Preeclampsia Review PDF

International Journal of Environmental Research and Public Health Review Preeclampsia: Recent Advances in Predicting, Preventing, and Managing the Maternal and Fetal Life-Threatening Condition Kai-Jung Chang 1 , Kok-Min Seow 2,3 and Kuo-Hu Chen 1,4, *...

International Journal of Environmental Research and Public Health Review Preeclampsia: Recent Advances in Predicting, Preventing, and Managing the Maternal and Fetal Life-Threatening Condition Kai-Jung Chang 1 , Kok-Min Seow 2,3 and Kuo-Hu Chen 1,4, * 1 Department of Obstetrics and Gynecology, Taipei Tzu-Chi Hospital, The Buddhist Tzu-Chi Medical Foundation, Taipei 231, Taiwan 2 Department of Obstetrics and Gynecology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan 3 Department of Obstetrics and Gynecology, National Yang-Ming Chiao-Tung University, Taipei 112, Taiwan 4 School of Medicine, Tzu-Chi University, Hualien 970, Taiwan * Correspondence: [email protected]; Tel.: +886-2-6628-9779 Abstract: Preeclampsia accounts for one of the most common documented gestational complications, with a prevalence of approximately 2 to 15% of all pregnancies. Defined as gestational hypertension after 20 weeks of pregnancy and coexisting proteinuria or generalized edema, and certain forms of organ damage, it is life-threatening for both the mother and the fetus, in terms of increasing the rate of mortality and morbidity. Preeclamptic pregnancies are strongly associated with significantly higher medical costs. The maternal costs are related to the extra utility of the healthcare system, more resources used during hospitalization, and likely more surgical spending due to an elevated rate of cesarean deliveries. The infant costs also contribute to a large percentage of the expenses as the babies are prone to preterm deliveries and relevant or causative adverse events. Preeclampsia imposes a considerable financial burden on our societies. It is important for healthcare providers and policy- makers to recognize this phenomenon and allocate enough economic budgets and medical and social resources accordingly. The true cellular and molecular mechanisms underlying preeclampsia remain largely unexplained, which is assumed to be a two-stage process of impaired uteroplacental perfusion with or without prior defective trophoblast invasion (stage 1), followed by general endothelial Citation: Chang, K.-J.; Seow, K.-M.; dysfunction and vascular inflammation that lead to systemic organ damages (stage 2). Risk factors for Chen, K.-H. Preeclampsia: Recent preeclampsia including race, advanced maternal age, obesity, nulliparity, multi-fetal pregnancy, and Advances in Predicting, Preventing, co-existing medical disorders, can serve as warnings or markers that call for enhanced surveillance and Managing the Maternal and Fetal of maternal and fetal well-being. Doppler ultrasonography and biomarkers including the mean Life-Threatening Condition. Int. J. arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), and serum pregnancy-associated Environ. Res. Public Health 2023, 20, plasma protein A (PAPP-A) can be used for the prediction of preeclampsia. For women perceived 2994. https://doi.org/10.3390/ as high-risk individuals for developing preeclampsia, the administration of low-dose aspirin on a ijerph20042994 daily basis since early pregnancy has proven to be the most effective way to prevent preeclampsia. Academic Editor: Jon Øyvind For preeclamptic females, relevant information, counseling, and suggestions should be provided to Odland facilitate timely intervention or specialty referral. In pregnancies complicated with preeclampsia, closer monitoring and antepartum surveillance including the Doppler ultrasound blood flow study, Received: 29 December 2022 biophysical profile, non-stress test, and oxytocin challenge test can be arranged. If the results are Revised: 4 February 2023 Accepted: 6 February 2023 unfavorable, early intervention and aggressive therapy should be considered. Affected females Published: 8 February 2023 should have access to higher levels of obstetric units and neonatal institutes. Before, during, and after delivery, monitoring and preparation should be intensified for affected gravidas to avoid serious complications of preeclampsia. In severe cases, delivery of the fetus and the placenta is the ultimate solution to treat preeclampsia. The current review is a summary of recent advances Copyright: © 2023 by the authors. regarding the knowledge of preeclampsia. However, the detailed etiology, pathophysiology, and Licensee MDPI, Basel, Switzerland. effect of preeclampsia seem complicated, and further research to address the primary etiology and This article is an open access article pathophysiology underlying the clinical manifestations and outcomes is warranted. distributed under the terms and conditions of the Creative Commons Keywords: preeclampsia; gestational hypertension; pregnancy induced hypertension; proteinuria Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Environ. Res. Public Health 2023, 20, 2994. https://doi.org/10.3390/ijerph20042994 https://www.mdpi.com/journal/ijerph  Int. J. Environ. Res. Public Health 2023, 20, x FOR PEER REVIEW 2 of 30 Keywords: preeclampsia; gestational hypertension; pregnancy induced hypertension; proteinuria Int. J. Environ. Res. Public Health 2023, 20, 2994 2 of 28 1. Introduction 1. Introduction Hypertensive disorder during pregnancy poses a substantial threat to both maternal Hypertensive and fetal disorder. health conditions during pregnancy Preeclampsia is poses one ofa the substantial threat to both most well-known maternal medical and fetal health conditions conditions that belong. Preeclampsia to this disease spectrum, which is one alsoofaccounts the most forwell-known one of the most medical conditions common that belong documented to this disease gestational spectrum, complications, which with also accounts a prevalence for one of 2the of approximately to most common 15% of all documented gestational pregnancies [2,3]. complications, It is depicted with acondition as a gestational prevalencewithofaapproximately hypertensive 2 to 15% of all disorder pregnancies diagnosed after [2,3]. 20 weeksIt isof depicted gestationasand a gestational condition with coexisting proteinuria a hypertensive or generalized edema, disorder and certain forms diagnosed afterof20hematologic disordersand weeks of gestation suchcoexisting as thrombocytopenia proteinuriaororsigns of generalized end organ edema, anddamage certain including renal impairment, forms of hematologic disordersabnormal such asliver function, pulmonary thrombocytopenia or signs of edema, end organanddamage cerebralincluding and visual disturbance renal [4,5].abnormal impairment, The definitions of gestational liver function, hyper- pulmonary edema, tension (pregnancy-induced hypertension) and preeclampsia are shown and cerebral and visual disturbance [4,5]. The definitions of gestational hypertension in Figure 1. Se- rious or long-term complications (pregnancy-induced hypertension) may result when preeclampsia and preeclampsia turns in are shown into a severe Figure type 1. Serious or or is left without being sufficiently treated. Multiorgan involvement long-term complications may result when preeclampsia turns into a severe type or ismay be seen in such cases, and thebeing left without impairment of uteroplacental sufficiently perfusion could treated. Multiorgan potentially involvement may lead betoseen gesta- in such tional complications and poor fetal outcomes including intrauterine fetal cases, and the impairment of uteroplacental perfusion could potentially lead to gestational growth re- striction and preterm complications delivery. and poor As the situation fetal outcomes worsens, including it may become intrauterine life-threatening fetal growth restriction and for both the mother and the fetus, in terms of increasing the rate of mortality and mor- preterm delivery. As the situation worsens, it may become life-threatening for both the bidity. mother and the fetus, in terms of increasing the rate of mortality and morbidity. Thedefinitions Figure 1.1. The Figure definitions of of gestational gestational hypertension hypertension (pregnancy-induced (pregnancy-induced hypertension) hypertension) and and preeclampsia. preeclampsia. Onestraightforward One straightforwardway waytoto categorize categorize preeclampsia preeclampsia is is to to subdivide subdivide ititinto intoearly-onset ear- and late-onset ly-onset groupsgroups and late-onset in accordance with with in accordance the gestational age age the gestational (GA). TheThe (GA). cutoff point is cutoff usually point set as GA is usually set34asweeks GA 34or GA weeks37 weeks, or GA and 37 we can subcategorize weeks, preeclampsia into and we can subcategorize the early-onset preeclampsia into(GAthe5 or >10 years) Autoimmune disease (esp. antiphospholipid syndrome, Maternal overweight/obesity (BMI > 30 or 35 kg/m2 ) systemic lupus erythematous) Multifetal gestation Young maternal age (20% lower odds of developing preeclampsia in the pregnant population compared to women with less adherence. 7.6. Exercise Many clinical and animal studies have identified significant or non-significant ef- fects of exercise during pregnancy on the reduction of gestational hypertensive disorders including preeclampsia. There are a few possible explanations in so for the results observed. To begin with, maternal exercise creates a transient hypoxic environment, which in turn promotes the compensatory proliferation of the trophoblastic, endothelial, and stromal cells of the pla- Int. J. Environ. Res. Public Health 2023, 20, 2994 23 of 28 centa, and consequently leads to improved placentation. Secondly, exercise stimulates antioxidant pathways and increases the number of mitochondria, relieving much of the oxidative stress that is linked to preeclampsia. Thirdly, exercise has an anti-inflammatory effect, which allows the body to maintain a healthy immune reaction, thus reducing the abnormal immune response to the fetus that is witnessed in preeclamptic patients. A review study in 2017 suggested that aerobic exercise is beneficial in pregnancy and should be encouraged. Whether or not aerobic exercise could reduce preeclampsia remained controversial in some studies, but overall, the review concluded that 30 to 60 min aerobic exercise two to seven times per week during pregnancy reduced the incidence of gestational hypertensive disorders and the rate of cesarean deliveries. However, this may not be the perfect regimen for every pregnant woman. The pre-pregnancy physical activity levels and maternal condition should always be taken into consideration for physi- cians to offer the best advice on the frequency, intensity, type, and time of exercise. 7.7. Long-Term Follow Up Last but not least, preeclampsia is a syndrome that develops before delivery, yet also demands extra healthcare in the long run. Long-term follow-up for potential complications is indicated since sequelae of the cardiovascular system, liver, and kidney could take place. Close surveillance for years is suggested, which requires alertness from a good medical team and good medical compliance from the patient herself. 8. Discussion The true cellular and molecular mechanisms underlying preeclampsia remain largely unexplained, which are assumed to be a two-stage process of impaired uteroplacental perfusion with or without prior defective trophoblast invasion (stage 1), followed by general endothelial dysfunction and vascular inflammation that lead to systemic organ damages (stage 2). Although the causes of preeclampsia are multi-factorial and cannot be described in a simple way, the aforementioned theories may provide a reasonable explanation for the results observed in past studies. Nevertheless, the detailed etiology, pathophysiology, and effect of preeclampsia seem complicated and remain to be clarified. As mentioned above, overweight including pre-pregnancy obesity and excessive weight gain during pregnancy predisposes women to the progression of preeclampsia. As a state of chronic inflammation, overweight will increase the risk of preeclampsia by means of activating macrophages, NK cells, and peripheral helper T cells within the placenta to produce inflammatory cytokines such as IL-6, IL-7, and TNF-α. Established on these findings and reasons, avoiding excessive weight gain before and during pregnancy, rather than merely using overweight as a predictor, may be the best strategy to prevent the occurrence of preeclampsia. Therefore, proper weight control for pregnant females can not only decrease the physical burden on the body but also reduce the risk of preeclampsia. Well-recognized risk factors for preeclampsia include race, advanced maternal age, obesity, nulliparity, multi-fetal pregnancy, and co-existing medical disorders. These factors can serve as warnings or markers to label pregnant women who need enhanced surveillance of maternal and fetal well-being. For at-risk females, appropriate information, counseling, and suggestions should be provided to facilitate a timely intervention or specialty referral. For pregnancies complicated with preeclampsia, closer monitoring and antepartum surveil- lance including a Doppler ultrasound blood flow study, biophysical profile, non-stress test, and oxytocin challenge test can be arranged. If the results are unfavorable, early intervention and aggressive therapy should be considered. Moreover, affected females should have access to higher levels of obstetric units and neonatal institutes. Before, during, and after delivery, monitoring and preparation should be intensified for affected gravidas to avoid serious complications of preeclampsia. In response to the potential physiological effect and psychological impact, consultation and discussion are usually beneficial for females diagnosed with preeclampsia. For severe cases, delivery of the fetus and placenta is the ultimate solution to treat preeclampsia. However, the determination of the appropriate Int. J. Environ. Res. Public Health 2023, 20, 2994 24 of 28 timing for delivery depends on the severity of maternal preeclampsia and the maturity of the fetus. It remains not fully understood with regard to the molecular level and pathologic mechanism of preeclampsia and its associated treatment. More studies are still required to investigate the role of anticoagulant therapy (such as aspirin, as described above) in preeclampsia. To minimize the heterogeneity of research in the future, the standardization of several critical factors in preeclampsia and the related treatment should be carefully considered. Two of the important factors are the timing and intensity of screening and intervention, which have a remarkable impact on the therapeutic effects. Furthermore, the severity and outcome in the individuals diagnosed with preeclampsia need standardization. Moreover, a larger sample size is also required to draw a reliable conclusion and to improve the reproducibility of the study result. 9. Conclusions Preeclampsia accounts for one of the most common documented gestational complica- tions, with a prevalence of approximately 2 to 15% of all pregnancies. It is life-threatening for both the mother and the fetus, in turn, increasing the rate of mortality and morbidity. Preeclamptic pregnancies are strongly associated with significantly higher medical costs. The maternal costs are related to the extra utility of the healthcare system, more resources used during hospitalization, and likely more surgical spending due to an ele- vated rate of cesarean deliveries. The infant costs also contribute to a large percentage of the expenses as the babies are prone to preterm deliveries and relevant or causative adverse events. Preeclampsia imposes a considerable financial burden on our societies. It is important for healthcare providers and policy-makers to recognize this phenomenon and allocate enough economic budgets and medical and social resources accordingly. The true cellular and molecular mechanisms underlying preeclampsia remain largely unexplained, which are assumed to be a two-stage process of impaired uteroplacental perfusion with or without prior defective trophoblast invasion (stage 1), followed by general endothelial dysfunction and vascular inflammation that lead to systemic organ damages (stage 2). Risk factors for preeclampsia, including race, advanced maternal age, obesity, nulli- parity, multi-fetal pregnancy, and co-existing medical disorders, can serve as warnings or markers that call for enhanced surveillance of maternal and fetal well-being. Doppler ultra- sonography and biomarkers including the mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), and serum pregnancy-associated plasma protein A (PAPP-A) can be used for the prediction of preeclampsia. For women perceived as high-risk individu- als for developing preeclampsia, the administration of low-dose aspirin on a daily basis since early pregnancy has proven to be the most effective way to prevent preeclampsia. For preeclamptic females, relevant information, counseling, and suggestions should be provided to facilitate timely intervention or specialty referral. In pregnancies complicated with preeclampsia, closer monitoring and antepartum surveillance including a Doppler ultrasound blood flow study, biophysical profile, non-stress test, and oxytocin challenge test can be arranged. If the results are unfavorable, early intervention and aggressive therapy should be considered. Affected females should have access to higher levels of obstetric units and neonatal institutes. Before, during, and after delivery, monitoring and preparation should be intensified for affected gravidas to avoid serious complications of preeclampsia. In severe cases, delivery of the fetus and placenta is the ultimate solution to treat preeclampsia. Although the aforementioned theories may provide a reasonable explanation for the results observed in the past studies, the detailed etiology, pathophysiology, and effect of preeclampsia seem complicated, and further research to address the primary etiology and pathophysiology underlying the clinical manifestations and outcomes is warranted. Int. J. Environ. Res. Public Health 2023, 20, 2994 25 of 28 Author Contributions: K.-J.C., K.-M.S. and K.-H.C. conceived the review and designed the search methods for the literature; K.-J.C. and K.-H.C. collected the data in the literature; K.-J.C., K.-M.S. and K.-H.C. performed data analyses; K.-J.C. and K.-H.C. wrote the review. All authors have read and agreed to the published version of the manuscript. Funding: This review and APC were funded by a grant from Taipei Tzu-Chi Hospital, Taiwan (TCRD-TPE-111-10) for K.-H.C. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in writing the manuscript, or in deciding to publish the results. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest. References 1. Say, L.; Chou, D.; Gemmill, A.; Tunçalp, Ö.; Moller, A.-B.; Daniels, J.; Gülmezoglu, A.M.; Temmerman, M.; Alkema, L. Global causes of maternal death: A WHO systematic analysis. Lancet Glob. Health 2014, 2, E323–E333. [CrossRef] [PubMed] 2. Jeyabalan, A. Epidemiology of preeclampsia: Impact of obesity. Nutr. Rev. 2013, 71, S18–S25. [CrossRef] [PubMed] 3. Mou, A.D.; Barman, Z.; Hasan, M.; Miah, R.; Hafsa, J.M.; Das Trisha, A.; Ali, N. Prevalence of preeclampsia and the associated risk factors among pregnant women in Bangladesh. Sci. Rep. 2021, 11, 21339. [CrossRef] [PubMed] 4. Brown, M.A.; Magee, L.A.; Kenny, L.C.; Karumanchi, S.A.; McCarthy, F.P.; Saito, S.; Hall, D.R.; Warren, C.E.; Adoyi, G.; Ishaku, S. The hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens. 2018, 13, 291–310. [CrossRef] 5. Chaemsaithong, P.; Sahota, D.S.; Poon, L.C. First trimester preeclampsia screening and prediction. Am. J. Obstet. Gynecol. 2022, 226, S1071–S1097.e2. [CrossRef] 6. Von Dadelszen, P.; Magee, L.A.; Roberts, J.M. Subclassification of preeclampsia. Hypertens. Pregnancy 2003, 22, 143–148. [CrossRef] 7. Cunningham, F.G.; Leveno, K.J.; Bloom, S.L.; Dashe, J.S.; Hoffman, B.L.; Casey, B.M.; Spong, C.Y. Williams Obstetrics, 25th ed.; McGraw Hill/Medical: New York, NY, USA, 2022; pp. 1086–1089. 8. Roberts, J.M.; Hubel, C.A. The two stage model of preeclampsia: Variations on the theme. Placenta 2009, 30 (Suppl. A), S32–S37. [CrossRef] 9. Atallah, A.; Lecarpentier, E.; Goffinet, F.; Doret-Dion, M.; Gaucherand, P.; Tsatsaris, V. Aspirin for prevention of preeclampsia. Drugs 2017, 77, 1819–1831. [CrossRef] 10. Duhig, K.; Vandermolen, B.; Shennan, A. Recent advances in the diagnosis and management of pre-eclampsia. F1000Res 2018, 7, 242. [CrossRef] 11. Yang, Y.; Le Ray, I.; Zhu, J.; Zhang, J.; Hua, J.; Reilly, M. Preeclampsia prevalence, risk factors, and pregnancy outcomes in Sweden and China. JAMA Netw Open 2021, 4, e218401. [CrossRef] 12. Zhang, M.; Wan, P.; Ng, K.; Singh, K.; Cheng, T.H.; Velickovic, I.; Dalloul, M.; Wlody, D. Preeclampsia among African American pregnant women: An update on prevalence, complications, etiology, and biomarkers. Obstet. Gynecol. Surv. 2020, 75, 111–120. [CrossRef] 13. Johnson, J.D.; Louis, J.M. Does race or ethnicity play a role in the origin, pathophysiology, and outcomes of preeclampsia? An expert review of the literature. Am. J. Obstet. Gynecol. 2022, 226, S876–S885. [CrossRef] 14. Sheen, J.-J.; Huang, Y.; Andrikopoulou, M.; Wright, J.D.; Goffman, D.; D’Alton, M.E.; Friedman, A.M. Maternal age and preeclampsia outcomes during delivery hospitalizations. Am. J. Perinatol. 2020, 37, 44–52. [CrossRef] 15. Lamminpää, R.; Vehviläinen-Julkunen, K.; Gissler, M.; Heinonen, S. Preeclampsia complicated by advanced maternal age: A registry-based study on primiparous women in Finland 1997–2008. BMC Pregnancy Childbirth 2012, 12, 47. [CrossRef] 16. Tyas, B.D.; Lestari, P.; Akbar, M.I.A. Maternal perinatal outcomes related to advanced maternal age in preeclampsia pregnant women. J. Family Reprod. Health 2019, 13, 191–200. [CrossRef] 17. Duckitt, K.; Harrington, D. Risk factors for pre-eclampsia at antenatal booking: Systematic review of controlled studies. BMJ 2005, 330, 565. [CrossRef] 18. Mayrink, J.; Souza, R.T.; Feitosa, F.E.; Filho, E.A.R.; Leite, D.F.; Vettorazzi, J.; Calderon, I.M.; Sousa, M.H.; Costa, M.L.; Baker, P.N.; et al. Incidence and risk factors for preeclampsia in a cohort of healthy nulliparous pregnant women: A nested case-control study. Sci. Rep. 2019, 9, 9517. [CrossRef] 19. Redman, C.W.; Sargent, I.L. Immunology of pre-eclampsia. Am. J. Reprod. Immunol. 2010, 63, 534–543. [CrossRef] 20. Bdolah, Y.; Elchalal, U.; Natanson-Yaron, S.; Yechiam, H.; Bdolah-Abram, T.; Greenfield, C.; Goldman-Wohl, D.; Milwidsky, A.; Rana, S.; Karumanchi, S.A.; et al. Relationship between nulliparity and preeclampsia may be explained by altered circulating soluble fms-like tyrosine kinase 1. Hypertens. Pregnancy 2014, 33, 250–259. [CrossRef] 21. Funai, E.F.; Paltiel, O.B.; Malaspina, D.; Friedlander, Y.; Deutsch, L.; Harlap, S. Risk factors for pre-eclampsia in nulliparous and parous women: The Jerusalem perinatal study. Paediatr. Perinat. Epidemiol. 2005, 19, 59–68. [CrossRef] Int. J. Environ. Res. Public Health 2023, 20, 2994 26 of 28 22. Roberts, J.M.; Bodnar, L.M.; Patrick, T.E.; Powers, R.W. The role of obesity in preeclampsia. Pregnancy Hypertens. 2011, 1, 6–16. [CrossRef] [PubMed] 23. Lopez-Jaramillo, P.; Barajas, J.; Rueda-Quijano, S.M.; Lopez-Lopez, C.; Felix, C. Obesity and preeclampsia: Common pathophysio- logical mechanisms. Front. Physiol. 2018, 9, 1838. [CrossRef] 24. Cincotta, R.B.; Brennecke, S.P. Family history of pre-eclampsia as a predictor for pre-eclampsia in primigravidas. Int. J. Gynaecol. Obstet. 1998, 60, 23–27. [CrossRef] [PubMed] 25. Boyd, H.A.; Tahir, H.; Wohlfahrt, J.; Melbye, M. Associations of personal and family preeclampsia history with the risk of early-, intermediate- and late-onset preeclampsia. Am. J. Epidemiol. 2013, 178, 1611–1619. [CrossRef] [PubMed] 26. Bergman, L.; Nordlöf-Callbo, P.; Wikström, A.K.; Snowden, J.M.; Hesselman, S.; Edstedt Bonamy, A.K.; Sandström, A. Multi-fetal pregnancy, preeclampsia, and long-term cardiovascular disease. Hypertension 2020, 76, 167–175. [CrossRef] 27. Battarbee, A.N.; Sinkey, R.G.; Harper, L.M.; Oparil, S.; Tita, A.T. Chronic hypertension in pregnancy. Am. J. Obstet. Gynecol. 2020, 222, 532–541. [CrossRef] 28. Weissgerber, T.L.; Mudd, L.M. Preeclampsia and diabetes. Curr. Diab. Rep. 2015, 15, 9. [CrossRef] 29. Jensen, D.M.; Damm, P.; Ovesen, P.; Mølsted-Pedersen, L.; Beck-Nielsen, H.; Westergaard, J.G.; Moeller, M.; Mathiesen, E.R. Microalbuminuria, preeclampsia, and preterm delivery in pregnant women with type 1 diabetes: Results from a nationwide Danish study. Diabetes Care 2010, 33, 90–94. [CrossRef] 30. Kattah, A. Preeclampsia and kidney disease: Deciphering cause and effect. Curr. Hypertens. Rep. 2020, 22, 91. [CrossRef] 31. Shetty, M.; Shetty, P.K.; Ramesh, A.; Thomas, B.; Prabhu, S.; Rao, A. Periodontal disease in pregnancy is a risk factor for preeclampsia. Acta Obstet. Gynecol. Scand. 2010, 89, 718–721. [CrossRef] 32. Palmsten, K.; Chambers, C.D.; Wells, A.; Bandoli, G. Patterns of prenatal antidepressant exposure and risk of preeclampsia and postpartum haemorrhage. Paediatr. Perinat. Epidemiol. 2020, 34, 597–606. [CrossRef] [PubMed] 33. Lokki, A.I.; Heikkinen-Eloranta, J.K.; Laivuori, H. The immunogenetic conundrum of preeclampsia. Front Immunol. 2018, 9, 2630. [CrossRef] [PubMed] 34. Hao, J.; Hassen, D.; Hao, Q.; Graham, J.; Paglia, M.J.; Brown, J.; Cooper, M.; Schlieder, V.; Snyder, S.R. Maternal and infant health care costs related to preeclampsia. Obstet. Gynecol. 2019, 134, 1227–1233. [CrossRef] 35. Stevens, W.; Shih, T.; Incerti, D.; Ton, T.G.; Lee, H.C.; Peneva, D.; Macones, G.A.; Sibai, B.M.; Jena, A.B. Short-term costs of preeclampsia to the United States health care system. Am. J. Obstet. Gynecol. 2017, 217, 237–248.e16. [CrossRef] [PubMed] 36. Fox, A.; McHugh, S.; Browne, J.; Kenny, L.C.; Fitzgerald, A.; Khashan, A.S.; Dempsey, E.; Fahy, C.; O’Neill, C.; Kearney, P.M. Estimating the cost of preeclampsia in the healthcare system: Cross-sectional study using data from SCOPE study (Screening for Pregnancy End Points). Hypertension 2017, 70, 1243–1249. [CrossRef] 37. Staff, A.C. The two-stage placental model of preeclampsia: An update. J. Reprod. Immunol. 2019, 134, 1–10. [CrossRef] 38. Sato, Y.; Fujiwara, H.; Konishi, I. Mechanism of maternal vascular remodeling during human pregnancy. Reprod. Med. Biol. 2012, 11, 27–36. [CrossRef] 39. Ridder, A.; Giorgione, V.; Khalil, A.; Thilaganathan, B. Preeclampsia: The relationship between uterine artery blood flow and trophoblast function. Int. J. Mol. Sci. 2019, 20, 3263. [CrossRef] 40. Roberts, J.M.; Gammill, H.S. Preeclampsia: Recent insights. Hypertension 2005, 46, 1243–1249. [CrossRef] 41. Lamarca, B. Endothelial dysfunction. An important mediator in the pathophysiology of hypertension during pre-eclampsia. Minerva Ginecol. 2012, 64, 309–320. 42. Boeldt, D.S.; Bird, I.M. Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia. J. Endocrinol. 2017, 232, R27–R44. [CrossRef] 43. Herse, F.; Dechend, R.; Harsem, N.K.; Wallukat, G.; Janke, J.; Qadri, F.; Hering, L.; Muller, D.N.; Luft, F.C.; Staff, A.C. Dysregulation of the circulating and tissue-based renin-angiotensin system in preeclampsia. Hypertension 2007, 49, 604–611. [CrossRef] 44. Irani, R.A.; Zhang, Y.; Zhou, C.C.; Blackwell, S.C.; Hicks, M.J.; Ramin, S.M.; Kellems, R.E.; Xia, Y. Autoantibody-mediated angiotensin receptor activation contributes to preeclampsia through tumor necrosis factor-alpha signaling. Hypertension 2010, 55, 1246–1253. [CrossRef] 45. Silva, B.R.; Pernomian, L.; Bendhack, L.M. Contribution of oxidative stress to endothelial dysfunction in hypertension. Front. Physiol. 2012, 3, 441. [CrossRef] 46. Schulz, E.; Gori, T.; Münzel, T. Oxidative stress and endothelial dysfunction in hypertension. Hypertens. Res. 2011, 34, 665–673. [CrossRef] 47. Acácio, G.L. Uterine artery Doppler patterns in abdominal pregnancy. Ultrasound Obstet. Gynecol. 2002, 20, 194–196. [CrossRef] 48. Kalafat, E.; Laoreti, A.; Khalil, A.; Da Silva Costa, F.; Thilaganathan, B. Ophthalmic artery Doppler for prediction of pre-eclampsia: Systematic review and meta-analysis. Ultrasound Obstet. Gynecol. 2018, 51, 731–737. [CrossRef] 49. Cipolla, M.J. The Cerebral Circulation; Morgan & Claypool Life Sciences: San Rafael, CA, USA, 2009. 50. Hammer, E.S.; Cipolla, M.J. Cerebrovascular dysfunction in preeclamptic pregnancies. Curr. Hypertens. Rep. 2015, 17, 64. [CrossRef] 51. Raschke, R. Cerebral perfusion pressure, and not cerebral blood flow, may be the critical determinant of intracranial injury in preeclampsia: A new hypothesis. Am. J. Obstet. Gynecol. 2003, 188, 860, author reply 860-1. [CrossRef] 52. Younes, S.T.; Ryan, M.J. Pathophysiology of cerebral vascular dysfunction in pregnancy-induced hypertension. Curr. Hypertens. Rep. 2019, 21, 52. [CrossRef] Int. J. Environ. Res. Public Health 2023, 20, 2994 27 of 28 53. Sonneveld, M.J.; Brussé, I.A.; Duvekot, J.J.; Steegers, E.A.; Grune, F.; Visser, G.H. Cerebral perfusion pressure in women with preeclampsia is elevated even after treatment of elevated blood pressure. Acta Obstet. Gynecol. Scand. 2014, 93, 508–511. [CrossRef] [PubMed] 54. Sibai, B.M.; Sarinoglu, C.; Mercer, B.M. Eclampsia: VII. Pregnancy outcome after eclampsia and long-term prognosis. Am. J. Obstet. Gynecol. 1992, 166, 1757–1763. 55. Hobson, E.V.; Craven, I.; Blank, S.C. Posterior reversible encephalopathy syndrome: A truly treatable neurologic illness. Perit. Dial. Int. 2012, 32, 590–594. [CrossRef] [PubMed] 56. McDermott, M.; Miller, E.C.; Rundek, T.; Hurn, P.D.; Bushnell, C.D. Preeclampsia: Association with posterior reversible encephalopathy syndrome and stroke. Stroke 2018, 49, 524–530. [CrossRef] [PubMed] 57. Bushnell, C.; Chireau, M. Preeclampsia and stroke: Risks during and after pregnancy. Stroke Res. Treat. 2011, 2011, 858134. [CrossRef] 58. Chen, C.W.; Jaffe, I.Z.; Karumanchi, S.A. Pre-eclampsia and cardiovascular disease. Cardiovasc. Res. 2014, 101, 579–586. [CrossRef] 59. Wu, P.; Haththotuwa, R.; Kwok, C.S.; Babu, A.; Kotronias, R.A.; Rushton, C.; Zaman, A.; Fryer, A.A.; Kadam, U.; Chew-Graham, C.A.; et al. Preeclampsia and future cardiovascular health: A systematic review and meta-analysis. Circ. Cardiovasc. Qual. Outcomes 2017, 10, e003497. [CrossRef] 60. Wojczakowski, W.; Kimber-Trojnar, Ż.; Dziwisz, F.; Słodzińska, M.; Słodziński, H.; Leszczyńska-Gorzelak, B. Preeclampsia and cardiovascular risk for offspring. J. Clin. Med. 2021, 10, 3154. [CrossRef] 61. Benschop, L.; Duvekot, J.J.; Roeters van Lennep, J.E. Future risk of cardiovascular disease risk factors and events in women after a hypertensive disorder of pregnancy. Heart 2019, 105, 1273–1278. [CrossRef] 62. Hammoud, G.M.; Ibdah, J.A. Preeclampsia-induced liver dysfunction, HELLP syndrome, and acute fatty liver of pregnancy. Clin. Liver Dis. 2014, 4, 69–73. [CrossRef] 63. Rahman, T.M.; Wendon, J. Severe hepatic dysfunction in pregnancy. Qjm 2002, 95, 343–357. [CrossRef] 64. Shekhar, S.; Diddi, G. Liver disease in pregnancy. Taiwan. J. Obstet. Gynecol. 2015, 54, 475–482. [CrossRef] 65. Van der Graaf, A.M.; Toering, T.J.; Faas, M.M.; Titia Lely, A. From preeclampsia to renal disease: A role of angiogenic factors and the renin-angiotensin aldosterone system? Nephrol. Dial. Transplant. 2012, 27 (Suppl. 3), iii51–iii57. [CrossRef] 66. Irani, R.A.; Xia, Y. The functional role of the renin-angiotensin system in pregnancy and preeclampsia. Placenta 2008, 29, 763–771. [CrossRef] 67. Stillman, I.E.; Karumanchi, S.A. The glomerular injury of preeclampsia. J. Am. Soc. Nephrol. 2007, 18, 2281–2284. [CrossRef] 68. Szczepanski, J.; Griffin, A.; Novotny, S.; Wallace, K. Acute kidney injury in pregnancies complicated with preeclampsia or HELLP syndrome. Front Med. 2020, 7, 22. [CrossRef] 69. Kristensen, J.H.; Basit, S.; Wohlfahrt, J.; Damholt, M.B.; Boyd, H.A. Pre-eclampsia and risk of later kidney disease: Nationwide cohort study. Bmj 2019, 365, l1516. [CrossRef] 70. Jhajharia, N.; Verma, M. Hematological changes in pregnancy induced hypertension in their third trimester at Jhalawar Medical College, Jhalawar, India. Int. J. Reprod. Contracept. Obstet. Gynecol. 2019, 8, 3497–3502. [CrossRef] 71. Paidas, M.J.; Hossain, N. Hematologic changes in pregnancy. In Hemostasis and Thrombosis in Obstetrics & Gynecology; Wiley- Blackwell: Hoboken, NJ, USA, 2010; pp. 1–11. 72. Elgari, M.M.; Khabour, O.F.; Alhag, S.M. Correlations between changes in hematological indices of mothers with preeclampsia and umbilical cord blood of newborns. Clin. Exp. Hypertens. 2019, 41, 58–61. [CrossRef] 73. Barton, J.R.; Sibai, B.M. Gastrointestinal complications of pre-eclampsia. Semin. Perinatol. 2009, 33, 179–188. [CrossRef] 74. Kaur, H.; Kolli, M. Acute pulmonary edema in pregnancy—Fluid overload or atypical pre-eclampsia. Cureus 2021, 13, e19305. [CrossRef] [PubMed] 75. Voelker, L.; Gemeda, M. Comparison of FMF and NICE Algorithms in Early Preeclampsia Screening at 11–13 Weeks Gestation —2019. Available online: https://core.ac.uk/download/pdf/224997877.pdf (accessed on 1 November 2022). 76. Paez Espinosa, E.V.; Murad, J.P.; Khasawneh, F.T. Aspirin: Pharmacology and clinical applications. Thrombosis 2012, 2012, 173124. [CrossRef] [PubMed] 77. Lim, S.; Li, W.; Kemper, J.; Nguyen, A.; Mol, B.W.; Reddy, M. Biomarkers and the prediction of adverse outcomes in preeclampsia: A systematic review and meta-analysis. Obstet. Gynecol. 2021, 137, 72–81. [CrossRef] [PubMed] 78. Antwi, E.; Amoakoh-Coleman, M.; Vieira, D.L.; Madhavaram, S.; Koram, K.A.; Grobbee, D.E.; Agyepong, I.A.; Klipstein- Grobusch, K. Systematic review of prediction models for gestational hypertension and preeclampsia. PLoS ONE 2020, 15, e0230955. [CrossRef] 79. Rolnik, D.L.; Nicolaides, K.H.; Poon, L.C. Prevention of preeclampsia with aspirin. Am. J. Obstet. Gynecol. 2022, 226, S1108–S1119. [CrossRef] 80. Rahnemaei, F.A.; Fashami, M.A.; Abdi, F.; Abbasi, M. Factors effective in the prevention of preeclampsia: A systematic review. Taiwan. J. Obstet. Gynecol. 2020, 59, 173–182. [CrossRef] 81. Roberge, S.; Bujold, E.; Nicolaides, K.H. Aspirin for the prevention of preterm and term preeclampsia: Systematic review and metaanalysis. Am. J. Obstet. Gynecol. 2018, 218, 287–293. [CrossRef] 82. Davidson, K.W.; Barry, M.J.; Mangione, C.M.; Cabana, M.; Caughey, A.B.; Davis, E.M.; Donahue, K.E.; Doubeni, C.A.; Kubik, M.; Li, L.; et al. Aspirin use to prevent preeclampsia and related morbidity and mortality: US Preventive Services Task Force recommendation statement. JAMA 2021, 326, 1186–1191. Int. J. Environ. Res. Public Health 2023, 20, 2994 28 of 28 83. Podymow, T.; August, P. Update on the use of antihypertensive drugs in pregnancy. Hypertension 2008, 51, 960–969. [CrossRef] 84. MacCarthy, E.P.; Bloomfield, S.S. Labetalol: A review of its pharmacology, pharmacokinetics, clinical uses and adverse effects. Pharmacotherapy 1983, 3, 193–219. [CrossRef] 85. Bone, J.N.; Sandhu, A.; Abalos, E.D.; Khalil, A.; Singer, J.; Prasad, S.; Omar, S.; Vidler, M.; von Dadelszen, P.; Magee, L.A. Oral antihypertensives for nonsevere pregnancy hypertension: Systematic review, network meta- and trial sequential analyses. Hypertension 2022, 79, 614–628. [CrossRef] 86. Odigboegwu, O.; Pan, L.J.; Chatterjee, P. Use of antihypertensive drugs during preeclampsia. Front. Cardiovasc. Med. 2018, 5, 50. [CrossRef] 87. National Institute of Child Health and Human Development. Hydralazine. In Drugs and Lactation Database (LactMed); National Institute of Child Health and Human Development: Bethesda, MD, USA, 2006; pp. 1–2. 88. Aali, B.S.; Nejad, S.S. Nifedipine or hydralazine as a first-line agent to control hypertension in severe preeclampsia. Acta Obstet. Gynecol. Scand. 2002, 81, 25–30. [CrossRef] 89. Haft, J.I. Use of the calcium-channel blocker nifedipine in the management of hypertensive emergency. Am. J. Emerg. Med. 1985, 3 (Suppl. 6), 25–30. [CrossRef] 90. Ferguson, J.E., 2nd; Schutz, T.; Pershe, R.; Stevenson, D.K.; Blaschke, T. Nifedipine pharmacokinetics during preterm labor tocolysis. Am. J. Obstet. Gynecol. 1989, 161, 1485–1490. [CrossRef] 91. Euser, A.G.; Cipolla, M.J. Magnesium sulfate for the treatment of eclampsia: A brief review. Stroke 2009, 40, 1169–1175. [CrossRef] 92. Sadeh, M. Action of magnesium sulfate in the treatment of preeclampsia-eclampsia. Stroke 1989, 20, 1273–1275. [CrossRef] 93. Fawcett, W.J.; Haxby, E.J.; Male, D.A. Magnesium: Physiology and pharmacology. Br. J. Anaesth. 1999, 83, 302–320. [CrossRef] 94. Chappell, L.C.; Brocklehurst, P.; Green, M.E.; Hunter, R.; Hardy, P.; Juszczak, E.; Linsell, L.; Chiocchia, V.; Greenland, M.; Placzek, A.; et al. Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): A randomised controlled trial. Lancet 2019, 394, 1181–1190. [CrossRef] 95. Smith, J.M.; Lowe, R.F.; Fullerton, J.; Currie, S.M.; Harris, L.; Felker-Kantor, E. An integrative review of the side effects related to the use of magnesium sulfate for pre-eclampsia and eclampsia management. BMC Pregnancy Childbirth 2013, 13, 34. [CrossRef] 96. Guida, J.P.; Surita, F.G.; Parpinelli, M.A.; Costa, M.L. Preterm preeclampsia and timing of delivery: A systematic literature review. Rev. Bras. Ginecol. Obstet. 2017, 39, 622–631. [CrossRef] [PubMed] 97. Espinoza, J.; Vidaeff, A.; Pettker, C.M.; Simhan, H. Gestational hypertension and preeclampsia: ACOG practice bulletin, number 222. Obstet. Gynecol. 2020, 135, E237–E260. 98. Pretorius, T.; Van Rensburg, G.; Dyer, R.A.; Biccard, B.M. The influence of fluid management on outcomes in preeclampsia: A systematic review and meta-analysis. Int. J. Obstet. Anesth. 2018, 34, 85–95. [CrossRef] [PubMed] 99. Perry, A.; Stephanou, A.; Rayman, M.P. Dietary factors that affect the risk of pre-eclampsia. BMJ Nutr. Prev. Health 2022, 5, 118–133. [CrossRef] 100. Minhas, A.S.; Hong, X.; Wang, G.; Rhee, D.K.; Liu, T.; Zhang, M.; Michos, E.D.; Wang, X.; Mueller, N.T. Mediterranean-style diet and risk of preeclampsia by race in the Boston birth cohort. J. Am. Heart Assoc. 2022, 11, e022589. [CrossRef] 101. Genest, D.S.; Falcao, S.; Gutkowska, J.; Lavoie, J.L. Impact of exercise training on preeclampsia: Potential preventive mechanisms. Hypertension 2012, 60, 1104–1109. [CrossRef] 102. Magro-Malosso, E.R.; Saccone, G.; Di Tommaso, M.; Roman, A.; Berghella, V. Exercise during pregnancy and risk of gestational hypertensive disorders: A systematic review and meta-analysis. Acta Obstet. Gynecol. Scand. 2017, 96, 921–931. [CrossRef] 103. Witvrouwen, I.; Mannaerts, D.; Van Berendoncks, A.M.; Jacquemyn, Y.; Van Craenenbroeck, E.M. The effect of exercise training during pregnancy to improve maternal vascular health: Focus on gestational hypertensive disorders. Front. Physiol. 2020, 11, 450. [CrossRef] Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.