What is known about the use of paroxetine during pregnancy?

Fråga: What is known about the use of paroxetine during pregnancy?

Sammanfattning: A total of 719 exposures to paroxetine during pregnancy have been found. Paroxetine and the other SSRIs do not appear to increase the risk of teratogenic effects. Neonatal withdrawal syndrome has been reported in a few case studies and these reactions seem to be more common for paroxetine than for the other SSRIs. Dose reduction prior to delivery has been suggested but this can, however, cause an increased risk of relapse. Long-term development of children exposed to paroxetine in utero has not been studied.

Svar: This question has previously been dealt with in Drugline (1-5) and an update and summary of the information in this area has been done. Available data concerning the use of paroxetine and the other selective serotonin reuptake inhibitors (SSRIs) during pregnancy do not suggest an association with teratogenicity. As a precaution, antidepressive therapy should always be administered at the lowest effective dose during pregnancy.

Data from the Swedish Medical Birth Register concerning the use of paroxetine in pregnant women does not imply an increased risk for major malformations compared to the general population (6). Among, 507 women exposed to paroxetine during pregnancy 18 (3.55%) delivered a child with a malformation. With a probability of 99%, the malformation rate is between 1.43 and 5.67%. The overall malformation rate in the population is 3.53%. There was, however, a higher incidence of hypospadias among children exposed to paroxetine in utero. Whether this is caused by paroxetine is unclear. Other factors cannot be ruled out. In addition, there were a few more cases of congenital heart defects than expected which is not seen for the other SSRIs. In 1999, a study from the Swedish Medical Birth Registry was published (7). The study contained 546 women using SSRIs during pregnancy out of which 122 used paroxetine. The frequency of stillborn infants, minor and major malformations did not differ from the general population.

In a prospective cohort study, the pregnancy outcome in 267 women treated with sertraline, paroxetine or fluvoxamine was evaluated (1-2,4,8). Out of these, 97 women used paroxetine. No significant differences in the incidence of major malformations, miscarriages, stillbirths, birth weight or gestational age between the cases and the controls were found. Pregnancy outcomes among women who took a SSRI throughout the pregnancy were no different to those treated only during the first trimester. The authors concluded that these drugs do not appear to increase the teratogenic risk when used in recommended doses. One of the major limitations of this study is that the three antidepressants were analysed as a group, instead of analysing each substance separately (9).

In a report from 1993, none of 63 infants whose mothers were treated with paroxetine during the first trimester were found to have any major malformations (10). Similarly, another report from 1995 did not find any defects among the 52 children exposed to paroxetine during the first trimester.

In general, women treated with antidepressants have a tendency to deliver pre-term more often than other women (7,11). This is seen not only for the SSRIs but also for other antidepressants and is possibly due to the patients underlying conditions or other factors (i.e. women using antidepressants tend to smoke more during their pregnancy than other women) rather than the antidepressant.

A few cases of neonatal withdrawal syndrome after third trimester SSRI exposure have been published (12-14). In a recent study, five case reports were presented of neonatal withdrawal syndrome after third trimester in utero SSRI exposure (12). The symptoms occurred within a few days after birth and lasted up to one month. Characteristic symptoms of SSRI induced withdrawal syndromes are irritability, constant crying, shivering, increased tonus, eating and sleeping difficulties and in worst case convulsions. Three of the infants had been exposed to paroxetine in utero.

The WHO adverse drug reaction-monitoring centre in Uppsala has received reports of a total of 54 cases of neonatal withdrawal syndrome (15). It should be noted that the WHO database does not include a homogeneous evaluation of reported cases due to differences among reporting countries. According to a study from 1996, withdrawal reactions after exposure to paroxetine are more common than after exposure to fluoxetine, sertraline or fluvoxamine (3,16). Infants exposed to SSRIs during the last trimester might need close follow-up for withdrawal syndromes after birth. Dose reduction or discontinuation of drug therapy a few weeks before labour has been suggested (9,17). This may, however, cause a relapse of the disease, which can be of greater clinical importance.

SSRIs are known to cause bleeding disorders in adults. Two case reports involving infants with increased hemorrhagic tendency after exposure to fluoxetine and paroxetine in utero have been reported (18). It is important to be aware of this increased risk of hemorrhage in the newborn after SSRI treatment.

The decision to prescribe an antidepressant during pregnancy must always be made after the consideration of the risks and benefits in each individual case (11,19). Discontinuation of antidepressant therapy may be associated with an increased risk of relapse and with an increased risk of suicide. Besides risk to the mother, there is an increased risk to the infant with prematurity and low birth weight. Theoretically, the development of the infant may also be affected, with delayed motor development, reduced growth and lower IQ than in infants of mothers treated for their depression. However, long-term effects of infants whose mothers were treated with paroxetine during pregnancy have not been studied and any conclusions in that area can therefore not be drawn. One study, observing children between the ages of 16 and 86 months who had been exposed to fluoxetine in utero has been done (19,20). The authors concluded that fluoxetine did not seem to affect neurobehavioral development.