Prevention and Treatment of Preeclampsia

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1		Agata M. Sakowicz	--	4595	2023-10-18 20:39:31

This entry is adapted from the peer-reviewed paper 10.3390/ijms241512100

Preeclampsia (PE) is a pregnancy-specific disorder affecting 4–10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main symptoms generally appear after week 20 of gestation, scientific studies indicate that the mechanism underpinning PE is initiated at the beginning of gestation. It is known that the pathomechanism of preeclampsia is strongly related to inflammation and oxidative stress, which influence placentation and provoke endothelial dysfunction in the mother.

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1. Introduction

The second most common disease associated with the gestation period, recognised in 4–10% of all pregnant women, is preeclampsia (PE) ^[1]. It generally manifests as the sudden occurrence of high blood pressure (>140/90 mmHg) accompanied by proteinuria developing after week twenty of gestation. However, proteinuria is not required to indicate preeclampsia; it is sufficient for hypertension to be present in previously normotensive women, complicated by at least one of the symptoms indicating an organ dysfunction. Although obstetrical and gynaecological societies share the common view that the appearance of organ dysfunction should be included in the diagnostic criteria of PE, individual organisations recommend different definitions of organ dysfunction. More specifically, renal dysfunction can be indicated by serum creatinine concentration >1 mg/dL or >1.1 mg/dL; liver dysfunction by transaminase levels elevated twofold over the reference range or ≥40 IU/L; haematological disorders by blood platelet levels <100,000/µL or <150,000/µL; or haemolysis. In addition, neurological disorders indicated by cerebral stroke, altered mental status, visual symptoms or severe headache with hyperreflexia, or other clinical symptoms such as uteroplacental dysfunction or pulmonary oedema are included in diagnostics criteria ^[2]. In addition, preeclampsia is also associated with certain risk factors that differ between cases with the early-onset form, i.e., before week 34 of gestation, and the late-onset occurring after week 34 of gestation ^[3]. Among these risk factors, those associated with inflammation are also common, i.e., chronic hypertension, diabetes mellitus, renal disease, autoimmunological disorders, or obesity ^[4].

2. The Possible Pathomechanism of Preeclampsia

It is believed that preeclampsia is mainly caused by the improper formation of the placenta at the beginning of pregnancy, i.e., several weeks before the manifestation of the first clinical symptoms.

Each gestation begins with an inflammatory reaction that develops in the maternal uterus before fertilisation. An increase in the activation of the nuclear factor kappa B (NFĸB) transcription factor in endometrial cells is already observed at the proliferative phase of the menstrual cycle ^[5]. This factor is known to regulate the expression of more than 400 genes including those related to inflammation (e.g., tumour necrosis factor alpha (TNFα), Interleukin 1, 6, 8 (IL1, IL6, IL8), or cyclooxygenase 2 (COX2)), antigen presentation (e.g., complement components B, C3, or C4), extracellular matrix degradation (e.g., metalloproteinases MMP1, MMP3, or MMP9), angiogenesis or apoptosis (e.g., p53, or proapoptotic Bcl-2 homologue (Bax)) ^[6]^[7]^[8]^[9]. Therefore, it is believed that NFĸB might play a critical role in preparing maternal tissues for the implantation, invasion of trophoblastic cells into the maternal decidua, and the transformation of maternal spiral arteries into wide and low-resistance vessels. However, in PE, the excessive activation of NFĸB augments the inflammatory reaction in the uterus; this disturbs the communication at the maternal–foetal interface, thus preventing correct placentation and maternal vessel remodelling. The levels of free radicals, inflammatory factors, including TNFα and IL6, as well as thromboxane 2, a product of arachidonic acid (AA) degradation by cyclooxygenases (COX), increase in maternal blood ^[10]^[11]. Moreover, the serum of preeclamptic mothers exhibits strong activation of the complement system, manifested as elevated C3a and C5a factors ^[12]. Under inflammatory conditions, the complement components, i.e., C1q, C4d, and the receptor for C5a, are diffused across the preeclamptic placentas ^[13]^[14]^[15]^[16]^[17]. Additionally, the incorrect remodelling of uterine vessels starves the placental cells of nutrients and oxygen, and so the cells start to secrete placental factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) or soluble endoglin (sEng) into the maternal circulation ^[18]. These factors slow the process of angiogenesis and augment systemic inflammation and exacerbate maternal endothelium dysfunction. Moreover, sFlt-1 has been found to reduce the bioavailability of vasodilatory nitric oxide (NO) and increase the sensitivity of the endothelial cells to proinflammatory factors present in the maternal circulation ^[19]^[20]. These dysfunctions interfere with the mechanisms regulating blood pressure, exacerbating maternal hypertension and thus preeclampsia.

3. The Preventive and Therapeutic Strategies Recommended by Obstetricians and Gynaecological Societies

Among the drugs recommended by obstetrical and gynaecological societies, aspirin (ASA) seems to be the most efficient for preventing preeclampsia, with data indicating around a 60% reduction in risk ^[21]. However, this drug is recommended only for high-risk groups, and its effectiveness depends on the time of starting therapy. Indeed, supplementation must begin before week sixteen of gestation; after this time, it has a less positive influence on gestation or can even increase the risk of an adverse outcome ^[21]^[22]^[23].

It is currently a mystery why starting aspirin supplementation after week sixteen is ineffective; it is also unknown which molecular pathways involved in the pathomechanism of PE are controlled by this agent.

ASA is mostly known as an inhibitor of arachidonic acid (AA) metabolism. It irreversibly blocks the activity of cyclooxygenase 1 and 2 (COX1, COX2) by acetylation, thus preventing the degradation of AA into prostaglandins (e.g., thromboxane and prostacyclin) ^[24]. Interestingly, some studies indicate that supplementation with low-dose ASA during pregnancy selectively blocks the production of proinflammatory thromboxane but not prostacyclin (PGI₂), which is known for its vasodilatory action ^[25]. This anti-inflammatory activity may be supported by its ability to inhibit NFĸB activation and nuclear translocation in maternal and placental cells. ASA also influences the phosphorylation and further degradation of IĸBα, one of the most common inhibitors of nuclear factor kappa B ^[26]^[27]. It is possible that these mechanisms may be of particular importance at the beginning of a preeclamptic gestation, in which the excessive inflammatory reaction might disturb the cross-talk between the maternal and foetal sides. However, when the process of placentation is completed, and other pathways start to dominate in maternal and trophoblastic cells, ASA might be not sufficient to reduce the inflammatory reaction.

Although it is able to regulate vasoconstriction by activating endothelial synthase of nitric oxide (eNOS), and inhibit apoptosis by acetylating p53 protein, it is not able to counter the problems associated with preeclamptic gestation ^[28]^[29]. As such, the initiation of ASA treatment after week 16 of pregnancy is ineffective.

Although various gynaecological and obstetrical societies advise the use of ASA as a prophylactic for PE, the recommended dosage in not consistent. The World Health Organisation (WHO) advises a minimal dose of 75 mg per day for high-risk women whereas other societies such as the International Society for the Study of Hypertension in Pregnancy (ISSHP) recommends higher doses, even up to 162 mg/day; similarly, the week of gestation reserved for initiation of treatment ranges from 11 to 20, with the optimum below week 16 of gestation ^[27].

Although all drugs used to treat preeclampsia are believed to counter high blood pressure, i.e., the main symptom of preeclampsia, their mechanism of action extends much further.

One of the most common antihypertensive drugs used to treat of preeclampsia is methyldopa. It acts as an agonist of α2-adrenergic receptors localised in the presynaptic space and inhibits the sympathetic system by controlling the release of norepinephrine from neurons. This medication substitutes for dihydroxyphenylalanine in the biosynthesis of neurotransmitters such as dopamine, norepinephrine, or epinephrine, and influences the production of their inactive forms. This impairs the signalling pathway from the baroreceptors, thus altering blood pressure ^[30]. Some studies indicate that methyldopa is implicated in the modulation of intracellular messengers including cyclic adenosine monophosphate (cAMP), known as a stronger inducer of Flt1 expression ^[31]. This might explain why methyldopa treatment inhibits the secretion of sFlt1 by the endothelial and placental cells after initiation, as observed in case–control and in vitro studies ^[31]^[32]^[33]^[34].

Interestingly, methyldopa also exerted a positive influence on endothelial cells by significantly increasing vascular endothelial growth factor (VEGF) production in the cell culture medium ^[32]. However, this effect was not observed in pregnant women; in fact, preeclamptic patients treated with methyldopa demonstrated significantly lower VEGF levels after 48 h from supplementation compared to the period before the initiation of treatment. The decrease in VEGF concentration was also dependent on the dose of methyldopa ^[35].

Another common drug used for reduction of high blood pressure in pregnancy is hydralazine, which was found to reduce VEGF levels in human umbilical vein endothelial cell (HUVEC) culture, thus negatively influencing the process of angiogenesis, migration, and proliferation in culture cells ^[36]. This mode of action was not observed in vivo. The intravenous infusion of hydralazine into mice significantly improved drug-mediated vasodilation, vascular tone, blood flow, and tissue perfusion. This rapid reaction occurred together with the acute induction of hypoxia factor type 1 alpha (HIF-1α) in the organs of the treated mice. In addition, the elevation of HIF-1α was accompanied by an increase in VEGF levels in both the serum and tissues isolated from animals ^[37]. It is therefore possible that in addition to the direct influx of the drug on the relaxation of arterial smooth muscle, the improvement in blood pressure parameters observed in preeclamptic women after hydralazine infusion may be due to the regulation of intracellular HIF-1α-dependent pathways, including those associated with VEGF production.

Like methyldopa, hydralazine is also implicated in the regulation of sFlt1: it appears to reduce the production of sFlt1 and significantly increase the integration of trophoblastic cells (i.e., HTR8/SVneo cells) into the endothelial cells in preeclamptic environment (i.e., rich in TNFα factor) ^[32]^[38]. Additionally, hydralazine also appears to regulate the inflammatory reaction; high doses reduce the production of IL6 and TNFα in placental explants as well as in peripheral blood mononuclear cells (PBMC) ^[39]^[40]. Low doses stimulate IL10 production in PBMCs, which is important for correct gestation, and is depleted in preeclamptic pregnancies ^[39]^[40]. Moreover, studies on animal models indicate that hydralazine improves neovasculargenesis and inhibits the production of reactive oxygen species (ROS) in endothelial cells ^[41].

Nifedipine, the next most common agent recommended by obstetrical and gynaecological societies as the first-line drug for treatment of preeclampsia also manifests a number of activities that go beyond the regulation of blood pressure. Similar to hydralazine, this agent is believed to reduce ROS levels and inhibit the expression of various compounds, including metalloproteinase 13 (MMP13), IL1β, IL6, TNFα, and cyclooxygenase 2 (COX-2) ^[42]. Many of these factors have been implicated in the pathomechanism of preeclampsia, and all of them are under the control of NFĸB. Indeed, some studies suggest that nifedipine realises its anti-inflammatory functions via the regulation of the NFĸB activation pathway ^[43]^[44]. It has been suggested that the drug inhibits the phosphorylation of inhibitor of nuclear factor kappa B (i.e., IĸBα), thus preventing the translocation of NFĸB from the cytoplasm to the nucleus. When present at low levels in the nucleus, it is not possible for NFĸB to regulate its target genes ^[27]^[45]. This may also explain why nifedipine supplementation appears to reduce the expression of the adhesion molecules, i.e., intracellular adhesion molecules 1 (ICAM-1) or selectin E (SelE) ^[46]. Both particles are under the control of NFĸB and both are significantly exposed on the endothelial cells in the conditions of high levels in inflammatory (e.g., TNFα or IL6) and placental factors (e.g., sFlt1 or sENG), as well as “placental debris”, i.e., in the environment typical for preeclampsia ^[27]. Moreover, hydralazine treatment benefits patients with hypertension by ameliorating angiogenesis and increasing the bioavailability of nitric oxide ^[47]^[48]^[49].

Another drug recommended by obstetrician and gynaecological societies for first-line treatment of both mild (i.e., >140/90 mmHg) and severe (i.e., >160/110 mmHg) hypertension is the β-blocker labetalol ^[50]. This may also increase the accessibility of nitric oxide to the endothelial cells. An in vitro study found this drug to counteract inhibition of eNOS expression by TNFα, at the mRNA level, in human uterine microvascular endothelial cells ^[34]. Moreover, labetalol inhibits superoxide production: labetalol reduced ROS levels in both human and rabbits three hours from injection ^[51]. Other beta-blockers accepted for the treatment of pregnancy hypertension, e.g., esmolol, also demonstrate antioxidant activity by inhibiting superoxide generation ^[52]^[53]. Moreover some beta blockers influence the arachidonic acid metabolism, reducing platelet aggregation and thromboxane generation; both processes are linked to the progression of preeclampsia ^[53]^[54]^[55].

The drugs recommended by obstetrical and gynaecological societies for preeclampsia treatment are known to present broad mechanisms of action, i.e., reducing high blood pressure and improving inflammation and oxidative stress, and ameliorating both maternal endothelial cell and placental dysfunction; however, it remains unclear why the therapy confers no clear benefits to pregnant women, and why only “cure” for preeclampsia is delivery, often prematurely ^[56]. It is highly probable that the time of application with regard to week of gestation makes a difference; also, the period of exposure to the antihypertensive drugs may be too short to activate their additional mechanisms of action to benefit the patient. Indeed, the clinical symptoms of preeclampsia occur suddenly when the maternal compensative mechanism fails. At this stage of the disease, serious structural and metabolic changes in placental and maternal endothelial cells have already occurred. The maternal storm of cytokines and ROS is too great to be inhibited by drugs that possess only mild anti-inflammatory or antioxidant properties as side effects: the concentrations of the placental factors, e.g., sFlt1 and sENG in the maternal bloodstream are too high for them to be scavenged or neutralised by antihypertensive agents alone. As a result, the destruction of maternal vascular endothelial and glomerular filtration barriers continues, exacerbating the symptoms of disease and threatening maternal and foetal life.

Therefore, there is a need to identify new preventive agents and drugs precisely focused on elimination at least one factor provoking the development or progress of preeclampsia. The mechanism of action of these drugs should not only focus on countering the factors impairing the metabolism of endothelial cells, but also treating, or preventing, the pathological mechanisms localised in the endothelial and placental cells. They should also aim to ameliorate the systemic inflammation and oxidative stress experienced by pregnant preeclamptic women.

4. Novel Therapies for the Prevention and Treatment of Preeclampsia

4.1. Statins—The Old Friends of the Cardiovascular System Offering New Perspectives in Preventing Preeclampsia

Statins inhibit Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase; an enzyme implicated in the biosynthesis of cholesterol in liver cells. Following oral administration, statins are rapidly absorbed and linked to the serum protein, and then their further metabolism depends on their physical properties, i.e., hydrophilic statins require active transport whereas lipophilic agents undergo passive diffusion through the cellular membrane of liver cells. They downregulate the level of intrahepatic cholesterol, improving the systemic expression of receptors for low-density lipoproteins (LDL), thus lowering the level of lipids in the bloodstream ^[57]. However, statins offer other clinical benefits to patients than just reducing lipoprotein levels.

Statins are implicated in the regulation of inflammation, whose exacerbation is believed to play a role in preeclampsia development. The drugs lower the levels of C-reactive protein, and this mode of action is independent of their ability to inhibit HMG-CoA reductase activity ^[57]. In vitro studies indicate that statins may block the secretion of proinflammatory cytokines and prevent to the differentiation of T lymphocytes into the Th1 subfraction, as observed in cells exposed to lipopolysaccharide (LPS), i.e., a strong activator of NFĸB ^[58]. Indeed, statins can inhibit NFĸB activation by different mechanisms, either dependent on or independent of lipid metabolism.

Statin treatment led to a reduction in LDL level, resulting in a depletion of their oxidative forms (oxy-LDL), these being strong stimulators of Toll-like receptors (TLRs); TLR signalling is one of the most important mechanisms that elevate IL6 and TNFα levels following increased NFĸB transcriptional activity ^[59]. Statins were also known to block the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IĸBα) in the proteasome, thus resulting in its further degradation. The inactive form of IĸBα remains linked to the NFĸB in the cytoplasm, thus making the NFĸB unable to migrate into the nucleus, where it regulates gene expression via its binding motif element on DNA ^[60]. Additionally, statins inhibit the mechanism of NFĸB activation by blocking phosphatidylinositol 3-kinase (PI3k)/kinase protein B (Akt) signalling. This pathway is activated in endothelial cells in response to TNFα stimulation ^[61]. It has also been Implicated in the generation of ROSIch, Iike inflammatory factors, have been involved in the pathomechanism of preeclampsia ^[62]^[63].

There is growing evidence that statin therapy influences the secretion of sFlt1 and sENG particles from primary trophoblast and placental cells living under unfavourable conditions ^[64]^[65]. This action has been observed both in vitro and in vivo. Indeed, studies based on various mouse and rat preeclamptic models indicate that animals treated by pravastatin demonstrated a depletion in sFlt1 and/or sENG factors ^[66]^[67]^[68]^[69]. This mechanisms might be dependent on the HMG-CoA reductase pathway ^[70] or it might be connected to the ability of statins to elevate haem oxygenase 1 (HO1) level, which is suppressed in the blood of preeclamptic mothers ^[71]. Both sFlt1 and sENG act as the soluble forms of receptors for PlGF, VEGF, or TGFβ in the bloodstream, thus preventing them from binding to the receptors localised on the cells ^[72] and disturbing the cellular processes regulated by PlGF, VEGF, or TGFβ. This results in endothelial damage, inhibits angiogenesis and impairs the process of vasodilatation ^[65]. Indeed, the endothelial damage is linked to the downregulation of endothelial nitric oxide synthase (eNOS) production, leading to a reduction in nitric oxide (NO) level, increased vasoconstriction and the development of hypertension.

Surprisingly, statins exert a beneficial influence on the endothelial cells, even in advances stages of dysfunction. They most likely upregulate the expression of eNOS by the PI3k/Akt mechanism or by the upregulation of haem oxygenase 1 level; this most likely facilitates their ability to elevate NO level and vessel relaxation ^[73]^[74]. At present (June 2023), a few studies evaluating the use of statins (i.e., pravastatin, rosuvastatin and atorvastatin) in the preeclamptic population are registered in the clinicaltrials.gov database, and three of them are still in progress (i.e., NCT04303806, NCT01717586, NCT03944512).

Although statins have been found to have a positive influence on reducing the risk of preeclampsia, or stabilizing its clinical features, the American Food and Drug Administration (FDA) still does not recommend the use of these drugs for all pregnant women. Statins reduce cholesterol levels, depleting its accessibility to the developing foetus and thus elevating the risk of miscarriages or foetal congenital defects. Indeed, supplementation of pregnant animals with the supraphysiologic doses of statins has been found to have a teratogenic effect on the foetuses ^[75]. Additionally, statin treatment has been found to impair gestational outcomes ^[76]^[77]. However, these initial concerns were not confirmed in recent animal and clinical trials, and in July 2021, the FDA allowed the use of statins during pregnancy but only in certain cases: among women with familiar hypercholesterolemia, those suffering from severed LDL cholesterol level, those with cardiovascular diseases, or in cases where the benefits are judged to outweigh any risk ^[78].

4.2. Anti-Inflammatory Agents in the Treatment of Preeclampsia

Placental cells expose the proteins CD55 and CD59 on their surface-inhibiting complement factors to regulate maternal immunological tolerance to the developing semi-allogenic foetus ^[79]. The strength of this exposure seems to be inflammation dependent. Preeclamptic placentas exhibit twofold and fourfold upregulation of genes coding for CD55 and CD59, respectively, suggesting that placental cells may attempt to compensate for the excessive reactivity of the maternal complement system ^[15], characterised by elevated C3a and C5a components in preeclamptic maternal plasma ^[12].

Additionally, immunohistochemical studies indicate that preeclamptic placentas demonstrate elevated deposition of the C4d complement and the receptor for the C5a complement (C5aR) ^[14]^[15]. The activation of the placental C5a/C5aR pathway results in placental dysfunction; in vitro studies indicate that complement C5a can inhibit angiogenesis and trophoblastic cell migration (i.e., HTR8/SVneo) ^[14]. Similarly, studies on tissues obtained from rats and mouse models of preeclampsia confirm strong activation of the complement system in preeclampsia, with increased expression of C3 complement factor observed in the vessels and placentas. Moreover, in mice, augmented generation of C5a complement factor was associated with impaired angiogenesis and VEGF production, and overexpression of sFlt1 by placental cells ^[80]. These findings suggest that the blockade of the complement system, leading to the inhibition of inflammation, might be an effective method for mitigating the symptoms of preeclampsia.

Eculizumab (Soliris) is a humanised monoclonal antibody class (Ig)G2/4 kappa that binds to the C5 complement. It inhibits the cleavage of C5 into its active forms, i.e., C5a and C5b, and hence it is believed that it might help the preeclamptic mother and foetus by silencing inflammation. Generally, this drug offers benefits for patients suffering from paroxysmal nocturnal haemoglobinuria, atypical haemolytic uremic syndrome, and other autoimmunological diseases that can lead to PE, such as antiphospholipid syndrome or lupus erythematosus: dysregulation of the complement system is a typical sign of PE ^[81]^[82]^[83]^[84]^[85].

Although it is well established that complement system is dysregulated in preeclampsia, little information exists about the beneficial effect of use of this drug in pregnant women. Some studies indicate that this drug is well tolerated and has a low potential to cross the placental barrier or to appear in maternal milk ^[86]. While eculizumab is generally not detected in the new-borns of mothers treated during pregnancy ^[87], supplementation of pregnant animals by two-to-eight times the standard dose of an analogous drug (Soliris) resulted in in an increased rate of developmental abnormities or foetal death; as such, the FDA awarded the drug a category C for pregnancy, i.e., it is allowed for use in pregnancy if the potential benefit justifies the potential risk to the foetus ^[88].

Therefore, the first reports concerning the use of eculizumab for preeclampsia treatment are based on cases suffering from other diseases coincident to preeclampsia, e.g., thrombotic microangiopathy (TMA) or antiphospholipid syndrome. These studies found that eculizumab can extend the time of gestation, which is especially important for women who develop early onset preeclampsia. Indeed, Soliris treatment extended gestation for another 17 days in women with TMA who developed the HELLP syndrome (i.e., H—haemolysis; EL—elevated liver enzymes level; LP—low platelets) at week 26 of gestation ^[89]. Eculizumab was found to have similar effects in other cases presenting preeclamptic symptoms between weeks 27 and 28 of gestation and additionally suffering from TMA or antiphospholytic syndrome ^[90]. At present, Soliris is in the second clinical trial phase (NCT04725812) to confirm its ability prolong pregnancy complicated between weeks 23 and 30 by preeclampsia.

Another candidate drug for the prevention of preeclampsia is etanercept, a TNFα inhibitor consisting of a complex of the extracellular fragment of the TNFα receptor with the Fc fragment of the human IgG antibody; this has offered promise in in vitro studies and animal preeclampsia-like models. Preeclampsia is strongly linked to the elevation of TNFα in maternal plasma. The administration of TNFα to pregnant animals increases the levels of placental factors, e.g., sFlt1 or sENG, in the blood and stimulates the maternal organism to produce autoantibodies against angiotensin II type I receptors (AT1-AA), which promotes placental insufficiency, renal damage, and maternal endothelial dysfunction ^[91]^[92]. The blockade of TNFα by etanercept in a stroke-prone spontaneously hypertensive rat (SPHSR) model improved the maternal blood pressure and function of the uterine artery, thus improving pregnancy ^[93].

Etanercept was also found to positively regulate blood pressure in a RUPP rat model of preeclampsia and additionally improve natural killer cell activation in maternal blood and placental samples ^[94]. Administration of etanercept also lowered the levels of circulating sFlt1 and ROS in placentas in an RUPP rat model of PE ^[95]^[96].

However, both animal and human studies indicate that this agent undergoes transplacental transmission and thus may influence foetal development ^[97]^[98]. Indeed, both the placentas and offspring of rats treated with etanercept presented some defects, i.e., the reduction in weight, visceral or skeletal abnormalities, and depletion of the area of the placental junctional zone in comparison to controls ^[99]. In humans, etanercept has been used to treat autoimmunological diseases even in gestation, resulting in significant decreases in placental–maternal ratio ^[98]; moreover, anti-TNFα therapy entailed a reduction in new-born weight and increased the risk of preterm bright and caesarean section ^[100].

The data regarding the influence of etanercept on blood pressure in mothers at high risk of preeclampsia suffering from autoimmunological diseases are also not consistent. Some randomised trials indicate that women treated with etanercept for immune diseases (a risk factor of PE) to the end of week 10 of gestation experience a lower risk of pregnancies complicated by hypertension than a placebo group ^[101]; however, other studies indicate no significant differences between exposed and nonexposed groups ^[102]. Additionally, some scientific reports suggest that therapy targeting TNFα might increase the risk of preeclampsia development in the population of treated women due to autoimmunological diseases ^[103]^[104]. However, none of these studies examined the influence of etanercept on the treatment of preeclampsia. Therefore, further clinical trials are warranted to determine whether inhibitors of TNFα might be use for the treatment or prolongation of gestation of women presenting the clinical symptoms of preeclampsia.

Sulfasalazine is an anti-inflammatory and antioxidant drug adopted for treatment of autoimmune bowel disease or rheumatoid arthritis. It is believed to be a potent inhibitor of NFĸB nuclear translocation. An in vitro study on SW620 human colonic epithelial cells previously stimulated by TNFα, i.e., a strong activator of NFĸB, found similar cytoplasmic NFĸB levels between cells treated with sulfasalazine and unstimulated controls. This may be the route by which the drug inhibits phosphorylation and thus degrades NFĸB inhibitors ^[105]^[106]. In consequence, the transcriptional activity of factor kappa B is suppressed, downregulating the expression of genes coding for inflammatory agents such as IL1β, IL6, IL8, or TNFα ^[107].

The ability of sulfasalazine to inhibit NFĸB activity, and thus the levels of inflammatory factors, make it a strong candidate for treating preeclampsia. This drug reduces high blood pressure in pregnant mice developing preeclampsia caused by injection of a nitric oxide synthase antagonist, i.e., L-NAME ^[108]. This suggests that sulfasalazine may prevent the endothelial dysfunction least by upregulating the activity of eNOS and the production of vasodilatory factors such as nitric oxide ^[109]. Sulfasalazine may exert its positive influence on vasoactivity of maternal vessels through its potential to increase placental PlGF production and reduce the secretion of sFlt1 in an epidermal growth factor receptor-dependent manner ^[110]^[111]^[112]. However, results of the early phase of clinical trials (ACTRN12617000226303) determining the pharmacokinetics of sulfasalazine and its effect on the clinical and biochemical parameters of PE are still under analysis.

Hydroxychloroquine (HCQ) is an immunomodulatory agent that can relieve inflammation. In addition to its antimalarial properties, it is frequently used for treating autoimmune diseases, including those that are risk factors for preeclampsia, i.e., lupus or antiphospholipid syndrome ^[113]^[114]. HCQ inhibits NFĸB activity by blockade of the phosphorylation of kappa B inhibitor, thus downregulating the levels of inflammatory factors controlled by NFĸB ^[115]^[116]. In consequence of hydroxychloroquine supplementation, the sFlt1 secretion is reduced in cytotrophoblastic cells, and proangiogenic factors, e.g., PlGF are increased in primary HUVECs ^[117]. Additionally, as HCQ possesses antithrombotic activity, it might prevent fibrin formation and thus eliminate the risk of placenta insufficiency and the development of preeclampsia ^[118]^[119].

Several studies indicate that HCQ is a promising agent against preeclampsia. Most clinical studies have included women with a high risk of preeclampsia who are also suffering from autoimmunological diseases. HCQ supplementation was associated with a higher rate of live births, a lower prevalence of pregnancy morbidity, and a lower chance of preeclampsia development ^[120]^[121]^[122]. However, little is known about the preventive effect of HCQ among women without autoimmunological diseases. This gap is currently being addressed by one ongoing study (NCT05287321, HUGS; Phase 3) registered in the clinicaltrials.gov database.

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Agata Sakowicz

Michalina Bralewska

Magda Rybak-Krzyszkowska

Mariusz Grzesiak

Tadeusz Pietrucha

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Entry Collection: Hypertension and Cardiovascular Diseases

Update Date: 18 Oct 2023

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