New Pharmacologic Therapy for Hypertension in Pregnancy

Abstract

This project is a thorough exploration of the biochemical and molecular signaling involved in preeclampsia and hypertension in pregnancy. It includes a detailed and documented review of the literature which is used to develop insight into future potential pharmacologic treatments for this complex disorder. There has been virtually no change for three decades in the treatment of hypertension in pregnancy and it’s many namesakes: Pre-eclampsia, gestational hypertension, superimposed preeclampsia, gestosis, etc. all of which shall be referred to in the rest of this article as PIH. In part this is because of an incomplete understanding of its physiology and pathophysiology, partly because the only widely accepted treatment, labetalol, does not work well and causes fetal growth restriction. This is a short review of what we know about PIH and normal placental physiology, what we surmise about the disease process and possible future pharmacologic interventions based on this knowledge, as well as new methods of determining fetal in utero health. Review ARTicle *Corresponding author: Byrne TJ, Maternal Fetal Medicine, Harlem Hospital, 506 Lenox Avenue, New York, NY 10037, USA Maternal Fetal Medicine, Harlem Hospital, USA iform mole is PIH, usually before the 20 weeks of pregnancy described to satisfy the usual definition of PIH. It must require the presence of at least partially intact placental villi. Patients who have choriocarcinoma in which there are both syncytiotrophoblasts and cytotrophoblasts but not placental villi, do not develop PIH even with advanced disease [3]. It seems logical that, since the presence of at least partially intact placental villi is required for PIH, there must be some communication between cytotrophoblasts and syncytiotrophoblasts as well as possibly fibroblasts in villi, and that the development of hypoxia in one or more layers leads to the development of clinical PIH. It may be however that there is simply not enough tissue volume or endothelial surface area in choriocarcinoma generating enough signals to produce PIH even in patients with advanced disease. Hypertension develops during pregnancy in several situations which may help elucidate a causation and may help us to treat patients before the final pathophysiologic pathway(s) have been elucidated. Patients with endothelial dysfunction such as lupus especially with active disease and antiphospholipid syndromes also have a predilection for later PIH [4,5]. Patients with endothelial dysfunction not involving excessive clotting such as von Willebrands disease do not have a predilection for developing PIH [6,7]. Hypercoaguability, by itself, apparently does not seem to predispose to PIH [8,9]. So the endothelial dysfunction or, more appropriately overactivity, which has been documented in both lupus and antiphospholipid syndrome is probably the cause of predilection to PIH. Patients with a placental infection such as syphilis or malaria also have an increased PIH incidence [10,11]. This may be from relative hypoxia or misdirected placental signals or increased inflammation in the presence of placental infection. Increased placenCheck for updates Where We Are (Pathophysiology) There are clinically determinable risk factors that increase the risk of a particular patient developing PIH. Old or young maternal age, nulliparity, a history of high blood pressure, obesity, first degree relative(s) who developed PIH, family history of early heart disease, histories of diabetes or insulin resistance, kidney disease, lupus, rheumatoid arthritis, thyroid disease, African descent and multiple gestation. All of these except multiple gestation are also known risk factors for later development of heart disease. The only major missing risk factor for heart disease is smoking which actually reduces the risk of developing PIH [1]. Development of PIH does not require the presence of a fetus [2]. One of the usual presenting signs of hydatidISSN: 2474-3690 DOI: 10.23937/2474-3690/1510041 Byrne. J Hypertens Manag 2019, 5:041 • Page 2 of 15 • tal mass i.e. diabetes, multiple pregnancy, but not from all causes such as large for gestational age fetuses also have an increased frequency of PIH [12-14]. Some pregnancies with small placentas such as from growth restriction also have an increased incidence of PIH and so fetuses with some trisomies or who have a placenta with abnormal chromosomes have a predilection for causing hypertension in their mothers during pregnancy and some do not [15,16]. Another cause of a small placenta leads to a marked decrease in the risk for preeclampsia. This is smoking. It has been noted and well documented that although smoking: Is a risk factor for IUGR, causes a decrease in placental size, and is one of the most prominent risk factors for later heart disease; it does not increase and in fact decreases the risk of PIH developing [17]. Finally sickle cell anemia and iron deficient anemia do not increase the risk of developing PIH although there is obviously less oxygen delivery per volume of blood delivered to the placental bed in both cases [18,19]. Residing above 3300 meters increases the risk of PIH [20]. There are purported pathology changes seen in placentas very early in pregnancy, long before the clinical development of PIH and they are not reversible at the present time. This leads to a placenta with less surface area and therefore less ability to extract oxygen and to a lesser extent, nutrients [21]. There has been a remarkable increase of our knowledge in the basic physiology of placenta growth and interaction between maternal and fetal tissues in early pregnancy [22]. In the first trimester fetal cells block or at least reduce blood flow into the fetal maternal combined vascular space. This blockade is then released. There is a large body of knowledge about growth factors produced in all pregnancies. It is possible that pregnancies destined to become hypertensive have an abnormal pattern of growth factors leading to abnormal placental growth and that abnormal growth later causes an abnormal secretion of vascular factors [23]. There are too many great investigators and investigations to mention in one article. For a good review of the latest information about the placenta and its growth and circulation I would refer you to several monographs, the latest published in 2010 [24-26]. A simplified (very) description of the present state of knowledge of differences in growth factors of early pregnancy between normal and PIH pregnancies is as follows [27]. There are differences in placentas from women destined to develop PIH and normal ones. One of the important growth factors for placental vessels is vascular endothelial growth factor, VEGF [28]. In PIH there is an increased level of soluble fms-like tyrosine kinase [29]. Soluble levels of this protein keep VEGF from activating membrane bound receptors for it which diminishes blood vessel growth [30,31]. Transforming growth factor betas (1-to at least 3) are also important in vessels invading the decidual bed [32,33]. Endoglin is a membrane bound protein that helps in TGFs interacting with cells [34]. Soluble endoglin apparently binds to circulating TGFs again reducing interaction with the membrane bound receptors leading to reduced vessel growth and invasion [35]. Increased levels of soluble endoglin are a risk factor for developing PIH [36]. Bone morphogenetic protein BMP, is another signaling protein with actions similar to TGF [37]. It is also bound and rendered ineffective by binding to soluble endoglin. Both of these soluble receptors sFlt and soluble endoglin are increased early in PIH patients leading to less blood vessels and less invasion in the decidua. PlGf a close homologue of VEGF is produced by the placenta, has similar purported actions as VEGF, and is similarly bound to s Flt s and interacts with VEGF receptors in a similar fashion as VEGF. There is an enzyme produced in the heart and the decidua called Corin that activates both atrial natriuretic peptide (ANP) and its close homologue brain natriuretic peptide (BNP) [38]. It has been found that in preeclampsia there is less activity of this enzyme leading to reduced activation of ANP receptors which are membrane bound producers of cyclic GMP [39]. This in the face of significant elevations of ANP and BNP in symptomatic patients [40]. There have been variants of Corin found in patients with African descendancy that have less trypsin-like enzymatic activity and which leads to less active ANP and BNP activity and hypertension later in life [41]. It has also been found that genetic mutations leading to a less active Corin also lead to preeclampsia [42]. All of these changes affect the growth and development of the placenta in the same way and are all probably at least additive if not multiplicative. So in summary in pregnancies destined to develop PIH the early signaling leading to invasion and vascular and probably cotyledon growth are all diminished leading to a lower maximum blood flow into the decidual bed and a diminished maximum placental absorptive surface area. How this leads to PIH in some but not all pregnancies is unknown at present. There are probably many more signaling proteins and systems that are deranged in PIH. I have brought these up specifically because they are well documented, have widespread agreement and provide insight into the early developmental abnormalities in PIH and lend credence to another pathophysiology that has many parallels if it is not exactly the same process as occurs in PIH and which already has many experimental pharmacotherapies that disease process is pulmonary hypertension. After the initial developmental abnormalities of reduced invasion and reduced cotyledon surface area at least in part caused by the previously mentioned signal aberrations there are features which distinguish PIH from normal pregnancy. There are uterine impedance ISSN: 2474-3690 DOI: 10.23937/2474-36