Two basic science researchers, a clinical researcher, and a physician-in-practice shed light on this poorly understood condition that poses great health risks for both pregnant mothers and their children.
Preeclampsia is a severe disorder of pregnancy, characterized by hypertension and proteinuria, affecting approximately 5% of all pregnancies. In addition to causing intrauterine growth retardation, perinatal mortality, and preterm birth, preeclampsia is a leading cause of maternal death. Despite the severity of preeclampsia, its etiology is poorly understood and its onset difficult to predict. Therefore, a major research focus has been aimed at achieving reliable and early diagnosis using serum markers and placental blood flow measurements. Basic science research has made strides in understanding structurefunction relations between serum molecules and pathology, and has been facilitated by the development of mouse models to investigate this disorder in tractable in vivo systems. The concerted efforts of practitioners and researchers have enabled development of management protocols for preeclampsia. In this TriPoint, two basic science researchers elucidate our current understanding of the molecular mechanisms of preeclampsia and a model system used to study them; a clinical researcher sheds light on expression analyses to identify therapeutic targets; and a physician-in-practice discusses the health risks in and clinical recommendations for women with a history of preeclampsia.
BASIC RESEARCHERS PERSPECTIVE
— Robin L. Davisson, PhD, and
Jenny L. Sones, DVM, PhD
Preeclampsia affects up to 10% of all pregnancies in the U.S., is responsible for 42% of maternal deaths worldwide, and significantly contributes to neonatal/infant morbidity and mortality. Th is devastating disease of pregnancy is characterized by a sudden late-gestational rise in maternal blood pressure and urinary protein levels. Even though the maternal signs of preeclampsia have been observed and described for centuries, the exact cause and cure remain elusive.
Because maternal signs only resolve upon delivery of the fetus and the placenta, it is widely accepted that the developing fetoplacental unit plays a causal role in the pathogenesis of preeclampsia. Biopsies of preeclamptic placentae have shown inadequate invasion of trophoblasts into the maternal decidua arterioles, resulting in reduced uteroplacental perfusion. A twostage disease model has been proposed to link these placental pathologies with the clinical presentation of preeclampsia. The first stage is thought to involve abnormal placentation characterized by poor trophoblast invasion, incomplete vascular remodeling, and placental hypoxia. The second stage manifests as the maternal syndrome of hypertension and proteinuria. The transition between the two stages is thought to be due to the release of factors from the abnormally developed placenta into the maternal circulation. Recent evidence strongly suggests placentally derived angiogenic factors play a central role in the progression of preeclampsia.
Animal Models of Preeclampsia
The initiation of fetoplacental pathologies has been extraordinarily difficult to study in humans due to logistical and ethical challenges associated with examining the first trimester. Therefore, animal models of preeclampsia are critically important for longitudinal investigation of early events. We have gleaned much insight into the pathophysiology surrounding the maternal syndrome from rodent models of preeclampsia. The RUPP (reduced uteroplacental perfusion) model surgically mimics impaired placental blood flow in late gestation pregnant rats. Another important rodent model involves infusion of an anti-angiogenic factor, sFlt. Although these models recapitulate aspects of the maternal syndrome and the angiogenic imbalances observed in humans, they cannot be used for studying key early pregnancy events that may initiate the disease process. Recently, several mouse strains with single gene mutations have been developed that phenocopy key features of preeclampsia. While these models allow the opportunity to investigate early pregnancy events, preeclampsia is a multifactorial disease that is unlikely to be monogenic.
Our laboratory discovered the first strain of mice to spontaneously develop a preeclampsialike syndrome, BPH/5. Non-pregnant BPH/5 mice exhibit modest elevations in blood pressure, a known risk factor for preeclampsia. Similar to humans, BPH/5 mice exhibit late-gestational proteinuria and a significant rise in mean arterial pressure during the second half of gestation that returns to baseline after delivery of the pups and placentae. In keeping with perinatal and neonatal morbidity/mortality observed in human preeclampsia, BPH/5 mice have small litter sizes due to in utero fetal demise and low-birthweight pups. Importantly, BPH/5 mice develop placental pathologies that precede the maternal syndrome, including inadequate remodeling of uterine spiral arteries with decreased trophoblast invasion. Hence, the spontaneous BPH/5 mouse model provides a valuable opportunity to interrogate early pregnancy events prior to the onset of the maternal syndrome.
Unraveling the Mystery of Preeclampsia
There is a growing body of evidence, both mouse and human, that supports the concept that early pregnancy events, such as uterine receptivity, implantation, and decidualization, have “ripple effects” that impact downstream pregnancy outcomes. These periimplantation events rely on appropriate ovarian hormone signaling as well as vasoactive agents, cytokines, growth factors, transcription factors, and morphogens that act in an autocrine, paracrine, and juxtacrine fashion. Dysregulations in any of these pathways have been linked to adverse pregnancy outcomes, such as placental insufficiency, intrauterine growth restriction, and preeclampsia. Interestingly, our recent data reveal that the BPH/5 mouse develops profound periimplantation defects, including embryo clustering, deferred implantation, defective decidualization, and altered ovarian hormone profiles that are associated with an abnormal molecular signature of embryo-uterine interactions. These early pregnancy changes of the maternal-fetal interface occur prior to the observed angiogenic imbalance seen during BPH/5 pregnancy. Indeed, inadequate uterine angiogenesis/vascularity at the time of implantation has been suggested.
Preeclampsia is a multifactorial disease of pregnancy whose onset is sudden and without warning. Although the diagnosis of preeclampsia is made by the clinical presentation of the maternal syndrome, the origins of preeclampsia begin much earlier in pregnancy. The use of certain animal models affords researchers the opportunity to investigate these key early pregnancy events, such as implantation, that may cause preeclampsia but cannot be thoroughly examined in humans.
CLINICAL RESEARCHER PERSPECTIVE
— Ravi I. Thadhani, MD, MPH
Maternal and Fetal Health
Preeclampsia classically presents as hypertension and proteinuria at > 20 weeks of gestation and/or < 48 hours after delivery. Its severity is classified based on the degree of hypertension and proteinuria and the presence of concomitant symptoms that occur secondary to kidney, brain, liver, and cardiovascular system involvement. There is currently no acceptable treatment, except for termination of the pregnancy and removal of the placenta. Although this benefits the mother, this solution is highly detrimental to the fetus, primarily when preeclampsia occurs very early in gestation.
Women with a history of preeclampsia have a higher risk for a recurrence and are more likely to have adverse pregnancy outcomes (preterm delivery, fetal growth restriction, abruptio placentae, and fetal death) in subsequent pregnancies. Neonatal mortality in hypertensive women is related to the infant’s birthweight and gestational age of delivery, therefore, prolongation of gestational age is of significant benefit for the preterm neonate. However, since delivery is the only definitive treatment for preeclampsia, delaying delivery of the fetus leaves the mother in a vulnerable, hypertensive state that increases the risk of adverse maternal outcomes.
Known risk factors associated with preeclampsia include the presence of antiphospholipid antibody syndrome, chronic hypertension, chronic renal disease, elevated body mass index, maternal age older than 40 years, multiple gestation, nulliparity, and pregestational or gestational diabetes mellitus. Urinary tract infection and periodontal disease during pregnancy have also been associated with an increased risk of preeclampsia, although evidence of relationships with other maternal infections such as HIV, chlamydia, CMV, or mycoplasma is lacking. Unfortunately, known risk factors, with the exception of first pregnancy, explain less than 25% of all women who develop preeclampsia.
Although the etiology of preeclampsia is not completely understood, numerous factors have been proposed to contribute to the development of preeclampsia, including lipoproteins, proinflammatory cytokines, chemokines and adhesion molecules, procoagulant molecules, and homocysteine, but the evidence to support the association with many of these factors remains weak.
Expression Analysis and Therapeutic Targets
By gene-expression profiling of placenta derived from women with and without preeclampsia, researchers have identified that messenger RNA encoding for Fms-like tyrosine kinase 1 (sFlt-1) is upregulated in preeclamptic placentas. sFlt-1 is a splice variant of the vascular endothelial growth factor (VEGF) receptor Flt-1, and in the circulation, acts as a potent VEGF and placental growth factor (PlGF) antagonist. The sFlt-1 molecule prevents angiogenesis, which is the primary physiologic function of VEGF. VEGF is also important in blood pressure regulation and for maintenance of normal glomerular filtration. The presence of excess circulating sFlt-1, via antagonism of VEGF and PlGF, is believed to lead to endothelial dysfunction, hypertension, and proteinuria and is sufficient to explain critical alterations that characterize preeclampsia.
In fact, administration of sFlt-1 to pregnant rats produces the classic lesion of preeclampsia, namely: hypertension, proteinuria, and glomerular endotheliosis. Endothelial function and renal microvascular reactivity in vitro is restored by exposure to exogenous VEGF and PlGF. Reduction of circulating sFlt-1 in mice by neutralization with adenoviral constructs of sFlt-1 and VEGF has been shown to mitigate preeclampsialike symptoms.
We demonstrated that highly elevated plasma levels of sFlt-1 and decreased levels of PlGF are present in pregnant women well before and during preeclampsia compared to normotensive controls. The increase in sFLt-1 was observed to occur early in the third trimester and precedes the clinical onset of preeclampsia by approximately three to five weeks. Levels of sFLt-1 together with PlGF can be used to predict subsequent development of preeclampsia and with very high sensitivity and specificity. Recently, others identified a threshold, based on a ratio of sFlt-1/PlGF above 85, that is highly predictive of imminent onset of preterm preeclampsia in pregnant women
Taken together, these data suggest that such factors can help predict preeclampsia onset and that sFlt-1, by binding to and antagonizing the effects of VEGF and PlGF, may have a role in the pathogenesis of preeclampsia. Along these lines, we have been conducting proof-of-concept clinical studies to determine whether excess sFlt-1 can be removed from the circulation of women with preterm preeclampsia. The intervention to remove sFlt-1 employs short-term apheresis using dextran sulfate adsorption columns and exploits the inherent elevated isoelectric point of the protein. We hope to demonstrate that this intervention (i.e., removal of sFlt-1 by apheresis) mitigates the hypertensive and proteinuria symptoms of preeclampsia and that, ultimately, pregnancies in women with very preterm preeclampsia can be prolonged via such intervention.
CLINICAL PRACTITIONER PERSPECTIVE
— Ellen W. Seely, MD
Future Risks in Women with a
History of Preeclampsia
The only known cure for preeclampsia is delivery of the pregnancy and although preeclampsia resolves with delivery, it has increasingly been recognized to predict increased risk for cardiometabolic diseases later in life of the affected patient. Therefore, a pregnancy complicated by preeclampsia serves as a “window” to the future, offering the potential to identify women of increased cardiometabolic risk and to intervene to decrease such risk.
History of Preeclampsia and Future
Over the past decade, there has been an increased focus on the link between a history of preeclampsia and cardiovascular disease (CVD). Several meta-analyses have consistently demonstrated that women with a history of preeclampsia have increased risk for CVD and cerebrovascular disease. According to the most recent meta-analysis, the odds ratio for an association between a history of preeclampsia and subsequent CVD was 2.28 (95% confidence interval, [CI], 1.87 to 2.77) and subsequent cerebrovascular disease was 1.77 (95% CI, 1.43 to 2.21). These results were similar to prior meta-analyses. Of note, some but not all, of the meta-analyses suggest that women with preterm (less than 37 weeks gestation) preeclampsia have the highest risk for CVD. In addition, in a survival analysis, women with a history of preeclampsia had increased risk of CVD death (hazard ratio 2.14 [95% CI, 1.29 to 3.57]). The risk of CVD death was magnified in women with preterm (less than 34 weeks gestation) preeclampsia (hazard ratio 9.54 [95% CI, 4.50 to 20.26]).
History of Preeclampsia and
Cardiometabolic Disease Risk Factors
Women with a history of preeclampsia have increased relative risk (3.13, 95% CI, 2.51 to 3.89) for the development of chronic hypertension, a major risk factor for both CVD and stroke. Some data suggest that women with prior preeclampsia are also at increased risk for Type 2 diabetes mellitus, another important risk factor for CVD. Dyslipidemia, with high triglyceride and low HDL cholesterol levels, has been reported in women with a prior preeclampsia.
A major limitation of current data is that studies are not controlled for many risk factors for CVD that may have developed subsequent to the pregnancy complicated by preeclampsia. Th is is important as some of these factors are risk factors for both the development of preeclampsia and for the development of CVD, such as obesity. In addition, lack of agreement upon and changes in the defi nitions of preeclampsia over time make the study populations heterogeneous and not directly comparable.
Link between a History of
Preeclampsia and Future CVD
Since preeclampsia and cardiovascular disease share common risk factors (e.g., obesity), it remains unclear whether preeclampsia unmasks CVD risk predisposition or whether it actually causes cardiovascular injury leading to CVD or a combination of these two. Given these issues, more research is needed to better understand the pathophysiologic link between a history of preeclampsia and future CVD. Such an understanding may lead to more targeted interventions to decrease CVD in women with this history.
Clinical Recommendations for Women
with a History of Preeclampsia
Given the strength of the association of prior preeclampsia with CVD, the American Heart Association (AHA) and the American College of Obstetrics and Gynecology (ACOG) have recently recommended that all women be asked about a history of preeclampsia when assessing CVD risk. When present, this history should be considered as a CVD risk factor. Th e AHA recommends that women with a history of preeclampsia be advised to stop smoking, follow a “Dietary Approaches to Stop Hypertension”-like diet, lose weight if overweight or obese, and engage in physical activity. Studies are needed to determine whether these lifestyle measures will decrease CVD events in women with a history of preeclampsia or whether more targeted therapies are needed.
The ACOG has provided screening recommendations for women with preterm (less than 37 weeks gestation) and recurrent preeclampsia as these women appear to be at the highest risk for future CVD. The ACOG recommendations include follow up of blood pressure and weight as well as laboratory determination of fasting glucose and lipids. Th e interval at which these should be determined is not specifi ed. Determining whether these screening recommendations will allow for interventions that will decrease CVD risk is not known and requires further study. Furthermore, whether women with preeclampsia at term would also benefit from this monitoring is unknown.
In summary, a clinical history of preeclampsia is associated with increased risk for CVD. Whether this risk is mediated solely through traditional CVD risk factors or through factors unique to prior preeclampsia requires further study. Given the strength of this link, women should be asked about a history of preeclampsia as a risk factor for CVD similar to the recommendation that a history of gestational diabetes be obtained as a risk factor for Type 2 diabetes. If a history of preeclampsia is obtained, attention should be focused on identifying and treating traditional cardiovascular risk factors (hypertension, hyperlipidemia, diabetes). Studies are needed to determine whether treatment of these risk factors is sufficient to decrease CVD in women with prior preeclampsia or whether more targeted treatment is required in this population. We are currently studying whether lifestyle modification can decrease progression to hypertension in women with recent preeclampsia.