Depression, anxiety, or both, during pregnancy are common complications during the perinatal period, with 15–20% of women experiencing depression at some point during their pregnancy. Considerable evidence suggests that untreated or undertreated maternal Axis I mood disorders can increase the risk for preterm birth, low birth weight, and alter neurobehavioral development in utero . Serotonin reuptake inhibitor antidepressants are often considered for antenatal therapy, with the goal of improving maternal mental health during pregnancy. Treatment with a serotonin-reuptake inhibitor, however, does not guarantee remission of depression, and in-utero serotonin reuptake inhibitor exposure has also been linked to increased risks for adverse infant outcomes. In this chapter, evidence linking serotonin reuptake inhibitor use with an increased risk for postnatal adaptation syndrome, congenital heart defects, and neonatal persistent pulmonary hypertension is reviewed. Management decisions should include attention to the continuum of depression symptoms, from subclinical to severe major depressive disorder and the long-term developmental risks that might also be associated with pre- and postnatal exposure.
Introduction
Between 15 and 20% of pregnant women suffer from depression or anxiety during the perinatal period . Although some women decline pharmacotherapy because of concerns about possible risks of teratogenicity, about 5–13% of pregnant women choose to treat their mood disorder with a serotonin reuptake inhibitor (SRI) antidepressant . Both the disease and its treatment pose risks for mothers and their neonates. Pharmacotherapy poses difficult decisions for the clinician and mother alike, and the evidence supporting a course that promotes both maternal and infant health is often conflicting. Not treating maternal depression is never an option. What are the best options to promoting optimal care for the development and behaviour of infants in mothers who are depressed during pregnancy?
Making sense of studies reporting on the effect of prenatal SRI exposure is challenged by conflicting and contradictory findings, some raising concern , whereas others offer reassurance . This might, in part, reflect the inherent challenge in distinguishing between the effects of the SRI exposure from the effects of the underlying indication for the drug treatment, the maternal mood disturbance, and related confounding influences. Compounding this is that a failure to treat maternal depression, anxiety, or both, effectively can lead to compromised prenatal care, increased risk of obstetrical complications, self-medication, substance abuse, or both, which further affects neonatal health . Thus, in examining the evidence, as imperfect as it is, it becomes critical to weigh the risks and benefits of exposing the fetus to maternal mental illness against the risks and benefits of exposure to psychotropic medicines. In this chapter, we aim to present a synthesis of the research evidence on the effects of maternal mood disorders (depression, anxiety, or both) and the use of SRI medicines on neonatal health as a way to guide clinical care of exposed neonates. Three key outcomes (postnatal adaptation syndrome, congenital malformations and persistent pulmonary hypertension) will be used as examples to guide clinical care of the exposed neonate.
Two classes of medications are often combined and referred to as SRIs: selective serotonin reuptake inihibitors that include fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluvoxamine; and the selective-norepinephrine reuptake inhibitors, which include venlafaxine, desvenlafaxine, duloxetine, and milnacipran. For the sake of simplicity, no distinction will be made between exposures to either class in this chapter. These medications primarily act by blocking the serotonin transporter (5-HTT), which increases extracellular serotonin levels. Because SRIs readily cross the placenta and the blood–brain barrier , maternal prenatal SRI treatment alters central fetal serotonin (5-HT) levels. Serotonin is a widely distributed central neurotransmitter , and, given its key role as a developmental signal during early developmental periods , it is not surprising that concerns have been raised about the neurobehavioural consequences of altering early 5HT signalling during developmentally sensitive periods .
Research on the possible adverse outcomes of SRI exposure in utero , however, has reported contradictory findings, with many studies reporting no increased risk from exposure to SRIs in utero on infant outcomes . This confusion can be explained at least partially, by the key challenge of distinguishing between the effects of the SRI exposure and the effects of the underlying indication for the drug treatment, the maternal mood disturbance. Failure to treat maternal depression, anxiety, or both, effectively can lead to compromised prenatal care, increased risk of obstetrical complications, self-medication, substance abuse, or both, not to mention exposure to the detrimental effects of the illness itself. For the most part, the body of evidence that allows us to make clinical sense of these complex and contradictory research findings remains limited. Our challenge remains one of weighing the risks and benefits of exposing the fetus to maternal mental illness against the risks and benefits of exposure to psychotropic medicines. In this chapter, we aim to present a synthesis of the research evidence on the neonatal effects of prenatal maternal mood disorders and SRI exposure. Three key widely reported neonatal outcomes (postnatal adaptation syndrome, congenital malformations and persistent pulmonary hypertension) that are detectable immediately after delivery are used in this chapter to highlight how evidence might be used to guide a clinical approach to care of the newborn of depressed mothers treated with an SRI during pregnancy.
Prenatal maternal mood disturbances and neonatal outcomes
Undertreated maternal depression, anxiety during pregnancy, or both, have been shown to have adverse effects on the mother and the unborn child. Research has suggested that maternal depression, anxiety, or both, during pregnancy is an independent risk factor for operative delivery , preterm birth , and low birth weight . In a meta-analytic study, depression symptoms during pregnancy increased the relative risk of preterm birth by 39% and low birth weight by 49%. Risks for intrauterine growth restriction were also increased by 45% . The biological pathways that have been suggested to explain this include the dysregulation of the hypothalamic–pituitary–adrenal axis, increased uterine artery resistance in response to perceived stress, which leads to placental hypofusion, immune activation characteristic of depression, or both . Later studies, however, have failed to confirm the hypothesised relation between maternal stress and increased uterine artery resistance . Studies comparing the babies born to mothers with higher depression symptoms have reported that infants seem to have decreased motor tone, more abnormal reflexes, lower activity levels, less robustness and endurance, increased irritability, and inferior orientation compared with babies born to mothers with low depression scores .
Infants of women with high levels of prenatal anxiety were also shown to be irritable, more difficult to sooth, and were excessive criers as infants . At age 9 years, these same children (boys in particular) were hyperactive, showed signs of attention deficit, and engaged in aggressive behaviour . Antenatal maternal stress has also been reported to disrupt fetal neurobehavioral development , and antenatal depressed mood has been associated with neonatal irritability, atypical frontal electroencephalogram patterns, reduced vagal tone, elevated cortisol and norepinephrine, and lower dopamine and serotonin levels in the infant . Severe stress during pregnancy, especially early in gestation, results in delayed fetal maturation, disrupted emotional regulation, impaired cognitive performance during infancy, and decreased brain column in areas associated with learning and memory in children aged 6–8 years . Gestational depression is the strongest predictor of postpartum depression, thus suggesting that the relationship between maternal mental health and child developmental risk may actually begin long before birth .
Conflicting findings have also been reported, pointing to no adverse effects of maternal depression, anxiety, or both, on infant health . Key limitations in research examining the effect of mood disorders on infant outcomes include the use of instruments that are not valid for the diagnosis of an Axis I mood disorder, lack of consistency around the timing of assessment of maternal mood, and the lack of attention paid to potentially important confounding factors . Antenatal depression has been linked to known risk factors for adverse outcomes, including maternal smoking , gestational diabetes , pregnancy-induced hypertension , preeclampsia , and illicit drug use . Confounding or effect modification by socioeconomic status may also present an important issue in examining the relationship between depression and infant outcomes. A meta-analysis examining depression during pregnancy and the risk of preterm birth found that antenatal depression was associated with an elevated risk of preterm birth in women of lower socioeconomic status but not in women of middle- or upper-income status .
Serotonin reuptake inhibitors are often considered for antenatal therapy, with the goal of improving maternal mental health during pregnancy. Treatment with SRIs does not always predict remission of depression. A recent study by Yonkers et al. suggested that, regardless of whether women continue their antidepressant treatment during pregnancy, about 16% of women develop a major depressive episode during pregnancy. Dynamic changes also occur in the pharmacokinetics of SRIs during pregnancy, which may require alterations in drug doses to achieve optimal therapy . Without a change in dose, the efficacy of SRI treatment in pregnancy may be reduced. Thus, even in the presence of prenatal SRI treatment, pre- and postnatal maternal mood disturbances (and the inherent confounding factors of smoking, alcohol and socioeconomic status) continue and potentially contribute to an ongoing developmental risk for their infants. Thus, mothers and clinicians must carefully consider available evidence and balance potential benefits and risks of antenatal pharmacotherapy with the consequences of untreated or poorly treated mental illness.
Prenatal maternal mood disturbances and neonatal outcomes
Undertreated maternal depression, anxiety during pregnancy, or both, have been shown to have adverse effects on the mother and the unborn child. Research has suggested that maternal depression, anxiety, or both, during pregnancy is an independent risk factor for operative delivery , preterm birth , and low birth weight . In a meta-analytic study, depression symptoms during pregnancy increased the relative risk of preterm birth by 39% and low birth weight by 49%. Risks for intrauterine growth restriction were also increased by 45% . The biological pathways that have been suggested to explain this include the dysregulation of the hypothalamic–pituitary–adrenal axis, increased uterine artery resistance in response to perceived stress, which leads to placental hypofusion, immune activation characteristic of depression, or both . Later studies, however, have failed to confirm the hypothesised relation between maternal stress and increased uterine artery resistance . Studies comparing the babies born to mothers with higher depression symptoms have reported that infants seem to have decreased motor tone, more abnormal reflexes, lower activity levels, less robustness and endurance, increased irritability, and inferior orientation compared with babies born to mothers with low depression scores .
Infants of women with high levels of prenatal anxiety were also shown to be irritable, more difficult to sooth, and were excessive criers as infants . At age 9 years, these same children (boys in particular) were hyperactive, showed signs of attention deficit, and engaged in aggressive behaviour . Antenatal maternal stress has also been reported to disrupt fetal neurobehavioral development , and antenatal depressed mood has been associated with neonatal irritability, atypical frontal electroencephalogram patterns, reduced vagal tone, elevated cortisol and norepinephrine, and lower dopamine and serotonin levels in the infant . Severe stress during pregnancy, especially early in gestation, results in delayed fetal maturation, disrupted emotional regulation, impaired cognitive performance during infancy, and decreased brain column in areas associated with learning and memory in children aged 6–8 years . Gestational depression is the strongest predictor of postpartum depression, thus suggesting that the relationship between maternal mental health and child developmental risk may actually begin long before birth .
Conflicting findings have also been reported, pointing to no adverse effects of maternal depression, anxiety, or both, on infant health . Key limitations in research examining the effect of mood disorders on infant outcomes include the use of instruments that are not valid for the diagnosis of an Axis I mood disorder, lack of consistency around the timing of assessment of maternal mood, and the lack of attention paid to potentially important confounding factors . Antenatal depression has been linked to known risk factors for adverse outcomes, including maternal smoking , gestational diabetes , pregnancy-induced hypertension , preeclampsia , and illicit drug use . Confounding or effect modification by socioeconomic status may also present an important issue in examining the relationship between depression and infant outcomes. A meta-analysis examining depression during pregnancy and the risk of preterm birth found that antenatal depression was associated with an elevated risk of preterm birth in women of lower socioeconomic status but not in women of middle- or upper-income status .
Serotonin reuptake inhibitors are often considered for antenatal therapy, with the goal of improving maternal mental health during pregnancy. Treatment with SRIs does not always predict remission of depression. A recent study by Yonkers et al. suggested that, regardless of whether women continue their antidepressant treatment during pregnancy, about 16% of women develop a major depressive episode during pregnancy. Dynamic changes also occur in the pharmacokinetics of SRIs during pregnancy, which may require alterations in drug doses to achieve optimal therapy . Without a change in dose, the efficacy of SRI treatment in pregnancy may be reduced. Thus, even in the presence of prenatal SRI treatment, pre- and postnatal maternal mood disturbances (and the inherent confounding factors of smoking, alcohol and socioeconomic status) continue and potentially contribute to an ongoing developmental risk for their infants. Thus, mothers and clinicians must carefully consider available evidence and balance potential benefits and risks of antenatal pharmacotherapy with the consequences of untreated or poorly treated mental illness.
The effect of antenatal pharmacotherapy: serotonin reuptake inhibitors
Prenatal SRI exposure has been associated with increased risk of spontaneous miscarriage, congenital malformations, small-for-gestational age live birth, preterm birth, low birth weight, and persistent pulmonary hypertension (PPHN) . Some studies have reported increased risk for neurobehavioural disturbances associated with prenatal SRI exposure, whereas others have found no increased developmental vulnerability . This constantly evolving literature raises concern about how to manage mood disorders during pregnancy. Although numerous adverse outcomes have been reported after prenatal SRI exposure, we focus in this chapter on reviewing the evidence of three key neonatal outcomes associated with SRI exposure that might offer clues to guide clinical care.
Postnatal adaptation syndrome
Key findings
Soon after the introduction of SRIs in the late 1980s, reports of neonatal ‘withdrawal’ symptoms emerged, suggesting an association of neurobehavioral effects with prenatal drug exposure . This prompted public and scientific concern about the long-term neurodevelopmental consequences of in-utero exposure to SRIs . Importantly, some , but not all , studies reported neurobehavioral disturbances, leaving critical unanswered questions about whether outcomes after SRI exposure reflect a transient pharmacological effect, suppressed neurotransmitters, or sustained alterations in brain development reflecting teratogenicity associated with prenatal SRI antidepressant exposure.
Many cohort studies have reported that maternal SRI treatment in late pregnancy can result in impaired neonatal neurobehavioral adaptation , with the exception of one study that reported no differences in neonatal intensive care unit admission and Apgar scores between SRI exposed and unexposed infants . This impaired neonatal neurobehavioral adaptation is commonly called postnatal adaptation syndrome (PNAS) , and typically includes some combination of the following symptoms: respiratory distress , feeding difficulty jitteriness , temperature instability , sleep problems , tremors , shivering , restlessness , convulsions , jaundice, rigidity , and hypoglycaemia .
Despite the fact that these symptoms resemble an SRI withdrawal condition well recognised in adults, the underlying cause and clinical significance remains unclear . The severity of increased motor activity and tremors, and altered stress regulation , has been associated with increased SRI drug levels and pharmacogenetic metabolic factors , suggesting a potential pharmacologic toxicity. Fluoxetine has the longest half-life of the commonly used SRIs and the lowest risk of withdrawal among adults ; however, treatment in late pregnancy is associated with PNAS, perhaps reflecting neonatal drug toxicity . A dose-dependent relationship with the severity of PNAS symptoms has also been observed .
Symptoms associated with PNAS are also thought to reflect neurobehavioral changes associated with measures reflecting central serotonergic levels in utero , specifically, levels of the serotonin metabolite 5-HIAA . Neonates exposed to SRI have lower cord blood levels of a biomarker of early brain maturation and central serotonergic function (i.e. astroglial-specific calcium binding protein, S100B) . Exposure to SRIs has also been correlated with increased norepinephrine metabolite (dihydroxyphenylglycol), increased thyroid stimulating hormone, and reduced IGF-I cord blood levels , findings that may underlie impaired intrauterine growth in exposed neonates. How these findings affect child health risk over the first few years of life remains unclear; however, emerging evidence points to links between PNAS and development in early childhood. In children exposed to SRIs, externalising behaviours were associated with increased cord drug levels, particularly in children with a history of neonatal withdrawal symptoms . Further, Klinger et al. recently reported increased social behavioral disturbances in children aged 2 and 6 years with a history of PNAS .
Genetic variations may also play a role moderating the effect of prenatal SRI exposure, similar to differences in clinical effects of SRIs in adults . Allelic variations for the serotonin transporter SLC6A4 may influence the risk for PNAS, which suggests a gene–environment interaction. Two short alleles for the transporter were found to be associated with reduced 5-min Apgar scores, increased jitteriness, and increased muscular tone, whereas a different genotype was associated with low birth weight, and a third genotype was associated with respiratory distress and tachypnoea in prenatally exposed infants .
Risks
Although none of these manifestations are specific to prenatal SRI exposure, they occur in about 30% of exposed newborns , with an overall risk ratio for PNAS associated with late-pregnancy SRI treatment of 3.0 (95% CI 2.0 to 4.4) compared with SRI treatment in early pregnancy or no exposure . Neonates with late SRI exposure have been reported to have a special care nursery admission risk ratio of 2.6 (95% CI 1.4 to 4.7) and an overall respiratory difficulty risk ratio of 2.3 (95% CI 1.6 to 3.2) compared with neonates with early or no SRI exposure. Why some but not all neonates are at risk remains an unanswered and pressing question. To date, key questions about how prenatal maternal mood, fetal drug metabolism, or altered brain development sets developmental trajectories remain unanswered . Future studies need to account for the relationship between polypharmacy, possible substance abuse, and PNAS.
Clinical considerations
For the most part, PNAS symptoms are mild and self-limited. Where respiratory difficulties arise beyond mild upper airway congestion and transient tachypnoea, however, treatment with oxygen by mask and continuous positive airway pressure may be indicated. With increasing and unresolving symptoms, a high index of suspicion for concurrent disorders (e.g. infectious or neurological) and appropriate evaluations is essential. The average time of onset for PNAS symptoms ranges between birth to 3 days of age, and lasts for up to 2 weeks , with most infants having mild and transient symptoms. Neonatal medical management consists primarily of supportive care in special care nurseries .
Congenital heart defects
Key findings
Links between SRI exposure in utero and congenital malformations have attracted substantial scientific interest ; however, despite significant study, no consistent pattern has been found, which can be interpreted as evidence against morphological teratogenicity. The most consistent pattern examining malformations has been the finding of increased risk for congenital heart defects after first trimester exposure to SRIs (paroxetine in particular). Increased risk after first-trimester exposure to SRIs has been reported in numerous studies, including research by Glaxosmithkline (the manufacturer of paroxetine) , and across different populations, including Quebec , and British Columbia, Canada , Israel, Germany, Italy , Sweden , and Denmark . The increased risk for congenital heart defects was also reported when women who had received other antidepressants were studied as controls, as a way of reducing the likelihood of confounding by the underlying maternal depression . A dose–response relationship has also been reported .
In contrast, studies using data from teratogen information services have also reported no significant difference in the rate of major malformations among the children of women who took fluoxetine or other SRIs during pregnancy compared with the children of women who did not. The only one of these studies in which outcomes were determined by physical examination of the child (rather than by verbal report of the mother) did report a higher rate of minor congenital anomalies among exposed infants . It should be noted that all of these studies were underpowered to find small or moderate increases in risk. More recently, a large cohort study from Denmark has suggested that congenital malformations may be the result of confounding by indication as infants of mothers who continued SRI use during pregnancy and those who paused SRI use were both at similar levels of increased risk for congenital heart defects .
Finally, some reviews (both systematic and non-systematic) and meta-analyses of the association between SRI use in pregnancy and birth defects have been conducted. Two reviews concluded that relatively more consistency was apparent in the research on paroxetine and increased risk of cardiovascular malformations . A recent meta-analysis synthesising the current epidemiologic evidence on paroxetine use in early pregnancy and congenital heart defects reported an odds ratio of 1.46 (95% CI 1.17 to 1.82) for combined heart defects and first-trimester paroxetine use . Little evidence of publication bias or overall statistical heterogeneity was reported, and only weak evidence of associations with study characteristics was found. A meta-analysis examining first-trimester fluoxetine exposure and congenital heart defects reported an OR of 1.6 (95% CI 1.31 to 1.95) from cohort studies, but no increased risk was reported by two included case-control studies .
Risk
When an association is reported consistently, such as that between paroxetine use in early pregnancy and congenital heart defects, one must ask whether this is a reflection of the frequency with which the drug has been studied or prescribed. In this case, it is unlikely that this association is caused by either more frequency of study or more frequency of prescribing, as many studies reporting an increased risk analysed individual SRIs separately and had higher numbers of mothers treated with SRIs other than paroxetine.
Although the evidence on congenital heart defects is difficult to interpret, it has been consistently suggested that first-trimester paroxetine and fluoxetine use may slightly increase the risk of congenital heart defects. The meta-analysis estimates for first-trimester maternal paroxetine and fluoxetine treatment indicating an increased risk of about 1.5- and 1.6-fold, respectively, suggest that the risks of congenital heart defects in women treated with these SRIs in the first-trimester is about 1%. The risk of congenital heart defects in the general population is about 0.7%. Even small increases in risk, however, can become substantial public health issues if the drug in question is commonly used in pregnancy.
Clinical considerations
Although associations between particular SRIs and malformations have been reported, no single malformation has been reported with SRI exposures in general. Confusing the picture further, some uncertainty remains about the clinical significance of the defects detected after SRI exposure. The essential question becomes: what to do about risks that are small yet perceivable and, in a few cases, have important clinical implications? Clinically significant congenital heart defects are a leading cause of death in early infancy . If defects are not detected early, circulatory collapse may occur, with a substantial adverse effect on prognosis. Research has shown that the use of pulse oximetry, a non-invasive, easily administered test that is successful in detecting the most serious congenital heart defects after delivery, is effective in detecting critical congenital heart defects in asymptomatic newborn babies, and has been recommended as universal screening for all newborns . Given that more jurisdictions are beginning to use pulse oximetry for universal screening of asymptomatic newborns , the decision whether or not to screen neonates exposed to SRIs is becoming a moot point. In jurisdictions not currently undergoing universal screening, we suggest that pulse oximetry testing (an inexpensive and non-invasive test that is undertaken at the mother’s bedside) may be used for those concerned about detecting possible congenital heart defects in neonates exposed to SRIs, with appropriate follow up as required. The highest rate of false positives occurs when the test is carried out in the first 24 h after birth , necessitating testing be undertaken at the time of hospital discharge.
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