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Cerebral complications in preeclampsia contribute substantially to maternal mortality and morbidity. There is a lack of reliable and accessible predictors for preeclampsia-related cerebral complications. In this study, plasma from women with preeclampsia (n = 28), women with normal pregnancies (n = 28) and non-pregnant women (n = 16) was analyzed for concentrations of the cerebral biomarkers neurofilament light (NfL), tau, neuron-specific enolase (NSE) and S100B. Then, an in vitro blood-brain barrier (BBB) model, based on the human cerebral microvascular endothelial cell line (hCMEC/D3), was employed to assess the effect of plasma from the three study groups. Transendothelial electrical resistance (TEER) was used as an estimation of BBB integrity. NfL and tau are proteins expressed in axons, NSE in neurons and S100B in glial cells and are used as biomarkers for neurological injury in other diseases such as dementia, traumatic brain injury and hypoxic brain injury. Plasma concentrations of NfL, tau, NSE and S100B were all higher in women with preeclampsia compared with women with normal pregnancies (8.85 vs. 5.25 ng/L, p < 0.001; 2.90 vs. 2.40 ng/L, p < 0.05; 3.50 vs. 2.37 mu g/L, p < 0.001 and 0.08 vs. 0.05 mu g/L, p < 0.01, respectively). Plasma concentrations of NfL were also higher in women with preeclampsia compared with non-pregnant women (p < 0.001). Higher plasma concentrations of the cerebral biomarker NfL were associated with decreased TEER (p = 0.002) in an in vitro model of the BBB, a finding which indicates that NfL could be a promising biomarker for BBB alterations in preeclampsia. De två sista författarna delar sistaförfattarskapet.

Objective The role of antiphospholipid antibodies (aPL) during apparently normal pregnancy is still unclear. IgA aPL are prevalent in populations of African origin. Our aim was to measure all isotypes of anticardiolipin (anti-CL) and anti–β2 glycoprotein I (anti-β2GPI) in healthy pregnant and non-pregnant women of different ethnicities. Methods Healthy Sudanese pregnant women ( n = 165; 53 sampled shortly after delivery), 96 age-matched Sudanese female controls and 42 healthy pregnant and 249 non-pregnant Swedish women were included. IgA/G/M anti-CL and anti-β2GPI were tested at one time point only with two independent assays in Sudanese and serially in pregnant Swedes. IgA anti-β2GPI domain 1 and as controls IgA/G/M rheumatoid factor (RF), IgG anti–cyclic citrullinated peptide 2 (anti-CCP2) and anti–thyroid peroxidase (anti-TPO) were investigated in Sudanese females. Results Pregnant Sudanese women had significantly higher median levels of IgA anti-CL, IgA anti-β2GPI ( p 2GPI (both assays; p 2GPI occurrence was increased among Sudanese pregnant women compared with national controls. No corresponding increase during pregnancy was found for IgA anti-β2GPI domain 1 antibodies. Both IgG anti-CL and IgG control autoantibodies decreased during and directly after pregnancy among Sudanese. Serially followed Swedish women showed no changes in IgA aPL, whereas IgG/M anti-CL decreased. Conclusions IgA aPL are increased in Sudanese but not in Swedish women, without corresponding increase in IgA domain 1. Whether due to ethnicity and/or environmental influences the occurrence of IgA aPL during Sudanese pregnancies, and its clinical significance, is yet to be determined.

Objective: To identify the level of amniotic fluid lactate (AFL), placental growth factor (PLGF), and vascular endothelial growth factor (VEGF) at second trimester amniocentesis, and to compare levels in normal pregnancies with pregnancies ending in a miscarriage, an intrauterine growth restricted fetus (IUGR) or decreased fetal movements. Study design: A prospective cohort study. Amniotic fluid was consecutively collected at amniocentesis in 106 pregnancies. Fetal wellbeing at delivery was evaluated from medical files and compared with the levels of AFL, VEGF, and PLGF at the time of amniocentesis. Results: The median level of AFL was 6.9 mmol/l, VEGF 0.088 pg/ml, and PLGF 0.208 pg/ml. The median levels of AFL in pregnancies ended in miscarriage were significantly higher (10.7 mmol/l) compared to those with a live new-born (6.9 mmol/L, p = .02). The levels of VEGF (p = .2) and PLGF (p = .7) were not affected. In pregnancies with an IUGR, the median level of AFL was higher compared to those with normal fetal growth (p = .003). No differences VEGF (p = .5), but significant lower PLGF were found in IUGR pregnancies (p = .03). Conclusions: Pregnancies ending in a miscarriage or with IUGR had significantly higher median values of AFL but lower values of PLGF in the amniotic fluid at the time of second trimester amniocentesis compared to normal pregnancies.

Objective To evaluate if concentrations of the neuronal proteins neurofilament light chain and tau are changed in women developing preeclampsia and to evaluate the ability of a combination of neurofilament light chain, tau, S100B and neuron specific enolase in identifying neurologic impairment before diagnosis of preeclampsia. Methods A nested case-control study within a longitudinal study cohort was performed. 469 healthy pregnant women were enrolled between 2004-2007 and plasma samples were collected at gestational weeks 10, 25, 28, 33 and 37. Plasma concentrations of tau and neurofilament light chain were analyzed in 16 women who eventually developed preeclampsia and 36 controls throughout pregnancy with single molecule array (Simoa) method and compared within and between groups. S100B and NSE had been analyzed previously in the same study population. A statistical model with receiving characteristic operation curve was constructed with the four biomarkers combined. Results Plasma concentrations of neurofilament light chain were significantly increased in women who developed preeclampsia in gestational week 33 (11.85 ng/L, IQR 7.48-39.93 vs 6.80 ng/L, IQR 5.65-11.40) and 37 (22.15 ng/L, IQR 10.93-35.30 vs 8.40 ng/L, IQR 6.40-14.30) and for tau in gestational week 37 (4.33 ng/L, IQR 3.97-12.83 vs 3.77 ng/L, IQR 1.91-5.25) in contrast to healthy controls. A combined model for preeclampsia with tau, neurofilament light chain, S100B and neuron specific enolase in gestational week 25 displayed an area under the curve of 0.77, in week 28 it was 0.75, in week 33 it was 0.89 and in week 37 it was 0.83. Median week for diagnosis of preeclampsia was at 38 weeks of gestation. Conclusion Concentrations of both tau and neurofilament light chain are increased in the end of pregnancy in women developing preeclampsia in contrast to healthy pregnancies. Cerebral biomarkers might reflect cerebral involvement before onset of disease.

The use of antidepressant treatment during pregnancy is increasing, and selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressants in pregnant women. Serotonin plays a role in embryogenesis, and serotonin transporters are expressed in two-cell mouse embryos. Thus, the aim of the present study was to evaluate whether fluoxetine, one of the most prescribed SSRI antidepressant world-wide, exposure influences the timing of different embryo developmental stages, and furthermore, to analyze what protein, and protein networks, are affected by fluoxetine in the early embryo development. Human embryos (17 = 48) were randomly assigned to treatment with 0.25 or 0.5 IiM fluoxetine in culture medium. Embryo development was evaluated by time-lapse monitoring. The fluoxetine-induced human embryo proteome was analyzed by shotgun mass spectrometry. Protein secretion from fluoxetine-exposed human embryos was analyzed by use of high-multiplex immunoassay. The lower dose of fluoxetine had no influence on embryo development. A trend toward reduced time between thawing and start of cavitation was noted in embryos treated with 0.5 it M fluoxetine (p = 0.065). Protein analysis by shotgun mass spectrometry detected 45 proteins that were uniquely expressed in fluoxetine-treated embryos. These proteins are involved in cell growth, survival, proliferation, and inflammatory response. Culturing with 0.5 p M, but not 0.25 p M fluoxetine, caused a significant increase in urokinase-type plasminogen activator (uPA) in the culture medium. In conclusion, fluoxetine has marginal effects on the timing of developmental stages in embryos, but induces expression and secretion of several proteins in a manner that depends on dose. For these reasons, and in line with current guidelines, the lowest possible dose of SSRI should be used in pregnant women who need to continue treatment.

Introduction Tau, Neurofilament Light chain (NfL), S100B and Neuron Specific Enolase (NSE) are peripheral biomarkers of central nervous system injury. Women with preeclampsia suffer from an endothelial cell injury and might have an altered blood brain barrier which can be the underlying cause of eclampsia. Cognition and cortex volume are affected in women months to years after previous preeclampsia. No reliable predictors exist to predict eclampsia or longterm prognosis after preeclampsia. Objectives The primary aim of this study was to compare plasma levels of tau and NfL in healthy pregnant women and in women developing preeclampsia. The secondary aim was to investigate if plasma levels of tau, NfL, S100B and NSE could predict preeclampsia before onset of disease. Methods 469 healthy pregnant women were enrolled and plasma samples were collected at gestational weeks 10, 25, 28, 33 and 37. A nested case control study was performed where plasma concentrations of tau and NfL were analyzed in 16 women with preeclampsia and 36 randomly selected controls throughout pregnancy with single molecule array (Simoa) method. S100B and NSE have previously been analyzed in the same population. A predictive model with the four cerebral biomarkers for prediction of preeclampsia was constructed. Results Median time for diagnosis of preeclampsia was at 38 weeks of gestation. Plasma concentrations of NfL were significantly increased in women who developed preeclampsia in gestational week 33 and 37 (Fig. 1) and for tau in gestational week 37 (Fig. 2) in contrast to healthy controls. A predictive model for preeclampsia with tau, NfL, S100B and NSE in gestational 25 had an AUC of 0.77 (0.61–0.93), in week 28 AUC was 0.75 (0.56–0.95), in week 33 AUC was 0.89 (0.73–1.00) and in week 37 AUC was 0.83 (0.66–1.00). Conclusions Plasma concentrations of both tau and NfL are increased in the end of pregnancy in women developing preeclampsia in contrast to healthy pregnancies and cerebral biomarkers might predict preeclampsia 13 weeks before median time of diagnosis. Pathophysiological processes causing preeclampsia lead to endothelial injury and possibly blood brain barrier compromise alone or in combination with neuronal and glial damage very early in the course of disease.

Depressive symptoms during pregnancy are common and may have impact on the developing child. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant treatment, but unfortunately, these treatments can also negatively affect the behavioral development and health of a child during pregnancy. In addition, serotonin (5-HT) exerts neurotrophic actions with thus far not fully known effects in the offspring. The neurotrophic growth factor (NGF) is involved in neuronal cell survival and differentiation, and altered placenta levels have been found to increase the risk for pregnancy complications, similar to those found in women treated with SSRIs. We therefore investigated whether the NGF signaling pathway was altered in the placenta from women treated with SSRIs (n = 12) and compared them with placenta from depressed (n = 12) and healthy mothers (n = 12). Results from immunohistochemical stainings revealed that placental NGF protein levels of SSRI-treated women were increased in both trophoblasts and endothelial cells compared with depressed and control women. In addition, downstream of the NGF receptor TrkA, increased levels of the signaling proteins ROCK2 and phosphorylated Raf-1 were found in stromal cells and a tendency towards increased levels of ROCK2 in trophoblasts and endothelial cells in SSRI-treated women when compared to healthy controls. SSRI-treated women also displayed increased levels of phosphorylated ROCK2 in all placental cell types studied in comparison with depressed and control women. Interestingly, in placental endothelial cells from depressed women, NGF levels were significantly lower compared to control women, but ROCK2 levels were increased compared with control and SSRI-treated women. Taken together, these results show that the NGF signaling and downstream pathways in the placenta are affected by SSRI treatment and/or antenatal depression. This might lead to an altered placental function, although the clinical relevance of our findings still needs to be investigated.