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Abstract

Women with active psychiatric disorders who become pregnant face treatment dilemmas. Although results from studies are inconsistent, small but significant, risks on birth outcomes occur with exposure to untreated disorders, as well as to psychotropic medications. Prenatal antidepressant medication exposure may increase the risk for spontaneous miscarriage, preterm birth, cardiac malformations, persistent pulmonary hypertension of the newborn and postnatal adaptation syndrome. The use of valproate is contraindicated during pregnancy due to teratogenicity and neurocognitive delay and deficits. This review of selected studies will highlight some of the current issues with the use of psychotropic medications during pregnancy and the postpartum period.

Keywords

antidepressant antiepileptic antipsychotic birth outcome congenital malformations depression lithium persistent pulmonary hypertension of the newborn postnatal adaptation syndrome pregnancy

Epidemiology

Up to 15% of pregnant or postpartum women will have depression, with approximately half meeting the diagnostic criteria for major depressive disorder (MDD) [1]. This prevalence rate of depression is similar to rates reported in reproductive age women who are not perinatal. However, for women with a vulnerability to developing depressive episodes (e.g., a recurrent mood disorder), pregnancy and the postpartum period may be a time of risk. Concurrent anxiety symptoms and stress are common in many women who have MDD during pregnancy and the postpartum period.

Pregnant women with MDD are reported to demonstrate poor health behaviors, such as poor nutrition, lack of exercise, not taking prenatal vitamins and prescribed medications, poor compliance with prenatal care, increased smoking, and increased use of alcohol, and over-the-counter and illicit drugs [2]. Thoughts of self-harm and suicidal ideation occur in perinatal women and are often correlated with mood disorders and symptoms [3,4]. Perinatal women may have lower rates of completed suicide compared with women who are not perinatal, but suicide in the first postpartum year is a leading cause of maternal death in England and Australia [4,5].

Effects of untreated prenatal depression, anxiety & stress on the fetus

It is beyond the scope of this review to include the burgeoning literature examining fetal effects from untreated maternal depression, anxiety and stress. Studies have reported altered fetal response to vibroacoustic stimulation, altered fetal heart rate variability, changed movement and sleep patterns, altered attention, delayed fetal head and overall growth, increased maternal and fetal cortisol and corticotropin-releasing hormone, increase in C-reactive protein and pro-inflammatory cytokines, and decreased maternal–fetal attachment. In addition, there are potential epigenetic changes to placental genes involved in the hypothalamic–pituitary–adrenal axis [6].

Effects of untreated prenatal depression, anxiety & stress on birth outcome

A meta-analysis of 29 studies conducted from 1980 to 2009 reported that untreated prenatal depression was associated with small, but significant, increased risks of preterm birth (PTB) and low birth weight (LBW) [2]. PTB causes considerable neonatal morbidity and its decrease is a major public health objective. Some studies have reported small-for-gestational age, low Apgar scores and higher rates of cesarean delivery. Another recent review of 30 studies up to June 2010 reported that depression during pregnancy was associated with an increased risk for PTB and decreased intention to breastfeed [7]. The mechanism of how untreated depression, anxiety and stress would lead to PTB or LBW is unclear, but increased maternal and fetal cortisol and corticotropin-releasing hormone levels have been proposed. Low folate levels have been reported to add to the risk of depression on LBW and small-for-gestational age [8].

Effects of untreated perinatal depression on the infant & child

The effects of untreated prenatal depression on the offspring are difficult to identify since many mothers remain depressed in the first postnatal year and beyond. Again, it is beyond the scope of this review to summarize the growing literature examining short- and long-term effects from exposure to pre- and post-natal maternal depression. In the infant, reported effects of prenatal depression have included altered neonatal behavioral scores, altered cortisol reactivity, greater relative right frontal EEG asymmetry, decreased vagal tone, altered reactivity to pain or stress, altered temperament, altered attention, delayed neuromotor development and sleep problems. The literature examining the effects of untreated postnatal depression on child development is well-established [5], and negative effects include delayed motor and cognitive development, altered executive function, internalizing and externalizing disorders, and altered response to stress. In the older child and adolescent, increased risk of depression, anxiety disorders, attention deficit disorder and psychosis have been reported.

Antidepressants during pregnancy

Approximately 7% of women in the USA take a selective serotonin reuptake inhibitor (SSRI) during the first trimester, and sertraline is currently the most prescribed antidepressant during pregnancy, followed by fluoxetine, in the USA [9]. SSRI use in the year prior to delivery has been reported to be as high as 28.5% in The Netherlands [10]. Many women discontinue their antidepressant treatment once the pregnancy is recognized, either on their own or at the advice of a clinician [11]. It is unclear if discontinuation of antidepressants consistently leads to an increased risk of relapse of MDD, but a relapse is more probable in women with more previous episodes, longer length of illness and an episode in the 6 months prior to conception [12,13].

Fetal exposure to antidepressants occurs through the umbilical cord, across the placenta by transporter genes and through absorption from amniotic fluid. Antidepressant exposure in the fetus is influenced by the cord-to-maternal ratio of the antidepressant level, half-life of antidepressant, peak and trough levels of the antidepressant, cytochrome P450 genetic polymorphisms in the mother, fetus and placenta, and the unbound fraction of the antidepressant in the fetus [14]. Exposure to SSRIs may influence the development and ‘fine-tuning’ of the serotonergic system in the fetus [6]. Futher studies are needed to evaluate whether adverse birth outcomes are specifically associated with timing, length or maximum dose of antidepressant exposure [15]. Although the most recent studies have examined the newer antidepressant SSRIs and serotonin and norepinephrine reuptake inhibitors, similar findings on birth outcomes have been reported with tricyclic antidepressants [16].

Spontaneous miscarriage

Exposure to antidepressants during the first trimester is associated with an increased risk of spontaneous miscarriage (odds ratio: 1.4–1.6) [17,18]. Study results vary in whether the increased risk is statistically significant compared with nonexposure. Higher risk has been reported with venlafaxine and paroxetine [17]. Depression during the first trimester may also be associated with increased risk of spontaneous miscarriage and, to date, most studies do not control for maternal depression when examining spontaneous miscarriage rates with antidepressant exposure.

PTB & birth weight

Results of studies examining the effects of antidepressant exposure on birth outcomes have been inconsistent. Since women with psychiatric symptoms are not randomized to take antidepressants or placebo, it is difficult to separate the contribution from the underlying mood disorder and the associated behaviors that could be confounding variables [19]. Moreover, women receive prescriptions for antidepressant medications for several indications that are also not controlled for; for example, anxiety disorders [20]. Some studies have suggested that the effects of antidepressants on PTB or LBW may be additive to the effects of underlying maternal depression and anxiety on birth outcome.

A review of 23 studies up to June 2010 examined birth outcomes in women who took antidepressant medications during pregnancy [18]. This review reported a significant increased risk of PTB (pooled odds ratio of 1.55) with prenatal exposure to antidepressants. This review commented that the increased risk of PTB was equivalent to approximately 3 days shorter gestational age, which was considered a small effect [18]. Exposure to antidepressants was associated with a significantly lower birth weight compared with no exposure (pooled standardized mean difference of -0.10) [18]. The mean difference for birth weight was 74 g lower, which was considered a small effect [18]. This review also reported small, but statistically significant, decreases in gestational age, and 1 and 5 min Apgar scores with prenatal antidepressant exposure [18].

Multiple studies, several with large registry samples, have been published since the studies included in this review. Results have generally suggested increased odds ratio of 1.5–2.5 of PTB with prenatal exposure to antidepressants; however, studies vary in whether or not the increased risk is statistically significant. One study suggested that the risk with SSRI exposure was specific to PTB at 34–37 weeks [19]. Studies also continue to be inconsistent in the reporting of risks of LBW, gestational age and Apgar scores.

Congenital malformations

Studies examining the risks of congenital malformations with first trimester exposure to antidepressants have reported inconsistent results. A review of studies up to 2011 reported that if an increased risk does exist, it is a small increase in absolute risk, and no consistent organ anomaly has been reported with antidepressants as a class [21]. Another recent review of studies up to June 2010 reported that there is not an increased risk of congenital major malformations with antidepressants, but there may be a statistically significant, but not clinically significant, increased risk of cardiovascular malformations with antidepressants, particularly paroxetine [22]. Another recent meta-analysis reported a small, but significant, increased risk of cardiac malformations with paroxetine [23]. Increased risk of left outflow tract heart defects has been reported with bupropion [21]. The mechanism by which antidepressants might increase cardiac malformations is not clear, but altered serotonergic influence on cardiac development is hypothesized. The US FDA issued a warning in 2005 that paroxetine exposure during the first trimester may increase the risk of cardiac malformations, and paroxetine was changed to pregnancy category D. Fetal echocardiography with first trimester paroxetine exposure has been suggested [24].

Several studies have been published since the aforementioned reviews that have examined the risk of congenital malformations with antidepressant exposure. Study results continue to be inconsistent, and the small absolute increased risks could be due to the antidepressant, the underlying illness or other unknown factors [21]. One study reported increased rates of congenital malformations with SSRI exposure, but an increase was also found in women who had ‘paused’ their SSRI treatment throughout pregnancy, suggesting confounding by indication [25]. Interpretation of the growing number of study results is difficult since an increased odds ratio of 1.5 may be interpreted as significant in some studies, and not significant in other studies [20]. Most studies report increased odds ratio values between 1.2 and 2.0, with SSRI exposure considered a small increase in absolute risk of major congenital malformations, which may not be of clinical significance [21,26,27].

Persistent pulmonary hypertension of the newborn

Persistent pulmonary hypertension of the newborn (PPHN) occurs when there is failure of the normal relaxation in the fetal pulmonary vascular bed during the circulatory transition that occurs shortly after birth [28]. The elevated pulmonary hyptertension causes right-to-left shunting of extra pulmonary blood through the ductus arteriosus and foramen ovale, which can lead to hypoxemia, respiratory distress, acidosis and right heart failure [28]. PPHN occurs in 1–2 infants per 1000 live births with a 10–20% mortality risk that can vary with etiology. There are many risk factors for PPHN, such as meconium aspiration and cesarean section [29]. Etiological theories include increased vasoconstriction of smooth muscle cells and/or decreased production of nitric oxide, a potent vasodilator. SSRIs may influence serotonergic effects on pulmonary vascular smooth muscle endothelium and increase vasoconstriction [29,30]. PPHN may represent the severe end of a spectrum of respiratory difficulties with SSRI exposure [21].

As reviewed, three out of six studies have reported an increased risk (risk ratio up to 6) of PPHN with SSRI use in the second half of pregnancy [28,31]. The absolute risk is approximately 0.3% with SSRI use after week 20 of pregnancy [30]. This risk has been noted with fluoxetine, sertraline, paroxetine and citalopram, and is considered a class effect [30].

In July 2006, the FDA issued a Public Health Advisory stating that, in one study, PPHN was six-times more common in babies whose mothers took an SSRI antidepressant after the 20th week of pregnancy compared with babies whose mothers did not take an antidepressant. The FDA advised careful consideration of the potential benefits and risks of the medication for each individual pregnant patient. In December 2011, the FDA issued a Safety Announcement advising healthcare professionals not to alter their current clinical practice of treating depression during pregnancy due to conflicting findings of studies on SSRI use during pregnancy and the development of PPHN.

Postnatal adaptation syndrome

A recent review of studies up to June 2010 reported that antidepressant exposure during pregnancy was associated with an increased risk of postnatal adaptation syndrome (PNAS), respiratory distress and tremors [32]. Neonatal symptoms, including respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyper-reflexia, tremor, jitteriness, irritability and persistent crying, occur in up to 30% of newborns exposed to SSRIs and serotonin and norepinephrine reuptake inhibitors. Although an FDA alert in 2004 warned that neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors late in the third trimester may develop complications following delivery requiring prolonged hospitalization, respiratory support and tube feeding, the symptoms of PNAS are generally mild and usually resolve within days to 2 weeks [32].

It is unclear what causes PNAS, potential etiologies include serotonergic toxicity due to accumulation of the antidepressant in the neonate and withdrawal signs from the abrupt discontinuation of neonate exposure to the antidepressant [33]. Symptoms of PNAS may differ by antidepressant, maternal factors or neonatal factors [21,32]. Some studies have reported that PNAS is more likely with third trimester exposure to fluoxetine, paroxetine and venlafaxine [21], but not all studies confirm this. Exposure to prenatal depression without medication also leads to neonatal symptoms [34], and many studies of PNAS have not controlled for maternal depression or included systematic blinded ratings. Although the FDA made a suggestion in 2004 to taper antidepressants prior to expected delivery, there is no evidence that tapering the dose of an antidepressant prior to expected delivery lessens PNAS, and this strategy could increase the risk of postnatal depression [32].

Long-term effects on child development

A recent study reported that in utero exposure to SSRIs or maternal depression did not lead to altered infant weight, length or head circumference at 1 year of age [35]. Prenatal exposure to SSRIs, but not maternal depression, was associated with altered motor movements in 3–4-month-old infants [36], and lower gross motor, social–emotional and adaptive behavior in 10-month-old infants [37]. Another recent study reported that children between 3 and 7 years of age exposed in utero to SSRIs or venlafaxine did not differ from children exposed to untreated maternal depression on cognitive or behavioral measures [38]. However, a recent study reported that prenatal exposure to untreated depression, rather than exposure to prenatal antidepressant use, was associated with behavioral or emotional problems in children 4–5 years of age [39]. The results from studies are varied, and it is difficult to separate the effects of prenatal exposure to antidepressants from the exposure to the underlying prenatal illness and the influence of postnatal factors. A review reported that SSRI use during pregnancy has been associated with mild developmental delays in motor development and attention in children under the age of 3 years, but these delays are generally within normal limits and seem to resolve with age [40]. Thus, the possible effects of prenatal exposure to antidepressants may be significant, but transient. It is well established that continued exposure to untreated maternal depression during and beyond the first postnatal year continues to be a critical risk factor for developmental problems in childhood, and contributes to long-term psychopathology [5,38].

Autism

Two recent articles have reported an association between antidepressant use during pregnancy and increased risk of autism spectrum disorders in offspring. The larger study reported that the use of SSRIs or tricyclic antidepressants during the first trimester were associated with autism spectrum disorders without intellectual disability [41]. The smaller study reported that SSRI use at preconception, first trimester and at any point in the year prior to delivery was associated with an increased risk of autism spectrum disorder [42]. Both of these studies did not examine the presence or severity of depression during pregnancy, nor did they adjust for some behaviors that might be associated with prenatal depression.

Additional reported effects of prenatal antidepressant exposure

Antidepressants have been associated with pregnancy-induced hypertension [43,44] and preeclampsia [44,45], prolonged QT interval in the newborn [46], and increased infant mortality in the first postdelivery month [47] and year [48]. However, two recent studies reported no association between SSRIs during pregnancy and increased stillbirth, neonatal or postneonatal mortality [49,50]. Other recent, positive reports with SSRI use during pregnancy compared with no exposure include increased infant attention measured by P50 auditory sensory gating [51], accelerated infant speech perception [52] and increased infant readiness to interact at 3 months of age [53].

Antidepressants & breastfeeding

Antidepressant levels in the infant are influenced by the infant's age and capacity to metabolize the drug through hepatic enzymes, and premature infants may be more vulnerable to adverse effects [54]. Poor feeding, irritability, sedation and sleeping problems are possible adverse effects. The antidepressant exposure with breast feeding is much lower than during pregnancy, and a relative infant dose of 10% or less compared with the maternal dose is generally considered low risk [55]. Although the number of mother/infant pairs studied are low for many antidepressants, most studies report a relative infant dose less than 10% for almost all antidepressants examined to date. In particular, sertraline, paroxetine and nortriptyline levels in breastfeeding infants yield low-to-undetectable infant serum levels [55]. Fluoxetine is less preferred with breastfeeding due to higher infant serum levels, presumably due to the long half-life of fluoxetine and its metabolites, and high infant levels have also been reported with citalopram [54]. Doxepin is contraindicated with breastfeeding and there is one case report of seizure activity with bupropion. Sertraline or paroxetine should be considered first-line choices if efficacious for the mother; but, overall, antidepressants are considered compatible with breastfeeding [54].

Nonpharmacological treatments for perinatal depression

Perinatal women who want to minimize fetal and infant exposure to psychotropic medications should maximize the use of nonpharmacological options. Interpersonal psychotherapy has been specifically studied in perinatal women, and recent reports suggest efficacy with cognitive-behavior therapy and mindfulness. Mixed results have been reported with light therapy, omega-3-fatty acids, folate, St John's wort and acupuncture [56,57]. Further study on exercise and repetitive transcranial magnetic stimulation is needed. Electroconvulsive therapy can be very effective in perinatal women with severe psychiatric disorders that do not respond to pharmacological treatments [58].

Other psychotropic medications during pregnancy & with breastfeeding Benzodiazepines

Most studies do not report an increased risk of major congenital malformations with prenatal benzodiazepine use. Case-control studies have suggested an increased risk of oral cleft, but this has not been confirmed in cohort studies [59].

A possible increased risk of gastrointestinal malformations has been reported [59,60]. Concurrent SSRI use was reported to increase the risk of cardiac defects [61], but a recent study reported no significant increase in congenital malformations or cardiac defects with SSRIs alone, benzodiazepines alone or their combined use [62]. Benzodiazepines have been associated with increased risk of PTB, LBW and neonatal withdrawal symptoms [24,60]. The concurrent use of SSRIs has been reported to increase neonatal symptoms [63]. Although sedation is of concern as a side effect in breastfeeding infants, this has not been consistently reported [64].

Mood stabilizers

Lithium

A recent systematic review of cohort studies, case–control studies and case reports described no significant increased risk of Ebstein's anomaly or other congenital malformations with lithium [65]. Earlier reports suggested that there was a 20-fold increase in Ebstein's anomaly with fetal exposure to lithium in the first trimester, a risk of 0.1% (vs 0.005% without exposure), and a 1.2–7.7 risk ratio for any cardiac malformation [24]. Although the increase in absolute risk of cardiac malformations with lithium is low, a high-resolution ultrasound and fetal echo-cardiogram are recommended during the second trimester. Lithium levels and renal function need to be monitored throughout pregnancy due to increased fluid volume and lithium excretion in the second and third trimesters. Thyroid function tests and fetal growth also need to be monitored throughout pregnancy [66,67].

Reducing the lithium dose is recommended 24–48 h prior to delivery or at delivery, and adequate hydration during labor and delivery is important [66,67]. Following delivery, lithium dosing should be resumed at preconception levels, and serum levels should be measured often to rule out toxicity [66,68]. Neonatal complications have included ‘floppy baby syndrome’, nephrogenic diabetes insipidus, hypothyroidism, low muscle tone, lethargy, tachycardia, cyanosis and respiratory difficulties [24,66,67].

Breastfeeding requires caution since serum lithium levels in the infant can be 10–50% of maternal serum level. A recent study reported that mothers taking lithium who choose to breastfeed their infants should obtain frequent clinical pediatric assessments and targeted laboratory testing (e.g., lithium level, renal function and thyroid status) as indicated [68]. The infant should be monitored for hypotonia, poor feeding, sustained behavioral change and slow growth [68]. Few studies have examined the long-term effects of lithium. A recent study of children at 3–15 years of age exposed in utero to lithium reported no adverse effects on growth, neurological, behavioral and cognitive development [69].

Valproate

Multiple studies have reported that valproate is associated with high rates of malformations (~10%) with first trimester exposure and extensive types of malformations; for example, neural tube defects, decreased brain volume, craniofacial anomalies, cardiac defects, hypospadias and oral clefts [24,70,71]. Risks of malformations increase with increased doses of valproate and with use of multiple antiepileptic medications [71]. Newborns exposed to valproate may have lower Apgar scores, irritability, feeding difficulties and hypertonia [67,72]. Recent data have confirmed that exposure to valproate in pregnancy leads to lower IQ and delayed neurocognitive development in children up to 6 years of age [73]. This study also reported reduced right handedness and less benefit from folate with valproate. A FDA Drug Safety Communication in June 2011 warned that children born to mothers that took valproate during pregnancy have lower cognitive test scores than children who were unexposed to valproate. Pregnancy exposure to valproate was recently reported to be associated with an increase in autism and autism spectrum disorders [74,75].

Carbamazepine

The primary increased teratogenicity with carbamazepine is an increased risk of spina bifida (26 cases per 10,000 vs 10 cases per 10,000 with no exposure) [76]. Carbamazepine has also been associated with other neural tube defects, anomalous pulmonary venous return, facial dysmorphism, cleft palate, diaphragmatic hernia, skeletal abnormalities and hypospadias in some studies [24,72,76]. A recent study reported renal tract abnormalities with carbamazepine exposure [70]. An increase in PTB and LBW have been reported [67,72]. Several studies have reported normal infant cognitive and motor development with exposure to carbamazepine during pregnancy [40,73,75], but other studies have reported some developmental delays [77,78].

The use of carbamazepine or valproate during pregnancy necessitates monitoring that includes maternal drug levels and liver function tests throughout pregnancy. Complete blood count, thyroid function tests, B12 and folate levels should be obtained at baseline and as indicated [66]. The use of folic acid supplementation before pregnancy and during the first trimester may reduce the risk of neural tube defects. α-fetal protein assessment for open neural tube defect, and high-resolution ultrasound of the neural axis, face and heart during the second trimester are recommended [66,67]. Careful morphological examination of the neonate is necessary and monitoring for hepatic dysfunction, hypoglycemia, clotting abnormalities and withdrawal symptoms is recommended [66,67]. Both valproate and carbamazepine are considered to be compatible with lactation [24].

Lamotrigine

Use of lamotrigine during pregnancy has steadily increased in the past 10 years as teratogenicity reports with valproate and carbamazepine have increased [79]. Early reports had suggested an increased risk of oral clefts, but recent reports from multiple international registries fail to demonstrate an increased risk of congenital malformations with lamotrigine [71,80]. Lamotrigine doses may need to be adjusted closer to delivery or after delivery, owing to changes in its clearance [81].

Lamotrigine is considered compatible with breastfeeding, but the infant levels are variable (up to 46% of maternal dose) and caution is advised with high maternal doses [81]. Apnea was reported in one neonate whose mother was on a high dose of lamotrigine [81]. To date, several prospective studies have reported the absence of cognitive or developmental delay with exposure to lamotrigine during pregnancy [71,73,75,77,80], but lamotrigine has been associated with adverse development in some studies [78].

Topiramate

Topiramate exposure during pregnancy has been associated with increased risk of oral clefts (cleft lip and/or palate), hypospadias and brain maldevelopments [70,80,82]. Its use has also been associated with LBW and small-for-gestational age [80]. The FDA issued a warning about topiramate use during pregnancy and increased risk of oral clefts in March 2011.

Gabapentin

A recent study reported that there was no increase in rates of congenital malformations or spontaneous abortion with in utero exposure to gabapentin compared with no exposure, but there was a higher rate of PTB, LBW and need for neonatal intensive care or special-care nursery admission [83]. Other studies have reported no increased risk of major congenital malformations with gabapentin [80,84].

Levetiracetam

Recent studies have reported a low risk of major congenital malformations with levetiracetam [84,85]. Levetiracetam has also been reported to have no association with developmental delay compared with valproate [86].

There are few reports about newer antiepileptic medications and breastfeeding [81] or long-term effects on child development.

First-generation antipsychotics

Typical or first-generation antipsychotics (FGAs) are older and currently less in use. Major congenital malformations have generally not been reported to be increased with use of FGAs during pregnancy, or minimally increased [24,87]. Many of the studies examining congenital malformations with exposure to FGAs did not control for underlying psychiatric disorder or associated behaviors, which could be major confounders [87]. Exposure to FGAs has recently been reported to be associated with an increased risk of PTB [88].

There is an increased risk of transient neonatal complications with FGA use including extrapyramidal symptoms, motor restlessness, tremor, hypertonicity, dystonia and withdrawal symptoms. The FDA issued a Drug Safety Communication in February 2011 about potential risks of abnormal muscle movements and withdrawal symptoms in newborns whose mothers were treated with antipsychotics during the third trimester of pregnancy.

Minimal information has been available about long-term risks on child development from in utero exposure to FGAs. A recent study reported lower neuromotor performance in 6-month-old infants with in utero exposure to FGAs [89]. There has been minimal study of long-term effects of FGA exposure on child neurocognitive development.

Second-generation antipsychotics

Atypical or second-generation antipsychotics (SGAs) have increased in use during pregnancy, being used for schizophrenia, bipolar disorder and depression [90]. Major congenital malformations have not generally been reported to be increased with SGA use during pregnancy, or minimally increased [87]. A recent study reported an increased risk of cardiovascular defects with SGAs, generally atrial or ventricular septal defects [88]. Another recent study reported that olanzapine and/or clozapine was associated with an increased risk of macrocephaly [91]. SGAs have been associated with an increased risk of gestational diabetes [91], obesity, metabolic syndrome and hypertension [87].

SGAs have been associated with a risk of transient neonatal complications. The FDA Drug Safety Communication in February 2011 about potential risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers were treated with antipsychotics during the third trimester of pregnancy applies to SGAs, as well as FGAs. Clozapine has been associated with transient floppy baby syndrome, retinopathy, hypotonia, gastroesophageal reflux and hypoxemic encephalopathy [87]. It is recommended that infants exposed to in utero clozapine should be monitored weekly for the first 6 months to rule out agranulocytosis [87].

Minimal information has been available about long-term risks on child development from in utero exposure to SGAs. Recent studies have reported lower neuromotor performance in 6-month-old infants [89] and delayed development at 2 months that resolved by 12 months of age [92].

Sporadic case reports of adverse effects in breastfeeding infants have been reported with FGAs and SGAs, with no consistent patterns [93]. The infant serum levels of most antipsychotics are often detected but considered low. Olanzapine may be associated with an increased risk of extrapyramidal reactions in breastfeeding infants, and clozapine is considered to be contraindicated with breastfeeding [93] . In general, the minimum effective dose should be used with regular pediatrician follow-up to monitor the infant.

Conclusion & future perspective

There have been no efficacy studies of antidepressants during pregnancy, and few for postnatal depression. Yet perinatal women with mood disorders face the dilemma of whether to continue (or start) antidepressant medication with its small, but significant risks, or discontinue (or not start) the medication and expose the fetus and infant to the effects of untreated depression, anxiety and stress. Treatment decisions need to be individualized and involve the woman, her partner and her clinician. A woman's current symptom severity, previous disease course and treatment history, stage of pregnancy, and plans to breastfeed must be considered. Additionally, a woman's expectations and preferences about treatment should be taken into account.

Currently, recommendations about treatment are largely determined by symptom severity and functioning. Women with mild or moderate depression may want to taper and discontinue their antidepressant prior to or after conceiving, in order to avoid the risks of antidepressant exposure. Nonpharmacological strategies can be helpful and should be maximized. However, women with severe, recurrent depression who have a history of relapsing when they discontinue their antidepressant, should consider maintaining antidepressant treatment during pregnancy, even if they are asymptomatic or minimally symptomatic when they conceive [15].

Clinicians need to be aware of the latest research findings about both the short- and long-term risks of psychotropic medication exposure, as well as the risks of exposure to untreated psychiatric disorders. It is difficult for clinicians to keep up-to-date with the rapidly growing published studies in this field. Methodology varies in studies, results lead to varied interpretations, and studies that do not report increased risks are ‘ignored’ by academic clinicians and the media compared with studies that do report increased risks [26] . The pursuit of compensation for adverse outcomes further makes treating perinatal women with psychiatric disorders problematic for clinicians. There are websites that update and review published studies about the risks and benefits of available treatments for the perinatal women. It is hoped in the next few years, as the volume of data continue to increase, perinatal women and their clinicians can make informed and balanced treatment decisions.

Executive summary

Effects of untreated prenatal depression, anxiety & stress

There is growing literature demonstrating the effects of untreated prenatal depression, anxiety and stress on fetal activity and hypothalamic–pituitary–adrenal axis parameters.

Most studies suggest an increased risk of preterm birth.

There is a possible increased risk of low birth weight, small-for-gestational age and lower Apgar scores.

Birth outcomes with antidepressant medications

Studies do not often control for underlying illness, comorbidities and associated behaviors.

Although some studies suggest statistically significant increased risks with exposure to selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors and tricyclic antidepressants, the increase in absolute risks are small, and may not be of clinical significance.

There is a possible increased risk of spontaneous miscarriage.

Most studies report an increased risk of preterm birth.

There is a possible increased risk of low birth weight, small-for-gestational age and lower Apgar scores.

There is a possible increase in congenital malformations, but no consistent organ system anomaly has been implicated.

There is a probable increased risk of cardiac malformations with paroxetine.

There is an increased risk of persistent pulmonary hypertension of the newborn that occurs with exposure after 20 weeks gestation.

Postnatal adaptation symptoms occur in approximately 30% of neonates.

There have been reports of a possible increased risk of autism.

Negative effects of antidepressants on child development may be transient, and it is difficult to disentangle antidepressant effects from the negative effects on child development from continued maternal depression and other childhood environmental factors.

Lithium

Increased risk of Ebstein's anomaly and use in pregnancy is increasing.

Special monitoring through pregnancy and delivery is necessary.

Valproate & carbamazepine

Valproate is contraindicated during pregnancy due to high teratogenicity and neonatal symptoms.

Carbamazepine is associated with spina bifida and some neonatal symptoms.

Valproate is associated with lower IQ and delayed neurocognitive development in children up to the age of 6 years.

Valproate and carbamazepine require special monitoring throughout pregnancy. Lamotrigine

Most studies do not report an increased rate of congenital malformations.

Antipsychotics

There is a small, if any, increase in congenital malformations, and some neonatal symptoms have been reported.

There is a paucity of long-term studies on child development.

Breastfeeding

Most antidepressants are compatible with breastfeeding; sertraline, paroxetine and nortriptyline are the preferred choices.

Benzodiazepines may cause sedation in the breastfeeding infant.

Lithium level may be high in the breastfeeding infant, this requires additional monitoring.

Antiepileptics are generally considered compatible with breastfeeding, there is a paucity of data with newer antiepileptics.

Antipsychotics are generally considered compatible with breastfeeding, however, minimal data exist.

Financial & competing interests disclosure

T Pearlstein receives research support from Pfizer and has been a consultant for Ironwood Pharmaceuticals. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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14.

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16.

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17.

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23.

The effects of antidepressants on spontaneous abortion, preterm birth, low birth weight, small-for-gestational age and Apgar scores suggest that statistically signicant findings may not be clinically significant.

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25.

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26.

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27.

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28.

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29.

Good review of studies about antidepressants and congenital malformations.

30.

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42.

Good review of studies about antidepressants and postnatal adaptation syndrome.

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45.

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Excellent review of antiepileptic drugs, teratogenicity and neurodevelopment.

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Gentile

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Use of Psychotropic Medication during Pregnancy and the Postpartum Period

Abstract

Keywords

Epidemiology

Effects of untreated prenatal depression, anxiety & stress on the fetus

Effects of untreated prenatal depression, anxiety & stress on birth outcome

Effects of untreated perinatal depression on the infant & child

Antidepressants during pregnancy

Spontaneous miscarriage

PTB & birth weight

Congenital malformations

Persistent pulmonary hypertension of the newborn

Postnatal adaptation syndrome

Long-term effects on child development

Autism

Additional reported effects of prenatal antidepressant exposure

Antidepressants & breastfeeding

Nonpharmacological treatments for perinatal depression

Other psychotropic medications during pregnancy & with breastfeeding Benzodiazepines

Mood stabilizers

Lithium

Valproate

Carbamazepine

Lamotrigine

Topiramate

Gabapentin

Levetiracetam

First-generation antipsychotics

Second-generation antipsychotics

Conclusion & future perspective

Financial & competing interests disclosure

References