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The effect of perinatal exposures on the infant: Antidepressants and depression

https://doi.org/10.1016/j.bpobgyn.2013.09.001Get rights and content

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 [1], ∗[2]. 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 [1], [3]. 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 [4], [5], whereas others offer reassurance [6], [7], [8]. 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 [9], [10], [11]. 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 [12], maternal prenatal SRI treatment alters central fetal serotonin (5-HT) levels. Serotonin is a widely distributed central neurotransmitter [13], and, given its key role as a developmental signal during early developmental periods [14], it is not surprising that concerns have been raised about the neurobehavioural consequences of altering early 5HT signalling during developmentally sensitive periods ∗[13], ∗[15].

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 [16], [17]. 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.

Section snippets

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 [18], preterm birth [19], [20], [21], and low birth weight [20], [22], [23], [24]. In a meta-analytic study, depression symptoms during pregnancy increased the relative risk of preterm birth by 39% and low birth

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) ∗[2], [5], [52], [53], [54], [55], [56], [57]. Some studies have reported increased risk for neurobehavioural disturbances associated with prenatal SRI exposure, whereas others have found no increased developmental vulnerability [58], [59], [60]. This constantly

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 [61]. This prompted public and scientific concern about the long-term neurodevelopmental consequences of in-utero exposure to SRIs [62]. Importantly, some [58], [62], but not all [63], [64], studies reported neurobehavioral disturbances, leaving critical unanswered questions about whether outcomes after SRI

Key findings

Links between SRI exposure in utero and congenital malformations have attracted substantial scientific interest [52], [55], [88], [89]; 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

Key findings

Another area of considerable inconsistency within the research concerns the use of SRI antidepressants and the risk of neonatal persistent pulmonary hypertension (PPHN). This is defined as a failure of the normal relaxation in the fetal pulmonary vascular bed during the circulatory transition that occurs shortly after birth with varying severity. It presents as cyanosis and respiratory distress, and is characterised by pulmonary hypertension that causes right-to-left extra-pulmonary shunting of

Conclusion

Although research evidence would suggest that some clear increased risks are associated with both untreated maternal depression and in-utero SRI exposure, the clinical application of these findings may be challenging. This is not a setting where infant outcomes can be easily attributed to one causal factor, either the maternal depression or the SRI antidepressants. Rather, for most infants, health risks are a function between an interplay between psychological, pharmacological, genetic and

Conflict of interest

None declared.

Practice points

  • Untreated or undertreated maternal depression, anxiety, or both, does present a risk to the mother and the fetus.

  • Treating depression, anxiety, or both, with an SRI does not necessarily result in remission of the mental illness.

  • Evidence suggests that in utero exposure to SRI antidepressants increases the risk of postnatal adaptation syndrome, congenital malformations, and PPHN.

  • Consider first-line treatment with non-pharmacotherapy or psychotherapy for mild or

Acknowledgements

We are grateful to Ursula Brain, BA, for her editorial assistance in the preparation of this chapter. G.E.H is supported by the Canadian Institutes for Health Research, the Michael Smith Foundation for Health Research, Women's Health Research Institute and Neurodevnet. T.F.O is the R. Howard Webster Professor in Brain Imaging and Early Child Development at the University of British Columbia and his work is supported by the Child and Family Research Institute and the Canadian Institutes for

References (109)

  • R.H. Kelly et al.

    Psychiatric and substance use disorders as risk factors for low birth weight and preterm delivery

    Obstet Gynecol

    (2002)
  • M.P. Freeman

    Complementary and alternative medicine for perinatal depression

    J Affect Disord

    (2009)
  • J. Hilli et al.

    MAO-A and COMT genotypes as possible regulators of perinatal serotonergic symptoms after in utero exposure to SSRIs

    Eur Neuropsychopharmacol

    (2009)
  • B.G. Pollock et al.

    Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression

    Neuropsychopharmacology

    (2000)
  • L.S. Cohen et al.

    Birth outcomes following prenatal exposure to fluoxetine

    Biol Psychiatry

    (2000)
  • L. Riggin et al.

    The fetal safety of fluoxetine: a systematic review and meta-analysis

    J Obstet Gynaecol Can

    (2013)
  • S. Thangaratinam et al.

    Pulse oximetry screening for critical congenital heart defects in asymptomatic newborn babies: a systematic review and meta-analysis

    Lancet

    (2012)
  • S. Lakshminrusimha et al.

    Pulmonary vascular biology during neonatal transition

    Clin Perinatol

    (1999)
  • T.F. Oberlander et al.

    Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data

    Arch Gen Psychiatry

    (2006)
  • J.R. Daw et al.

    Prescription drug use in pregnancy: a retrospective, population-based study in British Columbia, Canada (2001–2006)

    Clin Ther

    (2011)
  • S. Alwan et al.

    Safety of selective serotonin reuptake inhibitors in pregnancy

    CNS Drugs

    (2009)
  • M.E.H. Hemels et al.

    Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis

    Ann Pharmacother

    (2005)
  • K.L. Wilson et al.

    Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not with maternal use of selective serotonin reuptake inhibitors

    Am J Perinatol

    (2011)
  • N. Byatt et al.

    Antidepressant use in pregnancy: a critical review focused on risks and controversies

    Acta Psychiatr Scand

    (2013)
  • V. Glover

    Maternal stress or anxiety during pregnancy and the development of the baby

    Pract Midwife

    (1999)
  • L. Andersson et al.

    Implications of antenatal depression and anxiety for obstetric outcome

    Obstet Gynecol

    (2004)
  • K. Lindgren

    Relationships among maternal–fetal attachment, prenatal depression, and health practices in pregnancy

    Res Nurs Health

    (2001)
  • J. Kim et al.

    Stereoselective disposition of fluoxetine and norfluoxetine during pregnancy and breast-feeding

    Br J Clin Pharmacol

    (2006)
  • P. Gaspar et al.

    The developmental role of serotonin: news from mouse molecular genetics

    Nat Rev Neurosci

    (2003)
  • T. Oberlander et al.

    Sustained neurobehavioral effects of exposure to SSRI antidepressants during development: molecular to clinical evidence

    Clin Pharm Ther

    (2009)
  • A. Einarson et al.

    Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study

    Am J Psychiatry

    (2001)
  • H. Malm et al.

    Risks associated with selective serotonin reuptake inhibitors in pregnancy

    Obstet Gynecol

    (2005)
  • T.K.H. Chung et al.

    Antepartum depressive symptomatology is associated with adverse obstetric and neonatal outcomes

    Psychosom Med

    (2001)
  • T. Field et al.

    Pregnancy anxiety and comorbid depression and anger: effects on the fetus and neonate

    Depress Anxiety

    (2003)
  • N.K. Grote et al.

    A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction

    Arch Gen Psychiatry

    (2010)
  • J. Dayan et al.

    Role of anxiety and depression in the onset of spontaneous preterm labor

    Am J Epidemiol

    (2002)
  • S. Hoffman et al.

    Depressive symptomatology during pregnancy: evidence for an association with decreased fetal growth in pregnancies of lower social class women

    Health Psychol

    (2000)
  • S.T. Orr et al.

    Maternal prenatal depressive symptoms and spontaneous preterm births among African–American women in Baltimore, Maryland

    Am J Epidemiol

    (2002)
  • J.A. Teixera et al.

    Association between maternal anxiety in pregnancy and increased uterine artery resistance

    BMJ

    (1999)
  • V. Glover

    Annual research review: prenatal stress and the origins of psychopathology: an evolutionary perspective

    J Child Psychol Psyc

    (2011)
  • T. Mendelson et al.

    Associations of maternal psychological factors with umbilical and uterine blood flow

    J Psychosom Obstet Gynaecol

    (2011)
  • S. Misri et al.

    Relation between prenatal maternal mood and anxiety and neonatal health

    Can J Psychiat

    (2004)
  • B.R.G. Van den Bergh et al.

    High antenatal maternal anxiety is related to ADHD symptoms, externalizing problems, and anxiety in 8- and 9-year olds

    Child Dev

    (2004)
  • B. Zuckerman et al.

    Maternal depressive symptoms during pregnancy, and newborn irritability

    J Dev Behav Pediatr

    (1990)
  • L. Allister et al.

    The effects of maternal depression on fetal heart rate response to vibroacoustic stimulation

    Dev Neuropsychol

    (2001)
  • C. Monk et al.

    Maternal stress responses and anxiety during pregnancy: effects on fetal heart rate

    Dev Psychobiol

    (2000)
  • N.M. Talge et al.

    Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?

    J Child Psychol Psyc

    (2007)
  • T.F. Oberlander et al.

    A tale of 2s: optimizing maternal-child health in the context of antenatal maternal depression and antidepressant use

    Can J Psychiatry

    (2012)
  • P. Dietz et al.

    Clinically identified maternal depression before, during, and after pregnancies ending in live births

    Am J Psychiatry

    (2007)
  • L. Andersson et al.

    Neonatal outcome following maternal antenatal depression and anxiety: a population-based study

    Am J Epidemiol

    (2004)
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