Selective serotonin reuptake inhibitors affect neurobehavioral development in the human fetus

Abstract

The aim of this prospective study was to investigate whether selective serotonin reuptake inhibitors (SSRIs) utilized by pregnant women influence fetal neurobehavioral development. In this observational study we investigated developmental milestones of fetal behavior during the pregnancy of women with psychiatric disorders who took SSRIs throughout gestation (medicated group; n=96) or who had discontinued medication early in gestation or before conception (unmedicated group; n=37). Healthy unexposed fetuses of women without mental disorders comprised the control group (n=130). Ultrasonographic observations of fetal behavior were made three times in pregnancy (T1-T3). Effects of SSRIs were studied over a wide range of dosages (low, standard, or high) and for different drug types. Fetuses exposed to standard or high SSRI dosages compared with control, unmedicated, or low-medicated fetuses showed significantly increased motor activity at the beginning (T1) and end of the second trimester (T2). They particularly exhibited disrupted emergence of non-rapid eye movement (non-REM; quiet) sleep during the third trimester, characterized by continual bodily activity and, thus, poor inhibitory motor control during this sleep state near term (T3). The SSRI effects on the fetus were dose related, but independent of SSRI type. The results demonstrate changes in fetal neurobehavioral development associated with standard and high SSRI dosages that are observable throughout gestation. A first-choice SSRI type was not apparent. Bodily activity at high rate during non-REM sleep in SSRI-exposed fetuses is an abnormal phenomenon, but its significance for postnatal development is unclear.

Figure 1

The 2 h fetal behavioral state recording made at 38 weeks of gestation from an unmedicated woman with psychiatric problems. Fetal state organization is normal and comparable with that seen in healthy unexposed fetuses in the comparison group. Presented are the original data for fetal heart rate (FHR), general movements (GMs), and rapid eye movements (REMs; upper panel); and the smoothed state profile indicating episodes of FHR pattern (HRPs A and B), and the presence (+) and absence (−) of GMs and EMs (lower panel). S1F, state 1F; S2F, state 2F; ^*no-state identified.

Figure 2

The 2 h fetal behavioral state recording made at 38 weeks of gestation from a woman with psychiatric problems and long-term use of a high-dose SSRI. Presented are the original data for fetal heart rate (FHR), general movements (GMs), and rapid eye movements (REMs; upper panel); and the smoothed state profile indicating episodes of fetal heart rate pattern (HRPs A and B), and the presence (+) and absence (−) of GMs and EMs (lower panel). Note disruption of the two 1F combinations (HRPA and absence of EM) through continual presence of GM bursts. S1F: state 1F; S2F: state 2F; ^*no-state identified.

Figure 3

Linkage (% of time) of pairs of behavioral state 1F parameters in the near-term fetus: heart rate pattern A (HRPA); general movements absent (GM−); and eye movements absent (EM−). Linkage data are presented for the comparison (control) and unmedicated groups, and for the three medicated subgroups with low, standard, and high SSRI exposure. There were no significant differences between the comparison and unmedicated groups. ^*P<0.001; SSRI-exposed subgroup vs unmedicated group.