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Cardio-Renal & Neurologic Complications of Preeclampsia: Current Concepts & Clinical Implications

by Tolu-Akinnawo1, Zeth Oluwaremilekun1, Abe Temidayo1, Nandakumar Bangalore Vittal2, Henry Okafor3, Chike Nzerue1

1Department of Internal Medicine, Meharry Medical College, USA

2Department of Neurology, Vanderbilt University School of Medicine, USA

3Division of Cardiology Vanderbilt University School of Medicine, Nashville, TN, USA

*Corresponding author: Chike Nzerue, Department of Internal Medicine, Meharry Medical College, Nashville, TN, USA

Received Date: 14 January, 2024

Accepted Date: 26 February, 2024

Published Date: 29 February, 2024

Citation: Tolu-Akinnawo, Oluwaremilekun Z, Temidayo A, Vittal NB, Okafor H, Nzerue C (2024) Cardio-Renal & Neurologic Complications of Preeclampsia: Current Concepts & Clinical Implications.J Preg Child Health 6: 122. DOI: https://doi.org/10.29011/JPCH-122.100022

Abstract

Preeclampsia, which afflicts 3-5% of pregnancies worldwide, has recently being recognized to be a cardio-renal syndrome, in which neurologic complications contribute to the morbidity and mortality of this syndrome. The precise pathogenesis of preeclampsia, itself, is not definitely elucidated, but an imbalance of angiogenic & anti-angiogenic factors appear at play. The acute neurologic complications of preeclampsia such as seizures, cerebral edema, stroke, and posterior reversible leukoencephalopathy syndrome (PRES) are the leading contributors to obstetric mortality and morbidity in many low to middle and some high income countries. In addition to these acute devastating complications, registry and other long-term data, over recent decades now reveal that chronic neurologic & cardiovascular complications in the mothers as well as the offspring of preeclamptic pregnancies also contribute to future morbidity. In this review, we evaluate putative biophysical mechanisms of these cardio-renal and neurologic complications in both mother & child, as well as clinical implications of these new findings. We outline a rational monitoring strategy for these late complications in preeclamptic mothers & children born from preeclamptic pregnancies. Preventive strategies, encompassing aspirin, calcium-vitamin D supplementation, exercise, pravastatin, and metformin, offer insights into mitigating preeclampsia risks. Active management, balancing antihypertensives and planned delivery, appears to yield positive outcomes. Future pathways emphasize advancements in pathogenesis research, early predictive biomarkers, personalized therapeutic approaches, and global health initiatives. The role of wearable devices, telemedicine, and continuous monitoring in maternal-fetal health surveillance is paramount. Specific attention to unraveling neurological complications and establishing long-term follow-up programs is crucial for comprehensive care.

Introduction

Preeclampsia, a complex, multi-system disease associated with hypertension after 20 weeks gestation, edema and/ or proteinuria continues to afflict about 2 to 4% of pregnancies worldwide [1,2], and neurologic complications play very significant roles in acute & long-term maternal morbidity and mortality [3].Although it has been known that neurologic complications presage a bad outcome since proposed by Hippocrates in 400 B.C [3], the neurologic complications have garnered little attention. Autopsy studies and large case series confirm a high prevalence of neurologic complications in preeclampsia [4-7]. Furthermore there is a high burden of preeclampsia on maternal and child health in USA [8]. Significant controversies have bedeviled an understanding of the precise pathogenesis, but a gathering consensus appears to favor abnormal placentation, placental ischemia, an imbalance between angiogenic and antiangiogenic factors, which leads to endothelial dysfunction and damage in several vascular beds [9-12].

This review assesses both pre-clinical and clinical evidence supporting the occurrence of cardiorenal and neurological complications in this disorder, delving into potential biophysical mechanisms affecting both preeclamptic mothers and offspring of preeclamptic pregnancies.

The need for a rational approach to monitoring of the women and children for emergent neurological disease is discussed.

Pathogenesis of preeclampsia as a cardiorenal syndrome

In normal pregnancy, the placental remodeling with epithelialto endothelial phenotype transformation (pseudovasculogenesis) happens seamlessly with elaboration of vasodilators such as Vascular Endothelial Growth Factors (VEGF) and others to provide oxygen & nutrients to the fetus [13-15]. This process is defective in preeclampsia leading to hypoxia and elaboration of excess vasoconstrictors like soluble fms-like tyrosine kinase 1 (sFlt-1) & soluble endoglin (sEng) [13-15].

Vascular endothelial growth factors (VEGF) play a critical role in vasculogenesis and maintenance of vascular integrity in adult tissues [13,14]. Imbalance between angiogenic and antiangiogenic factors appears to play an integral role in triggering the preeclampsia cascade. Several studies suggest that the finding of aberrant levels sFlt-1, PlGF, and sEng levels can predict preeclampsia better than any single marker, suggesting the combined action of several angiogenic factors to produce the clinical phenotype of preeclampsia [15]. Placental dysfunction, ischemia and hypoxia with widespread endothelial dysfunction and inflammation appear to contribute to the resulting widespread vasculopathy.

Recent data support the fact that preeclampsia meets the criteria for cardiorenal syndrome- disorders of the heart and kidneys in which acute or chronic dysfunction of one organ induces dysfunction in the other [16]. Survivors and offsprings of preeclamptic pregnancies suffer a high incidence of hypertension, cardiovascular and renal disease.

This is not surprising as the occurrence of endothelial dysfunction, inflammation (endothelitis) and oxidative stress makes the kidney and heart vulnerable. Processes such as endothelial cell swelling, fenestration obliteration, and capillary space invasion contribute to the decreased glomerular filtration rate observed in preeclampsia. Glomerular swelling- endothelioses is the hallmark pathologic lesion of preeclampsia in the glomeruli. Vascular endothelial growth factors (VEGF) play a critical role in vasculogenesis and maintenance of vascular integrity in adult tissues. Imbalance between angiogenic and anti-angiogenic factors contributes to triggering the preeclampsia cascade [16-19].

Consistent with these findings, a high concentration of sFlt-1 has been suggested to play a role in podocyte effacement, adding another layer to our understanding of the renal complications associated with this condition [17].

Several studies suggest that the finding of sFlt-1, PlGF, and sEng levels can predict preeclampsia better than any single marker, converging the combined action of several angiogenic factors to produce the clinical phenotype of preeclampsia. Survivors and offspring of preeclamptic pregnancies suffer a high incidence of hypertension cardiovascular and neurologic disease [20].

However, this placenta-centric view of preeclampsia (Figure 1), has been challenged by evidence over the last few years of maternal cardiovascular dysfunction, or maladaptation, as well as evidence of two clear phenotypes of preeclampsia: earlyonset and late onset preeclampsia, each with variable impact on fetal growth restriction [16-19]. The biochemical markers of endothelial dysfunction in preeclampsia such as placental growth factor/soluble fms-like tyrosine kinase -1, endoglin, aberrant VEGF levels may be seen in non-pregnant females and males with cardiovascular and kidney disorders [21,22]. Valensise et al. [23] postulated the hemodynamic differences between the early -onset phenotype, where placental insufficiency dominates the picture, where uterine artery resistance was high and maternal cardiac output (CO) was low, but systemic vascular resistance (SVR) was high, from late-onset phenotype where CO was high, but SVR & uterine artery pulsatility index were normal. In both phenotypes there is evidence of numerous, interconnecting dysfunctions of the heart, kidneys, arteries, veins and interconnecting systems driven largely by endothelial dysfunction, hypertension and vascular injury [21,22]. Interestingly, some studies show the presence of a placenta is not a sine qua non for the occurrence of preeclampsia, as cases of Bevacizumab toxicity has presented with preeclampsia and/ or a syndrome resembling PRES, in non pregnant patients [24,25].

Regardless of the operational pathophysiology, it is increasingly recognized that pre-eclampsia of both phenotypes meets the criteria for cardio-renal syndrome. Renal involvement manifests as proteinuria of variable severity which reach nephrotic range, in severe cases leading to acute tubular necrosis and acute kidney injury [26,27]. Kidney biopsy classically shows endotheliosis [28,29].

Neurological complications of preeclampsia, ranging from acute manifestations like seizures (eclampsia), Posterior Reversible Encephalopathy Syndrome (PRES)/ cerebral edema (Figure 3A-E), cerebral venous sinus thrombosis, subarachnoid hemorrhage, hemorrhagic (Fig 3A-3C) and ischemic strokes contribute significantly to mortality, particularly in the middle and some high-income countries [1,2,30]. Long-term complications, including epilepsy and vascular dementia (from periventricular white matter ischemia) are also implicated [30]. Of these complications, intracerebral hemorrhage appears to be most devastating and contributes to about 70% of mortality in some series [31].

 

Figure 1: Illustrating pathogenesis of preeclampsia based on initiation by abnormal placentation & uteroplacental insufficiency.

 

Figure 3A-3C: MRI Brain showing Left posterior parietal region hyperintense signal suggesting edema with hemorrhage (3A-Diffusion Weighted image, 3B-Axial T2-FLAIR image & 3C Sagittal FLAIR).

 

Figure 3D and 3E: MRI Brain showing Right occipital pole hyperintensity-suggesting edema due to PRES; 3D Sagital FLAIR and 3E Axial FLAIR.

MRAngiogram of head and neck was unremarkable suggesting absence of longstanding large vessel disease (not shown here). MRVenogram was normal as well (not shown here).

Biophysical effects of preeclampsia on the maternal brain

Several experimental models have been used to investigate changes in maternal brain that can explain the observed neurological complications of preeclampsia, such as genetic models based on sFlt-1 overexpression [27,32], surgical models based on reduced uterine perfusion, experimental models with altered inflammatory state [33], as well as potential role maternal inflammasomes & innate pathways [34]. These pathways have given an insight into alterations in cerebral autoregulation, blood-brain barrier integrity, excessive vasoconstrictor tone & hyperexcitability as well microvascular disease. These appear to play integral roles as shown in (Figure 2).

1. Changes in cerebral autoregulation:

The brain’s ability to maintain perfusion in the face of changes in systemic blood pressure (autoregulation) is a protective mechanism against neurologic injury. Both animal [35] and human studies [36,37] show derangements in cerebral autoregulation in preeclampsia. Whether these changes are causal or casual is unclear since some studies show impairment of autoregulation [38], while other studies show paradoxically improved autoregulation in preeclampsia [39].

2. Changes in blood-brain barrier integrity:

Preeclampsia & eclampsia are associated with cerebral edema in some cases; suggesting alteration of permeability of the blood brain barrier [39-41]. The precise mechanism underlying this increased permeability is unclear, although inflammation has been blamed. Consistent with these observations, markers of inflammation such as C-reactive protein levels, Tumor Necrosis Factor –alpha (TNF-α) are elevated in Preeclampsia [42-44]. The pattern of edema seen in preeclampsia and eclampsia appears to resemble that in the posterior reversible encephalopathy syndrome (PRES) which can complicate some cases of this disorder [45-47].

Bevacizumab (a VEGF inhibitor) toxicity may also produce a preeclampsia like illness with cerebral edema, PRES and seizures [24,25,48].

1. Hyperexcitability & vasoconstriction :

Although the state of pregnancy may lower seizure threshold [49], there is clear clinical evidence in preeclampsia of hyperexcitability and sympathetic overactivity [50]. The salutary effects of magnesium sulfate in reducing seizure threshold in preeclampsia has been postulated to derive from N-methyl-Daspartate (NMDA) antagonism and vasodilation [51,52].

2. Cerebral microvasculopathy:

Preeclampsia carries risks of stroke and cognitive decline in subsequent years after the disease [53-56]. The associations between stroke, dementia and white matter disease in later life are unclear.

The possible pathogenetic interactions that connect preeclampsia to neurologic complications are summarized in (Figure 2) below.

 

Figure 2: Showing biophysical changes that may contribute to neurological complications in preeclampsia.

Epidemiology, risk factors, and classification

Preeclampsia affects 4 million women globally [1,2]. Preeclampsia is a leading cause of maternal mortality, resulting in 70,000 maternal deaths annually. It also increases the risk of fetal death and preterm deliveries [57].

Risk factors

Table 1 highlights the risk factors for pre-eclampsia [1,2,57].

Positive risk factors

Positive risk factors

Negative risk factors

Family history of preeclampsia

Maternal Smoking

Molar pregnancies

Prolonged Sexual Cohabitation

Multiple pregnancy

Nulliparity

Advanced maternal age

Maternal comorbidities such as Diabetes Mellitus, Chronic Hypertension, Obesity, Chronic Kidney Disease, Systemic Lupus Erythematosus

Trisomy 13

Previous Placenta abruption or intrauterine fetal growth restriction

Table 1: Risk factors for pre-eclampsia.

In the USA the risks of hypertensive pregnancy disorders have increased predominantly among African American women, compared to Hispanic/ American Indian/ White/ Asian or PacificIslander women [58]. The risk of the rate of eclampsia has, however, declined in recent years due to more widespread antenatal care and the use of magnesium sulfate [59]. It is also important to note that women with preeclampsia or eclampsia have a 3-25% increased risk of severe complications in their index pregnancy, including the risk of abruptio placentae/ disseminated intravascular coagulation/ pulmonary edema/ and aspiration pneumonia [60].

Long-term maternal and fetal cardio-renal neurologic sequelae

The aftermath of preeclampsia extends into long-term health outcomes, encompassing cardio-renal and neurologic implications:

  • A meta-analysis demonstrated a threefold increased risk of chronic hypertension and a twofold increased risk of cardiovascular disease (CVD) and stroke after a 10-15-year follow-up. While these patients also present with additional risk factors for CVD, the persistent impact of preeclampsia on long-term health is evident [61-65].
  • Preeclampsia is associated with an increased risk of metabolic syndrome, prompting the ACOG Task Force’s recommendation for periodic assessments of blood pressure, lipids, fasting blood glucose, and body mass index (BMI) in women with a history of preeclampsia or preterm delivery [64].
  • Peripartum cardiomyopathy, a rare but serious complication, is linked to preeclampsia. Experimental studies in rodents suggest an antiangiogenic milieu as the primary contributor to its development. The severity of myocardial dysfunction correlates with levels of angiogenic markers, such as sFLT1 (Soluble fms-like tyrosine kinase-1) and sENG (Soluble endoglin) [65].
  • Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are notable long-term complications associated with preeclampsia. A meta-analysis reveals a fourfold increased risk of microalbuminuria at a mean of 7.1 years postpartum and an eightfold increased risk in those previously diagnosed with preeclampsia [66].

Neonates born to mothers with preeclampsia face an increased risk of respiratory distress syndrome and bronchopulmonary dysplasia. While the exact mechanisms remain unclear, elevated sFLT1 has been suggested as a potential pathway, impairing angiogenesis [65].

In relation to neurocognitive follow up, it appears children born to preeclamptic mothers carry an increased risk of developing cerebral palsy, stroke, impaired neurological development, anxiety and depression [20,66-69].

.The mechanisms underlying these neurological disorders in offspring of preeclamptic pregnancies are unclear, but there is evidence of microRNA dysregulation in the placental tissue of affected cases [70]. This means that preeclampsia can no longer be seen as just a pregnancy disease, considering risk for later disease in mother and child [71].

This underscores the ongoing significance of understanding the vascular dynamics that contribute to both short-term and longterm maternal and fetal outcomes in the context of preeclampsia.

Management

Prevention

The imperative to mitigate the severe short-term and longterm risks associated with preeclampsia necessitates proactive preventive measures:

a. Aspirin:A   landmark randomized study in 1985 suggested that prophylactic aspirin administration (50-162mg, daily) significantly reduces the risks of preeclampsia, fetal growth restriction (FGR), and stillbirth in at-risk women [72]. Subsequent meta-analyses support this, indicating a statistically significant but clinically modest 10% reduction in preeclampsia risk, particularly beneficial when administered to high-risk women before 16 weeks’ gestation [73,74]. However, a metanalysis of 16 trials of 18,907 women showed that aspirin was more beneficial in preventing pre-term disease (relative risk, 0.62;95% CI, 0.20-0.74) than in term preeclampsia (relative risk, 0.92;95%CI, 0.7-1.21) [75]. To be effective, it appears treatment should be started before 16 weeks of pregnancy [26].b. Calcium and Vitamin D Supplementation:Findings from a meta-analysis encompassing 30 trials demonstrated a significantly reduced risk of preeclampsia in high-risk patients with calcium and vitamin D supplementation [76]. Calcium supplementation is effective given with or without Vitamin D [26].c. Exercise:A   comprehensive meta-analysis of 27 trials highlighted a 25% reduction in the likelihood of gestational hypertension and preeclampsia in patients engaging in at least 260 metabolic equivalents of weekly task minutes [77].d. Pravastatin:As an oral statin with potential anti-inflammatory actions, pravastatin is a promising preventive measure. A trial demonstrated a 26.7% reduction in preeclampsia and preterm birth in high-risk patients taking daily pravastatin from the second trimester until delivery [78].e. Metformin:

Another meta-analysis showed a significant reduction in gestational weight, particularly when metformin is taken between 12-18 weeks, revealing its potential in mitigating preeclampsia risk [79].

Active management

While the ultimate treatment for preeclampsia is the delivery of the placenta, the risks of preterm birth necessitate a nuanced approach.

Oral Antihypertensives

The management of preeclampsia involves careful consideration of the risks associated with antihypertensive drug treatment during pregnancy. The avoidance of aggressive treatment options aims to prevent pharmacologically induced hypotension and potential adverse fetal outcomes. This concern is particularly significant in chronic hypertensive patients or those with prior kidney problems. Antihypertensive drugs, including methyldopa, labetalol, nifedipine, and hydralazine, are considered first line [8082]. The choice of therapy depends on the acuity and severity of hypertension, and the route of administration (oral or intravenous) is a crucial factor. Methyldopa, a centrally acting agent, exhibits a mild antihypertensive effect with a slow onset and is considered safe for long-term use, including during breastfeeding. Labetalol, a blocker of β- and α-adrenergic receptors, is known for its rapid onset of action and preservation of uteroplacental blood flow. However, caution is warranted due to potential maternal hepatotoxicity. Nifedipine, a calcium channel blocker, is generally safe and available in immediate-release oral or sustained-release tablet forms. Hydralazine, a direct vasodilator, is employed intravenously for acute severe hypertension.

Planned delivery:

The timing of active delivery initiation remains a topic of contention, involving considerations of gestational age, severity of preeclampsia, and gestational hypertension weighed against the risks of prematurity and its associated complications [83,84]. Clarifying optimal timing is paramount for achieving the delicate balance between maternal and fetal well-being.

Clinical issues in managing headaches in pregnant and postpartum women

Migraine and tension-type headaches represent the most common primary headaches globally, constituting 11.2% of the total years of life lived with disability in women aged 15 to 49 [85]. Acute headaches in pregnant or postpartum patients raise concern. In a recent retrospective study of postpartum patients requiring inpatient neurologic consultation for headaches, over 73% of cases were identified as secondary headaches, with postdural puncture headaches (45.7%) and postpartum preeclampsia (26.1%) being the most prevalent [86].

Other headaches observed during pregnancy and the puerperium include those stemming from cervical artery dissection, reversible cerebral vasoconstriction syndrome (RCVS), ischemic stroke, subarachnoid hemorrhage, and cerebral venous thrombosis. Due to the diagnostic challenges in differentiating between primary and secondary headaches in pregnancy and postpartum, a thorough history/physical examination and a high clinical index are imperative. Red flags in the clinical history should trigger additional neuroimaging and lab testing.

Utilizing the SCAN ME features can aid in guiding patients requiring neuroimaging [30]:

- S: Sudden/Severe/Seizure

- C: Change in position

- A: Altered mentation

- N: Neurologic deficits/Nausea

- M: Medications without relief

- E: Elevated blood pressure or temperature reading

When opting for imaging, Magnetic Resonance Imaging (MRI) is the preferred choice over Computed Tomography (CT) if immediately available to minimize radiation exposure. Fetal radiation from CT is low and can be considered if MRI is unavailable, contraindicated, or clinically necessary [87]. In cases with evident “red flags,” collaborative management with a neurologist is of paramount importance.

Future

The intricate landscape of preeclampsia, with its profound impact on maternal and neonatal health, demands a forwardlooking approach to unravel potential future pathways, that may influence therapy. As we navigate the complexities of prevention, management, and the intricacies of its pathogenesis, several avenues beckon for further exploration.

Genomic and biomarker research:

Advancements in genomics hold promise in uncovering the genetic predispositions that render certain individuals more susceptible to preeclampsia. Identifying specific biomarkers of placental, maternal or fetal dysfunction, such as angiogenic factors sFLT1 associated with early-stage preeclampsia could revolutionize diagnostic precision and therapeutic interventions, enhancing our ability to predict, prevent, and manage the condition more effectively. Levels of sFTL1 are higher in patients with earlyonset and severe disease compared to late or mild disease. Also, changes in the level of P1GF (Placenta growth factor) and sFLT1 are detected 6-10 weeks before the onset of preterm preeclampsia [88,89]. These angiogenic biomarkers also differentiate preeclampsia from similarly presenting conditions such as CKD, gestational thrombocytopenia, and chronic hypertension and can limit the use of invasive procedures such as renal biopsy [30,8386]. Fetal RNA was also significantly higher (tenfold) in women with preeclampsia than in normal pregnancies [90-92]. A recent study confirmed that an sFlt-1: PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically [93].

Precision medicine in management:

Tailoring interventions based on individual patient profiles, considering genetic makeup, comorbidities, and socio-economic factors, can pave the way for precision medicine in managing preeclampsia. Personalized treatment plans, including drug regimens, could mitigate adverse outcomes and enhance maternal and fetal well-being. Novel strategies are currently being employed to predict the disease earlier and hopefully treat preeclampsia and prolong gestation [94].

Advanced imaging techniques:

Innovations in imaging technologies, such as functional MRI and advanced ultrasound, offer an opportunity to delve deeper into the structural and functional changes within organs affected by preeclampsia. Enhanced visualization can provide critical insights into the progression of neurological and cardiorenal complications, guiding more targeted therapeutic strategies [87].

Neuroprotective interventions:

Given the significant impact of preeclampsia on neurological outcomes, the development of neuroprotective interventions becomes paramount. Exploring agents that safeguard the blood-brain barrier, mitigate hyperexcitability, and counteract vasoconstriction may hold the key to preventing severe complications like eclampsia and long-term neurological sequelae.

Longitudinal studies on maternal and fetal outcomes:

Conducting comprehensive longitudinal studies, tracking the health of mothers and their offspring over extended periods will deepen our understanding of the enduring effects of preeclampsia. Unraveling the complex interplay between angiogenic imbalance, maternal health, and fetal development can inform targeted interventions to mitigate long-term complications.

Integrated care models:

Future pathways should emphasize integrated care models seamlessly integrating obstetric care, cardiology, neurology, and nephrology. This holistic approach ensures a comprehensive understanding of the intricate connections between cardio-renal and neurologic complications of preeclampsia, leading to more cohesive and effective management strategies.

Telehealth and remote monitoring:

Leveraging telehealth and remote monitoring technologies can facilitate proactive and continuous monitoring of pregnant individuals at risk of preeclampsia. This approach enables early detection of warning signs, timely intervention, and a more patientcentric healthcare delivery model.

Patient education and empowerment:

Fostering patient education and empowerment is integral to any future pathway. Equipping individuals with knowledge about risk factors, symptoms, and the importance of regular prenatal care empowers them to participate actively in their healthcare journey, fostering a collaborative and informed approach.

Conclusion

A lot has been learned about the pathophysiology of preeclampsia and the connection to cardio-renal and neurological complications in the past few decades.While the pathogenesis, risk factors, and long-term complications are complex, preventive measures like aspirin, calcium-vitamin D supplementation, exercise, and emerging drugs offer avenues for risk reduction. The initial belief that this syndrome resolves completely on delivery of baby and placenta has been found to be an oversimplification by occurrence of cardiac and neurological disease in mothers and children who suffer early and late cardio-renal effects. That said, there remain immediate salutary benefits for the mother with expeditious delivery, but fetal risks may be increased. Looking forward, embracing technology for continuous monitoring and predictive biomarker research holds promise. Interdisciplinary collaboration is crucial for advancing our understanding and management strategies. There is now an understanding of the two predominant phenotypes in this disease relating to how variable contributions of abnormal placentation and pre-existing maternal cardiovascular dysfunction lead to cardio-renal and neurological complications. Neurological symptoms may presage deterioration. Further clinical and biophysical research will elucidate a unifying theory on these complications and direct optimal management strategies.

Acknowledgements

The authors acknowledge the contribution of Chiemaka Jeffrey Nzerue with design of Figures 1 & 2.

References

  1. GBD 2015 Maternal Mortality Collaborators (2015) Global, regional and national levels of maternal mortality, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet 388: 1775-1812.
  2. Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, et al. (2014) Global causes of maternal death: A WHO systematic analysis. Lancet Glob Health 2: e323-e333.
  3. Chesley L (2015) Introduction, history, controversies and definitions. In: Taylor JR, Cunningham FG, Lindheimer M, editors.Chesley’s hypertensive disorders in pregnancy. 4th edition: 1-24.
  4. Hibbard LT (1973) Maternal mortality due to acute toxemia. Obstet Gynecol 42: 263-270.
  5. Gibbs CE, Locke WE (1976) Maternal deaths in Texas, 1969 to 1973: A report of 501 consecutive maternal deaths from the Texas Medical Association’s Committee on Maternal Health. Am J Obs Gynecol 126: 687–692.
  6. Judy AE, McCain CL, Lawton ES, Morton CH, Main EK, Druzin ML (2019) Systolic hypertension, preeclampsia-related mortality, and stroke in California. Obstet Gynecol 133: 1151–1159.
  7. Hasegawa J, Ikeda T, Sekizawa A, Tanaka H, Nakata M, et al. (2015) Maternal death due to stroke associated with pregnancy-induced hypertension. Circ J 79: 1835–1840.
  8. Shih T, Peneva D, Xu X, Sutton A, Ttriche E, et al. (2016) The rising burden of preeclampsia in the United States impacts both maternal and child health. Am J Perinatol 33: 329-338.
  9. Katsi V, Skalis G, Vamvakou G, Tousoulis D, Makris T (2020) Postpartum hypertension. Curr Hypertens Rep 22: 58.
  10. Chang KJ, Seow KM, Chen KH (2023) Preeclampsia: Recent advances in predicting, preventing, and managing the maternal and fetal lifethreatening condition. Int J Environ Res Public Health 20: 2994.
  11. Yagel S, Cohen SM, Admati I, Skarbianskis N, Solt I, et al. (2023) Expert review: Preeclampsia type I and type II. Am J Obstet Gynecol MFM 5: 101203.
  12. Craici IM, Wagner SJ, Weissgerber TL, Grande JP, Garovic VD (2014) Advances in the pathophysiology of pre-eclampsia and related podocyte injury. Kidney Int 86: 275-285.
  13. Karthikeyan VJ, Lip GY (2011) Endothelial damage/dysfunction and hypertension in pregnancy. Front Biosci (Elite Ed) 3: 1100-1108.
  14. Kang DH, Finch J, Nakagawa T, Karumanchi SA, Kanellis J, et al. (2004) Uric acid, endothelial dysfunction and pre-eclampsia: Searching for a pathogenetic link. J Hypertens 22: 229-235.
  15. Orabona R, Sciatti E, Vizzardi E, Bonadei I, Valcamonico A (2017) Endothelial dysfunction and vascular stiffness in women with previous pregnancy complicated by early or late pre-eclampsia. Ultrasound Obstet Gynecol 49: 116-123.
  16. Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, et al. (2010) Cardio-renal syndromes: Report from the consensus conference of the Acute Dialysis Quality Initiative. Eur Heart J 31: 703–711.
  17. Armaly Z, Jadaon JE, Jabbour A, Abassi ZA (2018) Preeclampsia: Novel mechanisms and potential therapeutic approaches. Front Physiol 9: 973.
  18. Masini G, Foo LF, Tay J, Wilkinson IB, Valensise H, et al. (2022) Preeclampsia has two phenotypes which require different treatment strategies. Am J Obstet Gynecol 226: S1006-S1018.
  19. Stillman IE, Karumanchi SA (2007) The glomerular injury of preeclampsia. J Am Soc Nephrol 18: 2281-2284.
  20. Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DJP, et al. (2009) Pre-eclampsia is associated with increased risk of stroke in the adult offspring: The Helsinki birth cohort study. Stroke 40: 1176–1180.
  21. Gyselaers W (2022) Hemodynamic pathways of gestational hypertension and preeclampsia. Am J Obstet Gynecol 226: S988-S1005.
  22. Gyselaers W (2020) Preeclampsia is a syndrome with a cascade of pathophysiologic events. J Clin Med 9: 2245.
  23. Valensise H, Vassapolo B, Gagliardi G, Novelli GP (2008) Early and late preeclampsia: Two different hemodynamic states in the latent phase of the disease. Hypertension 52: 873-880.
  24. Lazarus M, Amundson S, Belani R (2012) An association between bevacizumab and recurrent posterior reversible encephalopathy syndrome in a patient presenting with deep vein thrombosis: A case report and review of the literature. Case Rep Oncol Med 2012: 819546.
  25. Cross SN, Ratner E, Rutherford TJ, Schwartz PE, Norwitz ER (2012) Bevacizumab-mediated interference with VEGF signaling is sufficient to induce a preeclampsia-like syndrome in nonpregnant women. Rev Obstet Gynecol 5: 2-8.
  26. Magee LA, Nicolaides KH, von Dadelszen P (2022) Preeclampsia. New Engl J Med 386: 1817-1832.
  27. Maynard SE, Min JY, Merchan J, Lim KH, Li J, et al. (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111: 649–658.
  28. Rana S, Burke SD, Karumanchi SA (2022) Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders. Am J Obstet Gynecol 226: S1019-S1034.
  29. Strevens H, Wide-Swensson D, Hansen A, Horn T, Ingemarsson I, et al. (2003) Glomerular endotheliosis in normal pregnancy and preeclampsia. BJOG 110: 831-836.
  30. Miller EC, Vollbracht S (2021) Neurology of preeclampsia and related disorders: An update in neuro-obstetrics. Curr Pain Headache Rep 25: 40.
  31. Hasegawa J, Ikeda T, Sekizawa A, Tanaka H, Nakata M, et al. (2015) Maternal death due to stroke associated with pregnancy-induced hypertension. Circ J 79: 1835-1840.
  32. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, et al. (2006) Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med355: 992–1005.
  33. Gatford KL, Andraweera PH, Roberts CT, Care AS (2020) Animal models of preeclampsia: Causes, consequences, and interventions. Hypertension 75: 1363–1381.
  34. Michalczyk M, Celewicz A, Celewicz M, Woźniakowska-Gondek P, Rzepka R (2020) The role of inflammation in the pathogenesis of preeclampsia. Yi Y-S, editor. Mediators Inflamm 2020: 3864941– 3864949.
  35. Johnson AC, Cipolla MJ (2018) Impaired function of cerebral parenchymal arterioles in experimental preeclampsia. Microvasc Res 119: 64–72.
  36. Sonneveld MJ, Brusse IA, Duvekot JJ, Steegers EAP, Grune F, Visser GH (2014) Cerebral perfusion pressure in women with preeclampsia is elevated even after treatment of elevated blood pressure. Acta Obstet Gynecol Scand 93: 508–511.
  37. Richards A, Graham D, Bullock R (1988) Clinicopathological study of neurological complications due to hypertensive disorders of pregnancy. J Neurol Neurosurg Psychiatry 51: 416–421.
  38. Warrington JP, Fan F, Murphy SR, Roman RJ, Drummond HA, et al. (2014) Placental ischemia in pregnant rats impairs cerebral blood flow autoregulation and increases blood-brain barrier permeability. Phys Rep 2: e12134.
  39. Maeda KJ, McClung DM, Showmaker KC, Warrington JP, Ryan MJ, et al. (2020) Endothelial cell disruption drives increased blood brain barrier permeability and cerebral edema in the Dahl SS/jr rat model of superimposed preeclampsia. Am J Physiol Heart Circ Physiol 320: H535-H548.
  40. Janzarik WG, Gerber A-K, Markfeld-Erol F, Sommerlade L, Allignol A, Reinhard M (2018) No long-term impairment of cerebral autoregulation after preeclampsia. Pregnancy Hypertens 13: 171–173.
  41. Wallace K, Bean C, Bowles T, Spencer S-K, Randle W, et al. (2018) Hypertension, anxiety, and blood-brain barrier permeability are increased in postpartum severe preeclampsia/hemolysis, elevated liver enzymes, and low platelet count syndrome rats. Hypertension 72: 946–954.
  42. Cornelius DC (2018) Preeclampsia: From inflammationto immunoregulation. Clin Med Insights Blood Disord 11:1179545X17752325.
  43. Huang Q, Hu B, Han X, Yang J, Di X, et al. (2020) Cyclosporin A ameliorates eclampsia seizure through reducing systemic inflammation in an eclampsia-like rat model. Hypertens Res 43: 263–270.
  44. Fang X, Liang Y, Chen D, Liu Y, Xie M, Zhang W (2020) Contribution of excess inflammation to a possible rat model of eclamptic reversible posterior leukoencephalopathy syndrome induced by lipopolysaccharide and pentylenetetrazol: A preliminary study. Cytokine 135: 155212.
  45. Brewer J, Owens MY, Wallace K, Reeves AA, Morris R, et al. (2013) Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Am J Obs Gynecol 208: 468.e1–e6.
  46. Mayama M, Uno K, Tano S, Yoshihara M, Ukai M, et al. (2016) Incidence of posterior reversible encephalopathy syndrome in eclamptic and patients with preeclampsia with neurologic symptoms. Am J Obs Gynecol 215: 239.e1–e5.
  47. Postma IR, Slager S, Kremer HPH, de Groot JC, Zeeman GG (2014) Long-term consequences of the posterior reversible encephalopathy syndrome in eclampsia and preeclampsia: A review of the obstetric and nonobstetric literature. Obstet Gynecol Surv 69: 287–300.
  48. Zuo PY, Chen XL, Liu YW, Xiao CL, Liu CY (2014) Increased risk of cerebrovascular events in patients with cancer treated with bevacizumab: A meta-analysis. PLoS One 9: e102484.
  49. Johnson AC, Nagle KJ, Tremble SM, Cipolla MJ (2015) The contribution of normal pregnancy to eclampsia. PLoS One 10: e0133953.
  50. Yousif D, Bellos I, Penzlin AI, Hijazi MM, Illigens BM-W, et al. (2019) Autonomic dysfunction in preeclampsia: A systematic review. Front Neurol 10: 816.
  51. Cotton DB, Hallak M, Janusz C, Irtenkauf SM, Berman RF (1993) Central anticonvulsant effects of magnesium sulfate on N-methyl-Daspartate-induced seizures. Am J Obs Gynecol 168: 974–978.
  52. Euser AG, Cipolla MJ (2005) Resistance artery vasodilation to magnesium sulfate during pregnancy and the postpartum state. Am J Physiol Heart Circ Physiol 288: H1521–H1525.
  53. Wu P, Haththotuwa R, Kwok CS, Babu A, Kotronias RA, et al. (2017) Preeclampsia and future cardiovascular health: A systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 10: e003497.
  54. Miller EC, Boehme AK, Chung NT, Wang SS, Lacey JV, et al. (2019) Aspirin reduces long-term stroke risk in women with prior hypertensive disorders of pregnancy. Neurology 92: e305–e316.
  55. Elharram M, Dayan N, Kaur A, Landry T, Pilote L (2018) Long-term cognitive impairment after preeclampsia: A systematic review and meta-analysis. Obstet Gynecol 132: 355–364.
  56. Basit S, Wohlfahrt J, Boyd HA (2018) Pre-eclampsia and risk of dementia later in life: Nationwide cohort study. BMJ 363: k4109.
  57. Harmon QE, Huang L, Umbach DM, Klungsøyr K, Engel SM, et al.(2015) Risk of fetal death with preeclampsia. Obstet Gynecol 125: 628-635.
  58. Shahul S, Tung A, Minhaj M, Nizamuddin J, Wenger J, et al. (2015) Racial disparities in comorbidities, complications, and maternal and fetal outcomes in women with preeclampsia/eclampsia. Hypertens Pregnancy 34: 506-515.
  59. Lo JO, Mission JF, Caughey AB (2013) Hypertensive disease of pregnancy and maternal mortality. Curr Opin Obstet Gynecol 25: 124132.
  60. Zhang J, Meikle S, Trumble A (2003) Severe maternal morbidity associated with hypertensive disorders in pregnancy in the United States. Hypertens Pregnancy 22: 203-212.
  61. Chen CW, Jaffe IZ, Karumanchi SA (2014) Pre-eclampsia and cardiovascular disease. Cardiovasc Res 101: 579-586.
  62. Bellamy L, Casas JP, Hingorani AD, Williams DJ (2007) Pre-eclampsia and risk of cardiovascular disease and cancer in later life: Systematic review and meta-analysis. BMJ 335: 974.
  63. Ahmed R, Dunford J, Mehran R, Robson S, Kunadian V, et al. (2014) Pre-eclampsia and future cardiovascular risk among women: A review. J Am Coll Cardiol 63: 1815–1822.
  64. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 122: 1122-1131.
  65. Patten IS, Rana S, Shahul S, Rowe GC, Jang C, et al. (2012) Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature 485: 333-338.
  66. McDonald SD, Han Z, Walsh MW, Gerstein HC, Devereaux PJ (2010) Kidney disease after preeclampsia: A systematic review and metaanalysis. Am J Kidney Dis 55: 1026-1039.
  67. Figueiró-Filho EA, Mak LE, Reynolds JN, Stroman PW, Smith GN, et al. (2017) Neurological function in children born to preeclamptic and hypertensive mothers: A systematic review. Pregnancy Hypertens 10: 1-6.
  68. Sun BZ, Moster D, Harmon QE, Wilcox AJ (2020) Association of preeclampsia in term births with neurodevelopmental disorders in offspring. JAMA Psychiatry 77: 823-829.
  69. Gumusoglu SB, Chilukuri ASS, Santillan DA, Santillan MK, Stevens HE (2020) Neurodevelopmental Outcomes of prenatal preeclampsia exposure. Trends Neurosci 43: 253-268.
  70. Hromadnikova I, Kotlabova K, Hympanova L, Krofta L (2015) Cardiovascular and cerebrovascular disease associated microRNAs are dysregulated in placental tissues affected with gestational hypertension, preeclampsia and intrauterine growth restriction. PLoS One 10: e0138383.
  71. Tranquilli AL, Landi B, Giannubilo SR, Sibai BM (2012) Preeclampsia: No longer solely a pregnancy disease. Pregnancy Hypertens 2: 350357.
  72. Beaufils M, Uzan S, Donsimoni R, Colau JC (1985) Prevention of preeclampsia by early antiplatelet therapy. Lancet 1: 840-842.
  73. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA, PARIS Collaborative Group (2007) Antiplatelet agents for prevention of preeclampsia: A meta-analysis of individual patient data. Lancet 369: 1791-1798.
  74. Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, et al. (2017) Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 377: 613–622.
  75. Roberge S, Bujold E, Nicolaides KH (2018) Aspirin for the prevention of preterm & term preeclampsia: Systematic review and metaanalysis. Am J Obstet Gynecol 218: 287-293.
  76. Woo Kinshella ML, Sarr C, Sandhu A (2022) Calcium for preeclampsia prevention: A systematic review and network metaanalysis to guide personalized antenatal care. BJOG 129: 1833-1843.
  77. Davenport MH, Ruchat SM, Poitras VJ, Garcia AJ, Gray CE, et al. (2018) Prenatal exercise for the prevention of gestational diabetes mellitus and hypertensive disorders of pregnancy: A systematic review and meta-analysis. Br J Sports Med 52: 1367-1375.
  78. Aldika Akbar MI, Azis MA, Riu DS, Wawengkang 1e, Ernawati E, et al. (2022) INOVASIA study: A multicenter randomized clinical trial of pravastatin to prevent preeclampsia in high risk patients. Am J Perinatol.
  79. Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, et al. (2016) Metformin versus placebo in obese pregnant women without diabetes mellitus. N Engl J Med 374: 434-443.
  80. Nij Bijvank SW, Hengst M, Cornette JC, Huigen S, van Winkelen A, et al. (2022) Nicardipine for treating severe antepartum hypertension during pregnancy: Nine years of experience in more than 800 women. Acta Obstet Gynecol Scand 101: 1017-1025.
  81. Magee LA, Namouz-Haddad S, Cao V, Koren G, von Dadelszen P (2015) Labetalol for hypertension in pregnancy. Expert Opin Drug Saf 14: 453-461.
  82. Wiciński M, Malinowski B, Puk O, Socha M, Słupski M (2020) Methyldopa as an inductor of postpartum depression and maternal blues: A review. Biomed Pharmacother 127: 110196.
  83. Chappell LC, Brocklehurst P, Green ME, Hunter R, Hardy P, et al. (2019) Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): A randomised controlled trial. Lancet 394: 1181-1190.
  84. Beardmore-Gray A, Seed PT, Fleminger J, Zwertbroek E, Bernanrdes T, et al. (2022) Planned delivery or expectant management in preeclampsia: An individual participant data meta-analysis. Am J Obstet Gynecol 227: 218-230.e8.
  85. GBD 2016 Headache Collaborators (2018) Global, regional, and national burden of migraine and tension-type headache, 1990-2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 17: 954-976.
  86. Vgontzas A, Robbins MS (2018) A hospital based retrospective study of acute postpartum headache. Headache 58: 845-851.
  87. Anderson A, Singh J, Bove R (2020) Neuroimaging and radiation exposure in pregnancy. Handbook Clin Neurol 171: 179-191.
  88. Leaños-Miranda A, Campos-Galicia I, Isordia-Salas I, et al. (2012) Changes in circulating concentrations of soluble fms-like tyrosine kinase-1 and placental growth factor measured by automated electrochemiluminescence immunoassays methods are predictors of preeclampsia. J Hypertens 30: 2173-2181.
  89. Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, et al. (2005) Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of preeclampsia. J Matern Fetal Neonatal Med 17: 3-18.
  90. Rolfo A, Attini R, Nuzzo AM, Piazzesse A, Parisi S, et al. (2013) Chronic kidney disease may be differentially diagnosed from preeclampsia by serum biomarkers. Kidney Int 83: 177-181.
  91. Verdonk K, Visser W, Russcher H, Danser AH, Steegers EA, van den Meiracker AH (2012) Differential diagnosis of preeclampsia: Remember the soluble fms-like tyrosine kinase 1/placental growth factor ratio. Hypertension 60: 884-890.
  92. Verlohren S, Herraiz I, Lapaire O, Schlembach D, Moerti M, et al. (2012) The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients. Am J Obstet Gynecol 206: 58.e1-58.e588.
  93. Velegrakis A, Kouvidi E, Fragkiadaki P, Sifakis S (2023) Predictive value of the sFlt-1/PlGF ratio in women with suspected preeclampsia: An update (Review). Int J Mol Med 52: 89.
  94. Sekizawa A, Purwosunu Y, Farina A, Shimizu H, Nakamura M, et al. (2010) Prediction of pre-eclampsia by an analysis of placenta-derived cellular mRNA in the blood of pregnant women at 15-20 weeks of gestation. BJOG 117: 557-564.

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