What is known about the use of fluoxetine during pregnancy?

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

Sammanfattning: Based on the available data on fluoxetine, with more than 1000 exposures, there is no indication that there is an increased risk of teratogenicity. There have, however, been cases of neonatal withdrawal syndrome. Dose reduction prior to delivery has been suggested but this can cause an increased risk of relapse. Further data on long-term neurobehavioural effects are needed. Data so far does however not suggest any differences among children whose mothers were treated with fluoxetine during pregnancy compared to other children.

Svar: This question has previously been dealt with in Drugline (1-4) and an update and summary of the information in this area has been done. In summary, available data gathered over the past decade does not imply an increased risk of teratogenic effects, spontaneous abortion or retarded neurodevelopment in children whose mothers were treated with fluoxetine during pregnancy. 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 fluoxetine in pregnant women does not infer an increased risk of malformations compared to the general population (5). Among, 340 women exposed to fluoxetine during pregnancy, 11 (3.24%) delivered a child with a malformation. With a probability of 99% the malformation rate is between 0.76 and 5.71%. The overall malformation rate in the population is 3.53%. In 1999, a study from the Swedish Medical Birth Registry was published (6). The study contained 546 women using SSRIs during pregnancy out of which 16 used paroxetine. The frequency of stillborn infants, minor and major malformations did not differ from the general population.

Fluoxetine is the selective serotonin reuptake inhibitor (SSRI) that has been studied most thoroughly. While no study indicate an increased risk of major malformations, Chambers et al noted an increased risk of multiple minor malformations in infants exposed to fluoxetine in utero during the first trimester (7,8). They also suggested that third trimester exposure to fluoxetine was associated with prematurity and poor neonatal adaptation (jitteriness, hypoglycemia, hypothermia, poor muscle tone and respiratory distress). This study has however been criticized. The study was not randomized and did not correct for the severity of the underlying disease of the women requiring pharmacotherapy during their pregnancy. Higher rates of prematurity may be related to maternal emotional state or other factors (ie women using antidepressants tend to smoke more during their pregnancy than other women) rather than to the medication. A meta-analysis of prospective studies in the area has been done, but there was no indication that there is a higher frequency of malformations than expected among infants exposed to fluoxetine during the first trimester (9).

A few cases of neonatal withdrawal syndrome after third trimester SSRI exposure have been published (10). In a recent study, five case reports were presented of neonatal withdrawal syndrome after third trimester in utero SSRI exposure. 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. One of the infants had been exposed to fluoxetine. He was prematurely delivered and on his second day of life he seemed irritable, agitated and had convulsions. The baby was treated with phenobarbital for one week.

The WHO adverse drug reaction-monitoring centre in Uppsala has received reports of a total of six cases of neonatal withdrawal syndrome (11). It should be noted that the WHO database does not include a homogeneous evaluation of reported cases due to differences among reporting countries. 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 (7,12). 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. One case report involving an infant with increased hemorrhagic tendency after exposure to fluoxetine in utero has also been reported (13). It is important to be aware of this increased risk of hemorrhage in the newborn after SSRI treatment.

Long-term neurobehavioural development has been sparsely studied. In one study 55 children whose mothers received fluoxetine were compared with 80 children whose mothers received tricyclic antidepressants and 84 children whose mothers had not been exposed to any drugs known to affect the fetus (4,8). Global IQ, language development and behavioural development were monitored between the ages 16 and 86 months and no differences were seen. The authors concluded that fluoxetine and tricyclic antidepressants do not affect neurobehavioural development. There is, however, one animal study that has shown that fluoxetine can produce changes, maybe permanent, in the brain of in utero exposed rats (14). Therefore, further investigation in this area is needed.

The decision to prescribe an antidepressant during pregnancy must always be made after consideration of the risks and benefits in each individual case (8,15). 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. The development of the infant may also be affected, with delayed motor development, reduced growth and lower IQ than infants of mothers treated for their depression.