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Bergman, L., Torres-Vergara, P., Penny, J., Wikström, J., Nelander, M., Leon, J., . . . Escudero, C. (2019). Investigating Maternal Brain Alterations in Preeclampsia: the Need for a Multidisciplinary Effort. Current Hypertension Reports, 21(9), Article ID 72.
Open this publication in new window or tab >>Investigating Maternal Brain Alterations in Preeclampsia: the Need for a Multidisciplinary Effort
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2019 (English)In: Current Hypertension Reports, ISSN 1522-6417, E-ISSN 1534-3111, Vol. 21, no 9, article id 72Article in journal (Refereed) Published
Abstract [en]

PURPOSE OF REVIEW: To provide insight into the mechanisms underlying cerebral pathophysiology and to highlight possible methods for evaluation, screening, and surveillance of cerebral complications in preeclampsia.

RECENT FINDINGS: The pathophysiology of eclampsia remains enigmatic. Animal studies show that the cerebral circulation in pregnancy and preeclampsia might be affected with increased permeability over the blood-brain barrier and altered cerebral blood flow due to impaired cerebral autoregulation. The increased blood pressure cannot be the only underlying cause of eclampsia and cerebral edema, since some cases of eclampsia arise without simultaneous hypertension. Findings from animal studies need to be confirmed in human tissues. Evaluation of brain alterations in preeclampsia and eclampsia is challenging and demands a multidisciplinary collaboration, since no single method can accurately and fully describe how preeclampsia affects the brain. Cerebral complications of preeclampsia are significant factors in maternal morbidity and mortality worldwide. No single method can accurately describe the full picture of how preeclampsia affects the brain vasculature and parenchyma. We recommend an international and multidisciplinary effort not only to overcome the issue of limited sample availability but also to optimize the quality of research.

Keywords
Biomarkers, Blood-brain barrier, Brain complications, Brain imaging, Eclampsia, Preclinical studies, Preeclampsia
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-392990 (URN)10.1007/s11906-019-0977-0 (DOI)000479197200001 ()31375930 (PubMedID)
Available from: 2019-09-12 Created: 2019-09-12 Last updated: 2019-09-25Bibliographically approved
Hastie, R., Bergman, L., Cluver, C. A., Wikman, A., Hannan, N. J., Walker, S. P., . . . Hesselman, S. (2019). Proton Pump Inhibitors and Preeclampsia Risk Among 157 720 Women: A Swedish Population Register-Based Cohort Study. Hypertension, 73(5), 1097-1103
Open this publication in new window or tab >>Proton Pump Inhibitors and Preeclampsia Risk Among 157 720 Women: A Swedish Population Register-Based Cohort Study
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2019 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 73, no 5, p. 1097-1103Article in journal (Refereed) Published
Abstract [en]

Preeclampsia is a hypertensive disorder of pregnancy with a high rate of maternal and neonatal morbidity and mortality. The only definite treatment is delivery. Preclinical investigations have identified proton pump inhibitors (PPIs), which are commonly used to treat reflux during pregnancy, as a potential treatment for preeclampsia. The aim of this study was to determine the association between PPI use during pregnancy and preeclampsia risk in a population-based register cohort. Using the Swedish Pregnancy Register, we conducted a cohort study of nulliparous pregnant women delivering from January 2013 to July 2017. Associations between PPI use and preeclampsia were investigated using logistic regression analyses with risk estimates presented as crude and adjusted odds ratios (aOR) with 95% CI. Of 157 720 nulliparous pregnant women, 6051 (3.8%) reported PPI use during pregnancy. PPI use during any point of pregnancy was associated with an increased risk of overall preeclampsia (aOR of 1.17; 95% CI, 1.04-1.32) and preeclampsia at term (aOR of 1.20; 95% CI, 1.04-1.39). However, PPI use recorded after 28 gestational weeks was associated with a reduced risk of preterm (delivery <37 weeks) preeclampsia (aOR of 0.63; 95% CI, 0.41-0.96) and early (delivery <34 weeks) preeclampsia (aOR of 0.41; 95% CI, 0.20-0.82). These findings highlight the heterogeneity of this disease, with a potential role PPIs for preventing preterm preeclampsia when used in close proximity to disease onset. Targeting PPI use to women at greatest risk of preterm preeclampsia may help prevent this severe form of disease.

Keywords
preeclampsia, pregnancy, prevention, proton pump inhibitors, risk
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-387603 (URN)10.1161/HYPERTENSIONAHA.118.12547 (DOI)000469352400029 ()30636550 (PubMedID)
Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-10-30Bibliographically approved
Nelander, M., Hannsberger, D., Sundström Poromaa, I., Bergman, L., Weis, J., Åkerud, H., . . . Wikström, A.-K. (2018). Assessment of cerebral perfusion and edema in preeclampsia with intravoxel incoherent motion MRI.. Acta Obstetricia et Gynecologica Scandinavica, 97(10), 1212-1218
Open this publication in new window or tab >>Assessment of cerebral perfusion and edema in preeclampsia with intravoxel incoherent motion MRI.
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2018 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 97, no 10, p. 1212-1218Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Cerebral complications are the main reasons for morbidity and mortality in preeclampsia and eclampsia. As yet, we do not know whether the pathophysiology entails hypo- or hyperperfusion of the brain, or how and when edema emerges, due to the difficulty of examining the cerebral circulation.

MATERIAL AND METHODS: We have used a non-invasive diffusion weighted-magnetic resonance imaging technique, intravoxel incoherent motion, to study cerebral perfusion on the capillary level and cerebral edema in women with preeclampsia (n = 30), normal pregnancy (n = 32), and non-pregnant women (n = 16). Estimates of cerebral blood volume, blood flow, and edema were measured in 5 different regions. These points were chosen to represent blood supply areas of both the carotid and vertebrobasilar arteries, and to include both white and gray matter.

RESULTS: Except for the caudate nucleus, we did not detect any differences in cerebral perfusion measures on a group level. In the caudate nucleus, we found lower cerebral blood volume and lower blood flow in preeclampsia than in either normal pregnancy (P = .01 and P = .03, respectively) or non-pregnant women (both P = .02). No differences in edema were detected between study groups.

CONCLUSION: The cerebral perfusion measures were comparable between the study groups, except for a portion of the basal ganglia where hypoperfusion was detected in preeclampsia but not in normal pregnancy or non-pregnant women.

Keywords
cerebral circulation, eclampsia, edema, intravoxel incoherent motion, magnetic resonance imaging, perfusion, preeclampsia
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-357423 (URN)10.1111/aogs.13383 (DOI)000444070900010 ()29786833 (PubMedID)
Funder
Swedish Research Council, 2014-3561
Available from: 2018-08-16 Created: 2018-08-16 Last updated: 2018-11-14Bibliographically approved
Bergman, L., Zetterberg, H., Kaihola, H., Hagberg, H., Blennow, K. & Åkerud, H. (2018). Blood-based cerebral biomarkers in preeclampsia: Plasma concentrations of NfL, tau, S100B and NSE during pregnancy in women who later develop preeclampsia - A nested case control study. PLoS ONE, 13(5), Article ID e0196025.
Open this publication in new window or tab >>Blood-based cerebral biomarkers in preeclampsia: Plasma concentrations of NfL, tau, S100B and NSE during pregnancy in women who later develop preeclampsia - A nested case control study
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 5, article id e0196025Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2018
National Category
Obstetrics, Gynecology and Reproductive Medicine Neurosciences
Identifiers
urn:nbn:se:uu:diva-358098 (URN)10.1371/journal.pone.0196025 (DOI)000431281900042 ()29719006 (PubMedID)
Funder
EU, European Research CouncilKnut and Alice Wallenberg FoundationSwedish Research Council, D 2013-2546Swedish Research Council, D0277902Swedish Research Council, D0277901Torsten Söderbergs stiftelse
Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2018-08-24Bibliographically approved
Nelander, M., Wikström, A.-K., Weis, J., Bergman, L., Larsson, A., Sundström Poromaa, I. & Wikström, J. (2018). Cerebral osmolytes and plasma osmolality in pregnancy and preeclampsia: a proton magnetic resonance spectroscopy study. American Journal of Hypertension, 31(7), 847-853
Open this publication in new window or tab >>Cerebral osmolytes and plasma osmolality in pregnancy and preeclampsia: a proton magnetic resonance spectroscopy study
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2018 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 31, no 7, p. 847-853Article in journal (Refereed) Published
Abstract [en]

Background: Cerebral complications contribute substantially to mortality in preeclampsia. Pregnancy calls for extensive maternal adaptations, some associated with increased propensity for seizures, but the pathophysiology behind the eclamptic seizures is not fully understood. Plasma osmolality and sodium levels are lowered in pregnancy. This could result in extrusion of cerebral organic osmolytes, including the excitatory neurotransmitter glutamate, but this remains to be determined. The hypothesis of this study was that cerebral levels of organic osmolytes are decreased during pregnancy, and that this decrease is even more pronounced in women with preeclampsia.

Method: We used proton magnetic resonance spectroscopy to compare levels of cerebral organic osmolytes, in women with preeclampsia (n=30), normal pregnancy (n=32) and non-pregnant controls (n=16). Cerebral levels organic osmolytes were further correlated to plasma osmolality, and plasma levels of glutamate and sodium.

Results: Compared to non-pregnant women, women with normal pregnancy and preeclampsia had lower levels of the cerebral osmolytes myo-inositol, choline and creatine (p=0.001 or less), and all these metabolites correlated with each other (p<0.05). Women with normal pregnancies and preeclampsia had similar levels of osmolytes, except for glutamate, which was significantly lower in preeclampsia. Cerebral and plasma glutamate levels were negatively correlated with each other (p<0.008), and cerebral myo-inositol, choline and creatine levels were all positively correlated with both plasma osmolality and sodium levels (p<0.05).

Conclusion: Our results indicate that pregnancy is associated with extrusion of cerebral organic osmolytes. This includes the excitatory neurotransmitter glutamate, which may be involved in the pathophysiology of seizures in preeclampsia.

Keywords
Preeclampsia, eclampsia, proton magnetic resonance spectroscopy, cerebral osmolytes, glutamate
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-341642 (URN)10.1093/ajh/hpy019 (DOI)000435458800015 ()29415199 (PubMedID)
Funder
Swedish Research Council, 2014-3561
Available from: 2018-02-12 Created: 2018-02-12 Last updated: 2018-08-29Bibliographically approved
Hesselman, S., Bergman, L., Högberg, U. & Jonsson, M. (2018). Risk of fistula formation and long-term health effects after a benign hysterectomy complicated by organ injury: A population-based register study. Acta Obstetricia et Gynecologica Scandinavica, 97(12), 1463-1470
Open this publication in new window or tab >>Risk of fistula formation and long-term health effects after a benign hysterectomy complicated by organ injury: A population-based register study
2018 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 97, no 12, p. 1463-1470Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: There is a paucity of data on the impact of organ injury on long-term outcomes after a hysterectomy for benign indications. The aim of this study was to investigate fistula formation and patient-reported long-term health outcomes after organ injury at the time of a hysterectomy.

MATERIAL AND METHODS: This was a population-based study of 22 538 women undergoing a hysterectomy between 2000 and 2014 in Sweden. Their medical history, characteristics of their surgery, and patient-reported outcomes were retrieved from Swedish national health and quality registers. Predictors for fistula formation were investigated with logistic regression and are presented as odds ratios with a 95% CI.

RESULTS: Fistulas were reported in 7% of women with organ injuries, compared with 0.4% of those without organ injuries (adjusted odds ratio 15.29 [9.81-23.85]). Laparotomy and postoperative infection were associated with postoperative fistulas. Most of the women reported having better health 1 year after the hysterectomy, but 7% of those with organ injuries and 24% of those with fistulas reported deteriorated health, compared with 2% of women without injuries.

CONCLUSION: Organ injury at the time of hysterectomy is associated with the development of fistulas involving the female genital tract and increases the proportion of women reporting deteriorated health 1 year after surgery.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-364827 (URN)10.1111/aogs.13450 (DOI)000449515200007 ()30168129 (PubMedID)
Funder
Swedish Research Council, 2012-00087
Available from: 2018-11-04 Created: 2018-11-04 Last updated: 2019-06-27Bibliographically approved
Nelander, M., Weis, J., Bergman, L., Larsson, A., Wikström, A.-K. & Wikström, J. (2017). Cerebral Magnesium Levels in Preeclampsia; A Phosphorus Magnetic Resonance Spectroscopy Study. American Journal of Hypertension, 30(7), 667-672
Open this publication in new window or tab >>Cerebral Magnesium Levels in Preeclampsia; A Phosphorus Magnetic Resonance Spectroscopy Study
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2017 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 30, no 7, p. 667-672Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Magnesium sulfate (MgSO4) is used as a prophylaxis for eclamptic seizures. The exact mechanism of action is not fully established. We used phosphorus magnetic resonance spectroscopy (31P-MRS) to investigate if cerebral magnesium (Mg2+) levels differ between women with preeclampsia, normal pregnant, and nonpregnant women.

METHODS: This cross-sectional study comprised 28 women with preeclampsia, 30 women with normal pregnancies in corresponding gestational week (range: 23-41 weeks) and 11 nonpregnant healthy controls. All women underwent 31P-MRS from the parieto-occipital region of the brain and were interviewed about cerebral symptoms. Differences between groups were assessed by analysis of variance and Tukey's post-hoc test. Correlations between Mg2+ levels and specific neurological symptoms were estimated with Spearman's rank test.

RESULTS: Mean maternal cerebral Mg2+ levels were lower in women with preeclampsia (0.12 mM ± 0.02) compared to normal pregnant controls (0.14 mM ± 0.03) (P = 0.04). Nonpregnant and normal pregnant women did not differ in Mg2+ levels. Among women with preeclampsia, lower Mg2+ levels correlated with presence of visual disturbances (P = 0.04). Plasma levels of Mg2+ did not differ between preeclampsia and normal pregnancy.

CONCLUSIONS: Women with preeclampsia have reduced cerebral Mg2+ levels, which could explain the potent antiseizure prophylactic properties of MgSO4. Within the preeclampsia group, women with visual disturbances have lower levels of Mg2+ than those without such symptoms.

Keywords
31P-magnetic resonance spectroscopy, blood pressure, eclampsia, hypertension, magnesium, magnetic resonance, preeclampsia.
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-319608 (URN)10.1093/ajh/hpx022 (DOI)000407115100009 ()28338765 (PubMedID)
Funder
Swedish Research Council, 2014-3561
Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2018-02-22Bibliographically approved
Dehaene, I., Bergman, L., Turtiainen, P., Ridout, A., Mol, B. W. & Lorthe, E. (2017). Maintaining and repeating tocolysis: A reflection on evidence. Seminars in Perinatology, 41(8), 468-476
Open this publication in new window or tab >>Maintaining and repeating tocolysis: A reflection on evidence
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2017 (English)In: Seminars in Perinatology, ISSN 0146-0005, E-ISSN 1558-075X, Vol. 41, no 8, p. 468-476Article, review/survey (Refereed) Published
Abstract [en]

It is inherent to human logic that both doctors and patients want to suppress uterine contractions when a woman presents in threatened preterm labor. Tocolysis is widely applied in women with threatened preterm labor with a variety of drugs. According to literature, tocolysis is indicated to enable transfer to a tertiary center as well as to ensure the administration of corticosteroids for fetal maturation. There is international discrepancy in the content and the implementation of guidelines on preterm labor. Tocolysis is often maintained or repeated. Nevertheless, the benefit of prolonging pregnancy has not yet been proven, and it is not impossible that prolongation of the pregnancy in a potential hostile environment could harm the fetus. Here we reflect on the use of tocolysis, focusing on maintenance and repeated tocolysis, and compare international guidelines and practices to available evidence. Finally, We propose strategies to improve the evaluation and use of tocolytics, with potential implications for future research.

Keywords
Preterm labor, Preterm birth, Tocolysis, Maintenance tocolysis, Repeated tocolysis, I-SPY
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-347725 (URN)10.1053/j.semperi.2017.08.005 (DOI)000418315700005 ()28943054 (PubMedID)
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-04-11Bibliographically approved
Bergman, L., Åkerud, H., Wikström, A. K., Larsson, M., Naessén, T. & Akhter, T. (2016). Cerebral Biomarkers in Women With Preeclampsia Are Still Elevated 1 Year Postpartum. American Journal of Hypertension, 29(12), 1374-1379
Open this publication in new window or tab >>Cerebral Biomarkers in Women With Preeclampsia Are Still Elevated 1 Year Postpartum
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2016 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 29, no 12, p. 1374-1379Article in journal (Refereed) Published
Abstract [en]

BACKGROUND There is evidence of cerebral involvement among women with preeclampsia. Levels of the cerebral biomarkers neuron-specific enolase (NSE) and S100B are elevated during pregnancy in women developing preeclampsia. It is although not known if these biomarkers return to normal range postpartum. The aim with this study was to compare levels of S100B and NSE during pregnancy and 1 year postpartum in women who have had preeclampsia to women with normal pregnancies. METHODS This study was a longitudinal study of cases (n = 53) with preeclampsia and controls (n = 58) consisted of normal pregnant women in matched gestational weeks. Plasma samples were collected at inclusion during pregnancy and 1 year postpartum. Plasma samples were analyzed for levels of S100B and NSE by enzyme-linked immunosorbent assays kits. RESULTS Levels of NSE and S100B in women with preeclampsia were higher during pregnancy than in women with normal pregnancies. One year postpartum, women who have had preeclampsia still had a higher median level of both NSE (5.07 vs. 4.28 mu g/l, P < 0.05) and S100B (0.07 vs. 0.06 mu g/l, P < 0.05) compared to women with previous normal pregnancies. High levels of NSE and S100B postpartum remained associated with previous preeclampsia after adjustment for confounding factors. Levels of NSE correlated to S100B during pregnancy and postpartum. CONCLUSIONS Levels of NSE and S100B are still elevated 1 year postpartum in women who have had preeclampsia in contrast to women with previous normal pregnancies. We hypothesize that there might be a persistent cerebral involvement among women with preeclampsia even 1 year postpartum.

Keywords
blood pressure, hypertension, Neurological dysfunction, NSE, preeclampsia, S100B
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-316434 (URN)10.1093/ajh/hpw097 (DOI)000392732700009 ()27653032 (PubMedID)
Funder
Swedish Society of MedicineSwedish Research Council, 2014-3561 D0277901
Available from: 2017-03-01 Created: 2017-03-01 Last updated: 2017-11-29Bibliographically approved
Bergman, L. & Åkerud, H. (2016). Plasma Levels of the Cerebral Biomarker, Neuron-Specific Enolase, are Elevated During Pregnancy in Women Developing Preeclampsia. Reproductive Sciences, 23(3), 395-400
Open this publication in new window or tab >>Plasma Levels of the Cerebral Biomarker, Neuron-Specific Enolase, are Elevated During Pregnancy in Women Developing Preeclampsia
2016 (English)In: Reproductive Sciences, ISSN 1933-7191, E-ISSN 1933-7205, Vol. 23, no 3, p. 395-400Article in journal (Refereed) Published
Abstract [en]

Objectives: Neuron-specific enolase (NSE) is considered to be a peripheral biomarker of central nervous system injury. The aim of this study was to compare levels of NSE throughout pregnancy, in healthy pregnant women and in women developing preeclampsia. Methods: A nested case-control study within a longitudinal study cohort was performed. Four hundred sixty nine healthy pregnant women were enrolled, and plasma samples were collected at gestational weeks 10, 25, 28, 33, and 37. Levels of NSE were analyzed in 16 women with preeclampsia and 36 controls throughout pregnancy with an enzyme-linked immunosorbent assay. Results: In gestational week 37, women who developed preeclampsia had significantly higher plasma levels of NSE than healthy pregnant controls (P < .001). The levels of NSE did not change between gestational weeks 10 and 37 in women who developed preeclampsia, but the levels decreased significantly in healthy pregnant controls (P < .001). Conclusion: In pregnant women developing preeclampsia, the levels of NSE remained high throughout pregnancy, whereas in healthy women, these tended to decline over time, especially at the 2 last time points. The result might be confounded in early pregnancy by extracerebral sources of NSE, such as the corpus luteum. Findings need to be confirmed in a larger prospective study.

Keywords
eclampsia, NSE, preeclampsia
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-281488 (URN)10.1177/1933719115604732 (DOI)000370719100015 ()26355117 (PubMedID)
Available from: 2016-03-30 Created: 2016-03-24 Last updated: 2017-11-30Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-5202-9428

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