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BACKGROUND: Cerebral complications in preeclampsia are leading causes of maternal mortality worldwide but the underlying pathophysiology is largely unknown and a challenge to study. Using an in vitro model of the human blood brain barrier (BBB), we explored the role of vascular endothelial growth factor receptor 2 (VEGFR2) in preeclampsia.

METHODS: The human brain endothelial cell line (hCMEC/D3) cultured on Tranwells insert were exposed (12 h) to plasma from women with preeclampsia (n=28), normal pregnancy (n=28) and non-pregnant (n=16) controls. Transendothelial electrical resistance (TEER) and permeability to 70 kDa FITC-dextran were measured for assessment of BBB integrity. We explored possible underlying mechanisms, with focus on expression of tight junction proteins and phosphorylation of two tyrosine residues of VEGFR2, associated with vascular permeability and migration (pY951) and cell proliferation (pY1175). Plasma concentrations of soluble FMS like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured in order to establish correlations with in vitro results.

RESULTS: hCMEC/D3 exposed to plasma from women with preeclampsia exhibited reduced TEER and increased permeability to 70 kDa FITC-dextran. Further, these cells up-regulated the mRNA levels of VEGFR2, as well as pY951-VEGFR2; but reduced pY1175-VEGFR2 (p&0.05 in all cases). No difference in mRNA expression of tight junction protein was observed between gruops. There was no correlation between angiogenic biomarkers and BBB permeability.

CONCLUSION: We present a promising in vitro model of the BBB in preeclampsia. Selective tyrosine phosphorylation of VEGFR2 may participate in the increased BBB permeability in preeclampsia irrespective of plasma concentrations of angiogenic biomarkers.

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.

Importance  Gestational hypertension, preeclampsia, and eclampsia are established risk factors for stroke and dementia later in life. Whether these pregnancy complications are associated with an increased risk of new-onset neurological disorders within months to years after giving birth is not known.

Objective  To explore whether gestational hypertension, preeclampsia, and eclampsia are associated with new-onset migraine, headache, epilepsy, sleep disorder, or mental fatigue within months to years after giving birth.

Design, Setting, and Participants  In this register-based cohort study, exposures were identified in the Swedish Medical Birth Register from 2005 to 2018. Follow-up was conducted using the National Patient Register, containing diagnoses from specialized inpatient and outpatient care. Follow-up started 42 days after delivery and continued until the first event, death, emigration, or the end of the follow-up period (2019). The risk was calculated with Cox regression analysis and expressed as adjusted hazard ratio (aHR) with a 95% CI. Through the Swedish Medical Birth Register, 659 188 primiparous women with singleton pregnancies between 2005 and 2018 were identified. Women with a diagnosis of chronic hypertension (n = 4271) or a prepregnancy neurological disorder (n = 6532) were excluded. The final study population included 648 385 women. Data analyses were conducted in 2023.

Exposures  Gestational hypertension, preeclampsia, and eclampsia.

Main outcome  The primary outcome was a composite neurological outcome of migraine, headache, epilepsy, sleep disorder, or mental fatigue.

Results  The study included 648 385 women with a mean age of 28.5 (SD, 5.0) years at the time of their first pregnancy. Women with gestational hypertension (n = 11 133), preeclampsia (n = 26 797), and eclampsia (n = 625) all had an association with increased risk for a new-onset neurological disorder compared with women with normotensive pregnancies. The aHR for gestational hypertension was 1.27 (95% CI, 1.12-1.45), 1.32 (95% CI, 1.22-1.42) for preeclampsia, and 1.70 (95% CI, 1.16-2.50) for eclampsia. When exploring individual outcomes, women with eclampsia were associated with more than a 5 times increased risk of epilepsy (aHR, 5.31; 95% CI, 2.85-9.89).

Conclusion and Relevance  In this study, gestational hypertension, preeclampsia, and eclampsia were associated with an increased risk of new-onset migraine, headache, epilepsy, sleep disorder, or mental fatigue within months to years after giving birth. Guidelines recommend follow-up after delivery for women with gestational hypertension and preeclampsia for their increased risk of cardiovascular disease. At these visits, caregivers should also pay attention to persisting or new-onset of neurological symptoms, since this group of women appears to be vulnerable to developing or experiencing neurological disorders.