Evelin Wacker

Atypical antipsychotic drugs and pregnancy outcome: a prospective, cohort study.

Abstract Women of childbearing age are often affected with psychotic disorders, requiring the use of antipsychotic medication during pregnancy. In the present study, we prospectively followed the pregnancies of 561 women exposed to second-generation antipsychotic agents (SGAs; study cohort) and compared these to 284 pregnant women exposed to first-generation antipsychotic agents (FGAs; comparison cohort I) and to 1122 pregnant women using drugs known as not harmful to the unborn (comparison cohort II). Subjects were enrolled through the Institute’s consultation service. Major malformation rates of SGA exposed were higher compared to comparison cohort II (adjusted odds ratio, 2.17; 95% confidence interval, 1.20–3.91), possibly reflecting a detection bias concerning atrial and ventricular septal defects. Postnatal disorders occurred significantly more often in infants prenatally exposed to SGAs (15.6%) and FGAs (21.6%) compared to 4.2% of comparison cohort II. Cumulative incidences of elective terminations of pregnancy were significantly higher in both the study cohort (17%) and comparison cohort I (21%) compared to comparison cohort II (3%), whereas the rates of spontaneous abortions did not differ. The numbers of stillbirths and neonatal deaths were within the reference range. Preterm birth and low birth weight were more common in infants exposed to FGAs. To conclude, our findings did not reveal a major teratogenic risk for SGAs, making the better studied drugs of this group a treatment option during pregnancy. Because neonates exposed to SGAs or FGAs in the last gestational week are at higher risk of postnatal disorders, delivery should be planned in clinics with neonatal intensive care units.

Oscillatory Correlates of Vibrotactile Frequency Processing in Human Working Memory

Previous animal research has revealed neuronal activity underlying short-term retention of vibrotactile stimuli, providing evidence for a parametric representation of stimulus frequency in primate tactile working memory (Romo et al., 1999). Here, we investigated the neural correlates of vibrotactile frequency processing in human working memory, using noninvasive electroencephalography (EEG). Participants judged the frequencies of vibrotactile stimuli delivered to the fingertip in a delayed match-to-sample frequency discrimination task. As expected, vibrotactile stimulation elicited pronounced steady-state evoked potentials, which were source-localized in primary somatosensory cortex. Furthermore, parametric analysis of induced EEG responses revealed that the frequency of stimulation was reflected by systematic modulations of synchronized oscillatory activity in nonprimary cortical areas. Stimulus processing was accompanied by frequency-dependent alpha-band responses (8–12 Hz) over dorsal occipital cortex. The critical new finding was that, throughout the retention interval, the stimulus frequency held in working memory was systematically represented by a modulation in prefrontal beta activity (20–25 Hz), which was source-localized to the inferior frontal gyrus. This modulation in oscillatory activity during stimulus retention was related to successful frequency discrimination, thus reflecting behaviorally relevant information. Together, the results complement previous findings of parametric working memory correlates in nonhuman primates and suggest that the quantitative representation of vibrotactile frequency in sensory memory entails systematic modulations of synchronized neural activity in human prefrontal cortex.

Pregnancy Outcome After Methotrexate Treatment for Rheumatic Disease Prior to or During Early Pregnancy: A Prospective Multicenter Cohort Study

High‐dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX.

No evidence for an increased risk of adverse pregnancy outcome after paternal low-dose methotrexate: an observational cohort study.

OBJECTIVE There is increasing awareness of the potential impact of paternal exposures on pregnancy outcome. In particular this applies to MTX, which is used in low doses for the treatment of RA and other inflammatory diseases. MTX is associated with a specific pattern of malformations in fetuses of exposed women, but there is uncertainty concerning the risk of paternal low-dose MTX. The aim of this study was to investigate whether paternal low-dose MTX therapy around conception has an unfavourable effect on pregnancy outcome. METHODS We performed a prospective observational cohort study involving pregnancies fathered by men who were treated with low-dose MTX around conception. Pregnancies were identified through our Teratology Information Service. Pregnancy outcomes were compared with a cohort neither exposed to MTX nor to other teratogens. Outcomes evaluated were major birth defects, spontaneous abortion (SAB), elective termination of pregnancy, gestational age at delivery, and birth weight. RESULTS A total of 113 pregnancies with paternal low-dose MTX treatment were compared with 412 non-exposed pregnancies. Neither the rate of major birth defects [odds ratio (OR) 1.02, 95% CI 0.05, 7.0) nor the risk of SAB (hazard ratio 1.19, 95% CI 0.65, 2.17) was increased. Gestational age at delivery and birth weights did not differ significantly between groups. The rate of electively terminated pregnancies was increased in the MTX-exposed patients compared with controls. CONCLUSION Our study does not confirm an increased risk of adverse pregnancy outcome after paternal low-dose MTX therapy. The reassuring findings do not support the necessity of a 3-month MTX-free interval until conception. In the case of unavoidable paternal MTX therapy, it seems reasonable not to postpone family planning.

Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study.

AIMS TNF-α inhibitors are considered relatively safe in pregnancy but experience is still limited. The aim of this study was to evaluate the risk of major birth defects, spontaneous abortion, preterm birth and reduced birth weight after first trimester exposure to TNF-α inhibitors. METHODS Pregnancy outcomes of women on adalimumab, infliximab, etanercept, certolizumab pegol or golimumab were evaluated in a prospective observational cohort study and compared with outcomes of a non-exposed random sample. The samples were drawn from pregnancies identified by institutes collaborating in the European Network of Teratology Information Services. RESULTS In total, 495 exposed and 1532 comparison pregnancies were contributed from nine countries. The risk of major birth defects was increased in the exposed (5.0%) compared with the non-exposed group (1.5%; adjusted odds ratio (ORadj ) 2.2, 95% CI 1.0, 4.8). The risk of preterm birth was increased (17.6%; ORadj 1.69, 95% CI 1.1, 2.5), but not the risk of spontaneous abortion (16.2%; adjusted hazard ratio [HRadj ] 1.06, 95% CI 0.7, 1.7). Birth weights adjusted for gestational age and sex were significantly lower in the exposed group compared to the non-exposed cohort (P = 0.02). As a diseased comparison group was not possible to ascertain, the influence of disease and treatment on birth weight and preterm birth could not be differentiated. CONCLUSIONS TNF-α inhibitors may carry a risk of adverse pregnancy outcome of moderate clinical relevance. Considering the impact of insufficiently controlled autoimmune disease on the mother and the unborn child, TNF-α inhibitors may nevertheless be a treatment option in women with severe disease refractory to established immunomodulatory drugs.

Tactile and visual motion direction processing in hMT+/V5

The human motion complex hMT+/V5 is activated not only by visual motion, but also by tactile and auditory motion. Whilst direction-selectivity has been found within this complex for visual and auditory stimuli, it is unknown whether hMT+/V5 also contains direction-specific information from the tactile modality. In the current study, we sought to investigate whether hMT+/V5 contains direction-specific information about visual/tactile moving stimuli. Leftward and rightward moving stimuli were presented in the visual and tactile modalities in an event-related fMRI design. Using region-of-interest-based multivariate pattern analysis we could decode the two motion directions for both tactile and visual stimuli in hMT+/V5. The activity patterns of the two modalities differed significantly, indicating that motion direction information from different modalities may be carried by distinct sets of neuronal populations. Our findings show that hMT+/V5 contains specific information about the direction of a moving stimulus in both the tactile and visual modalities, supporting the theory of hMT+/V5 being a multimodal motion area.

Observational Cohort Study of Pregnancy Outcome after First-Trimester Exposure to Fluoroquinolones

ABSTRACT Fluoroquinolones are avoided during pregnancy due to developmental toxicity in animals. The aim of this study was to assess the fetal risk after intrauterine fluoroquinolone exposure. We performed an observational study of a prospectively ascertained cohort of pregnant women exposed to a fluoroquinolone during the first trimester. Pregnancy outcomes were compared to those of a cohort exposed to neither fluoroquinolones nor teratogenic or fetotoxic drugs. The outcomes evaluated were major birth defects (structural abnormalities of medical, surgical, or cosmetic relevance), spontaneous abortion, and elective termination of pregnancy. Pregnancy outcomes of 949 women with fluoroquinolone treatment were compared with those of 3,796 nonexposed controls. Neither the rate of major birth defects (2.4%; adjusted odds ratio [ORadj], 0.91; 95% confidence interval [CI], 0.6 to 1.5) nor the risk of spontaneous abortion (adjusted hazard ratio [HRadj], 1.01; 95% CI, 0.8 to 1.3) was increased. However, there was a nonsignificant increase in major birth defects after exposure to moxifloxacin (6/93, 6.5%; crude odds ratio [ORcrude], 2.40; 95% CI, 0.8 to 5.6). Neither a critical exposure time window within the first trimester nor a specific pattern of birth defects was demonstrated for any of the fluoroquinolones. The rate of electively terminated pregnancies was increased among the fluoroquinolone-exposed women (HRadj, 1.32; 95% CI, 1.03 to 1.7). The gestational ages at delivery and birth weights did not differ between groups. Our study did not detect an increased risk of spontaneous abortion or major birth defects. These reassuring findings support the recommendation to allow fluoroquinolone use in early pregnancy in selected cases. After the use of moxifloxacin, a detailed fetal ultrasound examination should be considered.

Allopurinol Use during Pregnancy - Outcome of 31 Prospectively Ascertained Cases and a Phenotype Possibly Indicative for Teratogenicity

Allopurinol is a purine analogue that inhibits xanthine oxidase. It is mainly used for the treatment of hyperuricemia in patients with gout or tumor lysis syndrome. Experience with allopurinol in pregnancy is scarce. In 2011, Kozenko et al. reported on a child with multiple malformations after maternal treatment with allopurinol throughout pregnancy. Possible teratogenicity of allopurinol was proposed due to the similarity of the pattern of malformations in children with mycophenolate embryopathy. A possible common mechanism of both drugs, i.e. disruption of purine synthesis, was discussed. We report on the outcome of 31 prospectively ascertained pregnancies with allopurinol exposure at least during first trimester. Pregnancy outcomes were 2 spontaneous abortions, 2 elective terminations of pregnancy and 27 live born children. The overall rate of major malformations (3.7%) and of spontaneous abortions (cumulative incidence 11%, 95%-CI 3–40) were both within the normal range. However, there was one child with severe malformations including microphthalmia, cleft lip and palate, renal hypoplasia, low-set ears, hearing deficit, bilateral cryptorchidism, and micropenis. The striking similarity of the anomalies in this child and the case described by Kozenko et al. might be considered as a signal for teratogenicity. Thus, we would recommend caution with allopurinol treatment in the first trimester, until further data are available.

Maintenance and manipulation of somatosensory information in ventrolateral prefrontal cortex.

Neuroimaging studies of working memory (WM) suggest that prefrontal cortex may assist sustained maintenance, but also internal manipulation, of stimulus representations in lower‐level areas. A different line of research in the somatosensory domain indicates that neuronal activity in ventrolateral prefrontal cortex (VLPFC) may also represent specific memory contents in itself, however leaving open to what extent top‐down control on lower‐level areas is exerted, or how internal manipulation processes are implemented. We used functional imaging and connectivity analysis to study static maintenance and internal manipulation of tactile working memory contents after physically identical stimulation conditions, in human subjects. While both tasks recruited similar subareas in the inferior frontal gyrus (IFG) in VLPFC, static maintenance of the tactile information was additionally characterized by increased functional coupling between IFG and primary somatosensory cortex. Independently, during internal manipulation, a quantitative representation of the task‐relevant information was evident in IFG itself, even in the absence of physical stimulation. Together, these findings demonstrate the functional diversity of activity within VLPFC according to different working memory demands, and underline the role of IFG as a core region in sensory WM processing. Hum Brain Mapp 35:2412–2423, 2014.

Does the average drug exposure in pregnant women affect pregnancy outcome? A comparison of two approaches to estimate the baseline risks of adverse pregnancy outcome

The results of observational cohort studies on drug effects on pregnancy outcome may depend among others on suitable comparison cohorts. The aim of this investigation was to compare two distinct definitions of maternal exposure status for comparison cohorts.