Psychotropic drugs in pregnancy
Introduction
Approximately 3.0% of all pregnant women take psychotropic drugs during pregnancy (Molenaar et al., 2020) and the pre- and postpartum periods are widely considered as a period of increased vulnerability to psychiatric disorders (Bonari et al., 2004).
For every pregnancy, the baseline risk of a major congenital malformation is 1% to 3% of the population (McElhatton, 2013). All psychotropic drugs pass the placenta, meaning all fetuses are exposed to maternal psychotropics (Altshuler et al., 1996). The possible risks of psychotropic drug use during the first trimester of pregnancy include spontaneous abortion and malformations. In later pregnancy, risks of psychotropic medication might include pregnancy and perinatal complications such as low birth weight, prematurity, poor neonatal adaptation (feeding difficulties, irritability, tremor) and the possibility of longer-term neurobehavioral effects (Kohen, 2004).
Data on the effects of psychotropic medication are limited and sometimes conflicting, especially as the effect of underlying depression on maternal and fetal outcomes is often underestimated. There is an increasing body of evidence-based information indicating that it may be more harmful to both the mother and her baby if she is not treated appropriately when suffering from a severe psychiatric disorder (Bonari et al., 2004; Niethe & Whitfield, 2018).
Pregnant women should be involved in discussions about the risks and benefits of using – or not — pharmacological treatment. Ideally, decision making should occur before pregnancy, because many pregnancies are unplanned. If possible, drugs that are contraindicated during pregnancy (carbamazepine and especially valproate) should be avoided in women in childbearing age. In the case that these drugs are prescribed, women should be carefully informed about their teratogenic potential, and this discussion recorded in the medical record (NICE, 2018).
Principles of psychotropic medication use during pregnancy (adapted from Kohen, 2004)
A single medication at a higher dose is favoured over multiple medications
Medications with fewer metabolites are preferred
Higher protein binding decreases placental passage
Changing medications increases the exposure to the baby
Dose increase is frequently required in the third trimester due to increased blood volume, which changes rapidly post-partum and may require dose reduction
If a woman is being treated successfully with psychotropic medication before pregnancy, the same treatment should continue throughout pregnancy if there is no major risk of malformation
If pregnancy is planned and mental health is stable with a low risk of relapse, discontinuing psychotropic medication may be considered
Folic acid supplements are recommended in most country guidelines for all pregnant women because of the associated reduction in neural tube defects.
Specific ultrasound of the fetus should be performed in women on psychotropics to exclude major malformations, and joint working with antenatal care and monitoring programs are recommended.
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs are widely prescribed including during pregnancy, and are thought to be relatively safe (Anderson et al., 2020), there are some reports of morphological teratogenicity. A small increased absolute risk of rare defects such as omphalocele, anencephaly, craniosynostosis, cystic kidney and congenital heart defects has been reported. However, specific patterns of congenital malformations have not been demonstrated with SSRIs across studies (Byatt et al., 2013). Paroxetine is most controversial SSRI and has a specific connection to an increased risk of congenital malformations. First-trimester paroxetine exposure is associated with an increased prevalence of combined cardiac defects (Hinds et al., 2011).
A possible increase of spontaneous abortions, earlier delivery, lower birth weight and low APGAR scores, hypoglycemia and hyperbilirubinemia have been noted on connection with use of SSRIs during pregnancy (Chang et al., 2020; Xing et al., 2020).
Of all infants exposed to an SSRI in utero, around 30% develop symptoms of poor neonatal adaptation syndrome (PNAS) such as hypotonia, hypothermia, respiratory depression, cyanosis, arrhythmias and decrease sucking reflex (Grigoriadis & Peer, 2019). Some studies described an increased incidence of PNAS after exposure to paroxetine and fluoxetine compared to other SSRIs (Kieviet et al., 2013).
There is conflicting evidence regarding an elevated risk of persistent pulmonary hypertension of the newborn (PPHN) after exposure to SSRIs. The absolute risk cannot be determined, but is very small, less than 1% (Chambers et al., 2006).
Tricyclic antidepressants (TCAs)
Tricyclic antidepressants have been in use extensively for several decades. There is no increased risk of congenital malformations in the first trimester exposure (Ward and Zamorski, 2002). Nulman et al. (2002) found no increase in teratogenesis or later behavioral problems in children born to mothers taking tricyclic antidepressants during pregnancy. Of all infants exposed to tricyclic antidepressants in utero, 20%–50% develop PNA. Anticholinergic symptoms such as urinary retention and constipation are rare (Kieviet et al., 2013).
Monoamine oxidase inhibitors (MAOIs)
There is little evidence of risk for MAOIs in pregnancy. There is a report of teratogenicity from an animal study (Poulson and Robertson, 1964) and more recently of fetal death and birth defects in two human cases of polypharmacy use including MAOIs during pregnancy (Kennedy et al., 2017). Moreover, these drugs require the adoption of a low tyramine diet. MAOIs are therefore usually not recommended in pregnancy. Women on MAOIs should be switched to other antidepressants, ideally prior to pregnancy.
Venlafaxine, duloxetine, mirtazapine, trazodone, bupropion
There is lack of studies on these antidepressants. Prospective studies of mirtazapine (Djulus et al., 2006; Güngör et al., 2019), trazodone and nefazadone (Einarson et al., 2003), as well as bupropion (in a systematic review by Turner et al., 2019) revealed no increased risk of major malformations. Of note is that mirtazapine is increasing prescribed off-label for morning sickness (Gungor et al., 2019). One study found association between periconception use of venlafaxine and specific birth defects, however, sample sizes were small, confidence intervals were wide, and further studies are needed (Polen et al., 2013). Several prospective studies of venlafaxine found no association with adverse pregnancy or fetal outcomes (Einarson et al., 2001; Furu et al., 2015; Richardson et al., 2019).
Antipsychotics
Large, well-designed and controlled studies of antipsychotic drugs in pregnancy are lacking; however, most studies suggest that the group of antipsychotics seem to be safe in terms of teratogenicity during pregnancy, at least in monotherapy (Hillemacher et al., 2021).
Untreated bipolar disorder and schizophrenia are considered independent risk factors for congenital malformation, with both disorders linked to a slightly increased risk of obstetric complications for mothers (schizophrenia) and the newborn (bipolar disorder and schizophrenia) (Tosato et al., 2017). Maternal morbidity (schizophrenia but not bipolar disorder) may be associated with the worst neonatal outcomes (stillbirth, neonatal or infant deaths, and intellectual disability).
Conventional antipsychotics
Conventional antipsychotics have been in use for half a century and have shown that, generally, there is no increased teratogenic risk with high-potency conventional antipsychotics. Low-potency antipsychotics have a small increased risk of unspecific abnormalities (Menon, 2008).
A meta-analysis of pregnancy and birth complications in women with schizophrenia found that there is an increase in low birth weight, preterm birth and perinatal infant death, however the effect was small (Bennedsen, 1998). Extrapyramidal symptoms (increased muscle tone, tremors, agitation, dystonia, decreased sucking reflex, abnormal movements), jaundice, intestinal obstruction, unstable body temperature, respiratory distress, seizures and transient neuro-developmental delay can also occur (Gentile, 2010; Kieviet et al., 2013)
Atypical antipsychotics
A prospective observational cohort comparing typical and atypical antipsychotics and a control group did not find a significant difference between the rates of major malformations between those exposed to atypical or typical antipsychotics. However, the malformation rate was about twofold greater among those taking atypical antipsychotics compared to the reference group (odds ratio, 2.17). In the group exposed to atypicals, the most common major malformations were cardiovascular, and of the cardiac malformations, most were atrial or ventricular septal defects (Habermann et al., 2013).
A systematic review found that atypicals were not associated with increased defects or neurodevelopmental problems in newborns (Tosato et al., 2017). This same study noted that abrupt discontinuation of treatment-exposed mothers with bipolar disorder or schizophrenia led to a high risk of relapses during pregnancy.
Women receiving atypical antipsychotics, especially in polytherapy, experience more associated comorbidities and instrumental deliveries. The exposed neonates were more likely to be born premature, were admitted more often to the neonatal intensive care unit, presented with poor neonatal adaptation signs (Sadowski et al., 2013).
Atypical antipsychotics are associated with weight gain in mothers, induce maternal hyperglycemia and impaired glucose tolerance (Gentile, 2010). There are conflicting data on birth weight after exposure to atypical antipsychotics: some studies found a significantly increased risk of low birth weight and small for gestational age infants (Reis & Källén, 2008); on the other hand, there are studies that found that neonates exposed to atypical antipsychotics were significantly more likely to be large for gestational age compared with healthy controls (Newham et al., 2008). There are conflicting data on the development of gestational diabetes and atypical antipsychotic use. One study found that women who continued treatment with olanzapine or quetiapine had an increased risk of gestational diabetes that may be explained by the metabolic effects associated with these two drugs (Park et al., 2018). The overall current evidence suggests no significant relationship between antipsychotic drugs, including second- and first-generation antipsychotics, and the risk of gestational diabetes mellitus (Uguz, 2019).
There is a reported reluctance to continue clozapine in treatment resistant patients who become pregnant. A systematic review found poor quality limited evidence of low birth weight or higher APGAR scores following clozapine continuation in pregnancy, with the recommendation for a thorough risk/benefit analysis for each individual patient regarding clozapine continuation when pregnancy is confirmed (Thanigaivel et al., 2021).
Mood stabilizers
Lithium
Lithium is the most prescribed mood stabilizer during pregnancy. First trimester lithium exposure is associated with cardiovascular malformation, especially Ebstein´s anomaly. The period of maximum risk is 2-6 weeks after conception. The absolute risk is relatively small, reported at 0.05 – 0.1% (Cohen et al., 1994). A potential increase in the risk of neural tube defects should also be taken into consideration (Gentile, 2012).
Lithium exposure is associated with significantly more miscarriages and elective terminations of pregnancy. The rate of preterm deliveries is higher in the lithium exposed infants (Diav-Citrin et al., 2014). After intrauterine exposure to lithium is described the floppy infant syndrome. This syndrome is dose-related and consists of hypotonia, hypothermia, respiratory depression, cyanosis, arrhythmias and decrease sucking reflex. Other described lithium related symptoms are neonatal thyroid toxicity, nephrogenic diabetes insipidus, cardiovascular and renal dysfunctions, hyperbilirubinemia, hepatotoxicity and PPHN. These symptoms are generally self-limiting (Kiviet et al., 2013).
In women on maintenance treatment, serum lithium levels should be monitored every 4 weeks throughout the pregnancy, weekly in the later pregnancy. Dosage should be adjusted to match the lower end of the therapeutic range. Renal excretion of lithium increases significantly during the third trimester and increase of maternal dose is often necessary. Several days prior to delivery the dosage should be gradually tapered to 60–70% of the original maintenance level. Full pre-pregnancy dose should be resumed immediately postpartum. A high-resolution ultrasound and echocardiography of the fetus should be performed at 16-18th week of gestation to identify possible abnormalities.
Valproic acid
Valproic acid is associated with a variety of congenital abnormalities. The types of birth defects most often reported in valproate exposure during pregnancy are neural tube defects, orofacial clefts, congenital heart defects, hypospadias, and skeletal abnormalities (polydactyly, craniosynostosis) (Werler et al., 2011). Morrow et al. (2006) reported that for valproate monotherapy exposures 1% of the pregnancy outcomes were neural tube defects, 1.5% orofacial clefts, 0.7% congenital heart defects, 0.9% hypospadias and/or genitourinary tract defects, 0.5% gastrointestinal tract defects and 1.1% skeletal defects. A fetal valproate syndrome has been described, characterized by tall forehead with bifrontal narrowing, medial deficiency of eyebrows, infraorbital groove, trigonocephaly, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, epicanthic folds, long upper lip with thin vermillion borders, thick lower lip and small downturned mouth (Clayton-Smith and Donnai, 1995).
The effect of valproate is dose-dependent; risk of congenital malformations significantly increases at 600 mg/day, with the largest attributable risk observed at doses that exceeded 1000 mg/day. However, individual susceptibility is genetically determined, and even very low daily dosages can be teratogenic in some highly sensitive individuals (Diav-Citrin et al., 2008).
Moreover, valproic acid is a behavioral teratogen. Prenatal exposure to VPA was associated with impaired cognitive function, a lower verbal intelligence quotient, poorer adaptive behavior and a higher rate of maladaptive behaviors (Vinten et al., 2009).
Coagulopathies, hepatotoxicity, hypoglycemia and low birth weight are also described in association with valproic acid use in pregnancy (Menon 2008). The use of valproic acid should be avoided during pregnancy. Where continued use is essential, low dose monotherapy is strongly recommended. Folate supplements should be taken for at least one month before conception.
Carbamazepine
Carbamazepine is also associated with congenital abnormalities, although less then valproic acid. Increased risk of spina bifida, craniofacial (especially orofacial cleft) and cardiovascular abnormalities, urogenital malformations and growth retardation were documented (Menon 2008). On the other hand, some authors report that carbamazepine teratogenicity is relatively specific to spina bifida (Jentlik et al., 2010). A “fetal carbamazepine syndrome “was described, characterized by hypertelorism with epicanthic folds, mongoloid slant of the palpebral apertures, short nose, long philtrum, and hypoplasia of fingernails (Jones et al., 1990).
Carbamazepine is usually avoided during pregnancy. When taken, folate supplements before and in the first months of gestation and the use of vitamin K during the last trimester are recommended.
Lamotrigine
Some evidence suggests that exposure to lamotrigine could increase the risk of orofacial clefts, especially cleft palate in the offspring of women exposed to this drug in the first trimester of pregnancy (Holmes et al., 2008).
Benzodiazepines
Benzodiazepines are associated with a risk of oral cleft in newborns (Altshuler et al., 1996). The evidence from meta-analyses is conflicting; the data from newer studies do not indicate an increased risk (Bellantuono et al., 2013). However, case-control studies suggest a twofold increased risk of oral cleft (Enato et al., 2011).
Wikner et al. (2007) found a higher-than-expected number of infants with pyloric stenosis or alimentary tract atresia (especially the small intestine) after benzodiazepine exposure. However, this was without association to any specific benzodiazepine or hypnotic benzodiazepine receptor agonist.
An increased risk for preterm birth and low birth weight was reported. Third trimester use is associated with floppy infant syndrome. High medication dosages (equivalent of diazepam 30 mg) in combination with benzodiazepines with a long half-life appear to give the highest risk. Symptoms include hypotonia, hypothermia, respiratory depression, cyanosis, arrhythmias and decrease sucking reflex (Kieveit et al., 2013).
Conclusions
Psychotropic prescribing in pregnancy needs careful consideration of the risks and benefits of prescribing, or not. Patients should be encouraged to make informed decisions based on the latest evidence, with support from their families and spouses. Each pregnant patient is different, and no pregnancy is without risk. Untreated mental illness has clear negative effects on both mother and baby, which needs to be balanced against the potential known and unknown pharmacological risks of prescribed medications. Additionally, much data is unknown or contradictory. There are however clear higher risk groups of medications, including valproate and carbamazepine. As in every prescribing decision, a careful risk-benefit analysis, and full informed decision making are required.
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