The Use of Psychotropic Drugs During Pregnancy.

Patients with severe psychotic disorders face at least two challenges during pregnancy: the genetic risk of psychotic disorders and the risk of teratogenicity caused by psychotropic drugs. This paper reviewed the relevant literature regarding the issues surrounding use of antipsychotics, antidepressants in pregnant patients. The latest treatment guidelines and FDA recommendations are introduced.

Epidemiological data shows that the spontaneous abortion rate in early pregnancy and the incidence rate of congenital malformation were 10 to 20% and 2 to 3% respectively.[ In addition to life style and pre-pregnancy obesity, psychotic disorder during pregnancy was also an independent risk factor for fetal abnormality.[ Patients with severe psychotic disorders face at least 2 challenges in pregnancy: the genetic risk of psychotic disorders such as schizophrenia and the risk of teratogenicity caused by psychotropic drugs such as antipsychotics. The fetal abnormalities caused by drugs mainly include teratogenic effects 3 months before pregnancy, neonatal poisoning 3 months after pregnancy, and abnormal brain development and behavioral abnormalities due to prenatal exposure to psychotropic drugs shown in animal studies.[

1. The effects of common psychiatric drugs on pregnancy

1.1 Antipsychotics

Huybrechts and colleagues[ reported a nationwide cohort study (n=1,341,715) aiming to explore the overall risk of congenital malformation due to the exposure to antipsychotics in the early stage of pregnancy (first 3 months), especially the risk for heart defects. In general, among the pregnant women who never used antipsychotics in the early stage of pregnancy, there were 32.7 (95% CI, 32.4-33.0) cases of congenital malformation in every 1000 pregnancies. In comparison, among those who used atypical antipsychotics, the number was 44.5 (95% CI, 40.5-48.9); among those who used typical antipsychotics, the number was 38.2 (95% CI, 26.6-54.7). When the confounding factors were not adjusted, the atypical antipsychotics (RR 1.36; 95% CI, 1.24-1.50) could result in the increase of the risk of the overall deformity and cardiac malformation. In contrast, the typical antipsychotics (RR 1.17; 95% CI, 0.81-1.68) did not have this effect. After adjusting the confounders such as somatic diseases and the related behaviors, the typical antipsychotics (RR 0.90, 95% CI, 0.62-1.31) and atypical antipsychotics (RR 1.05, 95% CI, 0.96-1.16) both did not increase the risk of deformity.[

Beforehand, Petersen and colleagues[ based on the electronic health record survey grouped the patients who received antipsychotics treatment in pregnancy as group A (n=416); the patients who terminated the use of antipsychotics before pregnancy as group B (n=670); and the patients who did not receive antipsychotics before and during pregnancy as group C (n=318,434). The results showed that the incidence rate of preterm birth and low birth weight infants was higher in group A (10%) than group B (4.3%) and group C (3.9%), group A and group B (RRadj:2.04, 1.13-3.67) and group A and group C (RRadj: 1.43, 0.99-2.05). The incidence rate of major congenital malformations was higher in group A (3.4%) than in group B (2.2%) and group C (2%). However, there was no statistical significance in differences (group A and group B RRadj: 1.79, 0.72-4.47, group A and group C RRadj: 1.59, 0.84-3.00).

1.2 Antidepressants

A national birth cohort study in Finland[ revealed that mental disorders had adverse effects on the pregnancy outcome. The selective serotonin reuptake inhibitor (SSRIs) had a certain degree of protective effect on the outcome of pregnancy. Meanwhile, there was a negative impact on the future generations. The mothers who had mental illnesses and used SSRIs experienced lower risks of late preterm birth (32-36 weeks, OR 0.84, 0.74-0.96), very premature birth (<32 weeks, OR 0.52, 0.37-0.74), cesarean section (OR 0.70, 0.66-0.75), and childbirth or postpartum hemorrhage (OR 0.83, 0.71-0.96) than the mothers who had mental illnesses and never used SSRIs. However, the offspring of the former aforementioned mothers had a higher risk of neonatal complications including lower Apgar scoring (OR 1.68, 1.34 - 2.12), respiratory disorders (OR 1.40, 1.20 - 1.62), and neonatal care monitoring (OR 1.24, 1.14 - 1.35). The pregnant women with mental illnesses, whether on medication or not, had higher proportions of cesarean section and neonatal care compared with the non-exposed group.

In order to identify the correlation between the specific SSRIs and some birth defects, Reefhuis and colleagues[ conducted a population-based, multicenter case-control study. The results showed that citalopram and escitalopram monotherapies were not significantly associated with birth defects; citalopram and neural tube defects in later generations had a borderline association; fluoxetine was significantly associated with right ventricular outflow tract obstruction and early closure of cranial sutures; paroxetine was associated with anencephaly, atrial septal defect, right ventricular outflow tract obstruction, gastroschisis, and omphalocele. Nevertheless, sertraline did not lead to the above 5 common birth defects.

In recent years, the long-term impact to the later generations due to the use of SSRIs during pregnancy was a concern. Brown and colleagues[ conducted a prospective birth cohort study of 845,345 pregnant women from the Finland database. The results showed that the risk of language disorders increased significantly (HR 1.37; CI; 1.11-1.70; p=0.004) in the offspring of the pregnant women who had depression-related mental disorder and 2 purchases of SSRIs compared with the offspring of the pregnant women who had the disorder and did not use the medication. Compared with the offspring of the mothers that had the disorders, the risk of the language, academic, and motor disorders in the offspring of both the SSRIs user group and the non-medication group increased; in the last two disorders, there was no difference in the offspring of the SSRIs user group and non-medication group.

2. Effects of untreated mental disorders on pregnancy

The use of psychotropic drugs in pregnant patients has some risk. However, the risk of major congenital malformation was not high according to the above study. Furthermore, the disorder itself and the abnormal disorder-related behavior and the physical symptoms had critical impact on whether the medication was teratogenic.

Patients with mental disorders during pregnancy not seeking treatment could be a result of the disease-caused impairment of the mothers’ self-care and judgment abilities, leading to lack of obstetric care during pregnancy, weak impulse control, the harm to the fetus and newborn, which could include ignoring the baby and even infanticide.

For patients with a history of mental illness, especially recurrent patients, they might need to increase the dosage or combination of drugs when there is relapse as a result of withdrawal of the drug during pregnancy. Constance and colleagues[ examined 201 pregnant women with depressive disorder to compare the risk of relapse during pregnancy and drug maintenance. In the results, the frequency of recurrence was significantly increased in the women who stopped medication during pregnancy compared with those that maintained the drug treatment (HR 5; 95% confidence interval, 2.8-9.1; p<0.001).

Therefore, the creation of the treatment plan for the pregnant women should consider their coping ability during the untreated period of the disease, the threshold symptoms, the potential impact of the untreated psychiatric disorder on the fetus or infant, and the risk caused by the abrupt termination of drug therapy.

The Maudsley[ prescription guidelines suggested that women with schizophrenia could stop medication during pregnancy if there had not been a relapse in the past 2 years and that patients in a stable condition could stop medication completely during the first 3 months of pregnancy. They added that the original therapeutic drugs could be resumed during the fourth month of pregnancy starting with a small amount and gradually increasing to achieve therapeutic effect with the small dosage possible. At the same time, it is suggested that patients with severe or chronic psychotic symptoms, degenerative patients, or patients taking large doses of drugs should not get pregnant.

The Food and Drug Administration (FDA) classified drugs into A, B, C, D, and X, these 5 categories according to the drug safety. However, all kinds of flaws in this classification have made it unable to meet clinical needs. In Dec 2014, the FDA issued a draft directive that aimed to radically change the labels on drugs used during the pregnancy and lactation periods and in turn to summarize in narrative form the risk certain medications can carry towards pregnancy using current data.[ The new labels included such information as incidence of reproduction related adverse events, influence of dosage, effect the length of dosage can have, and effectiveness of dosage based on the gestational period. It emphasized the quantification of the relative risk, which is the risk of the same outcome in a medicated person versus an unmedicated person with the same illness. The new label also provided more information on the risk the mother’s illness has towards the fetus, dosage adjustment during and after pregnancy, adverse effects of the drugs on the fetus and newborn, as well as information related to labor and delivery. All of this information made it possible for patients to be better informed and weigh the pros and cons of taking the medication.