The Role of Adverse Pregnancy Outcomes in Heart Disease Prevention

Hello. This is Dr. Margot Minissian. I'm a research scientist at the Schmidt Heart Institute at Cedars-Sinai in Los Angeles, Calif. And I am a clinical lipid specialist and a cardiology nurse practitioner. And I direct a postpartum heart health program. And today, I'm going to discuss the role of adverse pregnancy outcomes in heart disease prevention. My disclosures are here. The objectives of today's webinar is to explain why adverse pregnancy outcomes are so important for heart disease prevention. And for you to be able to list two different types of adverse pregnancy outcomes that predispose women to increased cardiac risk. You will then be able to describe two heart healthy lifestyle interventions for women with an APO history. So with today's day and age, it's still hard to believe that only half of women know that heart disease is their number one killer. In fact, heart disease kills four times more women than breast cancer alone. And stroke is the number four cause of death for women in the United States. And women, unfortunately, are more likely to die from heart disease and stroke than men in particular for increased stroke risk. The new American College of Cardiology and American Heart Association guidelines emphasized risk enhancers for prevention of atherosclerotic cardiovascular disease or otherwise known as ASCVD. This includes a family history of premature ASCVD persistently elevated LDL greater or equal to 160 milligrams per deciliter, chronic kidney disease, metabolic syndrome and conditions that are specific to women. This would include gestational diabetes, pre-eclampsia, premature menopause and post-menopausal state, as well as inflammatory diseases, which we know are more common in women and ethnicity, such as African American and South Asian ancestry. It's wonderful to see that the new guidelines are making things more personalized medical approach by thinking of conditions that are more specific for women to help our risk calculators be more specific. Adverse pregnancy outcomes that are associated with increased cardiovascular risk include gestational diabetes, gestational hypertension, pre-eclampsia and eclampsia. Preterm delivery, which is defined as delivery due to rupture of membranes or labor that, you know, does results in a delivery of less than 37 weeks, as well as fetal growth restriction, which is defined as an infant of less than 5.5 pounds. And strikingly, this can occur in approximately 30% of pregnant women. So this is no small problem. And the reason why it's so important is that, as we've alluded to, heart disease, despite all of the things that we know about warding off heart disease, is still killing more women. In fact, more midlife women today are dying of heart disease, age 36 to 54 years of age. Their mortality rates are increasing where all other age categories are decreasing. And despite traditional, well-established ASCVD risk factors such as diabetes and hypertension and hyperlipidemia being able to predict heart disease trajectories in women, it's really not demonstrating the full picture. And despite the treatment of those risk factors, women are still increasingly dying in midlife. Adverse pregnancy outcomes, specifically those that are related to placental disorders, which include preterm delivery, pre-eclampsia and whether or not that is a spontaneous preterm delivery or a medically indicated preterm delivery, such as preterm pre-eclampsia, have been associated with later development of a woman having ASCVD, and these women with their increased risk have been reported. So a woman who delivers term pre-eclampsia, she has a 1.6 fold increased risk of heart disease later in life, where a woman who has spontaneous preterm delivery otherwise defined as resulting in a delivery without diabetes, without hypertension, without pre-eclampsia of a two fold increased risk, and a woman with preterm pre-eclampsia being the highest risk of up to eight fold risk. These data suggest that the level of future risk is associated with the type of adverse pregnancy outcome. And in the past, our epidemiologic studies have lumped women who deliver early altogether and would define them all as having preterm delivery. And women who've had pre-eclampsia, whether they delivered early or not, lumped all together. And so potentially, maybe some of the disconnect is the way that we've been collecting our data. Pregnancy is a dynamic time for a woman as cardiac output and blood volume increase during gestation, systemic vascular resistance decreases, causing decreases in vascular stiffness and vasodilation reaching nadir and the second to early third trimester at the time of delivery arterial stiffness increases. This is a healthy physiology as cardiac output and blood volume decrease and therefore maintains homeostasis. During pre-eclampsia vascular stiffness is increased and continues up to six months postpartum compared to normal pregnancies. On the contrary, our research has previously described decreased vascular resistance in women who experience a spontaneous preterm delivery compared to match controls immediately in the postpartum stages. Sattar and Greer were the first to describe the idea of pregnancy being a woman's first free physiological stress test. And as you can see in this diagram, the dotted line across the graph represents vascular or metabolic disease. The blue dotted line represents the healthy population, and then the red solid line represents the population who has an adverse pregnancy outcome such as pre-eclampsia. So once a woman moves across from her neonatal life, she goes into being a teenager and as a younger woman has her first pregnancy. The pregnancy itself exposes the vascular or metabolic disorder. Once she's done with the delivery, her vasculature and metabolic syndromes normalize until she gets pregnant again. And then you can see her hypertension or her lipids, the pre-eclampsia, whatever her metabolic or vascular impact is, is then seen. And then as time moves on, these women within their first five years after delivery, have increased risk of hypertension. There's also descriptions of some of these women having different types of cholesterol disorders, where women who have spontaneous preterm delivery have lower HDL, which is good cholesterol and pre-eclamptic women are also known to sometimes be more susceptible to familial hyperlipidemia or higher LDL numbers. So abnormal stress tests equals abnormal adverse pregnancy outcomes such as gestational diabetes, gestational hypertension, pre-eclampsia, preterm delivery and growth restriction. So let's talk a little bit more about pre-eclampsia specifically. So pre-eclampsia occurs in about 25% of preterm births and 2 to 5% of all births. Not a huge number, but definitely a substantial number. And recently documented is a description of a fourfold increased risk of hypertension and heart failure later in life. And this has been most notably described as having increased left ventricular mass and diastolic pressures at one year postpartum screenings. They also have a threefold higher incidence of type two diabetes. That's that metabolic component and a twofold across the scale risk of ASCVD and cardiovascular related death. Risk of CVD is higher in women exposed to early pre-eclampsia than those who are diagnosed with pre-eclampsia later in life. And we think that that's likely because the women who are able to carry full term usually may have metabolic risk factors, but the age of the woman oftentimes is driving the pre-eclampsia as opposed to the preterm pre-eclamptic, oftentimes these are ethnic minority women or those who have more of a vascular type of component. But regardless, the awareness piece of a woman who's experienced pre-eclampsia is an important component to keep her healthy. When we think about individual risk factors for the development of pre-eclampsia, chronic hypertension has an odds ratio of 3.8 fold, diabetes mellitus, 3.6 fold, and family history of heart disease being a 3.2 fold. And pre-eclampsia pathophysiology has been and remains complex. And unfortunately not as well understood as we would like it to be. In fact, when we think about it, we oftentimes think about it having more to do with the the placenta, being able to provide nutrients to to the developing embryo and having a lack of a successful trophoblast invasion, which might be playing a role in the development of pre-eclampsia and cytokines being produced by the placenta and resulting in placental ischemia, which is thought to promote the release of these cytokines and that results in endothelial cell dysfunction leading to the instability of vascular tone with vaso spasm in various locations. There also was an activation of the coagulation system with microthrombi forming in many organs and disturbance of cerebral auto regulation, resulting in higher cerebral perfusion pressures as a result of chronic hyperventilation. So definitely many different mechanisms that could potentially be at play. In the Women's Health Center here at Cedars-Sinai, we do a lot of research in women who have chest pain, but when they have an angiogram, they have open coronary arteries despite evidence of ischemia. And so potentially maybe we're seeing a similar pathophysiology where we're seeing microvascular dysfunction of the placenta, similar to what we've seen in the heart. So signs and symptoms to look out for pre-eclampsia, new onset hypertension with a systolic blood pressure greater than 140 millimeters per mercury or diastolic blood pressure greater than 90 millimeters of mercury after 20 weeks gestation or severe ranged blood pressures which are defined as greater than 160 over 100. This is accompanied by new onset protein in the urine, extremity edema. It can also be associated with liver function abnormalities, thrombocytopenia, pulmonary edema, cerebral, presenting as visual disturbances. And there can also be pre-eclampsia with the absence of protein in the urine. This is hypertension and hypertension being defined as two of these elevated blood pressures within a four hour range of one another, paired with thrombocytopenia, impaired liver function and renal insufficiency, as evidenced by elevations in creatinine, pulmonary edema or those visual disturbances that I had mentioned before. So my question to you is, is preterm pre-eclampsia the marathon of pregnancy? If an adverse pregnancy outcome is the first free physiological stress test, when we look at a woman's heart and what occurs physiologically over time, we see that in particular for pre-term pre-eclamptics, that they have asymptomatic left ventricle which oftentimes can demonstrate moderate or severe dysfunction and hypertrophy with left atrial remodeling, right ventricular systolic and diastolic dysfunction, which then leads to impaired relaxation. And many times when we look at healthy marathon runners, they actually have a very similar cardiac physiology as to these women who had developed pre-term pre-eclampsia. So once the placenta is gone and pre-eclampsia is known to be a disorder of the placenta, why is it that many of these women have residual complications that can continue, such as 40% developing essential hypertension, 1 to 2 years postpartum if that placenta is gone and those cytokines are gone? And they also have increased risk of stage B heart failure postpartum and are at risk of postpartum cardiomyopathy. So we really do worry more about these women who develop preterm pre-eclampsia less than 34 weeks predicting greater mortality in these mothers. And when you look at them across the cascade, as I had alluded to before, those who develop preterm versus term pre-eclamptic and preterm pre-eclamptic over different data sets. This is a paper by Jurgens, who is really the hallmark of describing this increased risk with these initial adverse pregnancy outcomes. So the OBGYN community has come out with guidelines for screening women for pre-eclampsia and there is always a balance that needs to take place between vigilance, screening and then not over over diagnosing those individuals who maybe are not actually going into pre-eclampsia and having unnecessary hospitalizations. So home measuring and in-office measuring of blood pressure throughout pregnancy is really an important factor. And earlier identification of women at risk for pre-eclampsia is really the most important step. There are currently no labs needed for blood pressures unless you start to see elevations over 140 over 90. There is a new blood test that is being developed and is under consideration by the FDA, called S Folate 1, which is an emerging biomarker that can predict pre-eclampsia up to 12 hours prior to its clinical presentation. So we're very excited about that. And once we see a woman who's had blood pressure greater than 140 over 90, and if it persists again over a four hour period of time, then a pre-eclampsia evaluation with appropriate blood tests is indicated. So let's talk about spontaneous preterm delivery. So unlike pre-eclampsia that has been added to the American College of Cardiology and American heart guidelines as an increased risk factor for heart disease later in life for women, spontaneous preterm delivery is not yet on that list. However, we have emerging data stating that it is indeed not yet benign. My colleagues and I had completed a mini meta analysis published in circulation that looked at spontaneous preterm delivery and those women having an associated two fold increased risk of ASCVD later in life. However, the mechanisms are poorly understood as to why this is, and much more research is is needed. And in fact my my pre doctoral work was in this field and we had actually seen that these women had the opposite result in their vasculature than what we thought was going to happen. So we looked at a pilot of 20 preterm women who delivered less than 34 or at 34 weeks, and we completed vascular function testing with a sigma core machine. You can see a picture of it down on the bottom left. It measures augmentation index and pulse wave velocity. And we completed that at 24 to 72 hours postpartum and again at six months postpartum, and we compared them to a matched cohort of healthy controls who we found had proper augmentation of their blood vessels as previously described in the slide of normal pregnancy, that the women with spontaneous preterm delivery actually had lower smooth muscle tone or essentially a sluggish response to needing to augment their blood vessels and that their vasculature actually just remained null. They also had lower good cholesterol or HDL compared to their term matched counterparts. This figure here demonstrates that the the orange box and dots represent the control participants, and the teal boxes represented the spontaneous preterm deliveries. And you can see we have two timepoints the initial time point. You can see this is at one and visit two, which was six months later. And the healthy controls to the left, their boxes are up higher and then they came back down at six months, which is the appropriate vascular augmentation. The spontaneous preterm delivery ladies never augmented their blood vessels. They remain sluggish right after delivery and saw no changes at six months and basically were back in alignment with the healthy controls back at six months. And so did they actually miss out on having their blood vessels, if you will, exercised during their pregnancy or not? So we will stay tuned to see what the results of our of our next study will tell us. So let's go ahead and turn the conversation now into really getting ahead of the game and how we can make a heart healthy difference in the postpartum setting and really setting a precedent for a healthy lifestyle that can alter the life course towards health for a woman who's experienced an adverse pregnancy outcome. So we had designed a postpartum heart health program, and the purpose of this program is to screen women's cardiovascular risk factors for those who we have described as having increased risk. We do postpartum hypertension management. We do that through nutrition as well as medication. We also screen those at risk for familial hyperlipidemia, and we also place them on nutritional and exercise regimens. You can see here my collaborators, and in fact, this is the new emerging idea of having heart health pregnancy teams. And there was a pregnancy and heart disease task force that was put together by the American College of Gynecology. My colleague, Dr. Janet White, served on this sorry, Dr. Janet Way and Janet and her colleagues, she's a cardiologist, but they had a very diverse group of experts go through and identify those risk factors as well as doing a detailed medical history. Did the woman smoke? How much physical activity has she done? How long did she breastfeed? Did she have a history of hypertension or diabetes or heart disease in the first place? Did she have a first degree family member who had a history of heart disease, hypertension or diabetes? What's their resting blood pressure and heart rate? What's their BMI and waist circumference? We know that that also is associated with increased risk of pre-eclampsia. And then biochemical testing, such as what's their cholesterol, their fasting glucose or oral glucose tolerance testing, if they had gestational diabetes and a urine protein assessment looking for a protein creatinine ratio. This helps us be able to further screen these women in the postpartum setting because believe it or not, it's hard to believe that they can also develop postpartum pre-eclampsia. We'll talk a little bit more about that. We also put together a postpartum heart health registry. This is, to our knowledge, a newer prospective registry. We have about 160 women currently participating to be able to institute early screening for heart disease, as well as mental health risk factors such as post-traumatic stress and depression and the postpartum setting. We're following these women longitudinally for the next five years and thereafter, really to be able to ultimately identify those women who will need an intervention, whether physiologically or psychologically. And we're really hoping that we'll be able to link this registry nationally. The women in particular, these postpartum heart health programs are important. They help to prevent readmission of women in that first 1 to 2 weeks postpartum. Women are at increased risk of postpartum pre-eclampsia. As you can see here, postpartum pre-eclampsia behaves very similarly as if they had pre-eclampsia during pregnancy. They are still at risk for seizures, stroke, organ damage and even death. And warning signs can be stomach pain, severe headaches, seeing spots or other visual changes, shortness of breath, swelling in your hands or face, feeling nauseous or even throwing up. If you have any of these symptoms or you have a patient that has these symptoms, you want to go to the emergency room and let your doctor know immediately. Being able to help women understand properly measuring their blood pressure is important. This is a diagram that I found on the pre-eclampsia.org website that I thought was a great visual that they would sit in a chair that has an appropriate backing, have both of their feet flat and firmly on the floor that the arm cuff is placed on your arm at the same level as your heart, usually relaxed on a table. And then the hardest part for most young mothers and and women in general, sitting and relaxing for 3 to 5 minutes, no talking, no distractions such as cell phones or babies crying can often be a challenge that we really want to try and encourage them to be able to obtain a true baseline blood pressure. In addition to understanding blood pressures and managing blood pressure, calculating out and ASCVD risk Plus, with the new estimator from the American College of Cardiology is an important factor. The calculator is validated in women 20 to 79 years of age for both African-American and white women. So this is a really wonderful tool that we're hoping to promote the utility of in OB GYN office, primary care doctors offices, advanced practice nurses offices, as well as in postpartum heart health clinics. It includes total cholesterol, HDL, which is the good cholesterol, LDL, which is the bad cholesterol, and whether or not they've had a history of diabetes, whether or not they were a former smoker or currently smoking, whether or not they are on hypertension treatment, whether or not they take a statin or cholesterol lowering pill, or if they are on aspirin therapy. In addition to calculating out whether or not they're at low, moderate or high risk of heart disease at that time, we review over nutritional lifestyle recommendations that will help improve both their blood pressure as well as their lipids. In our clinic we teach the DASH diet, which incorporates Mediterranean style eating plans, essentially fruits, vegetables and whole grains. It has about 30 to 35% fat intake, but less than 6% of those fats come from saturated fats and no trans fats, and that includes tropical oils such as coconut oil. It follows a lower sodium diet and a high potassium diet. So less than 2400 milligrams of salt a day and cutting down on processed, both meats as well as dietary fiber and being removed and sugar is being added, really being able to eat whole foods is really an important message and incorporating in these lifestyle changes to really be able to be reflective of over a lifetime. These are two examples of new PDFs that are available on the national Heart Lung and Blood Institute's website. They have six new PDFs that are out that are visually beautiful as well as very nicely described from describing the science that backs the DASH diet up to incorporating new types of foods and allowing for increased food variety, as well as a weekly menu planner and a meal planner. So very, very helpful, all able to be downloaded free of charge and we print them out for our patients in our clinic. And they really seem to like having in hand tangible papers to be able to look at and to write on. But nice because you can also email them and they can also have them on their smartphones. So the next step of our discussion will be for us to review a case presentation. The first case presentation is a 35 year old female who is a gravida 2 para 3, and she was referred by her OB-GYN. Now, she was referred because she had a history of preterm delivery with her first child, and then she developed subsequent pre-eclampsia with her second pregnancy, which were notably twins. Her postpartum course required antihypertensive treatment, so she she came on initially home on her labetalol, but seeing her six months postpartum, she was off her labetalol and she was no longer breastfeeding. And so she was referred to our postpartum heart health program for ASCVD risk assessment and nutritional and exercise counseling. So her past medical history, as I had stated, included preterm delivery with her first child, in vitro fertilization and pre-eclampsia in second pregnancy with twins. She had a history of Hashimoto's Thyroiditis. She had a prior dyslipidemia, a history of statin use by her report, but she had not been on statins for several years. She had done that remotely as a teenager and a history of postpartum hypertension which had been resolved. Now, interestingly enough, when I was taking down her family history, and this was something that was unaware by her OB at the time, was that her maternal grandmother had an MI in her early forties and she had a coronary artery bypass grafting in her maternal uncle at age 38. And this was quite striking. This family history, despite it not being a first degree relative. At this point, she was only on a prenatal multivitamin. She had lovely blood pressure in clinic 102 over 55. She had a heart rate of 67, fully saturated oxygen level on room air and a healthy body mass index of 22 kilograms per meter squared. Her physical exam was unremarkable for cardiopulmonary. We did screen her for familial hyperlipidemia and she had a total cholesterol of 309. An LDL of 236, an HDL of 56 and triglycerides 83. So she was meeting National guidelines for a diagnosis of familial hyperlipidemia, and her thyroid was within normal limits. We completed any EKG on her in clinic. We get baseline EKGs on all of our women who've had a history of a hypertensive disorder. And as you can see here, she has ST changes in her lateral wall and she has a dampened flattening of her STs and lead one. So her diagnosis include a family history of premature CAD familial hypercholesterolemia and an abnormal ECG, as well as a adverse pregnancy outcome history as well as a history of postpartum hypertension. So we started Atorvastatin 40 milligrams daily as the patient was no longer breastfeeding. And we also discussed protection with either condoms and family planning is very important. While younger childbearing women are taking statin for treatment of their familial hyperlipidemia. We completed a liver lipid panel 4 to 6 weeks after she was on the Atorvastatin to ensure that she achieved greater than a 50% reduction in her LDL with the hopes that we would get her LDL under 100 and closer to 70. One other factor that is important to mention is that statins have been suggested to be teratogenic if taken during the first trimester. So if you were to see a woman who became pregnant and was taking a statin, you would have her immediately stop the statin and discuss with her OB and her primary care doctor. We also had her go back and visit her endocrinologist to ensure that her thyroid, her thyroiditis was indeed under control. We also ran her on another and she completed what looked to be a nonischemic stress echo. But she did have an abnormal blood pressure response. Despite having a healthy baseline blood pressure of 107 over 55. Her peak blood pressure was able to go up to 192 over 94. And despite her healthy weight and her exercise, having a hypertensive response to exercise will require very close monitoring of her blood pressure to ensure that she is not having labile hypertension and where her blood pressure can be normal, normal, normal, and then have moments when she's running for an airplane, running after a child of it, popping up and being too high and resulting in left ventricular hypertrophy over time. So the ultimate goal of being able to alter the life course of disease. I bring you back to the figure where we saw from Sattar and this is a a modification that Dr. Janet Rich Edwards had contributed to the idea that we see the first pregnancy and the pre-eclampsia exposes the vascular dysfunction that with great lifestyle interventions such as baby aspirin, which is now known to help ward off pre-eclampsia, maybe other novel therapies that are underway improved blood pressure management and risk factor management and lifestyle implementation can you'll see the the second red line falling under the bar that potentially we could ward off even a second adverse pregnancy outcome from occurring again and then ultimately warding heart disease off altogether. So take home messages from today's discussion is that pregnancy serves as a woman's first stress test and a window to her future cardiovascular health, and that adverse pregnancy outcomes are present in about a third of pregnant women and are associated with increased maternal heart disease, as well as maternal depression, anxiety and PTSD. And that cardiovascular risk assessment is recommended in all women with a history of an adverse pregnancy outcome, and much needed research needs to occur to understand why women with APOs are at risk for this heart disease in the first place. And most importantly, for us to implement effective interventions that we already know work as well as come up and derive new interventions for the future. I would like to thank you for your time and attention, and please feel free to send me an email or a Twitter message. Thank you very much.