BackgroundWomen are at great risk for mood and anxiety disorders during their childbearing years and may become pregnant while taking antidepressant drugs. In the treatment of depression and anxiety disorders, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed drugs, while it is largely unknown whether this medication affects the development of the central nervous system of the fetus. The possible effects are the product of placental transfer efficiency, time of administration and dose of the respective SSRI.Methodology/Principal FindingsIn order to attain this information we have setup a study in which these parameters were measured and the consequences in terms of physiology and behavior are mapped. The placental transfer of fluoxetine and fluvoxamine, two commonly used SSRIs, was similar between mouse and human, indicating that the fetal exposure of these SSRIs in mice is comparable with the human situation. Fluvoxamine displayed a relatively low placental transfer, while fluoxetine showed a relatively high placental transfer. Using clinical doses of fluoxetine the mortality of the offspring increased dramatically, whereas the mortality was unaffected after fluvoxamine exposure. The majority of the fluoxetine-exposed offspring died postnatally of severe heart failure caused by dilated cardiomyopathy. Molecular analysis of fluoxetine-exposed offspring showed long-term alterations in serotonin transporter levels in the raphe nucleus. Furthermore, prenatal fluoxetine exposure resulted in depressive- and anxiety-related behavior in adult mice. In contrast, fluvoxamine-exposed mice did not show alterations in behavior and serotonin transporter levels. Decreasing the dose of fluoxetine resulted in higher survival rates and less dramatic effects on the long-term behavior in the offspring.ConclusionsThese results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner.

Objective The aim of this study was to determine the extent and patterns of antidepressant use before, during and after pregnancy in a large population in The Netherlands. Methods Health care records and prescription data from one of the largest Dutch health insurance companies were analysed. The study cohort consisted of 29,005 women who had live births in the period between January 2000 and July 2003. Antidepressant drug use during a specified period was defined as there being a record of a prescription during that period.Results During the first trimester of pregnancy 2% of all pregnant women of the study cohort were found to have taken antidepressants; in the second and third trimesters, this figure had dropped to 1.8% of all pregnancies. Antidepressant use before as well as during pregnancy was almost twofold higher in women over 35 years of age than in those under 35 years. Almost 60% of the women who used antidepressants before pregnancy stopped taking them in the first trimester, and a smaller number stopped thereafter. Of all women using antidepressants during pregnancy, one third started this medication during gestation. In the 3 months following delivery, the prevalence of antidepressant use was the same as before pregnancy (2.9%). There was no shift to benzodiazepines in the group of women who stopped taking antidepressants during pregnancy. Although paroxetine and fluoxetine were the most frequently used antidepressants among the study group, all modern antidepressants were used. Conclusion A considerable number of women are being exposed to antidepressants throughout pregnancy up until delivery. One consequence of this is that their newborns need special care and supervision during the first days of life. However, women who stop taking the medication may risk a relapse of their illness, and this may also have a negative effect on the child.

Differences in CYP2D6 genotype may have divergent effects on maternal plasma paroxetine concentrations during pregnancy, with therapeutic consequences. Accumulation of paroxetine in a considerable group of pregnant women will lead to unintended increased exposure of paroxetine to the unborn child. Knowledge about a patient's CYP2D6 genotype is indispensable when prescribing paroxetine in pregnancy [trialregister.nl Identifier ISRCTN25383361].

Sotalol is a potent antiarrhythmic agent in the treatment of fetal tachycardia. The placental transfer is excellent. Sotalol accumulates in amniotic fluid but not in the fetus itself. Therefore it seems that renal excretion in the fetus is efficient and greater than the oral absorption by fetal swallowing. The maternal blood level is not a reliable predictor of the chances of success of therapy. Sotalol is not associated with fetal growth restriction.

A new lidocaine dosing schedule was developed. This new regimen should have a lower risk of cardiac arrhythmias and appears to be as effective in term infants. For preterm infants the optimal regimen needs to be determined.