There is no absolute certainty about the safety of using any psychotropic medication in pregnancy. It is estimated that medication is a causative agent in about 5% of fetal congenital anomalies (Burt et al 2001). The use of psychotropic medication in the first trimester of pregnancy is associated with the potential risk of major malformations, in the second and third of long-term neurobehavioral consequences, in the third with the toxic effects on the fetus and the presence of withdrawal syndrome in the neonate. Treatment of women with mental illness which begins in pregnancy or is diagnosed before pregnancy, should be carefully considered for the risks linked with an abrupt discontinuation of an already established treatment, introduction of new treatment and also for the risk associated with avoiding any treatment at all. It would be best of course if all pregnancies were planned but, as we know, this remains within the sphere of wishful thinking of both doctors and their patients. It would be therefore advisable to educate patients and also refrain from using any treatment linked with the high risk of fetal malformation in the cases of women in reproductive age.
As we have already mentioned, we cannot be sure of any psychotropic drugs to be entirely safe for the fetus. Long-term neurobehavioural consequences, such as impaired development, neurological deficits and learning difficulties are currently the subject of intensive research and require further analysis and data collection (Richards and Paine 2013; Ball 2003). Alternative therapies should always be considered, such as: psychotherapy, light therapy, repetitive transcranial magnetic stimulation, electroconvulsive therapy, and herbal treatment (Richards and Paine 2013; Campagne 2007). It needs to be pointed out, however, that use of herbs and other non-prescription preparations is not without its own risks.
Complete discontinuation, on the other hand, of psychiatric treatment in pregnancy carries the risk of malnutrition, lack of cooperation with the gynaecologist-obstetrician (missed visits, non-compliance), attempts to self-abort, substance use, suicidal attempts, aggressive behaviour, and even the baby's death. (Miller 1993).
Research on the safety of using psychotropic drugs by pregnant women is scarce for obvious ethical reasons. In fact, we accumulate knowledge on the effects that psychotropic drugs have on the pregnancy over time; the longer a drug is available on the market, the more we know about it, mostly on the basis of monitoring the cases of women who become pregnant while receiving medication but are not aware of it straight away. Treatment of pregnant women should be based on the most recent data available from the medical literature.
The main principles that should guide doctors in treatment of pregnant patients with psychotropic drugs are listed in Table 1 (Kohen 2004; Taylor et al. 2008).
Table 1. Basic rules of psychopharmacology in pregnancy
|• Cooperation between a psychiatrist and gynecologist-obstetrician is absolutely necessary.
• Discuss with the patient the benefits and risks of treatment in pregnancy to herself and to the child
• Keep good medical records, describing all other risk factors for irregular pregnancy, childbirth and fetal development (record of other medication taken, somatic comorbidity of the mother, mother's addictions)
• Always plan treatment according to the most up-to-date medical literature.
• Consider other than pharmacological methods of treatment
• Recommend the folic acid to the patient as the prevention of neural tube defects
• Start treatment from the lowest possible dose and monitor frequently
• If possible, delay treatment to the second or even third trimester as the teratogenic risk is at its highest in the first trimester
• Avoid multiple psychotropic medication treatment
• If it is necessary to continue the treatment, reduce the dose and monitor for any adverse effects.
Kohen 2004; Taylor et al. 2008
The risk of perinatal psychosis in general population is 0.1-0.25% and in women with bipolar disorder it increases to 50%. Childbirth increases the risk of psychosis in women who have been healthy before. Patients whose history reveals psychosis after previous childbirths are at 50-90% risk of recurring psychosis (Taylor et al. 2008). Our knowledge of the treatment with first generation antipsychotics (FGAs) is reasonable, as they have been available on the market for a longer period of time. FGAs are considered to be drugs of low teratogenic risk. Out of the second generation antipsychotics (SGAs) clozapine's low teratogenic risk has been confirmed, although there have been reports of increased risk of diabetes in pregnancy followed by neonatal seizures and still births.
Olanzapine, quetiapine, and risperidone are also considered to be without teratogenic effects, although we are aware of the case of a 30-year-old patient with recurrent episodes of depression with psychotic symptoms, who was treated in pregnancy, from conception to birth with olanzapine at a dose of 10-15 mg/day; the baby was born with a meningocele and a complete fusion of the eyelids (Arora and Praharaj 2006). The case studies of women who took quetiapine throughout their pregnancy indicate the lack of malformations in the newborn (Tényi et al. 2002; Sandeep and Rohit 2012). Nonetheless, It must be emphasized, that data is so scarce that it is neither sufficient for determining causal links between fetal development and the use of medication nor for confirming the safety of its use in pregnancy.
Then again based on our own considerable experience we can confirm safety of using chlorpromazine (which may cause such side effects as constipation and drowsiness), trifluoperazine, haloperidol, olanzapine and clozapine, although the latter two increase the risk of gestational diabetes. Some experts recommend that FGAs should be suspended 5-10 days before childbirth to avoid withdrawal symptoms in the neonate (agitation, crying, increased sucking), or natural and artificial feeding should be used alternately. There is no need to observe these measures in case of the SGAs. (Taylor et al. 2008; Jarema and Rabe-Jablonska 2011).
Depression in the perinatal period and postpartum occurs in 10% of women. Most postpartum depressions begin during pregnancy. The risk of relapses is higher in women with episodes of depression in pregnancy, after childbirth or unrelated with pregnancy, and in women with bipolar disorder. It is recommended that medication is continued in pregnancy and childbirth (Taylor et al. 2008) in women who become pregnant while on antidepressants and are in the increased risk group for subsequent depressive episodes. (Taylor et al 2008).
In the case of depression of mild to moderate intensity, without psychotic symptoms or suicidal tendencies, the treatment of choice is cognitive-behavioural and interpersonal psychotherapy.
Disorders of greater intensity, in the absence of patient consent for psychotherapy or poor access to psychotherapy are the indicators for initiation of pharmacological treatment. Severe depression with suicidal tendencies, psychotic symptoms, denial of food intake should be treated in a hospital, with electroconvulsive therapy (ECT) being a serious consideration. It is also recommended that antidepressants are discontinued 2-3 weeks before delivery to avoid withdrawal symptoms and toxicity in the newborn (Malm et al 2005).
Among best-studied and recognized as safe for use during pregnancy are tricyclic antidepressants (TCAs): amitriptyline, imipramine (both with possible side-effects of drowsiness and constipation in women, and of withdrawal symptoms such as agitation, irritability, seizures in the newborn), and selective serotonin re-uptake inhibitors (SSRIs), with the exception of paroxetine. Fluoxetine is most recommended, even though its use is associated with increased risk of preterm birth and reduced birth weight. (Cohen 2004, Taylor et al. 2008).
If a patient is treated with a drug which is not a TCA or fluoxetine and discovers that she is pregnant, the advisable thing to do is to refer to the latest literature on the use of the drug in question. Pregnant women quite commonly use SSRIs which have not been linked with any fetal malformations, even if taken in the first trimester (Malm et al. 2005; Kallen and Olausson 2006). The exception is paroxetine, which if taken in the first trimester, is associated with an increased risk of heart defects (usually atrial septal defect), therefore the use of paroxetine in pregnancy and in women planning to become pregnant is not recommended (American College of Obstetrician and Gynecologists, 2006).
The study by Berard et al. (2006) indicated that it is only the use of paroxetine in doses above 25 mg/day in the first trimester of pregnancy that is associated with the higher risk of malformations and heart defects.
Taking an SSRI in the third trimester of pregnancy carries the risk of withdrawal syndrome in the newborn, and of persistent pulmonary hypertension, although the latter is rare (99% of mothers taking SSRIs have babies without pulmonary hypertension) (Sanz et al. 2005). Withdrawal symptoms in the newborn can be minimised by using natural and artificial feeding methods alternately (Taylor et al 2008).
When it comes to long-term neurobehavioral consequences on children, it is considered, on the basis of currently available knowledge, that fluoxetine has no impact on cognitive functions, development of language functions or behaviour at preschool and early school age (Nulman et al. 2002).
Interactions between oral hormonal contraception and mood stabilizers should be also considered. Lithium, valproic acid and SGAs do not interact with oral contraceptives. Carbamazepine, on the other hand, reduces their plasma concentration which is why patients should be advised to take additional protection against becoming pregnant. Lamotrigine does not affect the effectiveness of oral contraceptives, but they, in turn, reduce its plasma concentration and the dosage must be increased. Pregnant women receiving valproic acid or carbamazepine should take vitamin C at a dose of 20 mg/day due to the risk of its drug-related deficiency in the fetus (Jarema and Rabe-Jablonska 2011).
Women with bipolar disorder who plan becoming pregnant should be advised to discontinue taking mood stabilisers gradually as their as their sudden withdrawal is linked with the high-risk of relapse (Jarema and Rabe-Jabłońska 2011).
Women with long remission periods may discontinue their mood stabilizers before planned conception and then for the time of the first trimester. Sudden discontinuation of medication with the news of becoming pregnant should be avoided due to the high risk of relapse. None of the currently available mood stabilizers is fully safe. Valproic acid and carbamazepine exhibit dose-dependent teratogenic effects and are associated with the risk of spina bifida. Their use is to be avoided in pregnancy. If it is necessary to continue treatment, women should take folic acid to reduce the risk of spina bifida (Taylor et al 2008).
The use of lithium is associated with an increased risk of Ebstein's anomaly. The risk is at its highest when taking lithium in the first 2-6 weeks after conception, which is the time when most women are unaware of being pregnant. The most effective procedure is a slow withdrawal of lithium in women planning to become pregnant. If discontinuation of lithium causes the relapse of depression in pregnancy, the treatment can be reinstated, but in this case, in the sixth and eighteenth week of pregnancy, it is necessary to perform a screening ultrasound and echocardiography for the Ebstein's anomaly. In the third trimester the dose needs to be increased to continue remission, because the drug concentration decreases as a result of increased water retention. Lithium crosses the blood-placenta barrier and causes the neonatal goiter, hypotonia, lethargy and cardiac dysrhythmia. Use of lamotrigine is associated with the lower risk for the fetus, although it is linked with the higher incidence of cleft palate (Taylor et al 2008).
Sedatives and hypnotics
The use of benzodiazepines in pregnancy is contraindicated. In the first trimester they increase the risk of cleft lip and cleft palate, and in the third they can cause withdrawal symptoms in the newborn or floppy baby syndrome (muscle hypotonia, low Apgar scores, hyperthermia, impaired response to cold) (American Academy of Pediatrics, 2000).
As it has been already emphasized any treatment of pregnant women with psychotropic medication should be based on the most up-to-date research available. This is certainly true in case of zolpidem, which is a sleep inducing medication of the imidazopyridines group.
It is currently classified for its teratogenic potential by the U.S. Food and Drug Administration as category B i.e. animal studies indicate no risk to the fetus. However no well controlled human studies have been carried out, or the adverse effects in animals have not been confirmed in the group of pregnant women. Meantime there are reports published to the effect that pregnant women who receive zolpidem suffer from worrying gynaecological and obstetric complications and fetal malformations, without indicating a clear causal link between these and the use of zolpidem. Pregnant women who are treated with zolpidem for sleep disorders have been noted to have babies with lower birth weight and more frequently deliver prematurely; their babies more often suffer from congenital malformations and are more frequently delivered by caesarean section (Wang et al. 2010). Another observation of pregnant women treated with zolpidem revealed the occurrence of bowel deformations in the newborn (Wikner and Källén 2011). Juric et al. (2009) noted more frequent preterm deliveries and low birth weight although the variation was not statistically significant against a group of controls.
Promethazine, derivative of phenothiazine, which has sedative and sleep inducing effects, is widely used in persistent vomiting in pregnancy and appears to have no teratogenic effects on the fetus (Taylor et al. 2008).
Cognitive-behavioural and interpersonal psychotherapy are the methods of choice in the treatment of depressive disorders of mild and moderate intensity, without psychotic symptoms or suicidal tendencies (Jarema and Rabe-Jabłońska 2011). For anxiety disorders the method of choice for pregnant women is cognitive-behavioural psychotherapy (Marchesi 2008). Studies that compared the effectiveness of drug therapy with placebo and cognitive-behavioural psychotherapy in patients with panic attacks, found greater efficacy of cognitive-behavioural and pharmacological treatment over the placebo, and pointed to their similar efficacy in improving anxiety, agoraphobia, depression and overall quality of life (Mitte 2005).
Electroconvulsive therapy (ECT)
A depression episode with suicidal tendencies, psychotic symptoms and denial of food intake is, in case of pregnant women, indicative of the need for ECT treatment (Jarema and Rabe-Jabłońska 2011).
The method is considered safe both for the mother and the fetus. The analysis of 300 cases of pregnant women who underwent ECT revealed the occurrence of adverse symptoms in 9.3% of the cases, although these were not always causally traceable to ECT. Among the adverse side effects there were: vaginal bleeding, detachment of the placenta, uterine cramps, unexplained abdominal pain, preterm birth, miscarriage (Miller 1994). Bulut et al. (2013) evaluated 12 pregnant women, treated with ECT for mood disorders, and registered one preterm birth and club-foot in case of one of the babies, which was probably not causally linked to ECT. Among the effects harmful to the fetus, which are considered relevant to the ECT treatment, are the transient self-limiting arrhythmia (Debattista et al. 2003). Stillbirths, neonatal deaths, neonatal respiratory disorders seem to have no direct connection to the ECT (Miller et al. 1994). In fact ECT, even when used in the first trimester, seems safe for the mother and the fetus, (Lovas et al. 2011).
As with any treatment, there are also cases of serious ECT-related complications reported. Status epilepticus is generally speaking a rare ECT complication. One of the case studies published described a case of a woman with bipolar disorder who was treated with ECT at 22 weeks of gestation because of suicidal thoughts. The resulting status epilepticus caused a multisystem fetal damage and death (Balki et al. 2006). The authors of the study suggest that it would be advisable to introduce a procedure providing for immediate Caesarean section facility in case of pregnancies more advanced than the one described in the report.
Repetitive Transcranial Magnetic Stimulation (rTMS)
The method can be used as an alternative treatment for depression in pregnant women who refuse pharmacological care (Kim et al. 2009). Kim et al. (2011) evaluated 10 patients in the second and third trimester who underwent 20 rTMS sessions each. The condition of 7 of them improved clinically as far as the depressive symptoms were concerned. There were no reports of harmful effects on the fetus. Four patients reported mild headaches after the sessions. Due to the fact, however, that rTMS is therapeutically less effective, it cannot be treated as an alternative for ECT in treating depression with suicidal tendencies (Gahr et al. 2012).
Bright Light Therapy (BLT)
There is limited data available on the use of BLT in pregnant women who suffer from depression. Still the information we have is encouraging if only because BLT can be used at home and it has no adverse effects adherent in pharmacological treatment. Meta-analysis of research available indicates the overall safety of the method for the mother and the fetus and clinical improvement of the symptoms of depression (Krysta et al. 2012; Crowley and Youngstedt 2012).
The International Society for Affective Disorders (ISAD) suggested BLT as an alternative to pharmacological treatment of pregnant women who refuse pharmacological treatment or show intolerance for it, or in cases, in which the risk of taking medication exceeds its potential benefits. (Wirz-Justice et al. 2005). Yet BLT cannot be treated as an alternative to ECT in cases of depressive disorders with suicidal tendencies.
Although herbs are promoted as natural and safe treatment for many somatic complaints and as sedatives and sleep inducing preparations, they are not neutral to the organism of the pregnant woman and the fetus. This is why it is important to ask a patient during every visit whether she uses any herbal preparations and warn her against their excessive use. Facchinetti et al. (2012) asked 700 women within three days of childbirth if they had used herbal preparations in pregnancy; 189 of them admitted that they had used herbs every day throughout at least three months of their pregnancy and that they were usually preparations involving almond oil, chamomile and fennel. It has been proven, however, that almond oil, independently of such factors as multiple pregnancy, smoking, mother's age and other medication taken, doubles the risk of birth before the thirty seventh week of gestation.
Nordeng et al. (2012) asked the same question to 600 women within five days of childbirth and confirmed that herbal preparations had been taken by 39.7% of them, mostly ginger, iron-rich herbs, cranberry and Echinacea. The study confirmed a relationship between the use of herbs rich in iron with high birth weight, and of raspberries with increased frequency of the Caesarean section.
Psychopharmacology in pregnancy requires careful consideration, with the patient and her family, of any associated benefits and possible risks. In the cases in which the drug treatment is not strictly necessary, one should always consider alternatives, as none of psychotropic drugs is completely safe. Among the drugs deemed relatively safe for the mother and the fetus, i.e. those whose harmful effects have not been documented are:
• First-generation antipsychotics (FGAs): haloperidol, chlorpromazine, trifluperazyne,
• Second-generation antipsychotics (SGAs): clozapine, olanzapine
• Tricyclic antidepressants (TCAs): amitriptyline, imipramine,
• Selective serotonin reuptake inhibitors (SSRIs): fluoxetine,
• Drugs with sedative and hypnotic properties: zolpidem, promethazine.
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