Historical perspective

Concern for the use of antidepressants in pregnancy and the treatment of mental illness in pregnancy is not a new phenomenon, and its history has laid a foundation of anxiety that continues to influence clinical practice. Briefly, tricyclic antidepressants (TCA) were first introduced in 1959, a time that paralleled the thalidomide tragedy, and potential limb anomalies associated with amitriptyline were reported. Dr. William McBride, who reported deformities caused by thalidomide, examined infants and reported increased limb deformities associated with iminodibenzyl hydrochloride (associated with TCA use) during pregnancy . The article was covered by several press agencies and instigated a series of reports about the safety of these medications during pregnancy . Notably, the Lithium Registry of Babies reported, at the same time, a higher rate of Ebstein’s anomaly associated with lithium use in pregnancy . This is still taught as dogma to young clinicians and students, despite limited confirmation and critical reviews that show a more modest risk for cardiac defects . These combined experiences produced an overall negative attitude in the pharmacological treatment of mood disorders during pregnancy.

The first selective serotonin reuptake inhibitor (SSRI), fluoxetine, was introduced in the USA in 1987, and was followed by the addition of serotonin and norepinephrine uptake inhibitors (SNRIs) in the early 1990s. In the subsequent 25 years, SSRIs and to some degree, SNRIs, essentially replaced TCAs in North America, much of Europe, and modern Asia as primary treatments for depression and most anxiety disorders. Their widespread use expanded to significant use in the perinatal period. A review of healthcare databases indicated that over 6% of women are prescribed an antidepressant at some point during pregnancy .

The reproductive safety of SSRIs and SNRIs has been the focus of considerable scrutiny using a variety of methodologies. Post-marketing surveillance, pharmaceutical registries, poison control center reports, and academic centers have all made significant contributions to the literature. Investigations of the potential impact of antidepressants in pregnancy have extended beyond studies of teratogenic effects to include obstetrical complications, uterine blood flow, fetal activity, neonatal assessments, infant behaviour and growth, and long-term neurobehavioural development. These studies have produced a large database to inform clinical decision making.

Defining the clinical problem

The course of illness and the effect of maternal stress, depression, and anxiety during pregnancy have been covered elsewhere. Notably, several potential outcomes ascribed to antidepressant exposure are also seen with maternal stress, such as an increased risk of developing an autism spectrum disorder in the offspring . This complicates the ability to ferret out the effect of illness compared with treatment, and is a common problem of treating various conditions during pregnancy, such as epilepsy, severe nausea, and asthma.

The use of antidepressants during pregnancy seems to be increasing. On the basis of health records, investigators in the Netherlands found that 2% of women were prescribed antidepressants (SSRIs or TCAs) during pregnancy . In the USA, the number of women filling antidepressant prescriptions during pregnancy is as high as 8.7% , and an observation from The National Birth Defects Prevention Study indicates that antidepressant use during pregnancy has increased 300% from 1998 to 2005 .

Although the overall use of antidepressants in pregnancy seems to be increasing, discontinuation of antidepressant treatment during pregnancy is also increasing, with antidepressant use declining as pregnancy progresses . Pregnancy itself is a major determinant of antidepressant discontinuation, and confirmation of pregnancy is associated with a 1.8–3.5fold increase in discontinuation . This poses a difficult question about the long-term course of illness. Major depression was initially conceptualised as an episodic illness compared with the chronic nature of anxiety disorders. It is well documented that the number of depressive episodes increases the likelihood for a more chronic course of illness; therefore, depressive disorders are typically best controlled by continuous treatment with pharmacotherapy, proven psychotherapy techniques, or both . The potential consequence, if any, of antidepressant discontinuation during pregnancy in the long term course of illness for the mother has not been delineated.

Regulatory agencies provide sparse guidance for the use of medications in pregnancy. The current US Food and Drug Administration (FDA) pregnancy labels are based on the available knowledge of the use of medications in humans and animals during pregnancy. The FDA has proposed a new and more clinical friendly system that includes information about the risks, available data, and clinical considerations about the use of medications in pregnancy. The timing of this change and the extent to which existing medications will be reviewed and potentially re-classified with the new system, is not entirely clear .

Under the current system, most antidepressants are currently FDA pregnancy category C: ‘while there are animal studies indicating an adverse effect on the fetus, there are no adequate and well-controlled human studies and the drug can be used during pregnancy only if the potential benefit justifies the potential risk to the fetus’. Paroxetine and TCAs are category D: ‘there are adequate and well-controlled human studies indicating a risk to the fetus but the use of the drug in the pregnant woman may be acceptable despite the risk’ . Overall, the FDA recommends antidepressant use in pregnancy based on a risk–benefit decision on a case-by-case basis. Pregnant women routinely overestimate the risk to the fetus when not presented with proper medical information . Bonari et al. showed that, although gastrointestinal medications, antibiotics and antidepressants may have similar overall risks to the fetus, 87% of women believe that antidepressant risk to the fetus is higher. These ratings, the media flurry that occurs in response to a potential adverse effect, patient attitudes, misinformation, and the routine advertisement of legal action on television and the internet generate clinical angst and concern for medical liability when prescribing an antidepressant to pregnant women.

Effective treatment is only efficacious if it is appropriate, available, and affordable. One central component to the use of antidepressants in pregnancy debate is the efficacy of non-pharmacological treatment options. These treatment options for depression and anxiety during pregnancy are reviewed in other chapters. In a recent review, Domar et al. reported the potential benefits of psychotherapy and exercise in non-pregnant women as alternative treatment strategies in pregnancy. It is a laudable goal to apply such treatment strategies to pregnant women to potentially prevent antidepressant exposure during pregnancy. Exercise may not, however, be appropriate for all pregnant women, such as those with pre-term labour, a condition associated with maternal depression. The use of efficacious structured psychotherapies in lieu of antidepressants makes the assumption that trained psychotherapists are available and that patients are able to attend regular therapy sessions. Finally, the affordability of alternative treatments and some antidepressant medications are limited by the fact that, in the USA, over 20% of women in their reproductive years do not have health insurance, and over 40% of pregnancies in the USA are covered by Medicaid.

The clinical problems can be summarised as follows: (1) maternal depression, anxiety, and stress in pregnancy may pose risks to others and the fetus; (2) no definitive evidence shows that maternal depression and anxiety lay quiescent during pregnancy; (3) antidepressant use in pregnancy is increasing; (4) antidepressant discontinuation in pregnancy is common, and the risks are not fully delineated; (5) regulatory agency information, over estimation of risk by patients, and concerns for liability influence treatment decisions; and (6) non-pharmacological treatments may be efficacious but are not always viable options. In many cases, antidepressants may represent a necessary treatment option for women during pregnancy for which the clinician needs to be prepared.

Data limitations

Several methodological limitations are inherent to clinical investigations in pregnant women.

Fetal antidepressant exposure

Fetal psychotropic drug exposure is governed by the pharmacokinetic properties of the maternal, placental, and fetal compartments. The primary routes of fetal exposure are through umbilical circulation and amniotic fluid. Paired maternal and umbilical cord blood collected at delivery shows that TCAs and SSRIs achieve cord blood concentrations over 50% of those seen in maternal circulation and, in some cases, cord blood concentrations are equal to maternal blood concentrations. Tricyclic antidepressants and their metabolites pass readily into umbilical cord serum . Exposure to selective serotonin reuptake inhibitors results in higher umbilical cord transfer rates compared with TCAs, as SSRI cord serum–maternal serum ratios are between 0.52 and 1.1 depending on the compound . Metabolites (e.g. norfluoxetine and desmethylvenlafaxine), which in some cases are active at inhibiting the serotonin transporter, readily transfer across the placental barrier . Similarly, antidepressants are also found in amniotic fluid . Although significant differences exist between individual medications, animal exposure studies show that enough antidepressant crosses the placenta to block over 90% of the transporter sites in the rodent brain . The above data show that antidepressant exposure in pregnancy results in considerable fetal exposure, and does not indicate clinically meaningful differences in central nervous system exposure among individual antidepressants.

Maternal antidepressants dosing during pregnancy

Pregnancy can affect the metabolism and apparent clearance of centrally active medications. The clearance of several SSRIs has been shown to increase over the course of pregnancy , and our group demonstrated an increase in depressive scores for some women that required dose adjustment during pregnancy . Similarly, postpartum mothers taking citalopram, escitalopram, or sertraline, have also been shown to be in a potentially refractory metabolic state . If the decision to use antidepressants in pregnancy has been made, it is important to consider that adjusting the maternal dose over the course of pregnancy may be warranted to maintain maternal health. Clinicians should be cognisant that the fetus is exposed to the maternal serum concentration and not the maternal dose; therefore, dose adjustments (increase or decrease) would not significantly alter the extent of fetal central nervous exposure.

The extent of fetal exposure during pregnancy is also relevant to those women who choose to breast feed. Briefly, the exposure to antidepressants in breast feeding has been rigorously quantified, and pregnancy exposure is magnitudes of order greater than breast feeding exposure. Thus, if a woman takes an antidepressant in pregnancy, concerns about breast feeding exposure are not warranted.

Fetal antidepressant exposure

Fetal psychotropic drug exposure is governed by the pharmacokinetic properties of the maternal, placental, and fetal compartments. The primary routes of fetal exposure are through umbilical circulation and amniotic fluid. Paired maternal and umbilical cord blood collected at delivery shows that TCAs and SSRIs achieve cord blood concentrations over 50% of those seen in maternal circulation and, in some cases, cord blood concentrations are equal to maternal blood concentrations. Tricyclic antidepressants and their metabolites pass readily into umbilical cord serum . Exposure to selective serotonin reuptake inhibitors results in higher umbilical cord transfer rates compared with TCAs, as SSRI cord serum–maternal serum ratios are between 0.52 and 1.1 depending on the compound . Metabolites (e.g. norfluoxetine and desmethylvenlafaxine), which in some cases are active at inhibiting the serotonin transporter, readily transfer across the placental barrier . Similarly, antidepressants are also found in amniotic fluid . Although significant differences exist between individual medications, animal exposure studies show that enough antidepressant crosses the placenta to block over 90% of the transporter sites in the rodent brain . The above data show that antidepressant exposure in pregnancy results in considerable fetal exposure, and does not indicate clinically meaningful differences in central nervous system exposure among individual antidepressants.

Maternal antidepressants dosing during pregnancy

Pregnancy can affect the metabolism and apparent clearance of centrally active medications. The clearance of several SSRIs has been shown to increase over the course of pregnancy , and our group demonstrated an increase in depressive scores for some women that required dose adjustment during pregnancy . Similarly, postpartum mothers taking citalopram, escitalopram, or sertraline, have also been shown to be in a potentially refractory metabolic state . If the decision to use antidepressants in pregnancy has been made, it is important to consider that adjusting the maternal dose over the course of pregnancy may be warranted to maintain maternal health. Clinicians should be cognisant that the fetus is exposed to the maternal serum concentration and not the maternal dose; therefore, dose adjustments (increase or decrease) would not significantly alter the extent of fetal central nervous exposure.

The extent of fetal exposure during pregnancy is also relevant to those women who choose to breast feed. Briefly, the exposure to antidepressants in breast feeding has been rigorously quantified, and pregnancy exposure is magnitudes of order greater than breast feeding exposure. Thus, if a woman takes an antidepressant in pregnancy, concerns about breast feeding exposure are not warranted.

Congenital malformations

The best established end points of teratology are congenital malformations that may be indicative of a significantly disrupted fetal environment. The extant literature indicates that congenital malformations are not associated with prenatal exposure to TCAs or SSRIs , SSRIs alone , or atypical antidepressants . A study of Danish women showed an increased risk of congenital malformations and SSRI prescription redemption; however, a significant number of congenital malformations were reported in women who discontinued SSRI use before pregnancy (4.5% for those that discontinued compared with 4.9% with early pregnancy exposure and 6.8% in mid- to late-exposure), which indicates that other factors may be involved . A meta-analysis of first-trimester exposure to several classes of antidepressant confirmed these observations . Additional meta-analyses show no association or pattern of malformations related to antidepressant exposure.

Following the US Food and Drug Administration category change to D for paroxetine based on cardiovascular defects, additional scrutiny has taken place ( Table 1 ). Briefly, cardiovascular defects have been investigated in the context of prenatal antidepressant exposure due to serotonin regulation of cardiovascular function. GlaxoSmithKline’s own study of first trimester paroxetine exposure compared with other antidepressants showed an increased risk of cardiovascular malformations, mostly ventricular septal defects . Another study, however, found the opposite effect: first-trimester paroxetine exposure resulted in fewer cardiovascular malformations than unexposed infants . Prenatal exposure to the atypical antidepressant bupropion showed an increased risk for left outflow tract heart defects . A study of Danish birth registries found an association of SSRI prescription redemption and septal heart defects . A meta-analysis of seven studies in the USA and Europe reported an overall increased risk for cardiovascular malformations . Functional studies using echocardiograms have shown a twofold increased risk for mild non-syndromic heart defects caused by prenatal exposure to SSRIs . It is difficult to determine the potential for cardiovascular defects, predominantly septal, from the myriad of studies that have failed to find a similar association. A potential side-effect of SSRIs, however, is ‘bruising’ purportedly related to inhibition of prostaglandins, and whether or not this could account for the cardiovascular defects is unclear. The pre-clinical data have not consistently demonstrated an increase in similar or related malformations. Investigators will continue to examine this end point, as the data do not point to a significant association of prenatal antidepressant exposure and a specific pattern of congenital malformations.

Birth weight and gestational age at delivery

The potential effect of birth weight and gestational age have become important considerations in research outcomes secondary to the evidence supporting ‘fetal programming’ as a model of risk for later adult illnesses. Several studies have shown an association of prenatal SSRI use with low birth weight, shortened gestational length, or small size for gestational age . Several other studies have reported no association of prenatal SSRI use and adverse birth outcomes . Only a few of these studies control for the mental health status of the mother, and the outcomes are different between the studies . A population-based study of 860,215 women in the Swedish medical birth registry observed an increased risk for preterm birth (<37 weeks gestation) associated with antidepressant prescription redemption. Preterm birth risk was increased for SNRIs compared with SSRIs and late compared with early exposure .

The pre-clinical studies have produced conflicting results on the birth weight of pups and liter size. Briefly, investigations have found ‘no effect’ on pup weight or litter size; an ‘increase’ in fetal and neonatal weights; and ‘reduced’ birth weight in pups and reduced litter size. Studies using clinically relevant antidepressant dosing have failed to show changes in pup weight and liter size .

In summary, preclinical and clinical data have produced similar conflicting reports on birth weight, and indicate a modest risk for decreased birth weight associated with antidepressant exposure when weight is used as a continuous variable, and the clinical significance remains obscure. With the use of a stringent definition of low birth weight (low birth weight < 2500 g) the antidepressant does not increase the risk for a low birth weight baby. Completion of quality meta-analyses of studies that control for the effect of maternal depression, anxiety, and stress are needed, as it is not possible to conclude, with any certainty, the effect of prenatal antidepression exposure on gestational length.

Respiratory distress and pulmonary hypertension

Serotonin plays a modulatory role in respiratory control, with research indicating that the serotonin system has an inhibitory effect on respiration . Concerns for antidepression exposure and respiratory problems were first reported in 1982 in infants prenatally exposed to TCAs who had symptoms of respiratory acidosis, cyanosis, tachypnea, or both . Oberlander et al. used birth registry data from 120,000 patients, and found an association of respiratory distress in newborns with prenatal SSRI exposure even after controlling for severity of mental illness. The risk for respiratory distress was higher for TCA exposure compared with neonates exposed to SSRIs in two studies ; however, prenatal exposure to SSRIs still has an increased risk for respiratory distress .

Serotonin also has a significant role in vasoconstriction and has been hypothesised to play a role in pulmonary arterial hypertension . In a retrospective study, Chambers et al. observed an increased risk for persistent pulmonary hypertension during late pregnancy with prenatal SSRI exposure only (odds ratio 6.0). A second study found a more modest (odds ratio 2.0) association of persistent pulmonary hypertension of the newborn (PPHN) with SSRIs and SNRIs . Although this study may elucidate an important area to examine in the future, mental state and other potential exposures were not controlled for. The issue of antidepressants and the risk for PPHN was recently reviewed in detail .

Preclinical studies have also examined the effects of prenatal antidepressant exposure on pulmonary outcomes. Mice exposed to fluoxetine prenatally exhibited pulmonary hypertension as measured by increased right ventricle: left ventricle plus septum ratio or pulmonary arterial medial thickness. Arterial oxygen saturation was lower in pups exposed to fluoxetine, but this normalised by the third day of life. These findings were noted to be strongly indicative of pulmonary hypertension . Noorlander also reported that mice prenatally exposed to fluoxetine manifested decreased left ventricle wall thickness, a measure of dilated cardiomyopathy that is often associated with pulmonary hypertension. These preclinical findings provide some concordant data about the potential risk for persistent pulmonary hypertension of the newborn reported above.

The issue of PPHN is of serious concern; however, it is a relatively rare clinical condition affecting 1 in 1000. As such, clinical importance of the reported odds ratios needs to be considered. The clinical and preclinical data are concordant; thus, the patient should be informed of the risks.

Neonatal intensive care unit, neonatal symptoms, and antidepressant neonatal syndrome

Admission into the neonatal intensive care unit (NICU) is an easily identifiable end point that has been examined in the context of prenatal antidepressant exposure. One study found that longer exposure to prenatal SSRIs correlated with an increased rate of NICU admission with third-trimester exposure, increasing the risk of NICU admission compared with first-trimester exposure . The association of SSRI exposure and NICU admission remained even when controlling for maternal psychiatric illness . In contrast, another group reported that prenatal SSRI exposure did not increase the risk for neonatal intensive care unit admission when controlling for maternal mood . Given the potential association with respiratory symptoms noted above and neonatal symptoms discussed below, an increased rate of admission to the NICU is not surprising. It is unclear if documentation of antidepressant exposure warrants an indication for observation in the NICU.

The literature is laden with case reports and case studies of neonatal symptoms associated with antidepressant exposure in pregnancy that are often conflicting. Reports have included jaundice and jitteriness , infantile hypertrophic pyloric stenosis , necrotising enterocolitis , tachyarrhythmia , hypothermia , and a long QTC interval . In contrast, some studies without negative effects of prenatal antidepressant exposure on the infant have been published . These purported effects are important considerations for future investigations, but remain inconclusive at present.

The potential for an ‘antidepressant neonatal syndrome’ was first reported in 1973 by Webster et al. in an infant exposed to imipramine, a TCA. Notably, similar symptoms have also been reported with numerous centrally acting medications, including anti-epileptics and antihistamines. Reports of ‘jitteriness’ in prenatally-exposed infants , possible withdrawal symptoms consisting of ‘irritability’, or both, prompted warnings from the FDA and Canadian Health Care about neonatal symptoms. It went as far as suggesting that antidepressants should be discontinued before delivery to reduce the potential for such symptoms. A comprehensive review by Moses-Kolko et al. summarised the extant literature.

There is reasonable agreement that antidepressant exposure proximate to delivery is associated with higher rates of transient symptoms in the neonate. The absolute risk varies based on the symptom criteria used; however, it would be a conservative estimate that 10% will have some mild symptoms for patient-education purposes. Discontinuation of antidepressants before delivery has not been found to be beneficial, and it is pharmacologically unlikely that breast feeding while taking antidepressants would reduce the risk.

Neurobehavioral studies in neonates and children

The potential effect of prenatal antidepressant exposure on neurobehavioral development has received increased attention in the past decade. It is difficult to extrapolate the pre-clinical literature as a clinical guide in this domain of outcome secondary to the animal models and dosing schedules used in most studies. The effect of antidepressant exposure in pregnancy has been examined across a variety of age groups: neonate, infant, and toddler.

Sleep-pattern disruption is a reported finding associated with SSRI exposure . A study of fetal activity observed that increased fetal motor activity in the first and second trimesters was associated with SSRI exposure compared with a control group of depressed mothers not receiving medication. Additionally, SSRI exposure increased fetal movements in the third trimester and was purported to be indicative of disrupted non-rapid eye movement sleep . Examination of neonates prenatally exposed to SSRIs showed disrupted rapid eye movement sleep, slightly disrupted autonomic homeostasis, and increased motor activity in 1–2 day old neonates . Some animal studies, especially in sheep, have observed a similar disruption in sleep patterns associated with SSRI exposure in pregnancy.

Rating scales of infant development have also been used to assess the behavioural effects of prenatal SSRI exposure. The Brazelton Neonatal Behavioral Assessment Scale was used by one group who reported that neonates exposed to antidepressants had lower habituation, social-interactive, motor, and autonomic behaviour, but they did not control for maternal mood . In contrast, Suri et al. failed to find any effects of prenatal antidepressants and maternal depression at 6–8 weeks of age on the Brazelton Neonatal Behavioural Assessment Scale scores. Although neurologically normal as assessed by a paediatric neurologist, children examined at 12–40 months of age, using Bayley Scales of Infant Development, showed that length of antidepressant exposure, assessed as number of trimesters of SSRI use, increased the risk for lower Psychomotor Developmental Index and Behavioural Rating Scale scores .

The investigators also reported that prenatal exposure to SSRIs lowered psychomotor development between the ages of 6 and 40 months . This effect was still significant when controlling for maternal mood and comparing children exposed to antidepressant born to women with major depressive disorder . A second study, using the Bayley Scales of Infant Development, showed lower gross motor, social–emotional, and adaptive behaviour subscales at 10 months of age in infants with prenatal exposure to SSRIs, but failed to find this association in infants of depressed mothers who did not receive SSRI medications .

Only a few studies have examined long-term neurodevelopment in relation to prenatal SSRI exposure. A study evaluating fluoxetine or infants exposed to TCAs (ages 1–7 years old at follow up, n = 135 exposed infants) revealed no differences in perinatal complications, gestation age, cognition, IQ, or behaviour compared with unexposed controls . In a series of studies using the same small cohort of infants, Misri et al. evaluated prenatal exposure to fluoxetine, paroxetine or sertraline and maternal mood, and observed no changes in internalising behaviour compared with controls for prenatal SSRI exposure. Maternal anxiety and depressive symptoms did correlate with increased internalising behaviour in the offspring. Oberlander et al. conducted a 4-year follow-up study of infants exposed prenatally to sertraline, paroxetine, or fluoxetine ( n = 22) to examine internalising and externalising behaviours. They found that umbilical cord serum concentrations of antidepressants correlated with increased externalising behaviours in the children, but controlling for maternal mood abolished this finding. They also found that increased measures of aggressive behaviour were correlated with maternal stress levels and poor neonatal adaptation. Notably, controls were not exposed to prenatal antidepressants and the maternal mood was neither depressed nor anxious. These later studies illustrate the importance of maternal mood in discriminating the effects of prenatal antidepressant exposure from prenatal stress and maternal mood disorders.

Increased awareness of childhood neurodevelopmental disorders in recent years has prompted further investigation in relation to prenatal antidepressant exposure. The MarketScan database (insurance claims data), was used to show that exposure to bupropion during the second trimester correlated with increased risk of attention deficit hyperactivity disorder in children; however, SSRI exposure as a whole was not correlated with increased risk. Psychiatric disorders have differing degrees of heritability and, as might be predicted, psychiatric disorders in the mother were positively correlated with attention deficit hyperactivity disorder risk in the child . A population-based case control study reported an increased risk of developing childhood autism spectrum disorder following prenatal antidepressant exposure .

These neurobehavioural studies, while limited, do suggest a potential effect on sleep patterns consistent with purported side-effects of SSRIs, but the long-term significance is obscure. The conflicting data on longer term developmental data underscore the need to appropriately control for maternal mood and anxiety. Presently, it is not possible to offer definitive information, either negative or positive, about long-term development. It is reassuring that investigators are scrutinising a variety of neurobehavioural outcomes associated with antidepressant exposure in pregnancy, as this is a notable deficit for other centrally acting agents such as anti-emetics and antihistamines routinely prescribed in pregnancy. Further studies of these end points and longer-term follow up will be valuable in understanding the role(s) of illness and treatment in the developmental trajectory of offspring.