, physiological differences, and the difficulty of measuring human affective states in animals.

Future Directions and Conclusion

Our review of rodent studies suggests that results from perinatal exposure to both SSRIs and other common antidepressants may more consistently increase depressive-like, but not anxious behaviors, in offspring. Among studies of outcomes in humans, the majority of studies suggest that prenatal SSRI exposure does not increase risk for internalizing and anxious behaviors in young children, especially when maternal mood is controlled for using stringent analytic approaches [START_REF] Rommel | Long-Term Effects of Intrauterine Exposure to Antidepressants on Physical, Neurodevelopmental, and Psychiatric Outcomes: A Systematic Review[END_REF]. Moreover, to date research studying SSRI exposure and depressive behaviors remains limited and needs increased attention.

Emotional and behavioral dysregulation in early childhood has been linked to poor social adjustment and psychiatric diagnoses later in life [START_REF] Cicchetti | Maternal depressive disorder and contextual risk: Contributions to the development of attachment insecurity and behavior problems in toddlerhood[END_REF][START_REF] Nilsen | Pathways from maternal distress and child problem behavior to adolescent depressive symptoms: a prospective examination from early childhood to adolescence[END_REF][START_REF] Rutter | Continuities and discontinuities in psychopathology between childhood and adult life[END_REF].

Thus, understanding how perinatal maternal mental health and antidepressant treatment contributes to anxiety and depression behaviors in childhood should remain a critical research focus. Identifying factors that shape the development of anxiety and depression patterns across the early life span could lead to earlier mental health detection and prevention. Whether developmental exposure to SSRIs program processes that reflect that disruption of 5-HT homeostasis results in alterations in anxiety and depressive symptoms remains to be conclusively demonstrated in humans.

It remains a significant challenge to identify a main or direct effect of SSRI exposure in the context of such a complex phenomenon as maternal mood disorders during pregnancy.

Clarifying developmental risk in this setting requires continued studies that consider long-term behavioral outcomes in the context of stress, role of genetic variations, positive care-giving, and other possible factors that account for vulnerability and resiliency in this context. With this in mind, it may be less important to distinguish the component of behavior that is more susceptible to maternal mood or perinatal SSRI exposure, but instead focus on the context of the child's environment. Regardless of how perinatal SSRIs and perinatal maternal depressive symptoms contribute to the development of anxiety and depression symptoms in children, it remains an urgent undertaking to identify and treat maternal mood disorders during pregnancy [START_REF] Pawluski | Pregnancy: A final frontier in mental health research[END_REF]. Beyond SSRI exposure, poorly or undertreated depression during the peripartum and beyond has adverse consequences for mothers and their children. Finding ways to best promote optimal maternal and child health in the context of maternal perinatal mood disturbances remains essential.

Parity modifies the effects of fluoxetine and corticosterone on behavior, stress reactivity, and hippocampal neurogenesis. Neuropharmacology,105,[443][444][445][446][447][448][449][450][451][452][453]. Retrevied from: https://www.who.int/maternal_child_adolescent/topics/maternal/maternal_perinatal/en/ Yang, L. M., Hu, B., Xia, Y. H., Zhang, B. L., & Zhao, H. (2008). Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behavioural brain research, 188(1), 84-90. Yu, Q., Teixeira, C. M., Mahadevia, D., Huang, Y., Balsam, D., Mann, J. J., ... & Ansorge, M. S.

(2014). Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice. Molecular psychiatry, 19( 6), 688-698. Zheng, J., Xu, D. F., Li, K., Wang, H. T., Shen, P. C., Lin, M., .

Note. Arrows indicate significant differences (increases/ decreases) between SSRI exposed and controls on one task, ≠ = no differences, results were the same across all dose levels. SSRI = selective serotonin reuptake inhibitors, also includes serotonin norepinephrine reuptake inhibitors (SNRIs); Time = Timing of administration; Method admin = method of administration to mother Note. Arrows indicate significant differences (increases/ decreases) between medication exposed and controls on one task, ≠ = no differences. Results were the same across all dose levels unless specifically indicated (e.g., [START_REF] Bogi | Perinatal exposure to venlafaxine leads to lower anxiety and depression-like behavior in the adult rat offspring[END_REF]. Note: Arrows indicate significant differences (increases/ decreases) between SSRI and other antidepressant medications exposed and controls on one task to measure anxiety or depressive like behavior, ≠ = no differences between groups the one task, n = number of times a task intended to measure anxiety or depressive behavior has been reported in a peer reviewed study with those results. See Table 2 and 3 for details. Tasks that had different results depending on sex of rodent were included in the count (e.g., Elevated Plus

Other antidepressant medications: Table 3

Females

  unless otherwise indicated; Test Dates = Date of assessments; P = postnatal day; G = gestational day; M = male; F = female; FB = food bars; OA = oral administration; IP = intraperitoneal injection; SC = subcutaneous injection; ? = Timing not specified; DW = Drinking water; FLX = Fluoxetine; FLUV = Fluvoxamine; CIT = Citalopram; PAR = Paroxetine; ZIM = Zimelidine; ESC = Escitalopram; Lu = Lu10-134-C; SER = Sertraline; EPM = Elevated Plus Maze (measure of anxiety); EZM = Elevated zero maze (measure of anxiety); OFT = Open Field Test (measure of anxiety); LD -Light/ dark test (measure of anxiety); PAT = Passive avoidance test (measure emotionality, anxiety); MB = Marble Burying test (measure of anxiety-like behavior); NSFT = Novelty Suppressed Feeding (measure of anxiety/ depressive-like behavior); FST = Forced Swim Test (measure of depression-like behavior); TST = Tail suspension test (measure of depression-like behavior); SPT = Sucrose preference test (measure of depression-like behavior); High Novelty Responder/Low Novelty Responder (HR/LR) rat lines.

  Time = Timing of administration; Method admin = method of administration to mother unless otherwise indicated; Test Dates = Date of assessments; P = postnatal day; G = gestational day; M = male; F = female; FB = food bars; OA = oral administration; IP = intraperitoneal injection; SC = subcutaneous injection; ? = Timing not specified; DW = Drinking water; VEN = Venlafaxine, a serotonin-norepinephrine reuptake inhibitor; CLO = Clomipramine, a non-SRI used to treat depression; DES = Desipramine, a non-SRI used to treat depression; CLOL = Clorgyline, a non-SRI used to treat depression; IMI = Imipramine, a non-SRI used to treat depression; BU = Bupropion, non-SRI used to treat depression; BUS = buspirone, an non-SRI used to treat anxiety; NOM = Nomifensine, a non-SRI used to treat depression; RB = Reboxetine, an norepinephrine reuptake inhibitor that was used with Clorgyline; EPM = Elevated Plus Maze (measure of anxiety); EZM = Elevated zero maze (measure of anxiety); OFT = Open Field Test (measure of anxiety); MB = Marble Burying test (measure anxiety-like behavior; FST = Forced Swim Test (measure depression-like behavior).

Figure 2 .

 2 Figure 2. Schema summarizing rodent research on perinatal SSRI and other antidepressant medication exposure and offspring anxious or depressive like behavior

  n = 10, 40% ↓ Depression: n = 12, 48% ≠ Depression: n = 3, 12% Total n = 25

Table 2

 2 .. & Wang, R. (2011). Neonatal exposure to fluoxetine and fluvoxamine alteres spine density in mouse hippocampal CA1 pyramidal neurons. InternationalJjournal of Clinical and Experimental Pathology, 4(2), 162. Zohar, I., Shoham, S., & Weinstock, M. (2016). Perinatal citalopram does not prevent the effect of prenatal stress on anxiety, depressive-like behaviour and serotonergic transmission in adult rat offspring. European Journal of Neuroscience, 43(4), 590-600. Summary of rodent research investigating how perinatal SSRI exposure affects anxiety and depressive behavior

	Table 1
	Summary of human research investigating perinatal SSRI exposure and internalizing behavior in children
	Reference	# of Pt.	Group	Time	Design Age Measures	Results	Maternal Mood
	Grzeskowiak	210	AD	Prenatal	Retro 0-7 DSDQ	AD ≠ internalizing (emotional symptoms,	Controlled for
	et al., 2015	231	D-No AD				peer problems)	prenatal mental
		48,737	No AD				D-No AD ↑ internalizing	disturbances
	Malm et. al.,	15,729	SSRI	Prenatal	Retro 0-	Diagnosis of	SSRI ↑ Depression, ≠ anxiety	-
	2016	9,651	PD	or before	14	depression,
		7,980	P.SSRI	pregnancy		anxiety
		31,394	Control
	Liu et al.,	854,241	No AD	Prenatal	Retro 0-	Psychiatric	AD ↑ psychiatric disorder (e.g., mood;	-
	2017	30,079	AD Dis	and new	16	diagnosis	neurotic, stress related, and somatoform
		17,560	AD	users		codes in	disorder; behavioural and emotional)
		3,503	AD NU	during		children	compared to no AD use
				pregnancy
	Lupattelli et	290	SSRI	Early,	Prosp 1.5,	CBCL	Late-pregnancy SSRI only ↑ Anxiety,	Controlled for
	al., 2018	3,775	No SSRI	Mid, Late	3, 5		Depression at 5 years	prenatal anxiety
				(28+				and depression
				weeks)				symptoms
	Brandlistuen	112	AD	Prenatal	Retro 1.5,	CBCCL/2-3	AD ↑ Anxiety at 3 years than siblings	Controlled for
	et al., 2015	14,323	No AD		3			for prenatal and
			siblings					postpartum
								anxiety/
								depression
								symptoms, and
								lifetime
								depression
	El Marroun	69	SSRI	Prenatal	Retro 1.5,	Dutch version	SSRI ≠ affective problems	Controlled for
	et al., 2014	376	D-No		3, 6	of CBCL	MDS ↑ affective problems	prenatal and
		5531	SSRI					postpartum
			Control					depressive
								symptoms
	Oberlander et 33	SSRI	Prenatal	Prosp 3	CBCL	SSRI ↑ internalizing behavior	Controlled for

Table 3

 3 Summary of rodent research investigating other antidepressant medications to treat perinatal depression or anxiety and offspring anxiety and depressive behavior

	Test Dates Time	Drug dose/day Metho	Sex	Strain	Maternal	Results	Reference
				d			Stress
				admin
								Juvenile Testing (P21-50)
	~P21+	P8-21	CLO 40mg/kg IP	M	Wistar	Prenatal	CLO ↑ Depression (FST: increased immobility)	Yang et al., 2008
							Stress
	P25	G9-21	BUS	PI	M	Wistar	Prenatal	BUS ≠ Anxiety (EPM)	Mikhailenko &
			3.5mg/kg or				Stress	FLX & BUS ≠ Anxiety (EPM)	Butkevich, 2019
			FLX 10mg/kg					BUS ↓ Depression (FST: decreased immobility)
			& BUS					FLX & BUS ↓ Depression (FST: decreased
			3.5mg/kg					immobility)
								*BUS protected against the effects of prenatal stress
								on the EPM
								*BU, FLX & BUS protected against the effects of
								prenatal stress on the FST
	P25	G9-21	BUS	PI	F/M	Wistar	Prenatal	BUS ↓ Depression (FST: decreased immobility)	Butkevich &
			3.5mg/kg or				Stress	FLX & BUS ↓ Depression (FST: decreased	Mikhailenko, 2019
			FLX 10mg/kg					immobility)
			& BUS					*BU, FLX & BUS protected against the effects of
			3.5mg/kg					prenatal stress on the FST
								Adult Testing (P50+)
	P54	P7-21	DES 5mg/kg,	IP	M	Wistar	-	DES ↑ Depression (FST: increased immobility)	Hilakivi et al., 1988b
			NOM					NOM ↑ Depression (FST: increased immobility)
			10mg/kg
	P60	G6-P20 BU 15mg/kg	SC	F/M	Sprague-	-	BU ≠ ≠ ≠ Anxiety (EZM, OFT, MB)	Sprowles et al., 2017
						Dawley		BU ≠ Depression (FST)
	P60, P150 P7-18	DES 5mg/kg	IP	M	Wistar	-	DES ↑ ↑ Depression (FST: increased immobility at	Hilakivi et al., 1987b
								both time points)
	P60-85	G15-	VEN 7.5,	OA	F/M	Wistar	-	VEN 7.5mg ↓ ↓ Anxiety (EPM: more time in open	Bogi et al., 2018
		P20	37.5, 75mg/kg					arms, LD: more time in light-males only), ↓
								Depression (FST: decreased immobility)
								VEN 37.5mg ↓ ≠ Anxiety (LD: more time in light-
								females only; EPM: ≠), ↓ Depression (FST:
								decreased immobility-females only)
								VEN 75mg ≠ ≠ Anxiety (EPM, LD), ≠ Depression
								(FST)
	P84	P8-21	CLO 15mg/kg SC	M	Wistar	-	CLO ↑ Depression (FST: increased immobility)	Limón-Morales et al.,

Occurring before birth

During gestation and throughout lactation in rodent models. For simplicity these time pre-and post-natal time periods will be considered as 'perinatal' throughout the review unless otherwise specified.

Computerized literature and manual search was conducted to identify relevant English-language studies from first available year to July 2020

While some researchers report other aspects related to the OFT as indicators of anxiety, such as differences in the number of times of a rodent rears or "stands" up on its hind legs (e.g.,Grim & Frieder, 1987;[START_REF] Popa | Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: Evidence from sleep, stress, and behavior[END_REF], dips its head (e.g.,[START_REF] Butkevich | Effect of fluoxetine in prenatal period on nociceptive system reactivity and psychoemotional behavior in young female rats[END_REF], distance traveled (e.g.,Lee et al., 2012), or ambulation (e.g.,[START_REF] Hilakivi | Effects of neonatal treatment with clomipramine on adult ethanol related behavior in the rat[END_REF] Hilakivi 1988a; Lisboa et al., 2007), we will focus on the clear indicator of time in the centre of the OFT. For the EPM, some researchers may report differences in the number of entries in the closed or open arms (e.g.,[START_REF] Forcelli | Teratogenic effects of maternal antidepressant exposure on neural substrates of drug-seeking behavior in offspring[END_REF], however, again, we focused on the most definitive measure of anxiety and that is time spent on the open arms.

Some have suggested that this task is a better test of repetitive behavior, others have argued that it should be included as a comprehensive battery of tasks rather than relying only on the Elevated Plus Maze or the Elevated Zero Maze to measure anxiety[START_REF] Sprowles | Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open-field activity in Sprague-Dawley rats[END_REF].

We are grateful to Colleen Pawliuk, our librarian, and Ursula Brain, our research manager, for their assistance. S.M.H is supported by the BC Children's Hospital Research Institute (University of British Columbia), Brain Canada and Kids Brain Health Network, Developmental Neurosciences Research Training Award. L.C.M. is a professor in the School of Population and Public Health at the University of British Columbia and her work is supported by the BC Children's Hospital Research Institute and the Canadian Institutes for Health Research. J.L.P. is supported with funding from l'Institut des Neurosciences Cliniques de Rennes (INCR). T.F.O is the R. Howard Webster Professor in Brain Imaging and Child Development at the University of British Columbia and his work is supported by the BC Children's Hospital Research Institute and the Canadian Institutes for Health Research. Funding sources had no role in the study.

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Maze, [START_REF] Gobinath | Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis[END_REF] or if the tasks was only administered to females or males, see Table 2 for details. SSRI = selective serotonin reuptake inhibitors.